Fluorscan

Fluorscan may be available in the countries listed below.

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Fludeoxyglucose (18F)

Fludeoxyglucose (18F) is reported as an ingredient of Fluorscan in the following countries:

• Spain

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Deratil

Deratil may be available in the countries listed below.

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Itraconazole

Itraconazole is reported as an ingredient of Deratil in the following countries:

• Greece

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Feralice

Feralice may be available in the countries listed below.

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Iron Polymaltose

Iron Polymaltose is reported as an ingredient of Feralice in the following countries:

• Greece

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Virucalm

Virucalm may be available in the countries listed below.

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Acyclovir

Aciclovir is reported as an ingredient of Virucalm in the following countries:

• Switzerland

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Fenobarbital Klonal

Fenobarbital Klonal may be available in the countries listed below.

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Phenobarbital

Phenobarbital is reported as an ingredient of Fenobarbital Klonal in the following countries:

• Argentina

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Fentina

Fentina may be available in the countries listed below.

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Memantine

Memantine hydrochloride (a derivative of Memantine) is reported as an ingredient of Fentina in the following countries:

• Argentina

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Flospar

Flospar may be available in the countries listed below.

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Sparfloxacin

Sparfloxacin is reported as an ingredient of Flospar in the following countries:

• Vietnam

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Fitergol

Fitergol may be available in the countries listed below.

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

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Nicergoline

Nicergoline is reported as an ingredient of Fitergol in the following countries:

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Fentanyl-Acino

Fentanyl-Acino may be available in the countries listed below.

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Fentanyl

Fentanyl is reported as an ingredient of Fentanyl-Acino in the following countries:

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Bupicain + Adrenalina

Bupicain + Adrenalina may be available in the countries listed below.

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Bupivacaine

Bupivacaine hydrochloride (a derivative of Bupivacaine) is reported as an ingredient of Bupicain + Adrenalina in the following countries:

• Italy

Epinephrine

Epinephrine bitartrate (a derivative of Epinephrine) is reported as an ingredient of Bupicain + Adrenalina in the following countries:

• Italy

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Felodipin Sandoz

Felodipin Sandoz may be available in the countries listed below.

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Felodipine

Felodipine is reported as an ingredient of Felodipin Sandoz in the following countries:

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Ferplex Fol

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Ferrous Succinate

Ferrous Succinate is reported as an ingredient of Ferplex Fol in the following countries:

• Turkey

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Trolovol

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Penicillamine

Penicillamine is reported as an ingredient of Trolovol in the following countries:

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Nefopam

Scheme

Rec.INN

ATC (Anatomical Therapeutic Chemical Classification)

N02BG06

CAS registry number (Chemical Abstracts Service)

0013669-70-0

Chemical Formula

C17-H19-N-O

Molecular Weight

253

Therapeutic Category

Analgesic and antipyretic

Chemical Name

1H-2,5-Benzoxazocine, 3,4,5,6-tetrahydro-5-methyl-1-phenyl-

Foreign Names

• Nefopamum (Latin)
• Nefopam (German)
• Néfopam (French)
• Nefopam (Spanish)

Generic Names

• Nefopam (OS: DCIT, BAN)
• Néfopam (OS: DCF)
• Nefopam Hydrochloride (OS: BANM, USAN)
• Fenazoxine (IS)
• R 738 (IS)

Brand Names

• Acupan
  Biocodex, Tunisia; 3M, Bahrain; 3M, Israel; 3M, Kenya; 3M, Zimbabwe; Biocodex, France; Douglas, New Zealand; Meda, Belgium; Meda, United Kingdom; Meda, Ireland; Meda, Luxembourg



• Dosidol
  Domesco, Vietnam



• Glosic
  Glomed, Vietnam



• Nefogesic
  Dar-Al-Dawa, United Arab Emirates; Dar-Al-Dawa, Bahrain; Dar-Al-Dawa, Iraq; Dar-Al-Dawa, Lebanon; Dar-Al-Dawa, Libya; Dar-Al-Dawa, Nigeria; Dar-Al-Dawa, Oman; Dar-Al-Dawa, Saudi Arabia; Dar-Al-Dawa, Sudan; Dar-Al-Dawa, Yemen



• Nefopam
  Jelfa, Poland



• Nisidol
  Zenith Biochemicals, Vietnam



• Oxadol
  Pharma Riace, Russian Federation



• Panagesic
  Medochemie, Taiwan

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Glossary

BAN	British Approved Name
BANM	British Approved Name (Modified)
DCF	Dénomination Commune Française
DCIT	Denominazione Comune Italiana
IS	Inofficial Synonym
OS	Official Synonym
Rec.INN	Recommended International Nonproprietary Name (World Health Organization)
USAN	United States Adopted Name

Click for further information on drug naming conventions and International Nonproprietary Names.

Furadonins

Furadonins may be available in the countries listed below.

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Nitrofurantoin

Nitrofurantoin is reported as an ingredient of Furadonins in the following countries:

• Latvia


• Lithuania

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Simvador 20mg

1. Name Of The Medicinal Product

Simvastatin 20mg Tablets

Simvador 20mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 20 mg of simvastatin.

Excipients: Lactose monohydrate

For full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-Coated Tablet

Simvastatin 20 mg tablets, are tan coloured, oval shaped, biconvex, film-coated tablets, debossed with '20' on one side and breakline on the other side, containing Simvastatin 20 mg.

4. Clinical Particulars

4.1 Therapeutic Indications

Hypercholesterolaemia

Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate.

Treatment of homozygous familial hypercholesterolaemia as an adjunct to diet and other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are not appropriate.

Cardiovascular prevention

Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic cardiovascular disease or diabetes mellitus, with either normal or increased cholesterol levels, as an adjunct to correction of other risk factors and other cardioprotective therapy (see section 5.1).

4.2 Posology And Method Of Administration

The dosage range is 5-80 mg/day given orally as a single dose in the evening.

Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg/day given as a single dose in the evening. The 80-mg dose is only recommended in patients with severe hypercholesterolaemia and high risk for cardiovascular complications, who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks (see section 4.4 and 5.1).

Hypercholesterolaemia

The patient should be placed on a standard cholesterol-lowering diet, and should continue on this diet during treatment with Simvastatin. The usual starting dose is 10-20 mg/day given as a single dose in the evening. Patients who require a large reduction in LDL-C (more than 45 %) may be started at 20-40 mg/day given as a single dose in the evening. Adjustments of dosage, if required, should be made as specified above.

Homozygous familial hypercholesterolaemia

Based on the results of a controlled clinical study, the recommended dosage is Simvastatin 40 mg/day in the evening or 80 mg/day in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg. Simvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Cardiovascular prevention

The usual dose of Simvastatin is 20 to 40 mg/day given as a single dose in the evening in patients at high risk of coronary heart disease (CHD, with or without hyperlipidaemia). Drug therapy can be initiated simultaneously with diet and exercise. Adjustments of dosage, if required, should be made as specified above.

Concomitant therapy

Simvastatin is effective alone or in combination with bile acid sequestrants. Dosing should occur either> 2 hours before or> 4 hours after administration of a bile acid sequestrant. In patients taking ciclosporin, danazol, gemfibrozil or other fibrates (except fenofibrate) concomitantly with Simvastatin, the dose of Simvastatin should not exceed 10 mg/day. In patients taking amiodarone orverapamil concomitantly with Simvastatin, the dose of Simvastatin should not exceed 20 mg/day. In patients taking diltiazem or amtopidine concomitantly with Simvastatin, the dose of Simvastatin should not exceed 40mg/day (See sections 4.4 and 4.5.)

Dosage in renal insufficiency

No modification of dosage should be necessary in patients with moderate renal insufficiency. In patients with severe renal insufficiency (creatinine clearance < 30 ml/min), dosages above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

Use in the elderly

No dosage adjustment is necessary.

Use in children and adolescents (10-17 years of age)

For children and adolescents (boys Tanner Stage II and above and girls who are at least one year post-menarche, 10-17 years of age) with heterozygous familial hypercholesterolaemia, the recommended usual starting dose is 10 mg once a day in the evening. Children and adolescents should be placed on a standard cholesterol-lowering diet before simvastatin treatment initiation; this diet should be continued during simvastatin treatment.

