Ribavirin

Adult patients

Triple therapy

See prescribing information for boceprevir.

Dual therapy

The safety of ribavirin was assessed in four clinical studies in patients who had not previously taken interferon alfa-2b (patients who had not previously received interferon therapy): two studies examined the use of ribavirin in combination with interferon alfa-2b, two in combination with peginterferon alfa-2b.

Patients previously treated with interferon alfa-2b and ribavirin, or in whom treatment lasted less than the standard duration, may experience an improved safety profile compared to that described below.

Data on adverse reactions presented in the instructions for medical use of peginterferon alfa-2b and interferon alfa-2b may also be applicable to interferon monotherapy.

Adverse reactions are presented by class of organs and systems in decreasing order of frequency according to the following categories: very often (≥1/10); often (≥1/100 to and <1/10); uncommon (≥1/1000 and <1/100); rare (≥1/10000 to <1000); very rare (<1/10000); unknown. Within each frequency group, adverse reactions are presented in order of decreasing severity.

Infectious and parasitic diseases:

very often - viral infections, pharyngitis; often - bacterial infections (including sepsis), fungal infection, influenza, respiratory tract infections, bronchitis, infections caused by the herpes simplex virus, sinusitis, otitis media, rhinitis, urinary tract infections; uncommon - infection at the injection site, lower respiratory tract infection; rarely - pneumonia*.

Benign, malignant and unspecified neoplasms (including cysts and polyps):

often - unspecified neoplasms.

Blood and lymphatic system disorders:

very often - anemia, neutropenia; often - hemolytic anemia, leukopenia, thrombocytopenia, lymphadenopathy, lymphopenia; very rarely - aplastic anemia*; unknown - true erythrocyte aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura.

Immune system disorders:

uncommon - hypersensitivity; rare - sarcoidosis*, rheumatoid arthritis (new or worsening); unknown - Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus, vasculitis, acute hypersensitivity reactions, including urticaria, angioedema, bronchospasm, anaphylaxis.

Endocrine system disorders:

often - hypothyroidism, hyperthyroidism.

Metabolic and nutritional disorders

: very often - anorexia; often - hyperglycemia, hyperuricemia, hypocalcemia, dehydration, increased appetite; uncommon - diabetes mellitus, hypertriglyceremia*.

Mental disorders:

very often - depression, insomnia, emotional lability, anxiety; often - suicidal thoughts, psychosis, aggressive behavior, confusion, agitation, anger, mood swings, pathological behavior, nervousness, sleep disturbances, anxious dreams, decreased libido, apathy, tearfulness; infrequently - suicide attempts, panic attack, hallucinations; rarely - bipolar disorder*; very rarely - suicide*; unknown - homicidal thoughts*, mania*, change in mental status.

Nervous system disorders

: very often - headache, dizziness, dry mouth, difficulty concentrating; often - amnesia, memory impairment, fainting, migraine, ataxia, paresthesia, dysphonia, loss of taste, hypoesthesia, hyperesthesia, hypertonicity, drowsiness, impaired attention, tremor, taste perversion; uncommon - neuropathy, peripheral neuropathy; rarely - seizures (convulsions)*; very rarely - cerebral hemorrhage*, cerebrovascular ischemia*, encephalopathy*, polyneuropathy*; unknown - facial nerve paralysis, mononeuropathy.

Visual disorders:

often - blurred vision, blurred vision, conjunctivitis, eye irritation, eye pain, distortion of visual perception, pathology of the lacrimal glands, dry eyes; rarely - retinal hemorrhages*, retinopathy (including macular edema)*, retinal artery thrombosis*, retinal vein thrombosis*, optic neuritis*, papilledema*, decreased visual acuity or loss of visual fields*, retinal exudate.

Hearing and labyrinth disorders:

often - vertigo, hearing impairment or loss, ringing in the ears, ear pain.

Cardiac disorders:

often - palpitations, tachycardia; uncommon - myocardial infarction; rarely - cardiomyopathy*, arrhythmia*; very rarely - cardiac ischemia*; unknown - pericardial effusion*, pericarditis*.

Vascular disorders:

often - decreased blood pressure, increased blood pressure, “hot flashes”; rarely - vasculitis; very rarely - ischemia of peripheral tissues*.

