Pegasys, 180 mcg/0.5 ml 0.5 ml syringe-tubes

Pegasys is an immunomodulatory.

Pharmacodynamics

The structure of PEG directly affects the clinical and pharmacological characteristics of Pegasys^®. In particular, the size and degree of branching of PEG with a molecular weight of 40 kDa determines the absorption, distribution and excretion of peginterferon alfa-2a.

The activity of Pegasys^® should not be compared to other pegylated or unpegylated proteins of the same therapeutic class.

Like interferon alfa-2a, Pegasys^® has antiviral and antiproliferative activityin vitro.

In patients with chronic hepatitis C (CHC), the decrease in hepatitis C virus (HCV) RNA levels in response to Pegasys^® therapy at a dose of 180 mcg occurs in 2 phases. The first phase occurs 24-36 hours after the first injection of the drug, the second phase occurs over the next 4-16 weeks in patients with a sustained virologic response.

Ribavirin has no significant effect on virus kinetics during the first 4-6 weeks in those patients who receive combined therapy with ribavirin and pegylated interferon alfa-2a or interferon alfa.

Pharmacokinetics

Intake. After a single subcutaneous injection of 180 mcg of peginterferon alpha-2a in healthy subjects, the drug concentration in the serum begins to be determined after 3-6 hours.

The serum concentration reaches 80% of the maximum after 24 hours. Absorption of peginterferon alfa-2a is prolonged, C_max in serum is noted 72-96 hours after drug administration. Absolute bioavailability of peginterferon alfa-2a is 84% and is similar to that of interferon alfa-2a.

Distribution. Peginterferon alpha-2a is found mainly in blood and extracellular fluid. Volume of distribution in equilibrium state (V_ss) after intravenous administration is 6-14 l. According to the data of mass spectrometry, tissue distribution and autoradioluminography obtained in studies on rats, peginterferon alpha-2a is found in high concentration in blood and also in liver, kidney and bone marrow.

Metabolism. The peculiarities of the metabolism of peginterferon alpha-2a have not been fully studied; however, studies in rats indicate that the radiolabeled drug is excreted primarily by the kidneys.

Elimation. Systemic clearance of peginterferon alfa-2a in humans is 100 times lower than that of interferon alfa-2a. After intravenous administration, the terminal T_1/2 in healthy volunteers is 60-80 h, compared to 3-4 h for conventional interferon. After subcutaneous administration, terminal T_1/2 is about 160 h (84 to 353 h). The terminal T_1/2 after subcutaneous administration may indicate the duration of absorption of peginterferon alfa-2a rather than excretion.

Indications

Active ingredient

Composition

Active ingredient:

Peginterferon alpha-2a (40 kDa);

Auxiliary substances:

sodium chloride;

benzyl alcohol;

sodium acetate;

acetic acid glacial;

polysorbate 80;

sodium acetate solution 10%;

acetic acid 10%;

water for injection

How to take, the dosage

The treatment with Pegasys® should be under the supervision of a qualified physician experienced in therapy in patients with chronic hepatitis B and C. If Pegasys® ® is used in combination with ribavirin, the instructions for medical use of ribavirin should also be consulted.

The standard dosing regimen

The drug is given subcutaneously (p/k) in the anterior abdominal wall or thigh once a week.

Interaction

No pharmacokinetic interactions between Pegasys and ribavirin have been observed in ongoing clinical trials of combination therapy.

Interferon alpha may affect oxidative metabolic processes by reducing the activity of hepatic microsomal cytochrome P450 enzymes.

However, in healthy men, b/c administration of Pegasys at a dose of 180 mcg once a week for 4 weeks had no effect on the pharmacokinetics of mephenytoin, dapsone, debrisoquine, and tolbutamide; Therefore, in healthy men, treatment with Pegasys had no effect on the in vivo metabolic activity of cytochrome P4503A4, 2C9, 2C19, and 2D6 isoenzymes.

In the same study, there was an increase in the area under the concentration-time curve (AUC) of theophylline, which is a marker of cytochrome P450 isoenzyme 1A2 activity, by approximately 25%.

Pegasis is a moderate inhibitor of cytochrome P450 isoenzyme 1A2 activity. In patients receiving theophylline and Pegasys concomitantly, serum theophylline concentrations should be monitored and theophylline dose should be adjusted accordingly.

