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

Active substanceBoceprevirBoceprevir

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Viktrelis®

capsules inwards

Schering-Plau N. Labo. USA

Dosage form: & nbspcapsules

Composition:

1 capsule contains:

Active substance: bocetrevir 200 mg.

Excipients: cellulose microcrystalline 40 mg, lactose monohydrate 56 mg. pregelatinized starch 60 mg. croscarmellose sodium 24 mg. sodium lauryl sulfate 12 mg. magnesium stearate 8 mg.

Capsule cap: dye iron oxide red (EI72) 0.0377%. color of iron oxide yellow (E172) 0.5976%. titanium dioxide 0.7866%. gelatin 98.5781%.

Capsule Casing: iron-oxide dye yellow (E172) 0.1882%. titanium dioxide 2.6578%, gelatin 97.1540%.

Composition of ink SB-1100 red: shellac. ethanol, isopropanol. butanol, propylene glycol, ammonia solution concentrated, iron oxide red (E 172).

Description:

Hard gelatin capsules, size No. 0.

Capsule cap: opaque, yellowish-brown color, with the company logo printed with red food ink.

Capsule body: opaque, from almost white to light yellow, with the inscription "314" printed with red food ink.

Contents of the capsule: Powder from white to almost white.

Pharmacotherapeutic group:Antiviral agent

ATX: & nbsp

J.05.A.E.12 Boceprevir

Pharmacodynamics:

The drug Viktrelis® contains the active substance boceprevir. Boceprevir is an inhibitor NS3 protease of the hepatitis C virus (HCV). Boceprevir covalently, but reversibly binds to the alpha-ketoamide functional group of the active center of the serine protease NS3 (Ser139). which leads to inhibition of viral replication in human hepatitis C cells infected with the virus.

Antiviral activity in cell culture

The antiviral activity of boceprevir was assessed by biochemical analysis, determining the binding of slow inhibitors NS3 protease, as well as in the hepatitis C virus replicon system. Bocetrevir concentrations, in which 50% (IC₅₀) and 90% (IC₉₀) inhibition of the virus were respectively about 200 nM and 400 nM in a 72-hour study in cell culture. It is assumed that the loss of RNA replicon linearly depends on the time of action of boceprevir. Application of the drug Viktrelis® in a concentration corresponding to IC₉₀ within 72 hours led to a decrease in the concentration of RNA in replicon in 10 times. The prolonged exposure led to a decrease in the concentration of RNA in those who decided 100 times to the 15th day.

Evaluation of various combinations of bocetrevir with interferon alpha-2b. which resulted in 90% inhibition of the replicon RNA, showed an additive effect, with no signs of synergy or antagonism being found.

Resistance

The resistance of the virus to boceprevirov was assessed based on biochemical analysis and analysis of replicons. The biological activity of bocepreviir decreased 2-10 times with the presence of basic amino acid substitutions (RAVs-resistant-associated amino acid variants) V36M, T54A, R155K and V170A, which determine the resistance. The decrease in the activity of bocetrevir more than 50 times was observed in the presence of RAVs: A156T and A156V. It should be noted that replicons carrying RAV A156T, have less activity than replicons. bearing others RAVs. The multiplicity of increase in resistance caused by double RAVs, was approximately equal to the multiplicity of increase in resistance to the drug for individual RAVs.

According to generalized data from a study of patients who had not previously received antiviral therapy and patients with ineffective prior therapy with peginterferon alfa-2b and ribavirin for 4 weeks followed by therapy with the drug Viktrelis® in a dose of 800 mg three times a day in combination with Peginterferon alpha-2b and ribavirin, who participated in clinical trials III phase, RAVs were found in 15% of patients in both groups. RAVs were found in 53% of patients who received therapy with the drug Viktrelis® and who did not achieve a stable virologic response. Most often (> 25% of patients) are detectable RAVs were V36M (61%) and RI55K (68%) in patients infected with the genotype 1a virus and T54A (42%), T54S (37%), A156S (26%), V170A (32%) in patients infected with the genotype virus lb. In 6% of patients who took the drug Viktrelis®, sensitivity to interferon (decrease ≥I-log₁₀viral load at week 4 of treatment) was associated with less RAVs but compared with 41% of patients who experienced a decrease in viral load < l-log₁₀ (low sensitivity to interferon). After completing the course of therapy with the drug Wiktrelis® patients were taken blood samples for analysis for the presence of RAVs. In 31% of patients, a higher sensitivity to interferon was associated with the detection of less RAVs compared with 68% of patients who had a decrease in viral load at week 4 of treatment < l-log₁₀. In a generalized analysis, it was shown that the amount RAVs before the start of therapy, apparently, had no significant connection with the response to treatment in patients taking the drug Viktrelis® in combination with peginterferon alfa-2b and ribavirin.

The results of ongoing long-term follow-up 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 Viktrelis® over time, the virus containing RAVs, can return to the "wild" type.

Evaluation of the effect of the drug Viktrelis® per interval QTc

In a randomized multi-dose placebo-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 three times daily) and therapeutic (800 mg three times daily) doses in 36 healthy volunteers. Significant differences in QTc-intervals 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 time to reach the maximum concentration (T_max) in the blood, equal to 2 hours. Pharmacokinetic parameters - area under the curve "concentration-time" (AUC). the maximum (C_max) and the minimum (C_min) concentration - practically did not increase dose-dependent.

In particular, at doses equal to 800 mg and 1200 mg, these parameters were close, which implies a reduction in absorption with higher doses. The cumulation of boceprevir is minimal, and the pharmacokinetic equilibrium is reached approximately 1 day after taking the drug three times a day.

In healthy volunteers who only took boceprevir in a dose of 800 mg three times a day, the pharmacokinetics of the drug was characterized by the following indices: AUC 6147 ng * h / ml, FROM_max 1913 ng / ml and FROM_min 90 ng / ml. Pharmacokinetic parameters in healthy volunteers and in patients with viral hepatitis C were similar. Absolute bioavailability of the drug Viktrelis® not studied.

Effect of food on absorption

Wiktrelis® should be taken with food. Food increases the absorption of bocetrevir by 60% when taking a dose of 800 mg three 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, at meals or right after meals-also did not matter, so the drug Wiktrelis® can be taken regardless of the type and time of food intake.

Distribution

In the equilibrium state, the average apparent volume of the distribution of bocetrevir is approximately 772 liters. After taking a single dose of the drug Viktrelis®, equal to 800 mg. the 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 to form ketone-reduced metabolites that are inactive with respect to the hepatitis C virus. After a single dose of 800 mg of radiolabelled 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 isoenzymes CYP3A4 / 5, although to a lesser extent.

Excretion

Average half-life (t_1/2) bocetrevira and plasma is approximately 3.4 h. The average total clearance of bocetrephir is approximately 161 l / h. After a single oral administration of 800 mg of bocetrevir labeled with a radioactive isotope ¹⁴C, intestines and kidneys were derived approximately 79% and 9% of this dose, respectively. At the same time, in the form of unchanged boceprevir, about 8% and 3% of the intestine and kidneys were excreted, respectively, of the dose of the radiozotope labeled bocetrevir ¹⁴C. These data indicate that boceprevir is excreted mainly by the liver.

Pharmacokinetics in specific patient groups

Deti.

Safety, efficacy and pharmacokinetics of the drug Viktrelis® in children under the age of 18 years has not been studied.

