- Available:In stock345
- Availability date:2020-07-30
- Dosage form:Tablets
- In stock:345 Items
active ingredient: ribavirin;
1 tablet contains 200 mg of ribavirin;
excipients: pre-chelated starch, sodium starch glycolate (type a), microcrystalline cellulose, corn starch, magnesium stearate.
film shell: OPADRY® pink 03a14309 (hypromellose, talc, titanium dioxide (e 171), iron oxide yellow (e 172), Iron Oxide Red (E 172)), ethyl cellulose Aqueous Dispersion (solid), triacetin.
Dosage form. Film-coated tablets.
Basic physical and chemical properties: flat tablets of oval shape, film-coated, light pink to pink color, with the impression of RIB and 200 on one side and ROCHE on the other.
Direct-acting antiviral agents. Antiviral agents for the treatment of viral hepatitis C.
The ATX code. J05A P01
Ribavirin is a synthetic nucleoside analog that is active in vitro against some RNA and DNA viruses. The mechanism of action by which ribavirin acts against the hepatitis C virus is unknown.
In patients with chronic hepatitis C, a decrease in the level of hepatitis C virus RNA in response to therapy with Peginterferon alpha-2A at a dose of 180 mcg occurs in two phases. The first phase is noted 24-36 hours after the first injection of the drug, the second phase – within the next 4-16 weeks in patients with a stable virological response. Copegus® does not significantly affect viral Kinetics during the first 4-6 weeks in patients receiving combination therapy with copegus® and pegylated interferon alpha-2A or interferon alpha.
Ribavirin monotherapy does not affect the elimination of hepatitis virus (HCV RNA) or the improvement of liver histology after 6-12 months of treatment and during the next 6 months of follow-up.
Ribavirin is rapidly absorbed by oral administration of a single dose of copegus® (average Tmax = 1-2 hours). The average terminal half-life after taking a single oral dose of copegus® is from 140 to 160 hours. Published data on Ribavirin indicate extensive absorption-approximately 10% of the radioactively labeled dose is excreted in the faeces. However, absolute bioavailability is approximately 45-65%, apparently due to first-pass metabolism. There is a linear relationship between the dose and the AUCtf value with a single dose of 200-1200 mg of ribavirin. The average apparent clearance of ribavirin after taking a single oral dose of 600 mg of copegus® varies from 22 to 29 liters/hour. The volume of distribution after oral administration of copegus® is about 4,500 liters. Ribavirin does not bind to plasma proteins.
High pharmacokinetic intersubjective and intra-individual variability was found after taking a single oral dose of copegus® (variability in one person ≤ 25% relative to the area under the concentration-time curve and maximum concentration), which may be due to intensive first-pass metabolism and transfer within and outside the bloodstream.
Ribavirin transport in non-plasma blood components is most studied in red blood cells. It was found that the transfer is mainly carried out by a balancing es-type nucleoside carrier. This carrier is present in all cells and may be responsible for the high volume of distribution of ribavirin. The ratio of ribavirin concentrations in undiluted blood to blood plasma is about 60:1. most of the Ribavirin in the blood exists in the form of ribavirin nucleotides sequestered in red blood cells.
Ribavirin is metabolized in two ways:
1. reverse phosphorylation.
2.decomposition pathway, which includes deribosylation and amide hydrolysis to form a triazole metabolite of carboxylic acid. Ribavirin and its triazole urea and Triazole metabolites of carboxylic acid are excreted by the kidneys.
According to published data, after repeated use, ribavirin accumulates extensively in blood plasma, while the Auc12h value after a multiple dose differs 6 times from this value after a single oral administration. After oral administration of 600 mg twice a day, the equilibrium concentration is reached in about 4 weeks, the average equilibrium concentration in blood plasma is approximately 2200 ng/mL.
After discontinuation of the drug, the Half-Life of the drug is about 300 hours, which probably indicates a slow elimination from non-plasma compartments.
Influence of food.
The bioavailability of a single oral dose of copegus® (600 mg) was increased with simultaneous consumption of food rich in fat. The values of AUC parameters(0-192h) and maximum concentration increase by 42% and 66%, respectively, after taking copegus® during a high-fat breakfast compared to taking it on an empty stomach. The clinical significance of the results of the study of this single dose is unknown. Exposure to ribavirin after repeated administration with food was comparable to that of patients taking Peginterferon alfa-2a and copegus®, as well as interferon alpha-2b and ribavirin. To achieve optimal plasma concentrations of ribavirin, it is recommended to take ribavirin with a meal.
