Leprosy, Borderline Medications
Drugs associated with Leprosy, Borderline

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

Drug List:Rifadin-IvZagamZagam-Respipac

Serc

Serc-8

Serc-16

Betahistine dihydrochloride

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

In this leaflet:

1. What Serc is and what it is used for 2. Before you take Serc 3. How to take Serc 4. Possible side effects 5. How to store Serc 6. Further information What Serc is and what it is used for

Serc contains betahistine. This medicine is called a histamine analogue. It is used to treat:

dizziness (vertigo) ringing in the ears (tinnitus) hearing loss suffered by people with M?ni?re's disease

This medicine works by improving blood flow in the inner ear. This lowers the build up of pressure.

Before you take Serc Do not take Serc if: You are allergic to any of the ingredients in the tablets (see section 6 for further details). You have high blood pressure due to an adrenal tumour (phaeochromocytoma).

If any of the above applies to you, do not take this medicine and talk to your doctor.

Take special care and tell your doctor if: you have a stomach ulcer you have asthma you are pregnant or planning to become pregnant you are breast-feeding

If any of the above applies to you, talk to your doctor before taking this medicine. Your doctor will tell you whether it is safe for you to start taking this medicine. Your doctor may also want to monitor your asthma while you take Serc.

Taking other medicines

No interaction between Serc and other medicines are known. If you notice any unwanted effects tell your doctor or pharmacist.

Please tell your doctor or pharmacist if you are taking or have taken any other medicines, including medicines obtained without a prescription. This includes herbal medicines.

Taking Serc with food and drink

You can drink alcohol while taking Serc.

You can take Serc with or without food.

Pregnancy and breast-feeding

Do not take Serc if you are pregnant unless your doctor has decided that it is absolutely necessary. Ask your doctor for advice.

Do not breast-feed while using Serc unless instructed by your doctor. It is not known if Serc passes into breast milk.

Driving and using machines

You can drive and use machines while you are taking this treatment, so long as this medicine does not make you sleepy. Make sure you know how this medicine affects you before you drive or use machines.

How to take Serc How to take Serc Swallow the tablets with water. Take the tablet with or after a meal. How much Serc to take

Always follow your doctor’s instructions because your doctor might adjust your dose.

Serc is available in two strengths, an 8 mg tablet and a 16 mg tablet. The usual starting dose is 16 mg three times a day (48 mg). Your doctor may lower your dose to 8 mg three times a day (24 mg).

Keep taking your tablets. The tablets can take a while to start to work.

Serc is not recommended for use in children.

How to stop taking Serc

Keep taking your tablets until your doctor tells you to stop.

Even when you start feeling better, your doctor may want you to carry on taking the tablets for some time to make sure that the medicine has worked completely.

If you take more Serc than you should

If you or someone else takes too much Serc (an overdose), talk to a doctor or go to a hospital straight away. Take the medicine pack with you.

If you forget to take Serc

If you miss a tablet, wait until the next dose is due. Do not try to make up for the dose you have missed.

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

Serc Side Effects

Like all medicines Serc can cause side effects (unwanted effects or reactions), but not everyone gets them.

The following serious side effects may occur during treatment with Serc: Allergic reactions such as: swelling of your face, lips, tongue or neck. This may cause difficulty breathing. a red skin rash, inflamed itchy skin

If any of these side effects occur you should stop treatment immediately and contact your doctor.

Common side effects (at least 1 in 100 and less than 1 in 10 patients):

Nausea, indigestion.

Other side effects

Headache, itching, rash, hives, mild gastric complaints such as vomiting, stomach pain and bloating. Taking Serc with food can help reduce any stomach problems.

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

How to store Serc Keep out of the reach and sight of children. This medicine should preferably be locked in a cupboard or medicine cabinet. Do not use the tablets after the expiry date which is printed on the carton and blister pack. Do not store your tablets above 25°C and keep them in the original package. If your doctor stops your treatment, return any unused tablets to a 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 Serc contains

Each tablet contains 8 or 16 mg of betahistine dihydrochloride.

The tablets also contain microcrystalline cellulose, mannitol, citric acid monohydrate, colloidal anhydrous silica and talc.

What Serc looks like and contents of the pack

Serc-8 are round, flat and white to almost white with ‘256’ imprinted on the one face and "S" with an upside down triangle underneath on the reverse.

Serc-16 are round, biconvex, scored and white to almost white with ‘267’ imprinted on the one face and "S" with an upside down triangle underneath on the reverse.

Serc-8 is available in packs of 120 tablets and containers with 500 or 1000 tablets.

Serc-16 is available in packs of 84 tablets and containers with 500 or 1000 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisation Holder is:

Solvay Healthcare Ltd. Southampton SO18 3JD UK

The Manufacturer is:

Solvay Pharmaceuticals 01400 Ch?tillon-sur-Chalaronne France

This leaflet was last approved in July 2009.

Registered trademark

1068890 CL929

Mental Retardation Medications

There are currently no drugs listed for "Mental Retardation".

Definition of Mental Retardation: Mental retardation is described as below-average general intellectual function with associated deficits in adaptive behavior that occurs before age 18.

Learn more about Mental Retardation

Medical Encyclopedia:

Fragile X syndromeKrabbe diseaseMental retardationPolydactylyPrader-Willi syndromeTrisomy 13Trisomy 18Tuberous sclerosis Drug List:

Angiocardiography Medications
Topics under AngiocardiographyPediatric Angiocardiography (5 drugs) Drug List:

Zincfrin

Generic Name: phenylephrine and zinc ophthalmic (fen ill EFF rin and zink off THAL mick) Brand Names: Zincfrin

What is Zincfrin (phenylephrine and zinc ophthalmic)?

Phenylephrine ophthalmic causes decongestion in the eye by constricting blood vessels in the eye.

Zinc is used as an astringent to gently clear proteins and mucous from the outer surface of the eye.

Phenylephrine and zinc ophthalmic is used to relieve redness, burning, irritation, and dryness of the eye caused by wind, sun, smoke, smog, and other minor irritants.

Phenylephrine and zinc ophthalmic may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about Zincfrin (phenylephrine and zinc ophthalmic)? Do not touch the dropper to any surface, including the eyes or hands. The dropper is sterile. If it becomes contaminated, it could cause an infection in the eye.

