Ribavirin

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Instructions for Ribavirin

Composition Ribavirin:

Active substance: Ribavirin - 200 mg.
Excipients: microcrystalline cellulose - 90.0 mg,
potato starch - 15.0 mg,
colloidal silicon dioxide - 2.0 mg,
magnesium stearate - 4.0 mg, lactose monohydrate (milk sugar) - 89.0 mg.
The composition of the capsule body:
titanium dioxide - 1.0000%, dye iron oxide yellow - 0.0733%, gelatin - up to 100%.
The composition of the capsule cap:
titanium dioxide - 1.0000%, dye iron oxide yellow - 0.0733%, gelatin - up to 100%.

Pharmacodynamics Ribavirin:

Ribavirin is a synthetic analogue of nucleosides with a pronounced antiviral effect. It has a wide spectrum of activity against various DNA and RNA viruses. Ribavirin easily penetrates virus-infected cells and is rapidly phosphorylated by intracellular adenosine kinase mono-, di- and triphosphate. Ribavirin Covid

These metabolites, especially ribavirin triphosphate, have a pronounced antiviral activity. The mechanism of action of ribavirin is not well understood. However, it is known that inosine monophosphate dehydrogenase (IMP) is ribavirinibbing, this effect leads to a marked decrease in the level of intracellular guanosine triphosphate (GTP), which, in turn, is accompanied by a suppression of the synthesis of viral RNA and virus-specific proteins.

Ribavirin inhibits the replication of new virions, which ensures a decrease in viral load. Ribavirin selectively inhibits viral RNA synthesis without inhibiting RNA synthesis in normally functioning cells. The most sensitive DNA viruses to are herpes simplex virus, adenoviruses, cytomegaloviruses, smallpox viruses, Marek's disease; PHK viruses - influenza A, B viruses, paramyxoviruses (parainfluenza, mumps, Newcastle disease), reoviruses, arenaviruses (Lassa fever virus, Bolivian hemorrhagic fever), bunyaviruses (Rhigo fever virus, Crimean fever virus) (hemorrhagic fever virus with renal or pulmonary syndrome) paramyxoviruses, oncogenic RNA viruses.

Ribavirin insensitive DNA viruses - Varicella zoster, pseudorabies virus, natural smallpox; RNA viruses - enteroviruses, rhinoviruses, Semlica forest encephalitis virus.
Ribavirin has activity against hepatitis C virus (HCV). The mechanism of action of Ribavirin against HCV is not fully understood. It is believed that ribavirin triphosphate accumulates during phosphorylation and competitively inhibits the formation of guanosine triphosphate, thereby reducing the synthesis of viral RNA. It is also believed that the mechanism of synergistic action of ribavirin and alpha interferon against HCV is due to increased phosphorylation by interferon.

Pharmacokinetics Ribavirin:

Absorption: when administered orally, Ribavirin is rapidly absorbed in the gastrointestinal tract. Moreover, its bioavailability is more than 45%. Distribution: is distributed in plasma, airway mucosa secretion, and red blood cells.

A large amount of Ribavirin triphosphate accumulates in red blood cells, reaching a plateau by day 4 and persisting for several weeks after administration. The half-life is 3.7 hours. The volume of distribution (Vd) is 647 - 802 liters. During the course of administration, accumulates in plasma in large quantities.

The ratio of bioavailability indicators (AUC - the area under the curve "concentration / time") with repeated and single administration is 6. A significant concentration of Ribavirin (more than 67%) can be detected in cerebrospinal fluid after prolonged use. Slightly bound to plasma proteins.

The time to reach maximum plasma concentration is from 1 to 1.5 hours. The time to reach the therapeutic plasma concentration depends on the value of the minute volume of blood. The average maximum concentration (Cmax) in plasma: about 5 μmol per liter at the end of 1 week at a dose of 200 mg every 8 hours and about 11 μmol per liter at the end of 1 week at a dose of 400 mg every 8 hours.

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

Excretion: Ribavirin is excreted slowly from the body. The half-life (T1 / 2) after a single dose of 200 mg is from 1 to 2 hours from plasma and up to 40 days from red blood cells. After termination of the course, T1 / 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. Unchanged, about 7% of ribavirin is excreted in 24 hours and about 10% in 48 hours. Pharmacokinetics in special clinical conditions:

When taking the drug in patients with renal insufficiency, AUC and Cmax of Ribavirin increase, which is due to a decrease in true clearance. In patients with hepatic insufficiency (A, B and C degrees), the pharmacokinetics of Ribavirin does not change. After taking a single dose with food containing fats, the pharmacokinetics changes significantly (AUC and Cmax increase by 70%).

Ribavirin Side Effects:

From the nervous system: headache, dizziness, general weakness, malaise, insomnia, asthenia, depression, irritability, anxiety, emotional lability, nervousness, agitation, aggressive behavior, confused consciousness; rarely - suicidal tendency, increased tone of smooth muscles, tremors, paresthesias, hyperesthesia, hypesthesia, fainting.

