Arlansa® (Arlansa)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceNarlaprevirNarlaprevir
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  • Arlansa®
    pills inwards 
    R-PHARM, CJSC     Russia
    • Dosage form: & nbsptfilm-covered laths
    Composition:

    1 tablet contains:

    active substance: narlaprevir - 100 mg;

    Excipients: copovidone (Plasdone S-630) - 100.0 mg, microcrystalline cellulose 52.0 mg, sodium lauryl sulfate 15.0 mg, croscarmellose sodium 30.0 mg, silicon colloidal dioxide 1.5 mg, magnesium stearate 1.5 mg,

    film sheath: fall off II yellow (32K92800) - 12.0 mg (lactose monohydrate - 40%, hypromellose, E464 - 28%, titanium dioxide, E171 - 23.1%, triacetin - 8%, iron dye oxide yellow, E172 - 0.88% iron dye oxide red, E172 - 0.02%).

    Description:Prhodium-plated tablets coated with a film coat from almost white to yellow.

    Pharmacotherapeutic group:Antiviral agent
    ATX: & nbsp

    J.05.A.E.   Protease Inhibitors

    Pharmacodynamics:

    Mechanism of action

    Narlaprevir is a potent oral inhibitor NS3 serine protease of hepatitis C virus. Narlaprevir has an inhibitory effect by covalent but reversible binding to the serine active site of the protease of the hepatitis C virus via a ketoamide function. In this way, Narlaprevir inhibits polyprotein processing of the virus and prevents its replication in infected host cells.

    Antiviral activity in cell culture

    The antiviral activity of narlaprevir has been studied in the biochemical analysis of slow protease inhibitors and the hepatitis C virus replicon system, which is a well-studied model of viral replication. The inhibition constant (Ki) narlaprevir for NS3 proteases of the genotype lb is 7 nM. Also narlaprevir is active against genotypes 1a, 2a, 3a and 4 (Ki = 0.7 nM, 3 nM, 7 nM, and 16 nM, respectively). In the bicistronic replicon system of genotype 1b indicators of narlparivir IC50 (half maximal inhibitory concentration) and IC90 (90% inhibitory concentration) are 20 nM and 40 nM, respectively. In the system of the genotype replicon la IC90 narlaprevir is 140 nM. In the presence of 50% human serum IC50 narlaprevir in replicon 1b increases to 720 nM.

    Resistance

    In carrying out biochemical tests and replicon studies, cross resistance to narlaprevir was demonstrated with resistance mutations that occurred when other ketoamide protease inhibitors of the hepatitis C virus were used.

    The activity of narlaprevir moderately decreases with the following major mutations of the virus,associated with resistance to other protease inhibitors of hepatitis C virus: V36M (Ki = 12 nM, IC50 for replicon = 430 nM, IC90 = 940 nM), V170A (Ki = 30 nM, IC50 = 300 nM, IC90 = 900 nM) and T54A (Ki = 40 nM, IC50 = 400 nM, IC90 = 700 nM).

    The activity of narlaprevir is significantly reduced in respect of mutations at loci 155 (R155K) and 156 (A156S/T). The multiplicity of increase in resistance for double mutations is approximately equivalent to the sum of the indices for individual mutations (that is, the dependence is multiplicative rather than additive). Narlaprevir is fully active in relation to mutation D168V.
    Pharmacokinetics:

    Suction

    After narlaprevira destination inwardly postprandial doses of 300 mg - 1500 mg once daily in combination with ritonavir 100 mg once daily in healthy individuals average time to reach maximum concentration (TmOh) of narlaprevir were in the range of 2.5 hours to 4.5 hours. The values ​​of the maximum concentration (CmOh), the minimum concentration (Cmin) and the area under the "concentration-time" curve (AUC), quantitatively reflecting the concentration of narlaprevir in the body, increased proportionately

    increasing the dose of narlaprevir. Narlaprevir it is recommended to be taken with food, since with the appointment of narlaprevir after meals, the average total values AUC and Cmax increased in 1.8 and 2.8 times relative to those obtained in fasting conditions. Wherein there was no apparent delay in achieving TmOh after meals in comparison with dosing in fasting conditions.