Apply light pressure to the inside corner of the eye (near the nose) after each drop to prevent the fluid from draining down the tear duct.

Do not use phenylephrine and zinc ophthalmic more often or continuously for longer than 48 to 72 hours without consulting a doctor. Chronic use of this medication may damage the blood vessels (veins and arteries) in the eyes. Consult a doctor if your symptoms do not improve or appear to worsen.

Do not use phenylephrine and zinc ophthalmic if you have glaucoma, except under the direction of your doctor.

Use caution when driving, operating machinery, or performing other hazardous activities. Phenylephrine and zinc ophthalmic may cause blurred vision. If you experience blurred vision, avoid these activities. What should I discuss with my healthcare provider before using Zincfrin (phenylephrine and zinc ophthalmic)? Do not use phenylephrine and zinc ophthalmic if you have glaucoma, except under the supervision of your doctor.

Do not use phenylephrine and zinc ophthalmic after eye surgery, if you have an eye infection, if you have an eye injury, or if you have a problem with the normal tearing of your eyes without first talking to your doctor. Using phenylephrine and zinc ophthalmic under these circumstances could lead to absorption of the drug into your body, and the side effects could affect the heart.

Before using this medication, tell your doctor if you

have any type of heart condition, including high blood pressure;

take any medicines to treat a heart condition;

have asthma;

have diabetes; or

have thyroid problems.

You may not be able to use phenylephrine and zinc ophthalmic, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.

If you wear contact lenses, remove them before applying phenylephrine and zinc ophthalmic. Ask your doctor if contact lenses can be reinserted after application of the medication. Phenylephrine and zinc ophthalmic may contain a preservative (benzalkonium chloride), which may cause discoloration of contact lenses.

Phenylephrine and zinc ophthalmic is in the FDA pregnancy category C. This means that it is not known whether phenylephrine and zinc ophthalmic will be harmful to an unborn baby. Do not use this medication without first talking to your doctor if you are pregnant or could become pregnant during treatment. It is not known whether phenylephrine and zinc pass into breast milk. Do not use phenylephrine and zinc ophthalmic without first talking to your doctor if you are breast-feeding a baby. How should I use Zincfrin (phenylephrine and zinc ophthalmic)?

Use phenylephrine and zinc ophthalmic eyedrops exactly as directed by your doctor, or follow the directions that accompany the package. If you do not understand these instructions, ask your doctor, pharmacist, or nurse to explain them to you.

Wash your hands before and after using the eyedrops.

If you wear contact lenses, remove them before applying phenylephrine and zinc ophthalmic. Ask your doctor if contact lenses can be reinserted after application of the medication. Phenylephrine and zinc ophthalmic may contain a preservative (benzalkonium chloride), which may cause discoloration of contact lenses.

To apply the eyedrops:

Tilt the head back slightly and pull down on the lower eyelid. Position the dropper above the eye. Look up and away from the dropper. Squeeze out a drop and close the eye. Apply gentle pressure to the inside corner of the eye (near the nose) for about 1 minute to prevent the liquid from draining down the tear duct. Repeat the process in the other eye if needed.

Do not use phenylephrine and zinc ophthalmic more often or continuously for longer than 48 to 72 hours without consulting a doctor. Chronic use of this medication may damage the blood vessels (veins and arteries) in the eyes. Consult a doctor if your symptoms do not improve or appear to worsen. Do not touch the dropper to any surface, including the eyes or hands. The dropper is sterile. If it becomes contaminated, it could cause an infection in the eye. Do not use any eyedrop that is discolored or has particles in it. Store phenylephrine and zinc ophthalmic at room temperature away from moisture and heat. Keep the bottle properly capped. What happens if I miss a dose?

Apply the missed dose as soon as you remember. However, if it is almost time for the next regularly scheduled dose, skip the missed dose and apply the next one as directed. Do not use a double dose of this medication.

What happens if I overdose?

An overdose of this medication is unlikely to be harmful. If you do suspect an overdose, or if the drops have been ingested (taken by mouth), contact an emergency room or poison control center for advice.

What should I avoid while using Zincfrin (phenylephrine and zinc ophthalmic)? Do not touch the dropper to any surface, including the eyes or hands. The dropper is sterile. If it becomes contaminated, it could cause an infection in the eye. Use caution when driving, operating machinery, or performing other hazardous activities. Phenylephrine and zinc ophthalmic may cause blurred vision. If you experience blurred vision, avoid these activities.

If you wear contact lenses, remove them before applying phenylephrine and zinc ophthalmic. Ask your doctor if contact lenses can be reinserted after application of the medication. Phenylephrine and zinc ophthalmic may contain a preservative (benzalkonium chloride), which may cause discoloration of contact lenses.

Do not use phenylephrine and zinc ophthalmic more often or continuously for longer than 48 to 72 hours without consulting a doctor. Chronic use of this medication may damage the blood vessels (veins and arteries) in the eyes. Consult a doctor if your symptoms do not improve or appear to worsen. Zincfrin (phenylephrine and zinc ophthalmic) side effects

If you experience any of the following serious side effects, stop using phenylephrine and zinc ophthalmic and seek emergency medical attention or contact your doctor immediately:

an allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives);

an irregular or fast heart rate; or

high blood pressure (severe headache, blurred vision, or flushed skin).

Other, less serious side effects may be more likely to occur. Continue to use phenylephrine and zinc ophthalmic and talk to your doctor if you experience

burning, stinging, pain, or increased redness of the eye;

tearing or blurred vision;

headache;

tremor;

nausea;

sweating;

nervousness; or

dizziness; or

drowsiness.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

What other drugs will affect Zincfrin (phenylephrine and zinc ophthalmic)?

Do not use other eye medications during treatment with phenylephrine and zinc ophthalmic except under the direction of your doctor.

Although drug interactions between phenylephrine and zinc ophthalmic and drugs taken by mouth are not expected, they can occur. Before using this medication, tell your doctor if you are taking any of the following medicines:

a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil); or

a beta-blocker such as propranolol (Inderal), metoprolol (Lopressor, Toprol XL), or labetalol (Normodyne, Trandate).

You may not be able to use phenylephrine and zinc ophthalmic, or you may require a dosage adjustment or special monitoring during treatment if you are taking any of the medicines listed above.