Pharmacokinetics in special groups of patients
Patients with impaired renal function
Interactions with other drugs and other types of interactions.
The interaction of ribavirin with Peginterferon alpha-2A, interferon alpha-2b, and antacids was studied. Ribavirin concentrations are comparable with monotherapy and when used in combination with Peginterferon alpha-2A or interferon alpha-2b.
After the end of treatment with copegus®, the potential interaction period lasts up to 2 months (5 half-lives of ribavirin) due to the Long Half-Life.
The results of in vitro studies using human and rat liver microsomes indicate that Ribavirin metabolism is not mediated by the cytochrome P450 enzyme. Ribavirin does not inhibit cytochrome P450 enzymes. In this regard, there is a minimal potential for interactions associated with the P450 enzyme system.
Antacids. Concomitant administration of antacids containing aluminum, Methicone, and magnesium reduced the bioavailability of ribavirin at a dose of 600 mg, while AUCtf decreased by 14%. It is possible that the decrease in bioavailability in this study occurred as a result of delayed transit of ribavirin or modified ph. This interaction was considered clinically insignificant.
Nucleoside analogues. Ribavirin has been shown to inhibit phosphorylation of zidovudine and Stavudine in vitro. The clinical significance of these data is unknown. However, these data indicate the possibility that concomitant use of copegus® with zidovudine or Stavudine may lead to an increase in HIV viremia in blood plasma. Therefore, careful monitoring of human immunodeficiency virus RNA levels in the blood plasma of patients receiving concomitant treatment with copegus® and zidovudine and/or Stavudine is recommended. If the level of human immunodeficiency virus RNA increases, the question of concomitant use of copegus® with reverse transcriptase inhibitors should be reviewed.
Didanosine. Concomitant administration of Ribavirin and didanosine is not recommended. Exposure to didanosine or its active metabolite (dideoxiadenosine 5’-triphosphate) in vitro increases with concomitant use of didanosine and ribavirin. Concomitant use of these drugs can lead to fatal liver failure, peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia or lactic acidosis.
Azathioprine. Ribavirin, by inhibiting inosine monophosphate dehydrogenase, can affect the metabolism of azathioprine, which can lead to accumulation of 6-methylthioinosine monophosphate, which was associated with myelotoxicity in patients treated with azathioprine. Concomitant use of copegus® and Peginterferon alfa-2a with azathioprine should be avoided. In some cases, when the benefits of simultaneous use of Ribavirin and azathioprine predominate over the potential risk, careful monitoring of hematological parameters is recommended in order to detect myelotoxicity, in which treatment with these drugs should be discontinued (see the section "application features").
Patients with HIV–HCV coinfection: there were no pronounced signs of interaction in 47 patients with HIV-HCV coinfection who completed a 12–week pharmacokinetic study to study the effect of ribavirin on intracellular phosphorylation of certain nucleoside reverse transcriptase inhibitors (lamivudine and zidovudine or Stavudine). However, due to significant variability, the confidence intervals were quite wide. Concomitant use of nucleoside reverse transcriptase inhibitors did not affect plasma ribavirin exposure.
Increased anemia associated with ribavirin treatment was observed with concomitant use of zidovudine in the treatment regimen for HIV infection, although the exact mechanism of this phenomenon is unknown. Concomitant use of Ribavirin and zidovudine is not recommended due to the increased risk of anemia (see the section "application features"). If anemia occurs with concomitant use of Ribavirin and zidovudine, consideration should be given to replacing zidovudine in a combined antiretroviral regimen. This is especially important for patients with a history of zidovudine-induced anemia.
Copegus® should not be used as monotherapy.
Combination therapy with ribavirin and (peg)interferon alpha
Several serious adverse reactions associated with combination therapy with ribavirin and (peg)interferon alpha have been reported, which include:
- severe effects from the central nervous system (such as depression, suicidal thoughts and suicide attempts, aggressive behavior, etc);
- severe visual disorders;
- dental and periodontal disorders
- growth suppression in children and adolescents, which may be irreversible in some patients.
Before starting treatment, you should read the instructions for medical use (PEG)of interferon alpha for recommendations for monitoring and treating these adverse reactions.