From the cardiovascular system: decrease or increase in blood pressure, brady or tachycardia, palpitations, cardiac arrest. From the hemopoietic organs: hemolytic anemia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia; extremely rare - aplastic anemia.

From the respiratory system: dyspnea, cough, pharyngitis, shortness of breath, bronchitis, otitis media, sinusitis, rhinitis. From the digestive system: dry mouth, decreased appetite, nausea, vomiting, diarrhea, abdominal pain, constipation, taste perversion, pancreatitis, flatulence, stomatitis, glossitis, gum bleeding, hyperbilirubinemia.

From the sensory organs: lesion of the lacrimal gland, 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, angioedema, bronchospasm, anaphylaxis, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis. Other: hair loss, conjunctivitis, alopecia, impaired hair structure, dry skin, hypothyroidism, chest pain, thirst, fungal infection, viral infection, flu-like cider, sweating, lymphadenopathy.

Special conditions Ribavirin:

Teratogenicity of the drug should be taken into account, men and women of reproductive age during treatment and should use effective contraceptives within 7 months after the end of therapy.

Laboratory studies (a clinical blood test with a leukocyte count and platelet count, determination of electrolytes, creatinine content, liver function tests) should be performed before therapy, at 2 and 4 weeks, and then regularly.

During treatment with Ribavirin, the maximum decrease in hemoglobin is observed in most cases after 4-8 weeks from the start of treatment. With a decrease in hemoglobin below 110 mg / ml, the dose should be temporarily reduced by 400 mg per day, with a decrease in hemoglobin below 100 mg / ml, the dose should be reduced to 50% of the original.

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 (urticaria, angioedema, bronchospasm, anaphylaxis), the use of the drug should be stopped immediately. Transient rashes are not grounds for interrupting treatment. In connection with the possible deterioration of renal function in elderly patients, before using the drug, it is necessary to determine renal function, in particular creatinine clearance.

Impact on the ability to drive vehicles and other mechanisms: During the treatment period, persons experiencing fatigue, drowsiness or disorientation should refrain from driving vehicles and engaging in potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.

Indications Ribavirin:

Chronic hepatitis C (in combination with interferon alfa-2b or peginterferon alfa-2b): in primary patients who have not previously been treated with interferon alfa-2b or peginterferon alfa-2b; with exacerbation after a course of monotherapy with interferon alpha-2b or peginterferon alpha-2b; in patients immune to monotherapy with interferon alfa-2b or peginterferon alfa-2b.

Contraindications Ribavirin:

Hypersensitivity, pregnancy, lactation, chronic heart failure IIb-III century, myocardial infarction, renal failure (creatinine clearance - less than 50 ml / min), severe anemia, liver failure, decompensated liver cirrhosis, autoimmune diseases (including autoimmune hepatitis), untreatable thyroid diseases, severe depression with suicidal intentions, childhood and adolescence (up to 18 years).

Precautions :Women of reproductive age (pregnancy is undesirable), decompensated diabetes mellitus (with attacks of ketoacidosis); chronic obstructive pulmonary disease, pulmonary embolism, chronic heart failure, thyroid disease (including thyrotoxicosis), bleeding disorders, thrombophlebitis, myelodepression, hemoglobinopathy (including thalassemia, sickle cell anemia), depression suicidal tendency (including history), old age.

Drug Interactions Ribavirin:

Medicines containing magnesium and aluminum compounds, simethicone reduce the bioavailability of the drug (AUC decreases by 14%, has no clinical value).

When combined with interferon alfa-2b or peginterferon alfa-2b - synergistic action. The administration of Ribavirin during treatment with zidovudine and / or stavudine is accompanied by a decrease in their phosphorylation, which can 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 developing lactic acidosis. It does not affect the enzymatic activity of the liver with the participation of cytochrome P450. A high fat diet at the same time increases the bioavailability (AUC and Cmax increase by 70%).

Dosage Ribavirin:

Inside, without chewing and drinking with water, along with a meal of 0.8-1.2 g per day in 2 divided doses (morning and evening). At the same time, interferon alfa-2b is administered 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 with a body weight of up to 75 kg, the dose of is 1 g per day (0.4 g in the morning and 0.6 g in the evening); above 75 kg - 1.2 g per day (0.6 g in the morning and 0.6 g in the evening).

When combined with peginterferon alfa-2b with a body weight of less than 65 kg, the dose of Ribavirin is 0.8 g per day (0.4 g in the morning and 0.4 g in the evening); 65-85 kg - 1 g per day (0.4 g in the morning and 0.6 g in the evening); more than 85 kg (0.6 g in the morning and 0.6 g in the evening). The duration of treatment is 24 to 48 weeks; however, for previously untreated patients - at least 24 weeks, in patients with a genotype virus of 1-48 weeks. In patients immune to monotherapy with interferon alfa, as well as with relapse, at least 6 months to 1 year (depending on the clinical course of the disease and response to the therapy).