Drugs other than those listed here may also interact with phenylephrine and zinc ophthalmic. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines, including vitamins, minerals, and herbal products.

More Zincfrin resources Zincfrin Drug InteractionsZincfrin Support Group0 Reviews for Zincfrin - Add your own review/rating Compare Zincfrin with other medications Conjunctivitis, AllergicEye Dryness/RednessEye Redness/Itching Where can I get more information? Your pharmacist has additional information about phenylephrine and zinc ophthalmic written for health professionals that you may read. What does my medication look like?

Phenylephrine and zinc ophthalmic is available over-the-counter under the brand name Zincfrin in a 0.12% phenylephrine strength. Other brand or generic formulations of phenylephrine and zinc ophthalmic may also be available. Ask your pharmacist any questions you have about this medication, especially if it is new to you.

Prenatal Multivitamin with Minerals, Iron, and Folic Acid Chewable Caplet
Pronunciation: pree-NATE-al muhl-tee-VYE-ta-mins/MIN-er-als/EYE-urn/FOE-lik AS-idGeneric Name: Prenatal Multivitamin with Minerals, Iron, and Folic AcidBrand Name: Select-OB + DHA

Chlorpram Z Drops
Pronunciation: KLOR-oh-ZYE-le-nol/pra-MOX-een/zinkGeneric Name: Chloroxylenol/Pramoxine/ZincBrand Name: Examples include Chlorpram Z and Zinotic

Secondary Hyperparathyroidism Medications

Definition of Secondary Hyperparathyroidism: The parathyroids are four glands in the neck that produce parathyroid hormone to help control calcium metabolism. Excessive production of this hormone caused by increased activity of these glands is known as hyperparathyroidism. When this occurs in response to low blood calcium caused by another condition, the condition is called secondary hyperparathyroidism.

Drugs associated with Secondary Hyperparathyroidism

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

Learn more about Secondary Hyperparathyroidism

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Secondary hyperparathyroidism Drug List:HectorolSensiparZemplar

Interferon Alfacon-1
Pronunciation: IN-ter-FEER-on AL-fa-kon-1Generic Name: Interferon Alfacon-1Brand Name: Infergen

Pancreatin
Pronunciation: PAN-kree-a-tinGeneric Name: PancreatinBrand Name: Pan-2400

Lotemax Ointment
Pronunciation: LOE-te-PRED-nolGeneric Name: LoteprednolBrand Name: Lotemax

Hydroxyzine Suspension
Pronunciation: hye-DROX-i-zeenGeneric Name: HydroxyzineBrand Name: Vistaril

Lamisil Topical

Generic Name: terbinafine topical (ter BIN a feen TOP i kal) Brand Names: Athlete's Foot Cream, LamISIL AT, LamISIL AT Athletes Foot, LamISIL AT Jock Itch, LamISIL Topical

What is Lamisil Topical (terbinafine topical)?

Terbinafine is an antifungal medication. Terbinafine topical prevents fungus from growing on the skin.

Terbinafine topical (for the skin) is used to treat skin infections such as athlete's foot, jock itch, and ringworm infections.

Terbinafine topical may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Lamisil Topical (terbinafine topical)?

Use this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared.

Do not cover treated skin areas with a bandage or other covering unless your doctor has told you to.

Avoid getting this medication in your mouth or eyes. What should I discuss with my healthcare provider before using Lamisil Topical (terbinafine topical)? You should not use this medication if you are allergic to it. It is not known whether terbinafine topical will be harmful to an unborn baby. Do not use terbinafine topical without first talking to your doctor if you are pregnant. It is not known whether terbinafine topical passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. How should I use Lamisil Topical (terbinafine topical)?

Use this medication exactly as prescribed by your doctor. Do not use it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

Wash your hands before and after using this medication.

Clean and dry the affected area. Apply the medication as directed.

Use this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared.

For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after a few weeks of treatment.

Do not cover treated skin areas with a bandage or other covering unless your doctor has told you to.

Store terbinafine topical at room temperature away from moisture and heat. What happens if I miss a dose?

Apply the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to use the medicine and skip the missed dose. Do not apply extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention if you think you have used too much of this medicine.

An overdose of terbinafine topical is not likely to cause life-threatening symptoms.

What should I avoid while using Lamisil Topical (terbinafine topical)? Avoid getting this medication in your mouth or eyes. If it does get into any of these areas, rinse with water.

Avoid using other medications on the areas you treat with terbinafine topical unless your doctor has told you to.

Avoid wearing tight-fitting, synthetic clothing that doesn't allow air circulation. Wear loose-fitting clothing made of cotton and other natural fibers until your infection is healed.

Lamisil Topical (terbinafine topical) side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Stop using terbinafine topical and call your doctor at once if you have a serious side effect such as severe blistering, itching, redness, peeling, dryness, or irritation of the skin.

Less serious side effects are more likely, and you may have none at all.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Lamisil Topical (terbinafine topical)?

It is not likely that other drugs you take orally or inject will have an effect on topically applied terbinafine topical. But many drugs can interact with each other. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Lamisil Topical resources Lamisil Topical Side Effects (in more detail)Lamisil Topical Use in Pregnancy & BreastfeedingLamisil Topical Support Group0 Reviews for Lamisil Topical - Add your own review/rating Lamisil AT Prescribing Information (FDA) Lamisil AT Topical Advanced Consumer (Micromedex) - Includes Dosage Information Lamisil AT Cream MedFacts Consumer Leaflet (Wolters Kluwer) Lamisil AT Jock Itch Prescribing Information (FDA) Compare Lamisil Topical with other medications Tinea Versicolor Where can I get more information? Your pharmacist has additional information about terbinafine topical written for health professionals that you may read.

See also: Lamisil Topical side effects (in more detail)

Pedi-Dri

Generic Name: nystatin topical (nye STAT in) Brand Names: Mycostatin Topical, Nyamyc, Nystop, Pedi-Dri, Pediaderm AF

What is Pedi-Dri (nystatin topical)?

Nystatin is an antifungal medication. Nystatin prevents fungus from growing on your skin.

Nystatin topical (for the skin) is used to treat skin infections caused by yeast.

Nystatin topical is not for use to treat a vaginal yeast infection.

