Ribavirin-Lipint^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Vector-Medica, JSC (Russia)

Contact Information

Vector-Medica, JSC (Russia)

ATC Code

J05AP01 (Ribavirin)

Active Substance

Ribavirin (Rec.INN registered by WHO)

Dosage Form

Ribavirin-Lipint®

Lyophilisate for preparation of oral suspension 500 mg: fl. 1 or 6 pcs.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of oral suspension in the form of a powder or porous mass from white to light yellow in color; delamination, complete or partial, from the surface of the vial glass with the formation of a tablet-like structure is allowed; hygroscopic.

Excipients: sodium chloride – 30 mg, Lipoid Lecithin C100 (phospholipids (mixture with a percentage content of phosphatidylcholine not less than 94%)) – 900 mg, cholesterol – 100 mg, alpha-tocopherol acetate – 9 mg, methylparaben – 7 mg, lactose monohydrate – 870 mg.

500 mg – vials (1) – carton packs.
500 mg – vials (6) – carton packs.

Clinical-Pharmacological Group

Antiviral drug

Pharmacotherapeutic Group

Antiviral agent

Pharmacological Action

Antiviral drug, a synthetic nucleoside analogue with a pronounced antiviral effect.

Ribavirin easily penetrates into virus-affected cells and is rapidly phosphorylated by intracellular adenosine kinase into Ribavirin mono-, di-, and triphosphate. These metabolites, especially Ribavirin triphosphate, have a pronounced antiviral activity. The mechanism of action of ribavirin is not fully understood. It has been established that Ribavirin inhibits inosine monophosphate dehydrogenase (IMPDH), this effect leads to a pronounced decrease in the level of intracellular guanosine triphosphate (GTP), 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, selectively suppresses the synthesis of viral RNA without affecting RNA synthesis in normal human cells.

Ribavirin has a broad spectrum of activity against various DNA and RNA viruses. The DNA viruses most sensitive to ribavirin are herpes simplex virus, adenoviruses, CMV, poxvirus group viruses, Marek’s disease virus; RNA viruses – influenza A, B viruses, paramyxoviruses (parainfluenza, mumps, Newcastle disease), reoviruses, arenaviruses (Lassa fever virus, Bolivian hemorrhagic fever), bunyaviruses (Rift Valley fever virus, Crimean-Congo hemorrhagic fever virus), hantaviruses (hemorrhagic fever with renal or pulmonary syndrome virus) paramyxoviruses, oncogenic RNA viruses. DNA viruses insensitive to ribavirin – Varicella zoster, pseudorabies virus, natural cowpox; RNA viruses – 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 triphosphate accumulating during the phosphorylation of ribavirin competitively suppresses the formation of guanosine triphosphate, thereby reducing the synthesis of viral RNA. 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

Ribavirin is easily and almost completely absorbed from the gastrointestinal tract after a single oral dose. The absolute bioavailability is approximately 65-75%. Free Ribavirin does not bind to plasma proteins, liposomal Ribavirin binds to blood proteins and is rapidly distributed in the body (C_max was observed in the RES organs).

The elimination of ribavirin from the body is slow. The drug is excreted in the urine, both unchanged and in the form of metabolites, and only about 10% is excreted in the feces.

Indications

• Chronic hepatitis C (for primary therapy of previously untreated with interferon alpha-2b patients; for exacerbation after a course of monotherapy with interferon alpha-2b in patients not responsive to monotherapy with interferon alpha-2b). Treatment is carried out in combination with interferon alpha-2b.

ICD codes

Dosage Regimen

The drug is taken orally simultaneously with food.

Immediately before use, add 10-20 ml of distilled or cooled boiled water to the contents of the vial. When shaken for 1 to 5 minutes, a homogeneous suspension should form.

The dose of the drug is 1000 mg/day (1 vial in the morning and 1 vial in the evening). Interferon alpha-2b (Reaferon-EC, Lifeferon^®) is simultaneously prescribed at 3 million IU 3 times a week. The duration of the course of combination therapy is usually 24-48 weeks. (for previously untreated patients and patients with virus genotype 2 and 3 – at least 24 weeks, and for patients with virus genotype 1 – 48 weeks). In case of non-response to monotherapy with interferon alpha-2b or with relapse of the disease, the duration of the course is at least 6 months.

Adverse Reactions

From the nervous system: headache, dizziness, general weakness, malaise, insomnia, asthenia, depression, irritability, anxiety, emotional lability, nervousness, agitation, aggressive behavior, confusion, suicidal tendency, increased smooth muscle tone, tremor, paresthesia, hyperesthesia, hypoesthesia, fainting.

From the cardiovascular system: decrease or increase in blood pressure, bradycardia or tachycardia, palpitation sensation.

From the hematopoietic organs: hemolytic anemia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia, aplastic anemia.

From the respiratory system: shortness of breath, cough, pharyngitis, bronchitis, otitis media, sinusitis, rhinitis.

From the digestive system: dry oral mucosa, decreased appetite, nausea, vomiting, diarrhea, abdominal pain, constipation, taste perversion, pancreatitis, flatulence, stomatitis, glossitis, gum bleeding, hyperbilirubinemia.

