Ribasure

Category:

Description

RIBASURE (Ribavirin 200mg Capsules)

COMPOSITION:
Each Hard Gelatin Capsule Contains:

Ribavirin USP ………. 200 mg

PHARMACOLOGICAL CLASSIFICATION:

Antivirals for systemic use, nucleosides and nucleotides excl. reverse transcriptase inhibitors, ATC code: J05AB04.

PHARMACOLOGICAL ACTION:

Mechanism of action:

Ribavirin (RIBASURE) is a synthetic nucleoside analogue which has shown in vitro activity against some RNA and DNA viruses. The mechanism by which RIBASURE in combination with other medicinal products exerts its effects against HCV is unknown.

Pharmacodynamics:
Antiviral Activity in Cell Culture

The antiviral activity of Ribavirin in the HCV-replicon is not well understood and has not been defined because of the cellular toxicity of Ribavirin.

Resistance HCV genotypes show wide variability in their response to pegylated recombinant human interferon/ribavirin therapy. Genetic changes associated with the variable response have not been identified.

Cross-resistance

There is no reported cross-resistance between pegylated/non-pegylated interferons and Ribavirin.

Pharmacokinetics:
Absorption

Ribavirin is absorbed rapidly following oral administration of a single dose (mean Tmax= 1.5 hours), followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption, distribution and elimination are 0.05, 3.73 and 79 hours, respectively). Absorption is extensive with approximately 10 % of a radiolabelled dose excreted in the faeces. However, absolute bioavailability is approximately 45 %-65 %, which appears to be due to first pass metabolism.

Distribution

Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and has been identified to be primarily via an es-type equilibrative nucleoside transporter.

Biotransformation

Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway; 2) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite. Both ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are also excreted renally.

Elimination

Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC12hr.

Special populations:

Renal Dysfunction

The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of ribavirin to non HCV-infected subjects with varying degrees of renal dysfunction.

The multiple-dose pharmacokinetics of ribavirin cannot be accurately predicted in patients with renal dysfunction. Ribavirin is not effectively removed by hemodialysis.

Hepatic Dysfunction

The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg).

Elderly Patients

Pharmacokinetic evaluations in elderly subjects have not been performed.

Gender

There were no clinically significant pharmacokinetic differences noted in a single-dose trial of 18 male and 18 female subjects.

Pediatric Patients

The pharmacokinetics of RIBASURE (dose-normalized) is similar in adults and pediatric subjects.

INDICATIONS:
Chronic Hepatitis C (CHC) RIBASURE (ribavirin) in combination with interferon alfa-2b (pegylated and nonpegylated) is indicated for the treatment of Chronic Hepatitis C (CHC) in patients 3 years of age and older with compensated liver disease.

No safety and efficacy data are available for treatment of longer than one year.

CONTRA-INDICATIONS:
RIBASURE combination therapy is contraindicated in:

Women who are pregnant. RIBASURE may cause fetal harm when administered to a pregnant woman. RIBASURE is contraindicated in women who are or may become pregnant. If

Patients with autoimmune hepatitis.

Patients with hemoglobinopathies (e.g., thalassemia major, sickle-cellanemia)

Patients with creatinine clearance less than 50 mL/min.

Co-administration of RIBASURE and didanosine is contraindicated because exposure to the active metabolite of didanosine (dideoxyadenosine 5′-triphosphate) is increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving didanosine in combination with ribavirin.

WARNINGS:

Inhalation Use in patients requiring mechanical ventilation should only be undertaken by health care providers and staff familiar with this mode of administration and the ventilator being used.

Contraindicated in women who are pregnant and in the male partners of women who are pregnant. Instruct patients to avoid pregnancy and to use at least 2 reliable forms of effective contraception during therapy and for 6 months after completion of treatment.

Capsule/Oral solution Safety and efficacy not established in treatment with RIBASURE or in children younger than 3 years.Monitor Prior to starting therapy, screen women of childbearing potential for pregnancy and obtain baseline laboratory and hematologic values.
Children

Elderly Administer with caution, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and comorbidity. Ribavirin inhalation is not indicated for use in adults.

Hypersensitivity Severe acute hypersensitivity reactions have been rarely observed.

Renal Function Adjust dose & do not use RIBASURE in patients with CrCl less than 50 mL/min.

Hepatic FunctionDiscontinue therapy in patients who develop hepatic decomposition during treatment.

Dental disorders

Dental and periodontal disorders have been reported.

Fatalities

Death during or shortly after treatment with aerosolized ribavirin has been reported.

INTERACTIONS:
Antacids

Coadministration of ribavirin capsules with an antacid containing magnesium, aluminum, and simethicone resulted in a 14% decrease in mean ribavirin AUC. The clinical importance is unknown.

Didanosine

Lamivudine, stavudine, zidovudine

Thiopurines (eg, azathioprine, mercaptopurine)

Warfarin

Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females

Female patients

RIBASURE must not be used by females who are pregnant. Extreme care must be taken to avoid pregnancy in female patients.

Male patients and their female partners

Extreme care must be taken to avoid pregnancy in partners of male patients taking RIBASURE. RIBASURE accumulates intracellularly and is cleared from the body very slowly. It is unknown whether the RIBASURE that is contained in sperm will exert its potential teratogenic or genotoxic effects on the human embryo/foetus.

