Nerventra (Nerventra)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceLahinimodLahinimod
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  • Nerventra
    capsules inwards 
    Teva Pharmaceutical Enterprises Co., Ltd.     Israel
    • Dosage form: & nbspcapsules
    Composition:

    1 capsule contains: active substance lachinimodium sodium (in terms of lachinimode) 0.64 mg (0.60 mg); Excipients: mannitol 302.16 mg, meglumine 10.00 mg, sodium stearyl fumarate 3.20 mg.

    Gelatine capsule: titanium dioxide (E 171 2.0%, gelatin to 100%.

    The composition of black ink used to inscribe the capsule: shellac 59.42%, iron dye oxide black (E 172 24.65%, butanol 9.75%, water 3.249%, propylene glycol 1.3%, ethanol 1.08%, isopropanol 0.55%, ammonia water 0.001%.

    Description:

    Hard gelatin capsules number 1, almost white, opaque. Black ink on the capsule cover is inscribed "LAQ", on the body - "0.6 mg".

    The contents of the capsules are a granular powder of white or almost white color.

    Pharmacotherapeutic group:Immunomodulating agent
    ATX: & nbsp

    N.07.X.X   Other drugs for the treatment of diseases of the nervous system

    N.07.X.X.10   Lahinimod

    Pharmacodynamics:

    Lachinimod is an immunomodulating drug that has a protective effect on the central nervous system (CNS).

    In experimental studies on animals Lachinimod has demonstrated efficacy in various types of autoimmune encephalomyelitis and other inflammatory / autoimmune diseases.Despite the fact that the mechanism of action of lachinimod is not fully understood, several directions of its activity have been revealed.

    In particular, Lachinimod has a modulating effect on the immune system, it penetrates the blood-brain barrier and has a direct effect on the parenchymal cells of the central nervous system, without having a common immunosuppressive effect. In experimental models, this was manifested in a decrease in demyelination and a decrease in the number of axons.

    In clinical trials using lachinimod at a dose of 0.6 mg / day in the treatment of patients with relapsing-remitting multiple sclerosis, the efficacy of lachinimod was established, which was expressed in decreasing the activity of the disease, reducing atrophic processes in the brain, reducing the risk of recurrence of the disease and the number relapses, confirmed by the method of magnetic resonance therapy (MRI) with contrasting focal lesions with gadolinium, as well as slowing the progression of inv patients.

    Pharmacokinetics:

    The pharmacokinetic profile of lachinimod is characterized by high bioavailability, a high degree of binding to plasma proteins (more than 98%),low clearance (0.09 l / h), low volume distribution (about 10 liters), a long final half-life (about 80 hours). The pharmacokinetics of lachinimod is linear in the application at therapeutic doses of 0.05 to 0.24 mg per day. When applied once a day Lachinimod reaches equilibrium concentrations within 14 days. Concentration fluctuations during application once a day are insignificant (about 30%).

    Absorption

    When administered, the absolute bioavailability of lachinimod is about 90%. When taken on an empty stomach, absorption is rapid, and the maximum concentration in the plasma (CmOh) is reached within 1 hour after receiving Lachinimod. With the simultaneous intake of fatty high-calorie food, the time to reach the maximum concentration (TmOh) increases by 5 hours, CmOh - by 30%, the area under the curve "concentration-time" - by 10%.

    Distribution

    The equilibrium volume of the lachinimod distribution is independent of the dose and is about 10 liters. Lahinimod reversibly binds to blood plasma proteins, mainly with serum albumin. Binding to plasma proteins - 98%.

    Metabolism

    In clinical trials, it has been established that the systemic clearance of Lachinimoda is low, about 0.09 l / h. As Lachinimod does not bind to erythrocytes, its clearance when administered is 0.16 l / h (plasma clearance / 0.6), which corresponds to 0.2% of the hepatic blood flow.

    The main ways of metabolizing lachinimod are hydroxylation of 6-, 8-quinoline, hydroxylation of aniline and N- demethylation of quinoline ring. The oxidation of the lachinimod occurs mainly with the participation of the isoenzyme system CYP3A4. Metabolites, whose concentration is less than 1% after the administration of lachinimod, are not pharmacologically active.