Risk of teratogenic effects (see the section "use during pregnancy or lactation"). Before starting treatment with ribavirin, the doctor should fully inform patients about the teratogenic effect of Ribavirin, the need for reliable and long-term contraception, the likelihood of ineffectiveness of contraception methods and the possible consequences of pregnancy if it occurs during treatment with ribavirin. For laboratory pregnancy monitoring, see "laboratory parameters" in this section of the instructions.
Carcinogenicity. Some genotoxicity studies in vivo and in vitro have revealed the mutagenic effect of ribavirin. The potential carcinogenic effect of ribavirin cannot be excluded.
Hemodialysis and the cardiovascular system. A decrease in the level of hemoglobin to ® at a dose of 1000/1200 mg in combination with Peginterferon alpha-2A, and no more than 19% of patients who received a combination with interferon alpha-2A. with the combined use of ribavirin at a dose of 800 mg and Peginterferon alpha-2A for 24 weeks in 3% of patients, the level of hemoglobin decreased to ®, may worsen cardiac function and/or lead to exacerbation of coronary heart disease. Therefore, copegus® should be used with caution in patients with heart disease. Cardiac status should be evaluated before starting treatment and clinical monitoring should be performed throughout treatment. If cardiac function worsens, treatment with ribavirin should be discontinued (see the section "dosage and administration"). Patients with a history of congestive heart failure, myocardial infarction, and/or arrhythmias should be carefully monitored at present. Patients with heart disease are advised to perform electrocardiography before and during the course of treatment. Cardiac arrhythmias (mainly supraventricular) usually respond to standard treatment, but discontinuation of treatment may be necessary.
Data on the occurrence of pancytopenia and bone marrow suppression within 3-7 weeks after concomitant use of Ribavirin and Peginterferon with azathioprine have been published. Manifestations of myelotoxicity were reversible within 4-6 weeks after discontinuation of antiviral therapy for viral hepatitis C and concomitant administration of azathioprine and did not recur after continuing treatment separately with each of the drugs (see the section "interactions with other drugs and other types of interactions").
Combined treatment with copegus® and Peginterferon alfa-2a in patients with chronic hepatitis C, in which previous therapy was ineffective, has not been sufficiently studied in patients whose previous treatment was discontinued due to hematological side effects. When deciding whether to repeat treatment, doctors should carefully evaluate the benefits and risks.
Immediate hypersensitivity reactions. If an acute hypersensitivity reaction develops (for example, urticaria, angioedema, bronchospasm, anaphylaxis), copegus® should be discontinued immediately and appropriate treatment should be prescribed. Transient rashes do not require discontinuation of therapy.
Liver function. If decompensation of liver function develops during treatment with copegus® in combination with other drugs, therapy should be discontinued. If there is a progressive and clinically significant increase in ALT levels, despite a dose reduction, or with a simultaneous increase in direct bilirubin levels, treatment should be discontinued.
Impaired renal function. The pharmacokinetics of ribavirin change in patients with impaired renal function due to a decrease in ribavirin clearance. Therefore, before using copegus®, it is recommended to study renal function in all patients, and it is desirable to evaluate it by creatinine clearance. There was a significant increase in the concentration of Ribavirin in blood plasma in patients with serum creatinine levels > 20 mg/L or creatinine clearance (see sections "dosage and administration" and "pharmacokinetics").
Hemoglobin levels should be carefully monitored during treatment and adjusted if necessary during the entire treatment period (see the section "dosage and administration").
Patients after transplantation. The safety and efficacy of combinations of Peginterferon alfa-2a and copegus® in patients with liver and other organ transplantation have not been established. Cases of liver and kidney graft rejection have been reported with Peginterferon alfa-2a as monotherapy or in combination with copegus®.
HIV co-infection-hepatitis C virus (HCV). You should read the instructions for medical use of antiviral drugs that are taken simultaneously with the treatment of chronic hepatitis C, in order to get acquainted with the tactics of treating toxic phenomena specific to each drug, as well as possible cross-toxicity with ribavirin and other drugs. In the nr15961 study, the incidence of pancreatitis and/or lactic acidosis was 3% in patients receiving concomitant treatment with Stavudine and interferon with or without Ribavirin (in 12 out of 398 patients).
Patients with chronic hepatitis C and HIV coinfection receiving highly effective antiretroviral therapy may have an increased risk of serious side effects (lactic acidosis, peripheral neuropathy, pancreatitis).
