Friday, 31 August 2012

Provera Tablets 100 mg, Provera Tablets 200 mg & Provera Tablets 400 mg





1. Name Of The Medicinal Product



Provera Tablets 100 mg or Medroxyprogesterone Acetate Tablets 100 mg.



Provera Tablets 200 mg or Medroxyprogesterone Acetate Tablets 200 mg.



Provera® Tablets 400 mg


2. Qualitative And Quantitative Composition



1 tablet contains 100mg medroxyprogesterone acetate.



1 tablet contains 200 mg medroxyprogesterone acetate.



1 tablet contains 400 mg medroxyprogesterone acetate.



For excipients, see 6.1.



3. Pharmaceutical Form



Tablet.



4. Clinical Particulars



4.1 Therapeutic Indications



Progestogen indicated for the treatment of certain hormone dependant neoplasms, such as:



1. Endometrial carcinoma.



2. Renal cell carcinoma.



3. Carcinoma of breast in post menopausal women.



4.2 Posology And Method Of Administration



Route of administration: Oral.



Adults








Endometrial and renal cell carcinoma




200 - 600 mg daily




Breast carcinoma




400 - 1500 mg daily



The incidence of minor side-effects, such as indigestion and weight gain, increase with the increase in dose.



Response to hormonal therapy may not be evident until after at least 8-10 weeks of therapy.



Elderly patients : This product has been used primarily in the older age group for the treatment of malignancies. There is no evidence to suggest that the older age group is any less prepared to handle the drug metabolically than is the younger patient. Therefore the same dosage, contra-indications, and precautions would apply to either age group.



Children:The product is not anticipated for paediatric use in the indications recommended.



4.3 Contraindications



Medroxyprogesterone acetate is contraindicated in the following conditions:



• thrombophlebitis, thrombo-embolic disorders, and where there is a high risk of developing such manifestations [presence or history of atrial fibrillation, valvular disorders, endocarditis, heart failure, pulmonary embolism; thrombo-embolic ischaemic attack (TIA), cerebral infarction; atherosclerosis; immediate post surgery period]



• hypercalcaemia in patients with osseous metastases



• known sensitivity to medroxyprogesterone acetate or any component of the drug.



• impaired liver function or active liver disease.



• missed abortion, metrorrhagia, known or suspected pregnancy.



• undiagnosed vaginal bleeding.



• previous idiopathic or current venous thromboembolism (deep vein thrombosis, pulmonary embolism).



• active or recent arterial thromboembolic disease (e.g., angina, myocardial infarction).



• suspected or early breast carcinoma



Progestogens are known to be porphyrogenic. Patients with a history of attacks or aged under 30 are at greatest risk of an acute attack while on progesterone treatment. A careful assessment of potential benefit should be made where this risk is present.



4.4 Special Warnings And Precautions For Use



Warnings:



In the treatment of carcinoma of breast occasional cases of hypercalcaemia have been reported.



Unexpected vaginal bleeding during therapy with medroxyprogesterone acetate should be investigated.



Medication should not be readministered pending examination if there is sudden partial or complete loss of vision or if there is a sudden onset of proptosis, diplopia or migraine. If examination reveals papilloedema or retinal vascular lesions, medication should not be readministered.



Medroxyprogesterone acetate may produce Cushingoid symptoms.



Some patients receiving medroxyprogesterone acetate may exhibit suppressed adrenal function. Medroxyprogesterone acetate may decrease ACTH and hydrocortisone blood levels.



Treatment with medroxyprogesterone acetate should be discontinued in the event of:



• jaundice or deterioration in liver function



• significant increase in blood pressure



• new onset of migraine-type headache



Precautions:



Animal studies show that Provera possesses adrenocorticoid activity. This has also been reported in man, therefore patients receiving large doses continuously and for long periods should be observed closely for signs normally associated with adrenocorticoid therapy, such as hypertension, sodium retention, oedema, etc. Care is needed in treating patients with diabetes and/or arterial hypertension.



Before using Provera the general medical condition of the patient should be carefully evaluated.



This product should be used under the supervision of a specialist and the patient kept under regular surveillance.



Patients with the following conditions should be carefully monitored while taking progestogens:



• Conditions which may be influenced by potential fluid retention



o Epilepsy



o Migraine



o Asthma



o Cardiac dysfunction



o Renal dysfunction



• History of mental depression



• Diabetes (a decrease in glucose tolerance has been observed in some patients).



• Hyperlipidaemia



The pathologist (laboratory) should be informed of the patient's use of medroxyprogesterone acetate if endometrial or endocervical tissue is submitted for examination.



The physician/laboratory should be informed that medroxyprogesterone acetate may decrease the levels of the following endocrine biomarkers:



• Plasma/urinary steroids (e.g., cortisol, oestrogen, pregnanediol, progesterone, testosterone)



• Plasma/urinary gonadotrophins (e.g., LH and FSH)



• Sex-hormone-binding-globulin



The use of medroxyprogesterone acetate in oncology indications may also cause partial adrenal insufficiency (decrease in pituitary-adrenal axis response) during Metyrapone testing. Thus the ability of adrenal cortex to respond to ACTH should be demonstrated before metyrapone is administered.



Although medroxyprogesterone acetate has not been causally associated with the induction of thromboembolic disorders, any patient with a history or who develops this kind of event while undergoing therapy with medroxyprogesterone acetate should have her status and need for treatment carefully assessed before continuing therapy.



Risk of venous thromboembolism (VTE)



The risk of VTE has not been assessed for progesterone alone. However, VTE is a known risk factor of oestrogen-only and combined hormone replacement therapy. When prescribing medroxyprogesterone acetate for oncology indications the following precautions and risk factors should be considered in the light of the patient's condition, the dose of medroxyprogesterone acetate and the duration of therapy:



• Generally recognised risk factors for VTE include a personal or family history of VTE or known thromboembolic states, severe obesity (BMI > 30 kg/m2) and systemic lupus erythematosus



• The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery.



• If VTE develops after initiating therapy, medroxyprogesterone acetate should be discontinued. Patients should be told to contact their doctor immediately if they become aware of a symptom suggestive of potential thromboembolism (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).



4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction



Interaction with other medicaments



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



Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John's Wort (Hypericum Perforatum) may induce the metabolism of progestogens. Progestogen levels may therefore be reduced.



Aminoglutethimide has been reported to decrease plasma levels of some progestogens.



Concurrent administration of ciclosporin and MPA has been reported to lead to increased plasma ciclosporin levels and/or decreased plasma MPA levels.



Interactions with oral anti-coagulants have been reported rarely, but causality has not been established.



When used in combination with cytotoxic drugs, it is possible that progestogens may reduce the haematological toxicity of chemotherapy.



Special care should be taken when progestogens are administered with other drugs which also cause fluid retention, such as NSAIDs and vasodilators.



Other forms of interaction



Progestogens can influence certain laboratory tests (e.g., tests for hepatic function, thyroid function and coagulation).



4.6 Pregnancy And Lactation



Pregnancy



Medroxyprogesterone acetate is contraindicated in women who are pregnant. If medroxyprogesterone acetate is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the foetus.



Some reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female foetuses.



Infants from unintentional pregnancies that occur 1 to 2 months after injection of medroxyprogesterone acetate injectable suspension may be at an increased risk of low birth weight, which, in turn, is associated with an increased risk of neonatal death. The attributable risk is low because pregnancies while on medroxyprogesterone acetate are uncommon.



Lactation



Medroxyprogesterone acetate and/or its metabolites are secreted in breast milk. Therefore, the use of Provera whilst breast-feeding is not recommended.



4.7 Effects On Ability To Drive And Use Machines



No adverse effect has been reported.



4.8 Undesirable Effects



Reactions occasionally associated with the use of progestogens, particularly in high doses, are:



Breast: Tenderness, mastodynia or galactorrhoea.



Genitourinary: Abnormal uterine bleeding (irregular, increase, decrease), amenorrhoea, alterations of cervical secretions, cervical erosions, prolonged anovulation.



Central nervous system: Confusion, euphoria, loss of concentration, nervousness, insomnia, somnolence, fatigue, dizziness, depression, vision disorders and headache.



Skin and mucous membranes: Sensitivity reactions ranging from pruritus, urticaria, angioneurotic oedema, to generalised rash and anaphylaxis have occasionally been reported. Acne, alopecia or hirsutism have been reported in a few cases.



Allergy: Hypersensitivity reactions (e.g., anaphylaxis or anaphylactoid reactions, angioedema).



Gastro-intestinal/hepatobiliary: Constipation, diarrhoea, dry mouth, disturbed liver function, jaundice, vomiting, nausea and indigestion .



Metabolic and nutritional: Adrenergic-like effects (e.g., fine hand tremors, sweating, tremors, cramps in calves at night), corticoid-like effects (e.g., Cushingoid Syndrome), decreased glucose tolerance, diabetic cataract, exacerbation of diabetes mellitus, glycosuria.



Cardiovascular: Cerebral and myocardial infarction, congestive heart failure, increased blood pressure, palpitations, pulmonary embolism, retinal thrombosis, tachycardia, thromboembolic disorders, thrombophlebitis.



Haematological: Elevation of white blood cells and platelet count.