Nystatin topical may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Pedi-Dri (nystatin topical)? Do not use nystatin topical to treat any skin condition that has not been checked by your doctor. Nystatin topical (for the skin) is not for use to treat a vaginal yeast infection. Avoid getting this medication in your eyes or mouth. If this does happen, rinse with water.

Use this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared.

Call your doctor if your symptoms do not improve, or if they get worse while using nystatin topical. Do not share this medication with another person, even if they have the same symptoms you have. What should I discuss with my healthcare provider before using Pedi-Dri (nystatin topical)?

You should not use nystatin topical if you have ever had an allergic reaction to it.

FDA pregnancy category C. It is not known whether nystatin topical will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether nystatin topical passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. How should I use Pedi-Dri (nystatin topical)?

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Do not use nystatin topical to treat any skin condition that has not been checked by your doctor. Wash your hands before and after using this medication.

Clean and dry the skin before you apply nystatin topical.

Do not cover treated skin with bandages or dressings that do not allow air circulation unless your doctor tells you to.

Use this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared.

Call your doctor if your symptoms do not improve, or if they get worse while using nystatin topical. Do not share this medication with another person, even if they have the same symptoms you have. Store at room temperature away from moisture and heat. What happens if I miss a dose?

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. What should I avoid while using Pedi-Dri (nystatin topical)? Avoid getting this medication in your eyes or mouth. If this does happen, rinse with water.

Avoid wearing tight-fitting, synthetic clothing (such as nylon) that doesn't allow air circulation. Wear clothing made of loose cotton and other natural fibers until your infection is healed.

Pedi-Dri (nystatin topical) side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using nystatin topical and call your doctor at once if you have severe burning, itching, rash, pain, or other irritation where the medicine is applied.

Less serious side effects may include mild itching or irritation.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Pedi-Dri (nystatin topical)?

It is not likely that other drugs you take orally or inject will have an effect on topically applied nystatin topical. But many drugs can interact with each other. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Pedi-Dri resources Pedi-Dri Side Effects (in more detail)Pedi-Dri Use in Pregnancy & BreastfeedingPedi-Dri Support Group1 Review for Pedi-Dri - Add your own review/rating Compare Pedi-Dri with other medications Cutaneous CandidiasisVaginal Yeast Infection Where can I get more information? Your pharmacist can provide more information about nystatin topical.

See also: Pedi-Dri side effects (in more detail)

Methotrexate Tablets BP 10mg
1. Name Of The Medicinal Product Methotrexate Tablets B.P. 10 mg. 2. Qualitative And Quantitative Composition

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.

4.3 Contraindications 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

Maize Starch

Ph EUR 27.6mg

Lactose

Ph EUR 38.5mg

Pre gelatinized Starch (Prejel PA5)

Ph EUR 2.5mg

Polysorbate 80

Ph EUR 0.2mg

Microcrystalline Cellulose (AVICEL 101)

Ph EUR 18.2mg

Magnesium Stearate

Ph EUR 3.0mg

There is no overage included in the 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) 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

Edarbyclor
Dosage Form: tabletFULL PRESCRIBING INFORMATION WARNING: FETAL TOXICITY When pregnancy is detected, discontinue Edarbyclor as soon as possible [see Warnings and Precautions (5.1)]. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1)]. Indications and Usage for Edarbyclor

Edarbyclor contains an angiotensin II receptor blocker (ARB) and a thiazide-like diuretic and is indicated for the treatment of hypertension, to lower blood pressure.

Edarbyclor may be used in patients whose blood pressure is not adequately controlled on monotherapy.

Edarbyclor may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including thiazide-like diuretics such as chlorthalidone and ARBs such as azilsartan medoxomil. There are no controlled trials demonstrating risk reduction with Edarbyclor.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management of high blood pressure, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients; however, the blood pressure effect of Edarbyclor in blacks is similar to that in non-blacks. Many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

The choice of Edarbyclor as initial therapy for hypertension should be based on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of Edarbyclor.

Patients with moderate-to-severe hypertension are at a relatively high risk of cardiovascular events (e.g., stroke, heart attack, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. Consider the patient's baseline blood pressure, target goal and the incremental likelihood of achieving the goal with a combination product, such as Edarbyclor, versus a monotherapy product when deciding upon initial therapy. Individual blood pressure goals may vary based on the patient's risk.

Data from an 8-week, active-controlled, factorial trial provide estimates of the probability of reaching a target blood pressure with Edarbyclor compared with azilsartan medoxomil or chlorthalidone monotherapy [see Clinical Studies (14)].

Figures 1.a-1.d provide estimates of the likelihood of achieving target clinic systolic and diastolic blood pressure control with Edarbyclor 40/25 mg tablets after 8 weeks, based on baseline systolic or diastolic blood pressure. The curve for each treatment group was estimated by logistic regression modeling and is more variable at the tails.

Figure 1.a Probability of Achieving Systolic Blood Pressure <140 mmHg at Week 8 Figure 1.b Probability of Achieving Systolic Blood Pressure <130 mmHg at Week 8 Figure 1.c Probability of Achieving Diastolic Blood Pressure <90 mmHg at Week 8 Figure 1.d Probability of Achieving Diastolic Blood Pressure <80 mmHg at Week 8

For example, a patient with a baseline blood pressure of 170/105 mm Hg has approximately a 48% likelihood of achieving a goal of <140 mm Hg (systolic) and 48% likelihood of achieving <90 mm Hg (diastolic) on azilsartan medoxomil 80 mg. The likelihood of achieving these same goals on chlorthalidone 25 mg is approximately 51% (systolic) and 40% (diastolic). These likelihoods rise to 85% (systolic) and 85% (diastolic) with Edarbyclor 40/25 mg.

Edarbyclor Dosage and Administration Dosing Information

The recommended starting dose of Edarbyclor is 40/12.5 mg taken orally once daily. Most of the antihypertensive effect is apparent within 1 to 2 weeks. The dosage may be increased to 40/25 mg after 2 to 4 weeks as needed to achieve blood pressure goals. Edarbyclor doses above 40/25 mg are probably not useful.