The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy as recommended by the paediatric treatment recommendations (see sections 4.4 and 5.1). Adjustments should be made at intervals of 4 weeks or more.

The experience of simvastatin in pre-pubertal children is limited.

4.3 Contraindications

Hypersensitivity to simvastatin or to any of the excipients

Active liver disease or unexplained persistent elevations of serum transaminases.

Pregnancy and lactation (see section 4.6)

Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone) (see section 4.5).

4.4 Special Warnings And Precautions For Use

Myopathy/Rhabdomyolysis

Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with Simvastatin 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08% and 0.61% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

In a clinical trial in which patients with a history of myocardial infarction were treated with Simvastatin 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%. (See sections 4.8 and 5.1).

Creatine Kinase measurement

Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 x ULN), levels should be re-measured within 5 to 7 days later to confirm the results.

Before the treatment

All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.

Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a CK level should be measured before starting a treatment in the following situations:

• Elderly (age

- Female gender

• Renal impairment

• Uncontrolled hypothyroidism

• Personal or familial history of hereditary muscular disorders

• Previous history of muscular toxicity with a statin or fibrate

• Alcohol abuse.

In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with a different member of the class should only be initiated with caution. If CK levels are significantly elevated at baseline (> 5 x ULN), treatment should not be started.

Whilst on treatment

If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with a statin, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (> 5 x ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are < 5 x ULN, treatment discontinuation may be considered. If myopathy is suspected for any other reason, treatment should be discontinued.

If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.

A higher rate of myopathy has been observed in patients titrated to the 80mg dose (see section 5.1). Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy.

Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

Measures to reduce the risk of myopathy caused by medicinal product interactions (see also section 4.5)

The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of simvastatin with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone), as well as gemfibrozil, ciclosporin and danazol (see section 4.2).

The risk of myopathy and rhabdomyolysis is also increased by concomitant use of other fibrates or by concomitant use of amiodarone or verapamil with higher doses of simvastatin (see sections 4.2 and 4.5). The risk is increased by concomitant use of diltiazem or amlopidine with simvastatin 80 mg (see sections 4.2 and 4.5).

The risk of myopathy including rhabdomyolysis may be increased by concomitant administration of fusidic acid with statins (see section 4.5).

Consequently, regarding CYP3A4 inhibitors, the use of simvastatin concomitantly with itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see sections 4.3 and 4.5). If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Moreover, caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: ciclosporin, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and simvastatin should be avoided.

The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin, danazol or gemfibrozil. The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. The benefits of the combined use of simvastatin 10 mg daily with other fibrates (except fenofibrate), ciclosporin or danazol should be carefully weighed against the potential risks of these combinations. (See sections 4.2 and 4.5.)

Caution should be used when prescribing fenofibrate with simvastatin, as either agent can cause myopathy when given alone.

The combined use of simvastatin at doses higher than 20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).

The combined use of simvastatin at doses higher than 40 mg daily with diltiazem or amlopidine should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid

Physicians contemplating combined therapy with simvastatin and lipid

In an interim analysis of an ongoing clinical outcomes study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg and nicotinic acid/laropiprant 2000 mg/40 mg. Therefore, caution should be used when treating Chinese patients with simvastatin (particularly doses of 40 mg or higher) co

If the combination proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.5). Temporary suspension of simvastain treatment may be considered.

Hepatic effects

In clinical studies, persistent increases (to> 3 x ULN) in serum transaminases have occurred in a few adult patients who received simvastatin. When simvastatin was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pre-treatment levels.

It is recommended that liver function tests be performed before treatment begins and thereafter when clinically indicated. Patients titrated to the 80-mg dose should receive an additional test prior to titration, 3 months after titration to the 80-mg dose, and periodically thereafter (e.g., semi-annually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 x ULN and are persistent, simvastatin should be discontinued.

The product should be used with caution in patients who consume substantial quantities of alcohol.

As with other lipid-lowering agents, moderate (< 3 x ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Use in children and adolescents (10-17 years of age)

Safety and effectiveness of simvastatin in patients 10-17 years of age with heterozygous familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys Tanner Stage II and above and in girls who were at least one year post-menarche. Patients treated with simvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. (See sections 4.2, 4.8, and 5.1.) Adolescent females should be counselled on appropriate contraceptive methods while on simvastatin therapy (see sections 4.3 and 4.6). In patients aged < 18 years, efficacy and safety have not been studied for treatment periods> 48 weeks' duration and long-term effects on physical, intellectual, and sexual maturation are unknown. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-pubertal children and pre-menarchal girls.

Excipient

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

Pharmacodynamic interactions

Interactions with lipid-lowering medicinal products that can cause myopathy when given alone. The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration with fibrates. Additionally, there is a pharmacokinetic interaction with gemfibrozil resulting in increased simvastatin plasma levels (see below Pharmacokinetic interactions and sections 4.2 and 4.4). When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent. Adequate pharmacovigilance and pharmacokinetic data are not available for other fibrates. Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses (

Pharmacokinetic interactions

Prescribing recommendations for interacting agents are summarised in the table below (further details are provided in the text; see also sections 4.2, 4.3 and 4.4).

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Interacting agents	Prescribing recommendations
Potent CYP3A4 inhibitors: Itraconazole Ketoconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone	Contraindicated with simvastatin
Gemfibrozil	Avoid but if necessary, do not exceed 10 mg simvastatin daily
Ciclosporin Danazol Other fibrates (except fenofibrate)	Do not exceed 10 mg simvastatin daily
Amiodarone Verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem Amlopidine	Do not exceed 40 mg simvastatin daily
Fusidic acid	Patients should be closely monitored. Temporary suspension of simvastatin treatment may be considered.
Grapefruit juice	Avoid grapefruit juice when taking simvastatin

Effects of other medicinal products on simvastatin

Interactions involving CYP3A4

Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone. Concomitant administration of itraconazole resulted in a more than 10-fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite). Telithromycin caused an 11-fold increase in exposure to simvastatin acid.

Therefore, combination with itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: ciclosporin, verapamil, diltiazem (see sections 4.2 and 4.4).

Ciclosporin

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin particularly with higher doses of simvastatin (see sections 4.2 and 4.4). Therefore, the dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin. Although the mechanism is not fully understood, ciclosporin increases the AUC of simvastatin acid presumably due, in part, to inhibition of CYP3A4.

Danazol

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with higher doses of simvastatin (see sections 4.2 and 4.4).

Gemfibrozil

Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway (see sections 4.2 and 4.4).

Amiodarone

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone with higher doses of simvastatin (see section 4.4). In a clinical trial, myopathy was reported in 6 % of patients receiving simvastatin 80 mg and amiodarone. Therefore the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Calcium Channel Blockers

• Verapamil

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of verapamil with simvastatin 40 mg or 80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration with verapamil resulted in a 2.3

• Diltiazem

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with simvastatin 80 mg (see section 4.4). The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant diltiazem (see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem caused a 2.7

• Amlodipine

Patients on amlodipine treated concomitantly with simvastatin 80 mg have a slightly increased risk of myopathy. The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant amlodipine. In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with amlopidine, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Niacin (nicotinic acid)

Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co_max of simvastatin acid plasma concentrations.

Fusidic acid

The risk of myopathy may be increased by concomitant administration of fusidic acid with statins, including simvastatin. Isolated cases of rhabdomyolysis have been reported with simvastatin. Temporary suspension of simvastatin treatment may be considered. If it proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.4).

Grapefruit juice

Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (over 1 litre daily) of grapefruit juice and simvastatin resulted in a 7-fold increase in exposure to simvastatin acid. Intake of 240 ml of grapefruit juice in the morning and simvastatin in the evening also resulted in a 1.9-fold increase. Intake of grapefruit juice during treatment with simvastatin should therefore be avoided.

Effects of simvastatin on the pharmacokinetics of other medicinal products.

