Testosterone Enanthate Ampoules (Cambridge Laboratories)
What you should know about Testosterone Enantate Ampoules

Please read this leaflet carefully. This leaflet contains information about Testosterone Enantate Ampoules, which will be given to you by injection. Although you will not be taking this medicine yourself, this leaflet contains important information to help you understand how Testosterone Enantate is used. Keep it until the course of treatment has been finished, as you may want to read it again.

Always follow your doctor's advice, and if there is anything you do not understand, please ask your doctor or nurse to explain it.

What do Testosterone Enantate Ampoules contain?

Each ampoule contains 250 mg of Testosterone Enantate (the active ingredient) together with the inactive ingredients benzyl benzoate and castor oil for injection.

Testosterone Enantate is supplied in packs of 3 ampoules, each ampoule containing 1 ml.

Testosterone Enantate is an androgen, a male type of hormone.

The holder of the product licence for this medicine is

Cambridge Laboratories Limited Deltic House Kingfisher Way Silverlink Business Park Wallsend Tyne & Wear NE28 9NX

The ampoules are made by

Schering AG Berlin Germany What is Testosterone Enantate used for?

In men Testosterone Enantate is used when natural levels of this hormone are low, which can cause loss of interest in sex, low fertility and other problems. In women Testosterone Enantate is used to treat certain diseases of the breast.

When should Testosterone Enantate not be used?

Since androgens (male hormones) can stimulate the growth of cancer of the prostate gland, men must not be given Testosterone Enantate if they have prostatic cancer. For this reason, men should have regular examinations of the prostate gland during treatment with Testosterone Enantate. Men with breast cancer should not be given Testosterone Enantate.

Testosterone Enantate Ampoules should not be used to treat women who are pregnant or breast-feeding.

You should not be given Testosterone Enantate Ampoules if you have a liver tumour or a history of such tumours, if you have a kidney disease called nephrosis or if you have too much calcium in your blood.

What else should you know before having an injection of Testosterone Enantate?

Male hormones such as Testosterone Enantate are not suitable for increasing muscular development in healthy people or for increasing physical ability.

Special care is needed when Testosterone Enantate is used in the elderly and in patients with the following conditions:

Kidney problems Heart disease Liver disease High blood pressure Migraine Diabetes Cancer that has spread to the bones

If you suffer from any of these and think that the doctor who has prescribed Testosterone Enantate for you is not aware of this, you should tell him or her straight away.

Regular blood tests may be needed if you are also being treated with some medicines that slow down the clotting of the blood. Testosterone Enantate may be less effective in epileptic patients who are taking Phenobarbital, so if this applies to you please make sure that the doctor treating you knows about it.

How Testosterone Enantate is used

Testosterone Enantate is given by injection into a muscle, usually every 2 to 3 weeks. The injections are continued for as long as your doctor considers necessary, but men receiving long-term treatment may later be given injections at 3 to 6 week intervals.

If you would like any other information about the use of Testosterone Enantate, please ask your doctor or nurse.

Side-effects

When hormones such as Testosterone Enantate are used in high doses or over a long period of time, they may result in the retention of too much water, and even swelling of the ankles in some cases. If you have a tendency to this problem, make sure your doctor checks you very carefully while you are receiving treatment with Testosterone Enantate Ampoules.

Women who receive Testosterone Enantate may develop acne, increased growth of hair on the face and body, thinning of scalp hair and deepening of the voice (particular care is necessary in women whose occupations involve singing or speaking).

If men receive long-term and high-dose treatment with Testosterone Enantate, the number of sperms they produce is reduced. Men may experience frequent or persistent erections whilst under Testosterone Enantate treatment. If this happens, make sure to tell your doctor so that he may reduce the dose or stop the treatment in order to avoid injury to the penis.

Occasionally coughing, shortness of breath and changes in the circulation of the blood may develop while Testosterone Enantate is being injected or immediately after the injection.

The doctor may arrange for women receiving Testosterone Enantate to have regular blood tests. If these show an increased level of calcium, he will stop the treatment.

In very rare cases liver tumours have been observed after the use of hormones such as Testosterone Enantate. In a few isolated cases this has been followed by internal bleeding which can be life-threatening. Tell your doctor if you have any new "stomach" discomfort or pain that does not soon clear up.

Other side effects that have sometimes occurred with Testosterone Enantate are headache, depression, feeling sick, jaundice, breast enlargement in men, an increase in the number of red blood cells, anxiety, feeling weak, abnormal sensations, increased bone growth and premature sexual development in boys.

If you are worried about side-effects or if you think that Testosterone Enantate has caused any other side-effect, please tell your doctor, nurse or pharmacist about it.

Storing Testosterone Enanthate

Testosterone Enantate Ampoules should not be used after the expiry date given on the label. They should be stored away from light.

All medicines should be kept out of the reach of children.

Date of preparation of this leaflet: August 2001

Psychotherapeutic combinations

A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes.

Psychotherapeutic combinations are products that contain more than one agent to treat psychosis and other mood disorders. The different products have drugs combinations, which work by different mechanisms and the most appropriate combination is chosen depending on the symptoms and diagnosis. The combination used is aimed to achieve leveled mood or behavior.

See also

Medical conditions associated with psychotherapeutic combinations:

AgitationAnxietyBipolar DisorderDepression Drug List:Etrafon-ForteSymbyaxLimbitrolDuo-Vil-2-10

Hemolytic Anemia Medications

Definition of Hemolytic Anemia: Hemolytic anemia is a condition of an inadequate number of circulating red blood cells (anemia), caused by premature destruction of red blood cells. There are a number of specific types of hemolytic anemia which are described individually.

Drugs associated with Hemolytic Anemia

The following drugs and medications are in some way related to, or used in the treatment of Hemolytic Anemia. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

See sub-topics

Topics under Hemolytic AnemiaAutoimmune Hemolytic Anemia (4 drugs) G-6-PD Deficiency (0 drugs) Learn more about Hemolytic Anemia

Micromedex Care Notes:

Erythroblastosis FetalisHemolytic AnemiaJaundice In NewbornsRh Factor Incompatibility

Medical Encyclopedia:

Congenital spherocytic anemiaDrug-induced immune hemolytic anemiaHemolytic anemiaHemolytic anemia caused by chemicals and toxinsIron deficiency anemiaNewborn jaundiceRh incompatibility

Harvard Health Guide:

Symptoms and treatment for Hemolytic Anemia Drug List:BaycadronClinalog-InjectionDe-Sone-La-InjectionDexacen-4-InjectionDexamethasone-IntensolDexasone-La-InjectionKen-Jec-40-InjectionSolurex-InjectionTac-3-InjectionTriamcot-InjectionU-Tri-Lone-InjectionZema-Pak-10-Day

Methotrexate Tablet
1. Name Of The Medicinal Product

Methotrexate Tablets B.P. 2.5mg / Methotrexate Tablets B.P. 10 mg.

2. Qualitative And Quantitative Composition

Active Constituent Methotrexate Ph EUR 2.5mg.

Active Constituent Methotrexate Ph EUR 10.0 mg.

There is no overage included in the formulation.

3. Pharmaceutical Form

Tablet for oral administration.

4. Clinical Particulars 4.1 Therapeutic Indications

Methotrexate is indicated in the treatment of neoplastic disease, such as trophoblastic neoplasms and leukaemia and in the control of severe recalcitrant psoriasis which is not responsive to other forms of therapy.

4.2 Posology And Method Of Administration

ADULTS AND CHILDREN

Antineoplastic Chemotherapy

Methotrexate is active orally and parenterally. Methotrexate Injection B.P. may be given by the intramuscular, intravenous, intra-arterial or intrathecal routes. Dosage is related to the patient's body weight or surface area. Methotrexate has been used with beneficial effect in a wide variety of neoplastic diseases, alone and in combination with other cytotoxic agents.

Choriocarcinoma and Similar Trophoblastic Diseases

Methotrexate is administered orally or intramuscularly in doses of 15-30mg daily for a 5-day course. Such courses may be repeated 3-5 times as required, with rest periods of one or more weeks interposed between courses until any manifesting toxic symptoms subside.

The effectiveness of therapy can be evaluated by 24 hour quantitative analysis of urinary chorionic gonadotrophin hormone (HCG). Combination therapy with other cytotoxic drugs, has also been reported as useful.

Hydatidiform mole may precede or be followed by choriocarcinoma, and Methotrexate has been used in similar doses for the treatment of hydatidiform mole and chorioadenoma destruens.

Breast Carcinoma

Prolonged cyclic combination with Cyclophosphamide, Methotrexate and Fluorouracil has given good results when used as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. Methotrexate dosage was 40mg/m2 intravenously on the first and eighth days.

Leukaemia

Acute granulocytic leukaemia is rare in children but common in adults and this form of leukaemia responds poorly to chemotherapy.

Methotrexate is not generally a drug of choice for induction of remission of lymphoblastic leukaemia. Oral Methotrexate 3.3mg/m2 daily, and Prednisolone 40-60mg/m2 daily for 4-6 weeks has been used. After a remission is attained, Methotrexate in a maintenance dosage of 20-30mg/m2 orally or by I.M. injection has been administered twice weekly. Twice weekly doses appear to be more effective than daily drug administration. Alternatively, 2.5mg/kg has been administered I.V. every 14 days.

Meningeal Leukaemia

Some patients with leukaemia are subject to leukaemic invasions of the central nervous system and the CSF should be examined in all leukaemia patients.

Passage of Methotrexate from blood to the cerebrospinal fluid is minimal and for adequate therapy the drug should be administered intrathecally. Methotrexate may be given in a prophylactic regimen in all cases of lymphocytic leukaemia. Methotrexate is administered by intrathecal injection in doses of 200-500 microgram/kg body weight. The administration is at intervals of 2 to 5 days and is usually repeated until the cell count of cerebrospinal fluid returns to normal. At this point one additional dose is advised. Alternatively, Methotrexate 12mg/m2 can be given once weekly for 2 weeks, and then once monthly. Large doses may cause convulsions and untoward side effects may occur as with any intrathecal injection, and are commonly neurological in character.

Lymphomas

In Burkitt's Tumour, stages 1-2, Methotrexate has prolonged remissions in some cases. Recommended dosage is 10-25mg per day orally for 4 to 8 days. In stage 3, Methotrexate is commonly given concomitantly with other antitumour agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods, and in stage 3 they respond to combined drug therapy with Methotrexate given in doses of 0.625mg to 2.5mg/kg daily. Hodgkin's Disease responds poorly to Methotrexate and to most types of chemotherapy.

Mycosis Fungoides

Therapy with Methotrexate appears to produce clinical remissions in one half of the cases treated. Recommended dosage is usually 2.5 to 10mg daily by mouth for weeks or months and dosage should be adjusted according to the patient's response and haematological monitoring. Methotrexate has also been given intramuscularly in doses of 50mg once weekly or 25mg twice weekly.