    Distribution

    Narlaprevir moderately binds to plasma proteins (from 86.5% to 91.4%) and is characterized by a large volume of distribution, which implies extensive distribution in tissues.

    Metabolism

    Narlaprevir is extensively metabolized by oxidation, reduction, cleavage and N-dealkylation. Mainly the metabolism of narlaprevir and its main metabolite is provided by the cytochrome P450 3A4 isoenzyme (CYP3A4). Under isoenzyme CYP3A4 narlaprevir and its basic inactive metabolite are converted to oxidized metabolites. In this way, narlaprevir is an isoenzyme substrate CYP3A4. Also narlaprevir exhibits weak inhibitory properties with respect to the isoenzyme CYP3A4. When combined with narlaprevir with a potent inhibitor of isoenzyme CYP3A4 ritonavir, an increase in the concentration of narlaprevir is observed due to the optimization of minimal concentrations, which allows for a more convenient treatment regimen - once a day.

    Excretion

    The excretion of narlaprevir was studied in a study with radioactive isotopes, in which healthy volunteers received a dose of 400 mg 14With narlaprevir inside as a monotherapy or in combination with ritonavir. Narlaprevir predominantly excreted through the intestine (by 81.1%), kidney clearance makes a minimum contribution (3.14%) in withdrawal of narlaprevir. The half-life of narlaprevir in healthy volunteers at a dose of 200 mg was 2-7 hours.

    The use of ritonavir reduces clearance and significantly increases the period half-life of narlaprevir.

    Indications:

    Treatment of chronic hepatitis C virus caused by genotype 1 virus in patients over 18 years with compensated liver damage, in combination with ritonavir, peginterferon alfa and ribavirin, who have not previously received antiviral therapy with peginterferon alfa and ribavirin, or in which the previous two-component treatment with peginterferon alfa and ribavirin was ineffective.

    Arlans® can not be used as a monotherapy.

    Contraindications:

    - Corresponding contraindications to the use of ritonavir, peginterferon alfa and ribavirin, since narlaprevir should be used only in combination with these drugs;

    - Hypersensitivity to narlaprevir or to any other component of the drug;

    - Pregnancy or the period of breastfeeding (see section "Application during pregnancy and during breast-feeding");

    - severe neutropenia (neutrophil count <500 cells / mm3);

    - liver failure;

    - the previous treatment of chronic hepatitis C with protease inhibitors of hepatitis C virus (due to the lack of data on the use of Arlans ® in antiviral therapy in patients previously treated with hepatitis C virus protease inhibitors, as well as repeated courses of therapy with the drug Arlansa®);

    - Children under 18 years of age (no safety or efficacy data);

    - Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

    Carefully:

    - Joint reception with drugs that extend the QT interval requires careful monitoring of ECG parameters.

    The administration of multiple therapeutic doses of Arlans® (300 mg / day) in combination with ritonavir (100 mg / day) does not result in a significant lengthening of the adjusted QT interval. When the same Arlans® preparation was given at a dose of 1500 mg, repeatedly exceeding therapeutic, in combination with ritonavir 100 mg once a day for 5 days, the QT interval was prolonged.

    - Neutropenia, anemia.

    Women receiving treatment with Arlans® with ritonavir, peginterferon alfa and ribavirin, as well as female partners of men who receive a combination of these drugs, should be especially careful to prevent pregnancy. During treatment with this combination of drugs, women and men of childbearing age are recommended to use barrier method of contraception (condom and / or diaphragm / cervical cap).

    Since Arlansa® is used only in combination with ritonavir, peginterferon alfa and ribavirin, caution should be taken in all of these drugs.

