Simeprevir

Brand Janssen Pharmaceuticals N.V.

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Clinical Pharmacology

Simeprevir is an inhibitor of the hepatitis CNS3 / 4A virus protease, which plays a key role in viral replication. According to the results of the biochemical analysis of blood, simeprevir inhibited the proteolytic activity of recombinant proteases of the hepatitis C virus genotypes 1a and 1b NS3 / 4A with a median of Ki values of 0.5 and 1.4 nmol / l, respectively.

Indications

Treatment of chronic hepatitis C genotype 1 in combination with peginterferon alpha and ribavirin in adult patients with compensated liver disease (including liver cirrhosis) who have not previously received treatment or who have previous treatment (based on interferon (pegylated or non-pegylated) with or without ribavirin) was ineffective.

The drug Sovriad can not be used as monotherapy.

Composition

1 capsule contains:

Simeprevir sodium - 154.4 mg,

Excipients: sodium lauryl sulfate 1.25 mg, magnesium stearate 2.5 mg, silicon dioxide colloid 0.75 mg, croscarmellose sodium 12.5 mg, lactose monohydrate 78.4 mg.

The composition of the shell: titanium dioxide, gelatin.
Ink composition: shellac, ferric oxide black, propylene glycol.

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Dosage and Administration

The recommended dose of Sovriad is one capsule (150 mg) by mouth once a day with meals. The type of food does not affect the pharmacokinetic parameters of simeprevir. Capsules should be swallowed whole.

Sovriad must be used in combination with peginterferon alfa and ribavirin. Information on the method of administration and doses of peginterferon alfa and ribavirin are given in the appropriate instructions for use.

Duration of treatment

The recommended duration of treatment with Sovriad in combination with peginterferon alfa and ribavirin is 12 weeks.

In all patients, the drug therapy Sovriad must be started in combination with peginterferon alpha and ribavirin; treatment continues for 12 weeks. In patients who had not previously received treatment and patients with a relapse in history, including patients with cirrhosis of the liver, after completing the 12-week treatment with the Sovriad drug in combination with peginterferon alfa and ribavirin, peginterferon alpha and ribavirin therapy should be continued for 12 weeks (total duration of therapy - 24 weeks).

In patients with previous treatment failure (including no response or partial response), including patients with cirrhosis, after completing 12 weeks of therapy with the Sovriad drug in combination with peginterferon alfa and ribavirin, peginterferon alpha and ribavirin therapy should be continued for 36 weeks (total duration of therapy is 48 weeks).

Adverse reactions

The drug Sovriad must be used in combination with peginterferon alpha and ribavirin. Adverse reactions observed during therapy with peginterferon alpha and ribavirin are described in the respective instructions for use.

The general safety profile for the Sovriad drug combination, when used in combination with peginterferon alpha and ribavirin in patients with hepatitis C genotype 1, who have not previously received therapy, or with the ineffectiveness of previous interferon-based treatment with or without ribavirin, clinical studies of phase IIb (studies C205 and C206) and 3 clinical studies of phase III (studies C208, C216 and HPC3007).

Summary data from studies IIb and III included information on 1486 patients taking simeprevir in combination with peginterferon alpha and ribavirin (of which 924 patients took simeprevir at a dose of 150 mg 1 time / day for 12 weeks), and 540 patients who received placebo with peginterferon alpha and ribavirin.

Contraindications

Contraindications to therapy with peginterferon alpha and ribavirin also apply to combination therapy with the drug Sovriad: impaired renal function (Clcreatin

Carefully:patients with severe renal dysfunction (Cl creatinine CYP3A4, as well as with drugs that are the substrates of P-glycoprotein: antiarrhythmic drugs (amiodarone, disopyramide, flecainide, lidocaine (systemically), meksiletin, propafenon, quinidine), BKK (amlodipine, quinidine, amlodipine, melodinetin, quinidine), BKK (systemically), meksiletin, propafenone, quinidine, BKK , diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, verapamil), sedatives / anxiolytics (midazolam, triazolam).

Drug interactions

The main isoenzyme involved in the metabolism of simeprevir is CYP3A. Thus, the development of CYP3A isoenzyme-mediated clinically significant effects of other drugs on simeprevir pharmacokinetics is possible.

Simeprevir has no inducing effect on CYP1A2 or 3A4 isoenzymes in human hepatocytes. According to in vitro studies, simeprevir is a moderate inhibitor of the activity of CYP2A6, 2C8 and 2D6 isoenzymes (IC50 values> 32 μg / ml) and a weak inhibitor of CYP2C19 and 3A isoenzymes (IC50 values> 64 μg / ml).Simeprevir is not a clinically significant inhibitor of the enzyme activity of cathepsin A (IC50> 37 mcg / ml).

