Lefebron

Lefebron may be available in the countries listed below.

Ingredient matches for Lefebron

Ibuprofen

Ibuprofen is reported as an ingredient of Lefebron in the following countries:

• Peru

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Relistor

1. Name Of The Medicinal Product

Relistor 12 mg/0.6 ml solution for injection

2. Qualitative And Quantitative Composition

Each vial of 0.6 ml contains 12 mg methylnaltrexone bromide.

One ml of solution contains 20 mg methylnaltrexone bromide.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection.

Clear solution, colourless to pale

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of opioid

4.2 Posology And Method Of Administration

Posology

For adults only.

Relistor should be added to induce prompt bowel movements when response to usual laxative therapy has not been sufficient.

The recommended dose of methylnaltrexone bromide is 8 mg (0.4 ml Relistor) (for patients weighing 38

The usual administration schedule is one single dose every other day. Doses may also be given with longer intervals, as per clinical need.

Patients may receive two consecutive doses 24 hours apart, only when there has been no response (bowel movement) to the dose on the preceding day.

Patients whose weight falls outside of the ranges should be dosed at 0.15 mg/kg. The injection volume for these patients should be calculated:

Dose (ml) = patient weight (kg) x 0.0075

Renal impairment

In patients with severe renal impairment (creatinine clearance less than 30 ml/min), the dose of methylnaltrexone bromide should be reduced from 12 mg to 8 mg (0.4 ml Relistor) for those weighing 62 to 114 kg, or from 0.15 mg/kg to 0.075 mg/kg for those whose weight falls outside the 62 to 114 kg range (see section 5.2). There are no data available from patients with end-stage renal impairment on dialysis, and Relistor is not recommended in these patients (see section 4.4).

Hepatic impairment

No dose adjustment is necessary in patients with mild to moderate hepatic impairment (see section 5.2).

There are no data available from patients with severe hepatic impairment (Child-Pugh Class C), and Relistor is not recommended in these patients (see section 4.4).

Paediatric population

No data are available.There is no experience in children under the age of 18 (see section 5.2). Therefore, methylnaltrexone should not be used in the paediatric age group until further data become available.

Elderly population

No dose adjustment is recommended based on age (see section 5.2).

Method of administration

Relistor is given as a subcutaneous injection.

It is recommended to rotate injection sites. It is not recommended to inject into areas where the skin is tender, bruised, red, or hard. Areas with scars or stretch marks should be avoided.

The three areas of the body recommended for injection of Relistor are upper legs, abdomen, and upper arms.

Relistor can be injected without regard to food.

4.3 Contraindications

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

Use of methylnaltrexone bromide in patients with known or suspected mechanical gastrointestinal obstruction or acute surgical abdomen is contraindicated.

4.4 Special Warnings And Precautions For Use

Cases of gastrointestinal (GI) perforation have been reported in the postauthorisation period in patients using Relistor. Although patients had medical conditions that may be associated with localised or diffuse reduction of structural integrity in the wall of the GI tract (e.g., cancer, peptic ulcer, pseudo-obstruction), the use of Relistor may have contributed to these events.

Use Relistor with caution in patients with known or suspected lesions of the GI tract.

Advise patients to promptly report severe, persistent, and/or worsening symptoms.

The activity of methylnaltrexone bromide has been studied in patients with constipation induced by opioids. Therefore, Relistor should not be used for treatment of patients with constipation not related to opioid use.

If severe or persistent diarrhoea occurs during treatment, patients should be advised not to continue therapy with Relistor and consult their physician.

Data from clinical trials suggest treatment with methylnaltrexone bromide can result in the rapid onset (within 30 to 60 minutes on average) of a bowel movement.

Methylnaltrexone bromide treatment has not been studied in clinical trials for longer than 4 months, and should therefore only be used for a limited period (see section 5.2).

Relistor should only be used in patients who are receiving palliative care. It is added to usual laxative treatment.

Relistor is not recommended in patients with severe hepatic impairment or with end

Use of methylnaltrexone bromide in patients with colostomy, peritoneal catheter, active diverticular disease or fecal impaction has not been studied. Therefore, Relistor should only be administered with caution in these patients.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially sodium-free.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Methylnaltrexone bromide does not affect the pharmacokinetics of medicinal products metabolised by cytochrome P450 (CYP) isozymes. Methylnaltrexone bromide is minimally metabolised by CYP isozymes. In vitro metabolism studies suggest that methylnaltrexone bromide does not inhibit the activity of CYP1A2, CYP2E1, CYP2B6, CYP2A6, CYP2C9, CYP2C19 or CYP3A4, while it is a weak inhibitor of the metabolism of a model CYP2D6 substrate. In a clinical drug interaction study in healthy adult male subjects, a subcutaneous dose of 0.3 mg/kg of methylnaltrexone did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate.