Miscellaneous: Change in appetite, change in libido, oedema/fluid retention, hypercalcaemia, malaise, hyperpyrexia, weight gain, moon facies.



4.9 Overdose



No action required other than cessation of therapy.



5. Pharmacological Properties



5.1 Pharmacodynamic Properties



Pharmacotherapeutic group: Progestogens. ATC Code: L02A B



Medroxyprogesterone acetate has the pharmacological action of a progestogen.



5.2 Pharmacokinetic Properties



Medroxyprogesterone acetate is absorbed from the gastro intestinal tract with a single oral dose of 10-250 mg. The time taken to reach the peak serum concentration (Tmax) was 2-6 hours and the average peak serum concentration (Cmax) was 13-46.89 mg/ml.



Unmetabolised medroxyprogesterone acetate is highly plasma protein bound. Medroxyprogesterone acetate is metabolised in the liver.



Medroxyprogesterone acetate is primarily metabolised by faecal excretion as glucuronide conjugated metabolite.



Metabolised medroxyprogesterone acetate is excreted more rapidly and in a greater percentage following oral doses than after aqueous intramuscular injection



400 mg only:



The comparative bioavailability of medroxyprogesterone acetate (MPA) in sixteen healthy male volunteers was determined following the oral ingestion of 400 mg MPA as two Provera 200 mg tablets or as one Provera 400mg tablet. It is concluded that the bioavailability appeared to be equivalent in this group of volunteers.



5.3 Preclinical Safety Data



No further preclinical safety data available.



6. Pharmaceutical Particulars



6.1 List Of Excipients



Microcrystalline cellulose



Maize Starch



Byco C



Macrogol 400



Sodium starch glycollate



Docusate sodium



Sodium benzoate



Magnesium stearate



Isopropyl alcohol



Purified water



6.2 Incompatibilities



Not applicable.



6.3 Shelf Life



Provera 100mg: 36 months if stored in glass/HDPE bottles, or 24 month in blister packs.



Provera 200mg: 36 months if stored in glass/HDPE bottles, or 24 month in blister packs.



Provera 400mg: The shelf-life for Provera Tablets 400 mg is 36 months



6.4 Special Precautions For Storage



Provera 100mg: Store below 25°C. Bottle packs only: keep in a well closed container.



Provera 200mg: Store below 25°C.Bottle packs only: keep in a well closed container.



Provera 400mg: Store at controlled room temperature (15 - 30ºC).Bottle packs only: keep in a well closed container.



6.5 Nature And Contents Of Container



Provera 100mg: Amber glass bottle with screw cap containing 100 tablets. HDPE bottle with tamper evident cap containing 100 tablets. PVC/aluminium strip containing 30, 60 or 100 tablets.



Provera 200mg: Amber glass bottle with screw cap containing 100 tablets. HDPE bottle with tamper evident cap containing 100 tablets. PVC/aluminium strip containing 30, 60 or 100 tablets.



Provera 400mg: Glass/HDPE bottles of 60 tablets. PVC aluminium blisters of 30 tablets



6.6 Special Precautions For Disposal And Other Handling



None stated.



7. Marketing Authorisation Holder



Pharmacia Limited



Ramsgate Road



Sandwich



Kent



CT13 9NJ



UK



8. Marketing Authorisation Number(S)



Provera 100mg: PL 0032/0111



Provera 200mg: PL 0032/0112



Provera 400mg: PL 0032/0131



9. Date Of First Authorisation/Renewal Of The Authorisation



Provera 100mg: 7 November 1983/30 January 1996



Provera 200mg: 7 November 1983/30 January 1996



Provera 400mg: Date of first authorisation: 29 April 1986. Date of renewal of authorisation: 21 May 1998



10. Date Of Revision Of The Text



August 2007



LEGAL CATEGORY


POM



Company Reference: PVB1_0




Monday, 27 August 2012

Lidex-E


Generic Name: fluocinonide (Topical application route)

floo-oh-SIN-oh-nide

Commonly used brand name(s)

In the U.S.


  • Lidex

  • Lidex-E

  • Vanos

In Canada


  • Lidemol

  • Lidex Mild

  • Lidex Regular

  • Lyderm

  • Tcis

  • Tiamol

  • Topsyn

  • Trisyn

Available Dosage Forms:


  • Ointment

  • Emollient Cream

  • Cream

  • Solution

  • Gel/Jelly

Therapeutic Class: Corticosteroid, Strong


Pharmacologic Class: Adrenal Glucocorticoid


Uses For Lidex-E


Fluocinonide topical is used to help relieve redness, itching, swelling, or other discomfort caused by skin conditions. This medicine is a corticosteroid (cortisone-like medicine or steroid).


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


Before Using Lidex-E


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


Allergies


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


Pediatric


Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of fluocinonide topical in the pediatric population. However, because of this medicine's toxicity, it should be used with caution. Children may absorb large amounts through the skin, which can cause serious side effects. If your child is using this medicine, follow your doctor's instructions very carefully. For Vanos® cream, safety and efficacy have not been established in children younger than 12 years of age.


Geriatric


Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of Vanos® cream in the elderly. However, elderly patients are more likely to have age-related medical problems, which may require caution in patients receiving Vanos® cream.


No information is available on the relationship of age to the effects of fluocinonide topical in geriatric patients.


Pregnancy








Pregnancy CategoryExplanation
All TrimestersCAnimal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding


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


Interactions with Medicines


Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.


Interactions with Food/Tobacco/Alcohol


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


Other Medical Problems


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


  • Cushing's syndrome (adrenal gland disorder) or

  • Diabetes or

  • Hyperglycemia (high blood sugar) or

  • Intracranial hypertension (increased pressure in the head)—Use with caution. May make these conditions worse.

  • Infection of the skin at or near the place of application or

  • Large sores, broken skin, or severe skin injury at the place of application—The chance of side effects may be increased.

  • Perioral dermatitis (skin problem) or

  • Rosacea (skin problem)—Vanos® cream should not be used in patients with these conditions.

Proper Use of fluocinonide

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


It is very important that you use this medicine only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered. To do so may cause unwanted side effects or skin irritation.


This medicine is for use on the skin only. Do not get it in your eyes, nose, mouth, or vagina. Do not use it on skin areas that have cuts, scrapes, or burns. If it does get on these areas, rinse it off right away with water.


This medicine should only be used for skin conditions that your doctor is treating. Check with your doctor before using it for other conditions, especially if you think that a skin infection may be present. This medicine should not be used to treat certain kinds of skin infections or conditions, such as severe burns.


If you are using the Vanos® cream:


  • Do not use it on the face, groin, or underarms unless directed to do so by your doctor.

  • Do not use it for more than 2 weeks unless your doctor tells you otherwise.

To use:


  • Wash your hands with soap and water before and after using this medicine.

  • Apply a thin layer of this medicine to the affected area of the skin. Rub it in gently.

  • Do not bandage or otherwise wrap the skin being treated unless directed to do so by your doctor.

  • If the medicine is applied to the diaper area of an infant, do not use tight-fitting diapers or plastic pants unless directed to do so by your doctor.

  • If your doctor ordered an occlusive dressing or airtight covering to be applied over the medicine, make sure you know how to apply it. Occlusive dressings increase the amount of medicine absorbed through your skin, so use them only as directed. If you have any questions about this, check with your doctor.

Dosing


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


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


  • For topical dosage forms (cream, gel, ointment, or solution):
    • For redness, itching, and swelling of the skin:
      • Adults—Apply to the affected area of the skin two to four times per day.

      • Children—Apply to the affected area of the skin two to four times per day.



  • For topical dosage form (cream):
    • For atopic dermatitis:
      • Adults and children 12 years of age and older—Apply to the affected area of the skin once a day.

      • Children younger than 12 years of age—Use is not recommended.


    • For psoriasis:
      • Adults and children 12 years of age and older—Apply to the affected area of the skin one to two times per day.

      • Children younger than 12 years of age—Use is not recommended.



Missed Dose


If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.


Storage


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


Keep out of the reach of children.


Do not keep outdated medicine or medicine no longer needed.


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


Precautions While Using Lidex-E


It is very important that your doctor check the progress of you or your child at regular visits for any unwanted effects that may be caused by this medicine.


If your or your child's symptoms do not improve within a few days, or if they become worse, check with your doctor.


Using too much of this medicine or using it for a long time may increase your risk of having adrenal gland problems. The risk is greater for children and patients who use large amounts for a long time. Talk to your doctor right away if you or your child have more than one of these symptoms while you are using this medicine: blurred vision; dizziness or fainting; a fast, irregular, or pounding heartbeat; increased thirst or urination; irritability; or unusual tiredness or weakness.


Stop using this medicine and check with your doctor right away if you or your child have a skin rash, burning, stinging, swelling, or irritation on the skin.


Do not use cosmetics or other skin care products on the treated areas.