Edarbyclor may be used to provide additional blood pressure lowering for patients not adequately controlled on ARB or diuretic monotherapy treatment. Patients not controlled with azilsartan medoxomil 80 mg may have an additional systolic/diastolic clinic blood pressure reduction of 13/6 mm Hg when switched to Edarbyclor 40/12.5 mg. Patients not controlled with chlorthalidone 25 mg may have an additional clinic blood pressure reduction of 10/7 mm Hg when switched to Edarbyclor 40/12.5 mg.

Edarbyclor may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals.

Patients titrated to the individual components (azilsartan medoxomil and chlorthalidone) may instead receive the corresponding dose of Edarbyclor.

Edarbyclor may be taken with or without food [see Clinical Pharmacology (12.3)].

Edarbyclor may be administered with other antihypertensive agents as needed.

Prior to Dosing

Correct any volume depletion prior to administration of Edarbyclor, particularly in patients with impaired renal function or those treated with high doses of diuretics [see Warnings and Precautions (5.2)].

Patients who experience dose-limiting adverse reactions on chlorthalidone may be switched to Edarbyclor, initially with a lower dose of chlorthalidone [see Warnings and Precautions (5.4)].

Handling Instructions

As Edarbyclor is moisture sensitive, dispense and store Edarbyclor in its original container to protect Edarbyclor from light and moisture.

Dosage Forms and Strengths

Edarbyclor is supplied in the following dosage strengths:

40/12.5 mg: pale red, round, biconvex, film-coated tablets, approximately 9.7 mm in diameter, with "A/C" and "40/12.5" imprinted on one side. Each tablet contains 40 mg of azilsartan medoxomil and 12.5 mg of chlorthalidone. 40/25 mg: light red, round, biconvex, film-coated tablets, approximately 9.7 mm in diameter, with "A/C" and "40/25" imprinted on one side. Each tablet contains 40 mg of azilsartan medoxomil and 25 mg of chlorthalidone. Contraindications

Edarbyclor is contraindicated in patients with anuria [see Warnings and Precautions (5.3)].

Warnings and Precautions Fetal Toxicity

Azilsartan medoxomil

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Edarbyclor as soon as possible [see Use in Specific Populations (8.1)].

Chlorthalidone

Thiazides cross the placental barrier and appear in cord blood. Adverse reactions include fetal or neonatal jaundice and thrombocytopenia.

Hypotension in Volume- or Salt-Depleted Patients

In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Edarbyclor. Such patients are probably not good candidates to start therapy with more than one drug; therefore, correct volume prior to administration of Edarbyclor. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Impaired Renal Function

Edarbyclor

Monitor for worsening renal function in patients with renal impairment. Consider withholding or discontinuing Edarbyclor if progressive renal impairment becomes evident.

Azilsartan medoxomil

As a consequence of inhibiting the renin-angiotensin system, changes in renal function may be anticipated in susceptible individuals treated with Edarbyclor. In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g., patients with severe congestive heart failure, renal artery stenosis, or volume depletion), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. Similar results may be anticipated in patients treated with Edarbyclor [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. There has been no long-term use of azilsartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results are expected.

Chlorthalidone

In patients with renal disease, chlorthalidone may precipitate azotemia. If progressive renal impairment becomes evident, as indicated by increased blood urea nitrogen, consider withholding or discontinuing diuretic therapy.

Hypokalemia

Chlorthalidone

Hypokalemia is a dose-dependent adverse reaction that may develop with chlorthalidone. Co-administration of digitalis may exacerbate the adverse effects of hypokalemia.

Edarbyclor attenuates chlorthalidone-associated hypokalemia. In patients with normal potassium levels at baseline, 1.7% of Edarbyclor-treated patients, 0.9% of azilsartan medoxomil-treated patients, and 13.4% of chlorthalidone-treated patients shifted to low potassium values (less than 3.4 mmol/L).

Hyperuricemia

Chlorthalidone

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving chlorthalidone or other thiazide diuretics.

Adverse Reactions

The following potential adverse reactions with Edarbyclor, azilsartan medoxomil, or chlorthalidone and similar agents are included in more detail in the Warnings and Precautions section of the label:

Fetal toxicity [see Warnings and Precautions (5.1)] Hypotension in Volume- or Salt-Depleted Patients [see Warnings and Precautions (5.2)] Impaired Renal Function [see Warnings and Precautions (5.3)] Hypokalemia [see Warnings and Precautions (5.4)] Hyperuricemia [see Warnings and Precautions (5.5)] Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Edarbyclor has been evaluated for safety in more than 3900 patients with hypertension; more than 700 patients were treated for at least 6 months and more than 280 for at least 1 year. Adverse reactions have generally been mild and transient in nature.

Common adverse reactions that occurred in the 8-week factorial design trial in at least 2% of Edarbyclor-treated patients and greater than azilsartan medoxomil or chlorthalidone are presented in Table 1.

Table 1. Adverse Reactions Occurring at an Incidence of ?2% of Edarbyclor-treated Patients and > Azilsartan medoxomil or Chlorthalidone Preferred Term Azilsartan medoxomil

Bondronat 2mg and 6mg Concentrate for solution for infusion
1. Name Of The Medicinal Product

Bondronat 2 mg

Bondronat 6 mg

Concentrate for solution for infusion

2. Qualitative And Quantitative Composition

Bondronat 2 mg

One vial with 2 ml concentrate for solution for infusion contains 2 mg ibandronic acid (as 2.25 mg ibandronic acid, monosodium salt, monohydrate).

Bondronat 6 mg

One vial with 6 ml concentrate for solution for infusion contains 6 mg ibandronic acid (as 6.75 mg ibandronic acid, monosodium salt, monohydrate).

Excipients: Sodium (less than 1 mmol per dose).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Concentrate for solution for infusion.

Clear, colourless solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Bondronat is indicated in adults for

- Prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases.

- Treatment of tumour-induced hypercalcaemia with or without metastases.

4.2 Posology And Method Of Administration

Bondronat therapy should only be initiated by physicians experienced in the treatment of cancer.

Posology

Prevention of skeletal events in patients with breast cancer and bone metastases

The recommended dose for prevention of skeletal events in patients with breast cancer and bone metastases is 6 mg intravenous injection given every 3-4 weeks. The dose should be infused over at least 15 minutes. For infusion, the contents of the vials(s) should only be added to 100 ml isotonic sodium chloride solution or 100 ml 5% glucose solution.

