Ribavirin-SZ (Capsules) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

J05AP01 (Ribavirin)

Active Substance

Ribavirin (Rec.INN WHO registered)

Dosage Form

Ribavirin-SZ

Capsules 200 mg: 30, 60, or 120 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 0, white; capsule contents – powder white or white with a yellowish tint.

Excipients: lactose monohydrate (milk sugar) – 96 mg, colloidal silicon dioxide (aerosil) – 2 mg, magnesium stearate – 2 mg.

Capsule body composition titanium dioxide, gelatin.
Capsule cap composition titanium dioxide, gelatin.

10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (12) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.
60 pcs. – polymer jars (1) – cardboard packs.
60 pcs. – polymer bottles (1) – cardboard packs.
120 pcs. – polymer jars (1) – cardboard packs.
120 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug

Pharmacotherapeutic Group

Antiviral agent

Pharmacological Action

Ribavirin is a synthetic nucleoside analogue with pronounced antiviral action. It has a broad spectrum of activity against various DNA and RNA viruses.

Ribavirin easily penetrates virus-infected cells and is rapidly phosphorylated by intracellular adenosine kinase to mono-, di-, and triphosphate metabolites. These metabolites, especially ribavirin triphosphate, have pronounced antiviral activity.

The mechanism of action of ribavirin is not fully understood. However, it is known that Ribavirin inhibits inosine monophosphate dehydrogenase (IMPDH), this effect leads to a pronounced decrease in intracellular guanosine triphosphate (GTP) levels, which, in turn, is accompanied by suppression of viral RNA and virus-specific protein synthesis. Ribavirin inhibits the replication of new virions, which ensures a reduction in viral load. Ribavirin selectively inhibits viral RNA synthesis without suppressing RNA synthesis in normally functioning cells.

Ribavirin is effective against many DNA and RNA viruses. The DNA viruses most sensitive to ribavirin are: Herpes simplex viruses, poxviruses, Marek’s disease virus. DNA viruses insensitive to ribavirin are: Varicella zoster, pseudorabies virus, cowpox virus. The RNA viruses most sensitive to ribavirin are: influenza A, B viruses, paramyxoviruses (parainfluenza, mumps, Newcastle disease), reoviruses, oncogenic RNA viruses. RNA viruses insensitive to ribavirin are: enteroviruses, rhinoviruses, Semliki forest encephalitis virus.

Ribavirin is active against hepatitis C virus (HCV). The mechanism of action of ribavirin against HCV is not fully understood. It is assumed that the accumulating ribavirin triphosphate, as phosphorylation occurs, competitively suppresses the formation of guanosine triphosphate, thereby reducing viral RNA synthesis. It is also believed that the mechanism of the synergistic action of ribavirin and interferon alpha against HCV is due to the enhancement of ribavirin phosphorylation by interferon.

Pharmacokinetics

Absorption

When taken orally, Ribavirin is rapidly absorbed from the gastrointestinal tract. Its bioavailability is more than 45%. Time to reach C_max in plasma is from 1 to 1.5 hours. The time to reach therapeutic concentration in plasma depends on the cardiac output. The average C_max in plasma is about 5 µmol/L at the end of 1 week of use at a dose of 200 mg every 8 hours and about 11 µmol/L at the end of 1 week of use at a dose of 400 mg every 8 hours. After a single dose taken with fatty food, the pharmacokinetics of ribavirin change significantly (AUC and C_max increase by 70%).

Distribution

Ribavirin is distributed in plasma, respiratory mucosa secretion, and erythrocytes. A large amount of ribavirin triphosphate accumulates in erythrocytes, reaching a plateau by day 4 and persisting for several weeks after administration. The distribution half-life is 3.7 hours. V_d – 647-802 L. With course use, Ribavirin accumulates in plasma in large quantities. The ratio of bioavailability parameters (AUC) after repeated and single administration is 6. A significant concentration of ribavirin (more than 67%) can be detected in cerebrospinal fluid after prolonged use. It binds insignificantly to plasma proteins.

