Milrinone
Dosage Form: injection, solution
Milrinone Lactate Injection
Milrinone Lactate Injection
Rx only
Revised 04/2011
Milrinone DescriptionMilrinone Lactate Injection is a member of a new class of bipyridine inotropic/vasodilator agents with phosphodiesterase inhibitor activity, distinct from digitalis glycosides or catecholamines. Milrinone lactate is designated chemically as 1,6-dihydro-2-methyl-6-oxo-[3,4?-bipyridine]-5-carbonitrile lactate and has the following structure:
CH3CHOHCOOH
Milrinone is an off-white to tan crystalline compound with a molecular weight of 211.22 and a molecular formula of C12H9N3O. It is slightly soluble in methanol, and very slightly soluble in chloroform and in water. As the lactate salt, it is stable and colorless to pale yellow in solution. Milrinone Lactate is available as sterile aqueous solutions of the lactate salt of Milrinone for injection or infusion intravenously.
Sterile, single dose vials: Single dose vials of 10, 20 and 50 mL contain in each mL Milrinone lactate equivalent to 1 mg Milrinone and 47 mg Dextrose, Anhydrous, USP, in Water for Injection, USP. The pH is adjusted to between 3.2 and 4.0 with lactic acid or sodium hydroxide. The total concentration of lactic acid can vary between 0.95 mg/mL and 1.29 mg/mL. These vials require preparation of dilutions prior to administration to patients intravenously.
Pre-Mix Flexible Containers: The Flexible Containers provide two ready-to-use dilutions of Milrinone in volumes of 100 mL and 200 mL of 5% Dextrose Injection. Each mL contains Milrinone lactate equivalent to 200 mcg (0.2 mg) Milrinone. The nominal concentration of lactic acid is 0.282 mg/mL. Each mL also contains 49.4 mg Dextrose Anhydrous, USP. The pH is adjusted to between 3.2 and 4.0 with lactic acid or sodium hydroxide. The flexible plastic container is comprised of polypropylene with a foil overwrap. Water can permeate the plastic into the overwrap, but the amount is insufficient to significantly affect the pre-mix solution.
Milrinone - Clinical PharmacologyMilrinone is a positive inotrope and vasodilator, with little chronotropic activity different in structure and mode of action from either the digitalis glycosides or catecholamines.
Milrinone, at relevant inotropic and vasorelaxant concentrations, is a selective inhibitor of peak III cAMP phosphodiesterase isozyme in cardiac and vascular muscle. This inhibitory action is consistent with cAMP mediated increases in intracellular ionized calcium and contractile force in cardiac muscle, as well as with cAMP dependent contractile protein phosphorylation and relaxation in vascular muscle. Additional experimental evidence also indicates that Milrinone is not a beta-adrenergic agonist nor does it inhibit sodium-potassium adenosine triphosphatase activity as do the digitalis glycosides.
Clinical studies in patients with congestive heart failure have shown that Milrinone produces dose-related and plasma drug concentration-related increases in the maximum rate of increase of left ventricular pressure. Studies in normal subjects have shown that Milrinone produces increases in the slope of the left ventricular pressure-dimension relationship, indicating a direct inotropic effect of the drug. Milrinone also produces dose-related and plasma concentration-related increases in forearm blood flow in patients with congestive heart failure, indicating a direct arterial vasodilator activity of the drug.
Both the inotropic and vasodilatory effects have been observed over the therapeutic range of plasma Milrinone concentrations of 100 ng/mL to 300 ng/mL.
In addition to increasing myocardial contractility, Milrinone improves diastolic function as evidenced by improvements in left ventricular diastolic relaxation.
The acute administration of intravenous Milrinone has also been evaluated in clinical trials in excess of 1600 patients with chronic heart failure, heart failure associated with cardiac surgery, and heart failure associated with myocardial infarction. The total number of deaths, either on therapy or shortly thereafter (24 hours) was 15, less than 0.9%, few of which were thought to be drug-related.
PharmacokineticsFollowing intravenous injections of 12.5 mcg/kg to 125 mcg/kg to congestive heart failure patients, Milrinone had a volume of distribution of 0.38 liters/kg, a mean terminal elimination half-life of 2.3 hours, and a clearance of 0.13 liters/kg/hr. Following intravenous infusions of 0.2 mcg/kg/min to 0.7 mcg/kg/min to congestive heart failure patients, the drug had a volume of distribution of about 0.45 liters/kg, a mean terminal elimination half-life of 2.4 hours, and a clearance of 0.14 liters/kg/hr. These pharmacokinetic parameters were not dose-dependent, and the area under the plasma concentration versus time curve following injections was significantly dose-dependent.
Milrinone has been shown (by equilibrium dialysis) to be approximately 70% bound to human plasma protein.
The primary route of excretion of Milrinone in man is via the urine. The major urinary excretions of orally administered Milrinone in man are Milrinone (83%) and its 0-glucuronide metabolite (12%). Elimination in normal subjects via the urine is rapid, with approximately 60% recovered within the first two hours following dosing and approximately 90% recovered within the first eight hours following dosing. The mean renal clearance of Milrinone is approximately 0.3 liters/min, indicative of active secretion.
PharmacodynamicsIn patients with heart failure due to depressed myocardial function, Milrinone produced a prompt dose and plasma concentration related increase in cardiac output and decreases in pulmonary capillary wedge pressure and vascular resistance, which were accompanied by mild-to-moderate increases in heart rate. Additionally, there is no increased effect on myocardial oxygen consumption. In uncontrolled studies, hemodynamic improvement during intravenous therapy with Milrinone was accompanied by clinical symptomatic improvement, but the ability of Milrinone to relieve symptoms has not been evaluated in controlled clinical trials. The great majority of patients experience improvements in hemodynamic function within 5 to 15 minutes of initiation of therapy.
In studies in congestive heart failure patients, Milrinone when administered as a loading injection followed by a maintenance infusion produced significant mean initial increases in cardiac index of 25 percent, 38 percent, and 42 percent at dose regimens of 37.5 mcg/kg/0.375 mcg/kg/min, 50 mcg/kg/0.5 mcg/kg/min, and 75 mcg/kg/0.75 mcg/kg/min, respectively. Over the same range of loading injections and maintenance infusions, pulmonary capillary wedge pressure significantly decreased by 20 percent, 23 percent, and 36 percent, respectively, while systemic vascular resistance significantly decreased by 17 percent, 21 percent, and 37 percent. Mean arterial pressure fell by up to 5 percent at the two lower dose regimens, but by 17 percent at the highest dose. Patients evaluated for 48 hours maintained improvements in hemodynamic function, with no evidence of diminished response (tachyphylaxis). A smaller number of patients have received infusions of Milrinone for periods up to 72 hours without evidence of tachyphylaxis.
The duration of therapy should depend upon patient responsiveness.
Milrinone has a favorable inotropic effect in fully digitalized patients without causing signs of glycoside toxicity. Theoretically, in cases of atrial flutter/fibrillation, it is possible that Milrinone may increase ventricular response rate because of its slight enhancement of AV node conduction. In these cases, digitalis should be considered prior to the institution of therapy with Milrinone.
Improvement in left ventricular function in patients with ischemic heart disease has been observed. The improvement has occurred without inducing symptoms or electrocardiographic signs of myocardial ischemia.
The steady-state plasma Milrinone concentrations after approximately 6 to 12 hours of unchanging maintenance infusion of 0.5 mcg/kg/min are approximately 200 ng/mL. Near maximum favorable effects of Milrinone on cardiac output and pulmonary capillary wedge pressure are seen at plasma Milrinone concentrations in the 150 ng/mL to 250 ng/mL range.
Indications and Usage for MilrinoneMilrinone lactate injection is indicated for the short-term intravenous treatment of patients with acute decompensated heart failure. Patients receiving Milrinone should be observed closely with appropriate electrocardiographic equipment. The facility for immediate treatment of potential cardiac events, which may include life threatening ventricular arrhythmias, must be available. The majority of experience with intravenous Milrinone has been in patients receiving digoxin and diuretics. There is no experience in controlled trials with infusions of Milrinone for periods exceeding 48 hours.
ContraindicationsMilrinone lactate injection is contraindicated in patients who are hypersensitive to it.
WarningsWhether given orally or by continuous or intermittent intravenous infusion, Milrinone has not been shown to be safe or effective in the longer (greater than 48 hours) treatment of patients with heart failure. In a multicenter trial of 1088 patients with Class III and IV heart failure, long-term oral treatment with Milrinone was associated with no improvement in symptoms and an increased risk of hospitalization and death. In this study, patients with Class IV symptoms appeared to be at particular risk of life-threatening cardiovascular reactions. There is no evidence that Milrinone given by long-term continuous or intermittent infusion does not carry a similar risk.
The use of Milrinone both intravenously and orally has been associated with increased frequency of ventricular arrhythmias, including nonsustained ventricular tachycardia. Long-term oral use has been associated with an increased risk of sudden death. Hence, patients receiving Milrinone should be observed closely with the use of continuous electrocardiographic monitoring to allow the prompt detection and management of ventricular arrhythmias.
Precautions GeneralMilrinone should not be used in patients with severe obstructive aortic or pulmonic valvular disease in lieu of surgical relief of the obstruction. Like other inotropic agents, it may aggravate outflow tract obstruction in hypertrophic subaortic stenosis.
Supraventricular and ventricular arrhythmias have been observed in the high-risk population treated. In some patients, injections of Milrinone and oral Milrinone have been shown to increase ventricular ectopy, including nonsustained ventricular tachycardia. The potential for arrhythmia, present in congestive heart failure itself, may be increased by many drugs or combinations of drugs. Patients receiving Milrinone should be closely monitored during infusion.
Milrinone produces a slight shortening of AV node conduction time, indicating a potential for an increased ventricular response rate in patients with atrial flutter/fibrillation which is not controlled with digitalis therapy.
During therapy with Milrinone, blood pressure and heart rate should be monitored and the rate of infusion slowed or stopped in patients showing excessive decreases in blood pressure.
If prior vigorous diuretic therapy is suspected to have caused significant decreases in cardiac filling pressure, Milrinone should be cautiously administered with monitoring of blood pressure, heart rate, and clinical symptomatology.
There is no experience in controlled trials with infusions of Milrinone for periods exceeding 48 hours. Cases of infusion site reaction have been reported with intravenous Milrinone therapy (see ADVERSE REACTIONS). Consequently, careful monitoring of the infusion site should be maintained to avoid possible extravasation.
Use in Acute Myocardial InfarctionNo clinical studies have been conducted in patients in the acute phase of post myocardial infarction. Until further clinical experience with this class of drugs is gained, Milrinone is not recommended in these patients.
Laboratory Tests Fluid And ElectrolytesFluid and electrolyte changes and renal function should be carefully monitored during therapy with Milrinone. Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may predispose digitalized patients to arrhythmias. Therefore, hypokalemia should be corrected by potassium supplementation in advance of or during use of Milrinone.
Drug InteractionsNo untoward clinical manifestations have been observed in limited experience with patients in whom Milrinone was used concurrently with the following drugs: digitalis glycosides; lidocaine, quinidine; hydralazine, prazosin; isosorbide dinitrate, nitroglycerin; chlorthalidone, furosemide, hydrochlorothiazide, spironolactone; captopril; heparin, warfarin, diazepam, insulin; and potassium supplements.
Chemical InteractionsThere is an immediate chemical interaction which is evidenced by the formation of a precipitate when furosemide is injected into an intravenous line of an infusion of Milrinone. Therefore, furosemide should not be administered in intravenous lines containing Milrinone.
Carcinogenesis and Mutagenesis and Impairment of FertilityTwenty-four months of oral administration of Milrinone to mice at doses up to 40 mg/kg/day (about 50 times the human oral therapeutic dose in a 50 kg patient) was unassociated with evidence of carcinogenic potential. Neither was there evidence of carcinogenic potential when Milrinone was orally administered to rats at doses up to 5 mg/kg/day (about 6 times the human oral therapeutic dose) for twenty-four months or at 25 mg/kg/day (about 30 times the human oral therapeutic dose) for up to 18 months in males and 20 months in females. Whereas the Chinese Hamster Ovary Chromosome Aberration Assay was positive in the presence of a metabolic activation system, results from the Ames Test, the Mouse Lymphoma Assay, the Micronucleus Test, and the in vivo Rat Bone Marrow Metaphase Analysis indicated an absence of mutagenic potential. In reproductive performance studies in rats, Milrinone had no effect on male or female fertility at oral doses up to 32 mg/kg/day.
Animal ToxicityOral and intravenous administration of toxic dosages of Milrinone to rats and dogs resulted in myocardial degeneration/fibrosis and endocardial hemorrhage, principally affecting the left ventricular papillary muscles. Coronary vascular lesions characterized by periarterial edema and inflammation have been observed in dogs only. The myocardial/endocardial changes are similar to those produced by beta-adrenergic receptor agonists such as isoproterenol, while the vascular changes are similar to those produced by minoxidil and hydralazine. Doses within the recommended clinical dose range (up to 1.13 mg/kg/day) for congestive heart failure patients have not produced significant adverse effects in animals.
Pregnancy Pregnancy Category COral administration of Milrinone to pregnant rats and rabbits during organogenesis produced no evidence of teratogenicity at dose levels up to 40 mg/kg/day and 12 mg/kg/day, respectively. Milrinone lactate did not appear to be teratogenic when administered intravenously to pregnant rats at doses up to 3 mg/kg/day (about 2.5 times the maximum recommended clinical intravenous dose) or pregnant rabbits at doses up to 12 mg/kg/day, although an increased resorption rate was apparent at both
8 mg/kg/day and 12 mg/kg/day (intravenous) in the latter species. There are no adequate and well-controlled studies in pregnant women. Milrinone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Caution should be exercised when Milrinone lactate is administered to nursing women, since it is not known whether it is excreted in human milk.
Pediatric UseSafety and effectiveness in pediatric patients have not been established.
Use in Elderly PatientsThere are no special dosage recommendations for the elderly patient. Ninety percent of all patients administered Milrinone in clinical studies were within the age range of 45 to 70 years, with a mean age of 61 years. Patients in all age groups demonstrated clinically and statistically significant responses. No age-related effects on the incidence of adverse reactions have been observed. Controlled pharmacokinetic studies have not disclosed any age-related effects on the distribution and elimination of Milrinone.
ADVERSE REACTIONS Cardiovascular EffectsIn patients receiving Milrinone in Phase II and III clinical trials, ventricular arrhythmias were reported in 12.1%: Ventricular ectopic activity, 8.5%; nonsustained ventricular tachycardia, 2.8%; sustained ventricular tachycardia, 1% and ventricular fibrillation, 0.2% (2 patients experienced more than one type of arrhythmia). Holter recordings demonstrated that in some patients injection of Milrinone increased ventricular ectopy, including nonsustained ventricular tachycardia. Life-threatening arrhythmias were infrequent and when present have been associated with certain underlying factors such as preexisting arrhythmias, metabolic abnormalities (e.g. hypokalemia), abnormal digoxin levels and catheter insertion. Milrinone was not shown to be arrhythmogenic in an electrophysiology study. Supraventricular arrhythmias were reported in 3.8% of the patients receiving Milrinone. The incidence of both supraventricular and ventricular arrhythmias has not been related to the dose or plasma Milrinone concentration.
Other cardiovascular adverse reactions include hypotension, 2.9% and angina/chest pain, 1.2%.
In the post-marketing experience, there have been rare cases of “torsades de pointes” reported.
CNS EffectsHeadaches, usually mild to moderate in severity, have been reported in 2.9% of patients receiving Milrinone.
Other EffectsOther adverse reactions reported, but not definitely related to the administration of Milrinone include hypokalemia, 0.6%; tremor, 0.4%; and thrombocytopenia, 0.4%.
Isolated spontaneous reports of bronchospasm and anaphylactic shock have been received; and in the post-marketing experience, liver function test abnormalities and skin reactions such as rash have been reported.
Post-Marketing Adverse Event ReportsIn addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with Milrinone:
Isolated spontaneous reports of bronchospasm and anaphylactic shock.
Liver function test abnormalities and skin reactions such as rash.
Administration site conditions: Infusion site reaction.
OverdosageDoses of Milrinone may produce hypotension because of its vasodilator effect. If this occurs, administration of Milrinone should be reduced or temporarily discontinued until the patient's condition stabilizes. No specific antidote is known, but general measures for circulatory support should be taken.
Milrinone Dosage and AdministrationMilrinone Lactate in 5% Dextrose Injection should not be used for administering a loading dose. The information regarding loading dose for Milrinone is for 1 mg/mL vial only. A loading dose of Milrinone lactate injection (1 mg [base]/mL) should be administered followed by a continuous infusion (maintenance dose) according to the following guidelines:
LOADING DOSE — 50 mcg/kg: Administer slowly over 10 minutes The table below shows the loading dose in milliliters (mL) of Milrinone (1 mg/mL) by patient body weight (kg). Loading Dose (mL) Using 1 mg/mL Concentration Patient Body Weight kg) kg 30 40 50 60 70 80 90 100 110 120 mL 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0The loading dose may be given undiluted, but diluting to a rounded total volume of 10 or 20 mL (see Maintenance Dose for diluents) may simplify the visualization of the injection rate.
MAINTENANCE DOSE Infusion Rate Total Daily Dose(24 hours) Minimum 0.375 mcg/kg/min 0.59 mg/kg Administer as a continuous intravenous infusion Standard 0.50 mcg/kg/min 0.77 mg/kg Maximum 0.75 mcg/kg/min 1.13 mg/kg
Milrinone drawn from vials should be diluted prior to maintenance dose administration. The diluents that may be used are 0.45% Sodium Chloride Injection, USP; 0.9% Sodium Chloride Injection, USP; or 5% Dextrose Injection, USP. The table below shows the volume of diluent in milliliters (mL) that must be used to achieve 200 mcg/mL concentration for infusion, and the resultant total volumes.
Desired Infusion Concentration mcg/mL Milrinone1 mg/mL
(mL) Diluent
(mL) Total Volume
(mL) 200 10 40 50 200 20 80 100
The infusion rate should be adjusted according to hemodynamic and clinical response. Patients should be closely monitored. In controlled clinical studies, most patients showed an improvement in hemodynamic status as evidenced by increases in cardiac output and reductions in pulmonary capillary wedge pressure.
Note: See "Dosage Adjustment in Renally Impaired Patients." Dosage may be titrated to the maximum hemodynamic effect and should not exceed 1.13 mg/kg/day. Duration of therapy should depend upon patient responsiveness.
The maintenance dose in mL/hr by patient body weight (kg) may be determined by reference to the following table.
Note: Milrinone Lactate in 5% Dextrose Injection supplied in 100 mL and 200 mL Flexible Containers (200 mcg/mL in 5% Dextrose Injection) need not be diluted prior to use.
Milrinone Infusion Rate(mL/hr) Using 200 mcg/mL Concentration Maintenance Dose (mcg/kg/min) Patient Body Weight (kg) 30 40 50 60 70 80 90 100 110 120 0.375 3.4 4.5 5.6 6.8 7.9 9.0 10.1 11.3 12.4 13.5 0.400 3.6 4.8 6.0 7.2 8.4 9.6 10.8 12.0 13.2 14.4 0.500 4.5 6.0 7.5 9.0 10.5 12.0 13.5 15.0 16.5 18.0 0.600 5.4 7.2 9.0 10.8 12.6 14.4 16.2 18.0 19.8 21.6 0.700 6.3 8.4 10.5 12.6 14.7 16.8 18.9 21.0 23.1 25.2 0.750 6.8 9.0 11.3 13.5 15.8 18.0 20.3 22.5 24.8 27.0When administering Milrinone lactate by continuous infusion, it is advisable to use a calibrated electronic infusion device.
The Flexible Container has a concentration of Milrinone equivalent to 200 mcg/mL in 5% Dextrose Injection and is more convenient to use than dilutions prepared from the vials. To use the Flexible Container, tear the overwrap at the notch and remove the Pre-Mix solution container. Squeeze the container firmly to check for leaks. Discard the container if leaks are found since the sterility of the product could be affected. Do not add supplementary medication.
To prepare the container for administration of Milrinone intravenously, use aseptic techniques.
1. The flow control clamp of the administration set is closed.
2. The cover of the outlet port at the bottom of the container is removed.
3. Noting the full directions on the administration set carton, the piercing pin of the set is inserted into the port with a twisting motion until it is firmly sealed.
4. The container is suspended on the hanger.
5. The drop chamber is squeezed and released to establish the fill level.
6. The flow control clamp is opened to expel air from the set and then closed.
7. The set is attached to the venipuncture device, primed, and if not indwelling, the venipuncture is performed.
8. The rate of administration is controlled with the flow control clamp. WARNING - DO NOT USE IN SERIES CONNECTIONS. Caution: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.
Intravenous drug products should be inspected visually and should not be used if particulate matter or discoloration is present.
Dosage Adjustment in Renally Impaired PatientsData obtained from patients with severe renal impairment (creatinine clearance = 0 to 30 mL/min) but without congestive heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of Milrinone lactate. Reductions in infusion rate may be necessary in patients with renal impairment. For patients with clinical evidence of renal impairment, the recommended infusion rate can be obtained from the following table:
Creatinine Clearance(mL/min/1.73 m2) Infusion Rate
(mcg/kg/min) 5 0.20 10 0.23 20 0.28 30 0.33 40 0.38 50 0.43 How is Milrinone Supplied
Milrinone Lactate Injection is supplied as 10 mL single dose vials in a box of 10, NDC 0143-9710-10, or box of 25, NDC 0143-9710-25; as 20 mL single dose vials in a box of 10, NDC 0143-9709-10; as a 50 mL single dose vial in a box of 1, NDC 0143-9708-01, or box of 10, NDC 0143-9708-10, containing a sterile, clear, colorless to pale yellow solution. Each mL contains Milrinone lactate equivalent to 1 mg Milrinone.
Milrinone Lactate Injection in 5% Dextrose in Flexible Containers are supplied as 100 mL (200 mcg/mL) in 5% Dextrose Injection single units, NDC 0143-9719-10; as 200 mL (200 mcg/mL) in 5% Dextrose Injection single units, NDC 0143-9718-10.
StorageStore at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Avoid freezing.
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat.
Brief exposure of Flexible Containers up to 40?C (104?F) does not adversely affect the product.
Manufactured by:
HIKMA FARMAC?UTICA (PORTUGAL), S.A.
Estrada do Rio da M?, n? 8, 8A e 8B - Ferven?a,
2705 – 906 Terrugem SNT
PORTUGAL
Distributed by:
WEST-WARD PHARMACEUTICAL CORP.