Disorders of the respiratory system, chest and mediastinal organs:

very often - shortness of breath, cough; often - nosebleeds, respiratory disorders, respiratory tract congestion, sinusitis, swelling of the nasal mucosa, rhinorrhea, increased secretion of the mucous membrane of the upper respiratory tract, sore throat, non-productive cough; very rarely - pulmonary infiltrates*, pneumonitis*, interstitial pneumonitis*.

Gastrointestinal disorders:

very often - diarrhea, vomiting, nausea, abdominal pain; often - ulcerative stomatitis, stomatitis, ulcers in the mouth, colitis, pain in the right upper quadrant of the abdomen, dyspepsia, gastrointestinal reflux*, glossitis, cheilitis, bloating, bleeding gums, gingivitis, frequent loose stools, dental lesions, constipation, flatulence; infrequently - pancreatitis, pain in the oral cavity; rarely - ischemic colitis; very rarely - ulcerative colitis*; unknown - periodontal disorders, dental disorders, tongue pigmentation.

Disorders of the liver and biliary tract

: often - hepatomegaly, jaundice, hyperbilirubinemia *; very rarely - hepatotoxicity (including death)*.

Disorders of the skin and subcutaneous tissues:

very often - alopecia, itching, dry skin, rash; often - psoriasis, worsening of pre-existing psoriasis, eczema, photosensitivity reaction, maculopapular rash, erythematous rash, night sweats, hyperhidrosis, dermatitis, acne, furunculosis, erythema, urticaria, skin disorders, hematoma, increased sweating, hair structure disorder, nail disorders*; rarely - sarcoidosis of the skin; very rarely - Stevens-Johnson syndrome*, toxic epidermal necrolysis*, erythema multiforme and exudative*.

Musculoskeletal and connective tissue disorders:

very often - arthralgia, myalgia, pain in muscles and bones; often - arthritis, back pain, muscle spasms, pain in the limb; uncommon - bone pain, muscle weakness; rarely - rhabdomyolysis*, myositis*.

Renal and urinary tract disorders:

often - frequent urination, polyuria, abnormal urine parameters; rarely - renal dysfunction, renal failure*; very rarely - nephrotic syndrome*.

Disorders of the genital organs and mammary glands:

often - women: amenorrhea, menorrhagia, menstrual irregularities, dysmenorrhea, breast pain, ovarian dysfunction, vaginal disorders; men: impotence, prostatitis, erectile dysfunction, sexual dysfunction (without specifying an exact diagnosis)*.

General disorders and disorders at the injection site:

very often - inflammation at the injection site, reactions at the injection site, fatigue, chills, fever, flu-like symptoms, asthenia, irritability; often - chest pain, chest discomfort, peripheral edema, malaise, pain at the injection site, sensory disturbances, thirst; infrequently - swelling of the face; rarely - necrosis of the injection site.

Laboratory and instrumental data:

very often - weight loss; often - heart murmur.

* Since ribavirin is always prescribed in combination with interferon alfa, and the listed adverse reactions were registered in the post-marketing period, the frequency of reactions cannot be determined. The frequencies listed above are based on data from clinical studies of ribavirin in combination with interferon alfa-2b (pegylated and non-pegylated).

30% of patients taking ribavirin and peginterferon alfa-2b and 37% of patients taking ribavirin and interferon alfa-2b experienced a decrease in hemoglobin concentrations of more than 4 g/dL.

In 14% of adult patients and 7% of children 3 to 18 years of age taking ribavirin in combination with peginterferon alfa-2b or interferon alfa-2b, hemoglobin concentrations decreased to 10 g/dL or lower.

In most cases, mild degrees of anemia, neutropenia and thrombocytopenia (WHO grade 1 or 2) were reported. Some cases of severe neutropenia have been reported in patients taking ribavirin in combination with peginterferon alfa-2b (WHO grade 3: 39 of 186 [21%]; and WHO grade 4: 13 of 186 [7%]); leukopenia grade 3 according to the WHO scale was recorded in 7% of patients from this group.

Increases in uric acid and indirect bilirubin concentrations associated with hemolysis were observed in some patients receiving ribavirin in combination with peginterferon alfa-2b and interferon alfa-2b in clinical studies, but concentrations returned to baseline values 4 weeks after completion of treatment. Gout has been reported in a few cases among patients with elevated uric acid concentrations, but none required treatment changes and none were excluded from the clinical trials.