Special Instructions

Nervo-psychiatric disorders

In some patients, both during treatment with Pegasys® and for 6 months after discontinuation of treatment, severe CNS adverse reactions were observed, in particular: depression, suicidal ideation and suicide attempts.

There have been other CNS adverse reactions during therapy with interferon alfa, including aggressive behavior (sometimes directed at others), confusion, and mental status disorder.

Patients should be closely monitored for signs or symptoms of psychiatric disorders. If such symptoms occur, the clinician should be mindful of the potential seriousness of these adverse events and the need for appropriate treatment. If symptoms of psychiatric disorders persist or worsen or suicidal ideation is detected, it is recommended that therapy with Pegasys® be discontinued and appropriate treatment be given.

Patients with severe mental illness (including a history). If it is decided that treatment with Pegasys® is necessary in patients with severe mental illness (including a history of mental illness), therapy should be initiated only after appropriate evaluation and treatment of the mental disorder.

If Pegasys® is to be used in combination with ribavirin, be sure to also read the instructions for medical use of ribavirin.

All patients underwent liver biopsy before inclusion in HCV clinical trials, but in some cases (e.g., in patients with genotype 2 or 3) treatment may be possible without histologic confirmation.

Current clinical guidelines must be considered to determine if a liver biopsy is necessary before initiating treatment.

In patients with normal ALT levels, progression of fibrosis is usually slower than in patients with elevated ALT levels. This must be considered along with other factors (hepatitis C virus genotype, extrahepatic manifestations, risk of transmission, etc.) to decide whether treatment is appropriate.

Laboratory values before and during treatment

Before treatment with Pegasys® all patients are recommended to have routine general clinical and biochemical blood tests.

The initiation of therapy is possible with the following baseline measures:

– platelet count >90000 cells/μL,

– absolute neutrophil count >1500 cells/μL,

– compensated thyroid dysfunction (TTG and T4 within normal limits).

After initiation of therapy, total clinical blood counts should be repeated after 2 and 4 weeks, and biochemical blood counts after 4 weeks; laboratory tests should be performed periodically during therapy.

In clinical studies, treatment with Pegasys® has decreased both total white blood cell count and BUN, usually from the second week of therapy. A progressive decrease in ACH after 8 weeks of therapy was infrequent. The decrease was reversible after reducing the dose or discontinuing the drug, and in most patients the ACH reached a normal value after 8 weeks and returned to the initial value in all patients after about 16 weeks. Pegasys® therapy is associated with decreased platelet counts, which returned to baseline levels during the follow-up period after treatment. Dose changes may be necessary in some cases.

In clinical studies with combination treatment of Pegasys® and ribavirin, the occurrence of anemia (Hb levels

The occurrence of anemia (Hb levels

) has been shown in a clinical study. As with other interferons, caution should be exercised when prescribing Pegasys® in combination with other myelotoxic drugs.

The potential risks and benefits should be weighed before initiating therapy in patients with CHC who have failed prior therapy and have interrupted therapy due to hematologic adverse events, because the use of Pegasys® in these patients has not been well studied.

Endocrine system

The use of interferon alpha, including Pegasys®, has been observed to impair thyroid function or worsen pre-existing thyroid disease. Thyroid and T4 levels should be investigated before starting therapy with Pegasys®. Treatment with Pegasys® may be initiated or continued if TTH levels can be maintained within normal limits by medication. If clinical symptoms of possible thyroid dysfunction occur, TTG should be tested during therapy.

As with other interferon therapy, hypoglycemia, hyperglycemia, and diabetes mellitus have been observed with Pegasys®. Patients with the above conditions that are not adequately corrected should not start Pegasys® monotherapy or combination therapy with Pegasys®/ribavirin, and therapy should be discontinued if such conditions develop during treatment.

The cardiovascular system

Artial hypertension, supraventricular arrhythmias, congestive heart failure, chest pain, and myocardial infarction have been associated with therapy with interferon alfa, including Pegasys®. Patients with cardiovascular disease are advised to have an ECG before starting therapy. If cardiovascular status worsens, therapy should be interrupted or withdrawn. In patients with cardiovascular disease, anemia may necessitate dose reduction or discontinuation of ribavirin.