The organic cation transporter (OCT)-related drug-drug interaction potential between methylnaltrexone bromide and an OCT inhibitor was studied in 18 healthy subjects by comparing the single-dose pharmacokinetic profiles of methylnaltrexone bromide before and after multiple 400 mg doses of cimetidine. The renal clearance of methylnaltrexone bromide was reduced following multiple-dose administration of cimetidine (from 31 l/h to 18 1/h). However, this resulted in a small reduction in total clearance (from 107 1/h to 95 l/h). Consequently, no meaningful change in AUC of methylnaltrexone bromide, in addition to C_max, was observed before and after multiple-dose administration of cimetidine.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data with the use of methylnaltrexone bromide in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown. Relistor should not be used during pregnancy unless clearly necessary.

Breast-feeding

It is unknown whether methylnaltrexone bromide is excreted in human breast milk. Animal studies have shown excretion of methylnaltrexone bromide in breast milk. A decision on whether to continue/discontinue breast

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, as a pure peripherally restricted opioid antagonist, the likelihood that Relistor will affect such activities is low.

Dizziness may occur, and this may have an effect on driving and use of machines (see section 4.8).

4.8 Undesirable Effects

The most common drug

The adverse reactions are classified as: Very common (

Nervous system disorders

Common: Dizziness

Gastrointestinal disorders

Very common: Abdominal pain, nausea, diarrhoea, flatulence

Skin and subcutaneous tissue disorders

Common: Injection site reactions (e.g. stinging, burning, pain, redness, oedema), hyperhidrosis

Post Marketing Experience

Cases of gastrointestinal perforation have been reported in patients using Relistor (see section 4.4): frequency unknown.

4.9 Overdose

A study of healthy volunteers noted orthostatic hypotension associated with a dose of 0.64 mg/kg administered as an intravenous bolus.

In the event of an overdose, signs and symptoms of orthostatic hypotension should be monitored and reported to a physician. Treatment should be initiated as appropriate.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Peripheral opioid receptor antagonists, ATC code: A06AH01.

Mode of action

Methylnaltrexone bromide is a selective antagonist of opioid binding at the muIn vitro studies have shown methylnaltrexone bromide to be a mu_i] = 28 nM), with 8_i = 230 nM) and much reduced affinity for delta opioid receptors.

As a quaternary amine, the ability of methylnaltrexone to cross the blood

Clinical efficacy and safety

The efficacy and safety of methylnaltrexone bromide in the treatment of opioid

Study 301 compared methylnaltrexone bromide given as a single, double

Study 302 compared double

In both studies, there was no evidence to suggest differential effects of age or gender on safety or efficacy. The effect on race could not be analysed because the study population was predominantly Caucasian (88%).

Durability of response was demonstrated in Study 302, in which the laxation response rate was consistent from dose 1 through dose 7 over the course of the 2

The efficacy and safety of methylnaltrexone bromide were also demonstrated in open

The rate of laxation response was maintained throughout the extension studies for those patients who continued treatment.

There was no significant relationship between baseline opioid dose and laxation response in methylnaltrexone bromide

Effect on cardiac repolarisation

In a double

5.2 Pharmacokinetic Properties

Absorption

Methylnaltrexone bromide is absorbed rapidly, with peak concentrations (C_max) achieved at approximately 0.5 hours following subcutaneous administration. The C_max and area under the plasma concentration-time curve (AUC) increase with dose increase from 0.15 mg/kg to 0.5 mg/kg in a dose-proportional manner. Absolute bioavailability of a 0.30 mg/kg subcutaneous dose versus a 0.30 mg/kg intravenous dose is 82 %.

Distribution

Methylnaltrexone undergoes moderate tissue distribution. The steady

Biotransformation

Methylnaltrexone bromide is metabolised to a modest extent in humans based on the amount of methylnaltrexone bromide metabolites recovered from excreta. Conversion to methyl-6-naltrexol isomers and methylnaltrexone sulphate appears to be the primary pathway to metabolism. Each of the methyl-6-naltrexol isomers has somewhat less antagonist activity than parent compound, and a low exposure in plasma of approximately 8% of the drug

Elimination

Methylnaltrexone bromide is eliminated primarily as the unchanged active substance. Approximately half of the dose is excreted in the urine and somewhat less in faeces. The terminal disposition half_1/2) is approximately 8 hours.

Special populations

Hepatic insufficiency

The effect of mild and moderate hepatic impairment on the systemic exposure to methylnaltrexone bromide has been studied in 8 subjects each, with Child_max of methylnaltrexone. The effect of severe hepatic impairment on the pharmacokinetics of methylnaltrexone bromide has not been studied.

Renal impairment

In a study of volunteers with varying degrees of renal impairment receiving a single dose of 0.30 mg/kg methylnaltrexone bromide, renal impairment had a marked effect on the renal excretion of methylnaltrexone bromide. The renal clearance of methylnaltrexone decreased with increasing severity of renal impairment. Severe renal impairment decreased the renal clearance of methylnaltrexone bromide by 8_max was not significantly changed. No studies were performed in patients with end

Paediatric patients

No studies have been performed in the paediatric population (see section 4.2).