Lidex-E Side Effects


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


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


Incidence not known
  • Blistering, burning, crusting, dryness, or flaking of the skin

  • irritation

  • itching, scaling, severe redness, soreness, or swelling of the skin

  • redness and scaling around the mouth

  • thinning of the skin with easy bruising, especially when used on the face or where the skin folds together (e.g. between the fingers)

  • thinning, weakness, or wasting away of the skin

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


Less common
  • Fever

  • headache

  • muscle aches

  • sore throat

  • stuffy or runny nose

  • unusual tiredness or weakness

Incidence not known
  • Acne or pimples

  • burning and itching of the skin with pinhead-sized red blisters

  • burning, itching, and pain in hairy areas, or pus at the root of the hair

  • increased hair growth on the forehead, back, arms, and legs

  • lightening of normal skin color

  • lightening of treated areas of dark skin

  • reddish purple lines on the arms, face, legs, trunk, or groin

  • softening of the skin

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


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

See also: Lidex-E side effects (in more detail)



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


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


More Lidex-E resources


  • Lidex-E Side Effects (in more detail)
  • Lidex-E Use in Pregnancy & Breastfeeding
  • Lidex-E Drug Interactions
  • Lidex-E Support Group
  • 0 Reviews for Lidex-E - Add your own review/rating


  • Lidex-E Concise Consumer Information (Cerner Multum)

  • Lidex-E Prescribing Information (FDA)

  • Lidex-E Cream MedFacts Consumer Leaflet (Wolters Kluwer)

  • Lidex Prescribing Information (FDA)

  • Lidex Topical Solution Prescribing Information (FDA)

  • Vanos Prescribing Information (FDA)

  • Vanos Cream MedFacts Consumer Leaflet (Wolters Kluwer)



Compare Lidex-E with other medications


  • Atopic Dermatitis
  • Dermatitis
  • Psoriasis

Sunday, 26 August 2012

coagulation factor xiii Intravenous


FAK-tor THIR-teen HUE-man


Commonly used brand name(s)

In the U.S.


  • Corifact

Available Dosage Forms:


  • Powder for Solution

Therapeutic Class: Hemostatic


Uses For coagulation factor xiii


Factor XIII injection is used to prevent bleeding in patients with congenital Factor XIII deficiency.


Factor XIII is a protein that is produced naturally in the body. Corifact™ is a man-made protein produced to replicate the naturally occurring factor XIII in the body. It is used to stop bleeding by helping the blood to clot.


coagulation factor xiii is to be administered only by or under the supervision of your doctor or other health care professional.


Before Using coagulation factor xiii


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


Allergies


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


Pediatric


Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of Factor XIII in children.


Geriatric


Appropriate studies have not been performed on the relationship of age to the effects of Factor XIII in the geriatric population. Safety and efficacy have not been established.


Pregnancy








Pregnancy CategoryExplanation
All TrimestersCAnimal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding


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


Interactions with Medicines


Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.


Interactions with Food/Tobacco/Alcohol


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


Proper Use of coagulation factor xiii


A doctor or other trained health professional will give you coagulation factor xiii. coagulation factor xiii is given through a needle placed in one of your veins.


coagulation factor xiii is usually given every 28 days (4 weeks), depending on your recent blood test results.


coagulation factor xiii comes with a patient information leaflet. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.


Precautions While Using coagulation factor xiii


It is very important that your doctor check you or your child closely while you are receiving coagulation factor xiii to make sure it is working properly. Blood tests may be needed to check for unwanted effects.


coagulation factor xiii may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Tell your doctor or nurse right away if you or your child have a cough; difficulty with swallowing; dizziness; a fast heartbeat; wheezing; shortness of breath; trouble with breathing; chest tightness; swelling in your face, hands, tongue, or throat; a fever; chills; a runny nose or sneezing; itching or hives; or lightheadedness or faintness after you receive the medicine.


coagulation factor xiii may increase your chance of having blood clotting problems. Tell your doctor right away if you or your child have a sudden or severe headache, problems with vision or speech, chest pain, shortness of breath, or numbness or weakness while you are receiving coagulation factor xiii.


coagulation factor xiii is made from donated human blood. Some human blood products have transmitted certain viruses to people who have received them. The risk of getting a virus from medicines made from human blood has been greatly reduced in recent years. This is the result of required testing of human donors for certain viruses, and testing during the making of these medicines. Although the risk is low, talk with your doctor if you have concerns.


coagulation factor xiii Side Effects


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


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


More common
  • Bloody nose

  • bruise

  • collection of blood under the skin

  • deep, dark purple bruise

  • fever

  • itching, pain, redness, or swelling

Incidence not known
  • Blurred vision

  • chills

  • confusion

  • cough

  • difficult or labored breathing

  • difficulty swallowing

  • dizziness

  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position

  • fast heartbeat

  • hives

  • nausea

  • pain in the chest, groin, or legs, especially the calves

  • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue

  • red, scaly, swollen, or peeling areas of the skin

  • severe, sudden headache

  • shortness of breath

  • skin rash

  • slurred speech

  • sudden loss of coordination

  • sudden, severe weakness or numbness in the arm or leg

  • sudden, unexplained shortness of breath

  • sweating

  • tenderness, pain, swelling, warmth, skin discoloration, and prominent superficial veins over the affected area

  • tightness in the chest

  • unusual tiredness or weakness

  • vision changes

  • wheezing

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


More common
  • Abdominal or stomach pain

  • diarrhea

  • difficulty with moving

  • general feeling of discomfort or illness

  • headache

  • joint pain

  • loss of appetite

  • muscle aches and pains

  • muscle stiffness

  • runny nose

  • shivering

  • sore throat

  • sweating

  • trouble sleeping

  • vomiting

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


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

See also: coagulation factor xiii Intravenous side effects (in more detail)



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  • Factor XIII Deficiency

Friday, 24 August 2012

Esmolol





Dosage Form: injection
Esmolol HCL 10 mg/mL Injection 10mL Single Dose Vial

Description


Ready-to-use Vials

10 mL Vials

Iso-Osmotic Solution of Esmolol Hydrochloride in Sodium Chloride

For Intravenous Use

Can be used for direct intravenous use.

Esmolol Hydrochloride concentration = 10 milligrams/mL (10,000 micrograms/mL)

Single Patient Use Only

No Preservatives Added

Rx only




DESCRIPTION

Esmolol hydrochloride is a beta1-selective (cardioselective) adrenergic receptor blocking agent with a very short duration of action (elimination half-life is approximately 9 minutes). Esmolol Hydrochloride is:

(±)-Methyl p- [2-hydroxy-3- (isopropylamino) propoxy] hydrocinnamate hydrochloride and has the following structure:




Esmolol hydrochloride has the empirical formula C16H26NO4Cl and a molecular weight of 331.8. It has one asymmetric center and exists as an enantiomeric pair. Esmolol hydrochloride is a white to off-white crystalline powder. It is a relatively hydrophilic compound which is very soluble in water and freely soluble in alcohol. Its partition coefficient (octanol/water) at pH 7.0 is 0.42 compared to 17.0 for propranolol. Esmolol Hydrochloride Injection Esmolol Hydrochloride Injection is a clear, colorless to light yellow, sterile, nonpyrogenic, iso-osmotic solution of Esmolol

hydrochloride in sodium chloride. 100 mg, 10 mL Single Dose Vial– Each mL contains 10 mg Esmolol Hydrochloride, 5.9 mg Sodium Chloride, USP and Water for Injection, USP; buffered with 2.8 mg Sodium Acetate Trihydrate, USP and 0.546 mg Glacial Acetic Acid, USP. Sodium Hydroxide and/or Hydrochloric Acid added, as necessary to adjust pH to 5.0 (4.5-5.5).



Clinical Pharmacology


Esmolol hydrochloride is a beta1-selective (cardioselective) adrenergic receptor blocking agent with rapid onset, a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilizing activity at therapeutic dosages. Its elimination halflife after intravenous infusion is approximately 9 minutes. Esmolol hydrochloride inhibits the beta1 receptors located chiefly in cardiac muscle, but this preferential effect is not absolute and at higher doses it begins to inhibit beta2 receptors located chiefly in the bronchial and vascular musculature.


Pharmacokinetics and Metabolism

Esmolol hydrochloride is rapidly metabolized by hydrolysis of the ester linkage, chiefly by the esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylcholinesterase. Total body clearance in man was found to be about 20 L/kg/hr, which is greater than cardiac output; thus the metabolism of Esmolol hydrochloride is not limited by the rate of blood flow to metabolizing tissues such as the liver or affected by hepatic or renal blood flow. Esmolol hydrochloride has a rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes. Using an appropriate loading dose, steady-state blood levels of Esmolol hydrochloride for dosages from 50-300 mcg/kg/min (0.05-0.3

mg/kg/min) are obtained within five minutes. (Steady-state is reached in about 30 minutes without the loading dose.) Steady-state blood levels of Esmolol hydrochloride increase linearly over this dosage range and elimination kinetics are dose-independent over this range. Steady-state blood levels are maintained during infusion but decrease rapidly after termination of the infusion. Because of its short half-life, blood levels of Esmolol hydrochloride can be rapidly altered by increasing or decreasing the infusion rate and rapidly eliminated by discontinuing the infusion.