Patients with HIV–HCV coinfection and advanced cirrhosis receiving highly effective antiretroviral therapy may have an increased risk of decompensation of liver function and possibly death when combined with copegus® and interferons. The initial factors in patients with HIV-HCV co–infection and cirrhosis that may be associated with decompensation of liver function are: increased serum bilirubin, decreased hemoglobin, increased alkaline phosphatase or decreased platelet count, treatment with didanosine. Therefore, caution should be exercised when deciding whether to co-use Peginterferon alfa-2a and copegus® with highly effective antiretroviral therapy (see the section "interactions with other drugs and other types of interactions").
Concomitant treatment with ribavirin and zidovudine is not recommended due to the increased risk of anemia (see the section "interactions with other drugs and other types of interactions").
During the treatment of coinfected patients, careful monitoring is necessary to detect symptoms of hepatic decompensation (including ascites, encephalopathy, bleeding from varicose veins, impaired synthetic liver function; for example, Child–Pugh score ≥ 7). The Child–Pugh indicator does not always reliably reflect the presence of hepatic decompensation and may change under the influence of factors such as, for example, indirect hyperbilirubinemia, hypoalbuminemia due to drug therapy. If hepatic decompensation develops, copegus® therapy in combination with other medications should be discontinued immediately.
Concomitant administration of copegus® and didanosine is not recommended due to the risk of mitochondrial toxicity (see the section "interactions with other drugs and other types of interactions"). Concomitant administration of copegus® and Stavudine should be avoided in order to reduce the risk of cross-mitochondrial toxicity.
Laboratory parameters. Before starting treatment, it is necessary to conduct standard hematological and biochemical laboratory tests (general clinical blood test with counting of shaped elements, platelet count, electrolyte analysis, glucose level, serum creatinine content, liver function tests, uric acid level). Recommended laboratory parameters before starting treatment with copegus®: hemoglobin: ≥ 120 g/L (in women); ≥ 130 g/L (in men).
There are insufficient data on the efficacy and safety of combined treatment of patients with HIV–HCV coinfection with a CD4+ lymphocyte count of less than 200 cells/µL. Caution should be exercised when prescribing combination treatment to patients with low CD4+ lymphocyte counts.
Laboratory parameters should be evaluated at 2 and 4 weeks of therapy and periodically thereafter, if necessary.
Women of reproductive age should have routine pregnancy tests performed monthly during treatment and for 4 months after completion. Female partners of men receiving treatment with copegus® should conduct routine pregnancy tests on a monthly basis during treatment and within 7 months after the end of treatment.
Uric acid levels may increase with copegus® due to hemolysis. Therefore, in patients with a predisposition, uric acid levels should be carefully monitored for the development of gout.
Disposal of unused and expired medicines. The introduction of the drug into the external environment should be minimized. The drug should not be disposed of in wastewater or household waste. For disposal, it is necessary to use the so-called "waste collection system", if any.
Use during pregnancy or lactation.
Preclinical data. Ribavirin demonstrated significant teratogenic and / or embryotoxic potential in all animal species studied when used at doses significantly lower than the recommended doses for humans. Malformations of the skull, palate, eyes, jaw, limbs, skeleton, and gastrointestinal tract were observed. The frequency and severity of teratogenic effects increased with increasing ribavirin dose. The survival rate of the fetus and offspring was reduced.
Women. Copegus® should not be used during pregnancy (see the sections "contraindications" and "application features"). Patients should make every possible effort to avoid pregnancy. Treatment with copegus® can only be initiated after receiving a negative pregnancy test immediately before starting treatment. Any method of contraception can be ineffective, so it is very important that women of reproductive age use effective contraception during the entire treatment period, as well as for 4 months after the end of treatment; during this time, monthly pregnancy tests should be performed. If pregnancy occurs during treatment and within 4 months after its end, patients should be informed about the significant risk of teratogenic effects on the fetus due to the use of ribavirin.
Patients and their partners: male partners receiving copegus® should do everything possible to avoid pregnancy. Ribavirin accumulates intracellularly and is eliminated from the body very slowly. In animal studies, ribavirin caused changes in semen at doses lower than clinical ones. It has not been established whether ribavirin contained in semen has a teratogenic effect on fertilization of the egg. Thus, men and their partners of reproductive age should be informed about the need for effective contraception during the period of taking copegus®during treatment and for 7 months after the end of treatment. Before starting treatment, women should have a negative pregnancy test result. Men should use a condom to minimize the transmission of ribavirin to pregnant partners.
