Erivage ™ (Erivedge ™)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceWismodegibWismodegib
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  • Erivage ™
    capsules inwards 
    Hoffmann-La Roche Ltd.     Switzerland
    • Dosage form: & nbsp

    Capsules

    Composition:
    1 capsule contains:
    active substance: vismodegib - 150 mg;
    Excipients: cellulose microcrystalline - 87.3 mg, lactose monohydrate - 71.5 mg, sodium lauryl sulfate - 7.0 mg, povidone K29 / 32 - 10.5 mg, sodium carboxymethyl starch - 17.5 mg, talc - 3.5 mg, magnesium stearate - 1.7 mg; shell capsules: 71-81 mg (body - iron dye red oxide (E172), titanium dioxide (E171), gelatin; cap - iron dye oxide black (E172), titanium dioxide (E171), gelatin);
    ink for applying the inscription on the capsule: shellac, iron dye oxide black (E172).
    Description:Hard gelatin capsules number 1, the lid is gray, opaque, the case is light pink in color, opaque; on the cap the inscription "VISMO" is black, on the body there is the inscription "150mg" of black color. The contents of the capsules are a fine powder of white or almost white color.
    Pharmacotherapeutic group:Antitumor agent
    ATX: & nbsp

    L.01.X.X.43   Wismodegib

    Pharmacodynamics:
    Mechanism of action
    Vismodehib is a low molecular weight oral inhibitor of the Hedgehog signaling pathway. Activation of the Hedgehog signaling pathway through the SMO protein (Smoothened trans¬ membrane protein) leads to the activation and intra-nuclear localization of GLI transcription factors (glioma-associated oncogene, an oncogene associated with glioma) and the induction of the target genes of the Hedgehog signaling pathway.Many of these genes are involved in proliferation, cell survival and differentiation. Wismodegib It binds to SMO transmembrane protein and prevents the transmission of sig¬nala Hedgehog pathway.

    Pharmacokinetics:
    Suction
    Vismodegib - a substance with high permeability and low water solubility (class 2 according to the biopharmaceutical classification system (BCS)). Absolute bioavailability of vismodegra after one dose is 31.8% (coefficient of variation 14.5%). We saturate absorption process, as evidenced by the lack of a dose proportional increase in drug exposure following a single dose Vismodegib at a dose of 270 mg and a dose of 540 mg. In clinically relevant circumstances (state of equilibrium) vismodegib pharmacokinetic parameters are not changed under the influence of food. In this way, vismodegib can be taken regardless of food intake.
    Distribution
    The volume of the distribution of vismodex is from 16.4 to 26.6 liters. Wismodegib in clinically significant concentrations has a high degree of connection with human plasma proteins (97%) in vitro. Wismodegib binds both to plasma albumin and to alpha-1-acid glycoprotein.The binding process with the alpha1-acid glycoprotein in vitro is saturated in clinically significant concentrations. The binding to plasma proteins in ex vivo patients is> 99%. Vismodegib concentration largely correlates with the concentration of alpha-1-acid glycoprotein in a plasma concentration change alpha 1 acid glycoprotein, and total number Vismodegib plasma occur in parallel, and unbound plasma concentrations Vismodegib invariably low.
    Metabolism
    Wismodegib is slowly excreted by biotransformation, as well as excretion of unchanged drug.
    In the plasma vismodegib prevails unchanged, its concentration is more than 98% of all circulating components (vismodegib in unchanged form and its metabolites).
    The ways of metabolism of vismodegrabia in the human body include oxidation, glucuronization and to a minor degree the cleavage of the pyridine ring. The two most common metabolites of the oxidative process found in stool are formed in vitro with the participation of recombinant isoenzymes of cytochrome P450 (CYP) 2C9 and CYP3A4 / 5.
    Excretion
    After oral administration of a single dose of vismodegrab, the following pharmacokinetic profile is observed: the concentration of vismodegrab in the blood plasma is maintained at a constant level, and the calculated final half-life (T½) is 12 days.
    With prolonged intake of vismodegrabine once a day, its pharmacokinetics, apparently, is nonlinear. When one dose is taken, equilibrium concentrations are reached in patients faster (usually for about 7 days of continuous daily administration of the drug) than theoretically expected, given T½. In this case, the cumulation of the drug is lower than expected. It is estimated that with continuous daily intake of T½ vismodegraba in the equilibrium state is 4 days.
    After oral administration of the drug with a radioactive label vismodegib is absorbed and slowly excreted both by biotransformation and unchanged, with 82% of the administered dose being determined in the feces and 4.4% in the urine. Wismodegib and the associated metabolic products are derived mainly from bile.
    Pharmacokinetics in specific patient groups
    Patients of childhood and adolescents
    Data on the pharmacokinetics in children and adolescents are absent.
    Elderly patients
    There are limited data on the pharmacokinetics in elderly patients. Data from the population analysis of pharmacokinetic parameters allow
    suggest that age does not have a clinically significant effect on the equilibrium concentration of vismodegra.
    Patients with impaired renal function
    The drug is excreted by the kidneys in small amounts. Based on the population analysis of pharmacokinetic parameters, the kidney function (creatinine clearance) does not affect the pharmacokinetics of the vismodex. In this regard, it is not expected to affect the exposure of vismodegra function of kidneys of mild and moderate severity. There is insufficient data on patients with severe renal dysfunction.
    Patients with impaired hepatic function
    Based on the population analysis of pharmacokinetic parameters, the function of the liver (activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), concentration of total protein or total bilirubin) does not affect the pharmacokinetics of vismodex.According to limited data, the exposure of vismodegra does not increase in patients with mild, moderate and severe liver dysfunction.
    Floor
    Based on the population analysis of pharmacokinetic parameters, sex does not affect the pharmacokinetics of vismodex.
    Race
    Data on pharmacokinetics in patients not belonging to the Europoid race are limited.