From the sensory organs: lacrimal gland lesion, conjunctivitis, visual impairment, hearing impairment/loss, tinnitus.

From the musculoskeletal system: arthralgia, myalgia.

From the genitourinary system: hot flashes, decreased libido, dysmenorrhea, amenorrhea, menorrhagia, prostatitis.

Allergic reactions: skin rash, erythema, urticaria, hyperthermia, bronchospasm, anaphylaxis, photosensitivity, multiforme erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Other: hair loss, alopecia, impaired hair structure, dry skin, hypothyroidism, chest pain, thirst, fungal infection, viral infection (including herpes), flu-like syndrome, sweating, lymphadenopathy, graft rejection after liver and/or kidney transplantation.

Contraindications

• Chronic heart failure stage II-III;
• Myocardial infarction;
• Renal failure (creatinine clearance less than 50 ml/min);
• Severe anemia;
• Hepatic failure;
• Decompensated liver cirrhosis;
• Autoimmune diseases (including autoimmune hepatitis);
• Untreatable thyroid diseases;
• Severe depression with suicidal intentions;
• Lactose intolerance;
• Lactase deficiency;
• Glucose-galactose malabsorption;
• Childhood and adolescent age (under 18 years);
• Pregnancy;
• Lactation period;
• Increased sensitivity to the drug.

With caution the drug should be prescribed to women of reproductive age (pregnancy is undesirable), with decompensated diabetes mellitus (with ketoacidosis attacks), COPD, pulmonary embolism, chronic heart failure, with thyroid diseases (including thyrotoxicosis), blood clotting disorders, thrombophlebitis, myelodepression, hemoglobinopathies (including thalassemia, sickle cell anemia), patients with depression, suicidal tendency (including in history); patients with concomitant HIV infection (against the background of combined highly active antiretroviral therapy, there is a risk of lactic acidosis), elderly patients.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and lactation.

Pediatric Use

The use of the drug in children under 18 years of age is prohibited.

Geriatric Use

Use the drug with caution in elderly patients. Due to the possible deterioration of renal function in the elderly, renal function (including creatinine clearance) should be monitored before using the drug.

Special Precautions

Before starting hepatitis C therapy, the need for histological confirmation of the diagnosis should be assessed (treatment of patients with virus genotype 2 or 3 can be started without prior liver biopsy).

Men and women of reproductive age during therapy and for 7 months after the end of treatment should use effective contraceptive measures, taking into account the teratogenicity of ribavirin.

During ribavirin therapy, the maximum decrease in hemoglobin content in most cases is noted after 4-8 weeks from the start of treatment. If hemoglobin decreases below 100 mg/ml, the dose should be reduced by 50% from the initial dose. In most cases, the recommended dose changes ensure the restoration of hemoglobin levels. If hemoglobin decreases below 85 mg/ml, the drug should be discontinued. In case of acute manifestation of hypersensitivity reactions (urticaria, angioedema, bronchospasm, anaphylaxis), the use of the drug should be immediately discontinued. Transient rashes are not a reason for interrupting treatment.

The content of alpha-tocopherol acetate in the dosage form in the amount of 9 mg per vial is due to its use as an antioxidant. This amount, established experimentally, prevents the oxidation of the liposomal vesicles consisting of phospholipids contained in the finished dosage form. The amount of alpha-tocopherol acetate taken with the drug per day (2 vials contain 18 mg) is 6% of the maximum daily intake indicated in the Methodological Recommendations “Norms of physiological requirements for energy and nutrients for various groups of the population of the Russian Federation”.

Control of laboratory parameters

Complete blood count with leukocyte formula and platelet count, determination of electrolytes, creatinine content, liver function tests should be performed before the start of therapy, at 2 and 4 weeks of administration and then regularly. Due to the possible deterioration of renal function in the elderly, renal function (including creatinine clearance) should be monitored before using the drug.

Influence on the ability to drive vehicles, mechanisms

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

Overdose

No cases of overdose have been observed. Considering that the active substance is Ribavirin, an overdose may increase the severity of dose-dependent side effects.

Treatment: drug withdrawal; if necessary, symptomatic therapy is carried out.

Drug Interactions

When ribavirin and interferon alpha-2b are used together, a synergy of their action is noted.

During clinical use of various drugs in therapeutic doses in combination with ribavirin, no significant interaction was detected.

Prescription of ribavirin during the use of zidovudine and/or stavudine in patients with concomitant HIV infection is accompanied by a decrease in the phosphorylation of these drugs, which leads to HIV viremia and requires a change in the treatment regimen. When used simultaneously, drugs containing magnesium and aluminum compounds, as well as simethicone, reduce the bioavailability of the drug. It increases the concentration of phosphorylated metabolites of purine nucleosides (including didanosine, abacavir) and increases the associated risk of lactic acidosis.

When used simultaneously with azathioprine, it enhances the myelotoxicity of the latter.

Does not affect the enzymatic activity of the liver involving cytochrome P450. Simultaneous 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 in a place protected from light and out of the reach of children at a temperature up to 25°C (77°F).

Shelf Life

Shelf life – 2 years

Do not use after the expiration date.

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.