Eatontown NJ 07724 USA
Revised: 04/2011
PRINCIPAL DISPLAY PANELMilrinone Lactate Injection
10 mg/ 10 mL (1 mg/mL)
NDC 0143-9710-10
Milrinone Lactate Injection
20 mg / 20 mL (1 mg /1 mL)
NDC 0143-9709-10
Milrinone Lactate Injection
50 mg /50 mL (1 mg /1 mL)
NDC 0143-9708-10
Milrinone LACTATE
Milrinone lactate injection, solution Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0143-9710 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Milrinone LACTATE (Milrinone) Milrinone LACTATE 1 mg in 1 mL Inactive Ingredients Ingredient Name Strength ANHYDROUS DEXTROSE 47 mg in 1 mL LACTIC ACID 1 mg in 1 mL SODIUM HYDROXIDE WATER Product Characteristics Color Score Shape Size Flavor Imprint Code Contains Packaging # NDC Package Description Multilevel Packaging 1 0143-9710-10 10 mL In 1 VIAL None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077966 12/03/2010
Milrinone LACTATE
Milrinone lactate injection, solution Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0143-9709 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Milrinone LACTATE (Milrinone) Milrinone LACTATE 1 mg in 1 mL Inactive Ingredients Ingredient Name Strength ANHYDROUS DEXTROSE 47 mg in 1 mL WATER LACTIC ACID 1 mg in 1 mL SODIUM HYDROXIDE Product Characteristics Color Score Shape Size Flavor Imprint Code Contains Packaging # NDC Package Description Multilevel Packaging 1 0143-9709-01 10 mL In 1 VIAL None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077966 12/03/2010
Milrinone LACTATE
Milrinone lactate injection, solution Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0143-9708 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Milrinone LACTATE (Milrinone) Milrinone LACTATE 1 mg in 1 mL Inactive Ingredients Ingredient Name Strength ANHYDROUS DEXTROSE 47 mg in 1 mL WATER LACTIC ACID 1 mg in 1 mL SODIUM HYDROXIDE Product Characteristics Color Score Shape Size Flavor Imprint Code Contains Packaging # NDC Package Description Multilevel Packaging 1 0143-9708-01 50 mL In 1 VIAL None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077966 12/03/2010
Labeler - West-ward Pharmaceutical Corp (001230762) Establishment Name Address ID/FEI Operations Hikma Farmaceutica 452742943 MANUFACTURE Revised: 05/2011West-ward Pharmaceutical Corp More Milrinone resources Milrinone Side Effects (in more detail) Milrinone Dosage Milrinone Use in Pregnancy & Breastfeeding Milrinone Drug Interactions Milrinone Support Group 0 Reviews for Milrinone - Add your own review/rating Milrinone MedFacts Consumer Leaflet (Wolters Kluwer) milrinone Concise Consumer Information (Cerner Multum) Milrinone Lactate Monograph (AHFS DI) Primacor I.V. Concise Consumer Information (Cerner Multum) Compare Milrinone with other medications Heart Failure
Milrinone Lactate in Dextrose Injection
Dosage Form: injection
Milrinone Lactate in 5% Dextrose Injection
in INTRAVIA Plastic Container
Milrinone Lactate in Dextrose Injection DescriptionMilrinone lactate is a member of a new class of bipyridine inotropic/vasodilator agents with phosphodiesterase inhibitor activity, distinct from digitalis glycosides or catecholamines. Milrinone lactate is designated chemically as 1,6-dihydro-2-methyl-6-oxo-[3,4’-bipyridine]-5-carbonitrile lactate and has the following structure:
Milrinone is an off-white to tan crystalline compound with a molecular weight of 211.2 and a molecular formula of C12H9N3O. It is slightly soluble in methanol, and very slightly soluble in chloroform and in water. As the lactate salt, it is stable and colorless to pale yellow in solution. Milrinone is available as sterile aqueous solutions of the lactate salt of milrinone for infusion intravenously. The flexible containers provide two ready-to-use dilutions of milrinone in volumes of 100 mL and 200 mL of 5% Dextrose Injection. Each mL contains milrinone lactate equivalent to 200 mcg milrinone. The nominal concentration of lactic acid is 0.282 mg/mL. Each mL also contains 54.3 mg Dextrose Hydrous, USP. The pH is adjusted with lactic acid and/or sodium hydroxide pH 3.5 (3.2 - 4.0). The flexible container is manufactured from a specially designed multilayer plastic (PL 2408). Solutions in contact with the plastic container leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. The flexible container has a foil overwrap. Water can permeate the plastic into the overwrap, but the amount is insufficient to significantly affect the premixed solution.
Milrinone Lactate in Dextrose Injection - Clinical PharmacologyMilrinone is a positive inotrope and vasodilator, with little chronotropic activity different in structure and mode of action from either the digitalis glycosides or catecholamines. Milrinone, at relevant inotropic and vasorelaxant concentrations, is a selective inhibitor of peak III cAMP phosphodiesterase isozyme in cardiac and vascular muscle. This inhibitory action is consistent with cAMP mediated increases in intracellular ionized calcium and contractile force in cardiac muscle, as well as with cAMP dependent contractile protein phosphorylation and relaxation in vascular muscle. Additional experimental evidence also indicates that milrinone is not a beta-adrenergic agonist nor does it inhibit sodium-potassium adenosine triphosphatase activity as do the digitalis glycosides.
Clinical studies in patients with congestive heart failure have shown that milrinone produces dose-related and plasma drug concentration-related increases in the maximum rate of increase of left ventricular pressure. Studies in normal subjects have shown that milrinone produces increases in the slope of the left ventricular pressure-dimension relationship, indicating a direct inotropic effect of the drug. Milrinone also produces dose-related and plasma concentration-related increases in forearm blood flow in patients with congestive heart failure, indicating a direct arterial vasodilator activity of the drug.
Both the inotropic and vasodilatory effects have been observed over the therapeutic range of plasma milrinone concentrations of 100 ng/mL to 300 ng/mL.
In addition to increasing myocardial contractility, milrinone improves diastolic function as evidenced by improvements in left ventricular diastolic relaxation.
The acute administration of intravenous milrinone has also been evaluated in clinical trials in excess of 1600 patients, with chronic heart failure, heart failure associated with cardiac surgery, and heart failure associated with myocardial infarction. The total number of deaths, either on therapy or shortly thereafter (24 hours) was 15, less than 0.9%, few of which were thought to be drug-related.
PHARMACOKINETICSFollowing intravenous injections of 12.5 mcg/kg to 125 mcg/kg to congestive heart failure patients, milrinone had a volume of distribution of 0.38 liters/kg, a mean terminal elimination half-life of 2.3 hours, and a clearance of 0.13 liters/kg/hr. Following intravenous infusions of 0.20 mcg/kg/min to 0.70 mcg/kg/min to congestive heart failure patients, the drug had a volume of distribution of about 0.45 liters/kg, a mean terminal elimination half-life of 2.4 hours, and a clearance of 0.14 liters/kg/hr. These pharmacokinetic parameters were not dose-dependent, and the area under the plasma concentration versus time curve following injections was significantly dose-dependent.
Milrinone has been shown (by equilibrium dialysis) to be approximately 70% bound to human plasma protein.
The primary route of excretion of milrinone in man is via the urine. The major urinary excretions of orally administered milrinone in man are milrinone (83%) and its O-glucuronide metabolite (12%). Elimination in normal subjects via the urine is rapid, with approximately 60% recovered within the first two hours following dosing and approximately 90% recovered within the first eight hours following dosing. The mean renal clearance of milrinone is approximately 0.3 liters/min, indicative of active secretion.
PHARMACODYNAMICSIn patients with heart failure due to depressed myocardial function, milrinone produced a prompt dose and plasma concentration related increase in cardiac output and decreases in pulmonary capillary wedge pressure and vascular resistance, which were accompanied by mild-to-moderate increases in heart rate. Additionally, there is no increased effect on myocardial oxygen consumption. In uncontrolled studies, hemodynamic improvement during intravenous therapy with milrinone was accompanied by clinical symptomatic improvement, but the ability of milrinone to relieve symptoms has not been evaluated in controlled clinical trials. The great majority of patients experience improvements in hemodynamic function within 5 to 15 minutes of initiation of therapy.
In studies in congestive heart failure patients, milrinone when administered as a loading injection followed by a maintenance infusion produced significant mean initial increases in cardiac index of 25 percent, 38 percent, and 42 percent at dose regimens of 37.5 mcg/kg/0.375 mcg/kg/min, 50 mcg/kg/0.50 mcg/kg/min, and 75 mcg/kg/ 0.75 mcg/kg/min, respectively. Over the same range of loading injections and maintenance infusions, pulmonary capillary wedge pressure significantly decreased by 20 percent, 23 percent, and 36 percent, respectively, while systemic vascular resistance significantly decreased by 17 percent, 21 percent, and 37 percent. Mean arterial pressure fell by up to 5 percent at the two lower dose regimens, but by 17 percent at the highest dose. Patients evaluated for 48 hours maintained improvements in hemodynamic function, with no evidence of diminished response (tachyphylaxis). A smaller number of patients have received infusions of milrinone for periods up to 72 hours without evidence of tachyphylaxis.
The duration of therapy should depend upon patient responsiveness.
Milrinone has a favorable inotropic effect in fully digitalized patients without causing signs of glycoside toxicity. Theoretically, in cases of atrial flutter/fibrillation, it is possible that milrinone may increase ventricular response rate because of its slight enhancement of AV node conduction. In these cases, digitalis should be considered prior to the institution of therapy with milrinone.
Improvement in left ventricular function in patients with ischemic heart disease has been observed. The improvement has occurred without inducing symptoms or electrocardiographic signs of myocardial ischemia.
The steady-state plasma milrinone concentrations after approximately 6 to 12 hours of unchanging maintenance infusion of 0.50 mcg/kg/min are approximately 200 ng/mL. Near maximum favorable effects of milrinone on cardiac output and pulmonary capillary wedge pressure are seen at plasma milrinone concentrations in the 150 ng/mL to 250 ng/mL range.
Indications and Usage for Milrinone Lactate in Dextrose InjectionMilrinone is indicated for the short-term intravenous treatment of patients with acute decompensated heart failure. Patients receiving milrinone should be observed closely with appropriate electrocardiographic equipment. The facility for immediate treatment of potential cardiac events, which may include life-threatening ventricular arrythmias, must be available. The majority of experience with intravenous milrinone has been in patients receiving digoxin and diuretics. There is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours.
ContraindicationsMilrinone is contraindicated in patients who are hypersensitive to it.
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.
WarningsWhether given orally or by continuous or intermittent intravenous infusion, milrinone has not been shown to be safe or effective in the longer (greater than 48 hours) treatment of patients with heart failure. In a multicenter trial of 1088 patients with Class III and IV heart failure, long-term oral treatment with milrinone was associated with no improvement in symptoms and an increased risk of hospitalization and death. In this study, patients with Class IV symptoms appeared to be at particular risk of life-threatening cardiovascular reactions. There is no evidence that milrinone given by long-term continuous or intermittent infusion does not carry a similar risk.
The use of milrinone both intravenously and orally has been associated with increased frequency of ventricular arrhythmias, including nonsustained ventricular tachycardia. Long-term oral use has been associated with an increased risk of sudden death. Hence, patients receiving milrinone should be observed closely with the use of continuous electrocardiographic monitoring to allow the prompt detection and management of ventricular arrhythmias.
Precautions GeneralMilrinone should not be used in patients with severe obstructive aortic or pulmonic valvular disease in lieu of surgical relief of the obstruction. Like other inotropic agents, it may aggravate outflow tract obstruction in hypertrophic subaortic stenosis.
Supraventricular and ventricular arrhythmias have been observed in the high-risk population treated. In some patients, injections of milrinone and oral milrinone have been shown to increase ventricular ectopy, including nonsustained ventricular tachycardia. The potential for arrhythmia, present in congestive heart failure itself, may be increased by many drugs or combinations of drugs. Patients receiving milrinone should be closely monitored during infusion.
Milrinone produces a slight shortening of AV node conduction time, indicating a potential for an increased ventricular response rate in patients with atrial flutter/fibrillation which is not controlled with digitalis therapy.
During therapy with milrinone, blood pressure and heart rate should be monitored and the rate of infusion slowed or stopped in patients showing excessive decreases in blood pressure. If prior vigorous diuretic therapy is suspected to have caused significant decreases in cardiac filling pressure, milrinone should be cautiously administered with monitoring of blood pressure, heart rate, and clinical symptomatology.
There is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours. Cases of infusion site reaction have been reported with intravenous milrinone therapy (see ADVERSE REACTIONS). Consequently, careful monitoring of the infusion site should be maintained to avoid possible extravasation.
Use in Acute Myocardial InfarctionNo clinical studies have been conducted in patients in the acute phase of post myocardial infarction. Until further clinical experience with this class of drugs is gained, milrinone is not recommended in these patients.
Laboratory TestsFluid and electrolytes: Fluid and electrolyte changes and renal function should be carefully monitored during therapy with milrinone. Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may predispose digitalized patients to arrhythmias. Therefore, hypokalemia should be corrected by potassium supplementation in advance of or during use of milrinone.
Drug InteractionsNo untoward clinical manifestations have been observed in limited experience with patients in whom milrinone was used concurrently with the following drugs: digitalis glycosides; lidocaine, quinidine; hydralazine, prazosin; isosorbide dinitrate, nitroglycerin; chlorthalidone, furosemide, hydrochlorothiazide, spironolactone; captopril; heparin, warfarin, diazepam, insulin; and potassium supplements.
Chemical InteractionsThere is an immediate chemical interaction which is evidenced by the formation of a precipitate when furosemide is injected into an intravenous line of an infusion of milrinone. Therefore, furosemide should not be administered in intravenous lines containing milrinone.
Carcinogenesis, Mutagenesis, Impairment of FertilityTwenty-four months of oral administration of milrinone to mice at doses up to 40 mg/kg/day (about 50 times the human oral therapeutic dose in a 50 kg patient) was unassociated with evidence of carcinogenic potential. Neither was there evidence of carcinogenic potential when milrinone was orally administered to rats at doses up to 5 mg/kg/day (about 6 times the human oral therapeutic dose) for twenty-four months or at 25 mg/kg/day (about 30 times the human oral therapeutic dose) for up to 18 months in males and 20 months in females. Whereas the Chinese Hamster Ovary Chromosome Aberration Assay was positive in the presence of a metabolic activation system, results from the Ames Test, the Mouse Lymphoma Assay, the Micronucleus Test, and the in vivo Rat Bone Marrow Metaphase Analysis indicated an absence of mutagenic potential. In reproductive performance studies in rats, milrinone had no effect on male or female fertility at oral doses up to 32 mg/kg/day.
Animal ToxicityOral and intravenous administration of toxic dosages of milrinone to rats and dogs resulted in myocardial degeneration/fibrosis and endocardial hemorrhage, principally affecting the left ventricular papillary muscles. Coronary vascular lesions characterized by periarterial edema and inflammation have been observed in dogs only. The myocardial/endocardial changes are similar to those produced by beta-adrenergic receptor agonists such as isoproterenol, while the vascular changes are similar to those produced by minoxidil and hydralazine. Doses within the recommended clinical dose range (up to 1.13 mg/kg/day) for congestive heart failure patients have not produced significant adverse effects in animals.
Pregnancy Category COral administration of milrinone to pregnant rats and rabbits during organogenesis produced no evidence of teratogenicity at dose levels up to 40 mg/kg/day and 12 mg/kg/day, respectively. Milrinone did not appear to be teratogenic when administered intravenously to pregnant rats at doses up to 3 mg/kg/day (about 2.5 times the maximum recommended clinical intravenous dose) or pregnant rabbits at doses up to 12 mg/kg/day, although an increased resorption rate was apparent at both 8 mg/kg/day and 12 mg/kg/day (intravenous) in the latter species. There are no adequate and well-controlled studies in pregnant women. Milrinone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing MothersCaution should be exercised when milrinone is administered to nursing women, since it is not known whether it is excreted in human milk.
Pediatric UseSafety and effectiveness in pediatric patients have not been established.
Use in Elderly PatientsThere are no special dosage recommendations for the elderly patient. Ninety percent of all patients administered milrinone in clinical studies were within the age range of 45 to 70 years, with a mean age of 61 years. Patients in all age groups demonstrated clinically and statistically significant responses. No age-related effects on the incidence of adverse reactions have been observed. Controlled pharmacokinetic studies have not disclosed any age-related effects on the distribution and elimination of milrinone.
Adverse Reactions Cardiovascular EffectsIn patients receiving milrinone in Phase II and III clinical trials, ventricular arrhythmias were reported in 12.1%: Ventricular ectopic activity, 8.5%; nonsustained ventricular tachycardia, 2.8%; sustained ventricular tachycardia, 1% and ventricular fibrillation, 0.2% (2 patients experienced more than one type of arrhythmia). Holter recordings demonstrated that in some patients injection of milrinone increased ventricular ectopy, including nonsustained ventricular tachycardia. Life-threatening arrhythmias were infrequent and when present have been associated with certain underlying factors such as preexisting arrhythmias, metabolic abnormalities (e.g. hypokalemia), abnormal digoxin levels and catheter insertion. Milrinone was not shown to be arrhythmogenic in an electrophysiology study. Supraventricular arrhythmias were reported in 3.8% of the patients receiving milrinone. The incidence of both supraventricular and ventricular arrhythmias has not been related to the dose or plasma milrinone concentration.
Other cardiovascular adverse reactions include hypotension, 2.9% and angina/chest pain, 1.2%.
In the post-marketing experience, there have been rare cases of “torsades de pointes” reported.
CNS EffectsHeadaches, usually mild to moderate in severity, have been reported in 2.9% of patients receiving milrinone.
Other EffectsOther adverse reactions reported, but not definitely related to the administration of milrinone include hypokalemia, 0.6%; tremor, 0.4%; and thrombocytopenia, 0.4%.
Post-Marketing Adverse Event ReportsIn addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with Milrinone:
Isolated spontaneous reports of bronchospasm and anaphylactic shock.
Liver function test abnormalities and skin reactions such as rash.
Administration site conditions: Infusion site reaction.
OverdosageDoses of milrinone may produce hypotension because of its vasodilator effect. If this occurs, administration of milrinone should be reduced or temporarily discontinued until the patient's condition stabilizes. No specific antidote is known, but general measures for circulatory support should be taken.
Milrinone Lactate in Dextrose Injection Dosage and AdministrationMilrinone should be administered with a loading dose followed by a continuous infusion (maintenance dose) according to the following guidelines:
Loading Dose50 mcg/kg: Administer slowly over 10 minutes
Note: Milrinone (200 mcg/mL) in INTRAVIA Plastic Container is for intravenous infusion only.
Dosage recommendations using a 1 mg/mL concentration of milrinone are included for informational purposes only.
The table below shows the loading dose in milliliters (mL) of milrinone (1mg/mL) by patient body weight (kg).
Loading Dose (mL) Using 1 mg/mL Concentration Patient Body Weight (kg) kg 30 40 50 60 70 80 90 100 110 120 mL 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0The loading dose may be given undiluted, but diluting to a rounded total volume of 10 or 20 mL (see appropriate package insert for diluents) may simplify the visualization of the injection rate.
Maintenance Dose Infusion Rate Total Daily Dose(24 Hours) Minimum 0.375 mcg/kg/min 0.59 mg/kg Administer as a continuous intravenous infusion Standard 0.50 mcg/kg/min 0.77 mg/kg Maximum 0.75 mcg/kg/min 1.13 mg/kg
The infusion rate should be adjusted according to hemodynamic and clinical response. Patients should be closely monitored. In controlled clinical studies, most patients showed an improvement in hemodynamic status as evidenced by increases in cardiac output and reductions in pulmonary capillary wedge pressure.
Note: See "Dosage Adjustment in Renally Impaired Patients." Dosage may be titrated to the maximum hemodynamic effect and should not exceed 1.13 mg/kg/day. Duration of therapy should depend upon patient responsiveness.
The maintenance dose in mL/hr by patient body weight (kg) may be determined by reference to the following table.
Milrinone Infusion Rate (mL/hr) Using 200 mcg/mL Concentration Maintenance Dose (mcg/kg/min) Patient Body Weight (kg) 30 40 50 60 70 80 90 100 110 120 0.375 3.4 4.5 5.6 6.8 7.9 9.0 10.1 11.3 12.4 13.5 0.400 3.6 4.8 6.0 7.2 8.4 9.6 10.8 12.0 13.2 14.4 0.500 4.5 6.0 7.5 9.0 10.5 12.0 13.5 15.0 16.5 18.0 0.600 5.4 7.2 9.0 10.8 12.6 14.4 16.2 18.0 19.8 21.6 0.700 6.3 8.4 10.5 12.6 14.7 16.8 18.9 21.0 23.1 25.2 0.750 6.8 9.0 11.3 13.5 15.8 18.0 20.3 22.5 24.8 27.0 Dosage Adjustment in Renally Impaired PatientsData obtained from patients with severe renal impairment (creatinine clearance = 0 to 30 mL/min) but without congestive heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of milrinone. Reductions in infusion rate may be necessary in patients with renal impairment. For patients with clinical evidence of renal impairment, the recommended infusion rate can be obtained from the following table:
Creatinine Clearance(mL/min/1.73 m2) Infusion Rate
(mcg/kg/min) 5 0.20 10 0.23 20 0.28 30 0.33 40 0.38 50 0.43
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Milrinone Lactate in 5% Dextrose Injection is a clear, colorless to pale yellow solution.
DIRECTIONS FOR USEWhen administering Milrinone Lactate in 5% Dextrose Injection by continuous infusion, it is advisable to use a calibrated electronic infusion device.
To openTear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
Preparation for Administration(Use aseptic technique)
Suspend container from eyelet support. Remove protector from outlet port at bottom of container. Attach administration set. Refer to complete directions accompanying set.WARNING: DO NOT USE IN SERIES CONNECTIONS. Do not administer simultaneously with blood. Caution: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.
How is Milrinone Lactate in Dextrose Injection SuppliedBaxter’s Milrinone Lactate in 5% Dextrose Injection is supplied in INTRAVIA Plastic Container as follows:
2J0900 NDC 0338-6010-48 100 mL (200 mcg/mL) 2J0901 NDC 0338-6011-37 200 mL (200 mcg/mL)Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the product be stored at room temperature, 25° C (77° F); however, brief exposure up to 40° C (104° F) does not adversely affect the product.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
BAXTER and INTRAVIA are trademarks of Baxter International Inc.
07-19-54-485
Revised, September 2007
PACKAGE LABELING - PRINCIPAL DISPLAY PANEL
Container Label
LOT
EXP
2J0901
NDC 0338-6011-37
200 mL
MILRINONE
LACTATE
40 mg/200 mL
200 mcg (0.2 mg) per mL*
in 5% Dextrose Injection
*Each mL contains milrinone lactate
equivalent to 0.2 mg milrinone 0.282 mg
lactic acid 54.3 mg Dextrose Hydrous
USP in Water for Injection USP The pH
is adjusted with lactic acid and/or sodium
hydroxide pH 3.5 (3.2 - 4.0)
Sterile Nonpyrogenic Single dose No preservative is added
Usual Dosage intravenously as directed by a physician See
package insert
Cautions Check for minute leaks by squeezing bag firmly If
leaks are found discard bag as sterility may be impaired MUST
NOT BE USED IN SERIES CONECTIONS Do not administer
simultaneously with blood Use only if solution is clear
colorless to pale yellow
RX ONLY
Recommended storage Store at room temperature 25°C (77°F)
However brief exposure up to 40°C (104°F) does not adversely
affect the product Protect from freezing Avoid excessive heat
INTRAVIA container
Baxter and INTRAVIA are trademarks
of Baxter International Inc
US Pat Nos 5 849 843 5 998 019 Pat Pending
Baxter Logo
Baxter Healthcare Corporation
Deerfield IL 60015 USA
Made in USA
Carton Label
LOT
EXP
10 x 200 mL Single Dose IntraVia Containers
NDC 0338-6011-37
Code 2J0901
Milrinone Lactate
in 5% Dextrose Injection
40 mg/200 mL
Recommended storage: Store at room temperature (25°C/77°F); however brief exposure to
40°C (104°F) does not adversely affect the product. Protect from freezing. Avoid excessive heat.