A shorter (i.e. 15 min) infusion time should only be used for patients with normal renal function or mild renal impairment. There are no data available characterizing the use of a shorter infusion time in patients with creatinine clearance below 50 ml/min. Prescribers should consult the section Patients with Renal Impairment (see section 4.2) for recommendations on dosing and administration in this patient group.

Treatment of tumour-induced hypercalcaemia

Prior to treatment with Bondronat the patient should be adequately rehydrated with 9 mg/ml (0.9%) sodium chloride. Consideration should be given to the severity of the hypercalcaemia as well as the tumour type. In general patients with osteolytic bone metastases require lower doses than patients with the humoral type of hypercalcaemia. In most patients with severe hypercalcaemia (albumin-corrected serum calcium*

* Note albumin-corrected serum calcium concentrations are calculated as follows:

Albumin-corrected

Serum calcium (mmol/l)

=

serum calcium (mmol/l) - [0.02 x albumin (g/l)] + 0.8

Or

   

Albumin-corrected

Serum calcium (mg/dl)

=

serum calcium (mg/dl) + 0.8 x [4 - albumin (g/dl)]

To convert the albumin-corrected serum calcium in mmol/l value to mg/dl, multiply by 4.

   

In most cases a raised serum calcium level can be reduced to the normal range within 7 days. The median time to relapse (return of albumin-corrected serum calcium to levels above 3 mmol/l) was 18 - 19 days for the 2 mg and 4 mg doses. The median time to relapse was 26 days with a dose of 6 mg.

A limited number of patients (50 patients) have received a second infusion for hypercalcaemia. Repeated treatment may be considered in case of recurrent hypercalcaemia or insufficient efficacy.

Patients with hepatic impairment

No dosage adjustment is required (see section 5.2).

Patients with renal impairment

For patients with mild renal impairment (CLcr

Creatinine Clearance (ml/min)

Dosage / Infusion time 1

Infusion Volume 2

6 mg / 15 minutes

100 ml

4 mg / 1 hour

500 ml

<30

2 mg / 1 hour

500 ml

1 Administration every 3 to 4 week

2 0.9% sodium chloride solution or 5% glucose solution

A 15 minute infusion time has not been studied in cancer patients with CLCr <50 mL/min.

Elderly

No dose adjustment is required.

Paediatric population

The safety and efficacy of Bondronat in children and adolescents below age 18 years have not been established. No data are available.

Method of administration

For intravenous administration.

For single use only. Only clear solution without particles should be used.

Bondronat concentrate for solution for infusion should be administered as an intravenous infusion. For this purpose, the contents of the vials are to be added to 500 ml isotonic sodium chloride solution (or 500 ml 5% dextrose solution) and infused over two hours.

As the inadvertent intra-arterial administration of preparations not expressly recommended for this purpose as well as paravenous administration can lead to tissue damage, care must be taken to ensure that Bondronat concentrate for solution for infusion is administered intravenously.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients.

- Caution is to be taken in patients with known hypersensitivity to other bisphosphonates.

- Hypocalcaemia

4.4 Special Warnings And Precautions For Use

Patients with disturbances of bone and mineral metabolism

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Bondronat therapy for metastatic bone disease.

Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate

Osteonecrosis of the jaw (ONJ)

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

Patients with renal impairment

Clinical studies have not shown any evidence of deterioration in renal function with long term Bondronat therapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with Bondronat.

Patients with hepatic impairment

As no clinical data are available, dosage recommendations cannot be given for patients with severe hepatic insufficiency.

Patients with cardiac impairment

Overhydration should be avoided in patients at risk of cardiac failure.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

No interaction was observed when co-administered with melphalan/prednisolone in patients with multiple myeloma.

Other interaction studies in postmenopausal women have demonstrated the absence of any interaction potential with tamoxifen or hormone replacement therapy (oestrogen).

In relation to disposition, no drug interactions of clinical significance are likely. Ibandronic acid is eliminated by renal secretion only and does not undergo any biotransformation. The secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other active substances. In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats. Plasma protein binding is low at therapeutic concentrations and ibandronic acid is therefore unlikely to displace other active substances.

Caution is advised when bisphosphonates are administered with aminoglycosides, since both substances can lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existence of simultaneous hypomagnesaemia.

In clinical studies, Bondronat has been administered concomitantly with commonly used antineoplastics, diuretics, antibiotics and analgesics without clinically apparent interactions occurring.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, Bondronat should not be used during pregnancy.

Breast-feeding

It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration. Bondronat should not be used during lactation.

Fertility

There are no data on the effects of ibandronic acid from humans. In reproductive studies in rats by the oral route, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronic acid decreased fertility at high daily doses (see section 5.3).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (

Treatment of tumour induced hypercalcaemia

The safety profile for Bondronat in tumour-induced hypercalcaemia is derived from controlled clinical trials in this indication and after the intravenous administration of Bondronat at the recommended doses. Treatment was most commonly associated with a rise in body temperature. Occasionally, a flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain was reported. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

Table 1 Adverse Events in Controlled Clinical Trials in Tumour-Induced Hypercalcaemia after Treatment with Bondronat

System Organ Class

Very common

Common

Uncommon

Rare

Very rare

Immune system disorders

       

Hypersensitivity

Metabolism and nutritional disorders

 

Hypocalcaemia**

     

Respiratory, thoracic, and mediastinal disorders

       

Bronchospasm

Skin and subcutaneous tissue disorders

       

Angioneurotic oedema

Musculoskeletal and connective tissue disorders

 

Bone pain

Myalgia

   

General disorders and administration site conditions

Pyrexia

 

Influenza-like illness**, rigors

   

Note: Data for both the 2 mg and 4 mg doses of ibandronic acid are pooled.

**See further information below

Hypocalcaemia

Decreased renal calcium excretion may be accompanied by a fall in serum phosphate levels not requiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.

Influenza-like illness

A flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain has occurred. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

Prevention of skeletal events in patients with breast cancer and bone metastases

The safety profile of intravenous Bondronat in patients with breast cancer and bone metastases is derived from a controlled clinical trial in this indication and after the intravenous administration of Bondronat at the recommended dose.

Table 2 lists adverse drug reactions from the pivotal phase III study (152 patients treated with Bondronat 6 mg), i.e. adverse events with a remote, possible, or probable relationship to study medication, and from postmarketing experience.