Patients from violation ofFunctions liver

In the study in patients with chronic hepatic insufficiency of varying severity (mild, moderate and severe), clinically significant differences in pharmacokinetic parameters were not revealed, and dose adjustment ns is required.Application of the drug Viktrelis® 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) (see section "Contraindications"), for additional information on the use of the drug Viktrelis® in patients with compensated cirrhosis of the liver, refer to the section on "Specific guidance: Hepatic insufficiency."

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. Correction of a dose to patients with any stage of renal failure (including terminal) 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 hepatitis C virus (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 in patients who had previous antiviral treatment ineffective.

Contraindications:

Hypersensitivity to bocetrevira or any other component of the drug.
Autoimmune hepatitis.
Hepatic insufficiency (functional class B and C but Child-Pugh system more than 6 points) (see sections "Dosage and Administration" and "Pharmacokinetics").
Simultaneous use of drugs whose clearance is mediated by the action of isoenzymes CYP3A4 / 5 and for which elevated plasma concentrations are associated with serious and / or life-threatening adverse reactions, namely simultaneous use with midazolam and triazolam (for oral administration), astemizole, bepridil, pimozide, lumefantrine, halofantrine, propafenone, simvastatin.lovastatin, quetiapip, alfuzosin. doxazosium, silodosin, tamsulosin, tyrosine kinase inhibitors and ergot derivatives (dihydroergotamine, ergometrine, ergotamia, methylergometrin) (see "Interaction with other drugs"),
Pregnancy.
Children under 18 years of age (efficacy and safety not studied).
Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

For further information, refer to the instructions for use of peginterferon alfa and ribavirin.

Carefully:

Drugs containing drospirenone

Care should be taken when administering the drug Viktrelis® patients taking potassium-sparing diuretics or drugs containing drospirenone, since there is a risk of developing hyperkalemia. Consider the possibility of using alternative methods of contraception (see section "Interaction with other drugs").

Inductors of isosferment CYP3A4

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

Drugs that extend the interval QT

Caution should be exercised while using the drug Wiktrelis® with drugs that extend the interval QT, such as amiodarone, quinidia, methadone, pentamidine and some neuroleptics.

Antifungal drugs

Caution should be exercised while using the drug Wiktrelis® with ketoconazole or azole antifungal agents (itraconazole, posaconazole, voriconazole).

HIV protease inhibitors

It is not recommended simultaneous use of the drug Viktrelis® with HIV protease inhibitors (atazapavir / ritopavir, darunovir / rigonavir, loninavir / ritonavir).

Blocators of "slow" calcium channels

Caution should be exercised when using Wiktrelis ® with "slow" calcium channel blockers (amlodipip, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, verapamil) due to the possible increase in the concentration of the latter in the blood. Such patients should be monitored.

Pregnancy and lactation:

Fertility

Influence of the drug Viktrelis® human fertility has not been studied.The available pharmacodynamic / toxicological data showed that the effect of the drug Viktrelis® the fertility of rats was reversible.

Pregnancy

Wiktrelis® in combination with peginterferon alfa and ribavirin is contraindicated in pregnant women (see section "Contraindications").

Wiktrelis® had no effect on fetal development in rats and rabbits.

The effect of the drug Viktrelis® on pregnant women in accordance with the requirements of controlled clinical trials.

When treating bocicevir in combination with peginterferon alfa and ribavirin, special care should be taken to avoid pregnancy in women or partners of male patients. Women of childbearing age should take the drug Viktrelis® only with the use of reliable contraceptives, which should continue to be used within 4 months after discontinuation of therapy with the drug Viktrelis®. Male patients and their partners should use reliable contraceptive during treatment and for 7 months after treatment.

For further information, refer to the instructions for use of peginterferon alfa and ribavirin.

Breastfeeding period

The available pharmacodynamic / toxicological data showed the presence of boceprevir and its derivatives in the milk of rats. Decision regarding the termination of breastfeeding or treatment with Wiktrelis® should be taken taking into account the ratio of the benefits of breastfeeding for a child and the treatment for a woman.

Dosing and Administration:

Wiktrelis® 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 Viktrelis® is 800 mg orally three times a day at the same time as eating. The maximum daily dose of the drug Viktrelis® is 2400 mg.

Patients without cirrhosis of the liver who had not previously received antiviral therapy

- Begin therapy with peginterferon alfa and ribavirin for 4 weeks (weeks of treatment 1-4).

- At the 5th week of the preparations, peginterferon alfa and ribavirin add the drug Viktrelis® in a dose of 800 mg three times a day. The duration of therapy is determined depending on the virologic response (HCV RNA content) through the 8, 12 and 24 treatment regimens ("response therapy") (see. Table 1).

Table 1. Duration of treatment ("therapy and response") depending on the virologic response in patients without cirrhosis who had not previously received antiviral therapy.

Evaluation of results † *(HCV RNA content )**		Act
8 weeks of treatment	24 weeks of treatment	Act
Not determined	Not determined	Complete therapy with three drugs after 28 weeks of treatment.
Determined	Not determined	1. Continue taking all three drugs until the end of the 28th week of treatment. 2. Further take only peginterferon alfa and ribavirin before the end of the 48th week of treatment.

* In clinical studies, the content of HCV RNA in plasma was determined using a set of Roche COBAS^® TaqMan^® with a threshold of 9.3 IU / ml.

† Cancellation policy:

If the patient has an HCV RNA level greater than or equal to 1000 IU / ml after 8 weeks of treatment. all three drugs should be canceled. If the patient has HCV RNA levels greater than or equal to 100 IU / ml after 12 weeks of treatment, all three drugs should be discontinued. If the patient has 24 weeks of treatment is determined PNK HCV, all three drugs should be withdrawn

Patients without cirrhosis with an ineffective precursor antiviralRApia (patients partially responding to treatment or having recidiv)

- Begin therapy with peginterferon alfa and ribavirin for 4 weeks (weeks of treatment 1-4).

-On the 5th week of treatment, the drug Viktrelis is added to the preparations of peginterferon alfa and ribavirip® in a dose of 800 mg three times a day. The duration of therapy is determined depending on the virologic response (HCV RNA content) at 8, 12 and 24 weeks of treatment ("response therapy") (see. table 2).

table 2. Duration of treatment ("response therapy") depending on the virologic response in patients without cirrhosis with ineffective prior therapy (patients partially responding to treatment or having a relapse) *.

Evaluation of results † (HCV RNA content )**		Act
8 pedel treatment	24 weeks of treatment	Act
Not determined	He is determined	Continue therapy with three drugs until treatment is complete after 36 weeks.
Determined	Not determined	Continue the use of all three drugs until a full 36 weeks of treatment. 2. Further accept only peginterferon alfa and ribavirin up to a full 48 weeks of treatment.

* Patients. partially responded to treatment, are patients who have had their viral load reduced to > 2-log₁₀ after 12 weeks, but a sustained virologic response was not achieved; patients who had a relapse. are patients with undetectable levels of HCV RNA at the end of the treatment period and subsequent detectable levels of HCV RNA in the blood plasma at the end of the observation period.

** In clinical studies, the content of HCV RNA in plasma was determined using a set of Roche COBAS® TaqMan^® from threshold of 9.3 IU / ml.