    Indications:

    Metastatic or locally advanced basal cell carcinoma in adults:

    • after relapse after surgical treatment;
    • if inexpediency of surgical treatment or radiation therapy.
    Contraindications:

    Hypersensitivity to vismodegib or any other component of the drug.

    Pregnancy and the period of breastfeeding.

    Age to 18 years.

    Severe renal impairment (creatinine clearance <30 mL / min).

    Simultaneous use with preparations containing St. John's Wort.

    Carefully:
    Patients with rare hereditary diseases, such as intolerance to g-lactose, deficiency of lactase or glucose-galactose malabsorption.
    Violations of liver function from moderate to severe to severe forms (score ≥7 on the Child-Pugh scale).

    Pregnancy and lactation:
    Pregnancy
    The drug Erivestjtm is contraindicated during pregnancy in connection with embryotoxic action. Preclinical studies have shown that inhibitors of the Hedgehog signaling pathway, such as vismodegib, are embryotoxic and / or teratogenic in various animal species and can cause severe developmental defects, such as cranio-fascial anomalies, defects in midline structures, limb defects.
    In case of pregnancy or absence of menstruation. In the case of pregnancy, the absence of menstruation, or if a possible pregnancy is suspected, the patient should immediately inform the doctor in charge of this.
    Contraception in men and women
    Women of reproductive age should use 2 recommended methods of contraception (one highly effective contraceptive method + barrier method) during the treatment period and within 24 months after the completion of treatment with Erivage ™, as well as in the absence of menstruation or their irregularity.
    Male Patients
    Wismodegib penetrates into the seminal fluid. To prevent the potential effect of vismodegra on the fetus,male patients (even after a vasectomy) should always use a condom (if possible with a spermicidal agent) during intercourse during the treatment with the Erivage ™ drug and within 2 months after the last drug intake.
    Recommended highly effective methods of contraception (taking into account medical feasibility):
    - combined hormonal contraceptives;
    - subcutaneous hormonal implants;
    - hormonal patches;
    - hormonal contraceptives (levonorgestrel-releasing intrauterine system, depot-medroxyprogesterone acetate);
    - tubal sterilization, vasectomy;
    - intrauterine device (IUD).
    Recommended methods of barrier contraception:
    - condom (if possible with a spermicidal agent);
    - diaphragm (if possible with a spermicidal agent).
    Breastfeeding period
    The drug Erivage ™ is contraindicated in the period of breastfeeding in connection with the possibility of causing serious malformations in children. Women should abstain from breastfeeding during therapy with Erivage ™ and within 24 months after their last intake.
    Fertility
    Special studies to study the possible adverse effects of the drug Erivage ™ on fertility have not been conducted. However, the data obtained in animal studies indicate that fertility in females and males can be irreversibly disrupted as a result of therapy with Erivage ™. In addition, in women of reproductive age, amenorrhea was observed in clinical trials.
    Due to the possibility of the development of irreversible loss of fertility as a result of treatment with vismodegib, patients should be given a recommendation on the preservation of sperm and eggs before starting treatment with the drug Erivage ™.