Breast-feeding. It is not known whether ribavirin penetrates into breast milk. Due to potential adverse reactions in infants who are breastfed, breast-feeding should be discontinued before starting treatment.
Ability to influence the reaction rate when driving vehicles or other mechanisms.
Copegus® does not affect or has little effect on the ability to drive vehicles or work with other mechanisms. However, when used in combination with Peginterferon alpha-2A or interferon alpha-2A, some effects may occur. For more information, see the instructions for medical use of medicines that are prescribed in combination with copegus®.
No cases of overdose with copegus®have been reported in clinical trials. Hypocalcemia and hypomagnesemia were observed when the maximum recommended dose was exceeded by more than 4 times. In many of these cases, ribavirin was administered intravenously. Due to the large volume of distribution, ribavirin is not significantly eliminated by hemodialysis.
A characteristic feature of the safety profile of ribavirin is hemolytic anemia, which occurs during the first weeks of therapy. Hemolytic anemia associated with the use of ribavirin can lead to deterioration of cardiac function and/or deterioration of existing cardiac pathology. Some patients also experienced an increase in uric acid and indirect bilirubin levels associated with hemolysis (see Section "application specifics").
The adverse reactions listed in this section have been observed in clinical trials and/or obtained from spontaneous reports mainly when copegus® is used in combination with interferon alpha-2A or Peginterferon alpha-2A.
Adverse reactions in patients treated with copegus® in combination with interferon alpha-2A were generally the same as those observed with copegus® in combination with Peginterferon alfa-2a.
In each group, the frequency of adverse reactions is presented in descending order of severity.
See also the instructions for medical use of other medications with which copegus® is used in combination.
Chronic hepatitis C
The most common adverse reactions with combined treatment with copegus® and Peginterferon alfa-2a at a dose of 180 mcg were usually mild or moderate and did not require dose adjustment or discontinuation of the drug.
Chronic hepatitis C in patients who did not respond to previous therapy
Overall, the safety profile of copegus® in combination with Peginterferon alfa-2a in patients who did not respond to previous treatment was comparable to that in patients who had not previously received treatment. In a clinical trial that included 48 - or 72-week treatment of patients who did not respond to previous therapy with pegylated interferon alpha-2b/ribavirin, laboratory abnormalities or adverse events resulted in discontinuation of Peginterferon alpha-2A and copegus® in 6% and 7%, respectively, with a treatment duration of 48 weeks and in 12% and 13%, respectively, with a treatment duration of 72 weeks. Similarly, in patients with cirrhosis or transition to cirrhosis, the frequency of discontinuation of Peginterferon alpha-2A and copegus® therapy was higher in the 72-week treatment group (13% and 15%) than in the 48-week treatment group (6% and 6%). The study did not include patients who had discontinued previous treatment (pegylated interferon alpha-2b/ribavirin) due to hematological toxicity.
In another clinical study, patients who did not respond to previous therapy with advanced fibrosis or cirrhosis (3-6 Ishak scores) and an initial platelet count of no more than 50,000/mm3 received a 48-week course of treatment. Hematological disorders noted in the first 20 weeks of the study included anemia (in 26% of patients, the hemoglobin level was 3 in patients, the absolute neutrophil count was 3) and thrombocytopenia (in 13% of patients, the platelet count was 3) (See the section "application features").
HIV co-infection-chronic hepatitis C
The safety profile of Peginterferon alfa-2a in monotherapy or in combination with ribavirin in patients with HIV-HCV coinfection was comparable to that in patients with HCV. Other adverse events that occurred in ≥ 1% to ≤ 2% of patients with HIV–HCV coinfection with combined treatment with Peginterferon alpha-2A and ribavirin include: hyperlactacidemia/lactic acidosis, influenza, pneumonia, emotional lability, apathy, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia. Peginterferon alpha-2A therapy was associated with a decrease in the absolute number of CD4+ lymphocytes in the first 4 weeks of treatment without changing their percentage. The number of CD4+ lymphocytes returned to baseline after dose reduction or discontinuation of therapy. Administration of Peginterferon alfa-2a did not negatively affect the HIV viral load during therapy and during the follow-up period after the end of therapy. Data on the use of patients with a CD4+ lymphocyte count of less than 200 cells/µL are limited (see the instructions for medical use of Peginterferon alpha-2A).