Patients with HCV/HIV co-infection

In patients with HCV/HIV co-infection taking ribavirin in combination with peginterferon alfa-2b, other adverse reactions (not observed in patients with hepatitis C alone) with an incidence of >5% were: oral candidiasis (14%), acquired lipodystrophy (13%), decreased CD4 lymphocyte concentration (8%), decreased appetite (8%), increased gamma-glutamyl transferase activity (9%), back pain (5%), increased blood amylase activity (6%) , increased concentration of lactic acid in the blood (5%), cytolytic hepatitis (6%), increased lipase activity (6%) and pain in the extremities (6%).

Mitochondrial toxicity

Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients taking NRTIs and ribavirin for the treatment of hepatitis C (see section 4.4).

Laboratory values in patients with HCV/HIV co-infection

According to the study, a decrease in absolute neutrophil count below 500 cells/mm3, as well as a decrease in platelet count below 50,000/mm3, was observed in 4% (8/194) of patients taking ribavirin in combination with peginterferon alfa-2b.

Anemia (hemoglobin <9.4 g/dL) was reported in 12% (23/194) of patients receiving ribavirin in combination with peginterferon alfa-2b.

Decreased CD4 count

Treatment with ribavirin in combination with peginterferon alfa-2b was associated with a decrease in absolute CD4+ cell counts during the first 4 weeks without a decrease in the percentage of CD4+ cells. The decrease in CD4+ cell counts was reversible after dose reduction or discontinuation of therapy. The use of ribavirin in combination with peginterferon alfa-2b did not have a significant negative effect on the control of HIV viremia during or after treatment. Safety data for co-infected patients with CD4+ cell counts <200/μL are limited (n=25) (see Precautions section).

When taking antiretroviral drugs and drugs for the treatment of HCV together, to identify the specific toxicity of each drug and the development of cross-toxicity of ribavirin and peginterferon alfa-2b, you should read the instructions for medical use of each of the drugs used.

Children from 3 to 18 years (dual therapy only)

In combination with peginterferon alfa-2b

Overall, the adverse reaction profile in children was consistent with that observed in adults, although the possibility of growth retardation was present.

During combination therapy with pegylated interferon alfa-2b and ribavirin for up to 48 weeks, a decrease in growth rate was observed, resulting in some patients being less than normal in height (see Precautions). Weight loss and growth failure were very common during treatment (at the end of treatment, mean decreases from baseline in weight and height were the 15th and 8th percentiles, respectively); growth velocity was also decreased (<3rd percentile in 70% of patients).

At the end of the 24-week post-treatment follow-up, mean decreases from baseline in weight and height were 3rd and 7th percentiles, respectively, and 20% of children experienced a decrease in height velocity (<3rd percentile). Ninety-four of 107 children participated in the five-year long-term study with follow-up. The effect of the drug on growth was lower in children treated for 24 weeks compared to children treated for 48 weeks. From pre-treatment to end of follow-up, height percentiles for children treated at 24 and 48 weeks decreased by 1.3 and 9.0 percentiles, respectively. Growth loss in 24% of children (11/46) treated for 24 weeks and 40% of children (19/48) treated for 48 weeks was >15th percentile from pre-treatment to the end of the five-year study with follow-up compared to baseline. 11% of children (5/46) treated for 24 weeks and 13% of children (6/48) treated for 48 weeks experienced a decline in height from baseline of more than 30 percentiles of height-for-age. from pre-treatment to the end of the five-year follow-up study. From pretreatment to the end of the five-year follow-up study, weight loss was 1.3 percentile in children treated for 24 weeks and 5.5 percentile in children treated for 48 weeks. Body mass index decreased by 1.8 and 7.5 percentiles, respectively.

In this study, the most common reactions in all patients were fever (80%), headache (62%), neutropenia (33%), fatigue (30%), anorexia (29%), and redness at the injection site (29%). In only 1 patient, treatment was discontinued due to the development of an adverse reaction (thrombocytopenia).

The majority of adverse reactions recorded in this study were mild to moderate in severity. Severe adverse reactions were reported in 7% (8/107) of cases and included pain at the injection site (1%), pain in the extremities (1%), headache (1%), neutropenia (1%) and fever (4%). ).