    Pregnancy and lactation:

    The combination of Arlans® with ritonavir, peginterferon alfa and ribavirin is contraindicated in pregnancy and during breastfeeding.Arlansa in studies in vivo did not demonstrate embryo and fetotoxicity, however, signs of toxicity to the mother's body were abolished. Besides, ribavirin, part of the combined antiviral therapy with Arlans®, has embryo and fetotoxicity and can cause birth defects and fetal death, and peginterferon alfa causes premature termination of pregnancy.

    Women receiving treatment with Arlans®, ritonavir, peginterferon alfa and ribavirin, as well as female partners of men who receive a combination of these drugs, should be especially careful to prevent pregnancy. During therapy, women and men of childbearing age should use the barrier method of contraception (condom and / or diaphragm / cervical cap).
    Dosing and Administration:

    Treatment should be conducted under close monitoring by a physician with sufficient experience in the therapy of chronic hepatitis C.

    Arlans® can not be used as a monotherapy.

    Arlans® should be used as a combination therapy with other antiviral drugs (ritonavir, peginterferon alfa and ribavirin).

    Arlanza® with ritonavir in combination with peginterferon alfa and ribavirin should be applied as follows:

    1-12 weeks - Arlansa® 200 mg + ritonavir 100 mg once a day + peginterferon alfa + ribavirin

    13-24 week - peginterferon alfa + ribavirin

    The total duration of treatment is 24 weeks.

    Arlanza® with ritonavir should be taken while eating at the same time. The choice of the dosage form and regimen for the application of peginterferon alfa and ribavirin should be performed by the attending physician.

    It is recommended to monitor the totalchemical analysis of blood, as well as the level of viral load.

    Abolition of therapy

    Combined treatment is recommended to be completely discontinued in the following cases;

    - With the development of virologic breakthrough (increase in the level of RNA of the virus hepatitis C at> 1 log 10 above the lowest level or detectable levels of hepatitis C virus RNA during treatment after the initial fall below the detection limit).

    - With a serum level of hepatitis C RNA of> 100 IU / ml at the 12th week of treatment, indicating insufficient treatment effectiveness and low probability of achieving a persistent virologic response.

    - At the onset of pregnancy of a patient receiving treatment with Arlans®, ritonavir, peginterferon alfa and ribavirin.

    - With the development of decompensated liver disease (cirrhosis of the liver of class B or C according to the Child-Pugh classification).

    Correction of dose or suspension of therapy

    Reducing the dose of Arlans® and / or ritonavir during therapy is not allowed.

    In case of cancellation of Arlan therapybecause of the development of unwanted reactions or an inadequate virologic response, the resumption of therapy with this drug is not allowed.

    In case of development of undesirable reactions potentially associated with peginterferon alfa or ribavirin and requiring correction of the dose or suspension of therapy with any of these drugs, it is necessary to follow the directions given in the instructions for the use of the respective drug.

    Side effects:

    Below are the undesirable reactions observed during treatment Arlansa® in combination with ritonavir, peginterferon alfa and ribavirin.

    To classify the frequency of side effects, the WHO classification was used: very often (> 1 case for 10 prescriptions), often (> 1 case per 100 prescriptions) and infrequently (<1 case per 100 prescriptions).

    Infectious and parasitic diseases:

    infrequently: pharyngitis, herpesvirus infection.

    Violations of the blood and lymphatic system:

    often: anemia, leukopenia, neutropenia, lymphopenia, thrombocytopenia.

    Immune system disorders:

    infrequently: hypersensitivity.

    Disorders from the endocrine system:

    infrequently: hypothyroidism.

    Disorders from the metabolism and nutrition:

    often: decreased appetite, hyperuricemia;

    infrequently: hypertriglyceridemia.

    Disorders from the psyche:

    infrequently: sleep disorder, insomnia, decreased interest.

    Disturbances from the nervous system:

    often: headache, dysgeusia;

    infrequently: drowsiness, dizziness.