Adverse reactions during combination therapy with copegus® and Peginterferon alpha-2A or interferon alpha-2A in patients with viral hepatitis C
The following categories are used to describe the frequency of adverse reactions: very common (≥1/10), common (≥ 1/100 and > 1/10000 and
Infections and infestations: common – upper respiratory tract infections, bronchitis, oral candidiasis, herpes simplex; non – common – lower respiratory tract infections, pneumonia, urinary tract infections, skin infections; rarely common-endocarditis, otitis externa.
From the blood and lymphatic system: very common – anemia, neutropenia; common – thrombocytopenia, lymphadenopathy; rarely common – pancytopenia; very rarely common – aplastic anemia; frequency unknown* – true red blood cell aplasia.
Immune system disorders: rare-sarcoidosis, thyroiditis; rarely common – anaphylaxis, systemic Shepherd's disease, rheumatoid arthritis; very rarely common – idiopathic or thrombotic thrombocytopenic purpura; frequency unknown*–liver and kidney graft rejection, Vogt–Koyanagi-Harad disease.
Endocrine disorders: common-hypothyroidism, hyperthyroidism; non – common-diabetes mellitus.
Metabolic disorders: very common – anorexia; non – common-dehydration.
Mental disorders: very common-depression, insomnia; common – mood swings, emotional disorders, anxiety, aggressiveness, nervousness, decreased libido; common – suicidal thoughts, hallucinations, anger; rarely common – suicide, mental disorders; frequency unknown* – mania, bipolar disorder, homicidal ideas.
From the nervous system: very common – headache, dizziness, impaired concentration; common – memory disorders, syncopal States, weakness, migraine, hypesthesia, hyperesthesia, paresthesia, tremor, taste disorders, nightmares, drowsiness; rare – peripheral neuropathy; rarely common – coma, convulsions, paralysis of the facial nerve; very rarely common-cerebral ischemia.
From the side of the visual organs: common – visual impairment, pain in the eyeball, inflammatory eye diseases, xerophthalmia; rare – retinal hemorrhage; rarely common – optical neuropathy, edema of the optic disc, retinal vascular damage, retinopathy, corneal ulcer; very rarely common – vision loss; frequency unknown* – serious cases of retinal detachment.
From the side of the hearing organs and vestibular apparatus: common – vertigo, ear pain, ringing in the ears; non – common-hearing loss.
Cardiac disorders: common-tachycardia, palpitations, peripheral edema; rarely common – myocardial infarction, congestive heart failure, angina pectoris, supraventricular tachycardia, arrhythmia, atrial fibrillation, pericarditis.
Vascular disorders: common-hot flashes, hypotension; non – common – hypertension; rarely common-brain hemorrhage, vasculitis.
From the respiratory system, chest and mediastinal organs: very common – dyspnoea (shortness of breath), cough; common – dyspnoea (shortness of breath) during physical exertion, nosebleeds, nasopharyngitis, sinus edema, nasal congestion, rhinitis, sore throat; rare – wheezing; rarely common – interstitial pneumonitis (including deaths), pulmonary embolism.
From the gastrointestinal tract: very common – diarrhea, nausea, abdominal pain; common – vomiting, dyspepsia, dysphagia, ulceration of the oral mucosa, bleeding gums, glossitis, stomatitis, flatulence, constipation, dryness of the oral mucosa; common – gastrointestinal bleeding, cheilitis, gingivitis; rarely common-peptic ulcer, pancreatitis; frequency unknown* – ischemic colitis, ulcerative colitis, pigmentation of the tongue.
From the hepatobiliary system: rare – impaired liver function; rarely common – liver failure, cholangitis, fatty liver dystrophy.
From the skin and subcutaneous tissue: very common – alopecia, dermatitis, pruritus, dry skin; common – rashes, increased sweating, psoriasis, urticaria, eczema, skin reactions, photosensitization reactions, night sweats; very rare – toxic epidermal necrolysis, Stevens–Johnson syndrome, angioedema, erythema multiforme.
From the musculoskeletal system and connective tissue: very common – myalgia, arthralgia; common – back pain, arthritis, muscle weakness, bone pain, neck pain, musculoskeletal pain, muscle cramps; rarely common-myositis; frequency unknown* – rhabdomyolysis.
From the side of the kidneys and urinary system: frequency unknown* – renal failure, nephrotic syndrome.
From the reproductive system and mammary glands: common – impotence.
General disorders and reactions at the injection site: very common – fever, chills, pain, asthenia, fatigue, irritability; common – chest pain, flu-like syndrome, malaise, lethargy, hot flashes, thirst.