Significant adverse reactions in this patient population were nervousness (8%), aggression (3%), anger (2%), depression/depressed mood (4%), and underactive thyroid (3%). 5 patients took levothyroxine for hypothyroidism/increased thyroid-stimulating hormone (TSH) concentrations.

In combination with interferon alfa-2b

In a clinical study of 118 children 3 to 18 years of age receiving combination therapy with interferon alfa-2b and ribavirin, 6% discontinued treatment due to adverse reactions. Overall, the adverse reaction profile in a limited population of children 3 to 18 years of age was similar to that observed in adults, however, in the pediatric population, there was concern regarding growth retardation as a decrease in height velocity was observed during treatment (average 9 percentile decrease in height) and body weight (average weight loss 13th percentile). At 5 years of follow-up, the children's mean height was 44 percentile, which was below the normal population mean and less than their mean initial height (48 percentile). Twenty (21%) of 97 children had >15 percentile height decline, of whom 10 of 20 children had >30 percentile height decline from the start of treatment to the end of long-term follow-up (up to 5 years). For 14 of these patients, final height in adulthood (10–12 years after completion of therapy) was known, which showed that 12 patients had a height deficit (greater than 15 percentile).

During combination therapy with interferon alfa-2b and ribavirin for up to 48 weeks, a decrease in growth rate was observed, resulting in some patients being less than normal in height by adulthood. The decrease in mean height percentile compared to baseline at the end of the long-term follow-up period predominated in prepubertal children (see section "Special Instructions").

In addition, injection site lesions, fever, anorexia, vomiting, and emotional lability were more common in children 3 to 18 years of age compared to adult patients.

Dose changes were required in 30% of cases, mainly due to anemia and neutropenia.

The adverse reactions listed below are based on data from two multicenter clinical studies of ribavirin in combination with interferon alfa-2b or peginterferon alfa-2b in children 3 to 18 years of age.

Infectious and parasitic diseases

: very often - viral infection, pharyngitis; often - fungal infection, bacterial infection, lung infections, nasopharyngitis, streptococcal pharyngitis, otitis media, sinusitis, dental abscess, influenza, oral herpes, infections caused by the herpes simplex virus, urinary tract infections, vaginitis, gastroenteritis; infrequently - pneumonia, ascariasis, enterobiasis, herpes zoster.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

: often - unspecified neoplasms.

Blood and lymphatic system disorders:

very often - anemia, neutropenia; often - lymphadenopathy, thrombocytopenia.

Endocrine system disorders:

very often - hypothyroidism; often - hyperthyroidism, virilism.

Metabolic and nutritional disorders:

very often - anorexia, decreased appetite, increased appetite; often - hypertriglyceridemia, hyperuricemia.

Mental disorders

: very often - depression, insomnia, emotional lability; often - suicidal thoughts, aggressive behavior, confusion, behavioral disorder, agitation, somnambulism, anxiety, mood changes, restlessness, nervousness, sleep disturbance, pathological dreams, apathy; infrequently - behavioral disorders, depressed mood, emotional disorders, fear, disturbing dreams.

Nervous system disorders:

very often - headache, dizziness; often - hyperkinesis, tremor, dysphonia, paresthesia, hypoesthesia, hyperesthesia, impaired concentration, drowsiness, poor quality of sleep; infrequently - neuralgia, lethargy, psychomotor agitation.

Visual disorders:

often - conjunctivitis, eye pain, blurred vision, disorders of the lacrimal glands; infrequently - hemorrhages in the conjunctiva, itching in the eyes, keratitis, blurred vision, photophobia.

Hearing and labyrinth disorders:

often - vertigo.

Cardiac disorders:

often - tachycardia, palpitations.

Vascular disorders:

often - pallor of the skin, “hot flashes”; infrequently - decreased blood pressure.

Disorders of the respiratory system, chest and mediastinal organs:

often - shortness of breath, rapid breathing, nosebleeds, cough, nasal congestion, nasal irritation, rhinorrhea, sore throat; Uncommon: wheezing, nasal discomfort.

Gastrointestinal disorders:

very often - abdominal pain, pain in the upper abdomen, vomiting, diarrhea, nausea; often - oral ulcers, ulcerative stomatitis, stomatitis, aphthous stomatitis, dyspepsia, cheilosis, glossitis, gastroesophageal reflux, rectal disorders, constipation, loose stools, toothache, dental disorders, stomach discomfort, oral pain cavities; infrequently - gingivitis.