Table 2 Adverse Drug Reactions Occurring in Patients with Metastatic Bone Disease due to Breast Cancer Treated with Bondronat 6 mg administered intravenously

System Organ Class

Very common

Common

Uncommon

Rare

Very rare

Infections and infestations

 

Infection

Cystitis, vaginitis, oral candidiasis

   

Neoplasms benign, malignant, and unspecified

   

Benign skin neoplasm

   

Blood and lymphatic system disorders

   

Anaemia, blood dyscrasia

   

Endocrine disorders

 

Parathyroid disorder

     

Metabolism and nutrition disorders

   

Hypophosphataemia

   

Psychiatric disorders

   

Sleep disorder, anxiety, affection lability

   

Nervous system disorders

 

Headache, dizziness, dysgeusia (taste perversion)

Cerbrovascular disorder, nerve root lesion , amnesia, migraine, neuralgia, hypertonia, hyperaestesia, paraesthesia circumoral, parosmia

   

Eye disorders

 

Cataract

 

Ocular inflammation†**

 

Ear and labyrinth disorders

   

Deafness

   

Cardiac disorders

 

Bundle branch block

Myocardial ischaemia, cardiovascular disorder, palpitations

   

Respiratory, thoracic, and mediastinal disorders

 

Pharyngitis

Lung oedema, stridor

   

Gastrointestinal disorders

 

Diarrhoea, vomiting, dyspepsia, gastrointestinal pain, tooth disorder

Gastroenteritis, gastritis, mouth ulceration, dysphagia, cheilitis

   

Hepatobiliary disorders

   

Cholelithiasis

   

Skin and subcutatneous tissue disorders

 

Skin disorder, ecchymosis

Rash, alopecia

   

Musculoskeletal and connective tissue disorders

 

Osteoarthritis, myalgia, arthralgia, joint disorder

 

Atypical subtrochanteric and diaphyseal femoral fractures† (bisphosphonate class adverse reaction)

Osteonecrosis of jaw†**

Renal and urinary disorders

   

Urinary retention, renal cyst

   

Reproductive system and breast disorders

   

Pelvic pain

   

General disorders and administration site conditions

 

Influenza-like illness, oedema peripheral, asthenia, thirst

Hypothermia

   

Investigations

 

Gamma-GT increased, creatinine increased

Blood alkaline phosphatase increase, weight decrease

   

Injury, poisoning and procedural complications

   

Injury, injection site pain

   

**See further information below.

†Identified in postmarketing experience.

Osteonecrosis of jaw

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see section 4.4).

Ocular inflammation

Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with ibandronic acid. In some cases, these events did not resolve until the ibandronic acid was discontinued.

4.9 Overdose

Up to now there is no experience of acute poisoning with Bondronat concentrate for solution for infusion. Since both the kidney and the liver were found to be target organs for toxicity in preclinical studies with high doses, kidney and liver function should be monitored. Clinically relevant hypocalcaemia should be corrected by intravenous administration of calcium gluconate.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmaco-therapeutic group: Drugs for treatment of bone diseases, bisphosphonate, ATC Code: M05BA06

Ibandronic acid belongs to the bisphosphonate group of compounds which act specifically on bone. Their selective action on bone tissue is based on the high affinity of bisphosphonates for bone mineral. Bisphosphonates act by inhibiting osteoclast activity, although the precise mechanism is still not clear.

In vivo, ibandronic acid prevents experimentally-induced bone destruction caused by cessation of gonadal function, retinoids, tumours or tumour extracts. The inhibition of endogenous bone resorption has also been documented by 45Ca kinetic studies and by the release of radioactive tetracycline previously incorporated into the skeleton.

At doses that were considerably higher than the pharmacologically effective doses, ibandronic acid did not have any effect on bone mineralisation.

Bone resorption due to malignant disease is characterized by excessive bone resorption that is not balanced with appropriate bone formation. Ibandronic acid selectively inhibits osteoclast activity, reducing bone resorption and thereby reducing skeletal complications of the malignant disease.

Clinical studies in the treatment of tumour-induced hypercalcaemia

Clinical studies in hypercalcaemia of malignancy demonstrated that the inhibitory effect of ibandronic acid on tumour-induced osteolysis, and specifically on tumour-induced hypercalcaemia, is characterised by a decrease in serum calcium and urinary calcium excretion.

In the dose range recommended for treatment, the following response rates with the respective confidence intervals have been shown in clinical trials for patients with baseline albumin-corrected serum calcium

For these patients and dosages, the median time to achieve normocalcaemia was 4 to 7 days. The median time to relapse (return of albumin-corrected serum calcium above 3.0 mmol/l) was 18 to 26 days.

Clinical studies in the prevention of skeletal events in patients with breast cancer and bone metastases

Clinical studies in patients with breast cancer and bone metastases have shown that there is a dose dependent inhibitory effect on bone osteolysis, expressed by markers of bone resorption, and a dose dependent effect on skeletal events.

Prevention of skeletal events in patients with breast cancer and bone metastases with Bondronat 6 mg administered intravenously was assessed in one randomized placebo controlled phase III trial with duration of 96 weeks. Female patients with breast cancer and radiologically confirmed bone metastases were randomised to receive placebo (158 patients) or 6 mg Bondronat (154 patients). The results from this trial are summarised below.

Primary efficacy endpoints

The primary endpoint of the trial was the skeletal morbidity period rate (SMPR). This was a composite endpoint which had the following skeletal related events (SREs) as sub-components:

- radiotherapy to bone for treatment of fractures/impending fractures

- surgery to bone for treatment of fractures

- vertebral fractures

- non-vertebral fractures.

The analysis of the SMPR was time-adjusted and considered that one or more events occurring in a single 12 week period could be potentially related. Multiple events were therefore counted only once for the purposes of the analysis. Data from this study demonstrated a significant advantage for intravenous Bondronat 6 mg over placebo in the reduction in SREs measured by the time-adjusted SMPR (p=0.004). The number of SREs was also significantly reduced with Bondronat 6 mg and there was a 40% reduction in the risk of a SRE over placebo (relative risk 0.6, p = 0.003). Efficacy results are summarised in Table 3.

