Bocepreviir - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Antiviral drugs

Included in the formulation

Viktrelis®

capsules inwards

Schering-Plau N. Labo. USA

АТХ:

J.05.A.E.12 Boceprevir

Pharmacodynamics:

The preparation contains in its composition the active ingredient boceprevir. Boceprevir is an inhibitor of the NS3 protease of the hepatitis C virus. Boceprevir covalently but reversibly binds to the alpha-ketoamide function of the active center of the serine protease NS3 (Ser139), which leads to inhibition of viral replication in hepatitis C virus infected host cells.

Antiviral activity in cell culture

The antiviral activity of boceprevir was evaluated by biochemical analysis, determining the binding of slow NS3 protease inhibitors and in the hepatitis C virus replicon system. Bocetrevir concentrations at which 50% (IC₅₀) and 90% (IC₉₀) inhibition of the virus, were respectively about 200 nmol and 400 nmol in a 72-hour study in cell culture. It is assumed that the loss of the RNA replicon is linearly dependent on the time of action of the bocestrovir. Application of the preparation in a concentration corresponding to IC₉₀, within 72 hours led to a decrease in the concentration of RNA in the replicon 10-fold. The prolonged exposure led to a decrease in the concentration of RNA in the replicon 100-fold by day 15.Evaluation of various combinations of boceprevir with interferon alpha-2b, which resulted in 90% inhibition of the RNA replicon, showed an additive effect, with no evidence of synergy or antagonism being found.

Resistance

The resistance of the virus to boceprevirov was assessed based on biochemical analysis and analysis of replicons. Biological activity of bocepreviir decreased 2-10 times with the following main amino acid substitutions (RAVs-resistant-associated amino acid variants): V36M, T54A, R155K and V170A, which determine resistance. The decrease in the activity of bocetrephir over 50 times was observed in the presence of the following RAVs: A156T and A156V. It should be noted that replicons carrying RAVs A156T, have less activity than replicons carrying other RAVs. The multiplicity of resistance increase due to double RAVs was approximately equal to the multiplicity of increase in resistance to the drug for individual RAVs associated with it.

In a generalized analysis of data on patients who have not previously received antiviral therapy and patients with ineffective prior therapy with peginterferon alfa-2b and ribavirin for 4 weeks and for patients with subsequent administration of the drug at a dose of 800 mg 3 times daily in combination with peginterferon alfa -2b and ribavirin in Phase III studies, RAVs were detected in 15% of patients. In 53% of patients who received drug therapy and did not achieve a stable virologic response, RAVs were detected. Most frequently (> 25% of patients), the detectable RAVs were V36M (61%) and R155K (68%) in patients infected with the genotype 1a virus, and T54A (42%), T54S (37%), A156S (26%) and V170A (32%) in patients infected with the genotype 1b virus. In 6% of patients who took the drug, sensitivity to interferon (decrease ≥ 1-log₁₀ viral load at week 4 of treatment) was associated with fewer RAVs compared to 41% of patients who had a viral load <1-log₁₀ (low sensitivity to interferon). After completing the course of therapy with the drug, blood samples were taken from the patients for analysis for the presence of RAVs. In 31% of patients, a higher sensitivity to interferon was associated with the detection of fewer RAVs than in 68% of patients who had a viral load <1-log at week 4₁₀. In a generalized analysis, the number of RAVs prior to initiation of therapy did not appear to have a significant association with the response to treatment in patients taking the drug in combination with peginterferon alfa-2b and ribavirin.

The results of an ongoing long-term study of patients who did not achieve a sustained virologic response with a median follow-up of about 2 years suggest that after the end of therapy with the drug, over time, RAVs can return to a "wild" type of virus.

Assessment of the effect of the drug on the interval QTc

In a randomized, multidose, placebo-controlled and actively controlled cross-over study, the evaluation of boceprevir was made with respect to its possible effect on QT / QTc intervals when used in super-therapeutic (1200 mg 3 times daily) and therapeutic (800 mg 3 times daily) doses in 36 healthy volunteers.

Significant differences in the intervals QTc between the groups of participants who received boceprevir and placebo, it is not revealed.