GS1 128 BARCODE PLACEMENT ONLY
(01)50303386011376
MILRINONE LACTATE IN DEXTROSE
milrinone lactate injection Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0338-6010 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MILRINONE LACTATE (MILRINONE) MILRINONE LACTATE 200 ug in 1 mL Inactive Ingredients Ingredient Name Strength LACTIC ACID 0.282 mg in 1 mL DEXTROSE MONOHYDRATE 54.3 mg in 1 mL Product Characteristics Color Score Shape Size Flavor Imprint Code Contains Packaging # NDC Package Description Multilevel Packaging 1 0338-6010-48 100 mL In 1 BAG None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA075834 06/02/2008
MILRINONE LACTATE IN DEXTROSE
milrinone lactate injection Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0338-6011 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MILRINONE LACTATE (MILRINONE) MILRINONE LACTATE 200 ug in 1 mL Inactive Ingredients Ingredient Name Strength LACTIC ACID 0.282 mg in 1 mL DEXTROSE MONOHYDRATE 54.3 mg in 1 mL Product Characteristics Color Score Shape Size Flavor Imprint Code Contains Packaging # NDC Package Description Multilevel Packaging 1 0338-6011-37 200 mL In 1 BAG None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA075834 06/02/2008
Labeler - Baxter Healthcare Corporation (005083209) Establishment Name Address ID/FEI Operations Baxter Healthcare SA dba Baxter Healthcare of Puerto Rico 189326168 MANUFACTURE Revised: 10/2010Baxter Healthcare Corporation More Milrinone Lactate in Dextrose Injection resources Milrinone Lactate in Dextrose Injection Side Effects (in more detail)Milrinone Lactate in Dextrose Injection Use in Pregnancy & BreastfeedingMilrinone Lactate in Dextrose Injection Drug InteractionsMilrinone Lactate in Dextrose Injection Support Group0 Reviews for Milrinone Lactate in Dextrose Injection - Add your own review/rating Compare Milrinone Lactate in Dextrose Injection with other medications Heart Failure
Natrecor
nesiritide
Dosage Form: injection, powder, lyophilized, for solution
Natrecor® (nesiritide)
FOR INTRAVENOUS INFUSION ONLY
Natrecor DescriptionNatrecor® (nesiritide) is a sterile, purified preparation of a new drug class, human B-type natriuretic peptide (hBNP), and is manufactured from E. coli using recombinant DNA technology. Nesiritide has a molecular weight of 3464 g/mol and an empirical formula of C143H244N50O42S4. Nesiritide has the same 32 amino acid sequence as the endogenous peptide, which is produced by the ventricular myocardium.
Natrecor is formulated as the citrate salt of rhBNP, and is provided in a sterile, single-use vial. Each 1.5 mg vial contains a white- to off-white lyophilized powder for intravenous (IV) administration after reconstitution. The quantitative composition of the lyophilized drug per vial is: nesiritide 1.58 mg, mannitol 20.0 mg, citric acid monohydrate 2.1 mg, and sodium citrate dihydrate 2.94 mg.
Mechanism of ActionHuman BNP binds to the particulate guanylate cyclase receptor of vascular smooth muscle and endothelial cells, leading to increased intracellular concentrations of guanosine 3'5'-cyclic monophosphate (cGMP) and smooth muscle cell relaxation. Cyclic GMP serves as a second messenger to dilate veins and arteries. Nesiritide has been shown to relax isolated human arterial and venous tissue preparations that were precontracted with either endothelin-1 or the alpha-adrenergic agonist, phenylephrine.
In human studies, nesiritide produced dose-dependent reductions in pulmonary capillary wedge pressure (PCWP) and systemic arterial pressure in patients with heart failure.
In animals, nesiritide had no effects on cardiac contractility or on measures of cardiac electrophysiology such as atrial and ventricular effective refractory times or atrioventricular node conduction.
Naturally occurring atrial natriuretic peptide (ANP), a related peptide, increases vascular permeability in animals and humans and may reduce intravascular volume. The effect of nesiritide on vascular permeability has not been studied.
PharmacokineticsIn patients with congestive heart failure (CHF), Natrecor administered intravenously by infusion or bolus exhibits biphasic disposition from the plasma. The mean terminal elimination half-life (t1/2) of Natrecor is approximately 18 minutes and was associated with approximately 2/3 of the area-under-the-curve (AUC). The mean initial elimination phase was estimated to be approximately 2 minutes. In these patients, the mean volume of distribution of the central compartment (Vc) of Natrecor was estimated to be 0.073 L/kg, the mean steady-state volume of distribution (Vss) was 0.19 L/kg, and the mean clearance (CL) was approximately 9.2 mL/min/kg. At steady state, plasma BNP levels increase from baseline endogenous levels by approximately 3-fold to 6-fold with Natrecor infusion doses ranging from 0.01 to 0.03 mcg/kg/min.
EliminationHuman BNP is cleared from the circulation via the following three independent mechanisms, in order of decreasing importance: 1) binding to cell surface clearance receptors with subsequent cellular internalization and lysosomal proteolysis; 2) proteolytic cleavage of the peptide by endopeptidases, such as neutral endopeptidase, which are present on the vascular lumenal surface; and 3) renal filtration.
Special PopulationsAlthough Natrecor is eliminated, in part, through renal clearance, clinical data suggest that dose adjustment is not required in patients with renal insufficiency. The effects of Natrecor on PCWP, cardiac index (CI), and systolic blood pressure (SBP) were not significantly different in patients with chronic renal insufficiency (baseline serum creatinine ranging from 2 mg/dL to 4.3 mg/dL), and patients with normal renal function. The population pharmacokinetic (PK) analyses carried out to determine the effects of demographics and clinical variables on PK parameters showed that clearance of Natrecor is proportional to body weight, supporting the administration of weight-adjusted dosing of Natrecor (i.e., administration on a mcg/kg/min basis). Clearance was not influenced significantly by age, gender, race/ethnicity, baseline endogenous hBNP concentration, severity of CHF (as indicated by baseline PCWP, baseline CI, or New York Heart Association [NYHA] classification), or concomitant administration of an ACE inhibitor.
Effects of Concomitant MedicationsThe co-administration of Natrecor with enalapril did not have significant effects on the PK of Natrecor. The PK effect of co-administration of Natrecor with other IV vasodilators such as nitroglycerin, nitroprusside, milrinone, or IV ACE inhibitors has not been evaluated. During clinical studies, Natrecor was administered concomitantly with other medications, including: diuretics, digoxin, oral ACE inhibitors, anticoagulants, oral nitrates, statins, class III antiarrhythmic agents, beta-blockers, dobutamine, calcium channel blockers, angiotensin II receptor antagonists, and dopamine. Although no PK interactions were specifically assessed, there did not appear to be evidence suggesting any clinically significant PK interaction.
PharmacodynamicsThe recommended dosing regimen of Natrecor is a 2 mcg/kg IV bolus followed by an intravenous infusion dose of 0.01 mcg/kg/min. With this dosing regimen, 60% of the 3-hour effect on PCWP reduction is achieved within 15 minutes after the bolus, reaching 95% of the 3-hour effect within 1 hour. Approximately seventy percent of the 3-hour effect on SBP reduction is reached within 15 minutes. The pharmacodynamic (PD) half-life of the onset and offset of the hemodynamic effect of Natrecor is longer than what the PK half-life of 18 minutes would predict. For example, in patients who developed symptomatic hypotension in the VMAC (Vasodilation in the Management of Acute Congestive Heart Failure) trial, half of the recovery of SBP toward the baseline value after discontinuation or reduction of the dose of Natrecor was observed in about 60 minutes. When higher doses of Natrecor were infused, the duration of hypotension was sometimes several hours.
Clinical TrialsNatrecor has been studied in 10 clinical trials including 941 patients with CHF (NYHA class II–III 61%, NYHA class IV 36%; mean age 60 years, women 28%). There were five randomized, multi-center, placebo- or active-controlled studies (comparative agents included nitroglycerin, dobutamine, milrinone, nitroprusside, or dopamine) in which 772 patients with decompensated CHF received continuous infusions of Natrecor at doses ranging from 0.01 to 0.03 mcg/kg/min. (See the ADVERSE REACTIONS section for relative frequency of adverse events at doses ranging from the recommended dose up to 0.03 mcg/kg/min). Of these patients, the majority (n = 541, 70%) received the Natrecor infusion for at least 24 hours; 371 (48%) received Natrecor for 24–48 hours, and 170 (22%) received Natrecor for greater than 48 hours.
In controlled trials, Natrecor has been used alone or in conjunction with other standard therapies, including diuretics (79%), digoxin (62%), oral ACE inhibitors (55%), anticoagulants (38%), oral nitrates (32%), statins (18%), class III antiarrhythmic agents (16%), beta-blockers (15%), dobutamine (15%), calcium channel blockers (11%), angiotensin II receptor antagonists (6%), and dopamine (4%). Natrecor has been studied in a broad range of patients, including the elderly (42% > 65 years of age), women (30%), minorities (26% black), and patients with a history of significant morbidities such as hypertension (67%), previous myocardial infarction (50%), diabetes (44%), atrial fibrillation/flutter (34%), nonsustained ventricular tachycardia (25%), ventricular tachycardia/fibrillation (12%), preserved systolic function (9%), and acute coronary syndromes less than 7 days before the start of Natrecor (4%).
The VMAC (Vasodilation in the Management of Acute Congestive Heart Failure) trial was a randomized, double-blind study of 489 patients (246 patients requiring a right heart catheter, 243 patients without a right heart catheter) who required hospitalization for management of shortness of breath at rest due to acutely decompensated CHF. The study compared the effects of Natrecor, placebo, and IV nitroglycerin when added to background therapy (IV and oral diuretics, non-IV cardiac medications, dobutamine, and dopamine). Patients with acute coronary syndrome, preserved systolic function, arrhythmia, and renal insufficiency were not excluded. The primary endpoints of the study were the change from baseline in PCWP and the change from baseline in patients' dyspnea, evaluated after three hours. Close attention was also paid to the occurrence and persistence of hypotension, given nesiritide's relatively long (compared to nitroglycerin) PK and PD half-life.
Natrecor was administered as a 2 mcg/kg bolus over approximately 60 seconds, followed by a continuous fixed dose infusion of 0.01 mcg/kg/min. After the 3-hour placebo-controlled period, patients receiving placebo crossed over to double-blinded active therapy with either Natrecor or nitroglycerin. The nitroglycerin dose was titrated at the physician's discretion. A subset of patients in the VMAC trial with central hemodynamic monitoring who were treated with Natrecor (62 of 124 patients) were allowed dose increases of Natrecor after the first 3 hours of treatment if the PCWP was ? 20 mm Hg and the SBP was ? 100 mm Hg. Dose increases of a 1 mcg/kg bolus followed by an increase of the infusion dose by 0.005 mcg/kg/min were allowed every 3 hours, up to a maximum dose of 0.03 mcg/kg/min. Overall, 23 patients in this subset had the dose of Natrecor increased in the VMAC trial.
In a second double-blind study, 127 patients requiring hospitalization for symptomatic CHF were randomized to placebo or to one of two doses of Natrecor (0.015 mcg/kg/min preceded by an IV bolus of 0.3 mcg/kg, and 0.03 mcg/kg/min preceded by an IV bolus of 0.6 mcg/kg). The primary endpoint of the trial was the change in PCWP from baseline to 6 hours, but the effect on symptoms also was examined.
Effects on SymptomsIn the VMAC study, patients receiving Natrecor reported greater improvement in their dyspnea at 3 hours than patients receiving placebo (p = 0.034).
In the dose-response study, patients receiving both doses of Natrecor reported greater improvement in dyspnea at 6 hours than patients receiving placebo.
Effects on HemodynamicsThe PCWP, right atrial pressure (RAP), CI, and other hemodynamic variables were monitored in 246 of the patients in the VMAC trial. There was a reduction in mean PCWP within 15 minutes of starting the Natrecor infusion, with most of the effect seen at 3 hours being achieved within the first 60 minutes of the infusion (see Pharmacodynamics).
In several studies, hemodynamic parameters were measured after Natrecor withdrawal. Following discontinuation of Natrecor, PCWP returns to within 10% of baseline within 2 hours, but no rebound increase to levels above baseline state was observed. There was also no evidence of tachyphylaxis to the hemodynamic effects of Natrecor in the clinical trials.
The following table and graph summarize the changes in the VMAC trial in PCWP and other measures during the first 3 hours.
Mean Hemodynamic Change from Baseline Effects at 3 Hours Placebo(n = 62) Nitroglycerin
(n = 60) Natrecor
(n = 124) * p < 0.05 compared to placebo † Based on all treated subjects: placebo n = 142, nitroglycerin n = 143, Natrecor n = 204 Pulmonary capillary wedge pressure (mm Hg) -2.0 -3.8 -5.8* Right atrial pressure (mm Hg) 0.0 -2.6 -3.1* Cardiac index (L/min/M2) 0.0 0.2 0.1 Mean pulmonary artery pressure (mm Hg) -1.1 -2.5 -5.4* Systemic vascular resistance (dynes*sec*cm-5) -44 -105 -144 Systolic blood pressure† (mm Hg) -2.5 -5.7* -5.6*
The VMAC study does not constitute an adequate effectiveness comparison with nitroglycerin. In this trial, the nitroglycerin group provides a rough landmark using a familiar therapy and regimen.
Effect on Urine OutputIn the VMAC trial, in which the use of diuretics was not restricted, the mean change in volume status (output minus input) during the first 24 hours in the nitroglycerin and Natrecor groups was similar: 1279 ± 1455 mL and 1257 ± 1657 mL, respectively.
Indications and Usage for NatrecorNatrecor (nesiritide) is indicated for the intravenous treatment of patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity. In this population, the use of Natrecor reduced pulmonary capillary wedge pressure and improved dyspnea.
ContraindicationsNatrecor is contraindicated in patients who are hypersensitive to any of its components. Natrecor should not be used as primary therapy for patients with cardiogenic shock or in patients with a systolic blood pressure < 90 mm Hg.
WarningsAdministration of Natrecor should be avoided in patients suspected of having, or known to have, low cardiac filling pressures.
Precautions GeneralParenteral administration of protein pharmaceuticals or E. coli-derived products should be attended by appropriate precautions in case of an allergic or untoward reaction.
Natrecor is not recommended for patients for whom vasodilating agents are not appropriate, such as patients with significant valvular stenosis, restrictive or obstructive cardiomyopathy, constrictive pericarditis, pericardial tamponade, or other conditions in which cardiac output is dependent upon venous return, or for patients suspected to have low cardiac filling pressures (see CONTRAINDICATIONS).
RenalNatrecor may affect renal function in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with Natrecor may be associated with azotemia. When Natrecor was initiated at doses higher than 0.01 mcg/kg/min (0.015 and 0.03 mcg/kg/min), there was an increased rate of elevated serum creatinine over baseline compared with standard therapies, although the rate of acute renal failure and need for dialysis was not increased. In the 30-day follow-up period in the VMAC trial, 5 patients in the nitroglycerin group (2%) and 9 patients in the Natrecor group (3%) required first-time dialysis.
CardiovascularNatrecor may cause hypotension. In the VMAC trial, in patients given the recommended dose (2 mcg/kg bolus followed by a 0.01 mcg/kg/min infusion) or the adjustable dose, the incidence of symptomatic hypotension in the first 24 hours was similar for Natrecor (4%) and IV nitroglycerin (5%). When hypotension occurred, however, the duration of symptomatic hypotension was longer with Natrecor (mean duration was 2.2 hours) than with nitroglycerin (mean duration was 0.7 hours). In earlier trials, when Natrecor was initiated at doses higher than the 2 mcg/kg bolus followed by a 0.01 mcg/kg/min infusion (i.e., 0.015 and 0.03 mcg/kg/min preceded by a small bolus), there were more hypotensive episodes and these episodes were of greater intensity and duration. They were also more often symptomatic and/or more likely to require medical intervention (see ADVERSE REACTIONS). Natrecor should be administered only in settings where blood pressure can be monitored closely, and the dose of Natrecor should be reduced or the drug discontinued in patients who develop hypotension (see Dosing Instructions). The rate of symptomatic hypotension may be increased in patients with a blood pressure < 100 mm Hg at baseline, and Natrecor should be used cautiously in these patients. The potential for hypotension may be increased by combining Natrecor with other drugs that may cause hypotension. For example, in the VMAC trial in patients treated with either Natrecor or nitroglycerin therapy, the frequency of symptomatic hypotension in patients who received an oral ACE inhibitor was 6%, compared to a frequency of symptomatic hypotension of 1% in patients who did not receive an oral ACE inhibitor.
Drug InteractionsNo trials specifically examining potential drug interactions with Natrecor were conducted, although many concomitant drugs were used in clinical trials. No drug interactions were detected except for an increase in symptomatic hypotension in patients receiving oral ACE inhibitors (see PRECAUTIONS, Cardiovascular).
The co-administration of Natrecor with IV vasodilators such as nitroglycerin, nitroprusside, milrinone, or IV ACE inhibitors has not been evaluated (these drugs were not co-administered with Natrecor in clinical trials).
Carcinogenesis, Mutagenesis, Impairment of FertilityLong-term studies in animals have not been performed to evaluate the carcinogenic potential or the effect on fertility of nesiritide. Nesiritide did not increase the frequency of mutations when used in an in vitro bacterial cell assay (Ames test). No other genotoxicity studies were performed.
Pregnancy Category CIt is not known whether Natrecor can cause fetal harm when administered to pregnant women or if it can affect reproductive capacity. A developmental reproductive toxicology study was conducted in pregnant rabbits using doses up to 1440 mcg/kg/day given by constant infusion for 13 days. At this level of exposure (based on AUC, approximately 70 ? human exposure at the recommended dose) no adverse effects on live births or fetal development were observed. Natrecor should be used during pregnancy only if the potential benefit justifies any possible risk to the fetus.
Nursing MothersIt is not known whether this drug is excreted in human milk. Therefore, caution should be exercised when Natrecor is administered to a nursing woman.
Pediatric UseThe safety and effectiveness of Natrecor in pediatric patients has not been established.
Geriatric UseOf the total number of subjects in clinical trials treated with Natrecor (n = 941), 38% were 65 years or older and 16% were 75 years or older. No overall differences in effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. Some older individuals may be more sensitive to the effect of Natrecor than younger individuals.
Adverse ReactionsAdverse events that occurred with at least a 3% frequency during the first 24 hours of Natrecor infusion are shown in the following table.
Adverse Event VMAC Trial Other Long Infusion Trials Nitroglycerin(n = 216) Natrecor Recommended Dose
(n = 273) Control*
(n = 256) Natrecor
mcg/kg/min 0.015
(n = 253) 0.03
(n = 246) * Includes dobutamine, milrinone, nitroglycerin, placebo, dopamine, nitroprusside, or amrinone Cardiovascular Hypotension 25 (12%) 31 (11%) 20 (8%) 56 (22%) 87 (35%) Symptomatic Hypotension 10 (5%) 12 (4%) 8 (3%) 28 (11%) 42 (17%) Asymptomatic Hypotension 17 (8%) 23 (8%) 13 (5%) 31 (12%) 49 (20%) Ventricular Tachycardia (VT) 11 (5%) 9 (3%) 25 (10%) 25 (10%) 10 (4%) Non-sustained VT 11 (5%) 9 (3%) 23 (9%) 24 (9%) 9 (4%) Ventricular Extrasystoles 2 (1%) 7 (3%) 15 (6%) 10 (4%) 9 (4%) Angina Pectoris 5 (2%) 5 (2%) 6 (2%) 14 (6%) 6 (2%) Bradycardia 1 (< 1%) 3 (1%) 1 (< 1%) 8 (3%) 13 (5%) Body as a Whole Headache 44 (20%) 21 (8%) 23 (9%) 23 (9%) 17 (7%) Abdominal Pain 11 (5%) 4 (1%) 10 (4%) 6 (2%) 8 (3%) Back Pain 7 (3%) 10 (4%) 4 (2%) 5 (2%) 3 (1%) Nervous Insomnia 9 (4%) 6 (2%) 7 (3%) 15 (6%) 15 (6%) Dizziness 4 (2%) 7 (3%) 7 (3%) 16 (6%) 12 (5%) Anxiety 6 (3%) 8 (3%) 2 (1%) 8 (3%) 4 (2%) Digestive Nausea 13 (6%) 10 (4%) 12 (5%) 24 (9%) 33 (13%) Vomiting 4 (2%) 4 (1%) 2 (1%) 6 (2%) 10 (4%)
Adverse events that are not listed in the above table that occurred in at least 1% of patients who received any of the above Natrecor doses included: Tachycardia, atrial fibrillation, AV node conduction abnormalities, catheter pain, fever, injection site reaction, confusion, paresthesia, somnolence, tremor, increased cough, hemoptysis, apnea, increased creatinine, sweating, pruritus, rash, leg cramps, amblyopia, anemia. All reported events (at least 1%) are included except those already listed, those too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population.
In placebo and active-controlled clinical trials, Natrecor has not been associated with an increase in atrial or ventricular tachyarrhythmias. In placebo-controlled trials, the incidence of VT in both Natrecor and placebo patients was 2%. In the PRECEDENT (Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Natrecor Therapy) trial, the effects of Natrecor (n = 163) and dobutamine (n = 83) on the provocation or aggravation of existing ventricular arrhythmias in patients with decompensated CHF was compared using Holter monitoring. Treatment with Natrecor (0.015 and 0.03 mcg/kg/min without an initial bolus) for 24 hours did not aggravate pre-existing VT or the frequency of premature ventricular beats, compared to a baseline 24-hour Holter tape.
Clinical LaboratoryIn the PRECEDENT trial, the incidence of elevations in serum creatinine to > 0.5 mg/dL above baseline through day 14 was higher in the Natrecor 0.015 mcg/kg/min group (17%) and the Natrecor 0.03 mcg/kg/min group (19%) than with standard therapy (11%). In the VMAC trial, through day 30, the incidence of elevations in creatinine to > 0.5 mg/dL above baseline was 28% and 21% in the Natrecor (2 mcg/kg bolus followed by 0.01 mcg/kg/min) and nitroglycerin groups, respectively.
Effect on MortalityData from all seven studies in which 30-day data were collected are presented in the chart below. The data depict hazard ratios and confidence intervals of mortality data for randomized and treated patients with Natrecor® relative to active controls through day 30 for each of the 7 individual studies (Studies 311, 325, 326, 329 [PRECEDENT], 339 [VMAC], 341 [PROACTION], and 348 [FUSION I]).
The figure (on logarithmic scale) also contains a plot for the six studies involving hospitalized or Emergency Department patients combined (n = 1507), and for all 7 studies combined (n = 1717). The percentage is the Kaplan-Meier estimate.
The figure below represents 180-day mortality hazard ratios for randomized and treated patients from all five individual studies where 180-day data were collected, 16 week hazard ratios for Study 348 (180-day data were not collected), and the five studies with 180-day data pooled (n = 1404).
There were few deaths in these studies, so the confidence limits around the hazard ratios for mortality are wide. The studies are also small, so some potentially important baseline imbalances exist among the treatment groups, the effects of which cannot be ascertained.
Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of Natrecor. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: hypersensitivity reactions.
OverdosageOverdose with Natrecor therapy has been reported and is primarily the result of either a miscalculated Natrecor dose or a mechanical error such as an infusion-pump malfunction or an infusion-pump programming error. The most frequently reported adverse event reported with Natrecor overdose is hypotension, which may be asymptomatic and most often resolves with drug stoppage, although in some cases hypotension may persist for several hours beyond discontinuation. Treatment of Natrecor overdose should include drug discontinuation and the administration of supportive measures (see PRECAUTIONS — Cardiovascular).
Natrecor Dosage and AdministrationThe Natrecor bolus must be drawn from the prepared infusion bag.
Natrecor (nesiritide) is for intravenous use only. There is limited experience with administering Natrecor for longer than 48 hours. Blood pressure should be monitored closely during Natrecor administration.
If hypotension occurs during the administration of Natrecor, the dose should be reduced or discontinued and other measures to support blood pressure should be started (IV fluids, changes in body position). In the VMAC trial, when symptomatic hypotension occurred, Natrecor was discontinued and subsequently could be restarted at a dose that was reduced by 30% (with no bolus administration) once the patient was stabilized. Because hypotension caused by Natrecor may be prolonged (up to hours), a period of observation may be necessary before restarting the drug.
PreparationThe Natrecor bolus must be drawn from the prepared infusion bag.
Reconstitute one 1.5 mg vial of Natrecor by adding 5 mL of diluent removed from a pre-filled 250 mL plastic IV bag containing the diluent of choice. After reconstitution of the vial, each mL contains 0.32 mg of nesiritide. The following preservative-free diluents are recommended for reconstitution: 5% Dextrose Injection (D5W), USP; 0.9% Sodium Chloride Injection, USP; 5% Dextrose and 0.45% Sodium Chloride Injection, USP, or 5% Dextrose and 0.2% Sodium Chloride Injection, USP. Do not shake the vial. Rock the vial gently so that all surfaces, including the stopper, are in contact with the diluent to ensure complete reconstitution. Use only a clear, essentially colorless solution. Withdraw the entire contents of the reconstituted Natrecor vial and add to the 250 mL plastic IV bag. This will yield a solution with a concentration of Natrecor of approximately 6 mcg/mL. The IV bag should be inverted several times to ensure complete mixing of the solution. Use the reconstituted solution within 24 hours, as Natrecor contains no antimicrobial preservative. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstituted vials of Natrecor may be stored at 2–25°C (36–77°F) for up to 24 hours. Dosing InstructionsThe Natrecor bolus must be drawn from the prepared infusion bag.
The recommended dose of Natrecor is an IV bolus of 2 mcg/kg followed by a continuous infusion of 0.01 mcg/kg/min. Natrecor should not be initiated at a dose that is above the recommended dose.
Prime the IV tubing with 5 mL of the solution for infusion prior to connecting to the patient's vascular access port and prior to administering the bolus or starting the infusion.
The administration of the recommended dose of Natrecor is a two step process:
Step 1. Administration of the IV Bolus
After preparation of the infusion bag, as described previously, withdraw the bolus volume (see Weight-Adjusted Bolus Volume table) from the Natrecor infusion bag, and administer it over approximately 60 seconds through an IV port in the tubing.
Bolus Volume (mL) = Patient Weight (kg) / 3
Natrecor Weight-Adjusted Bolus Volume Administered Over 60 Seconds (Final Concentration = 6 mcg/mL) Patient Weight (kg) Volume of Bolus (mL = kg/3) 60 20.0 70 23.3 80 26.7 90 30.0 100 33.3 110 36.7Step 2. Administration of the Continuous Infusion
Immediately following the administration of the bolus, infuse Natrecor at a flow rate of 0.1 mL/kg/hr. This will deliver a Natrecor infusion dose of 0.01 mcg/kg/min.
To calculate the infusion flow rate to deliver a 0.01 mcg/kg/min dose, use the following formula (see the following Weight-Adjusted Infusion Flow Rate for Dosing table):
Infusion Flow Rate (mL/hr) = Patient Weight (kg) ? 0.1
Natrecor Weight-Adjusted Infusion Flow Rate for a 0.01 mcg/kg/min Dose following Bolus (Final Concentration = 6 mcg/mL) Patient Weight (kg) Infusion Flow Rate (mL/hr) 60 6 70 7 80 8 90 9 100 10 110 11 Dose AdjustmentsThe dose-limiting side effect of Natrecor is hypotension. Do not initiate Natrecor at a dose that is higher than the recommended dose of a 2 mcg/kg bolus followed by an infusion of 0.01 mcg/kg/min. In the VMAC trial there was limited experience with increasing the dose of Natrecor above the recommended dose (23 patients, all of whom had central hemodynamic monitoring). In those patients, the infusion dose of Natrecor was increased by 0.005 mcg/kg/min (preceded by a bolus of 1 mcg/kg), no more frequently than every 3 hours up to a maximum dose of 0.03 mcg/kg/min. Natrecor should not be titrated at frequent intervals as is done with other IV agents that have a shorter half-life (see Clinical Trials).
Chemical/Physical InteractionsNatrecor is physically and/or chemically incompatible with injectable formulations of heparin, insulin, ethacrynate sodium, bumetanide, enalaprilat, hydralazine, and furosemide. These drugs should not be co-administered as infusions with Natrecor through the same IV catheter. The preservative sodium metabisulfite is incompatible with Natrecor. Injectable drugs that contain sodium metabisulfite should not be administered in the same infusion line as Natrecor. The catheter must be flushed between administration of Natrecor and incompatible drugs.
Natrecor binds to heparin and therefore could bind to the heparin lining of a heparin-coated catheter, decreasing the amount of Natrecor delivered to the patient for some period of time. Therefore, Natrecor must not be administered through a central heparin-coated catheter. Concomitant administration of a heparin infusion through a separate catheter is acceptable.
STORAGEStore below 25°C. Do not freeze. Keep the vial in the outer carton in order to protect from light.
How is Natrecor SuppliedNatrecor (nesiritide) is provided as a sterile lyophilized powder in 1.5 mg, single-use vials. Each carton contains one vial and is available in the following package:
1 vial/carton (NDC 65847-205-25)
US patent No. 5,114,923 and 5,674,710.
Manufactured for Scios Inc.
Titusville, NJ 08560
Copyright 2007 Scios Inc.
Revised: June 2009
PRINCIPAL DISPLAY PANEL - 1.5 mg Vial CartonScios Inc.
NDC 65847-205-25
Natrecor®
(nesiritide)
for Injection
1.5 mg
Single-use vial
For IV Infusion Only
Store below 25°C. Do not freeze. Keep the vial
in the outer carton in order to protect from light.
Rx only
Natrecor
nesiritide injection, powder, lyophilized, for solution Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 65847-205 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength NESIRITIDE (NESIRITIDE) NESIRITIDE 1.5 mg in 5 mL Inactive Ingredients Ingredient Name Strength MANNITOL 20 mg in 5 mL CITRIC ACID MONOHYDRATE 2.1 mg in 5 mL TRISODIUM CITRATE DIHYDRATE 2.94 mg in 5 mL Product Characteristics Color WHITE (white to off white) Score Shape Size Flavor Imprint Code Contains Packaging # NDC Package Description Multilevel Packaging 1 65847-205-25 1 VIAL In 1 CARTON contains a VIAL, SINGLE-USE 1 5 mL In 1 VIAL, SINGLE-USE This package is contained within the CARTON (65847-205-25)
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020920 08/01/2001
Labeler - Scios Inc. (015904436) Establishment Name Address ID/FEI Operations Hospira, Inc. 030606222 MANUFACTURE Establishment Name Address ID/FEI Operations Sandoz GmbH, BiochemiestraB 10 300220969 MANUFACTURE, ANALYSIS Establishment Name Address ID/FEI Operations Sandoz GmbH, A-6330 Schaftenau 301698247 MANUFACTURE Revised: 08/2010Scios Inc. More Natrecor resources Natrecor Side Effects (in more detail)Natrecor Use in Pregnancy & BreastfeedingNatrecor Drug InteractionsNatrecor Support Group0 Reviews for Natrecor - Add your own review/rating Natrecor Monograph (AHFS DI) Natrecor Consumer Overview Natrecor Advanced Consumer (Micromedex) - Includes Dosage Information Natrecor MedFacts Consumer Leaflet (Wolters Kluwer) Nesiritide Professional Patient Advice (Wolters Kluwer) Compare Natrecor with other medications Heart Failure
Cimetidine Hydrochloride
Class: Histamine H2-Antagonists
VA Class: GA301
CAS Number: 51481-61-9
Brands: Tagamet
Histamine H2 receptor antagonist.b
Uses for Cimetidine Hydrochloride Duodenal UlcerShort-term treatment of active duodenal ulcer (endoscopically or radiographically confirmed).a b
Maintainence of healing and reduction in recurrence of duodenal ulcer.a b
Pathologic GI Hypersecretory ConditionsLong-term treatment of Zollinger-Ellison syndrome, multiple endocrine adenomas, systemic mastocytosis.a b
Gastric UlcerShort-term treatment of active benign gastric ulcer.a b
Gastroesophageal Reflux (GERD)Short-term treatment of erosive esophagitis (endoscopically diagnosed) in patients with GERD.118
Treatment of symptomatic GERD†.105 106 123 288
Self-medication as initial therapy to achieve acid suppression, control symptoms, and prevent complications of less severe symptomatic GERD†.288
Upper GI BleedingPrevention of upper GI bleeding resulting from stress-related mucosal damage (erosive esophagitis, stress ulcers) in critically ill patients.118 142 143 144 145 146 147 152 153 154 155 156 157 161 162 163 164 165 166 170 171 172 173 174 175 176 177 179 188 191
Treatment of upper GI bleeding† secondary to hepatic failure, esophagitis, duodenal or gastric ulcers when hemorrhage is not caused by major blood vessel erosion.b
Heartburn (pyrosis), Acid Indigestion (hyperchlorhydria), or Sour StomachShort-term self-medication for relief of heartburn symptoms in adults and adolescents?12 years of age.c
Short-term self-medication for prevention of heartburn symptoms associated with acid indigestion (hyperchlorhydria) and sour stomach brought on by ingestion of certain foods and beverages in adults and children ?12 years of age.c
Allergic Conditions and Urticarias†124 125 126 127 128 129 130 131 132 133 134 135 136 137 Cimetidine Hydrochloride Dosage and Administration AdministrationAdminister orally, IV, or IM.118
Administer by IM or slow IV injection, or by intermittent or continuous IV infusion in hospitalized patients with pathological GI hypersecretory conditions or intractable duodenal ulcer, or when oral therapy is not feasible.118
Oral AdministrationAdminister with or without food; administration with food may delay and slightly decrease absorption, but achieves maximum antisecretory effect when stomach is no longer protected by food buffering effect. Administer oral tablets with water.b
Antacids may be given as necessary for pain relief, but not at the same time.a b
For duodenal ulcer treatment, administration once daily at bedtime is the regimen of choice because of a high healing rate, maximal pain relief, decreased drug interaction potential, and maximal compliance.117 118 119
For gastric ulcer treatment, administration once daily at bedtime is the regimen of choice because of convenience and decreased drug interaction potential.118
For gastroesophageal reflux, once-daily dosing is not considered appropriate.288
IM AdministrationMay be administered undiluted.a b
Intermittent Direct IV Injection DilutionDilute 300 mg to 20 mL with 0.9% sodium chloride injection or other compatible IV solution before direct IV injection (see Compatibility under Stability).118
Rate of AdministrationInject over ?5 minutes.118
Intermittent IV infusion ReconstitutionReconstitute ADD-Vantage vials according to manufacturer’s directions.118
DilutionDilute 300 mg in at least 50 mL of 0.9% sodium chloride injection or 5% dextrose injection or other compatible IV solution (see Compatibility under Stability).118
No additional dilution required for commercially available infusion solution (300 mg cimetidine in 50 mL of 0.9% sodium chloride injection).a
Rate of AdministrationOver 15–20 minutes.118
Continuous IV Infusion DilutionDilute 900 mg in 100–1000 mL of a compatible IV solution (see Compatibility under Stability).a b
Rate of AdministrationOver 24 hours.a b
Adjust rate to individual patient requirements.a b
Volume <250 mL: use controlled-infusion device (e.g., pump).a b
DosageDosage of cimetidine hydrochloride expressed in terms of cimetidine.118
Pediatric Patients20–40 mg/kg daily in divided doses has been used in a limited number of children when potential benefits are thought to outweigh the possible risks.118
Heartburn, Acid Indigestion, or Sour Stomach Heartburn Relief (Self-medication) OralAdolescents ?12 years of age: 200 mg once or twice daily, or as directed by a clinician.268
Prevention of Heartburn (Self-medication) OralAdolescents ?12 years of age: 200 mg once or twice daily or as directed by a clinician; administer immediately (or up to 30 minutes) before ingestion of causative food or beverage.c
Adults General Parenteral DosageParenteral dosage regimens for GERD have not been established.a
General parenteral dosage (in hospitalized patients with pathologic hypersecretory conditions or intractable ulcer, or for short-term use when oral therapy is not feasible):a
IM300 mg every 6–8 hours.118
Intermittent Direct IV Injection300 mg every 6–8 hours.118
300 mg more frequently if increased daily dosage is necessary (i.e., single doses not >300 mg), up to 2400 mg daily.118
Intermittent IV Infusion300 mg every 6–8 hours.118
300 mg more frequently if increased daily dosage is necessary (i.e., single doses not >300 mg), up to 2400 mg daily.118
Continuous IV infusion900 mg over 24 hours (37.5 mg/hour).a b See Pathologic GI Hypersecretory Conditions under Dosage: Adults.
For more rapid increase in gastric pH, a loading dose of 150 mg may be given as an intermittent infusion before continuous infusion.a b
Duodenal Ulcer Treatment of Active Duodenal Ulcer OralDosage of choice: 800 mg once daily at bedtime.117 118 119
Patients with ulcer >1 cm in diameter who are heavy smokers (i.e., ?1 pack daily) when rapid healing (e.g., within 4 weeks) is considered important:118 1.6 g daily at bedtime.117 118 119
Administer for 4–6 weeks unless healing is confirmed earlier.117 118 If not healed or symptoms continue after 4 weeks, additional 2–4 weeks of full dosage therapy may be beneficial.118 More than 6–8 weeks at full dosage is rarely needed.118
Healing of active duodenal ulcers may occur in 2 weeks in some, and occurs within 4 weeks in most patients.117 118 119 120 121 122
Other regimens (no apparent rationale for these other than familiarity of use) that have been used:117 118 300 mg 4 times daily with meals and at bedtime; 200 mg 3 times daily and 400 mg at bedtime; 400 mg twice daily in the morning and at bedtime.b
Maintenance of Healing of Duodenal Ulcer Oral400 mg daily at bedtime.118 Efficacy not increased by higher dosages or more frequent administration.b
Pathologic GI Hypersecretory Conditions Zollinger-Ellison Syndrome Oral300 mg 4 times daily with meals and at bedtime.118
Higher doses administered more frequently may be necessary;a b adjust dosage according to response and tolerance but in general, do not exceed 2400 mg daily.a
Continue as long as necessary.118
Continuous IV InfusionMean infused dose of 160 mg/hour (range: 40-600 mg/hour) in one study.a
Gastric Ulcer OralPreferred regimen: 800 mg once daily at bedtime.118
Alternative regimen: 300 mg 4 times daily, with meals and at bedtime.118
Monitor to ensure rapid progress to complete healing.a b
Studies limited to 6 weeks, efficacy for >8 weeks not established.118
GERDOnce daily (at bedtime) not considered appropriate therapy.288
Treatment of Symptomatic GERD† Oral300 mg 4 times daily has been used.105 106 123
Treatment of Erosive Esophagitis Oral800 mg twice daily or 400 mg 4 times daily (e.g., before meals and at bedtime) for up to 12 weeks.118
Upper GI Bleeding Prevention of Upper GI Bleeding Continuous IV Infusion50 mg/hour; loading dose not required.118
Safety and efficacy of therapy beyond 7 days has not been established.118
Alternative dosage: Some clinicians recommend 300-mg IV loading dose over 5–20 minutes, then continuous IV infusion at 37.5–50 mg/hour; titrate with 25-mg/hour increments up to 100 mg/hour based on gastric pH (e.g., to maintain a pH of at least 3.5–4).118 143 144 173 174 176 188
Intermittent IV doses may be less effective in preventing upper GI bleeding than continuous IV infusion.155 172 173 174 175 176 177 178 188 189 191
Treatment of Upper GI Bleeding† Oral1–2 g daily in 4 divided doses has been used.b
IV1–2 g daily in 4 divided doses has been used.b
Heartburn, Acid Indigestion, or Sour Stomach Heartburn (Self-medication) Oral200 mg once or twice daily, or as directed by clinician.268
Maximum 400 mg in 24 hours, but not continuously for >2 weeks except under clinician supervision.c
Prevention of Heartburn (Self-medication) Oral200 mg once or twice daily or as directed by a clinician; administer immediately (or up to 30 minutes) before ingestion of causative food or beverage.c
Maximum 400 mg in 24 hours, but not continuously for >2 weeks except under clinician supervision.c
Prescribing Limits Pediatric Patients Heartburn, Acid Indigestion, or Sour Stomach Heartburn (Self-Medication) OralAdolescents ?12 years of age: Maximum 400 mg in 24 hours, but not continuously for >2 weeks except under clinician supervision.c
Prevention of Heartburn (Self-medication) OralAdolescents ?12 years of age: Maximum 400 mg in 24 hours, but not continuously for >2 weeks except under clinician supervision.c
Adults General Parenteral DosageGeneral parenteral dosage (hospitalized patients with pathologic hypersecretory conditions or intractable duodenal ulcer, or short-term use when oral therapy is not feasible):
Direct IV injectionMaximum 2.4 g daily.a
Maximum 300 mg per dose.a
Maximum concentration 300 mg/20 mL.a
Maximum injection rate: 20 mL over not less than 5 minutes (4 mL per minute).a
Intermittent IV InfusionMaximum 2.4 g daily.a
Maximum 300 mg per dose.a
Maximum concentration 300 mg/50 mL.a
Maximum infusion rate: 15–20 minutes.a
GERD Short-term Treatment of Erosive Esophagitis OralSafety and efficacy beyond 12 weeks of administration have not been established.a
Heartburn, Acid Indigestion, or Sour Stomach Heartburn Relief (Self-medication) OralMaximum 400 mg in 24 hours, but not continuously for >2 weeks except under clinician supervision.c
Prevention of Heartburn (Self-medication) OralMaximum 400 mg in 24 hours, but not continuously for >2 weeks except under clinician supervision.c
Duodenal Ulcer Intermittent Direct IV InjectonMaximum 2.4 g daily.a
Intermittent IV InfusionMaximum 2.4 g daily.a
Gastric Ulcer Short-term treatment of Active Benign Gastric Ulcer OralSafety and efficacy beyond 8 weeks have not been established.118
Intermittent Direct IV InjectionMaximum 2.4 g daily.a
Intermittent IV InfusionMaximum 2.4 g daily.a
Pathologic GI Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome) OralMaximum usually 2.4 g daily.118
Intermittent Direct IV InjectionMaximum 2.4 g daily.a
Intermittent IV InfusionMaximum 2.4 g daily.a
Upper GI Bleeding Prevention of Upper GI Bleeding Continuous IV InfusionSafety and efficacy beyond 7 days have not been established.a
Special Populations Renal Impairment Severe (Clcr< 30 mL/minute) Oral300 mg every 12 hours.118
Accumulation may occur; use lowest frequency of dosing compatible with adequate response.118
Increase frequency to every 8 hours or more frequently (with caution) if required.118
Presence of hepatic impairment may require further dosage reduction.118
Direct IV Injection300 mg every 12 hours.118
Accumulation may occur; use lowest frequency compatible with adequate response.118
Increase frequency to every 8 hours or more frequently (with caution) if required118
Presence of hepatic impairment may require further dosage reduction.118
Continuous IV InfusionPrevention of Upper GI Bleeding: One-half recommended dosage (i.e., 25 mg/hour).118
HemodialysisDecreases blood levels; administer at the end of hemodialysis and every 12 hours during interdialysis.b
Hepatic ImpairmentMay require further dosage reduction in the presence of severe renal impairment.118
Cautions for Cimetidine Hydrochloride ContraindicationsKnown hypersensitivity to cimetidine or any ingredient in the formulation.118
Warnings/Precautions General Precautions Cardiovascular EffectsRapid IV administration associated rarely with hypotension, cardiac arrhythmias; avoid.a b
Gastric MalignancyResponse to cimetidine does not preclude presence of gastric malignancy.118
CNS EffectsReversible confusional states reported, especially in geriatric (i.e., ?50 years) and severely ill (e.g., hepatic or renal disease, organic brain syndrome) patients.118 b Usually occurs within 2–3 days after initiating cimetidine and resolves within 3–4 days after discontinuance.118 b
Respiratory EffectsAdministration of H2-receptor antagonists has been associated with an increased risk for developing certain infections (e.g., community-acquired pneumonia).302 303
Specific Populations PregnancyCategory B.a
Pregnant women should consult a clinician before using for self-medication.268
LactationDistributed into milk.118 Generally, do not nurse during therapy with cimetidine.118
Nursing women should consult a clinician before using for self-medication.268
Pediatric UseSafety and efficacy not established in children <16 years of age; do not use unless potential benefits outweigh risks.118
Safety and efficacy for self-medication not established in children <12 years of age; do not use unless directed by a clinician.c
Renal ImpairmentDosage adjustments necessary in patients with severe renal impairment.118 (See Renal Impairment under Dosage and Administration.)
Hepatic ImpairmentFurther dosage adjustments may be necessary in presence of severe renal impairment.118 (See Hepatic Impairment under Dosage and Administration.)