Simvastatin does not have an inhibitory effect on cytochrome P450 3A4. Therefore, simvastatin is not expected to affect plasma concentrations of substances metabolised via cytochrome P450 3A4.

Oral anticoagulants

In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. Very rare cases of elevated INR have been reported. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

4.6 Pregnancy And Lactation

Pregnancy: Simvastatin is contraindicated during pregnancy (see section 4.3).

Safety in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to Simvastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies over the background incidence.

Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking Simvastatin or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with Simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia. For these reasons, Simvastatin must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant.

Treatment with Simvastatin must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. (See section 4.3.)

Lactation: It is not known whether simvastatin or its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk and because of the potential for serious adverse reactions, women taking Simvastatin should not breast-feed their infants (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

Simvastatin has no or negligible influence on the ability to drive and use machines.

However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported rarely in post-marketing experiences.

4.8 Undesirable Effects

The frequencies of the following adverse events, which have been reported during clinical studies and/or post-marketing use, are categorized based on an assessment of their incidence rates in large, long-term, placebo-controlled, clinical trials including HPS and 4S with 20,536 and 4,444 patients, respectively (see section 5.1). For HPS, only serious adverse events were recorded as well as myalgia, increases in serum transaminases and CK. For 4S, all the adverse events listed below were recorded. If the incidence rates on simvastatin were less than or similar to that of placebo in these trials, and there were similar reasonably causally related spontaneous report events, these adverse events are categorized as “rare”.

In HPS (see section 5.1) involving 20,536 patients treated with 40 mg/day of Simvastatin (n = 10,269) or placebo (n = 10,267), the safety profiles were comparable between patients treated with Simvastatin 40 mg and patients treated with placebo over the mean 5 years of the study. Discontinuation rates due to side effects were comparable (4.8 % in patients treated with Simvastatin 40 mg compared with 5.1 % in patients treated with placebo). The incidence of myopathy was < 0.1 % in patients treated with Simvastatin 40 mg. Elevated transaminases (> 3 x ULN confirmed by repeat test) occurred in 0.21 % (n = 21) of patients treated with Simvastatin 40 mg compared with 0.09 % (n = 9) of patients treated with placebo.

The frequencies of adverse events are ranked according to the following: Very common (> 1/10), Common (

Investigations:
Rare:	increases in serum transaminases (alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase) (see section 4.4 Hepatic effects), elevated alkaline phosphatase; increase in serum CK levels (see section 4.4).
Blood and lymphatic system disorders:
Rare:	anaemia
Nervous system disorders:
Rare:	headache, paresthesia, dizziness, peripheral neuropathy
Very rare:	memory impairment
Gastrointestinal disorders:
Rare:	constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis
Hepato-biliary disorders:
Rare:	hepatitis/jaundice
Very rare:	hepatic failure
Skin and subcutaneous tissue disorders:
Rare:	rash, pruritus, alopecia
Musculoskeletal, connective tissue and bone disorders:
Rare:	myopathy*, rhabdomyolysis (see section 4.4), myalgia, muscle cramps
*In a clinical trial, myopathy occurred commonly in patients treated with Simvastatin 80 mg/day compared to patients treated with 20 mg/day (1.0% vs 0.02%, respectively).
General disorders and administration site conditions:
Rare:	asthenia
An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.

Psychiatric disorders:

Very rare: insomnia

The following adverse events have been reported with some statins:

• Sleep disturbances, including insomnia and nightmares

• Sexual dysfunction

• Depression

• Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)

Children and adolescents (10-17 years of age)

In a 48-week study involving children and adolescents (boys Tanner Stage II and above and girls who were at least one year post-menarche) 10-17 years of age with heterozygous familial hypercholesterolaemia (n = 175), the safety and tolerability profile of the group treated with simvastatin was generally similar to that of the group treated with placebo. The long-term effects on physical, intellectual, and sexual maturation are unknown. No sufficient data are currently available after one year of treatment. (See sections 4.2, 4.4, and 5.1.)

4.9 Overdose

To date, a few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. There is no specific treatment in the event of overdose. In this case, symptomatic and supportive measures should be adopted.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: HMG-CoA reductase inhibitor

ATC-Code: C10A A01

After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to the corresponding active beta-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3 hydroxy – 3 methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.

Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of Simvastatin may involve both reduction of VLDL cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with Simvastatin. In addition, Simvastatin moderately increases HDL-C and reduces plasma TG. As a result of these changes the ratios of total- to HDL-C and LDL- to HDL-C are reduced.

High Risk of Coronary Heart Disease (CHD) or Existing Coronary Heart Disease

In the Heart Protection Study (HPS), the effects of therapy with Simvastatin were assessed in 20,536 patients (age 40-80 years), with or without hyperlipidaemia, and with coronary heart disease, other occlusive arterial disease or diabetes mellitus. In this study, 10,269 patients were treated with Simvastatin 40 mg/day and 10,267 patients were treated with placebo for a mean duration of 5 years. At baseline, 6,793 patients (33 %) had LDL-C levels below 116 mg/dL; 5,063 patients (25 %) had levels between 116 mg/dL and 135 mg/dL; and 8,680 patients (42 %) had levels greater than 135 mg/dL.

Treatment with Simvastatin 40 mg/day compared with placebo significantly reduced the risk of all cause mortality (1328 [12.9 %] for simvastatin-treated patients versus 1507 [14.7 %] for patients given placebo; p = 0.0003), due to an 18 % reduction in coronary death rate (587 [5.7 %] versus 707 [6.9 %]; p = 0.0005; absolute risk reduction of 1.2 %). The reduction in non-vascular deaths did not reach statistical significance. Simvastatin also decreased the risk of major coronary events (a composite endpoint comprised of non-fatal MI or CHD death) by 27 % (p < 0.0001). Simvastatin reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral and other noncoronary revascularization procedures by 30 % (p < 0.0001) and 16 % (p = 0.006), respectively. Simvastatin reduced the risk of stroke by 25 % (p < 0.0001), attributable to a 30 % reduction in ischemic stroke (p < 0.0001). In addition, within the subgroup of patients with diabetes, Simvastatin reduced the risk of developing macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations, or leg ulcers by 21 % (p = 0.0293). The proportional reduction in event rate was similar in each subgroup of patients studied, including those without coronary disease but who had cerebrovascular or peripheral artery disease, men and women, those aged either under or over 70 years at entry into the study, presence or absence of hypertension, and notably those with LDL cholesterol below 3.0 mmol/l at inclusion.

In the Scandinavian Simvastatin Survival Study (4S), the effect of therapy with Simvastatin on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomised, double-blind, placebo-controlled study, patients with angina or a previous myocardial infarction (MI) were treated with diet, standard care, and either Simvastatin 20-40 mg/day (n = 2,221) or placebo (n = 2,223) for a median duration of 5.4 years. Simvastatin reduced the risk of death by 30 % (absolute risk reduction of 3.3 %). The risk of CHD death was reduced by 42 % (absolute risk reduction of 3.5 %). Simvastatin also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent nonfatal MI) by 34 %. Furthermore, Simvastatin significantly reduced the risk of fatal plus nonfatal cerebrovascular events (stroke and transient ischemic attacks) by 28 %. There was no statistically significant difference between groups in non-cardiovascular mortality.

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) evaluated the effect of treatment with Simvastatin 80 mg versus 20 mg (median follow-up 6.7 yrs) on major vascular events (MVEs; defined as fatal CHD, non-fatal MI, coronary revascularization procedure, non-fatal or fatal stroke, or peripheral revascularization procedure) in 12,064 patients with a history of myocardial infarction. There was no significant difference in the incidence of MVEs between the 2 groups Simvastatin 20 mg (n = 1553; 25.7 %) vs. Simvastatin 80 mg (n = 1477; 24.5 %); RR 0.94, 95 % CI: 0.88 to 1.01. The absolute difference in LDL-C between the two groups over the course of the study was 0.35 ± 0.01 mmol/L. The safety profiles were similar between the two treatment groups except that the incidence of myopathy was approximately 1.0 % for patients on Simvastatin 80 mg compared with 0.02 % for patients on 20 mg. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1 %.