Liver function impairment

Pegasys® should be discontinued if hepatic failure develops. As with therapy with other interferon alfa, increased ALT levels compared to baseline have been observed during therapy with Pegasys®, including patients with virologic response. If there is a progressive or clinically significant increase in ALT levels despite dose reduction or if this increase is accompanied by an increase in direct bilirubin levels, therapy should be discontinued.

In contrast to CHC, in CGV, exacerbation of liver disease is not uncommon and is accompanied by a transient and potentially significant increase in ALT levels. In clinical trials, a sudden marked increase in ALT during therapy with Pegasys® in patients with CGV was accompanied by mild changes in other laboratory parameters without signs of decompensation of liver function. In half of the cases of a sudden increase in ALT level exceeding 10 times the upper limit of normal, the dose of Pegasys® was reduced or therapy was temporarily withdrawn until normalization of the index, while in the other half of patients the therapy was continued without changes. It is recommended that liver function be monitored more frequently in all cases.

Hypersensitivity reactions

In therapy with interferon alfa serious immediate-type hypersensitivity reactions (e.g., urticaria, angioedema, bronchospasm, anaphylaxis) are rarely observed. In cases of such reactions, the therapy is withdrawn and appropriate drug therapy is immediately prescribed.

A transient rash does not require discontinuation of therapy.

Autoimmune diseases

The occurrence of autoantibodies and autoimmune diseases has been described during treatment with interferon alfa. Patients with a predisposition to develop autoimmune diseases are at increased risk. Patients with signs or symptoms similar to those of autoimmune diseases should be carefully evaluated and the benefit/risk ratio of continued interferon therapy re-evaluated.

Fever and infections

While fever may be associated with the flu-like syndrome common with interferon therapy, other causes of persistent fever (particularly serious bacterial, viral, and fungal infections) should be excluded, especially in patients with neutropenia. Serious infections (bacterial, viral, fungal) have been reported when taking interferon alfa, including Pegasys®. Appropriate specific therapy should be administered immediately and Pegasys® should be stopped.

Ophthalmologic changes

As with therapy with other interferons, treatment with Pegasys® retinopathy, including retinal hemorrhages, cottonwood exudates, optic disc edema, optic neuritis, and thrombosis of retinal arteries or veins have rarely been reported.

All patients should have an ophthalmologic examination to determine fundus pathology before therapy. If there are complaints of visual acuity deterioration or narrowing of the visual fields, a complete ophthalmologic examination should be performed immediately. Patients with concomitant diseases of the visual organ (e.g., diabetic or hypertensive retinopathy) should undergo additional examinations during therapy with Pegasys®. If ophthalmic disease occurs or worsens, therapy should be discontinued.

Respiratory changes

As with interferon alfa therapy, adverse respiratory reactions, including dyspnea, pulmonary infiltrates, pneumonia, and pneumonitis, have been observed with Pegasys® therapy. If persistent infiltrates or infiltrates of unclear genesis or respiratory dysfunction occur, therapy should be discontinued.

Skin changes

The use of interferon alfa has been associated with exacerbation or induction of psoriasis and sarcoidosis. Pegasys® should be administered with caution in psoriasis patients, and consideration should be given to withdrawing therapy if the disease appears or worsens.

HIV-CCV co-infection

Before starting treatment, you should carefully review the possible side effects of the antiretroviral drugs that the patient will be taking with the HCV therapy drugs. In patients who received stavudine and interferon with or without ribavirin concomitantly, the incidence of pancreatitis and/or lactate acidosis was 3% (12/398).

Patients with HIV-HCV co-infection receiving highly active antiretroviral therapy (HAART) may be at risk for developing lactate acidosis.

Hence, caution should be exercised when adding Pegasys® and ribavirin to HAART (see instructions for the medical use of ribavirin).

In co-infected patients with severe cirrhosis receiving HAART, combination therapy with ribavirin and interferons, including Pegasys®, increases the risk of fatal liver failure. Baseline parameters that may be associated with hepatic decompensation in patients with co-infection and cirrhosis include: elevated serum bilirubin, reduced Hb, elevated ALP or reduced platelet count, and treatment with didanosine.

The concomitant use of ribavirin and zidovudine is not recommended because of the increased risk of anemia.

In co-infected patients, liver function should be monitored closely during therapy by assessing the Child-Pugh score. Therapy should be discontinued immediately at a Child-Pugh score of >7.