† Cancellation policy:

If the patient has an HCV RNA level greater than or equal to 1000 IU / ml after 8 weeks of treatment. all three drugs should be canceled. If the patient has 12 weeks of treatment, the HCV RNA content is greater than or equal to 100 IU / ml. all three drugs should be canceled. If the patient is determined after 24 weeks of treatment for HCV RNA, all three drugs should be withdrawn.

Patients with no response ("zero" response) to previous treatment

Patients who, with prior treatment with peginterferon alfa and ribavirin at 12 weeks, had a lower HCV RNA content less than 2-log₁₀(patients with a "zero" response), within 4 weeks should take peginterferon alfa and ribaviria, and then within 44 weeks, the drug Viktrelis® in a dose of 800 mg three times a day in combination with peginterferon alfa and ribavirin. If in these patients after 8 weeks of treatment the HCV RNA content is greater than or equal to 1000 IU / ml or after 12 weeks of treatment the viral load is greater than or equal to 100 IU / ml. or after 24 weeks of treatment, HCV RNA is detected. should stop taking all three drugs.

Patients with cirrhosis of the liver

Patients with compensated cirrhosis of the liver are prescribed peginterferon alfa and ribavirin for 4 weeks, followed by addition to therapy of the drug Wiktrelis® in a dose of 800 mg three times a day for 44 weeks. If the patient has an HCV RNA level greater than or equal to 1000 IU / ml after 8 weeks of treatment. or 12 HCV HCV levels are greater than or equal to 100 IU / ml, or after 24 weeks of treatment, HCV RNA is detected, all sin preparations should be discontinued.

For more information on the use of the drug Viktrelis® in patients with compensated cirrhosis of the liver should refer to the section "Special instructions.Liver failure".

Skipping reception of the next vine of the drug

If the patient missed taking the dose of the drug and until the next dose remains less than 2 hours, then the missed dose should be taken ns.

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 Viktrelis®.

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.

For further information, refer to the instructions for use of peginterferon alfa and ribavirin.

Wiktrelis® should be taken only in combination with peginterferon alfa and ribavirin.

Renal insufficiency

Patients with any degree of renal failure do not need a dose adjustment of the drug Viktrelis® (see section "Pharmacological properties").

Liver failure

Patients with any degree of liver failure do not need a dose adjustment of the drug Viktrelis ®.Wiktrelis® in combination with peginterferon alfa and ribavirin is contraindicated in patients with decomppezirovanny liver cirrhosis (functional class of cirrhosis of liver B and C in the Child-Pugh system more than 6 points) (see the sections "Pharmacological properties" and "Contraindications").

For more information on the use of the drug Viktrelis® in patients with compensated cirrhosis of the liver, refer to the section on "Specific guidance: Hepatic insufficiency."

Children

Safety, efficacy and pharmacokinetics of the drug Viktrelis® in children under the age of 18 years have not been studied.

Elderly patients

The number of elderly patients (65 years and older) who took part in the clinical trials of the drug Viktrelis® was insufficient to determine whether the therapeutic response was different in the elderly patient group from a group of young patients. As a result of other clinical studies, the differences in the responses in young and elderly patients to the study drug were found.

HIV co-infection (virus human immunodeficiency)

Wiktrelis® in combination with pegingerferon alfa and ribavirin was evaluated in a study with the participation of 98 patients (64 of whom received the preparation of Wiktrelis®), co-infected with the human immunodeficiency virus (HIV) and hepatitis C virus (genotype 1) and not previously treated with chronic viral hepatitis C.

Data on drug interaction with antiviral (HIV) agents are given in table 4 of the section "Interaction with other medicinal products".

Co-infected with the hepatitis B virus

Safety and efficacy of the drug Viktrelis®, used alone or in combination with peginterferon alfa and ribavirin for the treatment of chronic viral hepatitis C (genotype 1), in patients co-infected with the hepatitis B virus and hepatitis C virus have not been studied.

Patients after organ transplantation

Safety and efficacy of the drug Viktrelis®, used alone or in combination with pegingerferon alfa and ribavirin for the treatment of chronic viral hepatitis C (genotype I), in patients who underwent liver or other organ transplantation have not been studied. Data on the drug interaction with immunosuppressants are given in Table 4 of the section"Interaction with other medicinal products".

Cancellation policy

Treatment should be discontinued in all patients with HCV RNA levels greater than or equal to 1000 IU / ml after 8 weeks of treatment, or if the patient has a HCV RNA level greater than or equal to 100 IU / ml after 12 weeks of treatment, or if the patient is diagnosed with HCV RNA via 24 weeks of treatment.

Side effects:

The safety profile is based on the combined data on the safety of two clinical trials involving about 1500 patients taking Wiktrelis® in combination with peginterferon alfa-2b and ribavirin: one study involving patients who had not previously received therapy and another study involving patients who had failed previous therapy.

The most frequent adverse reactions were increased fatigue, anemia, nausea, headache and dysgeusia.

The most common reason for the decrease in the doses of the drugs was anemia, which often developed in patients who received therapy with the drug Viktrelis® in combination with peginterferon alfa-2b and ribavirin. than in patients receiving only pegingerferon alpha-2b and ribavirin.

Undesirable reactions are given below and differentiated according to system-organ classes with the frequency of occurrence: very often (≥ 1/10): often (from ≥ 1/100 to <1/10): infrequently (from ≥ 1/1000 to <1/100); rarely (from ≥ 1/10000 to <1/1000); is unknown (the frequency can not be estimated from the available data).

Table 3. Undesirable reactions, revealed during clinical trials and during the post-dose application of the drug Viktrelis® in combination with peginterferon alfa-2b and ribavrin†‡