Consistent with the high rate of blood-based metabolism of Esmolol hydrochloride, less than 2% of the drug is excreted unchanged in the urine. Within 24 hours of the end of infusion, approximately 73-88% of the dosage has been accounted for in the urine as the acid metabolite of Esmolol hydrochloride. Metabolism of Esmolol hydrochloride results in the formation of the corresponding free acid and methanol. The acid metabolite has been shown in animals to have about 1/1500th the activity of Esmolol and in normal volunteers its blood levels do not correspond to the level of beta blockade. The acid metabolite has an elimination half-life of about 3.7 hours and is excreted in the urine with a patients with renal disease, with the elimination half-life increased to about ten-fold that of normals, and plasma levels considerably elevated. Methanol blood levels, monitored in subjects receiving Esmolol hydrochloride for up to 6 hours at 300 mcg/kg/min (0.3 mg/kg/ min) and 24 hours at 150 mcg/kg/min (0.15 mg/kg/min), approximated endogenous levels and were less than 2% of levels usually associated with methanol toxicity. Esmolol hydrocloride has been shown to be 55% bound to human plasma protein, while the acid metabolite is only 10% bound.


Pharmacodynamics

Clinical pharmacology studies in normal volunteers have confirmed the beta blocking activity of Esmolol hydrochloride, showing reduction in heart rate at rest and during exercise, and attenuation of isoproterenol-induced increases in heart rate. Blood levels of Esmolol hydrochloride have been shown to correlate with extent of beta blockade. After termination of infusion, substantial recovery from beta blockade is observed in 10-20 minutes. In human electrophysiology studies, Esmolol hydrochloride produced effects typical of a beta blocker; a decrease in the heart rate, increase in sinus cycle length, prolongation of the sinus node recovery time, prolongation of the AH interval during normal sinus rhythm and during atrial pacing, and an increase in antegrade Wenckebach cycle length. In patients undergoing radionuclide angiography, Esmolol hydrochloride, at dosages of 200 mcg/kg/min (0.2 mg/kg/min), produced reductions in heart rate, systolic blood pressure, rate pressure product, left and right ventricular ejection fraction and cardiac index at rest, which were similar in magnitude to those produced by intravenous propranolol (4 mg). During exercise, Esmolol hydrochloride produced reductions in heart rate, rate pressure product and cardiac index which were also similar to those produced by propranolol,

but produced a significantly larger fall in systolic blood pressure. In patients undergoing cardiac catheterization, the maximum therapeutic dose of 300 mcg/kg/min (0.3 mg/kg/min) of Esmolol hydrochloride produced similar effects and, in addition, there were small, clinically insignificant increases in the left ventricular end diastolic pressure and pulmonary capillary wedge pressure. At thirty minutes after the discontinuation of Esmolol hydrochloride infusion, all of the hemodynamic parameters had returned to pretreatment levels. The relative cardioselectivity of Esmolol hydrochloride was demonstrated in 10 mildly asthmatic patients. Infusions of Esmolol hydrochloride [100, 200 and 300 mcg/kg/min (0.1, 0.2 and 0.3 mg/kg/min)] produced no significant increases in specific airway resistance compared to placebo. At 300 mcg/kg/min (0.3 mg/kg/min), Esmolol hydrochloride produced slightly enhanced bronchomotor sensitivity to dry air stimulus. These effects were not clinically significant, and Esmolol hydrochloride was well tolerated by all patients. Six of the patients also received intravenous propranolol, and at a dosage of 1 mg, two experienced significant, symptomatic bronchospasm requiring bronchodilator treatment. One other propranolol-treated patient also experienced dry air-induced bronchospasm. No adverse pulmonary effects were observed in patients with COPD who received therapeutic dosages of Esmolol hydrochloride for treatment of supraventricular tachycardia (51 patients) or in perioperative settings (32 patients).


Supraventricular Tachycardia

In two multicenter, randomized, double-blind, controlled comparisons of Esmolol hydrochloride with placebo and propranolol, maintenance doses of 50 to 300 mcg/kg/min (0.05 to 0.3 mg/kg/min) of Esmolol hydrochloride were found to be more effective than placebo and about as effective as propranolol, 3-6 mg given by bolus injections, in the treatment of supraventricular tachycardia, principally atrial fibrillation and atrial flutter. The majority of these patients developed their arrhythmias postoperatively. About 60-70% of the patients treated with Esmolol hydrochloride had a desired therapeutic effect (either a 20% reduction in heart rate, a decrease in heart rate to less than 100 bpm, or, rarely, conversion to NSR) and about 95% of those who responded did so at a dosage of 200 mcg/kg/min (0.2 mg/kg/min) or less. The average effective dosage of Esmolol hydrochloride was approximately 100-115 mcg/ kg/min (0.1-0.115 mg/kg/min) in the two studies. Other multicenter baseline-controlled studies gave essentially similar results. In the comparison with propranolol, about 50% of patients in both the Esmolol hydrochloride and propranolol groups were on concomitant digoxin. Response rates were slightly higher with both beta blockers in the digoxin-treated patients. In all studies significant decreases of blood pressure occurred in 20-50% of patients, identified either as adverse reaction reports by investigators, or by observation of systolic pressure less than 90 mmHg or diastolic pressure less than 50 mmHg. The hypotension was symptomatic (mainly diaphoresis or dizziness) in about 12% of patients, and therapy was discontinued in about 11% of patients,

about half of whom were symptomatic. In comparison to propranolol, hypotension was about three times as frequent with Esmolol hydrochloride, 53% vs. 17%. The hypotension was rapidly reversible with decreased infusion rate or after discontinuation of therapy with Esmolol hydrochloride. For both Esmolol hydrochloride and propranolol, hypotension was reported less frequently in patients receiving concomitant digoxin.



Indication and Usage


Supraventricular Tachycardia

Esmolol hydrochloride is indicated for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a short-acting agent is desirable. Esmolol hydrochloride is also indicated in noncompensatory sinus tachycardia where, in the physician’s judgment, the rapid heart rate requires specific intervention. Esmolol hydrochloride is not intended for use in chronic settings where transfer to another agent is anticipated.


Intraoperative and Postoperative Tachycardia and/or Hypertension

Esmolol hydrochloride is indicated for the treatment of tachycardia and hypertension that occur during induction and tracheal intubation, during surgery, on emergence from anesthesia, and in the postoperative period, when in the physician’s judgment such specific intervention is considered indicated. Use of Esmolol hydrochloride to prevent such events is not recommended.



Contraindications


Esmolol hydrochloride is contraindicated in patients with sinus bradycardia, heart block greater than first degree, cardiogenic shock or overt heart failure (see WARNINGS).



Warnings


Hypotension

In clinical trials 20-50% of patients treated with Esmolol hydrochloride have experienced hypotension, generally defined as systolic pressure less than 90 mmHg and/or diastolic pressure less than 50 mmHg. About 12% of the patients have been symptomatic (mainly diaphoresis or dizziness). Hypotension can occur at any dose but is dose-related so that doses beyond 200 mcg/kg/min (0.2 mg/kg/ min) are not recommended. Patients should be closely monitored, especially if pretreatment blood pressure is low. Decrease of dose or termination of infusion reverses hypotension, usually within 30 minutes.


Cardiac Failure

Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. Continued depression of the myocardium with beta blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, Esmolol hydrochloride should be withdrawn. Although withdrawal may be sufficient because of the short elimination half-life of Esmolol hydrochloride, specific treatment may also be considered (seeOVERDOSAGE). The use of Esmolol hydrochloride for control of ventricular response in patients with supraventricular arrhythmias should be undertaken with caution when the patient is compromised hemodynamically or is taking other drugs that decrease any or all of the following: peripheral resistance, myocardial filling, myocardial contractility, or electrical impulse propagation in the myocardium. Despite the rapid onset and offset of the effects of Esmolol hydrochloride, several cases of death have been reported in complex clinical states where Esmolol hydrochloride was presumably being used to control ventricular rate.


Intraoperative and Postoperative Tachycardia and/or Hypertension

Esmolol hydrochloride should not be used as the treatment for hypertension in patients in whom the increased blood pressure is primarily due to the vasoconstriction associated with hypothermia.

Bronchospastic Diseases

PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS. Because of its relative beta1 selectivity and titratability, Esmolol hydrochloride may be used with caution in patients with bronchospastic diseases. However, since beta1 selectivity is not absolute, Esmolol hydrochloride should be carefully titrated to obtain the lowest

possible effective dose. In the event of bronchospasm, the infusion should be terminated immediately; a beta2 stimulating agent may be administered if conditions warrant but should be used with particular caution as patients already have rapid ventricular rates.


Diabetes Mellitus and Hypoglycemia

Esmolol hydrochloride should be used with caution in diabetic patients requiring a beta blocking agent. Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.



Precautions


General

Infusion concentrations of 20 mg/mL were associated with more serious venous irritation, including thrombophlebitis, than concentrations of 10 mg/mL. Extravasation of 20 mg/mL may lead to a serious local reaction and possible skin necrosis. Concentrations greater than 10 mg/mL or infusion into small veins or through a butterfly catheter should be avoided. Because the acid metabolite of Esmolol hydrochloride is primarily excreted unchanged by the kidney, Esmolol hydrochloride should be administered with caution to patients with impaired renal function. The elimination half-life of the acid metabolite was prolonged tenfold and the plasma level was considerably elevated in patients with end-stage renal disease. Care should be taken in the intravenous administration of Esmolol hydrochloride as sloughing of the skin and necrosis have been reported in association with infiltration and extravasation of intravenous infusions.