Primary Hypercholesterolaemia and Combined Hyperlipidaemia

In studies comparing the efficacy and safety of simvastatin 10, 20, 40 and 80 mg daily in patients with hypercholesterolemia, the mean reductions of LDL-C were 30, 38, 41 and 47 %, respectively. In studies of patients with combined (mixed) hyperlipidaemia on simvastatin 40 mg and 80 mg, the median reductions in triglycerides were 28 and 33 % (placebo: 2 %), respectively, and mean increases in HDL-C were 13 and 16 % (placebo: 3 %), respectively.

Clinical Studies in Children and Adolescents (10-17 years of age)

In a double-blind, placebo-controlled study, 175 patients (99 boys Tanner Stage II and above and 76 girls who were at least one year post-menarche) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (heFH) were randomized to simvastatin or placebo for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level> 189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy and received simvastatin 40 mg or placebo.

Simvastatin significantly decreased plasma levels of LDL-C, TG, and Apo B. Results from the extension at 48 weeks were comparable to those observed in the base study.

After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0- 289.0 mg/dL) in the simvastatin 40 mg group compared to 207.8 mg/dL (range: 128.0-334.0 mg/dL) in the placebo group.

After 24 weeks of simvastatin treatment (with dosages increasing from 10, 20 and up to 40 mg daily at 8- week intervals), simvastatin decreased the mean LDL-C by 36.8 % (placebo: 1.1 % increase from baseline), Apo B by 32.4 % (placebo: 0.5 %), and median TG levels by 7.9 % (placebo: 3.2 %) and increased mean HDL-C levels by 8.3 % (placebo: 3.6 %). The long-term benefits of simvastatin on cardiovascular events in children with heFH are unknown.

The safety and efficacy of doses above 40 mg daily have not been studied in children with heterozygous familial hypercholesterolaemia. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

5.2 Pharmacokinetic Properties

Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.

The pharmacokinetic properties have been evaluated in adults. Pharmacokinetic data in children and adolescents are not available.

Absorption

In man simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is the primary site of action of the active form. The availability of the betahydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5 % of the dose. Maximum plasma concentration of active inhibitors is reached approximately 1-2 hours after administration of simvastatin.

Concomitant food intake does not affect the absorption. The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of medicinal product occurred after multiple dosing.

Distribution

The protein binding of simvastatin and its active metabolite is> 95 %.

Elimination

Simvastatin is a substrate of CYP3A4 (see sections 4.3 and 4.5). The major metabolites of simvastatin present in human plasma are the beta-hydroxyacid and four additional active metabolites. Following an oral dose of radioactive simvastatin to man, 13 % of the radioactivity was excreted in the urine and 60 % in the faeces within 96 hours. The amount recovered in the faeces represents absorbed medicinal product equivalents excreted in bile as well as unabsorbed medicinal product. Following an intravenous injection of the beta-hydroxyacid metabolite, its half-life averaged 1.9 hours. An average of only 0.3 % of the IV dose was exc

Adalimumab

In the US, Adalimumab (adalimumab systemic) is a member of the following drug classes: antirheumatics, TNF alfa inhibitors and is used to treat Ankylosing Spondylitis, Crohn's Disease, Crohn's Disease - Acute, Crohn's Disease - Maintenance, Juvenile Idiopathic Arthritis, Psoriasis, Psoriatic Arthritis, Reiter's Syndrome and Rheumatoid Arthritis.

US matches:

• Adalimumab


• Adalimumab Subcutaneous

Scheme

Rec.INN

ATC (Anatomical Therapeutic Chemical Classification)

L04AA17,L04AB04

CAS registry number (Chemical Abstracts Service)

0331731-18-1

Chemical Formula

C6428-H9912-N1694-O1987-S46

Molecular Weight

144190

Therapeutic Categories

Anti-inflammatory agent

Disease-modifying antirheumatic drug, DMARD

Monoclonal antibody

Tumor necrosis factor alpha (TNF-α) inhibitor

Chemical Name

Immunoglobulin G 1 (human monoclonal D2E7 heavy chain anti-human tumor necrosis factor), disulfide with human monoclonal D2E7kappa-chain, dimer (WHO)

Foreign Names

• Adalimumabum (Latin)
• Adalimumab (German)
• Adalimumab (French)
• Adalimumab (Spanish)

Generic Names

• Adalimumab (OS: BAN, USAN)
• D 2E7 (IS)
• LU 200134 (IS)

Brand Names

• Humira
  Abbott, Argentina; Abbott, Australia; Abbott, Belgium; Abbott, Bulgaria; Abbott, Bahrain; Abbott, Brazil; Abbott, Canada; Abbott, Switzerland; Abbott, Chile; Abbott, Colombia; Abbott, Costa Rica; Abbott, Czech Republic; Abbott, Germany; Abbott, Denmark; Abbott, Ecuador; Abbott, Spain; Abbott, Finland; Abbott, France; Abbott, United Kingdom; Abbott, Greece; Abbott, Hong Kong; Abbott, Croatia (Hrvatska); Abbott, Hungary; Abbott, Ireland; Abbott, Israel; Abbott, Iceland; Abbott, Italy; Abbott, Japan; Abbott, Luxembourg; Abbott, Mexico; Abbott, Netherlands; Abbott, Norway; Abbott, New Zealand; Abbott, Oman; Abbott, Peru; Abbott, Poland; Abbott, Portugal; Abbott, Sweden; Abbott, Singapore; Abbott, Slovenia; Abbott, Slovakia; Abbott, Turkey; Abbott, Taiwan; Abbott, United States; Abbott, South Africa; Abbott Laboratories, Austria

International Drug Name Search

Glossary

BAN	British Approved Name
IS	Inofficial Synonym
OS	Official Synonym
Rec.INN	Recommended International Nonproprietary Name (World Health Organization)
USAN	United States Adopted Name
WHO	World Health Organization

Click for further information on drug naming conventions and International Nonproprietary Names.

Imotil

Generic Name: loperamide (Oral route)

loe-PER-a-mide

Commonly used brand name(s)

In the U.S.

• Diamode


• Imodium


• Imodium A-D


• Imogen


• Imotil


• Imperim


• Kaodene A-D


• Kao-Paverin Caps

Available Dosage Forms:

• Tablet


• Capsule


• Liquid


• Tablet, Chewable


• Solution


• Capsule, Liquid Filled

Therapeutic Class: Antidiarrheal

Uses For Imotil

Loperamide is a medicine used along with other measures to treat diarrhea. Loperamide helps stop diarrhea by slowing down the movements of the intestines.

In the U.S., loperamide capsules are available only with your doctor's prescription.

Before Using Imotil

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

This medicine should not be used in children under 6 years of age unless directed by a doctor. Children, especially very young children, are very sensitive to the effects of loperamide. This may increase the chance of side effects during treatment. Also, the fluid loss caused by diarrhea may result in a serious health problem (dehydration). Loperamide may hide the symptoms of dehydration. For these reasons, do not give medicine for diarrhea to children without first checking with their doctor. If you have any questions about this, check with your health care professional.

Geriatric

The fluid loss caused by diarrhea may result in a serious health problem (dehydration). Loperamide may hide the symptoms of dehydration. For this reason, elderly persons with diarrhea, in addition to using medicine for diarrhea, must receive a sufficient amount of liquids to replace the fluid lost by the body. If you have any questions about this, check with your health care professional.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

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

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

• Saquinavir

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

• Gemfibrozil


• Itraconazole

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:

• Colitis (severe)—A more serious problem of the colon may develop if you use loperamide

• Dysentery—This condition may get worse; a different kind of treatment may be needed

• Liver disease—The chance of severe central nervous system (CNS) side effects may be greater in patients with liver disease

Proper Use of loperamide

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

Do not use loperamide to treat your diarrhea if you have a fever or if there is blood or mucus in your stools. Contact your doctor.

For safe and effective use of this medicine:

• Follow your doctor's instructions if this medicine was prescribed.


• Follow the manufacturer's package directions if you are treating yourself.