Pregnancy

The use of RIBASURE is contraindicated during pregnancy. RIBASURE has been shown in preclinical studies to be teratogenic and genotoxic.

Breast-feeding

It is not known whether RIBASURE is excreted in human milk.

Fertility

Preclinical data

– Fertility: In animal studies, RIBASURE produced reversible effects on spermatogenesis.

– Teratogenicity: Significant teratogenic and/or embryocidal potential have been demonstrated for RIBASURE in all animal species in which adequate studies have been conducted, occurring at doses as low as one twentieth of the recommended human dose.

– Genotoxicity: RIBASURE induces genotoxicity.

DOSAGE AND DIRECTIONS FOR USE:

RIBASURE capsules are to be administered orally each day in two divided doses (morning and evening) with food.

Adults

The recommended dose and duration of RIBASURE depends on patient’s weight and on the medicinal product that is used in combination.

In the cases in which no specific dose recommendation is made, the following dose should be used: Patient weight: < 75 kg =1,000 mg and > 75 kg = 1,200 mg.

Dose modification for adverse reactions

Dose modification for adults

Dose reduction of RIBASURE depends on the initial RIBASURE posology which depends on the medicinal product that is used in combination with RIBASURE.

SPECIAL PRECAUTIONS FOR USE:

RIBASURE must be used in combination with other medicinal products.

There are several serious adverse reactions associated with the RIBASURE. These include:

– Severe psychiatric and central nervous system effects (such as depression, suicidal ideation, attempted suicide and aggressive behaviour, etc.)

– Growth inhibition in children and adolescents that may be irreversible in some patients

– Increased thyroid stimulating hormone (TSH) in children and adolescents

– Severe ocular disorders

– Dental and periodontal disorders.

Cardiovascular

Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders must be closely monitored

Teratogenic risk

Prior to initiation of treatment with RIBASURE the physician must comprehensively inform both male and female patients of the teratogenic risk of RIBASURE, the necessity of effective and continuous contraception, the possibility that contraceptive methods may fail and the possible consequences of pregnancy should it occur during or following treatment with RIBASURE.

Acute hypersensitivity

If an acute hypersensitivity reaction (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) develops, RIBASURE must be discontinued immediately and appropriate medical therapy instituted.

Liver function

Any patient developing significant liver function abnormalities during treatment must be monitored closely.

Renal impairment

The pharmacokinetics of RIBASURE is altered in patients with renal dysfunction due to reduction of apparent clearance in these patients.

Potential to exacerbate immunosuppression

Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the administration of a peginterferon and RIBASURE concomitantly with azathioprine.

SIDE EFFECTS:

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using ribavirin and call your doctor at once if you have a serious side effect such as:

problems with your vision;

fever, chills, body aches, flu symptoms;

severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate;

stabbing chest pain, wheezing, feeling short of breath;

severe depression, hallucinations, thoughts of suicide or hurting yourself;

chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling; or

pale or yellowed skin, dark colored urine, easy bruising or bleeding, confusion, or unusual weakness.

Less serious side effects may include:

headache;

muscle pain;

dry mouth;

nausea; vomiting, stomach pain, loss of appetite;

weight loss;

feeling tired or irritable;

anxiety, mood changes; or

pain, swelling, or irritation where the interferon injection was given.

Special Populations:

Elderly (≥ 65 years of age)

There does not appear to be a significant age-related effect on the pharmacokinetics of RIBASURE. Paediatric patients (children 3 years of age and older and adolescents)

RIBASURE may be used in combination with peginterferon alfa-2b or interferon alfa-2b. The safety and efficacy of ribavirin used together with direct-acting-anti-virals in these patients has not been established. No data are available.

Renal impairment

The pharmacokinetics of RIBASURE is altered in patients with renal dysfunction due to reduction of apparent creatinine clearance in these patients. Hepatic impairment

No pharmacokinetic interaction appears between RIBASURE and hepatic function.

KNOWN SYMPTOMS OF OVERDOSAGE:

There is limited experience with overdosage. Acute ingestion of up to 20 g of RIBASURE capsules, interferon alfa-2b ingestion of up to 120 million units, and subcutaneous doses of interferon alfa-2b up to 10 times the recommended doses have been reported. Primary effects that have been observed are increased incidence and severity of the adverse reactions related to the therapeutic use of RIBASURE. However, hepatic enzyme abnormalities, pain pills online hemorrhage, and myocardial infarction have been reported with  administration of single subcutaneous doses of interferon alfa-2b that exceed dosing recommendations.

PRESENTATION:

140 capsules pack in HDPE bottle, seal & label them

STORAGE INSTRUCTIONS:

Store below 30ºC. Protect from light. Keep in a well closed container.

KEEP OUT OF REACH OF CHILDREN.

MARKETED  BY:

Aprazer Healthcare Pvt. Ltd.

B-256, 2nd Floor Naraina Phase 1,

New Delhi (INDIA)  1100028

MANUFACTURED BY:

Mcneil & Argus Pharmaceuticals Ltd.

100, Rampur Sarsehri Road,

Ambala Cantt – 133001, Haryana (INDIA)

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