Cotellick (COTELLIC®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceKobimetinibKobimetinib
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  • Cotellick
    pills inwards 
    Hoffmann-La Roche Ltd.     Switzerland
    • Dosage form: & nbspTfilm-covered abeys.
    Composition:

    1 tablet, film-coated, contains:

    active substance: kobimetinib - 20.00 mg (in the form of cobimetinib hemifumarate - 22.20 mg);

    Excipients: cellulose microcrystalline - 54.72 mg; lactose monohydrate - 36.48 mg, croscarmellose sodium - 4.80 mg, magnesium stearate - 1.80 mg;

    film sheath1: polyvinyl alcohol - 1.92 mg, titanium dioxide (E171) - 1.20 mg, macrogol 2 - 0,97 mg, talc - 0,71 mg.

    1 It is allowed to use a commercially available mixture for film coating of identical composition (for example, Opadry II White 85F18422).

    2 The synonym is polyethylene glycol, PEG 3350.

    Description:

    Round, biconvex tablets, film-coated, white; on one side of the tablet is an engraving of "SOV".

    Pharmacotherapeutic group:antitumor agent - protein tyrosine kinase inhibitor
    ATX: & nbsp

    L.01.X.E   Protein kinase inhibitors

    Pharmacodynamics:

    Mechanism of action

    The pathway of mitogen-activated protein kinase MAPK (Mitogen-Activated Protein Kinase) / extracellular signal-regulated kinase ERK (Extracellular signal Regulated Kinase) is the main signaling pathway that regulates cell proliferation, cell cycle, cell survival, angiogenesis, and cell migration.

    Cotellic is an oral high selective allosteric inhibitor of kinases MEK1 / 2 (MAPK/ERK Kinase). In biochemical and cytological studies cobimetinib demonstrated a high inhibitory ability, as well as activity against a wide range of tumors in vivo on tumor xenograft models, including tumors carrying mutations BRAF and KRAS.

    In biochemical and structural studies, the interaction of cobimetinib with MEK was demonstrated, with insignificant sensitivity to the dynamic conformational changes observed during the transition of MEK to the phosphorylated form. As a result, cobimetinib retains the binding ability and inhibitory activity in phosphorylation of MEK. Kobimetinib showed the highest activity with respect to the lines of tumor cells and tumors with high MEK phosphorylation levels, which is often observed in tumors with mutations BRAF.

    In pre-clinical studies, treatment with cobimetib-MAPK-disregulated tumor cells and tumors results in phosphorylation of kinases ERK1/2, the only known substrates are MEK 1/2.

    The signal transmission via the MARK pathway depends on the activity of the kinases ERK1/2, which phosphorylate protein targets in the cytoplasm and nucleus, which in turn induce the progression of the cell cycle, cell proliferation, cell survival and migration.In this way, cobimetinib counteracts promitogenic and oncogenic activity induced through the MAPK pathway by inhibiting MEK 1/2.

    The combination of vemurafenib and Cotellik inhibits the reactivation of the MAPK pathway through MEK 1/2 due to simultaneous exposure to BRAF and MEK, leading to more pronounced suppression of signal transduction, apoptosis of a larger number of tumor cells, and increased tumor responses in pre-clinical models compared with vemurafenib monotherapy.

    Preclinical safety data

    Carcinogenicity

    Studies of carcinomnib carcinogenicity have not been conducted.

    Mutagenicity

    Standard genotoxicity studies yielded negative results.

    Other

    Interval lengthening QT

    In conditions in vitro Cobimetinib causes a moderate inhibition of the ionic hERGchannel (concentration required for inhibition hERGchannel (IC50) = 0.5 μM [266 ng / ml]), which is approximately 18 times greater than the maximum concentration in the blood plasma (CmOh) when administered at a dose of 60 mg (CmOh unbound formulation = 14 ng / ml [0.03 μM]). IC50 vemurafenib for hERG (0.6 μM) in combination with 0.3 μM cobimetinib was approximately 2 times lower than the previously determined IC50 with monotherapy with vemurafenib.

    When treating patients with Cotellic in combination with vemurafenib, there was no additional clinical effect on lengthening the interval QT.