    Dosing and Administration:

    The drug Erivage ™ should be prescribed and administered only under the supervision of a specialist with sufficient experience and knowledge in the field of treatment of this nosology.

    Standard dosing regimen

    Inside for 150 mg, once a day, regardless of food intake.

    Capsule should be swallowed whole, washed down with water.

    It is impossible to open the capsule!

    If evidence of disease progression or development of unacceptable toxicity appears, therapy with Erivage ™ should be discontinued.

    Skipping the next dose

    If Erivage ™ was missed, then you should resume it at the usual time; Do not take the missed dose or increase it.

    Dosing in special cases

    Elderly patients

    Dose adjustments in patients aged ≥65 years is not required.

    Patients of childhood and adolescents

    The safety and efficacy of Erivage ™ in children and adolescents has not been established. Patients of childhood and adolescents should not take the drug Erivage ™.

    Patients with impaired renal function

    The drug is excreted by the kidneys in small amounts. The safety and efficacy of Erivage ™ for patients with impaired renal function has not been studied. According to the population pharmacokinetic analysis, violations of the kidneys of mild and moderate severity do not affect the exposure of vismodegra. There is insufficient data on patients with severe renal dysfunction.

    Patients with impaired hepatic function

    The safety and efficacy of Erivage ™ for patients with impaired liver function has not been studied. According to limited data in patients with impaired liver function, the exposure of vismodegra does not increase,However, in patients with impaired liver function of moderate and severe degree, careful monitoring is required to determine whether adverse reactions occur.

    Side effects:
    The most common ≥30% of patients), unwanted reactions were muscle spasms, alopecia, dysgeusia, weight loss, fatigue and nausea.
    To describe the frequency of undesired reactions, the following classification is used: very often (≥10%), often (≥1% and <10%), infrequently (≥0.1% and <1%), rarely (≥0.01% and <0.1%), very rarely (<0.01%).
    In general, in patients with metastatic and locally advanced basal cell carcinoma, the safety profile was not different and is described below.
    Metabolic disorders: very often - a decrease in appetite; often - dehydration.
    Impaired nervous system: very often - dysgeusia (distortion of taste perception), agesia; often - hypogeous.
    Disturbances from the gastrointestinal tract: very often - nausea, diarrhea, constipation, vomiting; often - abdominal pain, pain in the upper abdomen, dyspepsia.
    Disturbances from the skin and subcutaneous tissues: ooften is alopecia; often - the loss of eyebrows and eyelashes, a violation of hair growth, rash, itching.
    Disturbances from the osteomuscular and connective tissue: very often - muscle spasms; often - arthralgia, musculoskeletal pain, pain in the extremities, back pain, chest pain, myalgia, pain in the side.

    On the part of the reproductive system: very often - amenorrhea (observed in 3 of 10 patients who are in the pre-menopausal period).