Pharmacokinetics:

Absorption and bioavailability

After oral administration boceprevir was absorbed at an average TC_max in blood, equal to 2 hours. Pharmacokinetic parameters: area under the curve "concentration-time" (AUC), C_maxand C_minthe concentrations did not practically change in a dose-dependent manner. For example, at doses equal to 800 mg and 1200 mg, these parameters were close, which implies a reduction in absorption when higher doses are used.The cumulation of boceprevir is minimal, and the pharmacokinetic equilibrium is achieved approximately 1 day after taking the drug 3 times a day.

In healthy volunteers who only took boceprevir in a dose of 800 mg 3 times a day, the pharmacokinetics of the drug was characterized by the following indices: AUC 6,147 ng×h / ml, C_max 1913 ng / ml and C_min 90 ng / ml. Pharmacokinetic parameters in healthy volunteers and in patients with viral hepatitis C were similar. Absolute bioavailability of the drug has not been studied.

Effect of food on absorption

The drug should be taken with food. Food increases the absorption of bocetrevir by 60% when taking a dose of 800 mg 3 times daily compared with fasting. The bioavailability of boceprevir was the same regardless of the type of food (high or low fat). The time of taking the drug - before meals, during meals or immediately after meals, also did not matter, so the drug can be taken regardless of the type and time of eating.

Distribution

In the equilibrium state, the average apparent volume of the boceprevir distribution is approximately 772 liters. After receiving a single dose of the drug equal to 800 mg, binding to plasma proteins is approximately 75%. Boceprevir is a mixture of two diastereoisomers that rapidly interconvert in plasma. The predominant diastereoisomer is a pharmacologically active substance, and the other diastereoisomer is inactive.

Metabolism

In studies in vitro shown, that boceprevir is metabolized predominantly through the aldo-keto-reductase-mediated pathway with the formation of ketone-reduced metabolites that are inactive with respect to the hepatitis C virus. After a single dose of 800 mg of radiolabeled bocepetrevir ¹⁴C, the most common circulating metabolites are diastereoisomeric mixtures of ketone-reduced metabolites with an average concentration about 4 times that of bocetrevir. Boceprevir is also subjected to oxidative metabolism mediated by CYP3A4 / 5 isoenzymes, albeit to a lesser extent.

Excretion

Average half-life bocetrevira from the plasma is approximately 3.4 hours. The average total clearance of bocetrevir is about 161 l / h. After ingestion of a single dose of 800 mg of bocetrevir, labeled radioactive isotope ¹⁴C, approximately 79% and 9% of this dose were excreted by the intestines and kidneys, respectively. At the same time, in the form of unchanged boceprevir, about 8% and 3% of the dose of bocetre- vir labeled with a radioactive isotope was excreted by the intestine and kidneys ¹⁴C, respectively. These data indicate that boceprevir is excreted mainly by the liver.

Pharmacokinetics in specific patient groups

Children

The safety, efficacy and pharmacokinetics of the drug in children under the age of 18 years have not been studied.

Patients with impaired hepatic function

In the study in patients with chronic hepatic insufficiency of varying severity (mild, moderate and severe), clinically significant differences in pharmacokinetic parameters were not detected, and dose adjustment is not required. The use of the drug in combination with peginterferon alfa and ribavirin is contraindicated in patients with decompensated liver cirrhosis.

Patients with impaired renal function

Clinically significant differences in pharmacokinetic parameters in healthy volunteers and in patients with terminal stage of renal failure were not observed, and dose adjustment for such patients and patients with any stage of renal failure is not required.

Gender identity

In adults, there were no differences in pharmacokinetic parameters, depending on gender.

Race

Population pharmacokinetic analysis showed that race does not have a clear effect on the pharmacokinetics of the drug.

Age

Population pharmacokinetic analysis showed that age does not have an obvious effect on the pharmacokinetics of the drug.

Indications:Treatment of chronic viral hepatitis C (genotype 1 of the hepatitis C virus) in combination with peginterferon alfa and ribavirin in adult patients (18 years and older) with compensated liver disease who had not previously received antiviral therapy, or patients in whom previous antiviral treatment was ineffective .