Immunocompromised PatientsIncreased possibility of Strongyloides stercoralis hyperinfection with decreased gastric acidity.118 269 270
Common Adverse EffectsHeadache,118 144 dizziness, somnolence, diarrhea.118
With ?1 month of therapy: gynecomastia.118 b
With IM therapy: transient pain at injection site.118
Interactions for Cimetidine HydrochlorideInhibits hepatic microsomal enzyme systems, decreases hepatic metabolism of some drugs.118 If necessary, adjust dosage of hepatically metabolized drugs when cimetidine therapy is initiated or discontinued.b
Specific DrugsDrug
Interaction
Comments
Alcohol
Possible increased blood alcohol concentrations,256 257 258 259 260 261 263 264 265 psychomotor impairment256 257 258 259 260 261 267
Potential for psychomotor impairment controversial, 256 257 258 259 260 261 267 but use caution during performance of hazardous tasks requiring mental alertness, physical coordination257 258 261
Antacidsb
Decreased cimetidine absorptionb
Administer 1 hour before or after cimetidine in the fasting state, or 1 hour after cimetidine is taken with food.a b
Benzodiazepines118
Potential for delayed elimination, increased blood concentrations of certain benzodiazepines (e.g., diazepam, chlordiazepoxide, triazolam)118
Adjust dosage if needed b
Calcium-channel blockers (e.g., nifedipine)a
Potential for delayed elimination, increased blood concentrations of nifedipine118
Adjust dosage if needed b
Ketoconazole118
Absorption of ketoconazole may be affected by altered gastric pH118
Administer ?2 hours before cimetidine118
Lidocaine118
Potential for delayed elimination, increased blood concentrations of lidocaine118
Adverse effects reported, adjust dosage if needed b
Metronidazole118
Potential for delayed elimination, increased blood concentrations of metronidazole118
Adjust dosage if neededb
Myelosuppressive drugs (e.g., alkylating agents [e.g., carmustine], antimetabolites) and/or therapies (radiation)b
May potentiate myelosuppressionb
Phenytoin118
Potential for delayed elimination, increased blood concentrations of phenytoin118
Adverse effects reported, adjust dosage if needed b
Propranolol118
Potential for delayed elimination, increased blood concentrations of propranolol118
Adjust dosage if needed b
Theophylline118
Potential for delayed elimination, increased blood concentrations of theophylline118
Adverse effects reported, adjust dosage if needed b
Triamterene108
Potential for delayed elimination, increased blood concentrations of triamterene118
Consider potential of clinically important interaction108
Tricyclic Antidepressants118
Potential for delayed elimination, increased blood concentrations of certain tricyclic antidepressants118
Adjust dosage if neededb
Warfarin118
Potential for delayed elimination, increased blood concentrations of warfarin118
Monitor PT, adjust dosage if neededb
Cimetidine Hydrochloride Pharmacokinetics Absorption BioavailabilityOral: 60–70%.b
Onset?70% decrease in basal acid secretion within 45 minutes after single 300- or 400-mg IV dose in healthy males.100
DurationDosage Regimen
Effect On Acid Secretion
Comments
Oral: 800 mg at bedtime in duodenal ulcer patients118
Mean hourly nocturnal secretion decreased by 85% over 8 hours.118
No effect on daytime acid secretion118
Oral: 1600 mg at bedtime in duodenal ulcer patients 118
Mean hourly nocturnal secretion decreased by 100% over 8 hours, 35% decrease for additional 5 hours.118
Moderate (<60%) 24-hour suppression118
Oral: 400 mg twice daily in duodenal ulcer pateints118
Nocturnal secretion decreased by 47–83% over 6–8 hours 118
Moderate (<60%) 24-hour suppression118
Oral: 300 mg 4 times daily in duodenal ulcer patients118
Nocturnal secretion decreased by 54% over 9 hours118
Moderate (<60%) 24-hour suppression118
Oral: Single 300-mg dose within 1 hour after meal in duodenal ulcer patientsa
Food-stimulated secretion decreased by 50% for 1 hour, then 75% for 2 hours.a
Oral: 300-mg dose at breakfast in duodenal ulcer patientsa
Continued suppression for 4 hours, with partial suppression after luncha
Effect enhanced and maintained by additional 300-mg dose with luncha
Oral: 300-mg dose with foodb
Mean gastric pH 3.5–4 at 1 hour, 5.5–6.1 at 4 hoursb
Oral: Single dose 300 mg with fooda
Mean gastric pH: 3.5, 3.1, 3.8, 6.1 at hour 1, 2, 3, 4, respectivelya
Placebo mean gastric pH: 2.6, 1.6, 1.9, 2.2 at hour 1, 2, 3, 4, respectivelya
Oral: 300–400 mg in fasting state in duodenal ulcer patientsb
Anacidity for up to 8 hoursb
Oral: 300 mg in duodenal ulcer patientsb
Basal gastric acid output decreased by 90% for 4 hoursb
Meal-stimulated acid secretion by 66% for 3 hoursb
IV continuous infusion: mean dosage of 160 mg/hour (range:40-600 mg/hour) in pathologic hypersecretory conditionsb
Maintained secretion at ?10 mEq/hourb
IV continuous infusion (37.5 mg/hour or 900 mg daily) in patients with active or healed duodenal or gastric ulcerb
Maintained gastric pH at >4 for >50% of the time at steady-state.b
Intermittent injection: (300 mg every 6 hours or 1200 mg daily) in patients with active or healed duodenal or gastric ulcerb
Maintained gastric pH at >4 for >50% of the time at steady-state.b
IV: Single 300- or 400-mg dose in healthy males
?70% decrease in basal acid secretion maintained for 4–4.5 hours100
Food
Delays, slightly decreases absorption.b However, administration with meals achieves maximum blood concentrations and antisecretory effect when stomach is no longer protected by food buffering effect.b
Distribution ExtentWidely distributed throughout the body.b
Distributed into human milk.b
Crosses the placenta in animals.b
Plasma Protein Binding15–20%.b
Elimination MetabolismMetabolized to sulfoxide (major metabolite) and 5-hydroxymethyl derivatives in liver.a b More extensively metabolized after oral than parenteral administration.a
Elimination RouteExcreted principally in urine.a b Single oral dose: 48% (unchanged) excreted in urine over 24 hours.a IV or IM: about 75% (unchanged) excreted in urine within 24 hours.a Single IV dose of radiolabeled cimetidine: 80–90% (50–73% unchanged, remainder as metabolites) excreted in urine over 24 hours.b About 10% excreted in feces.b
Half-life2 hours.a
After IV administration in children 4.1–15 years of age: Apparent biphasic decline of plasma cimetidine and cimetidine sulfoxide concentrations with half-lives of 1.4 and 2.6 hours, respectively.102
Special Populations2.9 hours in patients with Clcr 20–50 mL/minute.b 3.7 hours in patients with Clcr <20 mL/minute.b 5 hours in anephric patients.b
Stability Storage Oral Liquid and TabletsTight, light-resistant containers at 15–30°C.b
Parenteral Injection15–30°C.b Protect from light.b Do not refrigerate.b Stable in most IV solutions for at least 3 days at room temperature in concentrations of 1.2–5 mg/mL,b but use within 48 hours when diluted as directed.118 b
Injection for IV infusion only15–30°C.b Protect from excessive heat; brief exposure up to 40°C does not adversely affect stability.b Stable through the labeled expiration date when stored as recommended.118
CompatibilityFor information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral Solution CompatibilityHIDCompatible
Amino acids 3.5, 5.5, or 8.5% with electrolytes
Amino acids 5.5 or 8.5%
Dextrose 5% with Ascor-B-Sol
Dextrose 5% and Electrolyte #48
Dextrose 5% and Electrolyte #75
Dextrose 5% in Ringer’s injection, lactated
Dextrose 5% in sodium chloride 0.2, 0.45, or 0.9%
Dextrose 10% in sodium chloride 0.9%
Dextrose 5% in water
Dextrose 10% in water
Dextrose 5% in water with vitamins
Fructose 5% and Electrolyte #48
Fructose 5% and Electrolyte #75
Invert sugar 5% in water
Invert sugar 10% in water
Ionosol B in dextrose 5% in water
Ionosol MB in dextrose 5% in water
Ionosol T in dextrose 5% in water
Mannitol 10% in water
Normosol M, 900 cal
Normosol M in dextrose 5% in water
Normosol M and Surbex T in dextrose 5% in water
Normosol R
Normosol R, pH 7.4
Normosol R in dextrose 5% in water
Plasma-Lyte 56 in dextrose 5% in water
Plasma-Lyte M in dextrose 5% in water
Ringer’s injection
Ringer’s injection, lactated
Sodium bicarbonate 5%
Sodium chloride 0.9%
Drug Compatibility Admixture CompatibilityHIDCompatible
Acetazolamide sodium
Amikacin sulfate
Aminophylline
Atracurium besylate
Cefoxitin sodium
Chlorothiazide sodium
Ciprofloxacin
Clindamycin phosphate
Colistimethate sodium
Dexamethasone sodium phosphate
Digoxin
Epinephrine HCl
Erythromycin lactobionate
Ethacrynate sodium
Flumazenil
Furosemide
Gentamicin sulfate
Insulin, regular
Isoproterenol HCl
Lidocaine HCl
Lincomycin HCl
Meropenem
Metaraminol bitartrate
Methylprednisolone sodium succinate
Midazolam HCl
Norepinephrine bitartrate
Penicillin G potassium
Phytonadione
Polymyxin B sulfate
Potassium chloride
Protamine sulfate
Quinidine gluconate
Sodium nitroprusside
Tacrolimus
Vancomycin HCl
Verapamil HCl
Vitamin B complex
Vitamin B complex with C
Incompatible
Amphotericin B
Variable
Ampicillin sodium
Cefazolin sodium
Metoclopramide HCl
Y-Site CompatibilityHIDCompatible
Acyclovir sodium
Amifostine
Aminophylline
Anakinra
Anidulafungin
Atracurium besylate
Aztreonam
Bivalirudin
Cisplatin
Cladribine
Clarithromycin
Cyclophosphamide
Cytarabine
Dexmedetomidine HCl
Diltiazem HCl
Docetaxel
Doxorubicin HCl
Doxorubicin HCl liposome injection
Enalaprilat
Esmolol HCl
Etoposide phosphate
Fenoldopam mesylate
Filgrastim
Fluconazole
Fludarabine phosphate
Foscarnet sodium
Gallium nitrate
Gemcitabine HCl
Granisetron HCl
Haloperidol lactate
Heparin sodium
Hetastarch in lactated electrolyte injection (Hextend)
Hetastarch in sodium chloride 0.9%
Idarubicin HCl
Inamrinone lactate
Labetalol HCl
Levofloxacin
Linezolid
Melphalan HCl
Meropenem
Methotrexate sodium
Midazolam HCl
Milrinone lactate
Nicardipine HCl
Ondansetron HCl
Oxaliplatin
Paclitaxel
Pancuronium bromide
Pemetrexed disodium
Piperacillin sodium–tazobactam sodium
Propofol
Remifentanil HCl
Sargramostim
Tacrolimus
Teniposide
Theophylline
Thiotepa
Topotecan HCl
Vecuronium bromide
Vinorelbine tartrate
Zidovudine
Incompatible
Allopurinol sodium
Amphotericin B cholesteryl sulfate complex
Amsacrine
Cefepime HCl
Indomethacin sodium trihydrate
Lansoprazole
Warfarin sodium
ActionsActionsInhibits basal and stimulated gastric acid secretion.b
Competitively inhibits histamine at parietal cell H2 receptors.b
Weak antiandrogenic effect.b
Advice to PatientsImportance of patients informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs.289
Importance of taking antacids on an empty stomach 1 hour before or 1 hour after oral administration of cimetidine, or 1 hour after the drug is taken with food,b but not at same time as oral cimetidine.a b
Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.289
Before self-medication, importance of consulting clinician if taking warfarin, theophylline, or phenytoin.268
Importance of following dosage instructions when cimetidine is administered for self-medication, unless otherwise directed by a clinician.c
Importance of promptly informing clinician of persistent abdominal pain or difficulty swallowing.268
Importance of informing patients of other important precautionary information. (See Cautions.)
PreparationsExcipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
CimetidineRoutes
Dosage Forms
Strengths
Brand Names
Manufacturer
Oral
Solution
300 mg/mL*
Cimetidine Hydrochloride Oral Solution
Actavis, Duramed, Endo, Hi-Tech, Morton Grove, Pharmaceutical Associates, Teva
Tagamet (with parabens, povidone, and propylene glycol)
GlaxoSmithKline
Tablets, film-coated
200 mg*
Tagamet HB 200
GlaxoSmithKline
Tagamet HB (with povidone)
GlaxoSmithKline
300 mg*
Tagamet (with povidone and propylene glycol)
GlaxoSmithKline
400 mg*
Tagamet Tiltab (with povidone and propylene glycol)
GlaxoSmithKline
800 mg*
Tagamet Tiltab (with povidone and propylene glycol; scored)
GlaxoSmithKline
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Cimetidine HydrochlorideRoutes
Dosage Forms
Strengths
Brand Names
Manufacturer
Oral
Solution
300 mg (of cimetidine) per 5 mL*
Tagamet HCl (with alcohol 2.8% parabens and propylene glycol)
GlaxoSmithKline
Parenteral
Injection
150 mg (of cimetidine) per mL
Cimetidine Hydrochloride Injection
Norcuron
Generic Name: Vecuronium Bromide
Class: Neuromuscular Blocking Agents
VA Class: MS200
Chemical Name: 1-[(2?,3?,5?,16?,17?)-3,17-bis(acetyloxy)-2-(1-piperidinyl) androstan-16-yl]-1-methylpiperidinium bromide
Molecular Formula: C34H57N2O4•Br
CAS Number: 50700-72-6
Should be administered only by individuals experienced in the use of neuromuscular blocking agents.1
IntroductionNondepolarizing neuromuscular blocking agent.1 3 4 5
Uses for Norcuron Skeletal Muscle RelaxationProduction of skeletal muscle relaxation during surgery after general anesthesia has been induced.1
Facilitation of endotracheal intubation;1 15 16 30 39 40 41 46 54 63 68 71 77 80 113 117 124 129 131 142 however, succinylcholine generally is preferred in emergency situations where rapid intubation is required.110 111 112 141 145 A single dose should not be used in place of succinylcholine for rapid sequence induction of anesthesia (“crash intubation”).141
Treatment to increase pulmonary compliance during assisted or controlled respiration after general anesthesia has been induced.1
Has been used for facilitation of mechanical ventilation in intensive care setting.1 186 187 188 189 190 191 192 193
Norcuron Dosage and Administration GeneralAdjust dosage carefully according to individual requirements and response.1 2
Assess neuromuscular blockade and recovery in patients undergoing anesthesia; a peripheral nerve stimulator is recommended to accurately monitor the degree of muscle relaxation and to minimize the possibility of overdosage.1
To avoid patient distress, administer only after unconsciousness has been induced.141
Facilitation of Endotracheal IntubationEndotracheal intubation for nonemergency surgical procedures generally can be performed within 2.5–3 minutes following administration of 0.08- to 0.1-mg/kg dose.1 61 75 (See Onset and also Duration under Pharmacokinetics.)
Maintenance of Neuromuscular BlockadeRepeated administration of maintenance doses appears to have little, if any, cumulative effect on duration of neuromuscular blockade.1 16 17 40 51 62 71 72 80 93 143
Rate of spontaneous recovery from neuromuscular blockade following discontinuance of maintenance infusion usually is comparable to that following administration of a single IV injection.1
Close monitoring recommended to avoid excessive dosage when continuous infusion is employed.30 33 39 113
Reversal of Neuromuscular BlockadeTo reverse neuromuscular blockade, administer a cholinesterase inhibitor (e.g., neostigmine, pyridostigmine, edrophonium), usually in conjunction with an antimuscarinic (e.g., atropine, glycopyrrolate) to block adverse muscarinic effects of the cholinesterase inhibitor.1 2 11 16 17 18 19 28 39 40 41 43 44 45 46 47 88 137 143
AdministrationAdminister IV only;1 do not administer IM.144
IV AdministrationFor solution and drug compatibility information, see Compatibility under Stability.
Administer initial (intubating) dose by rapid IV injection;1 administer maintenance dosage for prolonged surgical procedures by intermittent IV injection or continuous IV infusion.1
Consult specialized references for specific procedures and techniques of administration.HID
Do not mix in the same syringe or administer through the same needle as an alkaline solution.1
ReconstitutionReconsititute vial containing 10 or 20 mg of vercuronium bromide with 10 or 20 mL of bacteriostatic water for injection, respectively, to provide a solution containing 1 mg/mL.1 2 Use within 5 days.1
When reconstituted with other compatible solutions (see Solution Compatibility under Stability), use within 24 hours and discard unused portions.1
DilutionFor continuous IV infusion, dilute the reconstituted solution to the desired concentration (usually 0.1 or 0.2 mg/mL) in a compatible IV solution (see Solution Compatibility under Stability).1 2 30 80 113 Use within 24 hours.1
DosageAvailable as vecuronium bromide; dosage expressed in terms of the salt.1
Pediatric Patients Skeletal Muscle Relaxation Initial (Intubating) Dosage IVChildren 7 weeks to 1 year of age may receive dosages recommended for adults.27 148 (See Adults under Dosage and Administration.)
Children 1–9 years of age may require slightly higher initial doses than adults.1 2 27 28 (See Adults under Dosage and Administration.)
Children >10 years of age should receive dosages recommended for adults.1 2 (See Adults under Dosage and Administration.)
Maintenance Dosage Intermittent IV InjectionChildren 7 weeks to 1 year of age may receive doses recommended for adults; however, less frequent administration may be necessary.27 148 (See Adults under Dosage and Administration and also see Pediatric Use under Cautions.)
Children 1–9 years of age may require more frequent doses than adults.1 2 28 (See Adults under Dosage and Administration.)
Children >10 years of age should receive dosages recommended for adults.1 2 (See Adults under Dosage and Administration.)
Continuous IV InfusionDosage recommendations not established; administration by continuous IV infusion not adequately studied.1
Adults Skeletal Muscle Relaxation Initial (Intubating) Dosage IV0.08–0.1 mg/kg.1 2 (See Onset and also Duration under Pharmacokinetics.)
Reduce initial dosage by about 15% (i.e., to 0.06–0.085 mg/kg) when administered >5 minutes after administration of enflurane, isoflurane, or halothane has been initiated or after steady-state anesthesia has been achieved.1 2 See Interactions: Specific Drugs.
If larger initial dose is required, 0.15–0.28 mg/kg has been administered in patients undergoing halothane anesthesia with minimal adverse cardiovascular effects as long as ventilation was adequately maintained.1 2
If administering following succinylcholine, reduce dosage to 0.05–0.06 mg/kg with balanced anesthesia or 0.04–0.06 mg/kg with inhalation anesthesia.1 2
Maintenance Dosage Intermittent IV Injection0.01–0.015 mg/kg, administered as necessary, in patients receiving balanced anesthesia.1 2
0.008–0.012 mg/kg, administered as necessary, in patients receiving inhalation anesthesia.144 Increase dose (i.e., to >0.01–0.015 mg/kg) if longer intervals between doses are desirable.1
Administer first maintenance dose generally 25–45 minutes after the initial dose in patients undergoing balanced or inhalation anesthesia.1 2
Administer repeat maintenance doses at relatively regular intervals (i.e., from 12–15 minutes in patients undergoing balanced anesthesia or at slightly longer intervals in those undergoing enflurane or isoflurane anesthesia).1 2
Continuous IV InfusionInitially, 1 mcg/kg per minute.1 Adjust infusion rate to maintian 90% neuromuscular blockade; 0.8–1.2 mcg/kg per minute usually maintains continuous neuromuscular blockade in most patients.1 39
Initiate continuous IV infusion only after early spontaneous recovery from initial IV dose is evident (approximately 20–40 minutes after rapid IV administration of initial dose1 30 33 39 76 80 113 118 ).1 Required infusion rates decrease progressively and become relatively constant within 30–50 minutes.30 39 113
May need to reduce infusion rate by about 25–60% approximately 45–60 minutes following initial IV dose if steady-state anesthesia has been induced with enflurane or isoflurane.1 Reduction in infusion rate may not be necessary if steady-state anesthesia has been induced with halothane.1
Special Populations Hepatic ImpairmentData currently insufficient for specific dosage recommendations.1 Some clinicians suggest usual initial dose;141 151 others suggest a reduced initial dose.141 Adjust maintenance dosing (probably with reduced doses) carefully according to patient’s response.141 151 (See Hepatic Impairment under Cautions.)
Renal ImpairmentUsual initial and maintenance doses recommended for patients with renal failure who are optimally prepared with dialysis prior to surgery; monitor carefully to determine interval between doses.141 149 (See Renal Impairment under Cautions.)
Manufacturer recommends consideration of decreased initial dose if emergency surgery is necessary in patients with severe renal failure (i.e., Clcr <10 mL/minute) who are not optimally prepared with dialysis;1 2 however, most clinicians believe that usual initial dose may be given.141 Adjust maintenance doses carefully according to patient’s response.141
Geriatric PatientsDosage necessary to maintain steady-state neuromuscular blockade30 32 33 may be decreased.
Burn PatientsSubstantially increased doses may be required due to development of resistance.175 (See Burn Patients under Cautions.)
Intensive Care SettingDosage recommendations not established for prolonged, continuous IV infusions during mechanical ventilation in intensive care settings.1 (See Intensive Care Setting under Cautions.)
Patients with Neuromuscular DiseaseAdminister small test dose (e.g., 0.005–0.02 mg/kg)141 144 and monitor response.1 (See Neuromuscular Disease under Cautions.)
Other PopulationsPatients in whom substantial histamine release would be particularly hazardous (e.g., patients with clinically important cardiovascular disease) or patients with any history suggesting a greater risk of histamine release (e.g., a history of severe anaphylactoid reactions or asthma): Administer slowly over 1–2 minutes or longer; discontinue administration if any signs of histamine release occur.141 144 (See Histamine Release under Cautions.)
Cautions for Norcuron ContraindicationsKnown hypersensitivity to vercuronium bromide or any ingredient in the formulation.144
Warnings/Precautions Warnings Respiratory EffectsPotential for severely compromised respiratory function and respiratory paralysis.1 110 111 127 128
Should be used only by individuals experienced in the use of neuromuscular blocking agents and in the maintenance of an adequate airway and respiratory support.1 2 Facilities and personnel necessary for intubation, administration of oxygen, and assisted or controlled respiration should be immediately available.1
IV cholinesterase inhibitor (e.g., neostigmine, pyridostigmine, edrophonium) should be readily available.1 18 19 39 40 41 44 88 (See Reversal of Neuromuscular Blockade under Dosage and Administration.)