Use a specially marked measuring spoon or other device to measure each dose accurately. The average household teaspoon may not hold the right amount of liquid.

Importance of diet and fluid intake while treating diarrhea:

• In addition to using medicine for diarrhea, it is very important that you replace the fluid lost by the body and follow a proper diet. For the first 24 hours, you should eat gelatin, and drink plenty of caffeine-free clear liquids, such as ginger ale, decaffeinated cola, decaffeinated tea, and broth. During the next 24 hours you may eat bland foods, such as cooked cereals, bread, crackers, and applesauce. Fruits, vegetables, fried or spicy foods, bran, candy, caffeine, and alcoholic beverages may make the condition worse.


• If too much fluid has been lost by the body due to the diarrhea, a serious condition (dehydration) may develop. Check with your doctor as soon as possible if any of the following signs or symptoms of too much fluid loss occur:
  
  • Decreased urination
  
  
  • Dizziness and lightheadedness
  
  
  • Dryness of mouth
  
  
  • Increased thirst
  
  
  • Wrinkled skin
  
  

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 diarrhea:
  
  • For oral dosage form (capsules):
    
    • Adults and teenagers—The usual dose is 4 milligrams (mg) (2 capsules) after the first loose bowel movement, and 2 mg (1 capsule) after each loose bowel movement after the first dose has been taken. No more than 16 mg (8 capsules) should be taken in any twenty-four-hour period.
    
    
    • Children 8 to 12 years of age—The usual dose is 2 mg (1 capsule) three times a day.
    
    
    • Children 6 to 8 years of age—The usual dose is 2 mg (1 capsule) two times a day.
    
    
    • Children up to 6 years of age—Use is not recommended unless directed by your doctor.
    
    
  
  
  • For oral dosage form (oral solution):
    
    • Adults and teenagers—The usual dose is 4 teaspoonfuls (4 mg) after the first loose bowel movement, and 2 teaspoonfuls (2 mg) after each loose bowel movement after the first dose has been taken. No more than 8 teaspoonfuls (8 mg) should be taken in any twenty-four-hour period.
    
    
    • Children 9 to 11 years of age—The usual dose is 2 teaspoonfuls (2 mg) after the first loose bowel movement, and 1 teaspoonful (1 mg) after each loose bowel movement after the first dose has been taken. No more than 6 teaspoonfuls (6 mg) should be taken in any twenty-four-hour period.
    
    
    • Children 6 to 8 years of age—The usual dose is 2 teaspoonfuls (2 mg) after the first loose bowel movement, and 1 teaspoonful (1 mg) after each loose bowel movement after the first dose has been taken. No more than 4 teaspoonfuls (4 mg) should be taken in any twenty-four-hour period.
    
    
    • Children up to 6 years of age—Use is not recommended unless directed by your doctor.
    
    
  
  
  • For oral dosage form (tablets):
    
    • Adults and teenagers—The usual dose is 4 mg (2 tablets) after the first loose bowel movement, and 2 mg (1 tablet) after each loose bowel movement after the first dose has been taken. No more than 8 mg (4 tablets) should be taken in any twenty-four-hour period.
    
    
    • Children 9 to 11 years of age—The usual dose is 2 mg (1 tablet) after the first loose bowel movement, and 1 mg (½ tablet) after each loose bowel movement after the first dose has been taken. No more than 6 mg (3 tablets) should be taken in any twenty-four-hour period.
    
    
    • Children 6 to 8 years of age—The usual dose is 2 mg (1 tablet) after the first loose bowel movement, and 1 mg (½ tablet) after each loose bowel movement after the first dose has been taken. No more than 4 mg (2 tablets) should be taken in any twenty-four-hour period.
    
    
    • Children up to 6 years of age—Use is not recommended unless directed by your doctor.
    
    
  
  

Missed Dose

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

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Imotil

Loperamide should not be used for more than 2 days, unless directed by your doctor. If you will be taking this medicine regularly for a long time, your doctor should check your progress at regular visits.

Check with your doctor if your diarrhea does not stop after two days or if you develop a fever.

Imotil 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:

Rare

• Bloating


• constipation


• loss of appetite


• stomach pain (severe) with nausea and vomiting

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

Rare

• Skin rash

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:

Rare

• Dizziness or drowsiness


• dryness of mouth

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: Imotil side effects (in more detail)

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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 Imotil resources

• Imotil Side Effects (in more detail)
• Imotil Use in Pregnancy & Breastfeeding
• Imotil Drug Interactions
• Imotil Support Group
• 1 Review for Imotil - Add your own review/rating

• Loperamide Prescribing Information (FDA)


• Imodium Consumer Overview


• Imodium MedFacts Consumer Leaflet (Wolters Kluwer)


• Imodium Prescribing Information (FDA)


• Imodium A-D MedFacts Consumer Leaflet (Wolters Kluwer)


• Loperamide Hydrochloride Monograph (AHFS DI)

Compare Imotil with other medications

• Diarrhea
• Diarrhea, Acute
• Diarrhea, Chronic
• Lymphocytic Colitis
• Traveler's Diarrhea

Distaph

Distaph may be available in the countries listed below.

Ingredient matches for Distaph

Dicloxacillin

Dicloxacillin sodium salt (a derivative of Dicloxacillin) is reported as an ingredient of Distaph in the following countries:

• Australia

International Drug Name Search

Mitoxantrone Hydrochloride

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: 1,4-dihydroxy-5,8-bis[[2-[2-hydroxyethyl)amino]ethyl]amino]9,10-anthracenedione dihydrochloride
Molecular Formula: C₂₂H₂₈N₄O₆• 2HCl
CAS Number: 70476-82-3
Brands: Novantrone

• Experience of Supervising Clinician


• 
  

  Administer only under the supervision of qualified clinicians experienced in the use of cytotoxic therapy.^{1 9}

  
  

• Administration Warnings


• 
  

  Administer slowly into a freely running IV infusion solution.^{1 2} Do not administer by IM, sub-Q, intra-arterial, or intrathecal injection.^{1 3}

  
  


• 
  

  Severe local tissue necrosis if extravasation occurs.¹ (See Local Effects under Cautions.)

  
  


• 
  

  Severe and sometimes irreversible neurotoxicity reported following intrathecal administration.¹ (See Neurotoxicity under Cautions.)

  
  

• Myelosuppression


• 
  

  Severe myelosuppression may occur.¹ Generally avoid use in patients with baseline neutrophil count <1500/mm³, except for treatment of acute myeloid (myelogenous, nonlymphocytic) leukemia.¹ Monitor hematologic status carefully.¹ (See Hematologic Effects under Cautions.)

  
  

• Myocardial Toxicity


• 
  

  Possible cardiotoxicity and potentially fatal CHF during or months to years after therapy;¹ risk increases with increasing cumulative dose.^{2 18 26}

  
  


• 
  

  Risk factors (history of or current cardiovascular disease, prior or concomitant irradiation to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs) may increase risk of cardiotoxicity.^{1 2 3 18 19 20 26} However, toxicity may occur regardless of whether cardiac risk factors are present.¹ (See Cardiotoxicity under Cautions.)

  
  


• 
  

  Risk of CHF developing in cancer patients is estimated to be 2.6% at cumulative dose of up to 140 mg/m².¹

  
  


• 
  

  Prior to initiation of therapy, evaluate all patients for cardiac signs/symptoms by history and physical examination and determine baseline left ventricular ejection fraction (LVEF) by echocardiogram or multigated radionuclide angiography (MUGA).¹

  
  


• 
  

  Do not initiate therapy in patients with multiple sclerosis if baseline LVEF is <50%.¹

  
  


• 
  

  In patients with multiple sclerosis, evaluate LVEF by echocardiogram or MUGA prior to each dose; do not administer additional doses if LVEF decreases to <50% or if a clinically important reduction in LVEF occurs.¹

  
  


• 
  

  Patients with multiple sclerosis should not receive cumulative dose >140 mg/m².¹

  
  

• Secondary Acute Myelogenous Leukemia (AML)


• 
  

  Secondary AML reported in patients treated with mitoxantrone; risk of refractory secondary leukemias increases when anthracyclines are combined with other DNA-damaging antineoplastics, after extensive exposure to cytotoxic drugs, or when anthracycline doses have been escalated.¹ (See Carcinogenicity under Cautions.)