According to in vitro studies, simeprevir is a substrate of drug transport proteins, including P-glycoprotein, MRP2, BCRP, OATP1B1, OATP2B1 and OATP1B3. Simeprevir inhibits the OATP1B1 and NTCP uptake transport proteins, as well as the active transfer proteins from the cell P-glycoprotein / MDR1, MRP2 and BSEP. Proteins OATP1B1 and MRP2 are involved in the transport of bilirubin to hepatocytes and back. Combined use of simeprevir with potent inhibitors of CYP3A isoenzyme can lead to a significant increase in simeprevir plasma levels, while combined use with powerful inducers of CYP3A isoenzyme can significantly reduce the level of simeprevir in plasma and lead to the loss of its effectiveness. Thus, the combined use of the drug Sovriad with substances that are potent inhibitors or inducers of the activity of the CYP3A isoenzyme is not recommended. Simeprevir is a weak inhibitor of the activity of CYP1A2 and 3A4 isoenzymes in the intestine, while there is no effect on the activity of CYP3A4 isoenzyme in the liver. The combined use of the drug Sovriad with drugs, metabolized mainly by CYP3A4 isoenzyme, can lead to an increase in the concentration of these drugs in plasma.

The combined use of the drug Sovriad with drugs that are substrates of the transport proteins OATP1B1 and P-glycoprotein can lead to an increase in the concentration of such drugs in plasma.

Pregnancy and Lactation

Full-scale controlled clinical trials of simeprevir in pregnant women have not been conducted. Animal studies have demonstrated the effect of simeprevir on reproductive function.

The use of the drug Sovriad in combination with peginterferon alfa and ribavirin is contraindicated during pregnancy, including during pregnancy, the partner of the man receiving treatment, due to the fact that the use of ribavirin was observed significant teratogenic and / or resulting in the death of embryos effects. Extreme care must be taken to prevent pregnancy in women undergoing treatment, as well as in female partners of men undergoing treatment. Patients capable of childbirth, as well as patients with partners capable of childbirth, should begin taking ribavirin only if they use a combination of two effective contraceptives throughout the treatment, as well as within 6 months after it ends.

Information on use during lactation is given in the appropriate instructions for use of peginterferon alfa and ribavirin.

It is not known whether simeprevir and its metabolites are excreted in human breast milk. When used in rats during lactation, simeprevir was detected in the plasma of breast-fed rats, which was probably due to the excretion of simeprevir with breast milk. Because of the possible adverse effects of Sovriad on infants, it is necessary to decide whether to stop breastfeeding or to cancel / refuse therapy with the Sovriad drug, taking into account the advantages of breastfeeding for the child and the positive effects of therapy on the mother.

Special instructions

Do not use the drug Sovriad as a means of monotherapy.

Simeprevir should be prescribed in combination with peginterferon alfa and ribavirin. Thus, before starting therapy, you should read the instructions on the use of peginterferon alfa and ribavirin.

The special instructions described for peginterferon alfa and ribavirin are also relevant in combination therapy with simeprevir.

Pregnancy and Contraception Requirements

Since the Sovriad medicinal product is intended for use in combination with peginterferon alfa and ribavirin, indications regarding pregnancy and contraceptive requirements for all drugs that are part of this combination apply to combination therapy.

Ribavirin can cause malformations and / or death of the fetus during fetal development. Thus, extreme care must be taken to avoid pregnancy in women receiving treatment and in men who are treated.

Women capable of childbearing and their partners, as well as men undergoing treatment with their partners during therapy and during the period specified in the instructions for use of ribavirin, should use a combination of 2 effective methods of contraception after it ends.

Measurement of laboratory parameters during therapy with Sovriad in combination with peginterferon alfa and ribavirin

Hepatitis C virus RNA levels should be assessed at weeks 4 and 12 according to clinical indications. To monitor the level of RNA of the hepatitis C virus during therapy, it is recommended to use a sensitive quantitative analysis of the RNA of the hepatitis C virus.

Requirements for the baseline, as well as the results of a general clinical blood test, biochemical blood test (including liver enzymes and bilirubin tests) and pregnancy tests obtained during treatment and after it are given in pregnancy instructions given in peginterferon alfa and ribavirin.

Use in patients after the failure of previous therapy with direct action antiviral drugs against viral hepatitis C

The safety and efficacy of simeprevir in patients after the failure of previous therapy with simeprevir or other direct-acting antiviral drugs for the treatment of hepatitis C has not been studied.

Use in patients with other genotypes of hepatitis C virus

Currently, there are insufficient clinical data to support the use of the Sovriad drug in patients with hepatitis C genotypes 2, 3, 5 or 6, so the Sovriad drug should not be used in such patients.