    Disturbances on the part of the organ of sight:

    infrequently: eye pain.

    Heart Disease:

    infrequently: tachycardia.

    Vascular disorders:

    infrequently: arterial hypertension.

    Disturbances from the respiratory system, chest and mediastinal organs:

    often: cough;

    infrequently: tachypnea.

    Disorders from the gastrointestinal tract:

    often: nausea, diarrhea;

    infrequent: pain in the upper abdomen, dry mouth, unusual feces, vomiting, abdominal discomfort, cheilitis, gastroesophageal reflux, bleeding gums, anal itching, anal fissure, proctalgia.

    Disturbance of the liver and bile ducts:

    often: hyperbilirubinemia.

    Disturbances from the skin and subcutaneous tissues:

    often: itching, alopecia, urticaria, rash (Papular, macular);

    infrequently: xeroderma, dry skin, dermatitis, eczema, hyperhidrosis, rash

    Disturbances from the musculoskeletal and connective tissue:

    often: myalgia, arthralgia;

    infrequently: back pain, pain in the limb.

    Disorders from the kidneys and urinary tract:

    infrequently: hemaglobinuria, proteinuria.

    Violations of the genitals and mammary gland:

    infrequently: bartholinitis.

    General disorders and disorders at the site of administration:

    very often: asthenia;

    often: flu-like condition, chills, pyrexia, fatigue, pain;

    infrequently: hyperthermia.

    Laboratory and instrumental data:

    very often: a decrease in hemoglobin;

    often: weight loss, increased body temperature, increased activity of gamma-glutamyl transferase, a decrease in the number of platelets;

    infrequently: a decrease in the number of neutrophils, a decrease in the number of leukocytes, an increase in activity of aspartate aminotransferase, an increase in the activity of alkaline phosphatase in the blood, an increase in blood pressure, an increase in the level of triglycerides in the blood.

    Overdose:

    The maximum concentration of narlaprevir in plasma was determined with the use of narlaprevir in a dose of 1500 mg once a day in combination with ritonavir at a dose of 100 mg once a day for 5 days.

    In this case, the toxicity of the drug was not observed.

    Data on the overdose of Arlans® are absent. It is necessary to carry out general preventive measures and careful monitoring of vital functions of the body. If the patient is conscious, vomiting should be induced, it is possible to use activated charcoal inside.

    Interaction:

    Narlaprevir is a substrate and a weak inhibitor of the CYP3A4 isoenzyme, in addition, ritonavir, a mandatory component of therapy with narlaprevir, is a potent inhibitor of the isoenzyme CYP3A4, so when used with drugs that are substrates, inhibitors and / or inducers isoenzyme CYP3A4, it is possible to change the concentration of both narlaprevir and ritonavir, as well as concomitant medications.

    It has been shown that taking Arlans® in therapeutic doses in combination with ritonavir does not lead to an elongation of the adjusted QT interval (QTcF).However, in doses that are many times higher than the therapeutic dose. Arlanza® in combination with ritonavir can prolong the QTcF interval.

    Therefore, the Arlans® drug should be used with caution in patients taking concomitant drugs that extend the QT interval.

    Because Arlansa® is used in combination with ritonavir, peginterferon alfa and ribavirin, possible inter-drug interactions of concomitant therapy with each of the Arlanza® therapy components should be considered.

    Special instructions:

    Do not use the drug Arlans® as a monotherapy (sections "Indications", "Method of administration and dose"). Arlans® should be given only in combination with ritonavir, peginterferon alfa and ribavirin. Therefore, before starting therapy, you should read the instructions for the use of ritonavir, peginterferon alfa and ribavirin.

    Specific guidelines for peginterferon alfa and ribavirin should also be taken into account during combined therapy with Arlans®.

    During the whole period of treatment it is recommended to monitor the parameters of the general and biochemical blood test, as well as the level of the viral load.