Disorders of the liver and biliary tract

: often - liver dysfunction; infrequently - hepatomegaly.

Disorders of the skin and subcutaneous tissues:

very often - alopecia, rash; often - itching, photosensitivity reaction, maculopapular rash, eczema, sweating, acne, skin diseases, nail structure disorders, skin discoloration, dry skin, erythema, hematoma; infrequently - pathological pigmentation, atopic dermatitis, peeling of the skin.

Musculoskeletal and connective tissue disorders:

very often - arthralgia, myalgia, muscle pain; often - pain in the limb, back pain, muscle contractures.

Renal and urinary tract disorders

: often - enuresis, urinary disorders, urinary incontinence, proteinuria.

Disorders of the genital organs and mammary glands

: often - women: amenorrhea, menorrhagia, menstrual irregularities, vaginal disorders; men: testicular pain; infrequently - women: dysmenorrhea.

General disorders and disorders at the injection site:

very often - inflammation at the injection site, reactions at the injection site, erythema at the injection site, pain at the injection site, fatigue, fatigue, fever, chills, flu-like symptoms, asthenia, malaise, irritability; often - chest pain, swelling, itching at the injection site, rash at the injection site, dryness of the injection site, feeling of cold; Uncommon: chest discomfort, pain in the face, hardening of the injection site.

Laboratory and instrumental data:

very often - decreased growth rate (decreased height and/or body weight at a given age); often - increased TSH concentration, increased thyroglobulin concentration; infrequently - positive antibodies to the thyroid gland.

Injuries, intoxications and complications of manipulations

: often - skin damage; infrequently - contusion.

Most changes in laboratory parameters in clinical studies of ribavirin/peginterferon alfa-2b were mild or moderate.

A decrease in the concentration of hemoglobin, leukocytes, platelets, neutrophils and an increase in bilirubin may require dose reduction or discontinuation of therapy (see “Dosage and Administration”). Although changes in laboratory values were observed during treatment with ribavirin/peginterferon alfa-2b in clinical studies, they returned to normal values several weeks after the end of therapy.

If any of the side effects listed in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.

Ribavirin, 200 mg, capsules, 30 pcs.

Adult patients

Triple therapy

See prescribing information for boceprevir.

Dual therapy

The adverse reactions listed below are based on data from clinical studies in interferon-naïve adult patients treated for 1 year and on data from post-marketing use of the drug. A number of adverse reactions, usually attributed to interferon therapy, but also reported with hepatitis C therapy (in combination with ribavirin) are presented below. Data on adverse reactions presented in the instructions for medical use of peginterferon alfa-2b and interferon alfa-2b may also be applicable to interferon monotherapy. Adverse reactions are presented by class of organs and systems in decreasing order of frequency according to the following categories: very often (≥1/10); often (≥1/100 to and <1/10); uncommon (≥1/1000 and <1/100); rare (≥1/10000 to <1000); very rare (<1/10000); unknown. Within each frequency group, adverse reactions are presented in order of decreasing severity.

Infectious and parasitic diseases: very often - viral infections, pharyngitis; often - bacterial infections (including sepsis), fungal infection, influenza, respiratory tract infections, bronchitis, infections caused by the herpes simplex virus, sinusitis, otitis media, rhinitis, urinary tract infections; uncommon - infection at the injection site, lower respiratory tract infection; rarely - pneumonia*.

Benign, malignant and unspecified neoplasms (including cysts and polyps): often - unspecified neoplasms.

Disorders of the blood and lymphatic system: very often - anemia, neutropenia; often - hemolytic anemia, leukopenia, thrombocytopenia, lymphadenopathy, lymphopenia; very rarely - aplastic anemia*; unknown - true erythrocyte aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura.

Immune system disorders: uncommon - hypersensitivity, rare - sarcoidosis*, rheumatoid arthritis (new or worsening); unknown - Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus, vasculitis, acute hypersensitivity reactions, including urticaria, angioedema, bronchospasm, anaphylaxis.

Endocrine system disorders: often - hypothyroidism, hyperthyroidism.