Psoriasis Chemotherapy

Cases of severe uncontrolled psoriasis, unresponsive to conventional therapy, have responded to weekly single, oral, I.M. or I.V. doses of 10-25mg per week, adjusted according to the patient's response. An initial test dose one week prior to initiation of therapy is recommended to detect any idiosyncrasy. A suggested dose range is 5-10mg.

An alternative dosage schedule consists of 2.5 to 5mg of Methotrexate administered orally at 12 hour intervals for 3 doses each week or at 8-hour intervals for 4 doses each week; weekly dosages should not exceed 30mg.

A daily oral dosage schedule of 2 to 5mg administered orally for 5 days followed by a rest period of at least 2 days may also be used. The daily dose should not exceed 6.25mg.

The patient should be fully informed of the risks involved and the clinician should pay particular attention to the appearance of liver toxicity by carrying out liver function tests before starting Methotrexate treatment, and repeating these at 2 to 4 month intervals during therapy. The aim of therapy should be to reduce the dose to the lowest possible level with the longest possible rest period. The use of Methotrexate may permit the return to conventional topical therapy which should be encouraged.

4.3 Contraindications

Significantly impaired renal function.

Significantly impaired hepatic function

Pre-existing blood dyscrasias, such as significant marrow hypoplasia, leukopenia, thrombocytopenia or anaemia.

Methotrexate is contraindicated in pregnancy.

Due to the potential for serious adverse reactions from methotrexate in breast fed infants, breast feeding is contra-indicated in women taking methotrexate.

Patients with a known allergic hypersensitivity to methotrexate should not receive methotrexate.

4.4 Special Warnings And Precautions For Use

WARNINGS

Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy.

Due to the possibility of fatal or severe toxic reactions, the patient should be fully informed by the physician of the risks involved and be under his constant supervision.

Deaths have been reported with the use of Methotrexate in the treatment of psoriasis.

In the treatment of psoriasis, Methotrexate should be restricted to severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established by biopsy and/or after dermatological consultation.

1. Full blood counts should be closely monitored before, during and after treatment. If a clinically significant drop in white-cell or platelet count develops, methotrexate should be withdrawn immediately. Patients should be advised to report all symptoms or signs suggestive of infection.

2. Methotrexate may be hepatotoxic, particularly at high dosage or with prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes, and periportal fibrosis have been reported. Since changes may occur without previous signs of gastrointestinal or haematological toxicity, it is imperative that hepatic function be determined prior to initiation of treatment and monitored regularly throughout therapy. If substantial hepatic function abnormalities develop, methotrexate dosing should be suspended for at least 2 weeks.Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function. Concomitant use of other drugs with hepatotoxic potential (including alcohol) should be avoided.

3. Methotrexate has been shown to be teratogenic; it has caused foetal death and/or congenital anomalies. Therefore it is not recommended in women of childbearing potential unless there is appropriate medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant psoriatic patients should not receive Methotrexate.

4. Renal function should be closely monitored before, during and after treatment. Caution should be exercised if significant renal impairment is disclosed. Reduce dose of methotrexate in patients with renal impairment. High doses may cause the precipitation of methotrexate or its metabolites in the renal tubules. A high fluid throughput and alkalinisation of the urine to pH 6.5 – 7.0, by oral or intravenous administration of sodium bicarbonate (5 x 625mg tablets every three hours) or acetazolamide (500mg orally four times a day) is recommended as a preventative measure. Methotrexate is excreted primarily by the kidneys. Its use in the presence of impaired renal function may result in accumulation of toxic amounts or even additional renal damage.

5. Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.

6. Methotrexate affects gametogenesis during the period of its administration and may result in decreased fertility which is thought to be reversible on discontinuation of therapy. Conception should be avoided during the period of Methotrexate administration and for at least 6 months thereafter. Patients and their partners should be advised to this effect.

7. Methotrexate has some immunosuppressive activity and immunological responses to concurrent vaccination may be decreased. The immunosuppressive effect of Methotrexate should be taken into account when immune responses of patients are important or essential.

8. Pleural effusions and ascites should be drained prior to initiation of methotrexate therapy.

9. Deaths have been reported with the use of methotrexate. Serious adverse reactions including deaths have been reported with concomitant administration of methotrexate (usually in high doses) along with some non-steroidal anti-inflammatory drugs (NSAIDs).

10. Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.

11. Systemic toxicity may occur following intrathecal administration. Blood counts should be monitored closely.

12. A chest X-ray is recommended prior to initiation of methotrexate therapy.

13. If acute methotrexate toxicity occurs, patients may require folinic acid.

PRECAUTIONS

Methotrexate has a high potential toxicity, usually dose related, and should be used only by physicians experienced in antimetabolite chemotherapy, in patients under their constant supervision. The physician should be familiar with the various characteristics of the drug and its established clinical usage.

Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests.

It should be noted that intrathecal doses are transported into the cardiovascular system and may give rise to systemic toxicity. Systemic toxicity of methotrexate may also be enhanced in patients with renal dysfunction, ascites, or other effusions due to prolongation of serum half-life.

Carcinogenesis, mutagenesis, and impairment of fertility: Animal carcinogenicity studies have demonstrated methotrexate to be free of carcinogenic potential. Although methotrexate has been reported to cause chromosomal damage to animal somatic cells and bone marrow cells in humans, these effects are transient and reversible. In patients treated with methotrexate, evidence is insufficient to permit conclusive evaluation of any increased risk of neoplasia.

Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy. In addition, methotrexate causes, embryotoxicity, abortion and foetal defects in humans. Therefore the possible risks of effects on reproduction should be discussed with patients of childbearing potential (see 'Warnings').

Patients undergoing therapy should be subject to appropriate supervision so that signs or symptoms of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Pretreatment and periodic haematological studies are essential to the use of Methotrexate in chemotherapy because of its common effect of haematopoietic suppression. This may occur abruptly and on apparent safe dosage, and any profound drop in blood cell count indicates immediate stopping of the drug and appropriate therapy. In patients with malignant disease who have pre-existing bone marrow aplasia, leukopenia, thrombocytopenia or anaemia, methotrexate should be used with caution, if at all.

In general, the following laboratory tests are recommended as part of essential clinical evaluation and appropriate monitoring of patients chosen for or receiving Methotrexate therapy: complete haemogram; haematocrit; urinalysis; renal function tests; liver function tests and chest X-ray.

The purpose is to determine any existing organ dysfunction or system impairment. The tests should be performed prior to therapy, at appropriate periods during therapy and after termination of therapy.

Liver biopsy may be considered after cumulative doses> 1.5g have been given, if hepatic impairment is suspected.

Methotrexate is bound in part to serum albumin after absorption, and toxicity may be increased because of displacement by certain drugs such as salicylates, sulphonamides, phenytoin, and some antibacterials such as tetracycline, chloramphenicol and para-aminobenzoic acid. These drugs, especially salicylates and sulphonamides, whether antibacterial, hypoglycaemic or diuretic, should not be given concurrently until the significance of these findings is established.

Vitamin preparations containing folic acid or its derivatives may alter response to Methotrexate.

Methotrexate should be used with extreme caution in the presence of infection, peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age. If profound leukopenia occurs during therapy, bacterial infection may occur or become a threat. Cessation of the drug and appropriate antibiotic therapy is usually indicated. In severe bone marrow depression, blood or platelet transfusions may be necessary.

Since it is reported that Methotrexate may have an immunosuppressive action, this factor must be taken into consideration in evaluating the use of the drug where immune responses in a patient may be important or essential.

In all instances where the use of Methotrexate is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgement of the physician. Reinstitution of Methotrexate therapy should be carried out with caution, with adequate consideration of further need for the drug and alertness as to the possible recurrence of toxicity.

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Methotrexate is extensively protein bound and may be displaced by certain drugs such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins, tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, so causing a potential for increased toxicity when used concurrently.

Concomitant use of other drugs with nephrotoxic or hepatotoxic potential (including alcohol) should be avoided.

Vitamin preparations containing folic acid or its derivatives may decrease the effectiveness of methotrexate.

Caution should be used when NSAIDs and salicylates are administered concomitantly with methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate and thereby may enhance its toxicity. Concomitant use of NSAIDs and salicylates has been associated with fatal methotrexate toxicity.

However, patients using constant dosage regimens of NSAIDs have received concurrent doses of methotrexate without problems observed.

Renal tubular transport is also diminished by probenecid and penicillins; use of these with methotrexate should be carefully monitored.

Severe bone marrow depression has been reported following the concurrent use of methotrexate and co-trimoxazole or trimethoprim. Concurrent use should probably be avoided.

Methotrexate-induced stomatitis and other toxic effects may be increased by the use of nitrous oxide.

An increased risk of hepatitis has been reported following the use of methotrexate and the acitretin metabolite, etretinate. Consequently, the concomitant use of methotrexate and acitretin should be avoided.

4.6 Pregnancy And Lactation

Abortion, foetal death, and/or congenital anomalies have occurred in pregnant women receiving Methotrexate, especially during the first trimester of pregnancy. Methotrexate is contraindicated in the management of psoriasis or rheumatoid arthritis in pregnant women. Women of childbearing potential should not receive Methotrexate until pregnancy is excluded. For the management of psoriasis or rheumatoid arthritis, Methotrexate therapy in women should be started immediately following a menstrual period and appropriate measures should be taken in men or women to avoid conception during and for at least 6 months following cessation of Methotrexate therapy.

Both men and women receiving Methotrexate should be informed of the potential risk of adverse effects on reproduction. Women of childbearing potential should be fully informed of the potential hazard to the foetus should they become pregnant during Methotrexate therapy. In cancer chemotherapy, Methotrexate should not be used in pregnant women or women of childbearing potential who might become pregnant unless the potential benefits to the mother outweigh the possible risks to the foetus.

Defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, and infertility have been reported in patients receiving Methotrexate.

Methotrexate is distributed into breast milk. Because of the potential for serious adverse reactions to Methotrexate in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

4.7 Effects On Ability To Drive And Use Machines

Not applicable

4.8 Undesirable Effects

The most common adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal distress. Although very rare, anaphylactic reactions to methotrexate have occurred. Others reported are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions as reported for the various systems are as follows:

Skin: Stevens-Johnson syndrome, epidermal necrolysis, erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration in psoriatic patients and rarely painful erosion of psoriatic plaques have been reported. The recall phenomenon has been reported in both radiation and solar damaged skin.

Blood: Bone marrow depression, leukopenia, thrombocytopenia, anaemia, hypogammaglobulinaemia, haemorrhage from various sites, septicaemia.

Alimentary System: Gingivitis, pharyngitis, stomatitis, anorexia, vomiting, diarrhoea, haematemesis, melaena, gastrointestinal ulceration and bleeding, enteritis, hepatic toxicity resulting in active liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis, or hepatic cirrhosis. In rare cases the effect of methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon.

Hepatic: Hepatic toxicity resulting in significant elevations of liver enzymes, acute liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis or cirrhosis or death may occur, usually following chronic administration.

