RIBASURE (Ribavirin 200mg Capsules)
Each Hard Gelatin Capsule Contains:
Ribavirin USP ………. 200 mg
Antiviral for systemic use, nucleosides and nucleotides excl. reverse transcriptase inhibitors, ATC code: J05AB04.
Mechanism of action:
Ribavirin (RIBASURE) is a synthetic nucleoside analog 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.
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 paginated recombinant human interferon/ribavirin therapy. Genetic changes associated with the variable response have not been identified.
There is no reported cross-resistance between regulated/non-regulated interferons and Ribavirin.
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 faces. However, absolute bioavailability is approximately 45 %-65 %, which appears to be due to first pass metabolism.
Ribavirin transport in non-plasma compartments has been most extensively studied in red cells and has been identified to be primarily via an as-type nucleoside transporter.
Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway; 2) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxy acid metabolite. Both ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are also excreted really.
Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC12hr.
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.
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.
There were no clinically significant pharmacokinetic differences noted in a single-dose trial of 18 male and 18 female subjects.
The pharmacokinetics of RIBASURE (dose-normalized) is similar in adults and pediatric subjects.
Chronic Hepatitis C (CHC) RIBASURE (ribavirin) in combination with interferon alfa-2b (pegylated and non-pegylated) is indicated for the treatment of Chronic Hepatitis C (CHC) in patients 3 years of age and older with a compensated liver disease. No safety and efficacy data are available for treatment of longer than one year.
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-cell anemia) 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.
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.
Monitor prior to starting therapy, screen women of childbearing potential for pregnancy and obtain baseline laboratory and hematologic values.
Children Capsule/Oral solution Safety and efficacy not established in treatment with RIBASURE or in children younger than 3 years.
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 less than 50 mL/min.
Hepatic Function Discontinue 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.
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)
Fertility, pregnancy and lactation Women of childbearing potential/contraception in males and females
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 partner’s Extreme care must be taken to avoid pregnancy in partners of male patients taking RIBASURE. RIBASURE accumulates intracellular 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/fetus.
The use of RIBASURE is contraindicated during pregnancy. RIBASURE has been shown in preclinical studies to be teratogenic and genotoxic. Breastfeeding
It is not known whether RIBASURE is excreted in human milk.
– 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.
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 phonology 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 behavior, 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
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:
nausea; vomiting, stomach pain, loss of appetite;
feeling tired or irritable;
anxiety, mood changes; or
pain, swelling, or irritation where the interferon injection was given.
Elderly (65 years of age)
There does not appear to be a significant age-related effect on the pharmacokinetics of RIBASURE. Pediatric 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 have not been established. No data are available.
Renal impairment: The pharmacokinetics of RIBASURE is altered in patients with renal dysfunction due to a 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, renal failure, hemorrhage, and myocardial infarction have been reported with administration of single subcutaneous doses of interferon alfa-2b that exceed dosing recommendations.
Store below 30ºC. Protect from light. Keep in a well-closed container.