  
  

Introduction

Antineoplastic agent; a synthetic anthracenedione.^{1 2 3 4 26}

Uses for Mitoxantrone Hydrochloride

Acute Myeloid Leukemia

A component of various chemotherapy regimens for remission induction in acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL).^{1 2 3 7 8 9 10 11 24} AML includes acute promyelocytic, monocytic, myelomonocytic, megakaryoblastic, and erythroid leukemias.^{1 23}

Used in combination with other antineoplastic agents in consolidation therapy regimens following induction of complete remission.^{1 8 10}

Prostate Cancer

Used as an alternative regimen for initial palliative treatment of advanced, symptomatic (i.e., painful) hormone-refractory prostate cancer (in combination with prednisone).^{1 12 13 14 22 24 26} Preferred first-line of treatment for hormone-refractory metastatic prostate cancer is docetaxel in combination with prednisone.²²

Multiple Sclerosis (MS)

Treatment of secondary (chronic) progressive, progressive-relapsing, or worsening relapsing-remitting MS.¹ Used to reduce neurologic disability and/or frequency of relapse.¹

Has been studied in patients with the following disease patterns: Gradually increasing disability with or without superimposed clinical relapses (secondary progressive and progressive-relapsing subtypes) and clinical relapses resulting in stepwise increases in disability, with substantially abnormal neurologic status between relapses (worsening relapsing-remitting disease).¹

Not recommended for use in patients with primary progressive MS.¹

Should not be used for treatment of MS in patients with baseline LVEF <50% (see Myocardial Toxicity in Boxed Warning).¹ Generally not recommended for use in those with hepatic impairment (see Hepatic Impairment under Cautions) or in those with neutrophil count <1500/mm³.¹

Non-Hodgkin’s Lymphoma

Used as a component of combination chemotherapy regimens for treatment of low-grade non-Hodgkin’s lymphoma†.²⁴

Mitoxantrone Hydrochloride Dosage and Administration

General

• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.¹

  
  

Acute Myeloid Leukemia

• 
  

  Appropriate hematologic monitoring required; adjunctive therapies (e.g., anti-infectives, blood and blood products) must be available during the expected period of medullary hypoplasia and severe myelosuppression.^{1 23} Ensure full hematologic recovery before initiating consolidation therapy and monitor closely.^{1 23} (See Hematologic Effects under Cautions.)

  
  

Administration

Administer by IV infusion.¹ Do not administer IM or sub-Q.¹ Do not administer by intra-arterial or intrathecal injection.¹ (See Neurotoxicity under Cautions.)

Safety of administration by routes other than IV not established.¹

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer diluted solution into tubing of a freely running IV solution of 0.9% sodium chloride injection or 5% dextrose injection, preferably via a Butterfly needle or other suitable device inserted into a large vein.¹

When possible, do not use veins over joints or in extremities with compromised venous or lymphatic drainage.¹

Avoid extravasation.¹ If signs or symptoms of extravasation occur, immediately stop the infusion and restart in another vein.¹ (See Local Effects under Cautions.) If sub-Q extravasation occurs or is suspected, elevation of the affected extremity and intermittent application of ice to the site may be useful.¹ Because of the progressive nature of extravasation reactions, close observation and surgery consultation recommended.¹

Handle cautiously (by trained nonpregnant personnel); use protective equipment (e.g., goggles, gloves, protective gowns).¹ Use care to avoid contact of the drug with skin, mucous membranes, and eyes.¹ If skin contact occurs, immediately rinse affected areas with copious amounts of warm water; use standard irrigation techniques immediately in the event of eye involvement.¹

Dilution

Must be diluted prior to IV infusion.^{1 2 3}

Dilute dose of mitoxantrone hydrochloride in 0.9% sodium chloride injection or 5% dextrose injection to a final volume of ≥50 mL.^{1 3} Solutions may be further diluted with 5% dextrose injection, 0.9% sodium chloride injection, or 5% dextrose and 0.9% sodium chloride injection.¹

Diluted solutions contain no preservatives; prepare immediately before use.¹

Rate of Administration

Administer diluted solution slowly over ≥3 minutes;^{1 2 3} infusions are typically administered over 15–30 minutes.^{3 15}

In patients with prostate cancer or multiple sclerosis, infuse dose over approximately 5–15 minutes.¹

Dosage

Available as mitoxantrone hydrochloride; dosage expressed in terms of mitoxantrone.¹

Adults

Acute Myeloid Leukemia

Induction Therapy

IV

12 mg/m² daily on days 1–3 in combination with cytarabine 100 mg/m² daily (as a continuous IV infusion over 24 hours) on days 1–7.^{1 8 10 11}

If antileukemic response to the first induction course is incomplete, a second induction course consisting of 2 days of mitoxantrone (12 mg/m² daily) and 5 days of cytarabine (100 mg/m² daily) may be given.^{1 8 10 11}

If severe or life-threatening nonhematologic toxicity is observed during the initial induction course, withhold second induction course until toxicity resolves.¹

Consolidation Therapy

IV

12 mg/m² daily on days 1 and 2 in combination with cytarabine 100 mg/m² daily (as a continuous IV infusion over 24 hours) on days 1–5.^{1 8 10} Administer initial consolidation course approximately 6 weeks after the final induction course; administer the second consolidation course generally 4 weeks after the initial course.^{1 8}

Prostate Cancer

IV

12–14 mg/m² once every 21 days; give as an adjunct to corticosteroid therapy (e.g., prednisone 5 mg orally twice daily, hydrocortisone 40 mg orally daily).^{1 14} Some clinicians recommend discontinuance of mitoxantrone (and continuation of corticosteroid therapy alone) in patients who are still responding after a cumulative mitoxantrone dose of 140 mg/m² due to risk of cardiac toxicity.¹⁴

Multiple Sclerosis

IV

12 mg/m² once every 3 months.¹

Prescribing Limits

Adults

Multiple Sclerosis

IV

Maximum cumulative lifetime dose: 140 mg/m².¹

Special Populations

Hepatic Impairment

Decreased clearance; dosage adjustment may be required, however, no specific dosage adjustment recommendations.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage reduction not required.^{15 16}

Cautions for Mitoxantrone Hydrochloride

Contraindications

• 
  

  Known hypersensitivity to mitoxantrone or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Hematologic Effects

Risk of myelosuppression, manifested predominantly as neutropenia;¹ may be severe and result in infection.¹

Frequent monitoring of hematologic parameters required; monitor CBC, including platelet count, prior to each course of therapy and if signs or symptoms of infection occur.¹

Do not initiate mitoxantrone in patients with preexisting drug-induced myelosuppression unless expected treatment benefit warrants risk.¹

Except for treatment of AML, use generally not recommended in patients with baseline neutrophil count <1500/mm³.¹

Cardiotoxicity

Risk of cardiotoxicity during or months to years after therapy.¹ Functional cardiac changes (e.g., decreases in LVEF, irreversible CHF), tachycardia, ECG changes including arrhythmias, and chest pain can occur.^{1 2 3 18 19 20 26} Risk of cardiotoxicity increases with increasing cumulative dose.^{2 18 26} (See Myocardial Toxicity in Boxed Warning.)