Urogenital System: Renal failure, azotaemia, cystitis, haematuria, defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, foetal defects, severe nephropathy. Vaginitis, vaginal ulcers, cystitis, haematuria and nephropathy have also been reported.

Pulmonary System: Infrequently an acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Acute pulmonary oedema has also been reported after oral and intrathecal use. Pulmonary fibrosis is rare. A syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses.

Central Nervous System: Headaches, drowsiness, blurred vision, aphasia, hemiparesis and convulsions have occurred possibly related to haemorrhage or to complications from intra-arterial catheterization. Convulsion, paresis, Guillain-Barre syndrome and increased cerebrospinal fluid pressure have followed intrathecal administration.

Other reactions related to, or attributed to the use of Methotrexate such as pneumonitis, metabolic changes, precipitation of diabetes, osteoporotic effects, abnormal changes in tissue cells and even sudden death have been reported.

There have been reports of leukoencephalopathy following intravenous methotrexate in high doses, or low doses following cranial-spinal radiation.

Adverse reactions following intrathecal methotrexate are generally classified into three groups, acute, subacute, and chronic. The acute form is a chemical arachnoiditis manifested by headache, back or shoulder pain, nuchal rigidity, and fever. The subacute form may include paresis, usually transient, paraplegia, nerve palsies, and cerebellar dysfunction. The chronic form is a leukoencephalopathy manifested by irritability, confusion, ataxia, spasticity, occasionally convulsions, dementia, somnolence, coma, and rarely, death. There is evidence that the combined use of cranial radiation and intrathecal methotrexate increases the incidence of leukoencephalopathy.

Additional reactions related to or attributed to the use of methotrexate such as osteoporosis, abnormal (usually 'megaloblastic') red cell morphology, precipitation of diabetes, other metabolic changes, and sudden death have been reported.

4.9 Overdose

Calcium Folinate (Calcium Leucovorin) is a potent agent for neutralizing the immediate toxic effects of Methotrexate on the haematopoietic system. Where large doses or overdoses are given, Calcium Folinate may be administered by intravenous infusion in doses up to 75mg within 12 hours, followed by 12mg intramuscularly every 6 hours for 4 doses. Where average doses of Methotrexate appear to have an adverse effect 6-12mg of Calcium Folinate may be given intramuscularly every 6 hours for 4 doses. In general, where overdosage is suspected, the dose of Calcium Folinate should be equal to or higher than, the offending dose of Methotrexate and should be administered as soon as possible; preferably within the first hour and certainly within 4 hours after which it may not be effective.

Other supporting therapy such as blood transfusion and renal dialysis may be required. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Methotrexate is an antimetabolite which acts principally by competitively inhibiting the enzyme, dihydrofolate reductase. In the process of DNA synthesis and cellular replication, folic acid must be reduced to tetrahydrofolic acid by this enzyme, and inhibition by Methotrexate interferes with tissue cell reproduction. Actively proliferating tissues such as malignant cells are generally more sensitive to this effect of Methotrexate. It also inhibits antibody synthesis.

Methotrexate also has immunosuppressive activity, in part possibly as a result of inhibition of lymphocyte multiplication. The mechanism(s) of action in the management of rheumatoid arthritis of the drug is not known, although suggested mechanisms have included immunosuppressive and/or anti-inflammatory effect.

5.2 Pharmacokinetic Properties

In doses of 0.1mg (of Methotrexate) per kg, Methotrexate is completely absorbed from the G.I. tract; larger oral doses may be incompletely absorbed. Peak serum concentrations are achieved within 0.5 - 2 hours following I.V. / I.M. or intra-arterial administration. Serum concentrations following oral administration of Methotrexate may be slightly lower than those following I.V. injection.

Methotrexate is actively transported across cell membranes. The drug is widely distributed into body tissues with highest concentrations in the kidneys, gall bladder, spleen, liver and skin. Methotrexate is retained for several weeks in the kidneys and for months in the liver. Sustained serum concentrations and tissue accumulation may result from repeated daily doses. Methotrexate crosses the placental barrier and is distributed into breast milk. Approximately 50% of the drug in the blood is bound to serum proteins.

In one study, Methotrexate had a serum half-life of 2-4 hours following I.M. administration. Following oral doses of 0.06mg/kg or more, the drug had a serum half-life of 2-4 hours, but the serum half-life was reported to be increased to 8-10 hours when oral doses of 0.037mg/kg were given.

Methotrexate does not appear to be appreciably metabolised. The drug is excreted primarily by the kidneys via glomerular filtration and active transport. Small amounts are excreted in the faeces, probably via the bile. Methotrexate has a biphasic excretion pattern. If Methotrexate excretion is impaired accumulation will occur more rapidly in patients with impaired renal function. In addition, simultaneous administration of other weak organic acids such as salicylates may suppress Methotrexate clearance.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Other Constituents 2.5 mg tablets

Maize Starch

Ph EUR

30.0mg

Lactose

Ph EUR

41.8mg

Pre gelatinized Starch (Prejel PA5)

Ph EUR

2.5mg

Polysorbate 80

Ph EUR

0.2mg

Microcrystalline Cellulose (AVICEL 101)

Ph EUR

20.0mg

Magnesium Stearate

Ph EUR

3.0mg

Other Constituents 10 mg tablets

Maize Starch

Ph EUR

27.6 mg

Lactose

Ph EUR

38.5 mg

Pre gelatinized Starch (Prejel PA5)

Ph EUR

2.5mg

Polysorbate 80

Ph EUR

0.2mg

Microcrystalline Cellulose (AVICEL 101)

Ph EUR

18.2 mg

Magnesium Stearate

Ph EUR

3.0mg

There is no overage included in either formulation.

6.2 Incompatibilities

Immediate precipitation or turbidity results when combined with certain concentrations of

Droperidol, Heparin Sodium, Metoclopramide Hydrochloride, Ranitidine Hydrochloride in

Syringe.

6.3 Shelf Life

60 months

6.4 Special Precautions For Storage

There are no specific storage requirements.

6.5 Nature And Contents Of Container

White polyethylene bottle with high density polyethylene screw closure containing 100 tablets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Faulding Pharmaceuticals Plc

Queensway

Royal Leamington Spa

Warwickshire, CV31 3RW

8. Marketing Authorisation Number(S)

2.5 mg tablets PL 04515/0004

10 mg tablets PL 04515/0005

9. Date Of First Authorisation/Renewal Of The Authorisation

9th September 1985/24th June 1996

10. Date Of Revision Of The Text

4th July 2001

Indorex

Indorex may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Indorex Permethrin

Permethrin is reported as an ingredient of Indorex in the following countries:

Germany New Zealand Piperonyl Butoxide

Piperonyl Butoxide is reported as an ingredient of Indorex in the following countries:

Germany New Zealand Pyriproxyfen

Pyriproxyfen is reported as an ingredient of Indorex in the following countries:

Germany New Zealand

International Drug Name Search

Adrenergic bronchodilators

A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes.

Adrenergic bronchodilators (specifically beta2-adrenoreceptor agonists) dilate the bronchi by a direct action on the beta2-adrenoreceptors on the bronchial smooth muscle and relax the muscle.

There are two categories of beta2-adrenoreceptor agonists used in asthma. The short acting adrenergic bronchodilators are used on an as needed basis to control symptoms of asthma. The longer acting bronchodilators are used regularly, twice daily, as adjunct therapy in patients whose asthma is poorly controlled by inhaled corticosteroids.

See also

Medical conditions associated with adrenergic bronchodilators:

Adams-Stokes SyndromeAllergic ReactionsAsthmaAsthma, acuteAsthma, MaintenanceAsystoleAV Heart BlockBronchitisBronchospasm During AnesthesiaBronchospasm ProphylaxisCardiac ArrhythmiaCOPDCOPD, AcuteCOPD, MaintenanceElectromechanical DissociationPremature LaborShock Drug List:IsuprelForadilXopenex-Hfa-AerosolBrovanaAlupentMaxairXopenex-ConcentrateBrethineVentolin-Hfa-AerosolProair-Hfa-AerosolVentolinAccuneb-SolutionAdrenalinAiret-SolutionAsthmahaler-AerosolBronkometerEpipen-2-PakEpipen-Jr-Auto-InjectorEpipen-Jr-Auto-InjectorMedihaler-IsoTornalateTwinject-Auto-InjectorTwinject-Auto-Injector-Two-Pack

ardeparin Subcutaneous

ar-de-PAR-in

Available Dosage Forms:

Injectable Solution

Therapeutic Class: Anticoagulant

Pharmacologic Class: Low Molecular Weight Heparin

Uses For ardeparin

Ardeparin is used to prevent deep venous thrombosis, a condition in which harmful blood clots form in the blood vessels of the legs. These blood clots can travel to the lungs and can become lodged in the blood vessels of the lungs, causing a condition called pulmonary embolism. Ardeparin is used for several days after knee replacement surgery, while you are unable to walk. It is during this time that blood clots are most likely to form. Ardeparin also may be used for other conditions as determined by your doctor.

Ardeparin is available only with your doctor's prescription.

Before Using ardeparin

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For ardeparin, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to ardeparin or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Studies on ardeparin have been done only in adult patients, and there is no specific information comparing use of ardeparin in children with use in other age groups.

Geriatric

ardeparin has been tested and has not been shown to cause different side effects or problems in older people than it does in younger adults.

Pregnancy Pregnancy Category Explanation All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking ardeparin, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using ardeparin with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Aceclofenac Acemetacin Alclofenac Alteplase, Recombinant Anistreplase Antithrombin, Recombinant Apazone Benoxaprofen Bromfenac Bufexamac Carprofen Citalopram Clometacin Clonixin Dexketoprofen Diclofenac Diflunisal Dipyrone Droxicam Escitalopram Etodolac Etofenamate Felbinac Fenbufen Fenoprofen Fentiazac Floctafenine Flufenamic Acid Fluoxetine Flurbiprofen Fluvoxamine Ibuprofen Indomethacin Indoprofen Isoxicam Ketoprofen Ketorolac Lornoxicam Meclofenamate Mefenamic Acid Meloxicam Nabumetone Naproxen Niflumic Acid Nimesulide Oxaprozin Oxyphenbutazone Paroxetine Phenylbutazone Pirazolac Piroxicam Pirprofen Propyphenazone Proquazone Reteplase, Recombinant Sertraline Streptokinase Sulindac Suprofen Tenecteplase Tenidap Tenoxicam Tiaprofenic Acid Tolmetin Urokinase Zomepirac

Using ardeparin with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Aspirin Benorilate Choline Magnesium Trisalicylate Mesalamine Olsalazine Salicylamide Salicylic Acid Salsalate Sodium Salicylate Sodium Thiosalicylate Trolamine Salicylate Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of ardeparin. Make sure you tell your doctor if you have any other medical problems, especially:

Bleeding problems or Eye problems caused by diabetes or high blood pressure or Heart infection or High blood pressure (hypertension) or Kidney disease or Liver disease or Stomach or intestinal ulcer (active) or Stroke—The risk of bleeding may be increased

Also, tell your doctor if you have received ardeparin or heparin before and had a reaction to either of them called thrombocytopenia (a low platelet count in the blood), or if new blood clots formed while you were receiving the medicine.