Elderly population

In a study comparing single and multiple-dose pharmacokinetic profiles of intravenous methylnaltrexone bromide at a dose of 24 mg between healthy, young (18 to 45 years of age n=10) and elderly (65 years of age and over n=10) subjects, the effect of age on exposure to methylnaltrexone bromide was found to be minor. The mean steady_max and AUC for the elderly were 545 ng/ml and 412 ng·h/ml, approximately 8.1 % and 20 %, respectively, greater than those for young subjects. Therefore, no dose adjustment is recommended based on age.

Gender

No meaningful gender differences have been observed.

Weight

An integrated analysis of pharmacokinetic data from healthy subjects indicated that methylnaltrexone bromide mg/kg dose-adjusted exposure increased as body weight increased. The mean methylnaltrexone bromide exposure at 0.15 mg/kg over a weight range of 38 to 114 kg was 179 (range=139-240) ng^·h/ml. This exposure for the 0.15 mg/kg dose can be achieved with a weight-band-based dose adjustment using an 8 mg dose for body weight 38 to less than 62 kg and a 12 mg dose for body weight 62 to 114 kg, yielding a mean exposure of 187 (range =148-220) ng^·h/ml. In addition, the analysis showed that 8 mg dose for body weight 38 to less than 62 kg and a 12 mg dose for body weight 62 to 114 kg correspond to mean doses of 0.16 (range=0.21

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity. Cardiac effects were observed in some non-clinical studies in canines (prolongation of action potentials in Purkinje fibers or prolongation of the QTc interval). The mechanism of this effect is unknown; however, the human cardiac potassium ion channel (hERG) appears not to be involved.

Subcutaneous injections of Relistor at 150 mg/kg/day decreased fertility in rats. Doses up to 25 mg/kg/day (18 times the exposure [AUC] in humans at a subcutaneous dose of 0.3 mg/kg) did not affect fertility or general reproductive performance.

There was no evidence of teratogenicity in rats or rabbits. Subcutaneous injections of Relistor at 150/100 mg/kg/day to rats resulted in decreased offspring weights; doses up to 25 mg/kg/day (18 times the exposure [AUC] in humans at a subcutaneous dose of 0.3 mg/kg) had no effect on labour, delivery, or offspring survival and growth.

Methylnaltrexone bromide is excreted via the milk of lactating rats.

Studies have been conducted in juvenile rats and dogs. Following intravenous injection of methylnaltrexone bromide, juvenile rats were found to be more sensitive that adults rats to methylnaltrexone-related toxicity. In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs (incidences of convulsions and labored breathing) occurred at dosages (

Following intravenous injection of methylnaltrexone bromide for 13 weeks, similar methynaltrexone related toxicity was observed in both juvenile and adult dogs. In adult and juvenile dogs given methylnaltrexone bromide at 20 mg/kg/day, clinical signs indicative of CNS toxicity and prolongation of QTc interval were observed. No adverse effects occurred in either juvenile or adult dogs at a dose of 5 mg/kg/day (44 times the exposure {AUC} in adult humans at a subcutaneous dose of 0.15 mg/kg).

Carcinogenicity studies have not been conducted with Relistor.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride

Sodium calcium edentate

Glycine hydrochloride

Water for injections

Hydrochloric acid (to adjust pH)

Sodium hydroxide (to adjust pH)

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

3 years.

After withdrawl in the injection syringe:

Due to light sensitivity, the solution for injection should be used within 24 hours.

6.4 Special Precautions For Storage

This medicinal product does not require any special temperature storage conditions.

Keep the vial in the outer carton in order to protect from light.

For storage of the medicinal product in the syringe, see section 6.3.

6.5 Nature And Contents Of Container

Clear, Type I, flint glass, single

Each vial contains 0.6 ml of solution for injection.

The presentations of Relistor are:

1 vial of solution for injection

2 vials of solution for injection

2 sterile 1 ml injection syringes with retractable injection needle

4 alcohol swabs

7 vials of solution for injection

7 sterile 1 ml injection syringes with retractable injection needle

14 alcohol swabs

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Wyeth Europa Ltd.

Huntercombe Lane South

Taplow, Maidenhead

Berkshire SL6 0PH

UK

Tel: +44 1628 604 377

Fax +44 1628 666 368

8. Marketing Authorisation Number(S)

EU/1/08/463/001

EU/1/08/463/002

EU/1/08/463/003

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 02 July 2008

10. Date Of Revision Of The Text

3 September 2010

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.

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

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Fludrocortisone 21-acetate (a derivative of Fludrocortisone) is reported as an ingredient of Florinef in the following countries:

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Glossary

SPC	Summary of Product Characteristics (UK)

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