Metabolic and nutritional disorders: very often - anorexia; often - hyperglycemia, hyperuricemia, hypocalcemia, dehydration, increased appetite; uncommon - diabetes mellitus, hypertriglyceremia*.

Mental disorders: very often - depression, insomnia, emotional lability, anxiety; often - suicidal thoughts, psychosis, aggressive behavior, confusion, agitation, anger, mood swings, pathological behavior, nervousness, sleep disturbances, anxious dreams, decreased libido, apathy, tearfulness; infrequently - suicide attempts, panic attack, hallucinations; rarely - bipolar disorder*; very rarely - suicide*; unknown - homicidal thoughts*, mania*, change in mental status.

Nervous system disorders: very often - headache, dizziness, dry mouth, difficulty concentrating; often - amnesia, memory impairment, fainting, migraine, ataxia, paresthesia, dysphonia, loss of taste, hypoesthesia, hyperesthesia, hypertonicity, drowsiness, impaired attention, tremor, taste perversion; uncommon - neuropathy, peripheral neuropathy; rarely - seizures (convulsions)*; very rarely - cerebral hemorrhage*, cerebrovascular ischemia*, encephalopathy*, polyneuropathy*; unknown - facial nerve paralysis, mononeuropathy.

Visual disorders: often - blurred vision, blurred vision, conjunctivitis, eye irritation, eye pain, distortion of visual perception, pathology of the lacrimal glands, dry eyes; rarely - retinal hemorrhages*, retinopathy (including macular edema)*, retinal artery thrombosis*, retinal vein thrombosis*, optic neuritis*, papilledema*, decreased visual acuity or loss of visual fields*, retinal exudate.

Hearing and labyrinthine disorders: often - vertigo, hearing impairment or loss, ringing in the ears, ear pain.

Cardiac disorders: often - palpitations, tachycardia; uncommon - myocardial infarction; rarely - cardiomyopathy*, arrhythmia*; very rarely - cardiac ischemia*; unknown - pericardial effusion*, pericarditis*.

Vascular disorders: often - decreased blood pressure, increased blood pressure, hot flashes; rarely - vasculitis; very rarely - ischemia of peripheral tissues*.

Disorders of the respiratory system, chest and mediastinal organs: very often - shortness of breath, cough; often - nosebleeds, respiratory disorders, respiratory tract congestion, sinusitis, swelling of the nasal mucosa, rhinorrhea, increased secretion of the mucous membrane of the upper respiratory tract, sore throat, non-productive cough; very rarely - pulmonary infiltrates*, pneumonitis*, interstitial pneumonitis*.

Gastrointestinal disorders: very often - diarrhea, vomiting, nausea, abdominal pain; often - ulcerative stomatitis, stomatitis, ulcers in the mouth, colitis, pain in the right upper quadrant of the abdomen, dyspepsia, gastrointestinal reflux*, glossitis, cheilitis, bloating, bleeding gums, gingivitis, frequent loose stools, dental lesions, constipation, flatulence; uncommon - pancreatitis, pain in the oral cavity; rarely - ischemic colitis; very rarely - ulcerative colitis*; unknown - periodontal disorders, dental disorders, tongue pigmentation.

Disorders of the liver and biliary tract: often - hepatomegaly, jaundice, hyperbilirubinemia *; very rarely - hepatotoxicity (including death)*.

Disorders of the skin and subcutaneous tissues: very often - alopecia, itching, dry skin, rash; often - psoriasis, worsening of pre-existing psoriasis, eczema, photosensitivity reaction, maculopapular rash, erythematous rash, night sweats, hyperhidrosis, dermatitis, acne, furunculosis, erythema, urticaria, skin disorders, hematoma, increased sweating, hair structure disorder, nail disorders*; rarely - sarcoidosis of the skin; very rarely - Stevens-Johnson syndrome*, toxic epidermal necrolysis*, erythema multiforme and exudative*.

Musculoskeletal and connective tissue disorders: very often - arthralgia, myalgia, muscle and bone pain; often - arthritis, back pain, muscle spasms, pain in the limb; uncommon - bone pain, muscle weakness; rarely - rhabdomyolysis*, myositis*.

Disorders of the kidneys and urinary tract: often - frequent urination, polyuria, abnormal urine parameters; rarely - renal dysfunction, renal failure*; very rarely - nephrotic syndrome*.