Caution should be exercised when prescribing Pegasys® to patients with low CD4+ lymphocyte counts (due to insufficient data on efficacy and safety of Pegasys® in patients with HIV-CCV co-infection with CD4+ lymphocyte counts below 200 cells/mL).

Dental changes

Patients receiving combination therapy with Pegasys® and ribavirin have seen dental and periodontal pathology that can lead to tooth loss. In addition, long-term treatment with Pegasys® and ribavirin can cause dryness in the mouth, damaging the teeth and oral mucosa. Patients should brush their teeth carefully twice a day and have regular checkups with their dentist. Some patients may vomit, after which they should rinse their mouth thoroughly.

The use of peginterferon as long-term maintenance therapy (use outside the registered indication)

In a randomized, controlled trial (HALT-C) in patients with HCV and various stages of fibrosis who did not respond to prior therapy, Pegasys monotherapy® at a dose of 90 mcg per week for 3.5 years showed no significant reduction in the rate of fibrosis progression or associated clinical events.

Impact on driving and operating machinery. Pegasys® has little effect on the ability to drive vehicles and operate machines. If dizziness, drowsiness, confusion and weakness occur, you should refrain from driving a vehicle or operating machinery.

Contraindications

Side effects

The frequency and severity of the most common adverse reactions to treatment with Pegasys® and interferon alfa-2a are similar.

The most common adverse reactions when treated with Pegasys® at a dose of 180 mcg are generally mild to moderate and do not require dose adjustments or drug withdrawal.

CGV

For the duration of therapy (48 weeks) and during follow-up without treatment (24 weeks), the safety profile of Pegasys® was similar to that of CHC, although the frequency of side effects in CHC was significantly lower, except for the frequency of fever. Adverse events occurred in 88% of patients receiving Pegasys® compared to 53% of patients receiving lamivudine. Serious adverse events were reported in 6 and 4% of patients, respectively. In 5% of patients receiving Pegasys® and less than 1% of patients receiving lamivudine, therapy was withdrawn because of adverse events. The rate of drug withdrawal did not differ between patients with and without cirrhosis.

CHCV patients who have not previously responded to treatment

In general, the safety profile of Pegasys® in combination with ribavirin in previously unresponsive patients was similar to that of previously untreated patients.

In a clinical trial involving 72- and 48-week treatments in patients who had not responded to prior pegylated interferon alfa-2b/ribavirin therapy, laboratory abnormalities or adverse events led to discontinuation of Pegasys® in 12% of patients and withdrawal of ribavirin in 13% of patients treated for 72 weeks. In the group of patients treated for 48 weeks, laboratory abnormalities or adverse events led to Pegasys® withdrawal in 6% and ribavirin withdrawal in 7%. Similarly, in patients with cirrhosis, the rate of cancellation of Pegasys® and ribavirin therapy was higher in the group of patients treated for 72 weeks (13 and 15%) than in the group of patients treated for 48 weeks (6 and 6%). The study did not include patients with discontinuation of previous therapy (pegylated interferon alfa-2b/ribavirin) due to hematologic toxicity.

Another 48-week clinical trial included patients with severe fibrosis or cirrhosis (Ishak score 3 to 6) who had not previously responded to therapy and had a baseline platelet count ≥50000 cells/μL. In the first 20 weeks of the study, the following laboratory abnormalities in hematological parameters were observed: anemia (hemoglobin level less than 10 g/dL – in 26% of patients); neutropenia (absolute neutrophil count (ANR) less than 750 cells/μL – in 30% of patients); thrombocytopenia (platelet count less than 50000 cells/μL – in 13% of patients).

HIV-CCV co-infection

The safety profile of Pegasys® (monotherapy or combination with ribavirin) in patients with HIV-CCV co-infection is similar to that of HCV patients. Other adverse events that occurred in ≥1-≤2% of patients with HIV-CCV co-infection when treated with Pegasys®/ribavirin included: Hyperlactacidemia/lactate acidosis, influenza, pneumonia, emotional lability, apathy, tinnitus, sore throat and larynx, cheilitis, acquired lipodystrophy and chromaturia. Pegasys® therapy was associated with a decrease in absolute CD4+ lymphocyte counts in the first 4 weeks of treatment with no change in their percentage. CD4+-lymphocyte counts returned to baseline at dose reduction or after discontinuation of therapy. Administration of Pegasys® had no adverse effect on HIV viral load during therapy and during follow-up after therapy.