Metabolism

Ribavirin is phosphorylated in liver cells into active mono-, di-, and triphosphate metabolites, which are then metabolized to 1,2,4-triazolecarboxamide (amide hydrolysis to tricarboxylic acid and deribosylation to form a triazole carboxylic metabolite).

Excretion

Ribavirin is slowly eliminated from the body. T_1/2 after a single dose of 200 mg is from 1 to 2 hours – from plasma and up to 40 days – from erythrocytes. After the end of course use, T_1/2 is about 300 hours. Ribavirin and its metabolites are mainly excreted from the body by the kidneys, only about 10% is excreted through the intestines. In unchanged form, about 7% of ribavirin is excreted within 24 hours and about 10% within 48 hours.

Pharmacokinetics in special patient groups

In patients with renal failure, the AUC and C_max of ribavirin increase, which is due to a decrease in true clearance.

In patients with hepatic impairment (Child-Pugh class A, B and C), the pharmacokinetics of ribavirin do not change.

Indications

Chronic viral hepatitis C (in combination with interferon alfa-2b or peginterferon alfa-2b)

• In primary patients previously untreated with interferon alfa-2b or peginterferon alfa-2b;
• In case of relapse after a course of monotherapy with interferon alfa-2b or peginterferon alfa-2b;
• In patients unresponsive to monotherapy with interferon alfa-2b or peginterferon alfa-2b.

ICD codes

Dosage Regimen

The drug is taken orally, with meals. Capsules are swallowed whole, without chewing, and washed down with water.

The recommended dose is 0.8-1.2 g/day in 2 divided doses (morning and evening).

Interferon alfa-2b is simultaneously prescribed – subcutaneously 3 million IU 3 times a week or peginterferon alfa-2b – subcutaneously 1.5 µg/kg once a week. When combined with interferon alfa-2b in patients with body weight up to 75 kg, the ribavirin dose is 1 g/day (0.4 g in the morning and 0.6 g in the evening); above 75 kg – 1.2 g/day (0.6 g in the morning and 0.6 g in the evening). When combined with peginterferon alfa-2b in patients with body weight less than 65 kg, the ribavirin dose is 0.8 g/day (0.4 g in the morning and 0.4 g in the evening), with body weight 65-85 kg – 1 g/day (0.4 g in the morning and 0.6 g in the evening), more than 85 kg – 1.2 g/day (0.6 g in the morning and 0.6 g in the evening).

Duration of treatment is 24 – 48 weeks; for previously untreated patients – at least 24 weeks, for patients with genotype 1 virus – 48 weeks. For patients unresponsive to interferon alfa monotherapy, as well as in case of relapse – at least 6 months-1 year (depending on the clinical course of the disease and response to therapy).

Adverse Reactions

Nervous system disorders headache, dizziness, insomnia, depression, irritability, anxiety, emotional lability, nervousness, agitation, aggressive behavior, confusion; rarely – suicidal tendency, increased smooth muscle tone, tremor, paresthesia, hyperesthesia, hypoesthesia, syncope.

Eye disorders lacrimal gland lesion, conjunctivitis, visual impairment.

Ear and labyrinth disorders hearing impairment/loss, tinnitus.

Cardiac disorders decrease or increase in blood pressure, bradycardia or tachycardia, palpitation sensation, cardiac arrest.

Blood and lymphatic system disorders hemolytic anemia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia; extremely rarely – aplastic anemia.

Respiratory, thoracic and mediastinal disorders dyspnea, cough, pharyngitis, shortness of breath, bronchitis, otitis media, sinusitis, rhinitis.

Gastrointestinal disorders dry mouth, decreased appetite, nausea, vomiting, diarrhea, abdominal pain, constipation, taste perversion, pancreatitis, flatulence, stomatitis, glossitis, gum bleeding, hyperbilirubinemia.

Reproductive system and breast disorders decreased libido, dysmenorrhea, amenorrhea, menorrhagia, prostatitis.