Organs and organ systems	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:	Epiglottitis *, otitis media, sepsis
Benign, malignant and unspecified neoplasms (including cysts and polyps)
Rarely:	Neoplasms of the thyroid gland (nodular form)
Violations of the blood and lymphatic system
Often:	Anemia , neutropenia
Often:	Leukopenia , thrombocytopenia , agranulocytosis, pancytopenia
Infrequently:	Hemorrhagic diathesis, lymphadenopathy, limfonia
Rarely:	Hemolysis
Immune system disorders
Rarely:	Sarcoidosis *, porphyria (with the exception of acute)
Disorders from the endocrine system
Often:	Goiter, hypothyroidism
Infrequently:	Hyperthyroidism
Disorders from the metabolism and nutrition
Often:	Decreased appetite *
Often:	Dehydration , hyperglycemia , hypertriglyceridemia. hyperuricemia
Infrequently:	Hypokalemia *, eating disorders, diabetes, gout, hypercalcemia
Disorders of the psyche
Often:	Anxiety , depression , insomnia, irritability
Often:	Emotional lability, agitation, libido disorders, mood disorders, sleep disorders
Infrequently:	Aggression , homicidal thoughts , panic attacks , paranoia , abuse of psychotropic substances , suicidal thoughts , abnormal behavior, anger, apathy, confusion, changes in mental status, anxiety
Rarely:	Bipolar disorder , completed suicide , attempted suicide *, auditory hallucinations. visual hallucinations, mental decompensation
Disorders from the nervous system
Often:	Dizziness , headache
Often:	Gynesthesia , paresthesia , fainting *, amnesia, impaired attention, memory impairment. migraine, parosmia. tremor, vertigo
Infrequently:	* Peripheral neuropathy, cognitive dysfunction, hypersensitivity, confusion, loss of consciousness, mental impairment, neuralgia, lightheadedness
Rarely:	Cerebral ischemia *, encephalopathy
Disturbance of the organ of vision
Often:	Dry eyes, retinal exudate, blurred vision, blurred vision
Infrequently:	* retinal ischemia, retinopathy *, foreign body sensation in the eye, eye discomfort, conjunctival hemorrhage, conjunctivitis, pain in the eye, itching, swelling, eye, eyelid edema, tearing, eye redness, photophobia
Rarely:	Edema of the optic disc
Hearing impairment and labyrinthine disruption
Often:	Tinnitus
HOften:	Deafness *, discomfort in the ear, hearing impairment
Hapythe from the heart
Often:	Heart palpitations
Infrequently:	Tachycardia *, arrhythmia, cardiovascular disorders
Rarely:	Acute myocardial infarction , atrial fibrillation , ischemic heart disease , pericarditis , exudative pericarditis
Violation of the vessels
Often:	Arterial hypotension *, arterial hypertension
Infrequently:	Deep vein thrombosis *, blood tides, pallor, cold extremity syndrome
Rarely:	Venous thrombosis
Disturbances from the respiratory system, chest and mediastinum
Often:	Cough , shortness of breath
Often:	Nasal bleeding, congestion of the nose, pain in the oropharynx, obstruction of the respiratory tract, adnexal sinuses, difficulty breathing
Infrequently:	Pleural pains , pulmonary embolism , dryness in the throat, dinophonia. increased secretion of the upper respiratory tract, the formation of vesicles in the oropharynx
Rarely:	Pleural fibrosis *, orthopnea, respiratory failure
Disorders from the gastrointestinal tract
Often:	Diarrhea , nausea , vomiting *, dry mouth, perversion of taste
Often:	Abdominal pain , upper abdominal pain , constipation , gastroesophageal reflux disease , hemorrhoids *, abdominal discomfort, bloating,discomfort in the anorectal area, aphthous stomatitis, cheilitis, dyspepsia, flatulence, glossalgia, ulcers of the oral mucosa, oral pain, stomatitis, dental abnormalities
Infrequently:	Pain in the lower abdomen , gastritis , pancreatitis *, anal itching, colitis, dysphagia. a change in the color of feces, an increase in peristalsis, bleeding gums, pain in the gums, gingivitis, glossitis, dry lips, lonely phagia, procalgia, rectal bleeding. hypersecretion of saliva, hypersensitivity of teeth, discoloration of tongue, ulcers in tongue
Rarely:	Functional pancreatic insufficiency
Disturbances from the liver and bile ducts
Infrequently:	Hyperbilirubinemia
Rarely:	Cholecystitis*
Disturbances from the skin and subcutaneous tissues
Often:	Alopecia, dry skin, itching, rash
Often:	Dermatitis, eczema, erythema, hyperhidrosis, night sweats, peripheral edema, psoriasis, erythematous rash, macular rash, maculopapular rash, papular rash, itching rash, skin lesions
Infrequently:	Photosensitivity, skin ulcers, urticaria
Unknown:	Angioedema, drug rash with eosinophilia and systemic symptoms (DRESS-consrum). exfoliative rash, exfoliative dermatitis, Stevens-Johnson syndrome, toxic skin rashes, toxemia
Disturbances from musculoskeletal and connective tissue
Often:	Arthralgia, myalgia
Often:	Back pain , pain in the limbs , muscle spasms, muscle weakness, neck pain
Infrequently:	Musculoskeletal pain in the thorax *, arthritis, bone pain, joint swelling, musculoskeletal pain
Disorders from the kidneys and urinary tract
Often:	Pollakuria
Infrequently:	Dizuria, nocturia
Violations of the genitals and mammary gland
Often:	erectile disfunction
Infrequently:	Amenorrhea, menorrhagia, metrorrhagia
Rarely:	Aspermia
General disorders and disorders at the site of administration
Often:	Asthenia , chills, fatigue , fever *, flu-like syndrome
Often:	Discomfort in the area of difficult cells , chest pain , malaise *, sensation of body temperature changes, dryness of mucous membranes, pain
Infrequently:	Feeling of abnormal condition, worsening of healing processes, non-cardial pains in the chest
Deviations in the results of laboratory studies
Often:	Weight loss
Infrequently:	Heart noises, increased frequency heartbeats
Notes: * Includes unwanted reactions that occur during clinical trials. According to the researcher's assessment, they can be serious. †Because the drug Viktrelis is prescribed in combination with pegyuterferoeom alfa and ribavirin. it is necessary to read the appropriate section of the instructions for use and peginterferon alfa and ribavirin. ‡Reactions at the injection site were not included, as bocicevir is administered orally

Anemia

The development of anemia was observed in 49% patients who received the drug Viktrelis® in combination with peginterferon alfa-2b and ribavirin. compared with 29% patients who received only pegyuterferon alfa-2b and ribavirin. Addition of the drug Viktrelis® led to an additional decrease in the hemoglobin concentration by approximately 1 g/ dl. The mean decrease in hemoglobin concentration compared to the baseline was greater in patients who had previously received therapy compared to patients who had not received previous therapy. Due to the emergence of an anemia / hemolytic anemia, dose adjustment was performed in 26% of patients receiving the drug Wyclreis® in combination with peginterferon alfa-2b and ribavirin. compared with 13% of patients taking only pegyuterferon alpha-2b and ribavirin. In clinical studies, the proportion of patients who received erythropoietin for the treatment of anemia was 43% in the group of patients receiving the drug® in combination with peginterferon alfa-2b and ribavirin. compared with 24% in the group of patients treated only with peginterferon alfa-2b and ribavirin. Most patients with anemia with hemoglobin concentration < 10 g / dL (6.2 mmol / L) erythropoietin was obtained. The number of patients who received blood transfusion for the purpose of treating anemia was 3% in the group of patients taking the drug Viktrelis® in combination with peginterferon alfa-2b and ribavirin, but compared with <1% of patients taking only peginterferon alfa-2b and ribavirin.

Neutrophils

The number of patients with a reduced neutrophil count in the blood was higher in the group of patients receiving the preparation of Wiktrelis compared to the group of patients receiving only peginterferon alfa-2b preparations and ribavirin. Percentage of patients with grade 3 neutropenia (neutrophil count <0.75 x 10⁹ klestok / l) was higher in the group of patients receiving the drug Wiktrelis® (29%), compared with the placebo group (17%) in combination with peginterferon alfa-2b and ribavirin. Reduction of neutrophil concentration to <0.5 x 10⁹ cells / l (grade 4 neutropenia) was noted in 7% of patients in the group receiving the drug Viktrelis® in combination with peginterferon alfa-2b and ribavirin and in 4% of patients receiving only peginterferon alfa-2b and ribavirin.

Platelets

Reduction of platelet concentration was observed in 3% of patients receiving the preparation of Wiktrelis® in combination with peginterferon alfa-2b and ribavirin and in 1% of patients receiving only peginterferon alfa-2b and ribavirin. In both groups, patients with cirrhosis of the liver were at greater risk of developing grade 3-4 thrombocytopenia compared to patients without cirrhosis.

Other laboratory data

Addition of the drug Viktrelis® to the therapy with peginterferon alfa-2b and ribavirin was associated with an increase in the incidence of increased concentrations of uric acid, triglycerides and total cholesterol compared to that of peginterferon alfa-2b and ribavirin alone.