There are limited data on use in patients with CD4+ lymphocyte counts less than 200 cells/μL.

Some adverse reactions during Pegasys® HCV and CHCV monotherapy as well as during Pegasys® in combination with HCV ribavirin

The following categories are used to describe the frequency of adverse reactions: very common (≥1/10), common (≥1/100;

Infections: common – upper respiratory tract infections, bronchitis, oral candidiasis, herpes simplex, fungal and bacterial infections; infrequent – pneumonia, skin infections; rare – endocarditis, external otitis media.

Benign and malignant neoplasms: infrequent – liver neoplasia.

The blood and lymphatic system: frequently – thrombocytopenia, anemia, lymphadenopathy; rarely – pancytopenia; very rarely – aplastic anemia.

Immune system: infrequent – sarcoidosis, thyroiditis; rare – anaphylaxis, systemic lupus erythematosus, rheumatoid arthritis; very rare – idiopathic or thrombotic thrombocytopenic purpura, angioedema.

Endocrine system: frequently – hypothyroidism, hyperthyroidism; infrequently – diabetes mellitus; rarely – diabetic ketoacidosis.

Metabolic disorders: very common – anorexia; infrequent – dehydration.

Mental disorders: very common – depression,* anxiety, insomnia*; common – emotional disorders, mood changes, aggressiveness, nervousness, decreased libido; infrequent – suicidal thoughts, hallucinations; rare – suicide, mental disorders.

Nervous system: very common – headache, dizziness*, impaired concentration; common – memory disturbance, syncopal states, weakness, migraine, hypoesthesia, hyperesthesia, paresthesia, tremor, impaired sense of taste, nightmares, somnolence; infrequent – peripheral neuropathy; rare – coma, seizures, facial neuritis.

The visual organ: often – visual disturbance, pain in the eyeball, inflammatory eye disease, xerophthalmia; infrequent – retinal hemorrhage; rare – optic neuritis, optic nerve papilledema, retinal vascular lesions, retinopathy, corneal ulcer; very rare – vision loss.

Hearing organ: frequently – vertigo, pain in the ear; infrequently – hearing loss.

Cardiovascular system: frequently – tachycardia, palpitations, peripheral edema; infrequently – arterial hypertension; rarely – myocardial infarction, congestive heart failure, angina pectoris, supraventricular tachycardia, arrhythmia, atrial fibrillation, pericarditis, cardiomyopathy, cerebral hemorrhage, vasculitis.

Respiratory organs: very common – dyspnea, cough; common – dyspnea on exertion, nasal bleeding, nasopharyngitis, sinus swelling, stuffy nose, rhinitis, sore throat; infrequent – wheezing; rare – interstitial pneumonitis (including cases with fatal outcome), pulmonary embolism.

Gastrointestinal organs: very common – diarrhea*, nausea*, abdominal pain*; common – vomiting, dyspepsia, dysphagia, oral mucosa ulceration, bleeding gums, glossitis, stomatitis, flatulence, dry oral mucosa; infrequent – gastrointestinal bleeding; rare – peptic ulcer, pancreatitis.

Hepatobiliary disorders: infrequent – liver dysfunction; rarely – liver failure, cholangitis, fatty liver dystrophy.

The skin and its appendages: very common – alopecia, dermatitis, itching, dry skin; common – rash, increased sweating, psoriasis, urticaria, eczema, skin reactions, photosensitization reactions, night sweats; very rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

Muscular system: very often – myalgia, arthralgia; often – back, neck, bone pain, arthritis, muscle weakness, musculoskeletal pain, muscle cramps; rarely – myositis.

Prenal system: rarely – renal failure.

Reproductive system: often – impotence.

The body in general: very often – fever, shivering*, pain*, asthenia, weakness, irritability*, injection site reactions*; often – chest pain, flu-like syndrome, malaise, lethargy, hot flashes, thirst, weight loss.

*These adverse reactions occurred frequently (≥1/100;®.

Postmarketing observations

Nervous system: ischemic stroke (incidence not known).

Ocular system: as with other interferon alfa administration, serious cases of retinal detachment have been reported with Pegasys® (incidence not known).

Motor system: rhabdomyolysis (incidence not known).