    Excretion

    Lachinimod is excreted by the kidneys and bile mainly in the form of metabolites. Clinical studies have established that approximately 79% of the dose is taken within 14 days by kidneys (51%) and intestines (28%). About 3.5% of the Lachinimod is excreted unchanged. The half-life is about 80 hours.

    Pharmacokinetics in special clinical cases

    In patients with moderate renal insufficiency (creatinine clearance (CK) 30 - 59 ml / min / 1.73 m2) with the use of lachinimod in a dose of 0.6 mg CmOh did not differ from the values ​​of healthy volunteers, AUC increased by 1.4 times. Pharmacokinetics of lachinimod in patients with severe renal insufficiency (CC less than 30 ml / min / 1.73 m2) has not been studied, therefore, the use of lachinimod in this group of patients is not recommended.

    In patients with mild to moderate hepatic insufficiency (class A and B on the Child-Pugh scale) with lachinimod at a dose of 0.6 mg CmOh did not differ from the values ​​of healthy volunteers, AUC increased by 1.2 and 2.3 times, respectively. Pharmacokinetics in patients with severe hepatic insufficiency (class C on the Child-Pugh scale) has not been studied, therefore, the use of lachinimod in this group of patients is not recommended.

    Indications:

    Recurrent-remitting multiple sclerosis.

    Contraindications:

    Hypersensitivity to Lachynimoda or other components of the drug; severe hepatic insufficiency (class C on the Child-Pugh scale); severe renal failure (CC less than 30 ml / min / 1.73 m2); simultaneous application with isoenzyme inducers CYP3A4 (carbamazepine, efavirenz, phenobarbital, phenytoin, rifabutin, rifampicin); pregnancy; the period of breastfeeding; children's age till 18 years.

    Carefully:

    Patients of advanced age; simultaneous application with powerful (itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, erythromycin, telithromycin) or moderate (fluconazole, diltiazem, verapamil) inhibitors of isoenzyme CYP3A4; mild and moderate hepatic insufficiency, mild and moderate renal failure.

    Pregnancy and lactation:

    The drug Nerventra is contraindicated for use in pregnancy and during breastfeeding (insufficient data on safety and efficacy). Women of childbearing age must use reliable methods of contraception both during therapy with Nerventra and for 4 weeks after its completion.

    Dosing and Administration:

    Inside. Once a day, regardless of food intake. The capsule should be filled with a sufficient amount of liquid.

    In case of missed dose, it should be taken immediately and continue therapy on the same schedule from the next day.

    Patients with severe hepatic insufficiency use of the drug Nerventra is not recommended. In patients with mild and moderate hepatic insufficiency, dose adjustment is not required. Care should be taken when using the drug Nerventra in patients with mild and moderate hepatic insufficiency.

    Patients with severe renal insufficiency (SC less than 30 ml / min / 1.73 m2) use of the drug Nerventra is not recommended.In patients with mild and moderate renal insufficiency (CC greater than 30 ml / min / 1.73 m2) dose adjustment is not required. Care should be taken when using the drug Nerventra in patients with mild and moderate renal failure.

    Patients old age safety studies and efficacy have not been carried out, so use Nerventra in this group of patients should be cautious.

    Patients children's age up to 18 years of age, use of the drug Nerventra is not recommended (insufficient data on safety and efficacy).

    Side effects:

    The most frequent adverse reactions with Nerventra were headache (19.1%), back pain / neck (14.6%), abdominal pain (10.3%). Back pain / neck, as well as increased activity of "liver" transaminases (4.7%) were identified as safety markers.

    The presented undesirable reactions were revealed during clinical studies of the III phase. The frequency of unwanted reactions is indicated in brackets in comparison with placebo.

    The frequency of adverse reactions is classified according to the recommendations of the World Health Organization: very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; rarely - not less than 0,01%,but less than 0.1%; very rarely (including isolated cases) - less than 0.01%.

    From the side of the blood and lymphatic system: often anemia.

    From the central nervous system: very often - headache; often - anxiety.

    From the digestive tract: very often - abdominal pain; often - constipation, lesions of teeth and gums, bloating; infrequent - dryness of the oral mucosa.