Table 3 Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)

 

All Skeletal Related Events (SREs)

   

Placebo

n=158

Bondronat 6 mg

n=154

p-value

 

SMPR (per patient year)

1.48

1.19

p=0.004

Number of events (per patient)

3.64

2.65

p=0.025

SRE relative risk

-

0.60

p=0.003

Secondary efficacy endpoints

A statistically significant improvement in bone pain score was shown for intravenous Bondronat 6 mg compared to placebo. The pain reduction was consistently below baseline throughout the entire study and accompanied by a significantly reduced use of analgesics. The deterioration in Quality of Life was significantly less in Bondronat treated patients compared with placebo. A tabular summary of these secondary efficacy results is presented in Table 4.

Table 4 Secondary Efficacy Results (Breast cancer Patients with Metastatic Bone Disease)

 

Placebo

n=158

Bondronat 6 mg

n=154

p-value

Bone pain *

0.21

-0.28

p<0.001

Analgesic use *

0.90

0.51

p=0.083

Quality of Life *

-45.4

-10.3

p=0.004

* Mean change from baseline to last assessment.

There was a marked depression of urinary markers of bone resorption (pyridinoline and deoxypyridinoline) in patients treated with Bondronat that was statistically significant compared to placebo.

In a study in 130 patients with metastatic breast cancer the safety of Bondronat infused over 1 hour or 15 minutes was compared. No difference was observed in the indicators of renal function. The overall adverse event profile of ibandronic acid following the 15 minute infusion was consistent with the known safety profile over longer infusion times and no new safety concerns were identified relating to the use of a 15 minute infusion time.

A 15 minute infusion time has not been studied in cancer patients with a creatinine clearance of <50ml/min.

Paediatric population

The safety and efficacy of Bondronat in children and adolescents below age 18 years have not been established. No data are available.

5.2 Pharmacokinetic Properties

After a 2 hour infusion of 2, 4 and 6 mg ibandronic acid pharmacokinetic parameters are dose proportional.

Distribution

After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted into urine. In humans, the apparent terminal volume of distribution is at least 90 l and the amount of dose reaching the bone is estimated to be 40-50% of the circulating dose. Protein binding in human plasma is approximately 87% at therapeutic concentrations, and thus drug-drug interaction due to displacement is unlikely.

Biotransformation

There is no evidence that ibandronic acid is metabolized in animals or humans.

Elimination

The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but the apparent terminal half-life is generally in the range of 10-60 hours. However, early plasma levels fall quickly, reaching 10% of peak values within 3 and 8 hours after intravenous or oral administration respectively. No systemic accumulation was observed when ibandronic acid was administered intravenously once every 4 weeks for 48 weeks to patients with metastatic bone disease.

Total clearance of ibandronic acid is low with average values in the range 84-160 ml/min. Renal clearance (about 60 ml/min in healthy postmenopausal females) accounts for 50-60% of total clearance and is related to creatinine clearance. The difference between the apparent total and renal clearances is considered to reflect the uptake by bone.

Pharmacokinetics in special populations

Gender

Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.

Race

There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in ibandronic acid disposition. There are only very few data available on patients with African origin.

Patients with renal impairment

Exposure to ibandronic acid in patients with various degrees of renal impairment is related to creatinine clearance (CLcr). In subjects with severe renal impairment (mean estimated CLcr = 21.2 mL/min), dose-adjusted mean AUC0-24h was increased by 110% compared to healthy volunteers. In clinical pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 minutes infusion), mean AUC0-24 increased by 14% and 86%, respectively, in subjects with mild (mean estimated CLcr=68.1 mL/min) and moderate (mean estimated CLcr=41.2 mL/min) renal impairment compared to healthy volunteers (mean estimated CLcr=120 mL/min). Mean Cmax was not increased in patients with mild renal impairment and increased by 12% in patients with moderate renal impairment. For patients with mild renal impairment (CLcr

Patients with hepatic impairment

There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid since it is not metabolized but is cleared by renal excretion and by uptake into bone. Therefore dosage adjustment is not necessary in patients with hepatic impairment. Further, as protein binding of ibandronic acid is approximately 87% at therapeutic concentrations, hypoproteinaemia in severe liver disease is unlikely to lead to clinically significant increases in free plasma concentration.

Elderly

In a multivariate analysis, age was not found to be an independent factor of any of the pharmacokinetic parameters studied. As renal function decreases with age, this is the only factor that should be considered (see renal impairment section).

Paediatric population

There are no data on the use of Bondronat in patients less than 18 years old.

5.3 Preclinical Safety Data

Effects in non-clinical studies were observed only at exposures sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. As with other bisphosphonates, the kidney was identified to be the primary target organ of systemic toxicity.

Mutagenicity/Carcinogenicity:

No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence of effects on genetic activity for ibandronic acid.

Reproductive toxicity:

No evidence of direct foetal toxicity or teratogenic effects were observed for ibandronic acid in intravenously treated rats and rabbits. In reproductive studies in rats by the oral route effects on fertility consisted of increased preimplantation losses at dose levels of 1 mg/kg/day and higher. In reproductive studies in rats by the intravenous route, ibandronic acid decreased sperm counts at doses of 0.3 and 1 mg/kg/day and decreased fertility in males at 1 mg/kg/day and in females at 1.2 mg/kg/day. Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those expected for this class of drug (bisphosphonates). They include a decreased number of implantation sites, interference with natural delivery (dystocia), an increase in visceral variations (renal pelvis ureter syndrome) and teeth abnormalities in F1 offspring in rats.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium chloride

Acetic acid (99%)

Sodium acetate

Pramasone Cream
Pronunciation: HYE-droe-KOR-ti-sone/pram-OX-eenGeneric Name: Hydrocortisone/PramoxineBrand Name: Examples include Pramasone and Pramasone E

Fluoritab Fluoride Drops
Generic Name: sodium fluoride Dosage Form: oral dropsFluoritab Fluoride Drops 1 fluid ounce size

CONTAINS: SODIUM FLUORIDE IN AN AQUEOUS VEHICLE WITH PRESERVATIVE.

EACH 8 DROPS EQUIVALENT TO 1 MG. F. (FROM 2.2 MG SODIUM FLUORIDE)

Lactinol-E
Pronunciation: LACK-tick AS-id/VYE-tah-minGeneric Name: Lactic Acid with Vitamin EBrand Name: Generic only. No brands available.

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