In addition, tell your doctor if you have recently had medical surgery. This may increase the risk of serious bleeding when you are taking ardeparin.

Proper Use of ardeparin

If you are using ardeparin at home, your health care professional will teach you how to inject yourself with the medicine. Be sure to follow the directions carefully. Check with your health care professional if you have any problems using the medicine.

Put used syringes in a puncture-resistant, disposable container, or dispose of them as directed by your health care professional.

Dosing

The dose of ardeparin will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of ardeparin. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For injection dosage form: For prevention of deep venous thrombosis (leg clots) and pulmonary embolism (lung clots): Adults—The dose is given every twelve hours for up to fourteen days after surgery. Children—Use and dose must be determined by your doctor. Missed Dose

If you miss a dose of ardeparin, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using ardeparin

Tell all your medical doctors and dentists that you are using ardeparin.

Check with your doctor immediately if you notice any of the following side effects:

Bruising or bleeding, especially bleeding that is hard to stop. Bleeding inside the body sometimes appears as bloody or black, tarry stools, or faintness. Back pain; burning, pricking, tickling, or tingling sensation; leg weakness; numbness; paralysis; or problems with bowel or bladder function. ardeparin Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Stop taking ardeparin and get emergency help immediately if any of the following effects occur:

Less common Bleeding gums coughing up blood deep, dark purple bruise, pain, or swelling at the place of injection difficulty with breathing or swallowing dizziness headache increased menstrual flow or vaginal bleeding nosebleeds paralysis prolonged bleeding from cuts red or black, tarry stools red or dark brown urine shortness of breath unexplained pain, swelling, or discomfort, especially in the chest, abdomen, joints, or muscles unusual bruising vomiting of blood or coffee ground material weakness Rare Back pain burning, pricking, tickling, or tingling sensation leg weakness numbness problems with bowel or bladder function rash consisting of pinpoint, purple-red spots, often beginning on the legs

Check with your doctor as soon as possible if any of the following side effects occur:

Less common Fever Rare Skin rash, hives, or itching

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common Nausea pain at the injection site vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: ardeparin Subcutaneous side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More ardeparin Subcutaneous resources Ardeparin Subcutaneous Side Effects (in more detail)Ardeparin Subcutaneous Use in Pregnancy & BreastfeedingArdeparin Subcutaneous Drug InteractionsArdeparin Subcutaneous Support Group0 Reviews for Ardeparin Subcutaneous - Add your own review/rating Compare ardeparin Subcutaneous with other medications Deep Vein ThrombosisDeep Vein Thrombosis, Prophylaxis

Haldol

Generic Name: haloperidol (Oral route)

hal-oh-PER-i-dol

Oral route(Tablet)

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Although the causes of death in clinical trials were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational studies suggest that antipsychotic drugs may increase mortality. It is unclear from these studies to what extent the mortality findings may be attributed to the antipsychotic drug as opposed to patient characteristics. Haloperidol is not approved for the treatment of patients with dementia-related psychosis .

Commonly used brand name(s)

In the U.S.

Haldol

In Canada

Alti-Haloperidol Apo-Haloperidol Novo-Peridol Peridol Pms-Haloperidol Ratio-Haloperidol

Available Dosage Forms:

Tablet Solution

Therapeutic Class: Antipsychotic

Pharmacologic Class: Dopamine Antagonist

Chemical Class: Butyrophenone

Uses For Haldol

Haloperidol is used to treat nervous, emotional, and mental conditions (e.g., schizophrenia). It is also used to control the symptoms of Tourette's disorder. This medicine should not be used to treat behavior problems in older adult patients who have dementia.

Haloperidol is also used to treat severe behavioral problems (e.g., aggressive, impulsive behavior) or hyperactivity in children who have already been treated with psychotherapy or other medicines that did not work well.

This medicine is available only with your doctor's prescription.

Before Using Haldol

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of haloperidol in children younger than 3 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of haloperidol in the elderly. However, elderly women are more likely to have a side effect called tardive dyskinesia, and elderly patients are more likely to have age-related heart problems, which may require an adjustment in the dose for patients receiving haloperidol.

Pregnancy Pregnancy Category Explanation All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

Bepridil Cisapride Dronedarone Levomethadyl Mesoridazine Metoclopramide Pimozide Sparfloxacin Terfenadine Thioridazine

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Acecainide Ajmaline Alfuzosin Amiodarone Amisulpride Amitriptyline Amoxapine Apomorphine Aprindine Arsenic Trioxide Asenapine Astemizole Azimilide Azithromycin Bretylium Chloral Hydrate Chloroquine Chlorpromazine Ciprofloxacin Citalopram Clarithromycin Clomipramine Clozapine Crizotinib Dalfopristin Dasatinib Desipramine Dibenzepin Disopyramide Dofetilide Dolasetron Doxepin Droperidol Encainide Enflurane Erythromycin Flecainide Fluconazole Fluoxetine Foscarnet Gatifloxacin Gemifloxacin Granisetron Halofantrine Halothane Hydromorphone Hydroquinidine Ibutilide Imipramine Isoflurane Isradipine Ketoconazole Lapatinib Levofloxacin Lidoflazine Lithium Lopinavir Lorcainide Lumefantrine Mefloquine Methadone Milnacipran Moxifloxacin Nilotinib Norfloxacin Nortriptyline Octreotide Ofloxacin Ondansetron Paliperidone Paroxetine Pazopanib Pentamidine Perflutren Lipid Microsphere Pirmenol Posaconazole Prajmaline Probucol Procainamide Prochlorperazine Promethazine Propafenone Propranolol Protriptyline Quetiapine Quinidine Quinine Quinupristin Ranolazine Risperidone Salmeterol Saquinavir Sematilide Sertindole Sodium Phosphate Sodium Phosphate, Dibasic Sodium Phosphate, Monobasic Solifenacin Sorafenib Sotalol Spiramycin Sulfamethoxazole Sultopride Sunitinib Tedisamil Telavancin Telithromycin Tetrabenazine Toremifene Tramadol Trazodone Trifluoperazine Trimethoprim Trimipramine Vandetanib Vardenafil Vasopressin Vemurafenib Venlafaxine Voriconazole Ziprasidone Zolmitriptan Zotepine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Benztropine Betel Nut Bupropion Buspirone Carbamazepine Dextromethorphan Fluvoxamine Methyldopa Nefazodone Olanzapine Procyclidine Rifampin Rifapentine Tacrine Trihexyphenidyl Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

Breast cancer, history of or Chest pain or Heart or blood vessel disease, severe or Hyperprolactinemia (high prolactin in the blood) or Hypotension (low blood pressure) or Mania or Neuroleptic malignant syndrome, history of or Seizures or epilepsy, history of—Use with caution. May make these conditions worse. Central nervous system depression, severe or Coma or Dementia in elderly or Parkinson's disease—Should not be used in patients with these conditions. Heart rhythm problems (e.g., familial long QT-syndrome), history of or Hypokalemia (low potassium in the blood) or Hypomagnesemia (low magnesium in the blood) or Hypothyroidism (underactive thyroid) or Thyrotoxicosis (overactive thyroid)—May increase risk for more serious side effects. Proper Use of haloperidol

This section provides information on the proper use of a number of products that contain haloperidol. It may not be specific to Haldol. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. This is particularly important for elderly patients, since they may react very strongly to this medicine.

For patients taking the liquid form of this medicine:

This medicine is to be taken by mouth and it comes in a dropper bottle. Each dose is to be measured with the specially marked dropper provided with your bottle. Do not use other droppers since they may not deliver the correct amount of medicine. This medicine should be mixed with water or a beverage, such as orange juice, apple juice, tomato juice, or cola, and taken immediately after mixing.

Continue taking this medicine for the full time of treatment. Sometimes haloperidol must be taken for several days to several weeks before its full effect is reached.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage forms (solution and tablets): For nervous, emotional, or mental conditions: Adults and teenagers—At first, 0.5 to 5 milligrams (mg) two or three times a day. Your doctor may increase your dose if needed. However, the dose is usually not more than 100 mg per day. Older adults—At first, 0.5 to 2 milligrams (mg) two or three times a day. Your doctor may increase your dose if needed. However, the dose is usually not more than 100 mg per day. Children 3 to 12 years of age or weighing 15 to 40 kilograms (kg)—Dose is based on body weight and must be determined by your doctor. The usual dose is 50 to 150 micrograms per kg per day, given in divided doses two or three times a day. Your doctor may increase your dose if needed. However, the dose is usually not more than 6 mg per day. Children below 3 years of age—Use and dose must be determined by the doctor. Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Haldol

Your doctor should check your progress at regular visits, especially during the first few months of treatment with this medicine. The amount of haloperidol you take may be changed to meet the needs of your condition and to prevent side effects.

Do not stop taking this medicine without checking first with your doctor. Your doctor may want you to gradually reduce the amount you are taking before stopping completely. This will allow your body time to adjust and help avoid a worsening of your medical condition.

This medicine will add to the effects of alcohol and other CNS depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for allergies or colds; sedatives, tranquilizers, or sleeping medicine; prescription pain medicine or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above while you are using this medicine.

This medicine may cause some people to become dizzy, drowsy, or less alert than they are normally, especially as the amount of medicine is increased. Even if you take haloperidol at bedtime, you may feel drowsy or less alert on arising. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

Dizziness, lightheadedness, or fainting may occur, especially when you get up from a lying or sitting position. Getting up slowly may help. If this problem continues or gets worse, check with your doctor.

This medicine will often make you sweat less, causing your body temperature to increase. Use extra care not to become overheated during exercise or hot weather while you are taking this medicine, since overheating may result in heat stroke. Also, hot baths or saunas may make you feel dizzy or faint while you are using this medicine.

Haloperidol may cause your skin to be more sensitive to sunlight than it is normally. Exposure to sunlight, even for brief periods of time, may cause a skin rash, itching, redness or other discoloration of the skin, or a severe sunburn. When you begin taking this medicine:

Stay out of direct sunlight, especially between the hours of 10:00 a.m. and 3:00 p.m., if possible. Wear protective clothing, including a hat or sunglasses. Apply a sun block product that has a skin protection factor (SPF) of at least 15. Some patients may require a product with a higher SPF number, especially if they have a fair complexion. If you have any questions about this, check with your doctor. Apply a sun block lipstick that has an SPF of at least 15 to protect your lips. Do not use a sunlamp or tanning bed or booth.

If you have a severe reaction from the sun, check with your doctor.

Haloperidol may cause dry mouth. For temporary relief, use sugarless candy or gum, melt bits of ice in your mouth, or use a saliva substitute. However, if your mouth continues to feel dry for more than 2 weeks, check with your medical doctor or dentist. Continuing dryness of the mouth may increase the chance of dental disease, including tooth decay, gum disease, and fungus infections.