ICD-10

I.B15-B19.B18.2 Chronic viral hepatitis C

Contraindications:

Hypersensitivity to bocaprevir or any other component of the drug; autoimmune hepatitis; hepatic insufficiency (functional class B and C in the Child-Pugh system, more than 6 points); combined use of medicines,the clearance of which is mediated by the action of CYP3A4 / 5 isozymes, and for which elevated plasma concentrations are associated with serious and / or life-threatening adverse reactions. For example, drugs taken orally midazolam, amiodarone, astemizole, bepridil, pimozid, propafenone, quinidine, simvastatin, lovastatin and ergot derivatives (dihydroergotamine, ergometrine, ergotamine, methylergonovine); children under 18 years of age (efficacy and safety not studied); pregnancy.

Carefully:

Anemia

There have been reports of anemia in the treatment with peginterferon alfa / ribavirin. Adding the drug to the treatment regimen with peginterferon alfa and ribavirin leads to an additional decrease in hemoglobin concentration in serum. Before the start of combination therapy with the use of the drug and after 4 and 8 weeks of treatment, and also during the course of treatment if necessary, a complete blood test is required. Reducing the concentration of hemoglobin in the blood to less than 10 g / dl may serve as a basis for reducing the dose or stopping ribavirin and / or administering erythropoietin.

In a prospective, randomized controlled trial, the frequency of achieving a stable virologic response and overall tolerability of the drug was comparable with a decrease in ribavirin dose or with erythropoietin intake.

For information on dose reduction and / or discontinuation of ribavirin treatment, refer to the instructions for use of the ribavirin preparation.

Neutropenia

During clinical studies of phases II and III, the neutrophil concentration was less than 0.5×10⁹ cells / L in 7% of patients treated with a combination of peginterferon alfa-2b and ribavirin, compared with 4% of patients treated with only peginterferon alfa-2b and ribavirin. Three patients developed severe or life-threatening infections associated with neutropenia. In two patients, when taking the drug in combination with peginterferon alfa-2b and ribavirin, a life-threatening neutropenia was recorded. Before the beginning of combined therapy with the use of the drug, all patients need to conduct a general blood test. A complete blood test should be performed at 4, 8 and 12 weeks of treatment and further, if clinically feasible.If the concentration of neutrophils decreases, a dose reduction or abolition of peginterferon alfa and ribavirin may be required.

For information on dose reduction and / or discontinuation of ribavirin treatment, refer to the instructions for the use of peginterferon alfa and ribavirin.

Drugs containing drospirenone

Caution should be exercised when prescribing the drug in patients taking drugs containing drospirenone and patients taking potassium diuretics of moderate effect, since there is a risk of developing hyperkalemia. Alternative methods of contraception should be considered.

Inductors of the isoenzyme CYP3A4

It is not recommended simultaneous use of the drug with strong inducers of the isoenzyme CYP3A4 (rifampicin, carbamazepine, phenobarbital and phenytoin).

Monotherapy with hepatitis C virus protease inhibitors

Based on the results of clinical studies, the drug should not be used as a monotherapy for viral hepatitis C, since there is a high probability of drug resistance.It is not known what effect the preparation will have on the activity of the hepatitis C virus protease inhibitors used consistently, including the re-administration of the drug.

Use in patients with rare hereditary diseases

Patients with rare hereditary diseases, such as galactose intolerance, congenital lactase deficiency or glucose malabsorption syndrome and galactose, should not take the drug.

Pregnancy and lactation:

Fertility

The effect of the drug on human fertility has not been studied. The available pharmacodynamic and toxicological data showed that the effect of the drug on the fertility of rats was reversible.

Pregnancy

The drug had no effect on fetal development in rats and rabbits. The effect of the drug on pregnant women has not been studied in a framework that meets the requirements of controlled clinical trials. Women of childbearing age should take the drug only with the use of reliable contraceptives.

The drug in combination with peginterferon alfa and ribavirin is contraindicated in pregnant women.

Breastfeeding period

The available pharmacodynamic and toxicological data showed the presence of boceprevir and its derivatives in the milk of rats.