Disorders of the genital organs and mammary glands: often - women: amenorrhea, menorrhagia, menstrual irregularities, dysmenorrhea, pain in the mammary glands, ovarian dysfunction, vaginal disorders; men: impotence, prostatitis, erectile dysfunction, sexual dysfunction (without specifying an exact diagnosis)*.

General disorders and disorders at the injection site: very often - inflammation at the injection site, reactions at the injection site, fatigue, chills, fever, flu-like symptoms, asthenia, irritability; often - chest pain, chest discomfort, peripheral edema, malaise, pain at the injection site, sensory disturbances, thirst; infrequently - swelling of the face; rarely - necrosis of the injection site.

Laboratory and instrumental data: very often - loss of body weight; often - heart murmur.

*Since ribavirin is always prescribed in combination with interferon alfa, and the listed adverse reactions were registered in the post-marketing period, the frequency of reactions cannot be determined. The frequencies listed above are based on data from clinical studies of ribavirin in combination with interferon alfa-2b (pegylated and non-pegylated).

30% of patients taking ribavirin and peginterferon alfa-2b and 37% of patients taking ribavirin and interferon alfa-2b experienced a decrease in hemoglobin concentrations of more than 4 g/dL.

Patients with HCV/HIV co-infection

Mitochondrial toxicity

Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTIs and ribavirin for the treatment of hepatitis C (see section 4.4).

Laboratory values in patients with HCV/HIV co-infection.

Although hematological disorders such as neutropenia, thrombocytopenia and anemia occurred more often in patients with HCV/HIV co-infection, most of these reactions were correctable by changing the dose and rarely required discontinuation of therapy (see section "Special Instructions"). Hematologic abnormalities were reported more frequently in patients taking ribavirin in combination with peginterferon alfa-2b than in patients taking ribavirin in combination with interferon alfa-2b. According to the study, a decrease in absolute neutrophil count below 500 cells/mm3, as well as a decrease in platelet count below 50,000/mm3, was observed in 4% (8/194) of patients taking ribavirin in combination with peginterferon alfa-2b. Anemia (hemoglobin <9.4 g/dL) was reported in 12% (23/194) of patients receiving ribavirin in combination with peginterferon alfa-2b.

CD4 Tlymphocyte Counts
Treatment with ribavirin in combination with peginterferon alfa-2b was associated with a decrease in absolute CD4+ cell counts during the first 4 weeks, without a decrease in the percentage of CD4+ cells . The decrease in CD4+ cell counts was reversible after dose reduction or discontinuation of therapy. The use of ribavirin in combination with peginterferon alfa-2b did not have a significant negative effect on the control of HIV viremia during or after treatment. Safety data for co-infected patients with CD4+ cell counts <200/μL are limited (n=25) (see Precautions section).

Children from 3 to 18 years (dual therapy only)

In combination with peginterferon alfa-2b

In a clinical study of 107 children (3 to 18 years) receiving combination therapy with peginterferon alfa-2b and ribavirin, dose adjustments were required in 25% of cases, mostly due to anemia, neuropenia, and weight loss. Overall, the adverse reaction profile in children was consistent with that observed in adults, although the possibility of growth retardation was present. During combination therapy with pegylated interferon alfa-2b and ribavirin for up to 48 weeks, a decrease in growth rate was observed, resulting in some patients being less than normal in height (see Precautions). Weight loss and growth failure were very common during treatment (at the end of treatment, mean decreases from baseline in weight and height were the 15th and 8th percentiles, respectively); growth velocity was also decreased (<3rd percentile in 70% of patients).

In combination with interferon alfa-2b

Moreover, in this group of patients, suicidal ideation and suicide attempts were observed more often than in adults (2.4% compared with 1%) during treatment and during 6-month follow-up. As in adult patients, other mental disorders (for example, depression, emotional lability and drowsiness) also developed in children from 3 to 18 years of age (see section "Special instructions"). In addition, injection site lesions, fever, anorexia, vomiting, and emotional lability were more common in children 3 to 18 years of age compared to adult patients. Dose changes were required in 30% of cases, mainly due to anemia and neutropenia. The adverse reactions listed below are based on data from two multicenter clinical studies of ribavirin in combination with interferon alfa-2b or peginterferon alfa-2b in children 3 to 18 years of age.