Contact your doctor as soon as possible if you have chest pain or discomfort, a fast heartbeat, trouble breathing, or fever and chills. These can be symptoms of a very serious problem with your heart.

This medicine may cause tardive dyskinesia (a movement disorder). Check with your doctor right away if you have any of the following symptoms while taking this medicine: lip smacking or puckering, puffing of the cheeks, rapid or worm-like movements of the tongue, uncontrolled chewing movements, or uncontrolled movements of the arms and legs.

Stop taking this medicine and check with your doctor right away if you have any of the following symptoms while using this medicine: convulsions (seizures); difficulty with breathing; a fast heartbeat; a high fever; high or low blood pressure; increased sweating; loss of bladder control; severe muscle stiffness; unusually pale skin; or tiredness. These could be symptoms of a serious condition called neuroleptic malignant syndrome (NMS).

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Haldol Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common Difficulty with speaking or swallowing inability to move the eyes loss of balance control mask-like face muscle spasms, especially of the neck and back restlessness or need to keep moving (severe) shuffling walk stiffness of the arms and legs trembling and shaking of the fingers and hands twisting movements of the body weakness of the arms and legs Less common Decreased thirst difficulty in urination dizziness, lightheadedness, or fainting hallucinations (seeing or hearing things that are not there) lip smacking or puckering puffing of the cheeks rapid or worm-like movements of the tongue skin rash uncontrolled chewing movements uncontrolled movements of the arms and legs Rare Confusion convulsions (seizures) difficult or fast breathing fast heartbeat or irregular pulse fever (high) high or low blood pressure hot, dry skin, or lack of sweating increased blinking or spasms of the eyelid increased sweating loss of bladder control muscle stiffness (severe) muscle weakness sore throat and fever uncontrolled twisting movements of the neck, trunk, arms, or legs unusual bleeding or bruising unusual facial expressions or body positions unusual tiredness or weakness unusually pale skin yellow eyes or skin Incidence not known Continuing nausea or vomiting increase in the frequency of seizures loss of appetite swelling of the face tiredness and weakness

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose Difficulty with breathing (severe) dizziness (severe) drowsiness (severe) muscle trembling, jerking, stiffness, or uncontrolled movements (severe) unusual tiredness or weakness (severe)

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common Blurred vision changes in menstrual period constipation dryness of the mouth swelling or pain in the breasts (in females) unusual secretion of milk weight gain Less common Decreased sexual ability drowsiness increased sensitivity of the skin to sun (skin rash, itching, redness or other discoloration of skin, or severe sunburn) nausea or vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Haldol side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Haldol resources Haldol Side Effects (in more detail)Haldol Use in Pregnancy & BreastfeedingDrug ImagesHaldol Drug InteractionsHaldol Support Group9 Reviews for Haldol - Add your own review/rating Haldol Prescribing Information (FDA) Haldol MedFacts Consumer Leaflet (Wolters Kluwer) Haldol Concise Consumer Information (Cerner Multum) Haloperidol Monograph (AHFS DI) Haloperidol Professional Patient Advice (Wolters Kluwer) Haloperidol Prescribing Information (FDA) Haldol Decanoate MedFacts Consumer Leaflet (Wolters Kluwer) Haldol Decanoate Prescribing Information (FDA) Compare Haldol with other medications DementiaICU AgitationManiaNausea/VomitingPsychosisTourette's Syndrome

Methadone Hydrochloride Sugar Free 1mg / 1ml Oral Solution (Glass Packs)

Methadone Hydrochloride Sugar Free 1mg/1ml Oral Solution

Read all of this leaflet carefully before you start taking this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or pharmacist. This medicine has been prescribed only for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet 1. What Methadone Hydrochloride Sugar Free 1mg/1ml Oral Solution is and what it is used for 2. Before you take Methadone Hydrochloride Sugar Free 1mg/1ml Oral Solution 3. How to take Methadone Hydrochloride Sugar Free 1mg/1ml Oral Solution 4. Possible side effects 5. How to store Methadone Hydrochloride Sugar Free 1mg/1ml Oral Solution 6. Further information What Methadone Hydrochloride Sugar Free 1mg/1ml Oral Solution is and what it is used for

The name of your medicine is Methadone Hydrochloride Sugar Free 1mg/1ml Oral Solution (referred to as Methadone Solution in this leaflet). It contains methadone hydrochloride. This belongs to a group of medicines called Narcotic Analgesics.

Methadone is used:

to treat opioid drug addiction to treat moderate to severe pain Before you take Methadone Hydrochloride Sugar Free 1mg/1ml Oral Solution Do not take Methadone Solution and tell your doctor if: you are allergic (hypersensitive) to methadone or any other ingredients in this liquid (see section 6 below). An allergic reaction can include a rash, itching or shortness of breath you have severe breathing problems or a history of asthma. You must not use this medicine during an asthma attack. If you give this medicine to yourself (self-administration), wait until the asthma attack has passed and you are fully recovered you are taking Monoamine Oxidase Inhibitors (MAOIs) used to treat depression or if you have taken a MAOI medicine in the past two weeks (see ‘Taking other medicines’) you are dependent on any other drugs you are in labour children must not be given this medicine.

Do not take this medicine if any of the above apply to you. If you are not sure, talk to your doctor before taking methadone.

Take special care with Methadone Solution

Before you take this medicine, tell your doctor if:

you have liver or kidney problems you have epilepsy you are addicted to alcohol you have or have recently had a head injury you have low thyroid function (hypothyroid) you have problems with your adrenal glands. These are linked to your kidneys you have an enlarged prostate gland you have low blood pressure you are in shock you have a muscle weakness disease called myasthenia gravis you have bowel problems you have a history of irregular heart beat you have a history of heart disease you have a family history of people dying suddenly without cause you have low potassium, sodium or magnesium levels you are pregnant or breast-feeding you are extremely ill or an older person. You may be more sensitive to the medicine.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking methadone.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines bought without a prescription, including herbal medicines. This is because methadone can affect the way some other medicines work. Also some medicines can affect the way methadone works.

You must not take Methadone Solution:

at the same time or within 2 weeks of taking Monoamine Oxidase Inhibitors (MAOIs).

Some medicines can increase the risk of heart problems when used with methadone. Talk to your doctor before taking methadone if you are taking:

medicines for heart problems such as verapamil and enalapril medicines which affect electrolyte balance such as diuretics (water tablets) or lithium.

Tell your doctor if you are taking any of the following medicines:

medicines that dull your senses such as medicines for depression (for example, fluvoxamine, fluoxetine), medicines to help you sleep (including anaesthetics) and medicines to calm you down called tranquillisers cimetidine, used to treat stomach ulcers rifampicin, used to treat tuberculosis (TB) medicines used to treat epilepsy such as phenytoin, carbamazepine, phenobarbital and primidone medicines that make your urine acidic such as ascorbic acid (vitamin C) narcotic painkillers such as codeine and pentazocine naloxone used to reverse the effects of opioid drugs medicines used to stop opioid drugs working such as naltrexone and buprenorphine medicines used to treat HIV such as nevirapine, efavirenz and nelfinavir. The doctor may have to change the amount of methadone you take whilst on these medicines antibiotics such as ciprofloxacin or macrolide antibiotics for example erythromycin medicines used to treat fungal infections such as ketoconazole or fluconazole St. John’s Wort - a herbal preparation for depression.

If any of the above apply to you, talk to your doctor before taking Methadone Solution.

Taking Methadone Solution with food and drink

Do not drink alcohol whilst taking Methadone Solution. This is because Methadone Solution can make you feel sleepy and drinking alcohol will make you even more sleepy.

Pregnancy and Breast-feeding talk to your doctor before taking Methadone Solution if you are pregnant or likely to become pregnant take care if you are taking a pregnancy test as the methadone may interfere with the results you should not take this medicine whilst you are in labour do not breast-feed if you are taking Methadone Solution. Driving and using machines

Methadone Solution will severely affect your ability to drive or use machines, whilst taking it and afterwards. You should only start doing these activities again with the permission of your doctor.

Important information about what is in Methadone Solution:

This medicine contains:

methyl and propyl parahydroxybenzoates. These may cause an allergic reaction. This allergy may happen some time after starting the medicine liquid maltitol. If your doctor has told you that you cannot tolerate some sugars, see your doctor before taking this medicine. How to take Methadone Hydrochloride Sugar Free 1mg/1ml Oral Solution

Take this medicine as your doctor or pharmacist has told you. Look on the label and ask your doctor or pharmacist if you are not sure.

Taking this medicine this medicine contains 1mg of methadone in each 1ml take this medicine by mouth. Adults

For addiction

the starting dose is 10mg to 20mg (10ml to 20ml) each day the doctor can increase this to 40mg to 60mg (40ml to 60ml) each day.

For pain

the usual dose is 5mg to 10mg (5ml to 10ml) every 6 to 8 hours the dose may be changed by your doctor. Older people and very ill people if you have to have repeated doses of this medicine, the doctor may want to monitor you more closely. Children

Children must not take this medicine.

If you take more Methadone Solution than you should

If you take more of this medicine than you should, talk to a doctor or go to your nearest hospital straight away. Take the medicine pack with you.

If you forget to take Methadone Solution if you forget a dose do not take it. Wait until the next dose is due and take only that amount do not take a double dose (two doses at the same time) to make up for a forgotten dose. If you stop taking Methadone Solution do not stop taking this medicine unless your doctor tells you to as you may suffer withdrawal effects your doctor will tell you how to lower the dose gradually.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Possible side effects

Like all medicines, Methadone can cause side effects although not everybody gets them.

Stop taking this medicine and see a doctor straight away if you have an allergic reaction to Methadone Solution.

An allergic reaction may include:

swelling of your face, lips, tongue or throat or difficulty breathing or swallowing severe itching of your skin with raised lumps. Stop taking this medicine and see a doctor straight away if you have any of the following: heart problems. The signs of this may include changes in the way your heart beats, such as it beating faster or missed heart beats, breathing difficulties and dizziness if your breathing becomes slow and shallow. Keep taking the medicine but tell your doctor straight away if you get any of the following side effects: if you have asthma and it gets worse worsening of the pressure inside your head if you already have this condition following an injury to your brain or brain disease. Tell your doctor if you get any of these side effects: feeling sick (nausea) or being sick (vomiting) constipation sweating a lot more than usual feeling dizzy, particularly when standing up. This may be a sign that you have low blood pressure small pupils breast growth and production of breast milk difficulty in passing water (urine), pain in the lower back and abdomen caused by muscle spasms dry mouth, eyes or nose, facial flushing feeling drowsy, confused or restless changes in your mood, feeling "high" or over excited seeing or hearing things that are not there (hallucinations) headache, rashes low body heat (hypothermia) lower sexual urge or desire painful periods or lack of periods.

You may notice that some of the side effects become less severe with time as you get used to the methadone.