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 overdose with the drug Viktrelis® 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:

Wiktrelis® is a strong inhibitor of isoenzymes CYP3A4 / 5. The simultaneous use of the drug Viktrelis® and drugs, mainly metabolized by isoenzymes CYP3A4 / 5, can lead to an increase in their concentration in the plasma and promote the enhancement or prolongation of their therapeutic effect and the appearance of undesirable side reactions (cf. Table 4). Wiktrelis® in vitro does not inhibit isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2CI9, CYP2D6 or CYP2EI and not inducing isozymes CYPIA2, CYP2B6. CYP2C8, CYP2C9, CYP2C19 or CYP3A4 / 5.

In a study of drug interactions involving digoxin, preparation of Viktrelis® showed a limited ability to inhibit p-glycoprotein at clinically significant concentrations.One should expect an increase in the plasma concentration of substrates of the p-glycoprotein, which carries out their efflux, such as digoxia and dabigatran.

Wiktrelis® partially metabolized by isozymes CYP3A4 / 5. Joint use of the drug Viktrelis® with preparations inducing or inhibiting the activity of isoenzymes CYP3A4 / 5, may increase or decrease the concentration of bocetrephir.

In studies in vitro it was shown that boceprevir is a substrate of p-glycoprotein.

Wiktrelis® in combination with Peginterferon alpha and ribavirin is contraindicated in the case of combined use with drugs, the removal of which depends to a large extent on the activity of isoenzymes CYP3A4 / 5 and elevated plasma concentrations of which are associated with serious and / or life-threatening unwanted adverse reactions. These include oral drugs midazolam and triazolam. Astemizole, bepridil, pimozid, lumefantrine, halofantrine. Propafenone, simvastatin, lovastatin, quetiapine, alfuzosin, doxazosin, silodosin, tamsulosin, tyrosine kinase inhibitors and ergot derivatives (dihydroergogamin, ergometrine, ergogamine, methylergomethrin) (see section "Opposition").

Drugs used with caution

Drugs containing drospirenone

Care should be taken when administering the drug Viktrelis® patients taking potassium-sparing diuretics or drugs containing drospirenone, since there is a risk of developing hyperkalemia. Alternative methods of contraception should be considered (see "With caution").

Inductors of isoenzyme CYP3A4

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

Prenaratum tearing interval QT

Care should be taken when using the drug Wiktrelic®with drugs that extend the interval QT, such as amiodarone, quinidine. methadone, pentamidine and some antipsychotics.

Antifungal drugs

Caution should be exercised while using the drug Wiktrelis® with ketoconazole or azole antifungal agents (itraconazole, posaconazole, voriconazole).

HIV protease inhibitors

It is not recommended simultaneous use of the drug Viktrelis® with HIV protease inhibitors (atazanavir / ritonavir, darunovir / ritonavir, lopinavir / ritonavir).

Blocks of "slow" calcium channels

Caution should be exercised while using the drug Wiktrelis® with blockers of "slow" calcium channels (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, verapamil) due to a possible increase in the concentration of the latter in the blood. Such patients should be monitored.

Table 4. Data on pharmacokinetic interactions.

Medicines for therapeutic groups

Interaction*

(the expected mechanism of action, if known)

Recommendations but

joint

application

Antiarrhythmic drugs

Digoxin

(0.25 mg of digoxin once + 800 mg of the drug Viktrelis® three times a day)

Digoxin AUC ↑ 19% Digoxin C_max ↑ 18%

There is no need to adjust the dose of digoxin or Wiktrelis®. Patients receiving digoxin, should be monitored.

Antiviral drugs

Pegintsrfsron alpha-21)

(peginterferon alfa-2b 1.5 μg / kg subcutaneously once a week + Wiktrelis® 400 mg three times a day)

Boceprevir AUC ** ↔ Boceprevir C_max 1 12% Boceprevir FROM_min - not applicable Peginterferon alpha-2b AUC ↓ 1%^†‡

Pegipterferon alfa-2b C_max - not applicable

No dose adjustment of peginterferon alfa-2b and the preparation of Viktrelis is required®.

Antibiotics

Clarithromycin (in combination with diflunnsalom)

(clarithromycin: 500 mg three times a day + diflunisal 500 mg two or three times a day + PWiktrelis® 400 mg 2 times a day)

Boceprevir AUC ↑ 21% Boceprevir FROM_max ↑ 26% Boceprevir FROM_min ↓ 15%

Doctorrelis dose adjustment is not required® in combination with clarygromycin or in combination with clarithromycin and diflunisal.

Antifungal drugs

Ketoconazole

(ketocomazole 400 mg twice daily + preparation Wiktrelis®400 mg once)

Itraconazole, posaconazole, vorpconazole

Boceprevir AUC ↑ 131% Boceprevir FROM_max ↑ 41% Boceprevir FROM_min- not applicable (inhibition of isoenzymes CYP3A4 / 5

and / or p-glycoprotein)

The interaction was not studied.

Doctorrelis dose adjustment is not required® or ketoconazole.

It should be observed

caution when

simultaneous

the use of boceprevir

with ketoconazole or

azole

antifungal

drugs

(itraconazole,

posaconazole,

voriconazole).

Antiviral (HIV) means

HIV integrase inhibitor

Raltegravir

(raltegravir 400 mg once + preparation Wiktrelis® 800 mg three times a day)

Raltegravir 400 mg every 12 hours + preparation Wiktrelis 800 mg three times a day

Raltegravir AUC ↑ 4%***

Raltegravir FROM_max ↑ 11% Raltegravir FROM12h ↓25%

Boceprevir AUC ↓ 2% Boceprevir C_max ↓ 4% Boceprevir FROM8h ↓26%

HDo not adjust the dose of the drug Viktrelis® or raltegravir.

Nucleoside HIV reverse transcriptase inhibitors (NRTIs)

Tenofovir

(tenofovir 300 mg daily + preparation Wiktrelis® 800 mg three times a day)

Boceprevir AUC ↑ 8%** Boceprevir FROM_max ↑5% Boceprevir FROM_min ↑8%

Tenofovir AUC ↑5%

Tenofovir FROM_max ↑ 32%

HDo not adjust the dose of the drug Viktrelis® or tenofovir.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirsnz

(efavirins 600 mg daily + preparation Wiktrelis® 800 mg three times a day)

Boceprevir AUC↓ 19%**

Boceprevir FROM_max ↓8% Boceprevir FROM_min ↓44%

Efavirenz AUC ↑20% Efavirenz C_max↑11% (induction of isoenzyme CYP3A4 - impact on boceprevir).

When taking Wiktrelis® in combination with efavirenz minimal concentration FROM_min boceprevir in plasma decreased. The effect of this reduction in the minimum concentration C_min preparation Wiktrelis® the clinical consequences were not evaluated.

Etravirine

(etravirine 200 mg every I2 h + preparation Viktrelyc® 800 mg three times a day)

Boceprevir AUC↑ 10% Boceceptrir FROM_max ↑ 10% Boceprevir С8ч ↓12%

Etravirine AUC ↓ 23% of Etraviria FROM_max ↓24%

Etravirine FROM_min↓29%

A direct evaluation of the clinical significance of the decrease in these pharmacokinetic parameters of ovavirin was not carried out.