Probability of developing CHF is 2.6% at a cumulative dosage of 140 mg/m² in cancer patients; the overall probability of moderate or serious decreases in LVEF was 13% at a cumulative dosage of 140 mg/m².^{1 2}

Preexisting cardiac disease, prior radiotherapy to the mediastinal or pericardial region, and/or previous anthracycline (e.g., doxorubicin, epirubicin) therapy increase risk of mitoxantrone-induced cardiotoxicity; determine benefit-to-risk ratio before initiating therapy in patients previously treated with anthracyclines (e.g., daunorubicin, doxorubicin).^{1 2 3 18 19 20} Monitor LVEF regularly following initiation of therapy in patients previously treated with an anthracycline or with mediastinal radiotherapy and in those with preexisting cardiovascular disease.^{1 2 3 18 19 20 26}

Evaluate cardiac function prior to initiation of therapy.¹ Discontinue therapy in patients with LVEF <50% or a clinically important reduction in LVEF.¹

Monitor LVEF in patients with multiple sclerosis prior to each dose and if signs/symptoms of CHF develop.¹ (See Myocardial Toxicity in Boxed Warning.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.¹ Potentially teratogenic based on developmental effects of related agents.¹

Avoid pregnancy during therapy.¹ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹

Exclude pregnancy with a negative pregnancy test prior to each dose in women of childbearing potential with multiple sclerosis.¹

Carcinogenicity

Secondary AML reported in mitoxantrone-treated patients with cancer or multiple sclerosis; risk of refractory AML increases with concomitant use of cytotoxic drugs and/or radiation therapy.¹ (See Secondary Acute Myelogenous Leukemia [AML] in Boxed Warning.)

In clinical trials of breast cancer patients receiving mitoxantrone-containing adjuvant therapy, estimated risk of developing treatment-related leukemia at 4, 5, and 10 years was 2.2, 1.1, and 1.6%, respectively.¹

In patients with multiple sclerosis receiving mitoxantrone, risk of developing treatment-related leukemia was 0.25% after variable periods of follow up.¹

Neurotoxicity

Local or regional neuropathy (sometimes irreversible) has been reported following intra-arterial injection.¹ Neurotoxicity (e.g., paralysis with bowel and bladder dysfunction, seizures resulting in coma and severe neurologic sequelae) has been observed following intrathecal injection.¹ Do not administer by intra-arterial or intrathecal injection.¹

General Precautions

Adequate Patient Evaluation and Monitoring

Administer only under the supervision of qualified clinicians experienced in the use of cytotoxic therapy.^{1 27}

Closely observe patient and evaluate hematopoietic, hepatic, and cardiac function prior to and at regular intervals during therapy.¹ (See Warnings under Cautions.)

Treat systemic infections prior to beginning therapy or concomitantly with therapy.¹

Pregnancy test recommended prior to each dose in women of childbearing potential with multiple sclerosis. ¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Tumor Lysis Syndrome

Hyperuricemia may result from rapid lysis of tumor cells; monitor serum uric acid concentration.¹ Administer hypouricemic therapy (e.g., allopurinol) prior to initiating therapy for leukemia.¹

Local Effects

Extravasation may result in tissue necrosis; debridement and skin graft may be required.¹ Erythema, swelling, pain, or blue discoloration has been reported following extravasation.¹ Phlebitis has been reported at injection site.¹

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established.¹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹

Possibility exists of greater sensitivity to the drug and more frequent toxicity in some geriatric individuals.¹

Hepatic Impairment

Safety not established; use with caution in patients with cancer.¹ Use not recommended in patients with multiple sclerosis who have hepatic impairment (i.e., abnormal liver function test results).¹

Decreased clearance reported in patients with severe hepatic impairment (i.e., serum total bilirubin concentration >3.4 mg/dL).^{1 15} Manufacturer states that drug clearance and required dosage adjustments cannot be predicted from liver function test results; therefore, no specific dosage adjustment recommendations for patients with hepatic impairment.¹

Renal Impairment

Not studied in patients with renal impairment.¹

Common Adverse Effects

Nausea, diarrhea, anorexia, alopecia, menstrual disorders, amenorrhea, myelosuppression, infection, fever, stomatitis, asthenia, fatigue, edema, dyspnea.¹

Interactions for Mitoxantrone Hydrochloride

Does not inhibit CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro; may be a weak inducer of CYP2E1.¹

No formal pharmacokinetic drug interaction studies to date.¹ Clinically important drug interactions not reported; information on interactions in patients with multiple sclerosis is limited.¹

Specific Drugs

Drug	Interaction
Aspirin	Plasma protein binding of mitoxantrone not altered1
Corticosteroids	Interaction not observed1 Plasma protein binding of mitoxantrone not altered by prednisone or prednisolone1
Doxorubicin	Plasma protein binding of mitoxantrone not altered1
Heparin	Plasma protein binding of mitoxantrone not altered1
Methotrexate	Plasma protein binding of mitoxantrone not altered1
Phenytoin	Plasma protein binding of mitoxantrone not altered1

Mitoxantrone Hydrochloride Pharmacokinetics

Distribution

Extent

Extensively distributed into tissues.¹ Distributed into milk.¹ Low concentrations attained in brain, spinal cord, eye, and CSF in monkeys.¹

Plasma Protein Binding

78%.¹

Special Populations

Increased tissue penetration and protein binding in patients with abnormalities of the third space (e.g., edema, ascites, pleural effusion).³

Elimination

Metabolism

Metabolic pathways not elucidated.¹

Elimination Route

Eliminated in feces (25%) by the hepatobiliary system¹ and to a lesser extent in urine (approximately 10%)^{1 2 16 17} as unchanged drug or inactive metabolites.¹

Half-life

Triphasic; terminal half-life is approximately 23–215 hours (median: approximately 75 hours).¹

Special Populations

Severe hepatic impairment (serum total bilirubin concentration >3.4 mg/dL) decreases clearance.^{1 15} Decreased clearance may occur in patients with abnormalities of the third space (e.g., edema, ascites, pleural effusion).³

Stability

Storage

Parenteral

Injection Concentrate

15–25°C.¹ Do not freeze.¹

Undiluted concentrate may be stored for 7 days at 15–25°C or 14 days under refrigeration after puncture of the vial stopper.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Compatible with filters; during the manufacturing process, drug solution is passed through a 0.22-mcm filter without loss of potency.¹⁵

Solution Compatibility^HID

Compatible
Dextrose 5% in sodium chloride 0.9%
Dextrose 5% in water
Sodium chloride 0.9%

Drug Compatibility

Do not mix in the same infusion as heparin; precipitation may occur.¹

Admixture CompatibilityHID

Compatible
Cyclophosphamide
Cytarabine
Etoposide
Fluorouracil
Hydrocortisone sodium succinate
Potassium chloride
Variable
Hydrocortisone sodium phosphate

Y-Site CompatibilityHID

Compatible
Allopurinol sodium
Amifostine
Cladribine
Etoposide
Etoposide phosphate
Filgrastim
Fludarabine phosphate
Gemcitabine HCl
Granisetron HCl
Linezolid
Melphalan HCl
Ondansetron HCl
Oxaliplatin
Sargramostim
Teniposide
Thiotepa
Vinorelbine tartrate
Incompatible
Amphotericin B cholesteryl sulfate complex
Aztreonam
Cefepime HCl
Doxorubicin HCl liposome injection
Lansoprazole
Paclitaxel
Pemetrexed disodium
Piperacillin sodium–tazobactam sodium
Propofol

ActionsActions

• 
  

  A DNA-reactive agent¹ that interferes with the function of topoisomerase II, thereby preventing religation of DNA strand breaks.^{2 5 26}

  
  


• 
  

  Cytotoxic activity also may result from the aggregation and compaction of DNA via electrostatic cross-linking, generation of free radicals (which may cause breaks in DNA strands), inhibition of protein kinase C activity, and induction of apoptosis in leukemic cells.^{2 26}

  
  


• 
  

  Exerts a cytocidal effect on both proliferating and nonproliferating cultured human cells.¹

  
  


• 
  

  Produces concentration- and time-proportional delays in cell-cycle progression.³ Not considered cell-cycle specific; however, mitoxantrone is most cytotoxic to cells in late S phase.³

  
  


• 
  

  Possible additive or synergistic effects with other antineoplastic agents (e.g., cytarabine, amsacrine, cisplatin, doxorubicin, etoposide).²

  
  


• 
  

  Tumor resistance may occur as a result of increased P-glycoprotein expression, alteration of the levels or activity of topoisomerase II, enhanced DNA repair mechanisms, or a combination of these and other mechanisms.^{2 3 26}

  
  


• 
  

  Incomplete cross-resistance with anthracyclines has been demonstrated in vitro.^{2 3 7}