Infectious and parasitic diseases: very often - viral infection, pharyngitis; often - fungal infection, bacterial infection, lung infections, nasopharyngitis, streptococcal pharyngitis, otitis media, sinusitis, dental abscess, influenza, oral herpes, infections caused by the herpes simplex virus, urinary tract infections, vaginitis, gastroenteritis; infrequently - pneumonia, ascariasis, enterobiasis, herpes zoster.

Benign, malignant and unspecified neoplasms (including cysts and polyps): often - unspecified neoplasms.

Disorders of the blood and lymphatic system: very often - anemia, neutropenia; often - lymphadenopathy, thrombocytopenia.

Endocrine system disorders: very often - hypothyroidism; often - hyperthyroidism, virilism.

Metabolic and nutritional disorders: very often - anorexia, decreased appetite, increased appetite; often - hypertriglyceridemia, hyperuricemia.

Mental disorders: very often - depression, insomnia, emotional lability; often - suicidal thoughts, aggressive behavior, confusion, behavioral disorder, agitation, somnambulism, anxiety, mood changes, restlessness, nervousness, sleep disturbance, pathological dreams, apathy; infrequently - behavioral disorders, depressed mood, emotional disorders, fear, disturbing dreams.

Nervous system disorders: very often - headache, dizziness; often - hyperkinesis, tremor, dysphonia, paresthesia, hypoesthesia, hyperesthesia, impaired concentration, drowsiness, poor quality of sleep; infrequently - neuralgia, lethargy, psychomotor agitation.

Visual disorders: often - conjunctivitis, eye pain, blurred vision, disorders of the lacrimal glands; infrequently - hemorrhages in the conjunctiva, itching in the eyes, keratitis, blurred vision, photophobia.

Hearing and labyrinthine disorders: often - vertigo.

Cardiac disorders: often - tachycardia, palpitations.

Vascular disorders: often - pallor of the skin, “hot flashes”; infrequently - decreased blood pressure.

Disorders of the respiratory system, chest and mediastinal organs: often - shortness of breath, rapid breathing, nosebleeds, cough, nasal congestion, nasal irritation, rhinorrhea, sore throat; Uncommon: wheezing, nasal discomfort.

Gastrointestinal disorders: very often - abdominal pain, pain in the upper abdomen, vomiting, diarrhea, nausea; often - oral ulcers, ulcerative stomatitis, stomatitis, aphthous stomatitis, dyspepsia, cheilosis, glossitis, gastroesophageal reflux, rectal disorders, constipation, loose stools, toothache, dental disorders, stomach discomfort, oral pain cavities; infrequently - gingivitis.

Disorders of the liver and biliary tract: often - impaired liver function; infrequently - hepatomegaly.

Disorders of the skin and subcutaneous tissues: very often - alopecia, rash; often -

itching, photosensitivity reaction, maculopapular rash, eczema, sweating, acne, skin diseases, nail structure disorders, skin discoloration, dry skin, erythema, hematoma; infrequently - pathological pigmentation, atopic dermatitis, peeling of the skin.

Musculoskeletal and connective tissue disorders: very often - arthralgia, myalgia, muscle pain; often - pain in the limb, back pain, muscle contractures.

Renal and urinary tract disorders: often - enuresis, urinary disorders, urinary incontinence, proteinuria.

Disorders of the genital organs and mammary glands: often - women: amenorrhea, menorrhagia, menstrual irregularities, vaginal disorders; men: testicular pain; infrequently - women: dysmenorrhea.

General disorders and disorders at the injection site: very often - inflammation at the injection site, reactions at the injection site, erythema at the injection site, pain at the injection site, fatigue, fatigue, fever, chills, flu-like symptoms, asthenia, malaise, irritability; often - chest pain, swelling, itching at the injection site, rash at the injection site, dryness of the injection site, feeling of cold; Uncommon: chest discomfort, pain in the face, hardening of the injection site.

Laboratory and instrumental data: very often - decreased growth rate (decreased height and/or body weight at a given age); often - increased TSH concentration, increased thyroglobulin concentration; infrequently - positive antibodies to the thyroid gland.

Injuries, intoxications and complications of manipulation: often - skin damage; infrequently

contusion.

Most changes in laboratory parameters in clinical studies of ribavirin/peginterferon alfa-2b were mild or moderate.

If any of the side effects listed in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.