Drug Interactions

Catecholamine-depleting drugs, e.g., reserpine, may have an additive effect when given with beta blocking agents. Patients treated concurrently with Esmolol hydrochloride and a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may result in vertigo, syncope, or postural hypotension.

A study of interaction between Esmolol hydrochloride and warfarin showed that concomitant administration of Esmolol hydrochloride and warfarin does not alter warfarin plasma levels. Esmolol hydrochloride concentrations were equivocally higher when given with warfarin, but this is not likely to be clinically important. When digoxin and Esmolol hydrochloride were concomitantly administered intravenously to normal volunteers, there was a 10-20% increase in digoxin blood levels at some time points. Digoxin did not affect Esmolol hydrochloride pharmacokinetics. When intravenous morphine and Esmolol hydrochloride were concomitantly administered in normal subjects, no effect on morphine blood levels was seen, but Esmolol hydrochloride steady-state blood levels were increased by 46% in the presence of morphine. No other pharmacokinetic parameters were changed. The effect of Esmolol hydrochloride on the duration of succinylcholine-induced neuromuscular blockade was studied in patients undergoing surgery. The onset of neuromuscular blockade by succinylcholine was unaffected by Esmolol hydrochloride, but the duration of neuromuscular blockade was prolonged from 5 minutes to 8 minutes. Although the interactions observed in these studies do not appear to be of major clinical importance, Esmolol hydrochloride should be titrated with caution in patients being treated concurrently with digoxin, morphine, succinylcholine or warfarin. While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. Caution should be exercised when considering the use of Esmolol hydrochloride and verapamil in patients with depressed myocardial function. Fatal cardiac arrests have occurred in patients receiving both drugs. Additionally, Esmolol hydrochloride should not be used to control supraventricular tachycardia in the presence of agents which are vasoconstrictive and inotropic such as dopamine, epinephrine, and norepinephrine because of the danger of blocking cardiac contractility when systemic vascular resistance is high.


Carcinogenesis, Mutagenesis, Impairment of Fertility

Because of its short term usage no carcinogenicity, mutagenicity or reproductive performance studies have been conducted with Esmolol hydrochloride.


Pregnancy Category C

Teratogenicity studies in rats at intravenous dosages of Esmolol hydrochloride up to 3000 mcg/kg/min (3 mg/kg/min) (ten times the maximum human maintenance dosage) for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while a dosage of 10,000 mcg/kg/min (10 mg/kg/min) produced maternal toxicity and lethality. In rabbits, intravenous dosages up to 1000 mcg/kg/min (1 mg/kg/min) for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while 2500 mcg/kg/min (2.5 mg/kg/min) produced minimal maternal toxicity and increased fetal resorptions. Although there are no adequate and well-controlled studies in pregnant women, use of Esmolol in the last trimester of pregnancy or during labor or delivery has been reported to cause fetal bradycardia, which continued after termination of drug infusion. Esmolol hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.


Nursing Mothers

It is not known whether Esmolol hydrochloride is excreted in human milk; however, caution should be exercised when Esmolol hydrochloride is administered to a nursing woman.


Pediatric Use

The safety and effectiveness of Esmolol hydrochloride in pediatric patients have not been established.



Adverse Reactions


The following adverse reaction rates are based on use of Esmolol hydrochloride in clinical trials involving 369 patients with supraventricular tachycardia and over 600 intraoperative and postoperative patients enrolled in clinical trials. Most adverse effects observed in controlled clinical trial settings have been mild and transient. The most important adverse effect has been hypotension (see WARNINGS). Deaths have been reported in post-marketing experience occurring during complex clinical states where Esmolol hydrochloride was presumably being used simply to control ventricular rate (see WARNINGS, Cardiac Failure).


Cardiovascular

Symptomatic hypotension (diaphoresis, dizziness) occurred in 12% of patients, and therapy was discontinued in about 11%, about half of whom were symptomatic. Asymptomatic hypotension occurred in about 25% of patients. Hypotension resolved during Esmolol hydrochloride infusion in 63% of these patients and within 30 minutes after discontinuation of infusion in 80% of the remaining patients. Diaphoresis accompanied hypotension in 10% of patients. Peripheral ischemia occurred in approximately 1% of patients. Pallor, flushing, bradycardia (heart rate less than 50 beats per minute), chest pain, syncope, pulmonary edema and heart block have each been reported in less than 1% of patients. In two patients without supraventricular tachycardia but with serious coronary artery disease (post inferior myocardial infarction or unstable angina), severe bradycardia/sinus pause/asystole has developed, reversible in both cases with discontinuation of treatment.


Central Nervous System

Dizziness has occurred in 3% of patients; somnolence in 3%; confusion, headache, and agitation in about 2%; and fatigue in about 1% of patients. Paresthesia, asthenia, depression, abnormal thinking, anxiety, anorexia, and lightheadedness were reported in less than 1% of patients. Seizures were also reported in less than 1% of patients, with one death.


Respiratory

Bronchospasm, wheezing, dyspnea, nasal congestion, rhonchi, and rales have each been reported in less than 1% of patients.


Gastrointestinal

Nausea was reported in 7% of patients. Vomiting has occurred in about 1% of patients. Dyspepsia, constipation, dry mouth, and abdominal discomfort have each occurred in less than 1% of patients. Taste perversion has also been reported.


Skin (Infusion Site)

Infusion site reactions including inflammation and induration were reported in about 8% of patients. Edema, erythema, skin discoloration, burning at the infusion site, thrombophlebitis, and local skin necrosis from extravasation have each occurred in less than

1% of patients.


Miscellaneous

Each of the following has been reported in less than 1% of patients: Urinary retention, speech disorder, abnormal vision, midscapular pain, rigors, and fever.



Overdosage


Acute Toxicity

Overdoses of Esmolol hydrochloride can cause cardiac arrest. In addition, overdoses can produce bradycardia, hypotension, electromechanical dissociation and loss of consciousness. Cases of massive accidental overdoses of Esmolol hydrochloride have occurred due to dilution errors. Some of these overdoses have been fatal while others resulted in permanent disability. Bolus doses in the range of 625 mg to 2.5 g (12.5-50 mg/kg) have been fatal. Patients have recovered completely from overdoses as high as 1.75 g given over one minute or doses of 7.5 g given over one hour for cardiovascular surgery. The patients who survived appear to be those whose circulation could be supported until the effects of Esmolol hydrochloride resolved. Because of its approximately 9-minute elimination half-life, the first step in the management of toxicity should be to discontinue the Esmolol hydrochloride infusion. Then, based on the observed clinical effects, the following general measures should also be considered.

Bradycardia: Intravenous administration of atropine or another anticholinergic drug.

Bronchospasm: Intravenous administration of a beta2 stimulating agent and/or a theophylline derivative.

Cardiac Failure: Intravenous administration of a diuretic and/or digitalis glycoside. In shock resulting from inadequate cardiac contractility, intravenous administration of dopamine, dobutamine, isoproterenol, or amrinone may be considered.

Symptomatic Hypotension: Intravenous administration of fluids and/or pressor agents.



Dosage and Administration


Dosing Information:




SUPRAVENTRICULAR TACHYCARDIA

Dosage needs to be titrated, using ventricular rate as the guide.

An initial loading dose of 0.5 milligrams/kg (500 micrograms/kg) infused over a minute duration followed by a maintenance infusion of 0.05 milligrams/kg/min (50 micrograms/kg/min) for the next 4 minutes is recommended. This should give a rough guide with respect to the responsiveness of ventricular rate. After the 4 minutes of initial maintenance infusion (total treatment duration being 5 minutes), depending upon the desired ventricular response, the maintenance infusion may be continued at 0.05 mg/kg/min or increased step-wise (e.g. 0.1 mg/kg/min, 0.15 mg/kg/min to a maximum of 0.2 mg/kg/min) with each step being maintained for 4 or more minutes. If more rapid slowing of ventricular response is imperative, the 0.5 mg/kg loading dose infused over a 1 minute period may be repeated, followed by a maintenance infusion of 0.1 mg/kg/min for 4 minutes. Then, depending upon ventricular rate, another (and final) loading dose of 0.5 mg/kg/min infused over a 1 minute period may be administered followed by a maintenance infusion of 0.15 mg/kg/min. If needed, after 4 minutes of the 0.15 mg/kg/min maintenance infusion, the maintenance infusion may be increased to a maximum of 0.2 mg/kg/min. In the absence of loading doses, constant infusion of a single concentration of Esmolol reaches pharmacokinetic and pharmacodynamic steady-state in about 30 minutes. Maintenance infusions (with or without loading doses) may be continued for as long as 24 hours. The following table summarizes the above and assumes that 3 loading doses (the maximum recommended) are infused over 1 minute and incremental maintenance doses are required after each loading dose. There should be no 4th loading dose, but the maintenance dose may be incremented one more time.



























































Elapsed TimeLoading dose (over 1 minute)
Maintenance Dose (over 4 minutes)
(minutes)
Micrograms/kg/min
Milligrams/kg/min
micrograms/kg/min
Milligrams kg/min
0-1
500
0.5


1-5


50
0.05
5-6
500
0.5


6-10


100
0.1
10-11
500
0.5


11-15


150
0.15
15-16




16-20


*200
*0.2
more than 20


Maintenance dose titrated to heart rate or

other clinical endpoing.