The decision regarding the cessation of breastfeeding or drug treatment should be made taking into account the correlation of the benefits of breastfeeding for a child and the therapy for a woman.

Dosing and Administration:

The drug should be taken in combination with peginterferon alfa and ribavirin. Before using, you should read the instructions for the use of peginterferon alfa and ribavirin.

Dosing regimen

For oral administration. The recommended dose of the drug is 800 mg orally 3 times a day with meals. The maximum daily dose of the drug is 2400 mg.

Patients without cirrhosis who have not previously received antiviral therapy

Begin therapy with peginterferon alfa and ribavirin within 4 weeks.

At the 5th week of the preparations, peginterferon alfa and ribavirin add the drug in a dose of 800 mg, 3 times a day. The duration of therapy is determined depending on the virologic response at 8, 12 and 24 weeks of treatment.

Skipping the next dose of the drug

If the patient misses taking the dose and remains less than 2 hours before the next dose, then the missed dose should not be taken.

If the patient misses the dose and remains for 2 or more hours until the next dose, the patient should take the missed dose with the food and then follow the normal dosing regimen.

Dose change

It is not recommended to reduce the dose of the drug.

If a patient has serious unwanted side effects potentially associated with taking peginterferon alfa and ribavirin, the dose of peginterferon alfa and / or ribavirin should be reduced.

Renal insufficiency

Patients with any degree of renal failure do not need a dose adjustment.

Liver failure

Patients with any degree of hepatic insufficiency do not need a dose adjustment. The drug in combination with peginterferon alfa and ribavirin is contraindicated in patients with decompensated liver cirrhosis (functional class of cirrhosis of liver B and C in the Child-Pugh system is more than 6 points).

Children

The safety, efficacy and pharmacokinetics of the drug in children under the age of 18 years have not been studied.

Elderly patients

The number of elderly patients (65 years and older) who participated in the clinical trials of the drug was not sufficient to determine whether the therapeutic response was different in the elderly patient group from the young patients group. As a result of other clinical studies, differences in the responses in young and elderly patients to the study drug were not detected.

Co-infection with the human immunodeficiency virus

The safety profile and efficacy of the drug alone or in combination with peginterferon alfa and ribavirin for the treatment of chronic viral hepatitis C (genotype 1) for patients co-infected with human immunodeficiency virus and hepatitis C virus has not been established.

Co-infection with the hepatitis B virus

The safety and efficacy profile of the drug alone or in combination with peginterferon alfa and ribavirin for the treatment of chronic viral hepatitis C (genotype 1) for patients co-infected with hepatitis B virus and hepatitis C virus has not been studied.

Patients after organ transplantation

The safety and efficacy profile of the drug alone or in combination with peginterferon alfa and ribavirin for the treatment of chronic viral hepatitis C (genotype 1) in patients who underwent liver or other organ transplantation has not been studied.

Side effects:

Infectious and parasitic diseases

Often: bronchitis, inflammation of subcutaneous fat, simple herpes, influenza, fungal infections of the mouth, sinusitis.

Infrequently: gastroenteritis, pneumonia, staphylococcal infection, candidiasis, ear infections, fungal skin lesions, nasopharyngitis, onychomycosis, pharyngitis, respiratory tract infections, rhinitis, infectious skin lesions, urinary tract infections.

Rarely: otitis media, sepsis.

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

Rarely: neoplasm of thyroid gland (nodular form).

Violations of the blood and lymphatic system

Very often: anemia, neutropenia.

Often: leukopenia, thrombocytopenia.

Infrequently: hemorrhagic diathesis, lymphadenopathy, lymphopenia.

Rarely: hemolysis.

Immune system disorders

Rarely: sarcoidosis, porphyria (except acute).

Disorders from the endocrine system

Often: goiter, hypothyroidism.

Infrequently: hyperthyroidism.

Disorders from the metabolism and nutrition

Very often: decreased appetite.

Often: dehydration, hyperglycemia, hypertriglyceridemia, hyperuricemia.

Infrequent: hypokalemia, appetite disorders, diabetes, gout, hypercalcemia.

Disorders of the psyche

Very often: anxiety, depression, insomnia, irritability.