Rilpivirine

(rilpivirine 25 mg every 24 hours + preparation Wiktrelis® 800 mg three times a day)

Boceprevir AUC ↓6%** Boceprevir FROM_max ↓2% Boceprevir С8ч ↑4%

Rilpivirine AUC ↑39% Rilpivirine FROM_max ↑15% Rilpivirine FROM 24h ↑51%

(Influence at rilpivirine is due to inhibition of the isoenzyme CYP3A).

Doctorrelis dose adjustment is not required® and rilpivirin.

HIV protease inhibitors

Atazanavir / ritonavir

(atazanavir 300 mg + ritonavir I00 mg daily + preparation Wiktrelis® 800 mg three times a day)

Boceprevir AUC ↓5% Boceprevir C_max ↓7% Boceprevir FROM_min ↓18%

Atazanavir AUC ↓ 35% Atazanavir FROM_max ↓25% Atazanavir FROM_min ↓ 49%

Ritonavir AUC ↓ 36%

Ritonavir FROM_max ↓ 27%

Ritonavir FROM_min ↓ 45%

Not recommended joint reception atazanavir/ ritonavir and the drug Viktrelis®

Darunavir/ ritonavir

(daruiavir 600 mg + ritonavir 100 mg twice daily + preparation Vpttrelis® 800 mg three times a day)

Boceprevir AUC ↓ 32% Boceprevir FROM_max ↓ 25% Boceprevir FROM_min ↓ 35%

Darunavir AUC ↓ 44%

Darunavir C_max ↓ 36%

Darunavir FROM_min ↓ 59%

Ritonavir AUC ↓ 27%

Ritonavir FROM_max ↓ 13% Ritonavir FROM_min ↓ 45%

It is not recommended that joint darunovir / ritonavir and Wiktrelis®

Lopinavir / ritonavir

(loninavir 400 mg + ritonavir 100 mg twice daily + Viktrelis® 800 mg three times a day)

Boceprevir AUC ↓ 45% Boceprevir FROM_max ↓ 50% Boceprevir FROM_min↓ 57%

Lopinavir AUC ↓ 34% Lopinavir FROM_max ↓ 30% Lopinavir C min ↓ 43%

Ritonavir AUC ↓ 22%

Ritonavir C_max ↓ 12%

Ritonavir FROM_min ↓ 42%

HNo co-administration of lopinavir / ritonavir is recommended. PWiktrelis®.

Ritonavir

(ritonavir 100 mg once daily + preparation Wiktrelis® 400 mg three times a day)

Boceprevir AUC ↑ 19%

Boceprevir FROM_max ↓ 27%

Boceprevir FROM_min ↑ 4%

(due to inhibition of isoenzymes CYP3A4 / 5)

When taking the drug

Wiktrelis® combination with ritonavir concentration boceprevir decreases.

Neuroleptics

Quetiapine

The interaction was not studied

(Influence at quetiapine is due to inhibition of isoenzymes CYP3A4 / 5).

With the simultaneous use of quetiapine and the drug ViktrelIs® may increase the concentration of quetiapine in the plasma, which can lead to quetiapine toxicity, including coma. Simultaneous use of quetiapine with Wiktrelis® contraindicated (see section

"Contraindications").

Analgesic drugs / opioids

Buprenorphine / naloxone

(buprenorphine / naloxone 8/2 - 24/6 mg per day + preparation Wiktrelis® 800 mg three times a day)

Boceprevir

AUC ↓ 12%****

Boceprevir

FROM_max ↓ 18%****

Boceprevir FROM_min ↓ 5%****

Buprenorphine AUC ↑ 19%

Buprenorphine FROM_max ↑ 18%

Buprenorphine FROM_min ↑ 31%

Haloxone AUC ↑ 33%

Naloxone FROM_max ↑ 9%

No dosage adjustment of buprenorphine / naloxone or Wiktrelis®

Patients should be monitored for signs of opiate toxicity associated with the use of bocetrevira.

Methadone

(methadone 20-150 mg once daily + preparation Wiktrelis® 800 mg three times a day)

Boceprevir AUC ↓ 20%****

Boceprevir FROM_max ↑ 38%****

Boceprevir FROM_min ↑ 3%****

R-methanone AUC ↓ 15%

R-methanone FROM_max ↓ 10%

R-methanone FROM_min ↓ 19%

S-methanone AUC ↓ 22%

S-methanone FROM_max ↓ 17%

S-methanone FROM_min↓26%

(due to inhibition of the isoenzyme CYP3A4 / 5)

No dose adjustment for methadone or Wiktrelis®. Individual patients may require additional titration of the dose of methadone at the beginning / after the reception of the drug Viktrelis® to ensure the clinical effect of methadone.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Dnflunizel

(diflunizal 250 mg twice daily + preparation Wiktrelis® 800 mg two or three times a day)

Boceprevir AUC ↓ 4%

Boceprevir C_max ↓ 14%

Boceprevir C_min ↑31%

Doctorrelis dose adjustment is not required® or diflunisal.

Ibuprofen

(ibuprofen 600 mg three times a day + preparation Wiktrelis® 400 mg once)

Boceprevir AUC ↑ 4% Boceprevir FROM_max ↑ 6% Boceprevir FROM_min - not applicable

Doctorrelis dose adjustment is not required® or ibuprofep.

Antidepressants

Escitalopram

(escitalopram 10 mg once + preparation Wiktrelis® 800 mg three times a day)

Boceprevir AUC ↓ 9%

Boceprevir FROM_max ↑ 2%

Escitaloirs AUC ↓ 21%

Escitalopram FROM_max ↓ 19%

With the simultaneous use of escitalopram with the drug Viktrelis®the concentration of escitalopram decreased slightly. Selective serotonin reuptake inhibitors, such as escitalopram. have a wide

Therapeutic index, however, when combined with the preparation of Viktrelis® may need to adjust their doses.

Blocks of "slow" calcium channels

Amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, verapamil

The interaction was not studied.

Concentrations in the blood of blockers of "slow" calcium channels can increase with simultaneous use with the drug Viktrelis® .

Care should be taken when they are prescribed, and such patients should be monitored.

Glucocorticosteroids

Prednisone

(prednisone 40 mg once + preparation Wiktrelis® 800 mg three times a day)

Prednisone AUC ↑ 22%

Prednisone FROM_max ↓ 1%

Prednisolone AUC ↑37%

Prednisolone FROM_max ↑ 16%

He correction of the dose of Vitrectilis®. Patients receiving prednisone and preparation of Viktrelis®. must be monitored.

Gynolipidemic agents

Atorvastatin

(atorvastatii 40 mg once + preparation Wiktrelis® 800 mg three times a day)

Boceprevir AUC ↓ 5%

Boceprevir FROM_max ↑ 4%

Atorvastatin AUC ↑ 130%

Atorvastatin FROM_max ↑166% (inhibition of isoenzymes CYP3A4 / 5 and OATPBI)

The concentration of atorvastatin increased with simultaneous use with the drug Viktrelis®.

With simultaneous application

Atorvastatin with the drug Viktrelis®the lowest

effective dose of atorvastatin, but not exceeding the daily dose of 20 mg.