*As the desired heart rate or endpoint is approached, the loading infusion may be omitted and the maintenance infusion titrated to 300 mcg/kg/min (0.3 mg/kg/min) or downward as appropriate. Maintenance dosages above 200 mcg/kg/min (0.2 mg/kg/min) have not been shown to have significantly increased benefits. The interval between titration steps may be increased. In the treatment of supraventricular tachycardia, responses to Esmolol hydrochloride usually (over 95%) occur within the range of 50 to 200 micrograms/kg/min (0.05 to 0.2 milligrams/kg/min). The average effective dosage is approximately 100 micrograms/kg/ min (0.1 milligrams/kg/min) although dosages as low as 25 micrograms/kg/min (0.025 milligrams/kg/min) have been adequate in some patients. Dosages as high as 300 micrograms/kg/min (0.3 milligrams/kg/min) have been used, but these provide little added effect and increase the rate of adverse effects, so doses greater than 200 micrograms/kg/min are not recommended. Dosage of Esmolol hydrochloride in supraventricular tachycardia must be individualized by titration in which each step consists of a loading dosage followed by a maintenance dosage.

This specific dosage regimen has not been studied intraoperatively and, because of the time required for titration, may not be optimal for intraoperative use.

The safety of dosages above 300 mcg/kg/min (0.3 mg/kg/min) has not been studied.

In the event of an adverse reaction, the dosage of Esmolol hydrochloride may be reduced or discontinued. If a local infusion site reaction develops, an alternate infusion site should be used and caution should be taken to prevent extravasation. The use of butterfly needles should be avoided.

Abrupt cessation of Esmolol hydrochloride in patients has not been reported to produce the withdrawal effects which may occur with abrupt withdrawal of beta blockers following chronic use in coronary artery disease (CAD) patients. However, caution should still be used in abruptly discontinuing infusions of Esmolol hydrochloride in CAD patients.

After achieving an adequate control of the heart rate and a stable clinical status in patients with supraventricular tachycardia, transition to alternative antiarrhythmic agents such as propranolol, digoxin, or verapamil, may be accomplished.

A recommended guideline for such a transition is given below but the physician should carefully consider the labeling instructions for the alternative agent selected.








Alternative AgentDosage
Propranolol hydrochloride
10-20 mg q 4-6 hrs
Digoxin
0.125-0.5 mg q 6 hrs (p.o. or i.v.)
Verapamil
80 mg q 6 hrs

The dosage of Esmolol hydrochloride should be reduced as follows:

1. Thirty minutes following the first dose of the alternative agent, reduce the infusion rate of Esmolol hydrochloride by one-half (50%).

2. Following the second dose of the alternative agent, monitor the patient’s response and if satisfactory control is maintained for the first hour, discontinue Esmolol hydrochloride.

The use of infusions of Esmolol hydrochloride up to 24 hours has been well documented; in addition, limited data from 24-48 hrs

(N=48) indicate that Esmolol hydrochloride is well tolerated up to 48 hours.


INTRAOPERATIVE AND POSTOPERATIVE TACHYCARDIA AND/OR HYPERTENSION

In the intraoperative and postoperative settings it is not always advisable to slowly titrate the dose of Esmolol hydrochloride to a therapeutic effect. Therefore, two dosing options are presented: immediate control dosing and a gradual control when the physician has time to titrate.

1. Immediate Control

For intraoperative treatment of tachycardia and/or hypertension give an 80 mg (approximately 1 mg/kg) bolus dose over 30 seconds followed by a 150 mcg/kg/min infusion, if necessary. Adjust the infusion rate as required up to 300 mcg/kg/min to maintain desired heart rate and/or blood pressure.

2. Gradual Control

For postoperative tachycardia and hypertension, the dosing schedule is the same as that used in supraventricular tachycardia. To initiate treatment, administer a loading dosage infusion of 500 mcg/kg/min of Esmolol hydrochloride for one minute followed by a four-minute maintenance infusion of 50 mcg/kg/min. If an adequate therapeutic effect is not observed within five minutes, repeat the same loading dosage and follow with a maintenance infusion increased to 100 mcg/kg/min (see above SUPRAVENTRICULAR TACHYCARDIA).

Notes:

1. Higher dosages (250-300 mcg/kg/min) may be required for adequate control of blood pressure than those required for the treatment of atrial fibrillation, flutter and sinus tachycardia. One third of the postoperative hypertensive patients required these higher doses.

2. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.


Directions for Use of the 10 mL Ready-to-use Vial (10 milligrams/mL)

This dosage form is prediluted to provide a ready-to-use, iso-osmotic solution of 10 mg/mL Esmolol hydrochloride in sodium chloride recommended for Esmolol hydrochloride intravenous administration. It may be used to administer the appropriate Esmolol hydrochloride loading dosage infusions by hand-held syringe while the maintenance infusion is being prepared.

The 10 mL Ready-to-use Vial Esmolol hydrochloride at a concentration of 10 milligrams/mL. When using a 10 milligrams/mL concentration, a loading dose of 0.5 mg/kg infused over 1 minute period of time, for a 70 kg patient is 3.5 mL.


Compatibility with Commonly Used Intravenous Fluids

Esmolol hydrochloride was tested for compatibility with ten commonly used intravenous fluids at a final concentration of 10 mg

Esmolol Hydrochloride per mL. Esmolol hydrochloride was found to be compatible with the following solutions and was stable for at least 24 hours at controlled room temperature or under refrigeration:

• Dextrose (5%) Injection, USP

• Dextrose (5%) in Lactated Ringer’s Injection

• Dextrose (5%) in Ringer’s Injection

• Dextrose (5%) and Sodium Chloride (0.45%) Injection, USP

• Dextrose (5%) and Sodium Chloride (0.9%) Injection, USP

• Lactated Ringer’s Injection, USP

• Potassium Chloride (40 mEq/liter) in Dextrose (5%) Injection, USP

• Sodium Chloride (0.45%) Injection, USP

• Sodium Chloride (0.9%) Injection, USP

Esmolol hydrochloride is NOT compatible with Sodium Bicarbonate (5%) Injection, USP.

How Supplied


Esmolol Hydrochloride Injection

NDC 0641-2965-45, 100 mg - 10 mL Ready-to-use Vials, Package of 25

Store at 20#-25#C (68#-77#F). Excursions permitted to 15#-30#C (59#-86#F). [See USP Controlled Room Temperature.]

PROTECT FROM FREEZING. Avoid excessive heat.

Baxter is a registered trademark of Baxter International Inc.

Manufactured by

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)

Rev: April 2005



Sample Package Label










Esmolol 
Esmolol  injection










Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)52584-017 (0641-2965)
Route of AdministrationINTRAVENOUSDEA Schedule    








Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
Esmolol Hydrochloride (Esmolol)Esmolol Hydrochloride10 mg  in 1 mL





Inactive Ingredients
Ingredient NameStrength
No Inactive Ingredients Found


















Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains      














Packaging
#NDCPackage DescriptionMultilevel Packaging
152584-017-411 VIAL In 1 BAGcontains a VIAL, SINGLE-DOSE
110 mL In 1 VIAL, SINGLE-DOSEThis package is contained within the BAG (52584-017-41)










Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA01938604/01/2010


Labeler - General Injectables & Vaccines, Inc (108250663)
Revised: 04/2011General Injectables & Vaccines, Inc

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Wednesday, 22 August 2012

Eldepryl Syrup 10 mg / 5 ml





1. Name Of The Medicinal Product



Eldepryl 10 mg/5 ml Syrup


2. Qualitative And Quantitative Composition



Selegiline hydrochloride 10 mg /5 ml



For full list of excipients, see section 6.1



3. Pharmaceutical Form



Syrup for oral administration.



4. Clinical Particulars



4.1 Therapeutic Indications



Selegiline is indicated for the treatment of Parkinson's disease, or symptomatic parkinsonism. It may be used alone in early Parkinson's disease for symptomatic relief to delay the need for levodopa (with or without decarboxylase inhibitor) or as an adjunct to levodopa (with or without decarboxylase inhibitor). Selegiline in combination with maximal levodopa therapy is indicated particularly in patients who experience fluctuations in their condition such as 'end-dose' type fluctuations, 'on-off' symptoms or other dyskinesias.



4.2 Posology And Method Of Administration



10 mg daily either alone or as an adjunct to levodopa or levodopa/peripheral decarboxylase inhibitor. Selegiline may be administered either as a single dose in the morning or in two divided doses of 5 mg, taken at breakfast and lunch. When selegiline is added to a levodopa regimen it is possible to reduce the levodopa dosage by an average of 10-30%. Reduction of the levodopa dose should be gradual in steps of 10% every 3 to 4 days.



No dosage adjustment is required for patients with renal or hepatic impairment.



4.3 Contraindications



Eldepryl is contra-indicated in patients with known hypersensitivity (including severe dizziness or hypotension) to selegiline or any of the excipients used in this product.



Eldepryl is contra-indicated in patients receiving treatment with serotonin-agonists (e.g. sumatriptan, naratriptan, zolmitriptan and rizatriptan).



Selegiline is also contra-indicated for concomitant use with pethidine and other opioids.