Often: affective lability, agitation, libido disorders, mood disorders, sleep disorders.

Disturbances from the nervous system

Very often: dizziness, headache.

Often: hypoesthesia, paresthesia, fainting, amnesia, attention impairment, memory impairment, migraine, parosmia, tremor, dizziness.

Disturbances on the part of the organ of sight

Often: dry eyes, retinal exudate, blurred vision, poor eyesight.

Infrequent: retinal ischemia, retinopathy, sensory disorders, unpleasant sensations in the eye, conjunctival hemorrhage, conjunctivitis, pain in the eye, itching, swelling of the eyes, puffiness of the eyelids, tearing, hyperemia of the eyes, photophobia.

Rarely: edema of the optic disc.

Heart Disease

Often: palpitations.

Infrequent: tachycardia, arrhythmia, cardiovascular disorders.

Vascular disorders

Often: hypotension, hypertension.

Infrequent: thrombosis of deep veins, flushes of blood to the face, pallor, a syndrome of cold extremities.

Rarely: venous thrombosis.

Disturbances from the respiratory system, chest and mediastinal organs

Very often: cough, shortness of breath.

Often: nosebleeds, nasal congestion, pain in the oropharynx, obstruction of the respiratory tract, paranasal sinuses, wheezing.

Infrequent: pleural pain, pulmonary embolism, dryness in the throat, dysphonia, increased secretion of the upper respiratory tract, the formation of vesicles in the oropharynx.

Disorders from the gastrointestinal tract

Very often: diarrhea, nausea, vomiting, dry mouth, perversion of taste.

Often: abdominal pain, upper abdominal pain, constipation, gastroesophageal reflux disease, hemorrhoids, abdominal discomfort, abdominal distension, discomfort in the anorectal area, aphthous stomatitis, cheilitis, dyspepsia, flatulence, glossalgia, ulcers of the oral mucosa, pain in the oral cavity, stomatitis,violations of the teeth.

Disturbances from the liver and bile ducts

Infrequently: hyperbilirubinemia.

Rarely: cholecystitis.

Disturbances from the skin and subcutaneous tissues

Very often: alopecia, dry skin, itching, rash.

Often: dermatitis, eczema, erythema, hyperhidrosis, night sweats, peripheral edema, psoriasis, erythematous rash, macular rash, papular rash, itching rash, skin lesions.

Deviations in the results of laboratory studies

Very often: weight loss.

Overdose:

In healthy volunteers, who took within 5 days daily doses of the drug to 3600 mg, no subsequent adverse clinical reactions occurred.

Specific antidote for cases of drug overdose does not exist. Treatment of overdose should include general supportive therapy, monitoring of vital signs and monitoring of the clinical condition of the patient.

Interaction:

The drug is a potent inhibitor of CYP3A4 / 5 isoenzymes. Simultaneous use of the drug and drugs, mainly metabolized by CYP3A4 / 5 isoenzymes,It can lead to an increase in their concentration in the plasma and promote or enhance prolongation of their therapeutic effects and unwanted side reactions. A drug in vitro does not inhibit the isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 and does not induce isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4 / 5.

In a study of drug interactions involving digoxin, the drug showed a limited ability to inhibit P-glycoprotein in clinically significant concentrations.

The drug is partially metabolized by the action of the isoenzyme CYP3A4 / 5. The combined use of drugs with the drug, inducing or inhibiting the activity of isozymes CYP3A4 / 5, can contribute to increase or decrease the concentration of boceprevir.

Special instructions:

When using the drug it is allowed to store it at a temperature of no higher than 25 ° C for not more than 3 months.

Influence on ability to drive vehicles and work with mechanisms

The effect of the drug in combination with peginterferon alfa and ribavirin on the ability to drive vehicles and use various mechanisms has not been studied. However, some of the adverse reactions observed in patients may affect the ability to drive vehicles and work with different mechanisms.Individual reaction to the drug in combination with peginterferon alfa and ribavirin may differ. Patients should be informed that the use of the drug may cause fatigue, dizziness, fainting and blurred vision.

Instructions

Boceprevir (Boceprevirum)