When taken for a long period of time, it is possible that you may become dependent on methadone solution.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store Methadone Hydrochloride Sugar Free 1mg/1ml Oral Solution Keep out of the reach and sight of children Store below 25°C. Protect from light Do not use after the expiry date (month, year) stated on the label and carton If it is out of date or you no longer want it, take it back to the pharmacy Do not use Methadone Solution if you notice anything wrong with the medicine. Talk to your pharmacist Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. Further information What Methadone Solution contains The active ingredient is methadone hydrochloride The other ingredients are methyl hydroxybenzoate (E218), propyl hydroxybenzoate (E216), propylene glycol (E1520), caramel (E150), liquid maltitol (E965), patent blue (E131) and purified water. What Methadone Solution looks like and contents of the pack A green solution.

It comes in a brown glass bottle holding 30ml, 40ml, 50ml, 100ml or 500ml of solution.

Marketing Authorisation Holder and Manufacturer Rosemont Pharmaceuticals Ltd. Yorkdale Industrial Park Braithwaite Street Leeds LS11 9XE UK

This leaflet was last approved in December 2009

P0492

Viracept
Pronunciation: nel-FIN-a-virGeneric Name: NelfinavirBrand Name: Viracept

Aminocaproic Acid
Pronunciation: a-mee-noe-ka-PROE-ikGeneric Name: Aminocaproic AcidBrand Name: Amicar

Kristalose Crystals
Pronunciation: LAK-tyoo-loseGeneric Name: LactuloseBrand Name: Kristalose

Interhistin

Interhistin may be available in the countries listed below.

Ingredient matches for Interhistin Mebhydrolin

Mebhydrolin napadisilate (a derivative of Mebhydrolin) is reported as an ingredient of Interhistin in the following countries:

Indonesia

International Drug Name Search

Hectorol Capsules
Pronunciation: dox-ehr-kal-SIFF-eh-roleGeneric Name: DoxercalciferolBrand Name: Hectorol

Nastrosa 1mg film-coated tablets
1. Name Of The Medicinal Product

Nastrosa 1mg film-coated tablets

2. Qualitative And Quantitative Composition

Each tablet contains 1 mg anastrozole as active substance.

Excipients: Each tablet contains 90.3 mg lactose (as lactose monohydrate).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

White, round, biconvex, film-coated tablets. Debossed with '1' on one side and plain on the reverse side.

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of advanced breast cancer in postmenopausal women.

Efficacy has not been demonstrated in oestrogen receptor-negative patients unless they had a previous positive clinical response to tamoxifen.

4.2 Posology And Method Of Administration

Adults including the elderly:

One 1 mg tablet to be taken orally once a day.

Children:

Not recommended for use in children.

Renal impairment:

No dose change is recommended in patients with mild or moderate renal impairment.

Hepatic impairment:

No dose change is recommended in patients with mild hepatic disease.

 

4.3 Contraindications

Anastrozole is contraindicated in:

- premenopausal women.

- pregnant or lactating women.

- patients with severe renal impairment (creatinine clearance less than 20 ml / min)

- patients with moderate or severe hepatic disease

- patients with hypersensitivity to anastrozole or to any of the excipients as referenced in section 6.1.

Oestrogen-containing therapies should not be co-administered with anastrozole as they would negate its pharmacological action.

Concurrent tamoxifen therapy (see section 4.5)

4.4 Special Warnings And Precautions For Use

Anastrozole is not recommended for use in children as safety and efficacy have not been established in this group of patients.

The menopause should be defined biochemically in any patient where there is doubt about hormonal status.

There are no data to support the safe use of anastrozole in patients with moderate or severe hepatic impairment, or patients with severe impairment of renal function (creatinine clearance less than 20 ml/min).

Women with osteoporosis or at risk of osteoporosis, should have their bone mineral density formally assessed by bone densitometry e.g. DEXA scanning at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored.

There are no data available for the use of anastrozole with LHRH analogues. This combination should not be used outside clinical trials.

As anastrozole lowers circulating oestrogen levels it may cause a reduction in bone mineral density. Adequate data to show the effect of bisphosphonates on bone mineral density loss caused by anastrozole, or their utility when used prophylactically, are not currently available.

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Anastrozole inhibited cytochrome P450 1A2, 2C8/9 and 3A4 in vitro. A clinical interaction study indicated that anastrozole at a 1 mg dose does not significantly alter the pharmacokinetics of warfarin, a CYP2C9 substrate.

No clinically significant interactions between anastrozole and bisphosphonates have been identified.

Antipyrine and cimetidine clinical interaction studies indicate that co-administration of anastrozole with other drugs is unlikely to result in clinically significant drug interactions mediated by cytochrome P450.

A review of the clinical trial safety datatbase did not reveal evidence of clinically significant interaction in patients treated with anastrozole who also received other commonly prescribed drugs.

Tamoxifen should not be co-administered with anastrozole, as this may diminish its pharmacological action (see section 4.3).

4.6 Pregnancy And Lactation

Anastrozole is contraindicated in pregnant or lactating women.

Pregnancy

There are no data on the use of anastrozole in pregnant patients. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Anastrozole 1mg should not be used in pregnancy.

Lactation

It is unknown whether anastrozole is excreted in human milk. Anastrozole 1mg should nor be used during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

Anastrozole is unlikely to impair the ability of patients to drive and operate machinery. However, asthenia and somnolence have been reported with the use of anastrozole and caution should be observed when driving or operating machinery while such symptoms persist.

4.8 Undesirable Effects

The assessment of the side effects is based on the following frequencies:

Very common (

Common (

Uncommon (

Rare (

Very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Nervous system disorders

Common: Headache, mainly mild or moderate in nature

Carpal Tunnel Syndrome

Uncommon: Somnolence, mainly mild or moderate in nature

Gastrointestinal disorders

Common: Nausea, mainly mild or moderate in nature, diarrhoea, mainly mild or moderate

Uncommon: Vomiting, mainly mild or moderate in nature

Skin and subcutaneous tissue disorders

Common: Hair thinning, mainly mild or moderate in nature, Rash, mainly mild or moderate in nature

Very rare: Erythema multiforme, Stevens-Johnson syndrome, allergic reactions including angiooedema, urticaria and anaphylaxis

Musculoskeletal and connective tissue disorders

Common: Joint pain/stiffness, mainly mild or moderate in nature

Metabolism and nutrition disorders

Uncommon: Anorexia, mainly mild in nature, hypercholesterolaemia, mainly mild or moderate in nature

Vascular disorders

Very common: Hot flushes, mainly mild or moderate in nature

General disorders and administration site conditions

Common: Asthenia, mainly mild or moderate in nature

Hepatobiliary disorders

Common: Increases in alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase

Uncommon: Increases in gamma-GT and bilirubin, hepatitis

Reproductive system and breast disorders

Common: Vaginal dryness, mainly mild or moderate in nature

Uncommon: Vaginal bleeding, mainly mild or moderate in nature*

*Vaginal bleeding has been reported uncommonly, mainly in patients with advanced breast cancer during the first few weeks after changing from existing hormonal therapy to treatment with anastrozole. If bleeding persists, further evaluation should be considered.

As anastrozole lowers circulating oestrogen levels, it may cause a reduction in bone mineral density placing some patients at a higher risk of fracture (see section 4.4).

Elevated gamma-GT has been reported uncommonly (

The table below presents the frequency of pre-specified adverse events in the ATAC study, irrespective of causality, reported in patients receiving trial therapy and up to 14 days after cessation of trial therapy.

Adverse effects

Anastrozole

(N=3092)

Tamoxifen

(N=3094)

Hot flushes

1104 (35.7%)

1264 (40.9%)

Joint pain/stiffness

1100 (35.6%)

911 (29.4%)

Mood disturbances

597 (19.3%)

554 (17.9%)

Fatigue/asthenia

575 (18.6%)

544 (17.6%)

Nausea and vomiting

393 (12.7%)

384 (12.4%)

Fractures

315 (10.2%)

209 (6.8%)

Fractures of the spine, hip, or wrist/Colles

133 (4.3%)

91 (2.9%)

Wrist/Colles fractures

67 (2.2%)

50 (1.6%)

Spine fractures

43 (1.4%)

22 (0.7%)

Hip fractures

28 (0.9%)

26 (0.8%)

Cataracts

182 (5.9%)

213 (6.9%)

Vaginal bleeding

167 (5.4%)

317 (10.2%)

Ischaemic cardiovascular disease

127 (4.1%)

104 (3.4%)

Angina pectoris

71 (2.3%)

51 (1.6%)

Myocardial infarct

37 (1.2%)

34 (1.1%)

Coronary artery disorder

25 (0.8%)

23 (0.7%)

Myocardial ischaemia

22 (0.7%)

14 (0.5%)

Vaginal discharge

109 (3.5%)

408 (13.2%)

Any venous thromboembolic event

87 (2.8%)

140 (4.5%)

Deep venous thromboembolic events including PE

48 (1.6%)

74 (2.4%)

Ischaemic cerebrovascular events

62 (2.0%)

88 (2.8%)

Endometrial cancer

4 (0.2%)

13 (0.6%)

Fracture rates of 22 per 1000 patient-years and 15 per 1000 patient-years were observed for the anastrozole and tamoxifen groups, respectively, after a median follow-up of 68 months. The observed fracture rate for anastrozole is similar to the range reported in age-matched postmenopausal populations. It has not been determined whether the rates of fracture and osteoporosis seen in ATAC in patients on anastrozole treatment reflect a protective effect of tamoxifen, a specific effect of anastrozole, or both. The incidence of osteoporosis was 10.5% in patients treated with anastrozole and 7.3% in patients treated with tamoxifen.

4.9 Overdose

There is limited clinical experience of accidental overdosage. In animal studies, anastrozole demonstrated low acute toxicity. Clinical trials have been conducted with various dosages of anastrozole, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were well tolerated. A single dose of anastrozole that results in life-threatening symptoms has not been established. There is no specific antidote to overdosage and treatment must be symptomatic.

In the management of an overdose, consideration should be given to the possibility that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because anastrozole is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents – Endocrine therapy – Hormone antagonists and related agents – Enzyme inhibitors.

ATC code: L02B G03

Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, estradiol is produced primarily from the conversion of androstenedione to estrone through the aromatase enzyme complex in peripheral tissues. Estrone is subsequently converted to estradiol. Reducing circulating estradiol levels has been shown to produce a beneficial effect in women with breast cancer. In postmenopausal women, anastrozole at a daily dose of 1 mg produced estradiol suppression of greater than 80% using a highly sensitive assay.

Anastrozole does not possess any progestogenic, androgenic or oestrogenic activity. Daily doses of anastrozole up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard ACTH challenge testing. Corticoid supplements are therefore not needed.

An extensive phase III clinical study programme showed that anastrozole is an effective treatment of hormone-receptor positive breast cancer in post menopausal women.