Pravastatin

(pravastatin 40 mg once + preparation Wiktrelis® 800 mg three times a day)

Boceprevir AUC ↓ 6%

Boceprevir FROM_max ↓ 7%

Pravastatin AUC ↑ 63%

Lawyers FROM_max ↑ 49% (inhibition of isofermet OATPB1)

Simultaneous use of pravastagin with the drug Viktrelis® increased the concentration of pravastatin, while treatment with pravastatin may be started in the recommended doses. Patients receiving pravastatin and preparation of Viktrelis®, shouldMr.s to be under observation.

Immunosuppressive drugs

Cyclosporin

(ciclosporin 100 mg once + drug Wiktrelis® 800 mg once)

(ciclosporin 100 mg once + preparation Wiktrelis® 800 mg three times a day)

Boceprevir AUC ↑ 16%

Boceprevir FROM_max ↑ 8%

Cyclosporin AUC ↑ 168%

Cyclosporin FROM_max ↑101 %

(Influence at ciclosporin is due to inhibition of isoenzymes CYP3A4 / 5).

When used simultaneously with the drug Viktrelis® a correction of the dose of cyclosporine should be expected;

guided by

results

close monitoring

concentrations

cyclosporine in the blood,

control of kidney function

and adverse reactions,

associated with admission

cyclosporine.

Tacrolimus

(tacrolimus 0.5 mg once + preparation Wiktrelis® 800 mg once)

(tacrolimus 0.5 mg

once + preparation Wiktrelis® 800 mg three times and a day)

Boceprevir AUC ↔ Boceprevir FROM_max ↓ 3%

Tacrolimus AUC ↑ 1610%

Tacrolimus FROM_max ↑ 890%

(Influence at tacrolimus is due to inhibition of isoenzymes CYP3A4 / 5).

The simultaneous use of tacrolimus with the drug Viktrelis® requires a significant dose reduction and an increase in the interval

dosing for tacrolimus, with careful monitoring of tacrolimus concentration in the blood, control of kidney function and control of side effects associated with the application of tacrolimus.

Sirolimus

(sirolimus 2 mg once + preparation Wiktrelis® 800 mg three times a day)

BoceprevirAUC ↓ 5%

Boceprevir FROM_max ↓ 6%

Boceprevir C8h ↑ 21%

Sirolimus AUC ↑ 712%

Sirolimus C_max↑ 384%

(Influence at sirolimus is due to inhibition of isoenzymes CYP3A4 / 5).

With the simultaneous use of the drug Viktrelis® and sirolimus requires a significant reduction in the dose of sirolimus and an increase in the interval between doses in the constant monitoring of serum sirolimus concentration, as well as regular examination of the kidney function for possible side effects associated with the use of sirolimus.

Oral anticoagulants

Dabigatran

The interaction was not studied

(the effect on transport carried out by p-glycrocogenic in the intestine).

Doctorrelis dose adjustment is not required®. Patients receiving dabigatran and the drug Viktorslis®, should be monitored.

Contraceptive means

Drospirenone /

Ethinylestradiol

(drospirenone 3 mg once daily + ethinyl estradiol 0.02 mg once daily + preparation Wiktrelis® 800 mg three times a day)

Drospirenone AUC ↑ 99%

Drospirenone FROM_max ↑ 57% Ethinylestradiol AUC ↓ 24%

Ethinylestradiol C_max↔ (Drospirenone inhibits isoenzymes CYP3A4 / 5).

Care should be taken when using the drug Viktorslis® patients taking potassium-sparing diuretics or drugs containing drocopienone, since there is a risk of developing hyperkalemia. Consideration should be given to applications

altoof innovative methods of contraception (see the section "With caution").

Norethandron /

ethinyl estradiol

(norethindrone 1 mg once daily + ethinyl estradiol 0.035 mg once daily + preparation Wiktrelis® 800 mg three times a day)

Norethindrone AUC 0-24h ↓ 4% Norethindrone FROM_max ↓ 7%

Ethinylestradiol

AUC 0-24h. ↓ 26% Ethinylestradiol

FROM_max ↓ 21%

The concentration of ethinyl stadiol decreased with simultaneous use with bocetrevir. Based on the values of serum concentrations of progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH)that while simultaneous application of etil estradiol 0.035 mg / norethindrone 1 mg and the preparation of Viktrelis® ovulation is suppressed.

It is unlikely that the simultaneous use of the drug Viktrelis® and combined oral contraceptives containing

ethinylestradiol and at least 1 mg of norethindrone, affects the contraceptive effect (see the section on "Application during pregnancy and during breastfeeding").

Effect of simultaneous administration of the drug Viktrelis® and combined oral or other forms of hormonal contraceptives containing lower doses of norethindrone. to suppress ovulation is not studied.

Patients who use estrogens as hormone replacement therapy should be monitored for signs of estrogen deficiency.

Proton Pump Inhibitors

Omeprazole

(omeprazole 40 mg once a day + preparation Wiktrelis® 800 mg three times a day)

Boceprevir AUC ↓ 8%**

Boceprevir FROM_max ↓ 6%

Boceprevir C8h. ↑ 17%

Omeprazole AUC ↑ 6%**

Omeprazole FROM_max ↑ 3% Omeprazole С8ч ↑ 12%

Do not need a dose adjustment of omeprazole or a preparation of Viktrelis®.

Sedatives

Midazolam (for oral administration) (4 mg once + Wiktrelis®800 mg three times a day)

Triazolam (for oral administration)

Midazolam AUC ↑ 430%

Midazolam FROM_max ↑177% (inhibition of isoenzymes CYP3A4 / 5)

The interaction was not studied.

Simultaneous use of midazolam and triazolam (for oral administration) with the drug Viktrelis® contraindicated (see section

"Contraindications").

Algrazolam, mbdazolam, triazolam (intravenous administration)

Interactions are not studied (inhibition of isoenzymes CYP3A4 / 5).

A thorough clinical follow-up of cases of respiratory depression and / or a prolonged sedation during a simultaneous application of the drug Viktrelis® with intravenous administration benzodiazepines (alprazolam. Midazolam, triazolam). Correction of benzodiazepine dose is necessary.

Interaction of the drug Viktrelis ® with other drugs (change in the estimate of the average ratio when using the drug Viktrelis® in combination with other agents (when using only Vitretilis ®):

↓ corresponds to a decrease in the estimate of the average ratio;

↑ corresponds to an increase in the estimate of the average ratio:

↔testifies to the absence of changes.

** 0-8 hours

*** 0-12 hours

**** Compared with the data obtained from the group of "historical control."

† 0-168 h

‡Combined values are indicated AUC for cohorts of patients taking doses 200 mg and 400 mg.

Special instructions:

Anemia

There have been reports of anemia in the treatment with peginterferon alfa / ribavirin. Addition of the drug Viktrelis® in the treatment regimen with peginterferon alfa and ribavirin leads to an additional decrease in hemoglobin concentration in serum. The median time to decrease the serum hemoglobin concentration to less than 10 g / dL relative to the concentration at the beginning of therapy was similar in the groups of patients taking the preparation of Wyctrelis® in combination with peginterferon alfa and ribavirin (71 days with a total course duration of 15-337 days), and patients taking peginterferon alfa and ribavirin (71 days with a total course duration of 8-337 days). Before the beginning of therapy, and also at 2, 4, 8 and 12 weeks of treatment and further, in the presence of clinical expediency, a complete blood test (including the leukocyte formula) should be performed.Reduction of serum hemoglobin concentration below 10 g / dl may serve as a basis for reducing the dose of ribavirin and / or the administration of erythropoietin (epoetin alfa) (see the sections "Side effect" and "Pharmacodynamics"). If discontinuation of ribavirin therapy is required. then therapy with peginterferon alfa and the drug Viktrelis® should also be discontinued.