    Reduction of hemoglobin below the norm was noted at the 8-12 week of treatment in a larger proportion of patients who received Arlans® and ritonavir in combination with peginterferon alfa and ribavirin, in comparison with patients receiving only peginterferon alfa and ribavirin. At the beginning of therapy with Arlans® and ritonavir in combination with peginterferon alfa and ribavirin, a decrease in the absolute number of leukocytes was lower than normal, compared with patients receiving only peginterferon alfa and ribavirin. However, after the 4th week, treatment groups did not differ in this indicator.

    In case of development of undesirable reactions potentially associated with peginterferon alfa or ribavirin and requiring correction of the dose or suspension of therapy with any of these drugs, it is necessary to follow the directions given in the instructions for the use of the respective drug.

    To date, there is no data on the use of narl-retravir in patients with co-infection with viral hepatitis B and C. Nevertheless, it should be borne in mind that the elimination of the hepatitis C virus (HCV) during treatment can lead to an increase in the replicative activity of the hepatitis B virus HBV) and the transition of hepatitis B into the active phase.Prior to the initiation of the combined therapy for chronic hepatitis C with Arlans®, the patient should be examined for chronic, latent or transmitted HBV infection with the definition of serological markers: HBsAg, anti-HBc, anti-IIBs and HBV DNA. In patients with co-infection with HCV / HBV, the HBV viral load should be monitored prior to the initiation of a combination therapy with Arlans®, during and after treatment.

    Dose skip

    If the delay in taking narlaprevir is less than 12 hours, the missed dose of narl-retravir should be taken as soon as possible with food and the next day to resume the usual dosing regimen.

    If the delay in taking ritonavir is less than 12 hours, then the missed dose of ritonavir should be taken as soon as possible and the next day to resume the usual dosing regimen.

    If the patient forgot to accept and narlaprevir and ritonavir, and the delay in their admission was 12 hours or more, then missed doses of narlaprevir and ritonavir should not be taken on that day; the next day narlaprevir and ritonavir should be taken at the usual time.

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

    At the present time, no effects of narlaprevir have been identified that affect the ability to drive vehicles and mechanisms. There has been no special study of the impact of narl-retravir on the ability to drive vehicles and mechanisms.

    Because of the possibility of fatigue or drowsiness on the background of combined therapy with Arlans®, ritonavir. peginterferon alfa and ribavirin is not recommended to drive and / or complex equipment.

    Form release / dosage:

    Tablets, film-coated, 100 mg.

    Packaging:

    For the preparation packaged by Khovion PharmaScience, SA, Portugal, packaging - R-Pharm, Russia

    36 tablets in bottles of white matte high-density polyethylene (HDPE) containing two bags with a desiccant of 1 g. The vials are closed with polypropylene corking elements of two elements with protection against opening by children. Each bottle is glued self-adhesive label. Each bottle together with the instruction for use is placed in a pack of cardboard box.

    For the preparation, packing and packing of which is carried out by JSC R-Pharm, Russia

    For 28, 36 or 56 tablets in polyethylene bottles. The vials are closed with a cap made of polypropylene with a desiccant and with an autopsy control. Free space in the vial is filled with cotton wool by medical hygroscopic or sterile cotton ball medical. Each label is labeled with label paper or writing paper, or a self-adhesive label. Each bottle together with the instruction for use is placed in a pack of cardboard box.

    Storage conditions:

    In the dark place at a temperature of no higher than 25 FROM.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after expiry date.

    Terms of leave from pharmacies:On prescription
    Obsolete name of the trade product: & nbspNarlaprevir
    Date renamed: & nbsp24.10.2016
    Registration number:LP-003622
    Date of registration:12.05.2016 / 24.10.2016
    Expiration Date:12.05.2021
    The owner of the registration certificate:R-PHARM, CJSC R-PHARM, CJSC Russia
    Manufacturer: & nbsp
    Representation: & nbspR-PHARM, JSC R-PHARM, JSC Russia
    Information update date: & nbsp19.03.2018
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