5.2 Pharmacokinetic Properties

Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within two hours of dosing (under fasted conditions). Anastrozole is eliminated slowly with a plasma elimination half-life of 40 to 50 hours. Food slightly decreases the rate but not the extent of absorption. The small change in the rate of absorption is not expected to result in a clinically significant effect on steady-state plasma concentrations during once daily dosing of anastrozole. Approximately 90 to 95% of plasma anastrozole steady-state concentrations are attained after 7 daily doses. There is no evidence of time or dose-dependency of anastrozole pharmacokinetic parameters.

Anastrozole pharmacokinetics are independent of age in postmenopausal women.

Pharmacokinetics have not been studied in children.

Anastrozole is only 40% bound to plasma proteins.

Anastrozole is extensively metabolised by postmenopausal women with less than 10% of the dose excreted in the urine unchanged within 72 hours of dosing. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. The metabolites are excreted primarily via the urine. Triazole, the major metabolite in plasma, does not inhibit aromatase.

The apparent oral clearance of anastrozole in volunteers with stable hepatic cirrhosis or renal impairment was in the range observed in healthy volunteers.

5.3 Preclinical Safety Data

Acute toxicity

In acute toxicity studies in rodents, the median lethal dose of anastrozole was greater than 100 mg/kg/day by the oral route and greater than 50 mg/kg/day by the intraperitoneal route. In an oral acute toxicity study in the dog, the median lethal dose was greater than 45 mg/kg/day.

Chronic toxicity

Multiple dose toxicity studies utilized rats and dogs. No no-effect levels were established for anastrozole in the toxicity studies, but those effects that were observed at the low doses (1 mg/kg/day) and mid doses (dog 3 mg/kg/day; rat 5 mg/kg/day) were related to either the pharmacological or enzyme-inducing properties of anastrozole and were unaccompanied by significant toxic or degenerative changes.

Mutagenicity

Genetic toxicology studies with anastrozole show that it is not a mutagen or a clastogen.

Reproductive toxicology

Oral administration of anastrozole to female rats produced a high incidence of infertility at 1 mg/kg/day and increased pre-implantation loss at 0.02 mg/kg/day. These effects occurred at clinically relevant doses. An effect in man cannot be excluded. These effects were related to the pharmacology of the compound and were completely reversed after a 5-week compound withdrawal period.

Oral administration of anastrozole to pregnant rats and rabbits caused no teratogenic effects at doses up to 1.0 and 0.2 mg/kg/day respectively. Those effects that were seen (placental enlargement in rats and pregnancy failure in rabbits) were related to the pharmacology of the compound.

The survival of litters born to rats given anastrozole at 0.02 mg/kg/day and above (from day 17 of pregnancy to day 22 post-partum) was compromised. These effects were related to the pharmacological effects of the compound on parturition. There were no adverse effects on behaviour or reproductive performance of the first generation offspring attributable to maternal treatment with anastrozole.

Carcinogenicity

A two year rat oncogenicity study resulted in an increase in incidence of hepatic neoplasms and uterine stromal polyps in females and thyroid adenomas in males at the high dose (25 mg/kg/day) only. These changes occurred at a dose which represents 100-fold greater exposure than occurs at human therapeutic doses, and are considered not to be clinically relevant to the treatment of patients with anastrozole.

A two year mouse oncogenicity study resulted in the induction of benign ovarian tumours and a disturbance in the incidence of lymphoreticular neoplasms (fewer histiocytic sarcomas in females and more deaths as a result of lymphomas). These changes are considered to be mouse-specific effects of aromatase inhibition and not clinically relevant to the treatment of patients with anastrozole.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Tablet core:

Lactose monohydrate

Sodium starch glycolate (Type A)

Magnesium stearate

Film coating:

Opadry II white 85F18422 consisting of

Poly (vinyl alcohol) –partially hydrolysed

Titanium dioxide

Macrogol 3350

Talc

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions

6.5 Nature And Contents Of Container

PVC/PVDC aluminium blisters.

Pack sizes :

20, 28, 30. 84, 98, 100 and 300 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Niche Generics Limited,

1 The Cam Centre,

Wilbury Way,

Hitchin,

Hertfordshire,

SG4 0TW,

United Kingdom.

8. Marketing Authorisation Number(S)

PL 19611/0157.

9. Date Of First Authorisation/Renewal Of The Authorisation

3rd December 2009.

10. Date Of Revision Of The Text

January 2011

Premique Cycle 0.625mg / 10mg Coated Tablets
1. Name Of The Medicinal Product

Premique Cycle® 0.625mg/10mg Coated Tablets.

2. Qualitative And Quantitative Composition

Premique Cycle is a combination of conjugated estrogens* USP and medroxyprogesterone acetate (MPA) Ph.Eur.

Premique Cycle is composed of 14 tablets containing 0.625mg conjugated estrogens and 14 combination tablets containing 0.625mg conjugated estrogens and 10mg MPA.

*Conjugated estrogens contain sodium estrone sulphate, sodium equilin sulphate, 17?

3. Pharmaceutical Form

Premique Cycle is available for oral administration as conjugated estrogens 0.625mg tablets and conjugated estrogens/MPA (0.625mg/10mg) combination tablets. Conjugated estrogens 0.625mg tablets are white, oval, biconvex sugar-coated tablets marked “0.625”. Conjugated estrogens/MPA (0.625mg/10mg) combination tablets are green, oval, biconvex sugar-coated tablets marked “0.625/10”.

4. Clinical Particulars 4.1 Therapeutic Indications

• Hormone replacement therapy for estrogen deficiency symptoms in menopausal and postmenopausal women

• Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.

4.2 Posology And Method Of Administration

Adults:

Premique Cycle is available for oral use in a sequential regimen for treatment of women with a uterus. That is, for the first 14 days of each cycle (days 1-14), one white tablet containing conjugated estrogens 0.625mg is taken daily, and for the last 14 days (days 15-28), one green tablet containing conjugated estrogens 0.625mg and MPA 10mg is taken daily. There should be no break between packs.

For most post-menopausal women, therapy may be commenced at any convenient time, although if the patient is still menstruating, commencement on the first day of bleeding is recommended. In women transferring from another sequential hormone replacement therapy regimen, treatment should begin the day following completion of the prior regimen.

Patients should be advised that a regular withdrawal bleed will usually occur at the end of one cycle of Premique Cycle and the beginning of the next.

For treatment of postmenopausal symptoms: Conjugated estrogens 0.625mg daily for the first 14 days of each cycle, followed by conjugated estrogens/MPA (0.625mg/10mg) combination tablet daily on days 15 to 28.

For prevention and treatment of osteoporosis associated with estrogen deficiency: Conjugated estrogens 0.625mg daily for the first 14 days and conjugated estrogens/MPA (0.625mg/10mg) combination tablet taken daily on days 15 to 28. (See section 5.1 Pharmacological Properties)

Maintenance/Continuation/Extended Treatment:

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4 Special warnings and special precautions for use) should be used. Patients should be re-evaluated periodically to determine if treatment for symptoms is still necessary.

The benefits of the lower risk of endometrial hyperplasia and endometrial cancer due to adding a progestogen should be weighed against the increased risk of breast cancer (see sections 4.4 Special Warnings and Precautions for Use and 4.8 Undesirable Effects).

Forgotten tablet: If a tablet is forgotten, it should be taken as soon as the patient remembers, therapy should then be continued as before. If more than one tablet has been forgotten only the most recent tablet should be taken. The patient should not take double the usual dose to make up for the missed tablet.

Missed pills may cause breakthrough bleeding.

Elderly:

There are no special dosage requirements for elderly patients, but, as with all medicines, the lowest effective dose should be used.

Children:

Not recommended.

4.3 Contraindications

1. Known, past or suspected cancer of the breast.

2. Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer)

3. Undiagnosed abnormal genital bleeding.

4. Untreated endometrial hyperplasia

5. Active or past history of venous thromboembolism (e.g. deep vein thrombosis, pulmonary embolism)

6. Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction)

7. Acute liver disease or history of liver disease where the liver function tests have failed to return to normal.

8. Known hypersensitivity to the active substances or to any of the excipients of Premique Cycle tablets.

9. Porphyria

4.4 Special Warnings And Precautions For Use

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

1. Medical examination/Follow up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual women. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast Cancer' below). Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

2. Conditions that need supervision

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Premique Cycle, in particular:

? Leiomyoma (uterine fibroids) or endometriosis

? A family history of, or other risk factors for, thromboembolic disorders (see below)

? Risk factors for estrogen dependent tumours (e.g. 1st degree heredity for breast cancer)

? Hypertension

? Liver disorders (e.g. liver adenoma)

? Diabetes mellitus with or without vascular involvement

? Cholelithiasis

? Migraine or (severe) headaches

? Systemic lupus erythematosus (SLE)

? A history of endometrial hyperplasia (see below)

? Epilepsy

? Asthma

? Otosclerosis

3. Reasons for immediate withdrawal of therapy

Therapy should be discontinued if a contra-indication is discovered and in the following situations:

? Jaundice or deterioration in liver function

? Significant increase in blood pressure

? New onset of migraine-type headache

? Pregnancy

4. Endometrial Hyperplasia

The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods (see section 4.8 Undesirable effects). The addition of a progestogen for at least 12 days of the cycle in non-hysterectomised women greatly reduces this risk. Unless there is a previous diagnosis of endometriosis it is not recommended to add a progestogen in hysterectomised women.

The reduction in risk to the endometrium should be weighed against the increase in the risk of breast cancer of added progestogen (see 'Breast cancer' below and Section 4.8 Undesirable effects).

Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

5. Breast Cancer

A randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestogen combinations or tibolone for HRT for several years (see Section 4.8 Undesirable effects). For all HRT, an excess risk becomes apparent within a few years of use and increases with the duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

6. Venous thromboembolism

Hormone replacement therapy (HRT) is associated with a higher relative risk of developing venous thromboembolism (VTE) i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two to threefold higher risk for users compared with non-users. For non- users it is estimated that the number of cases of VTE that will occur over a 5-year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5-year period will be between 2 and 6 (best estimate 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.

Generally recognised risk factors for VTE include a personal or family history and severe obesity (Body Mass Index>30kg/m2) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.

Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4-6 weeks earlier, if this is possible. Treatment should not be restarted until the woman is completely mobilised.

If venous thromboembolism develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of potential thromboembolic symptoms (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

7. Coronary Artery Disease (CAD)

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and MPA. Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products, there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

8. Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate =1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

9. Ovarian Cancer

Long term (at least 5-10 years) use of estrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers different risk than estrogen-only products.

Other Conditions

10. Estrogens/progestogens may cause fluid retention and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Premique Cycle is increased.

11. The use of estrogen may influence the laboratory results of certain endocrine tests and liver enzymes.

Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered.

Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

Some patients dependent on thyroid hormone replacement therapy may require increased doses in order to maintain their free thyroid hormone levels in an acceptable range. Therefore, patients should have their thyroid function monitored more frequently when commencing concurrent treatment in order to maintain their free thyroid hormone levels in an acceptable range.