    From the liver and bile ducts: often - an increase in the activity of "hepatic" transaminases (alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), aspartate aminotransferase (ACT)).

    From the respiratory system: often - cough; infrequently - bronchospasm.

    From the skin and subcutaneous tissues: often - infectious skin lesions.

    From the side of the musculoskeletal and connective tissue: very often - pain in the back / neck; often - arthralgia; infrequently bursitis.

    From the side of the kidneys and urinary tract: often - urinary tract infections; infrequent - sudden urge to urinate.

    On the part of the reproductive system and mammary glands: often - a violation of the menstrual cycle, uterine bleeding.

    Other: often - peripheral edema, increased fibrinogen concentration, increased activity of amylase in serum.

    In placebo-controlled studies, back pain / neck pain was noted in 14.6% of patients treated with Nerventra with a dose of 0.6 mg and 8.3% in patients receiving placebo. Severe pain was noted in 0.7% of patients who received the drug Nerventra, and in 0.5% of patients who received placebo.

    In three cases, back pain was described as a serious adverse reaction with the use of the drug Nerventra. The condition of the two patients improved after symptomatic therapy, the third patient required fixation therapy at the level L5-S1. All patients continued to participate in the study.

    The Budda-Chiari syndrome was recorded once in a patient with a coagulation factor V mutation.

    In clinical trials, an increase in the activity of "liver" transaminases was noted in 9.3% of patients who received therapy with Nerventra, compared with 5.3% in the control group.

    A clinically significant increase in the activity of "liver" enzymes (3 times higher than the upper limit of the norm) was noted in 4.7% of patients who received therapy with Nerventra, more often in men. In 74% of patients the activity of "liver" enzymes decreased independently, despite the continued therapy.There was no concomitant increase in the concentration of total or direct bilirubin, there were no signs of hepatic insufficiency.

    Despite slight deviations in hemoglobin from normal, there is no direct correlation between the decrease in hemoglobin concentration in patients taking the drug Nerventra.

    Overdose:

    In the course of clinical studies, there were no cases of overdose with Nerventra. When taking a dose exceeding the recommended dose 4 times (2.4 mg per day), the safety profile remained similar to the safety profile of patients taking the recommended dose.

    Treatment: symptomatic therapy.

    Interaction:

    Lachinimod metabolism is carried out mainly with the participation of isoenzyme CYP3A4.

    Interaction with inhibitors of isoenzyme CYP3A4

    ■ With simultaneous use with ketoconazole at a dose of 400 mg per day for 28 days in healthy volunteers AUC lachinimoda increased 3.1 times without changing the index FROMmOh.

    ■ With simultaneous application with fluconazole at a dose of 200 mg per day for 21 days in healthy volunteers AUC lachinimoda increased by 2.5 times without changing the indicator FROMmOh.

    ■ When used simultaneously with cimetidine at a dose of 1600 mg per day for 21 days in healthy volunteers AUC and CmOh did not change.

    With simultaneous application of Lachinimoda and powerful (for example, itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, erythromycin, telithromycin) or moderate (for example, fluconazole, diltiazem, verapamil) inhibitors of isoenzyme CYP3A4 may rise AUC Lachinimoda. Avoid long (more than 1 month) use of such combinations.

    Interaction with inductance inducers CYP3A4

    When used simultaneously with rifampicin at a dose of 600 mg per day for 21 days in healthy volunteers AUC Lachinimoda decreased 5 times without changing the CmOh.

    With simultaneous application of Lachinimod with isoenzyme inducers CYP3A4 (eg, carbamazepine, efavirenz, phenobarbital, phenytoin, rifabutin, rifampicin), the concentration of lachinimod can decrease and, consequently, its effectiveness, therefore, the use of this combination is not recommended.