Use with caution in patients with pulmonary impairment or respiratory depression.b
Neuromuscular DiseasePossible exaggerated neuromuscular blockade in patients with neuromuscular disease (e.g., myasthenia gravis, Eaton-Lambert syndrome).1
Administer small test dose; monitor response carefully with a peripheral nerve stimulator.1 141 144
Sensitivity Reactions Hypersensitivity ReactionsHistamine-like hypersensitivity reactions (e.g., bronchospasm, flushing, redness, hypotension, and tachycardia) are not likely to occur.1 12 18 48 143
General Precautions Burn PatientsResistance to therapy can develop in burn patients,169 170 172 173 174 175 particularly those with burns over 25–30% or more of body surface area.175
Resistance becomes apparent ?1 week after the burn,169 170 171 172 173 174 175 peaks ?2 weeks after the burn,170 171 172 174 persists for several months or longer,170 172 and decreases gradually with healing.169 170 172 174
Consider possible need for substantially increased doses.175
Cardiovascular EffectsExhibits minimal cardiovascular effects;1 3 5 6 19 143 therefore, will not counteract the bradycardia induced by many anesthesia agents1 21 59 (e.g., high-dose fentanyl)122 143 or by vagal stimulation.141
Intensive Care SettingPossible prolonged paralysis and/or muscle weakness and atrophy.1
Continuous monitoring of neuromuscular transmission recommended during neuromuscular blocking agent therapy in intensive care setting.1 Do not administer additional doses before there is a definite response to nerve stimulation tests.1 If no response is elicited, discontinue administration until response returns.1
Impaired CirculationPossible delayed onset of action and delayed maximum effect in patients with impaired circulation or in those with cardiovascular disease or edema (vecuronium volume of distribution may be increased).1 2 141 Larger-than-usual initial doses are not recommended; caution advised when administering a subsequent dose before the maximum effect of the initial dose is attained.141
Electrolyte DisturbancesPossible prolonged paralysis in patients with electrolyte disturbances (e.g., increased plasma magnesium concentrations) or acid-base imbalances.186 187 189 190
Carefully monitor the degree of neuromuscular blockade with a peripheral nerve stimulator in patients with severe electrolyte disturbances (i.e., hypermagnesemia, hypokalemia, hypocalcemia)141 or diseases that result in electrolyte disturbances (e.g., adrenocortical insufficiency).141
Malignant HyperthermiaMalignant hyperthermia is rarely associated with use of neuromuscular blocking agents and/or potent inhalation anesthetics.b Insufficient data to determine whether vecuronium is capable of initiating the development of this condition.1
Be vigilant for possible development of malignant hyperthermia and prepared for its management in any patient undergoing general anesthesia.168
CarcinomatosisCarefully monitor the degree of neuromuscular blockade with a peripheral nerve stimulator.1
ObesityUse with caution in severely obese patients; maintenance of adequate airway and ventilation support prior to, during, and following administration of neuromuscular blocking agents may require particular care.1
Debilitated PatientsCarefully monitor the degree of neuromuscular blockade with a peripheral nerve stimulator in patients with severe debilitation.1
Specific Populations PregnancyCategory C.1
LactationNot known whether vercuronium is distributed into milk.1 141 Caution advised if used in nursing women.1 141
Pediatric UseSafety and efficacy not established in children <7 weeks of age.1 144
Has been used safely and effectively in children >7 weeks of age who were undergoing surgery.27 28 Children 7 weeks–1 year of age may be more sensitive than adults to the neuromuscular blocking effects and generally require 50% longer to recover from neuromuscular blockade.1 2 27 148
Vecuronium bromide that has been reconstituted with bacteriostatic water for injection containing benzyl alcohol should not be used in neonates.1 163 164 165 166 167
Geriatric UsePossible increased time to onset of neuromuscular blockade31 and decreased rate of recovery compared with younger adults.30 32 33
Hepatic ImpairmentProlonged duration of and rate of recovery from neuromuscular blockade.1 38 79 90
Use with caution; careful monitoring with a peripheral nerve stimulator recommended.1
Renal ImpairmentOnset and duration of and rate of recovery from neuromuscular blockade not substantially altered by renal dysfunction;1 74 84 149 however, possible prolonged duration of blockade in patients with severe renal impairment who have not undergone dialysis prior to surgery.1 2 Careful monitoring with a peripheral nerve stimulator recommended to avoid inadvertent overdosage; consider reduced initial dose.1
Common Adverse EffectsSkeletal muscle weakness.1
Interactions for Norcuron Specific DrugsDrug
Interaction
Comments
Acylaminopenicillins (e.g., mezlocillin, piperacillin)
Prolonged neuromuscular blockade158 159
Use with caution158 159
Anesthetics, general (enflurane, halothane, isoflurane)
Increased potency and prolonged duration of neuromuscular blockade1 2 3 13 14 18 23 73 89 129 143
Reduced vecuronium dosage may be required1 2 14 23 89 (See Dosage under Dosage and Administration)
Anti-infective agents (aminoglycosides, bacitracin, clindamycin, lincomycin, polymyxins, tetracyclines)
Possible prolonged duration of neuromuscular blockade1 2 3 13 18 156
Calcium-channel blocking agents (e.g., verapamil)
Possuble prolonged duration of neuromuscular blockade43
Dantrolene
Possible prolonged duration of neuromuscular blockade157
Magnesium salts
Increased neuromuscular blockade;1 141 154 155 reversal may be impeded1 141 155
Use with caution; reduce dosage as necessary1 141 154 155
Neuromuscular blocking agents, nondepolarizing
Possible increased neuromuscular blockade1
Concomitant administration not recommended1
Quinidine
Possible recurrence of paralysis1
Succinylcholine
Possible increased potency and prolonged duration of neuromuscular blockade1 2 3 21 33 62 124 131 132
Administer vecuronium in reduced dosage after effects of succinylcholine begin to dissipate1
Norcuron Pharmacokinetics Absorption BioavailabilityPoorly absorbed from the GI tract.b
OnsetTime to maximum neuromuscular blockade decreases as the dose increases.1 2 17 18 26 46 69 70 87
Following IV administration of 0.08–0.1 mg/kg, neuromuscular blockade begins within 1 minute and is maximal at 3–5 minutes.1 2
DurationDuration of neuromuscular blockade increases as the dose increases.1 2 17 47 70 80 87
Duration of clinically sufficient neuromuscular blockade induced by initial dose of 0.08–0.1 mg/kg under balanced or halothane anesthesia is about 25–30 or 30–40 minutes, respectively.2
Spontaneous recovery to about 25% of baseline generally occurs within 25–40 minutes under balanced anesthesia and is usually 95% complete 45–65 minutes after administration.1
The time necessary for 25–75% recovery from neuromuscular blockade following doses of 0.08–0.1 mg/kg under balanced or halothane anesthesia is about 15–25 minutes;1 144 recovery time following initial doses appears to be dose dependent.17 141
Special PopulationsHepatic dysfunction (i.e., cirrhosis, cholestasis) may prolong duration of and rate of recovery from neuromuscular blockade.1 38 79 90
In patients with severe renal impairment who have not undergone dialysis prior to surgery, duration of neuromuscular blockade may be prolonged.1 2
In geriatric patients, increased time of onset31 and decreased rate of recovery from neuromuscular blockade.30 32 33
In patients undergoing cardiopulmonary bypass surgery under induced hypothermia, duration of neuromuscular blockade may be prolonged.152
Distribution ExtentAppears to rapidly distribute into extracellular space.2 100 Undergoes rapid and extensive hepatic extraction.116 Crosses the placenta minimally;94 95 96 97 not known whether distributed into milk.144
Plasma Protein BindingApproximately 60–90%.1 2 57 99
Special PopulationsIn children <1 year of age, volume of distribution is increased.148 In geriatric patients, volume of distribution may be decreased.100 In patients with renal failure, volume of distribution may be slightly increased.74 84 104
Elimination MetabolismMetabolic fate not fully characterized in humans.1 2 3 106 116 143 In vitro, vecuronium undergoes spontaneous deacetylation to form hydroxy derivatives.9
Elimination RouteExcreted principally in feces via biliary elimination;1 38 79 90 143 also excreted in urine.1 2 106 116
Half-lifeBiphasic;1 3 18 26 38 84 94 95 98 104 terminal elimination half-life averages 65–75 minutes.1
Special PopulationsIn patients with cirrhosis, half-life averages 84 minutes.38
In patients with renal failure, half-life not substantially altered;84 104 potential for high plasma concentrations of 3-desacetyl vecuronium (neuromuscular blocking activity is ?50% of that of vecuronium).186 187 189 190 84 104
During late pregnancy, half-life decreases to about 35–40 minutes.1 2 94 95
Stability Storage Parenteral Powder for Injection15–30°C; protect from light.1 2
Following reconstitution with bacteriostatic water for injection containing benzyl alcohol, 2–8°C or room temperature (<30°C) for 5 days.1
Following reconstitution with sterile water for injection or other compatible solution (see Solution Compatibility under Stability), 2–8°C for 24 hours.1
CompatibilityFor information on systemic interactions resulting from concomitant use, see Interactions.
ParenteralUnstable in the presence of bases.10 11
Solution Compatibility1Compatible
Dextrose 5% in sodium chloride 0.9%
Dextrose 5% in water
Ringer's injection, lactated
Sodium chloride 0.9%
Drug Compatibility Admixture Compatibility1Compatible
Ciprofloxacin
Y-Site CompatibilityHIDCompatible
Aminophylline
Amiodarone HCl
Cefazolin sodium
Cefuroxime sodium
Cimetidine HCl
Clarithromycin
Co-trimoxazole
Diltiazem HCl
Dobutamine HCl
Dopamine HCl
Epinephrine HCl
Esmolol HCl
Fenoldopam mesylate
Fentanyl citrate
Fluconazole
Gentamicin sulfate
Heparin sodium
Hetastarch in lactated electrolyte injection (Hextend)
Hydrocortisone sodium succinate
Hydromorphone HCl
Isoproterenol HCl
Labetalol HCl
Linezolid
Lorazepam
Midazolam HCl
Milrinone lactate
Morphine sulfate
Nicardipine HCl
Nitroglycerin
Norepinephrine bitartrate
Propofol
Ranitidine HCl
Sodium nitroprusside
Vancomycin HCl
Incompatible
Amphotericin B cholesteryl sulfate complex
Diazepam
Etomidate
Furosemide
Thiopental sodium
ActionsActionsProduces skeletal muscle relaxation by causing a decreased response to acetylcholine (ACh) at the myoneural (neuromuscular) junction of skeletal muscle.b
Exhibits high affinity for ACh receptor sites and competitively blocks access of ACh to motor end-plate of myoneural junction; may affect ACh release.b
Blocks the effects of both the small quantities of ACh that maintain muscle tone and the large quantities of ACh that produce voluntary skeletal muscle contraction; does not alter the resting electrical potential of the motor end-plate or cause muscular contractions.b
Exhibits minimal cardiovascular effects.1 3 5 6 19 145
Appears to have little histamine-releasing activity.1 4 12 18 19 48 49 50 52 143 147 A less potent stimulator of histamine release than atracurium or pancuronium.52 147
Advice to PatientsImportance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease, neuromuscular disease).1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
PreparationsExcipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Vecuronium BromideRoutes
Dosage Forms
Strengths
Brand Names
Manufacturer
Parenteral
For injection, for IV use only
10 mg*
Vecuronium Bromide for Injection
Baxter, Bedford, Hospira, Sicor, Steris
20 mg*
Vecuronium Bromide for Injection
Baxter, Bedford, Hospira, Sicor, Steris
DisclaimerThis report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
References1. Organon Inc. Norcuron (vecuronium bromide) for injection prescribing information. West Orange, NJ; 1998 Feb.
2. Organon Inc. Product information form for American Hospital Formulary Service on Norcuron. West Orange, NJ; 1984 May.
3. Durant NN. Norcuron, a new nondepolarizing neuromuscular blocking agent. Semin Anesth. 1982; 1:47-56.
4. AMA Division of Drugs. AMA drug evaluations. 5th ed. Chicago: American Medical Association; 1983:419-44.
5. Miller RD. Is atracurium an ideal neuromuscular blocking drug? Anesth Analg (Cleveland). 1982; 61:721-2. Editorial. (IDIS 157359)
6. Savarese JJ. The new neuromuscular blocking drugs are here. Anesthesiology. 1981; 55:1-3. [IDIS 136052] [PubMed 6113792]
7. Bowman WC. New neuromuscular blocking drugs in anaesthetic practice. Pharm Int. 1983; 4:131-4.
8. Booij LHDJ, Vree TB, Crul JF. Org-NC45: a new steroidal non-depolarizing muscle relaxant. Pharm Weekbl Sci Ed. 1982; 1-4. (IDIS 145892)
9. Savage DS, Sleigh T, Carlyle I. The emergence of Org NC 45, 1-[(2?,3?,5?,16?,17?)-3, 17 bis(acetyloxy)-2-(1-piperidinyl) -androstan-16-yl]-1-methylpiperidinium bromide, from the pancuronium series. Br J Anaesth. 1980; 52(Suppl 1):3-9S.
10. Torda TA. Drug interactions with vecuronium and other competitive neuromuscular blockers. In: Agoston S, Bowman WC, Miller RD, Viby-Mogensen J, eds. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:72-8.
11. Baraka A, Noueihed R, Sinno H et al. Succinylcholine-vecuronium (Org NC 45) sequence for cesarean section. Anesth Analg. 1983; 62:909-13. [IDIS 176143] [PubMed 6137170]
12. Robertson EN, Booij LHDJ, Fragen RJ et al. Clinical comparison of atracurium and vecuronium (Org NC 45). Br J Anaesth. 1983; 55:125-9. [IDIS 165994] [PubMed 6131682]
13. Richardson FJ, Agoston S. Muscle relaxants. In: Dukes MNG, ed. Side effects of drugs. Annual 6. New York: Elsevier/North Holland Inc.; 1982:128-34.
14. Rupp SM, Miller RD, Gencarelli PJ. Vecuronium-induced neuromuscular blockade during enflurane, insoflurane, and halothane anesthesia in humans. Anesthesiology. 1984; 60:102-5. [IDIS 182089] [PubMed 6141748]
15. Gramstad L, Lilleaasen P. Dose-response relation for atracurium, Org NC 45 and pancuronium. Br J Anaesth. 1982; 54:647-51. [IDIS 152105] [PubMed 6123339]
16. Buzello W, N?ldge G. Repetitive administration of pancuronium and vecuronium (Org NC 45, Norcuron) in patients undergoing long lasting operations. Br J Anaesth. 1982; 54:1151-7. [IDIS 161115] [PubMed 6128011]
17. Fahey MR, Morris RB, Miller RD et al. Clinical pharmacology of Org NC 45 (Norcuron): a new nondepolarizing muscle relaxant. Anesthesiology. 1981; 55:6-11. [IDIS 136054] [PubMed 6113794]
18. Hilgenberg JC. Comparison of the pharmacology of vecuronium and atracurium with that of other currently available muscle relaxants. Anesth Analg. 1983; 62:524-31. [IDIS 170170] [PubMed 6132564]
19. Richardson FJ, Agoston SA. Muscle relaxants. In: Dukes MNG, ed. Side effects of drugs. Annual 7. New York: Elsevier/North Holland Inc; 1983:144-6.
20. Gramstad L, Lilleaasen P, Minsaas B. Comparative study of atracurium, vecuronium (Org NC 45) and pancuronium. Br J Anaesth. 1983; 55(Suppl 1):95-6S. [IDIS 172724] [PubMed 6687551]
21. Booij LHDJ, Robertson EN. Clinical comparison between vecuronium bromide and atracurium di-besylate. In: Agoston S, ed. Clinical experiences with Norcuron (Org NC 45, vecuronium bromide). Amsterdam: Excerpta Medica; 1983:38-45.
22. Booij LHDJ, Crul J
Maxipime
Generic Name: Cefepime Hydrochloride
Class: Fourth Generation Cephalosporins
Chemical Name: [6R - (6?,7?(Z)]] - 1 - [[7 - [[(2 - amino - 4 - thiazolyl)(methoxyimino)acetyl]amino] - 2 - carboxy - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - en - 3 - yl]methyl] -1-methylpyrrolidinium chloride monohydrochloride monohydrate
Molecular Formula: C19H25ClN6O5S2•HCl•H 2O
CAS Number: 123171-59-5
Antibacterial; ?-lactam antibiotic; fourth generation cephalosporin.1 2 6
Uses for Maxipime Intra-abdominal InfectionsTreatment of complicated intra-abdominal infections caused by Escherichia coli, viridans streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter, or Bacteroides fragilis; used in conjunction with IV metronidazole.1 37 69 70 92
Has been used alone for treatment of acute obstetric and gynecologic infections† (e.g., pelvic inflammatory disease [PID], pelvic surgical wound infection, postpartum endometritis),41 but safety and efficacy of cefepime monotherapy in these infections not established.1
Respiratory Tract InfectionsTreatment of moderate to severe pneumonia (with or without concurrent bacteremia) caused by susceptible Streptococcus pneumoniae.1 5 8 14 15 92
Treatment of moderate to severe pneumonia caused by susceptible P. aeruginosa, K. pneumoniae, or Enterobacter.1 5 8 14 15 92
Treatment of community-acquired pneumonia (CAP)40 43 caused by S. pneumoniae, Haemophilus influenzae†, Moraxella catarrhalis†, and Staphylococcus aureus†.43 ATS and IDSA recommend use of cefepime for treatment of CAP only when Ps. aeruginosa is known or suspected to be involved.56 For empiric treatment of CAP in patients with risk factors for Ps. aeruginosa, IDSA and ATS recommend a combination regimen that includes an antipneumococcal, antipseudomonal ?-lactam (cefepime, imipenem, meropenem, fixed combination of piperacillin and tazobactam) and ciprofloxacin or levofloxacin; one of these ?-lactams, an aminoglycoside, and azithromycin; or one of these ?-lactams, an aminoglycoside, and an antipneumococcal fluoroquinolone.56 If Ps. aeruginosa has been identified by appropriate microbiologic testing, these experts recommend treatment with a regimen that includes an antipseudomonal ?-lactam (cefepime, ceftazidime, aztreonam, imipenem, meropenem, piperacillin, ticarcillin) and ciprofloxacin, levofloxacin, or an aminoglycoside.56
Treatment of nosocomial pneumonia.67 68 69 For empiric therapy in severely ill patients or in those with late-onset disease or risk factor for multidrug-resistant bacteria, used in conjunction with either an aminoglycoside (amikacin, gentamicin, tobramycin) or an antipseudomonal fluoroquinolone (ciprofloxacin, levofloxacin).69 In hospitals where methicillin-resistant (oxacillin-resistant) Staphylococcus is common or if there are risk factors for these strains, initial regimen also should include vancomycin or linezolid.67 68 69
Skin and Skin Structure InfectionsTreatment of uncomplicated skin and skin structure infections caused by susceptible S. aureus (oxacillin-susceptible [methicillin-susceptible] strains only) or susceptible S. pyogenes (group A ?-hemolytic streptococci).1 3 5 6 7 8 14 17 92
Urinary Tract Infections (UTIs)Treatment of mild to moderate uncomplicated and complicated UTIs (including those associated with pyelonephritis and/or with concurrent bacteremia) caused by susceptible E. coli, K. pneumoniae, or Proteus mirabilis.1 3 5 6 8 9 16 92
Treatment of severe uncomplicated and complicated UTIs (including those associated with pyelonephritis and/or concurrent bacteremia) caused by susceptible E. coli or K. pneumoniae.1 6 7 14 45 92
Meningitis and Other CNS InfectionsTreatment of meningitis† caused by susceptible gram-negative bacteria (e.g., H. influenzae, Neisseria meningitidis, E. coli, E. aerogenes, Ps. aeruginosa) or gram-positive bacteria (e.g., S. pneumoniae, S. aureus, S. epidermidis).46 69 75 77 79 83 84
Safety and efficacy not established.1 92 Manufacturers caution that patients in whom meningeal seeding from a distant infection site or in whom meningitis is suspected or documented should receive an alternative anti-infective with demonstrated clinical efficacy in this setting.1 92 Some clinicians state additional study is needed regarding efficacy for treatment of meningitis, particularly for infections caused by penicillin- and/or cefotaxime-resistant S. pneumoniae.46 79 In addition, cefepime may not be a good choice for empiric treatment of meningitis if Acinetobacter may be involved.83
IDSA states cefepime is one of several alternatives that can be used for treatment of meningitis caused by H. influenzae or E. coli or treatment of meningitis caused by S. pneumonia susceptible to penicillins and third generation cephalosporins.75 For treatment of meningitis caused by Ps. aeruginosa, IDSA and other experts recommend a regimen that consists of an antipseudomonal cephalosporin (cefepime or ceftazidime) or carbapenem (imipenem or meropenem) given with or without an aminoglycoside (amikacin, gentamicin, tobramycin).69 75 76 Treatment should be guided by results of in vitro susceptibility tests.75
IDSA also recommends a regimen of cefepime and vancomycin as one of several regimens that can be used for empiric treatment of penetrating head trauma or postneurosurgical infections caused by S. aureus, coagulase-negative staphylococci (especially S. epidermidis), or aerobic gram-negative bacilli (including Ps. aeruginosa).75
SepticemiaTreatment of septicemia† caused by susceptible gram-negative bacteria.69
Select anti-infective for treatment of sepsis syndrome based on probable source of infection, gram-stained smears of appropriate clinical specimens, immune status of the patient, and current patterns of bacterial resistance within the hospital and local community.69 Some clinicians suggest that certain parenteral cephalosporins (i.e., cefepime, cefotaxime, ceftriaxone, ceftazidime) are good choices for treatment of gram-negative sepsis.69
For initial treatment of life-threatening sepsis in adults, some clinicians suggest that a third or fourth generation cephalosporin (i.e., cefepime, cefotaxime, ceftriaxone, ceftazidime), fixed combination of piperacillin and tazobactam, or a carbapenem (imipenem or meropenem) be used in conjunction with vancomycin with or without an aminoglycoside (amikacin, gentamicin, tobramycin).69
Empiric Therapy in Febrile Neutropenic PatientsEmpiric treatment of presumed bacterial infections in febrile neutropenic patients.1 26 34 35 36 58 59 62 69 92
Has been effective as monotherapy for empiric therapy in febrile neutropenic patients;34 35 36 58 59 62 used in conjunction with an aminoglycoside in more seriously ill patients.69 Manufacturers caution that safety and efficacy data are limited to date and monotherapy may not be appropriate in patients at severe risk of infection (e.g., those with a history of recent bone marrow transplantation, hypotension on presentation, underlying hematologic malignancy, or severe or prolonged neutropenia).1
Consult published protocols for the treatment of infections in febrile neutropenic patients for specific recommendations regarding selection of the initial empiric regimen, when to change the initial regimen, possible subsequent regimens, and duration of therapy in these patients.26 Consultation with an infectious disease expert knowledgeable about infections in immunocompromised patients also is advised.26 32 38
Maxipime Dosage and Administration AdministrationAdminister by IV infusion or deep IM injection.1 2 3 5 6 12 14 92
IM route should be used only for treatment of mild to moderate, uncomplicated or complicated UTIs caused by E. coli when this route is considered more appropriate.1 2 5
IV InfusionIf a Y-type administration set is used, discontinue other solution flowing through the tubing during cefepime infusion.1 2 92
Manufacturers recommend that aminoglycosides, ampicillin (>40 mg/mL), metronidazole, vancomycin, or aminophylline be administered separately from cefepime.1 2 92 (See Drug Compatibility under Compatibility.)