Selegiline should not be used in patients who are being treated with antidepressant drugs, including MAO inhibitors tricyclic antidepressants, serotonin noradrenalin reuptake inhibitors (venlafaxine) and selective serotonin reuptake inhibitors (e.g citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. See section 4.5 interactions).



Selegiline should also not be used with other drugs which are also monoamine oxidase inhibitors, e.g. linezolid.



Selegiline should not be used in combination with sympathomimetics (see section 4.5).



Selegiline should not be used in patients with active duodenal or gastric ulcer.



Selegiline should not be used in patients with other extrapyramidal disorders not related to dopamine deficiency.



Selegiline in combination with levodopa is contra-indicated in severe cardiovascular disease, arterial hypertension, hyperthyroidism, phaeochromocytoma, narrow-angle glaucoma, prostatic adenoma with appearance of residual urine, tachycardia, arrhythmias, severe angina pectoris, psychoses, advanced dementia and thyrotoxicosis.



4.4 Special Warnings And Precautions For Use



The precise dose at which selegiline becomes a non-selective inhibitor of all MAO has not been determined, but with doses higher than 10 mg/day there is a theoretical risk of hypertension after ingestion of tyramine-rich food.



Concomitant treatment with medicines which inhibit MAO-A, (or non-selective MAO inhibitors) can cause hypotensive reactions. Hypotension, sometimes sudden in onset, has been reported with conventional selegiline.



Special care should be taken when administering selegiline to patients who have labile hypertension, cardiac arrhythmias, severe angina pectoris, psychosis or a history of peptic ulceration as aggravation of these conditions may occur during treatment.



Although serious hepatic toxicity has not been observed, caution is recommended in patients with a history of hepatic dysfunction. Transient or continuing abnormalities with a tendency for elevated plasma concentrations of liver enzymes have been described during long-term therapy with conventional tablets of selegiline.



Selegiline should be used with caution in severe liver or kidney dysfunction.



Caution should be exercised in patients receiving MAO inhibitors during general anaesthesia in surgery.



Some studies concluded in an increased risk of mortality in patients receiving selegiline and levodopa compared to those receiving levodopa only. However, it is noteworthy that multiple methodological bias were identified in these studies and that a meta analysis and large cohort studies concluded that there was no significant difference in mortality in patients treated with selegiline to those treated with comparators or with the association selegiline/levodopa.



Studies have related the risk of an increased hypotensive response to concomitant administration of selegiline and levodopa, in patients with cardiovascular risk.



The addition of selegiline to levodopa may not be beneficial in those patients who experience fluctuations in response which are not dose dependent.



Caution is advised when selegiline is taken in combination with other centrally acting medicinal products and substances. The concomitant intake of alcohol should be avoided.



Since selegiline potentiates the effects of levodopa, the adverse effects of levodopa may be increased. When selegiline is added to the maximum tolerated dose of levodopa, involuntary movements and agitation may occur. Levodopa should be reduced by about 10 to 30% when selegiline is added to the treatment (see section 4.2 Posology and Method of Administration). When an optimum dose of levodopa is reached, adverse effects from the combination are less than those observed with levodopa on its own.



Oral suspension 10 mg/5 ml contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Additionally, sucrose may be harmful to the teeth. Oral suspension contains methyl, propyl and butyl parahyroxybenzoate as excipients, which may cause allergic reactions (possibly delayed).



4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction



Association contra-indicated (see section 4.3)



Sympathomimetics



Because of the risk of hypertension, co-administration of selegiline and sympathomimetics is contraindicated.



Pethidine



The concomitant administration of the selective MAO-B inhibitor selegiline and pethidine is contraindicated.



Selegiline should not be administered with any type of antidepressant.



Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenalin reuptake inhibitors (SNRIs)



When selegiline is used at its recommended dose, it selectively inhibits MAO-B. The combined use of the SSRI, fluoxetine and Eldepryl, should only be used under clinical supervision.



Serious reactions with signs and symptoms that may include diaphoresis, flushing, ataxia, hyperthermia, hyper/hypotension, seizures, palpitation, dizziness and mental changes that include agitation, confusion and hallucinations progressing to delirium and coma have been reported in some patients receiving a combination of selegiline and fluoxetine. Similar experience has been reported in patients receiving selegiline and two other serotonin reuptake inhibitors, sertraline and paroxetine. There is a potential risk of interaction with fluvoxamine and venlafaxine.



Because of the risk of confusion, hypomania, hallucination and manic episodes, agitation, myoclonus, hyperreflexia, incoordination, shivering, tremor, convulsion, ataxia, diaphoresis, diarrhea, fever, hypertension, which can be part of the serotonine syndrome, concomitant administration of selegiline and SSRIs or SNRIs is contraindicated.



Use of Eldepryl beyond the recommended dose could lead to non-selectivity and serious adverse effects.



Death has been reported to occur following the initiation of therapy with non-selective MAO inhibitors shortly after discontinuation of fluoxetine. Fluoxetine should not be used less than 14 days after discontinuation of selegiline. Since fluoxetine has a very long elimination half life, at least 5 weeks should be allowed after stopping fluoxetine and before starting selegiline. Selegiline should not be started until 2 weeks after stopping sertraline. For all other serotonin reuptake inhibitors, a time interval of 1 week is recommended between discontinuation of the serotonin reuptake inhibitor and initiation of selegiline. In general, selegiline should not be introduced after a drug that is known to interact with selegiline, until after 5 half lives of that drug have elapsed.



At least 14 days should lapse between the discontinuation of selegiline and initiation of treatment with any drug known to interact with selegiline.



A time interval of 24 hours is recommended between the discontinuation of selegiline and initiation of serotonin agonists.



Patients being treated with selegiline currently or within the past 2 weeks should receive dopamine only after careful risk-benefit assessment, as this combination enhances the risk of hypertensive reactions.



Tricyclic antidepressants



Severe CNS toxicity (serotonin syndrome) has been reported in patients with the combination of tricyclic antidepressants and selegiline. In one patient receiving amitriptyline and selegiline this included hyperpyrexia and death, and another patient receiving protriptyline and Selegiline experienced tremor, agitation, and restlessness followed by unresponsiveness and death two weeks after selegiline was added.



Other adverse reactions occasionally reported in patients receiving a combination of selegiline with various tricyclic antidepressants include hyper/hypotension, dizziness, diaphoresis, tremor, seizures and changes in behavioural and mental status. Therefore, the concomitant use of selegiline and tricyclic antidepressants is contraindicated.



Associations not recommended



MAO inhibitors



Concomitant administration of selegiline and MAO inhibitors may cause severe hypotension (see section 4.4).



Oral contraceptives



The combination of selegiline and oral contraceptives or drugs for hormone replacement therapy, should be avoided, as this combination may multiply the bioavailability of selegiline.



Food interactions



As selegiline is a specific MAO-B inhibitor, foods containing tyramine have not been reported to induce hypertensive reactions during selegiline treatment at recommended dosage (i.e., it does not cause the so-called “ cheese-effect ”). Therefore, no dietary restrictions are required. However, in case of combination of selegiline and conventional MAO inhibitors or MAO-A, dietary restrictions (i.e. avoidance of food with large amounts of tyramine such as aged cheese and yeast products) are recommended.



Concomitant administration of amantadine and anticholinergic drugs can lead to an increased occurrence of side-effects.



In view of the high degree of binding to plasma proteins by selegiline particular attention must be given to patients who are being treated with medicines with a narrow therapeutic margin / index such as digitalis and/or anticoagulants. Four patients receiving altretamine and a monamine oxidase inhibitor experienced symptomatic hypotension after four to seven days of concomitant therapy.



Concomitant use of hypertensive agents, antihypertensives, psychostimulants, central suppressant drugs (sedatives, hypnotics) and alcohol should be avoided.



Food interactions



As selegiline is a specific MAO-B inhibitor, foods containing tyramine have not been reported to induce hypertensive reactions during selegiline treatment at recommended dosage (i.e., it does not cause the so-called “ cheese-effect ”). Therefore, no dietary restrictions are required. However, in case of combination of selegiline and conventional MAO inhibitors or MAO-A, dietary restrictions (i.e. avoidance of food with large amounts of tyramine such as aged cheese and yeast products) are recommended.



4.6 Pregnancy And Lactation



Selegiline is indicated for the treatment of Parkinson's disease which, in most cases, is a disease occurring after childbearing age.



The available safety data concerning the use during pregnancy and lactation is insufficient to justify the use of selegiline in these patient groups. Studies in animals have shown reproductive toxicity at only high multiple of human doses.



As a precautionary measure, it is preferable to avoid the use of selegiline in pregnancy.



. It is unknown whether selegiline is excreted in human breast milk. The excretion of selegiline in milk has not been studied in animals. Physico-chemical data on selegiline point to excretion in breast milk and a risk to the suckling child cannot be excluded. Selegiline should not be used during breast-feeding.



4.7 Effects On Ability To Drive And Use Machines



Even when used correctly, this medicine may cause dizziness or can affect reaction capacity to the extent that driving or operating machinery is affected and therefore patients should be advised not to drive or use machines if they experience these adverse reactions during treatment.