Interaction with drugs

The combined use of the drug Sovriad with drugs that have a strong or moderate inducing or inhibitory effect on the isoenzyme CYP3A is not recommended, since this can lead to a significant decrease or increase in the concentration of simeprevir.

Combined use with other antiviral drugs of direct action for the treatment of hepatitis C

Data on the joint use of the drug Sovriad with telaprevir or boceprevir are not available. It is assumed that these inhibitors of the hepatitis C virus protease may exhibit cross-resistance. In this regard, their combined use is not recommended.

Use in combination with peginterferon alfa-2b

In clinical trials, patients receiving simeprevir in combination with peginterferon alfa-2b and ribavirin had slightly lower UVO12 rates, increased viral load and recurrence of viremia more often than in patients treated with simeprevir in combination with peginterferon alpha 2a and ribavirin.

Hepatitis B virus co-infection

The safety and efficacy of simeprevir in the treatment of hepatitis C in patients co-infected with the hepatitis B virus has not been studied.

Organ transplantation

The safety and efficacy of simeprevir in patients after organ transplantation has not been studied.

The combined use of the drug Sovriad with cyclosporine is not recommended, because at the same time concentration of a simeprevir can considerably increase.

Photosensitivity

Photosensitivity reactions (mainly mild or moderate) were observed in patients receiving Sovriad treatment in combination with peginterferon alpha and ribavirin.

It is necessary to use appropriate sun protection during therapy with Sovriad in combination with peginterferon alfa and ribavirin. The use of means to enhance tanning, as well as prolonged exposure to direct sunlight is contraindicated during therapy with Sovriad in combination with peginterferon alpha and ribavirin. In the event of photosensitivity reactions, it is necessary to consider the expediency of discontinuing therapy with Sovriad and to carefully monitor patients until the photosensitivity reactions disappear.

Rash

A rash was observed in patients undergoing Sovriad therapy in combination with peginterferon alfa and ribavirin. The rash most often appeared in the first 4 weeks of therapy, but its appearance is possible at any time during treatment. A severe rash and a rash requiring the discontinuation of Sovriad were also observed. The most common rash was mild or moderate. Patients with mild to moderate rash should be monitored by a doctor for possible progression of the rash, including the development of mucosal lesions (such as lesions of the oral mucosa, conjunctivitis) or systemic manifestations. If the rash becomes severe, the therapy with Sovriad should be canceled. Patients should be carefully monitored until the rash disappears.

Liver dysfunction

The concentration of simeprevir in the blood plasma is significantly increased in patients with severe hepatic dysfunction (Child-Pugh class C). The safety and efficacy of simeprevir has not been studied in patients with moderate to severe hepatitis C liver dysfunction (classes C and B on the Child-Pugh scale), as well as in patients with decompensation. Caution should be exercised in the appointment of the drug Sovriad such patients.

The use of simeprevir in patients with chronic hepatitis C genotype 1a

The rates of SVR therapy with Sovriad in combination with peginterferon alpha and ribavirin were reduced in patients with hepatitis C genotype 1a with NS3 Q80K polymorphism compared with patients without NS3 Q80K polymorphism. In the case of the availability of relevant tests, it is necessary to consider the possibility of determining the polymorphism of Q80K in patients with hepatitis C genotype 1a. In the case of such a determination, the test results should be taken into account when making a decision on the appointment of therapy with Sovriad in combination with peginterferon alfa and ribavirin. It is necessary to consider the possibility of using alternative therapy if the patient has a Q80K polymorphism, as well as if it is impossible to conduct appropriate testing.

Impact on the ability to drive vehicles and mechanisms. Currently, there are unknown any effects of the drug Sovriad on the ability to drive vehicles and mechanisms. Special studies to assess the impact of the drug Sovriad on the ability to drive vehicles and mechanisms was not conducted.

Combination therapy with simeprevir, peginterferon alpha and ribavirin may affect the patient's ability to drive vehicles and mechanisms. Information on the potential effects of peginterferon alpha and ribavirin on the ability to drive vehicles and machinery is given in the relevant instructions for use.

Overdosage

Information on overdose with simeprevir in humans is limited.With a single dose of simeprevir in doses up to 600 mg or with multiple doses in doses up to 400 mg 1 time / day for 5 days in healthy adult volunteers, as well as in a dose of 200 mg 1 time / day for 4 weeks in adult patients with hepatitis This drug is usually well tolerated.

Treatment.

The specific antidote is unknown. In case of overdose, maintenance therapy is recommended (for example, washing the gastrointestinal tract) and monitoring the patient's condition. Simeprevir is characterized by a high degree of binding to plasma proteins, so hemodialysis with a high degree of probability will not lead to a significant elimination of simeprevir.