Reconstitution and DilutionReconstitute vials for IV infusion with 0.9% sodium chloride, 5 or 10% dextrose, (1/6) M sodium lactate, 5% dextrose and 0.9% sodium chloride, lactated Ringer’s and 5% dextrose injection, Normosol-R, or Normosol-M in 5% dextrose injection.1
Reconstitute vials containing 500 mg, 1 g, or 2 g of cefepime with 5, 10, or 10 mL of one of these IV solutions, respectively, to provide solutions containing approximately 100, 100, or 160 mg/mL, respectively, and then dilute the appropriate dose in a compatible IV solution.1
Reconstitute ADD-Vantage vials containing 1 or 2 g of cefepime with 50 or 100 mL of 0.9% sodium chloride or 5% dextrose injection according to the manufacturer’s directions.1
Thaw the commercially available premixed injection (frozen) at room temperature (25°C) or under refrigeration (5°C); do not thaw by immersion in a water bath or by exposure to microwave radiation.92 A precipitate may have formed in the frozen injection, but should dissolve with little or no agitation after reaching room temperature.92 Discard thawed injection if an insoluble precipitate is present or if container seals or outlet ports are not intact or leaks are found.92 The injection should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete.92
Rate of AdministrationAdminister by IV infusion over approximately 30 minutes.1 92
IM Injection ReconstitutionFor IM injection, reconstitute vial containing 500 mg or 1 g of cefepime with 1.3 or 2.4 mL, respectively, of sterile water for injection, 0.9% sodium chloride, 5% dextrose, 0.5 or 1% lidocaine hydrochloride, or bacteriostatic water for injection (with parabens or benzyl alcohol) to provide a solution containing approximately 280 mg/mL.1 2
DosageAvailable as cefepime hydrochloride; dosage expressed in terms of cefepime, calculated on the anhydrous basis.1 92
Pediatric Patients General Pediatric Dosage IV or IMChildren 2 months to 16 years of age weighing <40 kg: 50 mg/kg every 12 hours.1 92
AAP recommends 100–150 mg/kg daily in 3 divided doses for treatment of mild to moderate infections and 150 mg/kg daily in 3 divided doses for treatment of severe infections in children >1 month of age.64
Respiratory Tract Infections Pneumonia IVChildren 2 months to 16 years of age weighing <40 kg: 50 mg/kg every 12 hours for 10 days.1 92
Skin and Skin Structure Infections Uncomplicated Infections IVChildren 2 months to 16 years of age weighing <40 kg: 50 mg/kg every 12 hours for 10 days.1 92
Urinary Tract Infections (UTIs) Uncomplicated or Complicated UTIs IV or IMChildren 2 months to 16 years of age weighing <40 kg: 50 mg/kg every 12 hours for 7–10 days.1 92
Empiric Therapy in Febrile Neutropenic Patients IVChildren 2 months to 16 years of age weighing <40 kg: 50 mg/kg every 8 hours for 7 days or until neutropenia resolves.1 92
Frequently reevaluate need for continued anti-infective therapy if fever resolves but neutropenia remains for >7 days.1 92
Adults Intra-abdominal Infections Complicated Infections IV2 g every 12 hours for 7–10 days; use in conjunction with IV metronidazole.1 92
Respiratory Tract Infections Moderate to Severe Pneumonia IV1–2 g every 12 hours for 10 days.1 92
1–2 g every 8–12 hours recommended for initial therapy of hospital-acquired pneumonia, ventilator-associated pneumonia, or healthcare-associated pneumonia.67 92
Skin and Skin Structure Infections Moderate to Severe Uncomplicated Infections IV2 g every 12 hours for 10 days.1 92
Urinary Tract Infections (UTIs) Mild to Moderate Uncomplicated or Complicated UTIs IV or IM0.5–1 g every 12 hours for 7–10 days.1 92
Severe Uncomplicated or Complicated UTIs IV2 g every 12 hours for 10 days.1 92
Empiric Therapy in Febrile Neutropenic Patients IV2 g every 8 hours for 7 days or until neutropenia resolves.1 34 35 36 92
Frequently reevaluate need for continued anti-infective therapy if fever resolves but neutropenia remains for >7 days.1 92
Prescribing Limits Pediatric PatientsDosage should not exceed recommended adult dosage.1 92
Special Populations Hepatic ImpairmentDosage adjustments not required.1 92
Renal ImpairmentDosage adjustments necessary in patients with Clcr ?60 mL/minute.1 92
Adults with Clcr ?60 mL/minute: Give an initial loading dose using the usually recommended adult dosage followed by maintenance dosage based on Clcr.1 92 (See Table 1 and Table 2.)
Table 1. Maintenance Dosage for Treatment of Infections in Adults with Renal Impairment192Clcr (mL/minute)
Initial dose: 500 mg
Initial dose: 1 g
Initial dose: 2 g
30–60
500 mg every 24 h
1 g every 24 h
2 g every 24 h
11–29
500 mg every 24 h
500 mg every 24 h
1 g every 24 h
<11
250 mg every 24 h
250 mg every 24 h
500 mg every 24 h
Table 2. Maintenance Dosage for Empiric Therapy in Febrile Neutropenic Adults with Renal Impairment192Clcr (mL/minute)
Initial Dose: 2 g
30–60
2 g every 12 h
11–29
2 g every 24 h
<11
1 g every 24 h
Adults undergoing hemodialysis: 1 g on the first day of treatment followed by 500 mg every 24 hours for treatment of infections or 1 g on the first day followed by 1 g every 24 hours for empiric therapy in febrile neutropenic patients.1 92 Administer the dose at the same time each day (given at completion of procedure on hemodialysis days).1 92
Adults undergoing CAPD: Give usually recommended dose once every 48 hours.1 2 6 10 12 92
Pediatric patients with renal impairment: Dosage adjustments required similar to those recommended for adults.1 92
Cautions for Maxipime ContraindicationsImmediate hypersensitivity to cefepime, other cephalosporins, penicillins, or other ?-lactams.1 92
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.92
Warnings/Precautions Warnings Superinfection/Clostridium difficile-associated Diarrhea and ColitisPossible emergence and overgrowth of nonsusceptible organisms with prolonged therapy.1 92 Careful observation of the patient is essential.1 92 Institute appropriate therapy if superinfection occurs.1 92
Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.1 92 C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) has been reported with nearly all anti-infectives, including cefepime, and may range in severity from mild diarrhea to fatal colitis.1 92 Hypertoxin producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1 92
Consider CDAD if diarrhea develops and manage accordingly.1 92 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1 92
If CDAD is suspected or confirmed may need to discontinue anti-infective therapy not directed against C. difficile.1 Some mild cases may respond to discontinuance alone.1 Manage moderate to severe cases with fluid, electrolyte, and protein supplementation, anti-infective therapy active against C. difficile (e.g., oral metronidazole or vancomycin), and surgical evaluation when clinically indicated.1 92
NeurotoxicitySerious adverse events, including life-threatening or fatal encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, coma), myoclonus, and seizures reported rarely.1 85 86 87 88 92 91 Nonconvulsive status epilepticus, characterized by alteration of consciousness without convulsions that is associated with continuous epileptiform EEG activity, also reported.85 91
Most cases of cefepime-associated neurotoxicity occurred in patients with renal impairment who received dosages of the drug inappropriately high for their renal status;1 85 86 87 88 91 92 some cases occurred in patients who received dosage adjusted for renal function1 92 or in patients with normal renal function.87 88
Symptoms of neurotoxicity generally were reversible and resolved after cefepime was discontinued and/or after hemodialysis.1 92
If seizures occur, discontinue the drug.1 92 Use anticonvulsant therapy if clinically indicated.1 92
Increased MortalityIn November 2007, FDA announced that a safety review of cefepime was initiated after a published meta-analysis described a higher risk of all-cause mortality in patients treated with cefepime compared with patients treated with comparator ?-lactams.72 73 74 The published meta-analysis looked at all-cause mortality data from 57 randomized controlled trials that compared cefepime with other ?-lactams for various indications.71 FDA began working with Bristol-Myers Squibb to further evaluate the findings presented in the published meta-analysis and additional safety data.72 73
On June 17, 2009, FDA announced that, although the safety review is ongoing, it has determined that cefepime remains an appropriate therapy for its approved indications based on results of FDA's additional meta-analyses.74 FDA performed meta-analyses based on both trial- and patient-level data derived from all available cefepime comparative clinical trials.74 Results of the trial-level meta-analysis indicated that all-cause mortality rates 30 days after treatment were 6.21% for cefepime-treated patients and 6% for comparator-treated patients.74 FDA's patient-level meta-analysis indicated that all-cause mortality rates 30 days after treatment were 5.63% for cefepime-treated patients and 5.68% for comparator-treated patients.74 In addition, in a trial-level meta-analysis of 24 febrile neutropenia trials, there was no statistically significant increase in mortality in cefepime-treated patients compared with comparator-treated patients.74 A review of deaths reported in 7 of these febrile neutropenia trials indicated that most patients appeared to have died from their underlying malignancies and/or comorbid conditions.74
As part of the continuing cefepime safety review, FDA and Bristol-Myers Squibb are in the process of using hospital drug utilization data to conduct additional separate analyses of cefepime-associated mortality.74 Results from these studies are unlikely to be available until at least summer 2010.74
Sensitivity Reactions Hypersensitivity ReactionsPossible hypersensitivity reactions, including rash (maculopapular or erythematous), pruritus, fever, eosinophilia, urticaria, anaphylaxis, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.1 92 a
If an allergic reaction occurs, discontinue cefepime and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen).1 92
Cross-hypersensitivityPartial cross-sensitivity among cephalosporins and other ?-lactam antibiotics, including penicillins and cephamycins.1 92 a
Prior to initiation of therapy, make careful inquiry concerning previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs.1 92 Cautious use recommended in individuals hypersensitive to penicillins:1 92 a avoid use in those who have had an immediate-type (anaphylactic) hypersensitivity reaction and administer with caution in those who have had a delayed-type (e.g., rash, fever, eosinophilia) reaction.a
General Precautions Selection and Use of Anti-infectivesTo reduce development of drug-resistant bacteria and maintain effectiveness of cefepime and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.1 92
When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.1 92 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1 92
History of GI DiseaseUse with caution in patients with a history of GI disease, particularly colitis.1 92 (See Superinfection/Clostridium difficile-associated Diarrhea and Colitis under Cautions.)
Arginine ContentCommercially available cefepime preparations contain l-arginine to adjust pH.1 92
At concentrations 33 times higher than the amount provided by the maximum recommended human cefepime dosage, arginine has altered glucose metabolism and transiently increased serum potassium concentrations.1 92 The effect of lower arginine concentrations not known.1 92
Specific Populations PregnancyCategory B.1 92
LactationDistributed into milk;1 6 92 use with caution.1 92
Pediatric UseSafety and efficacy not established in neonates or infants <2 months of age.1 92
Safety and efficacy have been established for use in pediatric patients 2 months to 16 years of age for treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia and for empiric therapy for febrile neutropenic patients.1 92 Use of cefepime in this age group supported by evidence from adequate and well-controlled adult studies and additional pharmacokinetic and safety data from pediatric studies.1 92
Not recommended for treatment of serious infections suspected or known to be caused by Haemophilus influenzae type b (Hib); manufacturers recommend use of an alternative anti-infective if the possibility of meningeal seeding from a distant infection site or meningitis is suspected or documented.1 92 (See Uses: Meningitis and Other CNS Infections.)
The commercially available premixed injection (frozen) containing 1 or 2 g of cefepime should not be used in pediatric patients unless the entire 1- or 2-g dose is required.92
Pharmacokinetic and adverse effect profiles similar to those reported in adults.1 92
Geriatric UseSafety and efficacy in those ?65 years of age similar to that in younger adults.1 92
Serious adverse effects (including life-threatening or fatal encephalopathy, myoclonus, and seizures) have occurred in geriatric patients who received cefepime dosage inappropriately high for their renal status.1 92
Substantially eliminated by kidneys; risk of toxicity may be greater in those with impaired renal function.1 92 Select dosage with caution and assess renal function periodically because of age-related decreases in renal function.1 92 (See Renal Impairment under Dosage and Administration.)
Hepatic ImpairmentPharmacokinetics not affected.1 92
Renal ImpairmentPossible decreased clearance and increased serum half-life.1 6 92
Serious adverse events, including life-threatening or fatal encephalopathy, may occur if inappropriately high dosage is used in patients with renal impairment.1 85 86 87 91 92 (See Neurotoxicity under Cautions.)
Dosage adjustments necessary in patients with Clcr ?60 mL/minute.1 2 92 (See Renal Impairment under Dosage and Administration.)
Common Adverse EffectsDiarrhea,1 24 33 92 nausea,1 24 33 92 vomiting,1 23 33 92 rash,92 local reactions (e.g., phlebitis, pain, inflammation).1 92
Interactions for Maxipime Specific Drugs and Laboratory TestsDrug or Test
Interaction
Comments
Aminoglycosides
Possible increased risk of nephrotoxicity and ototoxicity1 92
Closely monitor renal function if used concomitantly1 92
Tests for glucose
Possible false-positive reactions in urine glucose tests using Clinitest, Benedict’s solution, or Fehling’s solution1 92 a
Use glucose tests based on enzymatic glucose oxidase reactions (e.g., Clinistix, Tes-Tape)1 92 a
Maxipime Pharmacokinetics Absorption BioavailabilityNot appreciably absorbed from GI tract; must be administered parenterally.1
Almost completely absorbed following IM administration;1 44 peak serum concentrations attained within 1.4–1.6 hours.1
Distribution ExtentWidely distributed into tissues and fluids, including blister fluid,1 39 48 bronchial mucosa,1 sputum,1 bile,1 27 peritoneal fluid,1 27 appendix,1 gallbladder,1 27 and prostate.1
Distributed into CSF following IV administration in adults or pediatric patients.1 5 46 78 81 82 84 92
Distributed into milk.1 6
Plasma Protein Binding20%.1
Elimination MetabolismPartially metabolized in vivo to N-methylpyrrolidine (NMP), which is rapidly converted to the N-oxide (NMP-N-oxide).1
Elimination RouteEliminated principally unchanged in urine by glomerular filtration.1 47 49
In adults with normal renal function, 80–82% of a single dose excreted unchanged in urine;1 42 47 49 < 1% of the dose eliminated as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of the drug.1
Half-lifeAdults with normal renal function: 2–2.3 hours.1 3 39 49
Children 2 months to 16 years of age: 1.5-1.9 hours.44
Neonates <2 months of age: 4.9 hours.80
Special PopulationsPharmacokinetics not affected by hepatic impairment.1
Patients with renal impairment: Clearance decreased and plasma half-life prolonged.1 42 Half-life averages 4.9, 10.5, 13.5 hours in those with Clcr 31–60, 11–30, or <10 mL/minute, respectively.42
Stability Storage Parenteral Powder for Injection or Infusion2–25° C; protect from light.1
Powder and reconstituted solutions may darken; does not indicate loss of potency.1
Reconstituted IV solutions containing 1–40 mg/mL are stable for 24 hours at 20–25°C or 7 days at 2–8°C.1
IV solutions in ADD-Vantage vials are stable for 24 hours at 20–25°C or 7 days at 2–8°C at concentrations of 10–40 mg/mL in 0.9% sodium chloride or 5% dextrose injection.1
Reconstituted IM solutions containing 280 mg/mL are stable for 24 hours at 20–25°C or 7 days at 2–8°C.1 2
Injection (Frozen) for IV Infusion-20°C or lower.92 Thawed solutions are stable for 24 hours at room temperature (25°C) or 7 days under refrigeration (5°C).92
Do not refreeze after thawing.92
CompatibilityFor information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral Solution CompatibilityCompatible
Amino acids 4.25%, dextrose 25% with electrolytesHID
Dextrose 5% in Ringer’s injection, lactated1 HID
Dextrose 5% in sodium chloride 0.9%1 HID
Dextrose 5 or 10% in water1 HID
Normosol M in dextrose 5%1 HID
Normosol R1 HID
Normosol R in dextrose 5%
Sodium chloride 0.9%1 HID
Drug Compatibility Admixture CompatibilityHIDCompatible
Amikacin sulfate
Clindamycin phosphate
Heparin sodium
Potassium chloride
Theophylline
Vancomycin HCl
Incompatible
Aminophylline
Gentamicin sulfate
Tobramycin sulfate
Variable
Ampicillin sodium
Metronidazole
Metronidazole HCl
Y-Site CompatibilityHIDCompatible
Amikacin sulfate
Ampicillin sodium–sulbactam sodium
Anidulafungin
Aztreonam
Bivalirudin
Bleomycin sulfate
Bumetanide
Buprenorphine HCl
Butorphanol tartrate
Calcium gluconate
Carboplatin
Carmustine
Co-trimoxazole
Cyclophosphamide
Cytarabine
Dactinomycin
Dexamethasone sodium phosphate
Dexmedetomidine HCl
Docetaxel
Doxorubicin HCl liposome injection
Fenoldopam mesylate
Fluconazole
Fludarabine phosphate
Fluorouracil
Furosemide
Gentamicin sulfate
Granisetron HCl
Hetastarch in lactated electrolyte injection (Hextend)
Hydrocortisone sodium phosphate
Hydrocortisone sodium succinate
Hydromorphone HCl
Imipenem–cilastatin sodium
Leucovorin calcium
Lorazepam
Melphalan
Mesna
Methotrexate sodium
Methylprednisolone sodium succinate
Metronidazole
Milrinone lactate
Paclitaxel
Piperacillin sodium–tazobactam sodium
Ranitidine HCl
Remifentanil HCI
Sargramostim
Sodium bicarbonate
Sufentanil citrate
Thiotepa
Ticarcillin disodium–clavulanate potassium
Tobramycin sulfate
Valproate sodium
Zidovudine
Incompatible
Acetylcysteine
Acyclovir sodium
Amphotericin B
Amphotericin B cholesteryl sulfate complex
Chlordiazepoxide HCl
Chlorpromazine HCl
Cimetidine HCl
Ciprofloxacin
Cisplatin
Dacarbazine
Daunorubicin HCl
Diazepam
Diphenhydramine HCl
Doxorubicin HCl
Droperidol
Enalaprilat
Erythromycin lactobionate
Etoposide
Etoposide phosphate
Famotidine
Filgrastim
Floxuridine
Gallium nitrate
Ganciclovir sodium
Haloperidol lactate
Hydroxyzine HCl
Idarubicin HCl
Ifosfamide
Lansoprazole
Magnesium sulfate
Mannitol
Mechlorethamine HCl
Meperidine HCl
Metoclopramide HCl
Midazolam HCI
Mitomycin
Mitoxantrone HCl
Nalbuphine HCl
Nicardipine HCI
Ofloxacin
Ondansetron HCl
Phenytoin sodium
Plicamycin
Prochlorperazine edisylate
Promethazine HCl
Streptozocin
Theophylline
Vinblastine sulfate
Vincr
Merrem
Generic Name: Meropenem
Class: Carbapenems
Chemical Name: [4R-[3(3S*,5S*),4?,5?,6?(R)]]-3-[[5- [(Dimethylamino)carbonyl] - 3 - pyrrolidinyl]thio] - 6 - (1 - hydroxyethyl) - 4 - methyl - 7 - oxo - 1 - azabicyclo[3.2.0]hept - 2 - ene - 2 - carboxylic acid trihydrate
Molecular Formula: C17H25N3O5S•3H2OC17H25N3O5S
CAS Number: 119478-56-7
Antibacterial; carbapenem ?-lactam antibiotic.1 2 3
Uses for Merrem Intra-abdominal Tract InfectionsTreatment of intra-abdominal infections (complicated appendicitis, peritonitis) caused by susceptible viridans streptococci, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, or Peptostreptococcus.1 2 3 4 6 7 9 10 12 24 28 43
Has a broad spectrum of antibacterial activity against both aerobes and anaerobes; may be used empirically to treat intra-abdominal infections before identification of the causative organism.1 2 6 7 10
For immunosuppressed patients or those with severe intra-abdominal infections, IDSA recommends an initial empiric regimen with broad spectrum of activity such as meropenem or imipenem; a third or fourth generation cephalosporin (cefepime, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone) in conjunction with metronidazole; ciprofloxacin in conjunction with metronidazole; piperacillin-tazobactam; or aztreonam in conjunction with metronidazole.28 For mild to moderate community-acquired intra-abdominal infections, IDSA recommends an initial empiric regimen with narrower spectrum of activity such as ampicillin-sulbactam; cefazolin or cefuroxime in conjunction with metronidazole; ticarcillin-clavulanate; ertapenem; or a fluoroquinolone (ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin) in conjunction with metronidazole.28
For postoperative (nosocomial) intra-abdominal infections, IDSA recommends the empiric regimen be selected based on local nosocomial susceptibility patterns; these infections usually require treatment with multiple-drug regimens and often involve resistant organisms.28
MeningitisTreatment of bacterial meningitis caused by susceptible Streptococcus pneumoniae, Haemophilus influenzae (including ?-lactamase-producing strains), or Neisseria meningitidis in children ?3 months of age.1 2 8 10 Also has been used for treatment of meningitis in adults†.29 46
Efficacy for treatment of meningitis caused by highly penicillin- or cephalosporin-resistant S. pneumoniae has not been established.1 29 44 45
Can be used as monotherapy for meningitis caused by susceptible bacteria.1 Although not usually considered initial drug of choice,24 25 29 30 recommended as an alternative in children and adults for treatment of meningitis caused by S. pneumoniae or H. influenzae.24 25 29 30 Also may be useful for meningitis caused by susceptible gram-negative bacteria (e.g., Enterobacter†, Citrobacter†, Serratia marcescens†) resistant to usually recommended regimens.29
Respiratory Tract InfectionsTreatment of respiratory tract infections†, including community-acquired pneumonia (CAP) and nosocomial pneumonia.19 20 21 22 23 24 26 27
ATS, IDSA, and others consider meropenem an alternative, not a drug of first choice, for empiric treatment of CAP† caused by S. pneumoniae.19 20 23 26 ATS and IDSA suggest the drug be reserved for when CAP may be caused by Ps. aeruginosa,20 23 Klebsiella,23 or other gram-negative bacteria.23 Also may be considered when anaerobes are known or suspected to be involved.19
A drug of choice for empiric treatment of nosocomial pneumonia†.24 26 ATS, IDSA, and others recommend an antipseudomonal cephalosporin (cefepime, ceftazidime), antipseudomonal penicillin (piperacillin-tazobactam, ticarcillin-clavulanate), or antipseudomonal carbapenem (imipenem or meropenem) for initial therapy of hospital-acquired pneumonia, ventilator-associated pneumonia, or health-care associated pneumonia because these drugs have broad spectrum of activity against gram-positive, gram-negative, and anaerobic bacteria.24 26 27 In severely ill patients or in those with late-onset disease or risk factors for multidrug-resistant bacteria, initial regimen should also include an aminoglycoside (amikacin, gentamicin, tobramycin) or antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin) to improve coverage against Pseudomonas.24 26 In hospitals where oxacillin-resistant (methicillin-resistant) Staphylococcus are common or if there are risk factors for these strains, the initial regimen also should include vancomycin or linezolid.24 26 27 In hospitals where multidrug-resistant Ps. aeruginosa are frequent causes of nosocomial pneumonia, an initial regimen of cefepime or a carbapenem (imipenem or meropenem) in conjunction with an aminoglycoside is recommended.26 54
SepticemiaTreatment of septicemia† caused by susceptible bacteria.24
Skin and Skin Structure InfectionsTreatment of complicated skin and skin structure infections caused by susceptible S. aureus (including ?-lactamase-producing strains, but not oxacillin-resistant [methicillin-resistant] strains), S. pyogenes (group A ?-hemolytic streptococci), S. agalactiae (group B streptococci), viridans streptococci, Enterococcus faecalis (not vancomycin-resistant strains), Ps. aeruginosa, E. coli, Proteus mirabilis, B. fragilis, or Peptostreptococcus.1
Urinary Tract InfectionsTreatment of complicated urinary tract infections† caused by susceptible bacteria.38
Acinetobacter InfectionsTreatment of infections caused by Acinetobacter†;24 a drug of choice used with or without an aminoglycoside.24
AnthraxRecommended as one of several anti-infectives that can be included in multiple-drug regimens used for the treatment of anthrax†, including inhalational anthrax and anthrax meningitis.31 39
Has in vitro activity against Bacillus anthracis; data not available regarding in vivo activity.40
Bacillus InfectionsTreatment of infections caused by Bacillus cereus†.24 Vancomycin considered drug of choice; carbapenems (imipenem or meropenem) or clindamycin are alternatives.24
Burkholderia InfectionsTreatment of melioidosis† caused by Burkholderia pseudomallei.24 31 32 33 34 Severe illness requires an initial parenteral regimen of ceftazidime, imipenem, or meropenem (with or without concomitant co-trimoxazole or doxycycline), followed by a prolonged oral maintenance regimen of co-trimoxazole in conjunction with doxycycline or amoxicillin-clavulanate.31 34
Treatment of glanders† caused by B. mallei.31 34 Experience is limited regarding treatment of human cases; optimum regimens not identified.31 34 Some clinicians suggest streptomycin used in conjunction with tetracycline or chloramphenicol or imipenem monotherapy.24 Others suggest that, pending results of in vitro susceptibility tests, regimens used for treatment of melioidosis can be used for initial empiric treatment of glanders.34
The US Army Medical Research Institute of Infectious Diseases (USAMRIID) and European Commission’s Task Force on Biological and Chemical Agent Threats (BICHAT) state that the same treatment regimens recommended for naturally occurring melioidosis or glanders should be used if these Burkholderia infections occur in the context of biologic warfare or bioterrorism.31 34 These experts suggest that postexposure prophylaxis with doxycycline or co-trimoxazole for ?10 days can be attempted in such situations, but is of unproven benefit.31 34
Campylobacter InfectionsTreatment of systemic infections caused by Campylobacter fetus†;24 a drug of choice.24
Capnocytophaga InfectionsTreatment of infections caused by Capnocytophaga canimorsus†.24
Optimum regimens for treatment of Capnocytophaga infections not identified; some clinicians recommend use of penicillin G or, alternatively, a third generation cephalosporin (cefotaxime, ceftizoxime, ceftriaxone), a carbapenem (imipenem or meropenem), vancomycin, a fluoroquinolone, or clindamycin.24
Clostridium InfectionsTreatment of infections caused by Clostridium perfringens†; alternative to penicillin G for those with penicillin hypersensitivity or for polymicrobial infections.24 25
Nocardia InfectionsTreatment of infections caused by Nocardia†.24 25 Co-trimoxazole usually drug of first choice;24 alternatives include sulfisoxazole, a tetracycline (e.g., doxycycline, minocycline), a carbapenem (imipenem or meropenem), amikacin, ceftriaxone, amoxicillin-clavulanate, cycloserine, or linezolid.24 25
Rhodococcus InfectionsTreatment of infections caused by Rhodococcus equi†.24 Optimum regimens not identified; combination regimens usually recommended, including vancomycin given with a fluoroquinolone, rifampin, a carbapenem (imipenem or meropenem), or amikacin.24
Empiric Therapy inFebrile Neutropenic PatientsEmpiric anti-infective therapy of presumed bacterial infections in febrile neutropenic patients†.14 24 Used alone or in conjunction with other anti-infectives.14 24
Consult published protocols for the treatment of infections in febrile neutropenic patients for specific recommendations regarding selection of the initial empiric regimen, when to change the initial regimen, possible subsequent regimens, and duration of therapy in these patients.14 Consultation with an infectious disease expert knowledgeable about infections in immunocompromised patients also is advised.14
Merrem Dosage and Administration AdministrationAdminister by IV injection or infusion.1
For solution and drug compatibility information, see Compatibility under Stability.