Laboratory parameters: therapy with Pegasys® was accompanied by the following changes in laboratory parameters – increased ALT, hyperbilirubinemia, electrolyte disturbances (hypokalemia, hypocalcemia, hypophosphatemia), hypo- and hyperglycemia, hypertriglyceridemia.

In monotherapy with Pegasys® and combination therapy with ribavirin, elevated ALT levels were observed in 2% of patients, which led to dose reduction or discontinuation of treatment.

Pegasis® therapy was associated with decreased hematologic parameters (leukopenia, neutropenia, lymphopenia, thrombocytopenia and decreased hemoglobin levels), which improved with dose modification and returned to baseline levels 4-8 weeks after discontinuing therapy. In 24% (216/887) of patients who received 180 mcg of Pegasys® and 1000-1200 mg of ribavirin for 48 weeks, moderate severity neutropenia was observed (ACH 0.749-0.5-109/L), and 5% (41/887) of patients had severe neutropenia (ACH:9/L).

Interferon antibodies: neutralizing interferon antibodies were observed in 1-5% of patients receiving Pegasys®. As with other interferon therapy, neutralizing interferon antibodies were more frequently observed in CGV. However, no correlation between the appearance of antibodies and treatment efficacy was found.

Thyroid function: Therapy with Pegasys® was associated with clinically significant changes in laboratory measures of thyroid function that required medical intervention. The incidence (4.9%) of these changes was similar between Pegasys® and other interferons.

Laboratory parameters in HIV-CCV co-infection

While hematologic toxicity (neutropenia, thrombocytopenia, anemia) is more common in patients with HIV-CCV co-infection, most are corrected by dose changes and growth factors, and premature therapy withdrawal is rarely required. Decreases in absolute neutrophil counts below 500 cells/μL were observed in 13% of patients receiving Pegasys® monotherapy and 11% of patients receiving Pegasys®/ribavirin therapy. A decrease in platelets below 50,000 cells/μL was observed with Pegasys® monotherapy in 10% of patients and with combination therapy in 8%. Anemia was reported in 7% of patients receiving Pegasys® monotherapy and in 14% of patients receiving Pegasys®/ ribavirin (Hb level –

Overdose

Symptoms: Cases of Pegasys® overdose have been described when administered for 2 consecutive days (no weekly interval) and when administered daily for 1 week (total dose 1260 mcg per week). No unusual, serious and treatment-affecting adverse events were noted.

In clinical studies in renal cancer and chronic myeloleukemia the drug was administered in doses of up to 540 and 630 mcg per week.

The signs of toxicity limiting further use at these doses were weakness, increased liver enzyme activity, neutropenia and thrombocytopenia, which can also occur with treatment with conventional interferons.

Treatment: there is no specific antidote. Hemodialysis and peritoneal dialysis are ineffective.

Pregnancy use

Category C. The effect of Pegasys® on fertility has not been studied. When peginterferon alfa-2a, as well as other alpha-interferons were administered, a prolongation of the menstrual cycle, with a decrease and a later onset of maximum concentrations of 17β-estradiol and progesterone in animals was noted. Normalization of the menstrual cycle was observed after withdrawal of the drug.

The effect of peginterferon alfa-2a on male fertility has not been studied. However, administration of interferon alfa-2a for 5 months had no effect on fertility in animals.

The teratogenic effects of Pegasys® have not been studied. Interferon alfa-2a administration resulted in a significant increase in the number of spontaneous abortions in rhesus macaques. No teratogenic effects were observed in offspring born at term. However, when treated with Pegasys®, as with other alpha interferons, women of childbearing age should use effective contraceptive methods.

Pegasis® should not be prescribed during pregnancy.

It is not known whether Pegasys® or components of the drug are excreted in the breast milk. To rule out adverse effects of Pegasys® or ribavirin on the baby during lactation, either breastfeeding or therapy should be discontinued, given the potential benefits of therapy to the mother.

For combination with ribavirin: Category X.

Ribavirin has been shown in animal studies to have pronounced teratogenic effects and the ability to cause fetal death. Ribavirin is contraindicated in pregnant women and men whose partners are pregnant.

Ribavirin therapy should not be prescribed until a negative pregnancy test has been performed immediately before the intended start of therapy. Women who are fertile or men whose partners are fertile should be informed about the teratogenic effects of ribavirin and the need for effective contraception (at least 2 methods) during treatment and for 6 months after completion of therapy (see the instructions for the medical use of ribavirin).