    Laboratory and instrumental data: often - hypokalemia, hyponatremia and azotemia (3 degrees of severity according to the criteria of toxicity according to the scale of the National Cancer Institute (NCI- СТСАЕ) version 3.0), violations of laboratory parameters of liver function (such as increased activity of "liver" transaminases, alkaline phosphatase, gamma-glutamyltransferase and increased bilirubin concentration in the blood) *.

    * The frequency of individual unwanted reactions may differ from the frequency category "often".

    Other: very often - increased fatigue, weight loss; often - weakness, pain.

    Overdose:

    With the use of Erivage ™ in a dose 3.6 times higher than the recommended daily dose (150 mg), there was no increase in the concentration of the drug in the plasma or increased toxicity.

    Interaction:
    The effect of concomitant medications on vismodegib
    Drugs that alter acidity (pH) in the upper gastrointestinal tract (eg, proton pump inhibitors, H2-histamine receptor blockers, or antacids) can alter the solubility of the vismodegrain and reduce its bioavailability. However, special clinical studies to study the effect of drugs that alter pH in the stomach have not been carried out on the systemic exposure of vismodegra. It is unlikely that an increase in the dose of vismodegrabine when taken with such drugs will compensate for a decrease in its exposure. With the simultaneous use of vismodegraba with proton pump inhibitors, H2-histamine receptor blockers, or antacids, systemic exposure of vismodegra can decrease; The effect on the efficacy of vismodex is unknown. A similar effect can also be observed in patients with Ahlogridia.
    The results of in vitro studies indicate that vismodegib is a substrate of the efflux transporter of P-glycoprotein (P-gp) and isoenzymes CYP2C9 and CYP3A4. Systemic exposure and frequency of undesirable phenomena of vismodegrab can increase with simultaneous use with drugs that can inhibit P-gp (for example, clarithromycin, erythromycin, azithromycin, verapamil, ciclosporin), isoenzymes of CYP2C9 (amiodarone, fluconazole) and CYP3A4 (boceprevir, conivaptan, indinavir, intraconazole, ketoconazole, lopinavir / ritonavir, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole). Exposure of vismodegra can decrease with its simultaneous use with inducers CYP3A4 (rifampicin, carbamazepine, phenytoin, preparations containing St. John's wort pitted); The effect on the efficacy of vismodex is unknown.
    The influence of vismodegra on concomitant medications. Systemic exposure of rosiglitazone (substrate of the isoenzyme CYP2C8) or oral contraceptives (ethinyl estradiol and norethisterone) does not change when used together with vismodegib in cancer patients.
    According to in vitro studies vismodegib is potentially capable of inhibiting BCRP (a breast cancer resistance protein, a protein of resistance to breast cancer).