  
  


• 
  

  Inhibits B-cell, T-cell, and macrophage proliferation; impairs antigen presentation; and inhibits secretion of cytokines (interferon gamma, tumor necrosis factor, interleukin-2) in vitro.¹

  
  

Advice to Patients

• 
  

  Importance of providing patients who have multiple sclerosis with a copy of the manufacturer’s patient information prior to initiation of therapy and before each dose of the drug.¹

  
  


• 
  

  Importance of recognizing and reporting adverse effects of mitoxantrone, including myelosuppressive effects (and related precautions), CHF symptoms, and injection site pain.¹

  
  


• 
  

  Risk of irreversible myocardial toxicity and secondary leukemia.¹

  
  


• 
  

  Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.¹

  
  


• 
  

  Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.¹

  
  


• 
  

  Possible blue-green appearance of urine for 24 hours after administration; the white part of the eyes also may appear blue.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Mitoxantrone Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection concentrate, for IV infusion	2 mg (of mitoxantrone) per mL (20, 25, and 30 mg)	Novantrone	OSI Pharmaceuticals (comarketed by Serono)

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Novantrone 2MG/ML Concentrate (SERONO): 10/$1340.7 or 30/$3980.72

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions May 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. EMD Serono. Novantrone (mitoxantrone) for injection concentrate prescribing information. Rockland, MA; 2008 Aug.

2. Dunn CJ, Goa KL. Mitoxantrone: a review of its pharmacological properties and use in acute nonlymphoblastic leukaemia. Drugs Aging. 1996; 9:122-47. [PubMed 8820798]

3. Faulds D, Balfour JA, Chrisp P et al. Mitoxantrone: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer. Drugs. 1991; 41:400-49. [PubMed 1711446]

4. Chabner BA, Myers CE. Antitumor antibiotics. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia, PA: J. B. Lippincott; 1993:374-84.

5. Capranico G, Zunino F. DNA topoisomerase-trapping antitumour drugs. Eur J Cancer. 1992; 28A:2055-60. [PubMed 1329885]

6. Morrow CS, Cowan KH. Mechanisms of antineoplastic drug resistance. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia, PA: J. B. Lippincott; 1993:340-8.

7. McCauley DL. Treatment of adult acute leukemia. Clin Pharm. 1992; 11:767-96. [IDIS 300402] [PubMed 1521402]

8. Arlin Z, Case DC Jr, Moore J et al. Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Leukemia. 1990; 4:177-83. [PubMed 2179638]

9. Feldman EJ. Acute myelogenous leukemia in the older patient. Semin Oncol. 1995; 22(Suppl 1):21-4. [PubMed 7532322]

10. Pavlovsky S, Gonzalez Llaven J, Garcia Martinez MA et al. A randomized study of mitoxantrone plus cytarabine versus daunomycin versus cytarabine in the treatment of previously untreated adult patients with acute nonlymphocytic leukemia. Ann Hematol. 1994; 69:11-5. [PubMed 8061102]

11. Wahlin A, Hornsten P, Hedenus M et al. Mitoxantrone and cytarabine versus daunorubicin and cytarabine in previously untreated patients with acute myeloid leukemia. Cancer Chemother Pharmacol. 1991; 28:480-3. [PubMed 1934252]

12. Immunex Corporation. Mitoxantrone for injection concentrate: clinical use in hormone-resistant prostate cancer. Seattle, WA: 1996.

13. Vogelzang NJ. One hundred thirteen men with hormone-refractory prostate cancer died today. J Clin Oncol. 1996; 14:1753-5. [IDIS 369577] [PubMed 8656242]

14. Tannock IF, Osoba D, Stockler MR et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996; 14:1756-64. [IDIS 369578] [PubMed 8656243]

15. Immunex Corporation. Mitoxantrone for injection concentrate: technical monograph. Seattle, WA: 1994.

16. Birchall LA, Bailey NP, Blackledge GRP. An overview of mitozantrone. Br J Clin Pract. 1991; 45:208-11. [IDIS 292197] [PubMed 1805919]

17. Schleyer E, Kamischke A, Kaufmann CC et al. New aspects on the pharmacokinetics of mitoxantrone and its two major metabolites. Leukemia. 1994; 8:435-40. [PubMed 8127148]

18. Crossley RJ. Clinical safety and tolerance of mitoxantrone. Semin Oncol. 1984; 11(Suppl 1):54-8. [PubMed 6385266]

19. Mather FJ, Simon RM, Clark GM et al. Cardiotoxicity in patients treated with mitoxantrone: Southwest Oncology Group phase II studies. Cancer Treat Rep. 1987; 71:609-13. [IDIS 231761] [PubMed 3581099]

20. Posner LE, Dukart G, Goldberg J et al. Mitoxantrone: an overview of safety and toxicity. Invest New Drugs. 1985; 3:123-32. [PubMed 3894276]

21. Prostate Cancer Trialists’ Collaborative Groups. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomized trials with 3283 deaths in 5710 patients. Lancet. 1995; 346:265-9. [IDIS 352509] [PubMed 7630245]

22. Prostate cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 Mar 5.

23. Adult acute myeloid leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 Mar 3.

24. Anon. Drugs of choice for cancer. Treat Guidelin Med Lett. 2003; 1:41-52.

25. Immunex Corporation, Seattle, WA: Personal communication.

26. Wiseman LR, Spencer CM. Mitoxantrone: a review of its pharmacology and clinical efficacy in the management of hormone-resistant advanced prostate cancer. Drug Aging. 1997; 10:473-85.

27. Goodin DS, Arnason BG, Coyle PK et al. The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003; 61:1332-8. [PubMed 14638950]

28. Hartung HP, Gonsette R, König N et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002; 360:2018-25. [PubMed 12504397]

29. Edan G, Miller D, Clanet M et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry. 1997; 62:112-8. [PubMed 9048709]

30. Krapf H, Morrissey SP, Zenker O et al. Effect of mitoxantrone on MRI in progressive MS: results of the MIMS trial. Neurology. 2005; 65:690-5. [PubMed 16157900]

31. Bastianello S, Pozzilli C, D’Andrea F et al. A controlled trial of mitoxantrone in multiple sclerosis: serial MRI evaluation at one year. Can J Neurol Sci. 1994; 21:266-70. [PubMed 8000984]

32. Millefiorini E, Gasperini C, Pozzilli C et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. J Neurol. 1997; 244:153-9. [PubMed 9050955]

33. Tannock IF, de Wit R, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004; 351:1502-12. [PubMed 15470213]

34. Kantoff PW, Halabi S, Conaway M et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol. 1999; 17:2506-13. [PubMed 10561316]

35. Food and Drug Administration. Labeling and prescription drug advertising; content and format for labeling for human prescription drugs. 21 CFR Parts 201 and 202. Final Rule. [Docket No. 75N-0066] Fed Regist. 1979; 44:37434-67.

36. Department of Health and Human Services, Food and Drug Administration. Subpart B—Labeling requirements for prescription drugs and/or insulin. (21 CFR Ch. 1 (4-1-87 Ed.)). 1987:18-24.

37. Meistrich ML, Wilson G, Mathur K et al. Rapid recovery of spermatogenesis after mitoxantrone, vincristine, vinblastine, and prednisone chemotherapy for Hodgkin’s disease. J Clin Oncol. 1997; 15:3488-95. [PubMed 9396402]

38. Cavalla P, Rovei V, Masera S et al. Fertility in patients with multiple sclerosis: current knowledge and future perspectives. Neurol Sci. 2006; 27:231-9. [PubMed 16998725]

39. Azuno Y, Kaku K, Fujita N et al. Mitoxantrone and etoposide in breast milk. Am J Hematol. 1995; 48:131-2. [PubMed 7847330]

40. Food and Drug Administration. MedWatch—Safety alert: mitoxantrone [July 29, 2008]. From FDA web site.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1155-8.

More Mitoxantrone Hydrochloride resources

• Mitoxantrone Hydrochloride Side Effects (in more detail)
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• 1 Review for Mitoxantrone Hydrochloride - Add your own review/rating

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