IV Injection ReconstitutionReconstitute single-use vials containing 500 mg or 1 g with 10 or 20 mL, respectively, of sterile water for injection to provide a solution containing approximately 50 mg/mL.1 The vial should be shaken until dissolution occurs and then allowed to stand until the solution is clear.1
Rate of AdministrationThe appropriate dose of reconstituted solution should be injected over a period of 3–5 minutes.1
IV Infusion Reconstitution and DilutionReconstitute infusion vials containing 500 mg or 1 g with a compatible IV solution (e.g., 0.9% sodium chloride, 5% dextrose) to provide solutions containing approximately 2.5–50 mg/mL.1 Alternatively, reconstitute vials containing 500 mg or 1 g with 10 or 20 mL, respectively, of sterile water for injection and then further dilute in a compatible IV.1
Rate of AdministrationInfuse IV over 15–30 minutes.1
DosageAvailable as the trihydrate; dosage expressed in terms of anhydrous meropenem.13
To minimize risk of seizures, closely adhere to dosage recommendations, especially in patients with factors known to predispose to seizure activity; dosage adjustment recommended for patients with advanced age and/or renal impairment.1
Anticonvulsant therapy should be continued in patients with existing seizure disorders.1 (See CNS Effects under Cautions.)
Pediatric Patients Intra-abdominal Infections IVChildren ?3 months of age weighing ?50 kg: 20 mg/kg (up to 1 g) every 8 hours.1 2
Children ?3 months weighing >50 kg: 1 g every 8 hours.1
Meningitis IVChildren ?3 months of age weighing ?50 kg: 40 mg/kg (up to 2 g) every 8 hours.1 2
Children ?3 months weighing >50 kg: 2 g every 8 hours.1
Skin and Skin Structure Infections IVChildren ?3 months of age weighing ?50 kg: 10 mg/kg (up to 500 mg) every 8 hours.1
Children ?3 months weighing >50 kg: 500 mg every 8 hours.1
Burkholderia Infections† Initial Treatment of Severe Disease† IVChildren ?3 months of age weighing ?40 kg: 10–20 mg/kg every 8 hours.34
Children ?3 months weighing >40 kg: use adult dosage.34
Initial IV regimen continued for ?14 days and until clinical improvement occurs.31 34 When appropriate, switch to a prolonged oral maintenance regimen (e.g., co-trimoxazole with doxycycline, amoxicillin-clavulanate).31 34 Lifelong follow-up recommended for all patients to identify relapse.31
Adults Intra-abdominal Infections IV1 g every 8 hours.1
Meningitis† IV6 g daily.29 Dosage of 40 mg/kg every 8 hours (up to 6 g daily) has been used in conjunction with ceftriaxone or cefotaxime.46
Respiratory Tract Infections† Nosocomial Pneumonia† IV1 g every 8 hours.27
Skin and Skin Structure Infections IV500 mg every 8 hours.1
Burkholderia Infections† Initial Treatment of Severe Disease† IV25 mg/kg IV every 8 hours (up to 6 g daily) recommended by USAMRIID and others; concomitant co-trimoxazole (8 mg/kg of trimethoprim daily given IV in 4 divided doses) also may be indicated.31 32 33 Other clinicians recommend 0.5–1 g every 8 hours with or without co-trimoxazole.34
Initial IV regimen continued for ?14 days and until clinical improvement occurs.31 34 When appropriate, switch to a prolonged oral maintenance regimen (e.g., co-trimoxazole with doxycycline, amoxicillin-clavulanate).31 34 Lifelong follow-up recommended for all patients to identify relapse.31
Prescribing Limits Pediatric Patients IV2 g every 8 hours.1
Special Populations Hepatic ImpairmentDosage adjustments not required.1
Renal ImpairmentDosage adjustments recommended in adults with Clcr ?50 mL/minute.1 Data insufficient to make dosage recommendations for pediatric patients with renal impairment.1
Dosage for Adults with Renal Impairment1Clcr (mL/min)
Daily Dosage
26–50
usual dose every 12 hours
10–25
50% of usual dose every 12 hours
<10
50% of usual dose once every 24 hours
Manufacturer states data insufficient to make dosage recommendations in patients undergoing hemodialysis or peritoneal dialysis.1 Meropenem removed by hemodialysis; some clinicians suggest that supplemental doses be given after each hemodialysis session.47 48 Also removed by various forms of continuous renal replacement therapy, including continuous venovenous hemodiafiltration (CVVHDF), continuous venovenous hemofiltration (CVVHF), and continuous ambulatory peritoneal dialysis (CAPD).49 50 51 52 53 To avoid inadequate concentrations in anuric patients undergoing these procedures, some clinicians suggest dosage adjustments are necessary and should be based on characteristics of the specific procedure (e.g., filter or membrane type, amount of filtrate produced, dialysate flow rate).49 50 51 52 53
Geriatric PatientsNo dosage adjustments except those related to renal impairment.1 (See Renal Impairment under Dosage and Administration.)
Cautions for Merrem ContraindicationsKnown hypersensitivity to meropenem, other carbapenems, or any ingredient in the formulation.1
History of anaphylactic reaction to ?-lactams.1
Warnings/Precautions Warnings Superinfection/Clostridium difficile-associated ColitisPossible emergence and overgrowth of nonsusceptible organism.1 Careful observation of the patient is essential.1 Institute appropriate therapy if superinfection occurs.1
Treatment with anti-infectives may permit overgrowth of clostridia.1 Consider Clostridium difficile-associated diarrhea and colitis (antibiotic-associated pseudomembranous colitis) if diarrhea develops and manage accordingly.1
Some mild cases of C. difficile-associated diarrhea and colitis may respond to discontinuance alone.1 56 57 58 59 Manage moderate to severe cases with fluid, electrolyte, and protein supplementation; appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) recommended if colitis is severe.1 56 57 58 59
CNS EffectsSeizures and other CNS effects reported, especially in those with CNS disorders (e.g., brain lesions, history of seizures) or with bacterial meningitis and/or renal impairment.1
Do not exceed recommended dosage, especially in those with known factors that predispose to seizures.1 Anticonvulsant therapy should be continued in those with known seizure disorders.1
If focal tremors, myoclonus, or seizures occur, evaluate the patient neurologically, initiate anticonvulsant therapy if necessary, and determine whether meropenem dosage should be decreased or the drug discontinued.1
Sensitivity Reactions Hypersensitivity ReactionsSerious and occasionally fatal hypersensitivity reactions (e.g., anaphylaxis) reported with ?-lactams.1
If hypersensitivity occurs, discontinue meropenem and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen).1
Cross-hypersensitivityPartial cross-allergenicity among ?-lactam antibiotics, including penicillins, cephalosporins, and other ?-lactams.1
Prior to initiation of therapy, make careful inquiry concerning previous hypersensitivity reactions to meropenem, cephalosporins, penicillins, or other drugs.1
General Precautions Selection and Use of Anti-infectivesTo reduce development of drug-resistant bacteria and maintain effectiveness of meropenem and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.1
When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.1 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1
Laboratory MonitoringPeriodically assess organ system functions, including renal, hepatic, and hematopoietic, during prolonged therapy.1
Sodium ContentEach g of meropenem contains 3.92 mEq (90.2 mg) of sodium as sodium carbonate.1
Specific Populations PregnancyCategory B.1
LactationNot known whether distributed into milk.1 Use with caution.1
Pediatric UseSafety and efficacy not established in children <3 months of age.1
Geriatric UseNo substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1
Substantially eliminated by kidneys; risk of toxicity may be greater in patients with impaired renal function.1 Select dosage with caution and assess renal function periodically since geriatric patients are more likely to have renal impairment.1
No dosage adjustments except those related to renal function.1 (See Renal Impairment under Dosage and Administration.)
Hepatic ImpairmentPharmacokinetics not affected by hepatic impairment; dosage adjustments not required.1
Renal ImpairmentDecreased clearance.1 Dosage adjustments recommended in patients with Clcr ?50 mL/minute.1 (See Renal Impairment under Dosage and Administration.)
Common Adverse EffectsGI effects (diarrhea, nausea, vomiting, constipation), local reactions (pain and inflammation at injection site, phlebitis/thrombophlebitis), headache, anemia, rash, pruritus, sepsis, apnea, shock, glossitis, oral candidiasis.1
Interactions for Merrem Specific DrugsDrug
Interaction
Comments
Aminoglycosides
In vitro evidence of synergistic antibacterial effects against Ps. aeruginosa1
Probenecid
Decreased renal tubular secretion of meropenem; increased meropenem concentrations and AUC and prolonged half-life1
Concomitant use not recommended1
Valproic acid
Valproic serum concentrations may be decreased to subtherapeutic concentrations; possible increased risk of seizures1 35 36 37
Use concomitantly with caution36 55
Merrem Pharmacokinetics Distribution ExtentWell distributed into body tissues and fluids, including bronchial mucosa, lung, bile, gynecologic tissue (endometrium, myometrium, ovary, cervix, fallopian tube), muscle, heart valves, skin, and interstitial and peritoneal fluid.1
Distributed into CSF.1
Plasma Protein BindingApproximately 2%.1
Elimination MetabolismPartially metabolized; at least 1 metabolite is microbiologically active.1
Elimination RouteEliminated in urine as unchanged drug.1 70% of an IV dose eliminated in urine as unchanged drug.1
Half-lifeAdults with normal renal function: approximately 1 hour.1
Children 3 months to 2 years of age: approximately 1.5 hours.1
Special PopulationsPharmacokinetics not affected by hepatic impairment.1
Decreased clearance in patients with renal impairment.1
Stability Storage Parenteral Powder for Injection20–25°C.1 Do not freeze reconstituted or diluted solutions.1
Solutions for IV injection containing approximately 50 mg/mL prepared using water for injection are stable for 2 hours at 15–25°C or 12 hours at 4°C.1
Solutions for IV infusion containing 2.5–50 mg/mL prepared using 0.9% sodium chloride are stable for up to 2 hours at 15–25°C or 18 hours at 4°C; those prepared using 5% dextrose are stable for up to 1 hour at 15–25°C or 8 hours at 4°C.1 1
ADD-Vantage vials reconstituted to a concentration of 5–20 mg/mL using 0.45% sodium chloride are stable for up to 6 hours at 15–25°C or 24 hours at 4°C.1 ADD-Vantage vials reconstituted to a concentration of 1–20 mg/mL using 0.9% sodium chloride are stable for up to 4 hours at 15–25°C or 24 hours at 4°C;1 those prepared using 5% dextrose injection are stable 1 hours at 15–25°C or 8 hours at 4°C; .1
CompatibilityFor information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral Solution CompatibilityHIDIncompatible (by conventional definition, but recommended for dilution with use in shorter periods of time)
Dextrose 5% with potassium chloride 0.15%
Dextrose 5% in Ringer’s injection, lactated
Dextrose 5% with sodium bicarbonate 0.02%
Dextrose 2.5% in sodium chloride 0.45%
Dextrose 5% in sodium chloride 0.2 or 0.9%
Dextrose 5 or 10% in water
Mannitol 2.5 or 10%
Normosol M with dextrose 5%
Ringer’s injection
Ringer’s injection, lactated
Sodium bicarbonate 5%
Sodium chloride 0.45 or 0.9%
Sodium lactate (1/6) M
Drug Compatibility Admixture CompatibilityHIDCompatible
Aminophylline
Atropine sulfate
Cimetidine HCl
Dexamethasone sodium phosphate
Dobutamine HCl
Dopamine HCl
Enalaprilat
Fluconazole
Furosemide
Gentamicin sulfate
Heparin sodium
Magnesium sulfate
Metoclopramide HCl
Morphine sulfate
Norepinephrine bitartrate
Phenobarbital sodium
Ranitidine HCl
Vancomycin HCl
Incompatible
Amphotericin B
Metronidazole HCl
Multivitamins
Variable
Acyclovir sodium
Doxycycline hyclate
Ondansetron HCl
Zidovudine
Y-Site CompatibilityHIDCompatible
Aminophylline
Atenolol
Atropine sulfate
Cimetidine HCl
Dexamethasone sodium phosphate
Digoxin
Diphenhydramine HCl
Docetaxel
Enalaprilat
Fluconazole
Furosemide
Gentamicin sulfate
Heparin sodium
Linezolid
Metoclopramide HCl
Milrinone lactate
Morphine sulfate
Norepinephrine bitartrate
Phenobarbital sodium
Potassium chloride
Vancomycin HCl
Incompatible
Amphotericin B
Diazepam
Metronidazole HCl
Variable
Acyclovir sodium
Calcium gluconate
Doxycycline hyclate
Ondansetron HCl
Zidovudine
Actions and SpectrumActionsSynthetic carbapenem ?-lactam antibiotic; structurally and pharmacologically related to imipenem and ertapenem.1 2 3
Usually bactericidal in action.1
Like other ?-lactam antibiotics, antibacterial activity results from inhibition of bacterial cell wall synthesis.1
Spectrum of activity includes many gram-positive and -negative aerobic bacteria and some gram-positive and -negative anaerobic bacteria.1 Stable in the presence of a variety of ?-lactamases (including penicillinases, cephalosporinases, and extended-spectrum ?-lactamases).1
Gram-positive aerobes: Active in vitro and in clinical infections against Streptococcus pneumoniae (penicillin-susceptible strains only) and viridans streptococci.1 Also active in vitro against Staphylococcus aureus and S. epidermidis.1 Oxacillin-resistant (methicillin-resistant) staphylococci are resistant.1
Gram-negative aerobes: Active in vitro and in clinical infections against Escherichia coli, Haemophilus influenzae (including ?-lactamase-producing strains), Klebsiella pneumoniae, Neisseria meningitidis and Pseudomonas aeruginosa.1 Also active in vitro against Acinetobacter, Aeromonas hydrophila, Campylobacter jejuni, Citrobacter, Enterobacter, H. influenzae (ampicillin-resistant, non-?-lactamase-producing strains; BLNAR), Havnia alvei, K. oxytoca, Moraxella catarrhalis, Morganella morganii, Pasteurella multocida, Proteus mirabilis, P. vulgaris, Salmonella, Shigella, Serratia marcescens, and Yersinia enterocolitica.1
Anaerobes: Active in vitro and in clinical infections against Bacteroides fragilis, B. thetaiotaomicron, and Peptostretptococcus.1 Also active in vitro against B. distasonis, B. ovatus, B. uniformis, B. ureolyticus, B. vulgatus, Clostridium difficile, C. perfringens, Eubacterium lentum, Fusobacterium, Prevotella bivia, P. intermedia, P. melaninogenica, Porphyromonas asaccharolytica, and Propionibacterium acnes.1
Advice to PatientsAdvise patients that antibacterials (including meropenem) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1
Importance of completing full course of therapy, even if feeling better after a few days.1
Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with meropenem or other antibacterials in the future.1
Importance of informing clinicians of other medical conditions, including history of seizures.1
Importance of discontinuing therapy and informing clinician if an allergic or hypersensitivity reaction occurs.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
PreparationsExcipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Meropenem (Trihydrate)Routes
Dosage Forms
Strengths
Brand Names
Manufacturer
Parenteral
For injection, for IV use only
500 mg (of anhydrous meropenem)
Merrem I.V. (with sodium carbonate)
AstraZeneca
1 g (of anhydrous meropenem)
Merrem I.V. (with sodium carbonate)
AstraZeneca
Comparative PricingThis pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Merrem 1GM Solution (ASTRAZENECA): 1/$79.56 or 5/$386.17
Merrem 500MG Solution (ASTRAZENECA): 1/$39.99 or 10/$365.99
DisclaimerThis report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References1. AstraZeneca Pharmaceuticals. Merrem IV (meropenem) for injection for intravenous use only prescribing information. Wilmington, DE; 2005 May.
2. Wiseman LR, Wagstaff AJ, Brogden RN et al. Meropenem: a review of its antibacterial activity, pharmacokinetic properties and clinical efficacy. Drugs. 1995; 50:73-101. [PubMed 7588092]
3. Pryka RD, Haig GM. Meropenem: a new carbapenem antimicrobial. Ann Pharmacother. 1994; 28:1045-54. [IDIS 335809] [PubMed 7803882]
4. Condon RE, Walker AP, Sirinek KR et al. Meropenem versus tobramycin plus clindamycin for treatment of intraabdominal infections: results of a prospective, randomized, double-blind clinical trial. Clin Infect Dis. 1995; 21:544-50. [IDIS 354815] [PubMed 8527541]
5. Brismar B, Malmborg AS, Tunevall G et al. Meropenem versus imipenem/cilastatin in the treatment of intra-abdominal infections. J Antimicrob Chemother. 1995; 35:139-48. [IDIS 343753] [PubMed 7768761]
6. Geroulanos SJ and the Meropenem Study Group. Meropenem versus imipenem/cilastatin in intra-abdominal infections requiring surgery. J Antimicrob Chemother. 1995; 36(Suppl A):191-205. [IDIS 353291] [PubMed 8543495]
7. Huizinga WKJ, Warren BL, Baker LW et al. Antibiotic monotherapy with meropenem in the surgical management of intra-abdominal infections. J Antimicrob Chemother. 1995; 36(Suppl A):179-89. [IDIS 353290] [PubMed 8543493]
8. Klugman KP, Dagan R, and the Meropenem Meningitis Study Group. Randomized comparison of meropenem with cefotaxime for treatment of bacterial meningitis. Antimicrob Agents Chemother. 1995; 39:1140-6. [IDIS 346314] [PubMed 7625802]
9. Anonymous. Meropenem—an advatageous antibiotic? Drug and Therapeutics Bulletin. 1996; 34:53-5.
10. Bradley JS, Faulkner KL, Klugman KP. Efficacy, safety and tolerability of meropenem as empiric antibiotic therapy in hospitalized pediatric patients. Pediatr Infect Dis J. 1996; 15:749-57. [IDIS 372345] [PubMed 8858694]
11. Fukasawa M, Sumita Y, Harabe ET et al. Stability of meropenem and effect of 1?- methyl substitution on its stability in the presence of renal dehydropeptidase I. Antimicrob Agents Chemother. 1992; 36:1577-9. [PubMed 1510457]
12. Briceland LL, Tobin EH. Focus on meropenem: a broad-spectrum parenteral carbapenem antimicrobial agent. Formulary. 1996; 31:759-74.
13. Zeneca Pharmaceuticals, Wilmington, DE: Personal communication.
14. Hughes WT, Armstrong D, Bodey GP et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002; 34:730-51. [IDIS 479956] [PubMed 11850858]
15. Pizzo PA. Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med. 1993; 328:1323-32. [IDIS 313154] [PubMed 8469254]
16. Ramphal R, Gucalp R, Rotstein C et al. Clinical experience with single agent and combination regimens in the management of infection in the febrile neutropenic patient. Am J Med. 1996; 100(Suppl 6A):83S-89S. [IDIS 370422] [PubMed 8678102]
17. Viscoli C. The evolution of the empirical management of fever and neutropenia in cancer patients. J Antimicrob Chemother. 1998; 41(Suppl D):65-80. [IDIS 409104] [PubMed 9688453]
18. Rolston KV. Expanding the options for risk-based therapy in febrile neutropenia. Diagn Microbiol Infect Dis. 1998; 31:411-6. [PubMed 9635917]
19. Bartlett JG, Dowell SF, et al. Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis. 2000; 31:347-82. [IDIS 454042] [PubMed 10987697]
20. American Thoracic Society. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med. 2001; 163:1730-54. [IDIS 466552] [PubMed 11401897]
21. Bartoloni A, Strohmeyer M, Corti G et al. Multicenter randomized trial comparing meropenem (1.5 g daily) and imipenem/cilastatin (2 g daily) in the hospital treatment of community-acquired pneumonia. Drugs Exp Clin Res. 1999; 25:243-52. [PubMed 10713862]
22. Alvarez Lerma F and the Serious Infection Study Group. Efficacy of meropenem as monotherapy in the treatment of ventilator-associated pneumonia. J Chemother. 2001; 13:70-81. [PubMed 11233804]
23. Mandell LA, Bartlett JG, Dowell SF et al. Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Infect Dis. 2003; 37:1405-33. [IDIS 516151] [PubMed 14614663]
24. Anon. Choice of antibacterial drugs. Med Lett Treat Guid. 2004; 2:18-26.
25. Committee on Infectious Diseases, American Academy of Pediatrics. Red book: 2003 report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003.
26. Anon. Drugs for pneumonia. Med Lett Treat Guid. 2003; 1:83-8.
27. American Thoracic Society and the Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005; 171:388-416. [PubMed 15699079]
28. Solomkin JS, Mazuski JE, Baron EJ et al. Guidelines for the selection of anti-infective agents fo
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