    Special instructions:
    Death of an embryo or fetus or severe congenital malformations
    The drug Erivage ™ when taken by pregnant women can cause the death of an embryo or fetus, as well as severe congenital malformations.
    Acceptance of the drug Erivage ™ is contraindicated during pregnancy.
    According to the company developed by F. Hoffmann-La Roche Ltd.Pregnancy Preventative Program with Erivage ™ woman with reproductive potential, is defined as a sexually mature woman:
    - <50 years;
    - in the presence of menstruation in the previous 12 consecutive months;
    - in the absence of hysterectomy or bilateral oophorectomy or in the absence of a medically confirmed persistent syndrome of premature ovarian depletion;
    - in the absence of XY genotype, Turner syndrome or uterine agenesis;
    - in the absence of menstruation due to antitumor therapy.
    Recommendations
    For women with reproductive potential
    The Erivage ™ drug is contraindicated in patients who are unable to follow the recommendations of the Pregnancy Preventative Program for Erivage ™. A woman with reproductive potential:
    - should understand that there is a risk of a teratogenic effect of the drug Erivage ™ on an unborn child;
    - should not take the drug Erivage ™ if she is pregnant or planning a pregnancy;
    - should have a negative result of a valid pregnancy test,conducted under the supervision of a medical specialist within 7 days prior to initiation of therapy with Erivage ™ and monthly during therapy; should avoid pregnancy during therapy with Erivage ™ and within 24 months after taking the last dose;
    - should be able to follow recommendations on the use of effective methods of contraception;
    - should use 2 recommended methods of contraception during therapy with the drug Erivage ™ while maintaining sexual activity;
    - should inform the doctor if the following occurs during the therapy period or within 24 months after receiving the last dose of the drug Erivage ™: if pregnancy occurs or if there is a suspicion of pregnancy;
    o if there is no expected menstruation;
    o if there was sexual contact without contraception, which could lead to pregnancy;
    o if the patient needs to change contraception; should refuse breastfeeding during treatment with the drug Erivage ™ and within 24 months after taking the last dose.
    For men
    Wismodegib penetrates into the seminal fluid.
    To prevent the potential effect of vismodegra on the fetus, the male patient:
    - must understand that there is a risk of a teratogenic effect of the drug Erivage ™ on an unborn child with unprotected sexual contact with a pregnant woman;
    - should always use the recommended methods of contraception;
    - should inform the doctor in the event of pregnancy with his partner during his therapy with Erivage ™ or within 2 months after taking the last dose.
    For medical professionals
    The specialist should train patients so that they understand all of the above provisions of the Pregnancy Pregnancy Prevention Program for Erivage ™.
    Contraception
    Women of reproductive age During the treatment period and within 24 months after completion of the treatment with Erivage ™, and in the absence of menses or irregularities, two recommended contraceptive methods (one highly effective method of contraception + the barrier method) should be used.
    Men's should always use a condom (if possible with a spermicidal agent), even after a vasectomy,during sexual intercourse during therapy with Erivage ™ and within 2 months after the last dose.
    Pregnancy test
    Women with a reproductive potential should undergo a pregnancy test within 7 days before the start of therapy and monthly during the therapy. The pregnancy test should have a sensitivity of at least 50 mIU / mL and be administered by a medical professional. If you experience amenorrhoea while taking Erivage ™, patients should continue to take a pregnancy test.
    Restrictions in the appointment and dispensing of the drug to women with reproductive potential
    Primary appointment and release of the drug Erivage ™ should be performed within 7 days after a negative pregnancy outcome. The recipe for Erivage ™ can be prescribed only for 28 days of treatment, continuation of therapy requires a new prescription of the drug by a doctor.
    Influence on postnatal development
    Preclinical data suggest a potential risk of delayed growth and deformation of teeth in newborns and children.
    Blood donation
    Patients should not donate blood or its components during the treatment period and within 24 months after the last administration of Erivage ™.
    Sperm donation
    Sperm donation is prohibited during the treatment period and within 2 months after the last administration of Erivage ™.
    Influence on electrocardiographic parameters
    The drug Erivage ™ at the therapeutic dose does not affect the corrected QT interval (QTc).
    Excipients
    Since Erivage ™ capsules contain a lactose excipient, patients with rare hereditary diseases, such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption, should be taken with caution.
    The drug contains less than 1 mmol (23 mg) of sodium per dose, that is, it can be attributed to drugs that do not contain sodium.
    Instruction for disposal of unused product or expired
    Disposal of an unused product or product with expired shelf life should be in accordance with local requirements.

    Effect on the ability to drive transp. cf. and fur:Admission of the drug does not affect the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions, taking into account the profile of side effects.
    Form release / dosage:

    Capsules 150 mg

    Packaging:

    28 capsules are placed in white bottles of high-density polyethylene with a screw cap made of polypropylene, which opens when pressed. The method of opening the vial is shown on the lid in the form of a diagram with explanatory inscriptions.

    The neck of the bottle to ensure the control of the opening is hermetically sealed with aluminum foil with PVC coating. Each vial with the instruction for use is placed in a cardboard box.

    Storage conditions:
    2 years.
    Do not use after the expiration date printed on the package.

    Shelf life:

    Store at a temperature not exceeding 30 ° C. Keep out of the reach of children.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002252
    Date of registration:26.09.2013
    The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland
    Information update date: & nbsp23.08.2015
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