4.8 Undesirable Effects



The following undesirable effects have been reported with selegiline during clinical trials and/or post-marketing use. They are listed below as MedDRA preferred term by system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Very common (







































































































System Organ Class




Frequency




Undesirable effects




Infections and infestations




Uncommon




Pharyngitis




Blood and lymphatic system disorders




Uncommon




Leucocytopenia, thrombocytopenia




Metabolism and nutrition disorders




Uncommon




Loss of appetite




Psychiatric disorders




Common




Sleeping disorders, confusion, hallucinations, depression




Uncommon




Abnormal dreams, agitation, anxiety, psychoses, mood change


 


Not known




Hypersexuality


 


Nervous system disorders




Common




Abnormal movements (such as dyskinesias, akinesia, bradykinesia), dizziness, headache, impaired balance, tremor




Uncommon




mild transient sleep disorder


 


Eye disorders




Uncommon




Blurred vision




Ear and labyrinth disorders




Common




Vertigo




Cardiac disorders




Common




Bradycardia




Uncommon




Arrhythmias, palpitations, angina pectoris, supraventricular tachycardia


 


Vascular disorders




Common




hypotension, hypertension




Uncommon




Orthostatic hypotension


 


Rare




Postural hypotension


 


Respiratory, thoracic and mediastinal disorders




Common




Nasal congestion, sore throat




Uncommon




Dyspnoea


 


Gastrointestinal disorders




Very common




Stomatitis




Common




Nausea, constipation, diarrhoea, mouth ulceration


 


Uncommon




Dry mouth


 


Hepato-biliary disordrers




Uncommon




Transient rise of serum alanine aminotransferase (ALAT)




Skin and subcutaneous tissue




Common




Sweating increased




Uncommon




Hair loss, skin eruptions


 


Rare




Skin reactions


 


Muskuloskeletal and lymphatic system disorders




Common




Arthralgia, back pain, muscle cramps




Uncommon




Myopathy


 


Renal and urinary disorders




Uncommon




Micturition disorders




Not known




Urinary retention


 


General disorders and administration site conditions




Common




Fatigue




Uncommon




Chest pain, irritability, ankle oedema


 


Injury, poisoning and procedural complications




Common




Fall




Investigations




Common




Mild hepatic enzymes increased



As selegiline potentiates the effect of levodopa (levodopa should be usually given in association with a peripheral decarboxylase inhibitor), the side-effects of levodopa may be emphasised unless the dosage of levodopa is reduced. Selegiline combination therapy may permit further reduction of levodopa dose (even by 30 %). The most common undesirable effect reported for conventional tablets is dyskinesia (4% of patients) other side effects include restlessness, hyperkinesis, abnormal movements, agitation, confusion, hallucination, postural hypotension, cardiac arrhythmias. Once the optimum levodopa dose level has been established, the side-effects produced by the combination will usually be less than those caused by the levodopa therapy on its own.



4.9 Overdose



Selegiline is rapidly metabolised and the metabolites rapidly excreted. In cases of suspected overdosage the patient should be kept under observation for 24 to 48 hours.



No overdosage cases are known. Since the selective inhibition of MAO-B by selegiline is achieved only at doses recommended for the treatment of Parkinson's disease (5 to 10 mg/day).However, experience gained during selegiline's development reveals that some individuals exposed to doses of 600 mg/day selegiline suffered severe hypotension and psychomotor agitation.



Theoretically, overdosage causes significant inhibition of both MAO-A and MAO-B and thus, symptoms of overdosage may resemble those observed with non-selective MAO-inhibitors which can progress over 24 hours to include, different central nervous and cardiovascular system disorders. These include agitation, irritability, hyperactivity, drowsiness, tremor, severe headache, hallucination, alternating low and high blood pressure dizziness, faintness, vascular collapse, rapid and irregular pulse, precordial pain, respiratory depression and failure, severe muscle spasms, hyperpyrexia, diaphoresis coma and convulsions. There is no specific antidote and the treatment is symptomatic.



5. Pharmacological Properties



5.1 Pharmacodynamic Properties



Selegiline is a selective MAO-B-inhibitor which prevents dopamine breakdown in the brain. It also inhibits the reuptake of dopamine at the presynaptic dopamine receptor. These effects potentiate dopaminergic function in the brain and help to even out and prolong the effect of exogenous and endogenous dopamine. Thus, selegiline potentiates and prolongs the effect of levodopa in the treatment of parkinsonism. Since it does not interfere with the breakdown of 5-hydroxytryptamine (serotonin) or noradrenaline, it does not cause any hypertensive crises or changes in the plasma or urinary metabolites of these monoamines. Although dietary restrictions are not necessary during selegiline treatment, the inhibition of MAO-B in blood platelets can lead to a slight potentiation of the circulatory effects of any tyramine not broken down by gastrointestinal MAO-A during absorption.



The magnitude of increase in the urinary excretion of β-phenylethylamine over 24 hours is simply related to the area under the selegiline plasma concentration-time curve after any selegiline product. Urinary β-phenylethylamine increase reflects the degree of inhibition of MAO-B.



Double-blind studies on early phase Parkinsonian patients showed that patients receiving selegiline monotherapy manage significantly longer without levodopa therapy than controls receiving placebo. These patients could also maintain their ability to work longer.



The addition of selegiline to levodopa (with or without decarboxylase inhibitor) therapy helps to alleviate dose related fluctuations and end of dose deterioration.



When selegiline is added to such a regimen it is possible to reduce the levodopa dosage by an average of 30%. Unlike conventional MAO-inhibitors, which inhibit both the MAO-A and MAO-B enzyme, selegiline is a specific MAO-B inhibitor and can be given safely with levodopa.



Selegiline HCl does not cause the so called "cheese effect" either when used alone as monotherapy, or when used with other drugs, except for moclobemide or nonselective MAO-inhibitors.



5.2 Pharmacokinetic Properties



Selegiline HCl is readily absorbed from the gastrointestinal tract. The maximal concentrations are reached in 0.5-0.75h after oral administration in fasting state. The bioavailability is low; 10% (on the average; interindividual variation is large) of unchanged selegiline can reach the systemic circulation.



Selegiline is a lipophilic, slightly basic compound which quickly penetrates into tissues, also into brain. Selegiline is rapidly distributed throughout the body, the apparent volume of distribution being 500 1 after an intravenous 10 mg dose. 75-85% of selegiline is bound to plasma proteins at therapeutic concentrations. Selegiline HCl inhibits enzyme MAO-B irreversibly and enzyme activity only increases again after new enzyme is synthesised. The strong inhibitory effect platelet enzyme MAO-B activity after single 10 mg dose lasts over 24 h, and the platelet enzyme MAO-B activity returns to normal level approximately after 2 weeks



Selegiline is rapidly metabolised, mainly in the liver, into active metabolites desmethylselegiline, l-methamphetamine and to l-amphetamine, with elimination half-lives of 2.1h, 20.5 h and 17.7 h respectively. In vitro studies indicate that CYP2B6 is the main hepatic cytochrome P450 (CYP) enzyme involved in the metabolism of selegiline with a possible contribution of CYP3A4 and CYP2A6.



Selegiline AUC and desmethylselegiline AUC increase 2.7 fold and 1.5 fold respectively from day 1 to day 8 on dosing 10 mg od. However, the half-lives of selegiline (range, 1.5-3.5 h) and desmethylselegiline (range, 3.4 – 5.3 h) were found to be relatively short. Accordingly, the short half-lives of these compounds failed to predict the apparent accumulation.



The most likely explanation for the significant increase in selegiline and desmethylselegiline concentrations in serum which was observed during the 8-day multiple dose administration of selegiline HCl is saturation of MAO-B binding sties in tissues, as the rapid elimination of both selegiline and desmethyl selegiline cannot explain the apparent accumulation observed. However, decrease in the first-pass metabolism of selegiline on multiple dosing cannot be ruled out.



In humans, the three metabolites have been identified in plasma and urine after single and multiple doses of selegiline. The mean elimination half-life is 1.5-3.5 h for selegiline. The total body clearance of selegiline is about 240 I/h. The metabolites of selegiline are excreted mainly via the urine with about 15% occurring in the faeces.



5.3 Preclinical Safety Data



Selegiline has not been sufficiently tested for reproductive toxicity. Studies with selegiline revealed no evidence of mutagenic or carcinogenic effects. The only safety concerns for human use derived from animal studies were effects associated with an exaggerated pharmacological action.



6. Pharmaceutical Particulars



6.1 List Of Excipients



Methyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sucrose, xanthan gum T, saccharin sodium, flavour mango, purified water.



6.2 Incompatibilities



No other incompatibilities noted.



6.3 Shelf Life



36 months



6.4 Special Precautions For Storage



No special precautions.



6.5 Nature And Contents Of Container



Amber glass bottle (200 ml) sealed with a pilfer-proof type EPE/Aluminium Melinex screw cap. The container is packed in a cardboard box with a graduated dose dispenser.



6.6 Special Precautions For Disposal And Other Handling



None.



7. Marketing Authorisation Holder



Orion Corporation, Orionintie 1, FIN-02200 Espoo, Finland



8. Marketing Authorisation Number(S)



PL 27925/0006



9. Date Of First Authorisation/Renewal Of The Authorisation



1.7.1993/Renewal July 2007



10. Date Of Revision Of The Text



June 2011