Musculoskeletal and connective tissue disorders arthralgia, myalgia.

Immune system disorders skin rash, erythema, urticaria, hyperthermia, angioedema, bronchospasm, anaphylaxis, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

General disorders and administration site conditions general weakness, malaise, asthenia, hair loss, conjunctivitis, alopecia, impaired hair structure, dry skin, hypothyroidism, chest pain, thirst, fungal infection, viral infection, flu-like syndrome, sweating, lymphadenopathy, hot flashes.

Contraindications

• Chronic heart failure stage IIb-III;
• Myocardial infarction;
• Renal failure (creatinine clearance less than 50 ml/min);
• Hepatic failure;
• Decompensated liver cirrhosis;
• Severe anemia;
• Autoimmune diseases (including autoimmune hepatitis);
• Untreatable thyroid diseases;
• Severe depression with suicidal intentions;
• Childhood and adolescence under 18 years;
• Pregnancy;
• Lactation period;
• Hypersensitivity.

With caution the drug should be prescribed for decompensated diabetes mellitus (with ketoacidosis episodes); chronic obstructive pulmonary disease; pulmonary embolism; chronic heart failure; thyroid diseases (including thyrotoxicosis); blood clotting disorders; thrombophlebitis; myelodepression; hemoglobinopathies (including thalassemia, sickle cell anemia); depression, suicidal tendency (including in history); women of reproductive age (pregnancy is undesirable); elderly patients.

Use in Pregnancy and Lactation

The use of the drug is contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

The use of the drug is contraindicated in hepatic failure, decompensated liver cirrhosis, autoimmune hepatitis.

Use in Renal Impairment

The use of the drug is contraindicated in renal failure (creatinine clearance less than 50 ml/min).

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

With caution the drug should be prescribed to elderly patients.

Special Precautions

The teratogenicity of the drug should be considered. Men and women of reproductive age during treatment and for 7 months after the end of therapy must use effective contraceptive measures.

Laboratory tests (complete blood count with leukocyte differential and platelet count, determination of electrolytes, creatinine content, liver function tests) must be performed before the start of therapy, at 2 and 4 weeks, and then regularly.

During treatment with ribavirin, the maximum decrease in hemoglobin content in most cases is noted after 4-8 weeks from the start of treatment. If hemoglobin decreases below 110 mg/ml, the ribavirin dose should be temporarily reduced by 400 mg/day; if hemoglobin decreases below 100 mg/ml, the dose should be reduced to 50% of the original. In most cases, the recommended dose changes ensure restoration of hemoglobin levels. If hemoglobin decreases below 85 mg/ml, the drug should be discontinued.

In case of acute manifestation of hypersensitivity (urticaria, angioedema, bronchospasm, anaphylaxis), the use of the drug should be immediately discontinued. Transient rashes are not a reason for treatment interruption.

Due to the possible deterioration of renal function in elderly patients, renal function, in particular creatinine clearance, should be examined before using the drug.

Effect on ability to drive vehicles and operate machinery

During the treatment period, patients experiencing fatigue, drowsiness, or disorientation should refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms possible increase in the severity of adverse effects.

Treatment drug withdrawal, symptomatic therapy.

Drug Interactions

Medicinal products containing magnesium and aluminum compounds, simethicone reduce the bioavailability of the drug (AUC decreases by 14%, which is not clinically significant).

When used concomitantly with interferon alfa-2b or peginterferon alfa-2b – synergism of action.

The use of ribavirin during treatment with zidovudine and/or stavudine is accompanied by a decrease in their phosphorylation, which may lead to HIV viremia and require a change in the treatment regimen.

Increases the concentration of phosphorylated metabolites of purine nucleosides (including didanosine, abacavir) and the associated risk of lactic acidosis.

Does not affect the enzymatic activity of the liver involving cytochrome P450.

Concomitant intake of food high in fat increases the bioavailability of ribavirin (AUC and C_max increase by 70%).

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.