    Interaction with other medicinal products

    Substrates of the isoenzyme CYP1A2

    With the simultaneous use of caffeine with repeated doses of lachinimod (0.6 mg) in healthy volunteers AUC and CmOh caffeine decreased by 5 and 2 times, respectively. Lahinimod is a powerful inducer of isoenzyme CYP1A2 and can lead to a marked decrease in the concentration in the blood plasma of drugs that are metabolized by isoenzyme CYP1A2. With the simultaneous use of Lachinimoda with isoenzyme substrates CYP1A2 with a narrow therapeutic index (for example, ropinirole, clozapine, methadone, theophylline) it is necessary to regulate the dose of isoenzyme substrates CYP1A2 and monitor the clinical condition of the patient at the beginning of the application or when removing the lachinimod. At the beginning of the application of lachinimod in this combination, it is necessary to increase the dose of isoenzyme substrates CYP1A2 in order to maintain their effectiveness. If lachinimod is withdrawn, the dose of isoenzyme substrates CYP1A2 should be reduced to prevent an overdose that can lead to the development of serious adverse events on the part of isozyme substrates CYP1A2.

    Substrates of the isoenzyme CYP3A4

    With the simultaneous use of repeated doses of lachinimod (0.6mg) with midazolam in healthy volunteers, there was an increase AUC Midazolam approximately 1.5 times unchanged CmOh midazolam. Lahinimod is a weak isoenzyme inhibitor CYP3A4, that should be taken into account when used simultaneously with drugs with a narrow therapeutic index.

    Special instructions:

    The use of the drug Nerventra may be accompanied by a slight, asymptomatic increase in the activity of "liver" transaminases (ALT, GGT, ACT), which can usually occur within the first 6 months of treatment. Return to baseline activity level usually occurs within 3 months with continued treatment with the drug.

    In patients with severe hepatic insufficiency (grade C on the Child-Pugh scale), the use of the Nerventra drug should be avoided.

    In patients with severe renal insufficiency (CC less than 30 ml / min / 1.73 m2) use of the drug Nerventra is not recommended.

    The drug Nerventra is a powerful inducer of isoenzyme CYP1A2 systems of cytochrome P450 and when used simultaneously with drugs metabolized by isoenzyme CYP1A2, can lead to a significant decrease in their concentration in the blood plasma.

    With simultaneous application of the drug Nerventra with substrates isoenzyme CYP1A2 with a narrow therapeutic index may require dose adjustment and careful clinical observation of the patient at the beginning of treatment with the drug Nerventra or when it is canceled. At the beginning of treatment with the drug Nerventra, the dose of the substrate isoenzyme CYP1A2, may need to be increased to maintain its effectiveness. With the cancellation of the drug Nerventra, the dose of the substrate isoenzyme CYP1A2, may need to be reduced to prevent overdose and, as consequence, development of serious adverse events (see the section "Interaction with other medicinal products").

    With the simultaneous use of the drug Nerventra and powerful or moderate inhibitors of isoenzyme CYP3A4 may increase AUC Lachinimoda. It is necessary to avoid long (more than 1 month) simultaneous application of the drug Nerventra and powerful or moderate inhibitors of isoenzyme CYP3A4 (see the section "Interaction with other medicinal products").

    With simultaneous application of Lachinimod with isoenzyme inducers CYP3A4 the concentration of lachinimod in the blood plasma and its effectiveness may decrease. It is not recommended simultaneous application of Lachinimod with isoenzyme inducers CYP3A4 (see the section "Interaction with other medicinal products").

    In the early periods after the start of treatment with Nerventra, an asymptomatic decrease in the concentration of hemoglobin, usually of a transient nature, that does not require the cessation of the use of the Nerventra drug or the use of antianemic therapy, can be noted.

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

    Special studies were not conducted. However, in the case of development of undesirable reactions from the central nervous system, care should be taken when performing actions requiring increased concentration of attention and rapidity psychomotor reactions.

    Form release / dosage:

    Capsules 0.6 mg.

    Packaging:

    7 capsules in a blister of aluminum foil. 1.4 or 16 blisters together with instructions for use in a cardboard bundle.

    Storage conditions:

    Store at a temperature of no higher than 30 ° C in a dark place. Keep out of the reach of children.

    Shelf life:

    2 years. Do not use after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002125
    Date of registration:05.07.2013 / 13.01.2014
    The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel
    Manufacturer: & nbsp
    Representation: & nbspTeva Teva Israel
    Information update date: & nbsp30.03.2016
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