12. There is an increase in the risk of gallbladder disease in women receiving HRT (see conditions that need supervision)

13. A worsening of glucose tolerance may occur in some patients on estrogen/progestogen therapy and therefore diabetic patients should be carefully observed while receiving hormone replacement therapy.

This product contains lactose and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

14. Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.

15. Estrogens should be used with caution in individuals with severe hypocalcaemia.

16. There is no conclusive evidence of improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The metabolism of estrogens and progestogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.

Herbal preparations containing St John's wort (Hypericum perforatum) may induce the metabolism of estrogens and progestogens.

Clinically, an increased metabolism of estrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.

The response to metyrapone may be reduced.

Aminogluthimide administered concomitantly with MPA may significantly depress the bioavailiablity of MPA.

4.6 Pregnancy And Lactation

Pregnancy:

Premique Cycle is not indicated during pregnancy. If pregnancy occurs during medication with Premique treatment should be withdrawn immediately.

Clinically, data on a limited number of exposed pregnancies indicate no adverse effects of MPA on the foetus.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of estrogens and progestogens indicate no teratogenic or foetotoxic effect.

Lactation:

Premique Cycle is not indicated during lactation.

4.7 Effects On Ability To Drive And Use Machines

Premique Cycle should not affect the ability to drive or use machines.

4.8 Undesirable Effects

See also 4.4 Special warnings and special precautions for use.

Adverse drug reactions (ADRs)

The adverse reactions listed in the table are based on post-marketing spontaneous (reporting rate), clinical trials and class-effects. Breast pain is a very common adverse event reported in

System Organ Class

Very Common ADRs

(>1/10)

Common ADRs

(>1/100, < 1/10)

Uncommon ADRs

(>1/1000, <1/100)

Rare ADRs

(>1/10000, <1/1000)

Very Rare ADRs

(<1/10000), isolated reports

Infections and infestations

 

 

Vaginitis

Vaginal candidiasis

 

 

 

 

Neoplasms benign and malignant (including cysts and polyps)

 

 

 

 

 

 

Fibrocystic breast changes

Ovarian cancer

Enlargement of hepatic hemangiomas

Immune system disorders

 

 

 

 

 

 

Anaphylactic/ anaphylactoid reactions, including urticaria and angioedema

 

 

Metabolism and nutrition disorders

 

 

 

 

 

 

Glucose intolerance

Exacerbation of porphyria; hypocalcemia

Psychiatric disorders

 

 

Depression

Changes in libido; Mood disturbances;

 

Irritability

 

 

Nervous system disorders

 

 

 

 

 

Dizziness; Headache; Migraine; Anxiety

Stroke; Exacerbation of epilepsy;

Exacerbation of chorea

Eye disorders

 

 

 

 

Intolerance to contact lenses

None

Retinal vascular thrombosis

Cardiac disorders

 

 

 

 

 

 

Myocardial infarction

 

 

Vascular disorders

 

 

 

 

Pulmonary embolism

Superficial thrombophlebitis

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

 

Exacerbation of asthma

 

 

Gastrointestinal disorders

 

 

 

 

Nausea; Bloating; Abdominal pain

Vomiting; Pancreatitis

 

 

Hepatobiliary disorders

 

 

 

 

Gallbladder disease

None

Cholestatic jaundice

Skin and subcutaneous tissue disorders

 

 

 

 

Alopecia; acne; Pruritis

Chloasma/melasma; Hirsutism; Pruritus; Rash

 

 

Musculoskeletal, connective tissue and bone disorders

 

 

Arthralgias; Leg cramps

 

 

 

 

 

 

Reproductive system & breast disorders

Breast pain

Breakthrough bleeding/spotting dysmenorrhea, breast, tenderness, enlargement, discharge

Change in menstrual flow; Change in cervical ectropion and secretion

Galactorrhoea; Increased size of uterine leiomyomata

 

 

General disorders and administration site conditions

 

 

 

 

Oedema

 

 

 

 

Investigations

 

 

Changes in weight (increase or decrease) Increased triglycerides

 

 

 

 

Increase in blood pressure

Breast cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which>80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.

For estrogen plus progestogen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.

The MWS reported that, compared to never users, the use of various types of estrogen-progestogen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestogen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

• For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

• For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be

• For users of estrogen-only replacement therapy

 

 

• between 0 and 3 (best estimate = 1.5) for 5 years’ use

 

• between 3 and 7 (best estimate = 5) for 10 years’ use.

• For users of estrogen plus progestogen combined HRT

 

 

• between 5 and 7 (best estimate = 6) for 5 years’ use

 

• between 18 and 20 (best estimate = 19) for 10 years’ use.

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestogen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that:

• For 1000 women in the placebo group.

 

 

• About 16 cases of invasive breast cancer would be diagnosed in 5 years.

• For 1000 women who used estrogen plus progestogen combined HRT (CEE + MPA), the number of additional cases would be

 

 

• Between 0 and 9 (best estimate = 4) for 5 years’ use.

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4 Special warnings and special precautions for use).

Endometrial Cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2-to 12-fold greater compared with non-users. Adding a progestogen to estrogen-only therapy greatly reduces this increased risk.

Other adverse reactions reported in association with estrogen/progestogen treatment including Premique:

• Estrogen-dependent neoplasms benign and malignant, e.g. endometrial hyperplasia, endometrial cancer

• Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contra-indications and 4.4 Special Warnings and Precautions for Use.

• Myocardial infarction

• Stroke

• Skin and subcutaneous disorders: erythema multiforme, erythema nodosum, vascular purpura

• Probable dementia (see section 4.4 Special warnings and special precautions for use)

• Exacerbation of otosclerosis

4.9 Overdose

Symptoms of overdosage of estrogen-containing products in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding may occur in females. There is no specific antidote, and further treatment should be symptomatic.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

ATC Code: GO3F A12

Conjugated Estrogens

The active ingredients are primarily the sulphate esters of estrone, equilin sulphates, 17?-estradiol and 17?-estradiol. These substitute for the loss of estrogen production in menopausal women, and alleviate menopausal symptoms. Estrogens prevent bone loss following menopause or ovariectomy.

Progestogen:

As estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen reduces but does not eliminate the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Relief of estrogen-deficiency symptoms

In a 1-year clinical trial (n=2,808), vasomotor symptoms were assessed for efficacy during the first 12 weeks of treatment in a subset of symptomatic women (n=241) who had at least 7 moderate or severe hot flushes daily or 50 moderate to severe hot flushes during the week before randomisation. Premique 0.625mg/2.5mg (conjugated estrogens/medroxyprogesterone acetate) was shown to be statistically better than placebo at weeks 4, 8 and 12 for relief of both frequency and severity of moderate to severe vasomotor symptoms.

In two clinical trials, the incidence of amenorrhoea (no bleeding or spotting) increased over time in women treated with Premique 0.625mg/2.5mg. Amenorrhoea was seen in 68% of women at cycle 6 and 77% of women at cycle 12. Breakthrough bleeding and/or spotting appeared in 48% during the first 3 months, and in 24% of women during months 10-12 of treatment.

Prevention of osteoporosis

Epidemiological studies suggest a number of individual risk factors which contribute to the development of post-menopausal osteoporosis. These include: early menopause; family history of osteoporosis; thin, small frame; cigarette use; recent prolonged systemic corticosteroid use.

Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestogen – given to predominantly healthy women – reduces the risk of hip, vertebral and other osteoporotic fractures. HRT may also help prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.

After 3 years of treatment with Premique 0.625mg/2.5mg, the increase in lumbar spine bone mineral density (BMD) was 4.87% ± 0.66. The percentage of women who maintained (less than 1% BMD loss per year) or gained BMD in lumbar zone during treatment was 92%.

Premique 0.625mg/2.5mg also had an effect on hip BMD. The increase after 3 years was 1.94% ± 0.44 at total hip. The percentage of women who maintained (less than 1% BMD loss per year) or gained BMD in hip zone during treatment was 88%.

5.2 Pharmacokinetic Properties

Absorption

Conjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. However Premique contains a formulation of medroxyprogesterone acetate (MPA) that is immediately released and conjugated estrogens that are slowly released over several hours. MPA is well absorbed from the gastrointestinal tract. Table 1 summarises the mean pharmacokinetic parameters for unconjugated and conjugated estrogens, and medroxyprogesterone acetate following administration of 2 Premique 0.625/2.5mg and 2 Premique 0.625/5mg tablets to healthy postmenopausal women.

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. MPA is approximately 90% bound to plasma proteins but does not bind to SHBG.

Metabolism

Exogenous estrogens are metabolised in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulphate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant proportion of the circulating estrogens exists as sulphate conjugates, especially estrone sulphate, which serves as a circulating reservoir for the formation of more active estrogens. Metabolism and elimination of MPA occur primarily in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.

Excretion

Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulphate conjugates. Most metabolites of MPA are extracted as glucuronide conjugates with only minor amounts secreted as sulphates.

Table 1 – Pharmacokinetic parameters for Premique

Pharmacokinetic parameters for unconjugated and conjugated estrogens (CE) and medroxyprogesterone acetate (MPA)

Drug

2 x 0.625mg CE/2.5mg MPA Combination Tablets

(n=54)

2 x 0.625mg CE/5mg MPA Combination Tablets

(n=51)

           

PK Parameter

Arithmetic Mean

(%CV)

Cmax

(pg/mL)

tmax

(h)

t1/2

(h)

AUC

(pg.h/mL)

Cmax

(pg/mL)

tmax

(h)

t1/2

(h)

AUC

(pg.h/mL)

Unconjugated Estrogens

 

 

 

 

 

 

 

 

Nalfrx Suspension
Pronunciation: DEX-klor-fen-IR-a-meen/SOO-doe-e-FED-rin/pir-IL-a-meenGeneric Name: Dexchlorpheniramine/Pseudoephedrine/PyrilamineBrand Name: Nalfrx

Little Colds Decongestant/Cough Drops
Pronunciation: DEX-troe-meth-OR-fan/FEN-il-EF-rinGeneric Name: Dextromethorphan/PhenylephrineBrand Name: Examples include Albatussin Pediatric Drops and Little Colds Decongestant/Cough

Sodium Fluoride Chewable Tablets
Fluoride Chewable Tablets 1 mg

Active Ingredient: 1 mg of fluoride ion from 2.2 mg of sodium fluoride (NaF).

Inactive Ingredients: Lactose, Saccharine, Cherry Flavor, D&C Red #7 Calcium Lake, Magnesium Stearate.

DOSAGE AND ADMINISTRATION:

Dissolve in the mouth or chew before swallowing, preferably at bedtime after brushing teeth.

STORAGE:

Store at a Controlled Room Temperature 20?-25?C (68?-77?F)

743634

Manufactured for: Libertas Pharma, Inc.

InfectoDell

InfectoDell may be available in the countries listed below.

Ingredient matches for InfectoDell Potassium Hydroxide

Potassium Hydroxide is reported as an ingredient of InfectoDell in the following countries:

Germany

International Drug Name Search

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