When developing signs of anemia associated with therapy, it is recommended to reduce the dose of ribavirin.

In a prospective randomized controlled trial, the frequency of achieving a sustained virologic response and the overall tolerability of the drug Viktrelis® were comparable with a decrease in the dose of ribavirin or the use of erythropoietin. In this study, an increased risk of thromboembolism, including pulmonary embolism, acute myocardial infarction, cerebrovascular disease and deep vein thrombosis, was noted in the group of patients taking erythropoietin. compared with a group of patients who had a reduced dose of ribavirin.

For information on dose reduction and / or discontinuation of ribavirin treatment, refer to the ribavirin application manual.

Neutropenia

During clinical phase studies II and III in 7% of patients treated with a combination of the drug Viktrelis® with peginterferon alfa-2b and ribavirin, the neutrophil concentration was less than 0.5 x 10⁹ cells / l compared to 4% of patients treated with peginterferon alfa-2 aloneb and ribavirin. Three patients developed related c neutropenia serious or life-threatening infections. At two patients at reception of a preparation of Viktrels® in combination with peginterferon alfa-2b and ribavirin, a life-threatening neutropenia was recorded. A complete blood test (including the leukocyte formula) should be performed at 2, 4, 8 and 12 weeks of treatment and then, if clinically feasible. If the concentration of neutrophils decreases, a dose reduction of peginterferon alfa or discontinuation of therapy may be required. If cessation of therapy with peginterferon alfa is required, then ribavirin and Wiktrelis® should also be discontinued.

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

The use of combination with peginterferon alfa-2a in comparison with peginterferon alfa-2b

Treatment with a combination of the drug Viktrelis® with peginterferon alfa-2a and ribavirin compared with treatment with a combination of the drug Viktrelis® with peginterferon alfa-2b and ribavirin was associated with a higher degree of neutropenia (including grade 4 neutropenia) and a higher incidence of infection.

Other blood disorders

There have been reports of cases of development of pancytopenia in patients taking Wiktrelis® in combination with peginterferon alfa and ribavirin. A complete blood test (including the leukocyte formula) should be performed before the start of therapy, at 2, 4, 8 and 12 weeks of treatment and further during treatment, with clinical feasibility.

Hypersensitivity

With the combined scheme of treatment with the drug Viktrelis® with peginterferon alfa and ribavirin there were severe acute hypersensitivity reactions (eg, urticaria, angioedema). If such reactions occur, combination therapy should be discontinued and appropriate medication should be started immediately (sm.sections "Contraindications" and "Side effect").

Liver failure

Effectiveness and safety of the drug Viktrelis® in combination with peginterferon alfa and ribavirin have not been studied in patients with uncompensated hepatic cirrhosis (see the section Contraindications).

In published observational studies of patients with compensated cirrhosis of the liver, who received the drug Viktrelis® or telaprevir in combination with peginterferon alfa and ribavirin, it was shown that baseline platelet concentrations <100,000 / mm³ and serum albumin <35 g/ l in patients with compensated cirrhosis were the main factors predicting a legal outcome or a serious complication (severe infection or liver failure) during therapy.

Careful consideration should be given to the potential benefits and risks of using the drug Viktrelis® in combination with peginterferon alfa and ribavirin prior to initiation of therapy in patients with compensated cirrhosis who at the beginning of the study had a platelet count <100,000 / mm³ and serum albumin <35 g / l. If the therapy has already begun,it should be carefully monitored for the development of signs of infection and impaired liver function.

Patients co-infected with HIV

A drug Wiktrelis® in combination with peginterferon alfa and ribavirin was evaluated in a study with the participation of 98 patients (64 of whom were taking the drug Viktrelis®), co-infected with human immunodeficiency virus and hepatitis C virus (genotype I) and untreated chronic viral hepatitis C. Data for the drug interaction with antiviral (HIV) agents are given in Table 4 of the section "Interaction with Other Drugs".

Patients after organ transplantation

Safety and efficacy of the drug Viktrelis® applied alone or in combination with peginterferon alfa and ribavirin for the treatment of chronic viral hepatitis C (genotype I). patients who have undergone liver or other organ transplantation have not been studied. Data on drug interaction with immunosuppressants are given in table 4 of the section "Interaction with other drugs".

PepArats containing drospirenone

Inductors isoenzyme CYP3A4

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

Monotherapy with hepatitis C virus protease inhibitors

Based on the results of clinical trials, the drug Viktrelis should not be used as a monotherapy for viral hepatitis C, since there is a high probability of drug resistance (see the section "Pharmacodynamics").

It is not known what action Wiktrelis will have® on the activity of serially used protease inhibitors of the hepatitis C virus, including the repeated administration of the drug Viktrelis®.

Indicators of laboratory studies

In accordance with the instructions for the use of peginterferon alfa and ribavirin, laboratory tests should be conducted, including hematologic and biochemical tests (functional "hepatic" indicators), as well as control of pregnancy before, during and after therapy.

The content should be monitored PNK HCV during treatment at 8, 12 and 24 weeks and further, if clinically feasible.

A complete blood test (including the leukocyte formula) should be performed before the start of treatment, and after 2, 4, 8 and 12 weeks of treatment and further, if clinically feasible.

For more information on the use of the drug Viktrelis® in patients with compensated cirrhosis of the liver, refer to the section on "Specific guidance: Hepatic insufficiency."

Proarrhythmic effect

According to the available data, the drug Viktrelis® should be administered with caution to patients at risk of lengthening the interval QT (with a congenital elongated interval QT hypokalemia).

When using the drug Viktrelis® it is allowed to store it at a temperature not exceeding 25 FROM not more than 3 months.

Effect on the ability to drive transp. cf. and fur:

Influence of the drug Viktrelis® and combinations with peginterferon alpha and ribavirin on the ability to drive vehicles and use various mechanisms have 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 Viktrelis® in combination with peginterferon alpha and ribavirin can be different. Patients should be informed that use of the drug may cause fatigue, dizziness, fainting and blurred vision (see section "Side effect").

For further information, refer to the instructions for use of peginterferon alfa and ribavirin.

Form release / dosage:

Capsules 200 mg.

Packaging:

4 capsules per blister from Aklar^®/ PVC film and an easily peelable foil with a paper coating. 3 blisters are connected in a strip. On 7stripov together with the instruction but application in a pack of cardboard.

On 7 strips together with instructions for use in a pack of cardboard, four packs of cardboard in a carton box.

Storage conditions:

Store at a temperature of 2 to 8 ° C.

Keep out of the reach of children.

Shelf life:

2 years. Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002070

Date of registration:23.05.2013 / 30.06.2015

Expiration Date:23.05.2018

Date of cancellation:2017-09-05

The owner of the registration certificate:Schering-Plau N. Labo.Schering-Plau N. Labo. USA

Manufacturer: & nbsp

MSD INTERNATIONAL GmbH (Singapore Branch) Singapore

Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.

Information update date: & nbsp05.09.2017

Illustrated instructions

Instructions

Viktrelis® (Victrelis)