    According to the data of preclinical studies (the results of standard pharmacological studies on safety, toxicity studies with repeated use and genotoxicity), no specific risks for humans have been identified.

    Pharmacokinetics:

    Suction

    When taking cobimetinib in a dose of 60 mg in patients with oncological diseases, there is a moderate rate of absorption with a median time to the maximum concentration in the blood plasma (TmOh) 2.4 hours. Average CmOh in the equilibrium state and the area under the curve "concentration-time" (AUC0-24) are 273 ng / ml and 4340 ng * h / ml, respectively. The average value of the accumulation coefficient in the equilibrium state is approximately 2.4.

    Cobimetinib has a linear pharmacokinetics in the dosage range of about 3.5 mg to 100 mg.

    Absolute bioavailability of co-methimibe in healthy individuals is 45.9%. In healthy individuals it was shown that cobimetinib is intensively metabolized and excreted through the intestine. The degree of absorption is approximately 88%, indicating a high level of absorption and presystemic metabolism.

    The pharmacokinetics of cobimetinib does not change when the drug is taken with food (including a high-fat diet) compared to fasting in healthy individuals. Since the food does not affect the pharmacokinetics of cobimetinib, the drug can be taken regardless of food intake.

    Distribution

    Binding of cobimetinib with plasma proteins in vitro is 94.8%. In this case, there is no preferential binding to human erythrocytes (blood-plasma ratio 0.93).

    The volume of distribution in healthy individuals who received a dose of 2 mg intravenously (iv) is 1050 liters. According to the population pharmacokinetic analysis, the apparent volume of distribution in cancer patients is 806 liters.

    Metabolism

    The ratio of cobimetinib and its metabolites was studied in the study of mass balance in healthy individuals.

    On average, 94% of the dose is restored within 17 days. Kobimetinib intensively metabolized and excreted through the intestine; while there is no predominance of any of the metabolites.

    The main ways of metabolism of cobimetinibe are oxidation with the help of isoenzyme CYP3A and glucuronation by isoenzyme UGT2B7. Kobimetinib is the main substance found in the blood plasma. The share of oxidized metabolites in blood plasma is no more than 10% of the total number of circulating radioactivity, with no specific metabolites found in humans.

    The proportion of unchanged drug in feces and urine is 6.6% and 1.6% of the administered dose, respectively, indicating that cobimetinib mainly exposed to metabolism and in a small amount is excreted by the kidneys.

    Excretion

    After intravenous administration of cobimetinib in a dose of 2 mg, the average clearance is 10.7 l / h. The average apparent clearance in cancer patients after taking cobimetinib at a dose of 60 mg is 13.8 l / h.

    The average half-life of cobimetinib is 43.6 hours (range 23.1 to 69.6 hours).

    Pharmacokinetics in specific patient groups

    According to population pharmacokinetic analysis, gender, race, ethnicity, ECOG, as well as mild and moderate renal dysfunction do not affect the pharmacokinetics of cobimetib.

    Statistically significant covariates for clearance and volume distribution of cobimetinib are age and body weight, respectively.However, according to the results of the sensitivity analysis, none of these covariates have a clinically significant effect on the exposure in the equilibrium state.

    Floor

    According to the population pharmacokinetic analysis, sex does not affect the exposure of cobimetib.

    Elderly people

    According to the population pharmacokinetic analysis, age does not affect the exposure of cobimetinib.

    Patients with impaired renal function

    According to preclinical research and mass balance studies, cobimetinib predominantly metabolized with minimal kidney excretion. Special studies of the pharmacokinetics of cobimetinib in patients with impaired renal function have not been performed.

    According to the results of population pharmacokinetic data analysis in patients with mild to moderate renal impairment, as well as in patients with normal renal function (creatinine clearance> 90 ml / min), CC does not significantly affect the exposure of cobimetib.

    According to population pharmacokinetic analysis, renal dysfunction of mild to moderate severity does not affect the exposure of cobimetinib.

    There is insufficient data to determine the need for dose adjustment in patients with severe renal dysfunction.

    Patients with impaired hepatic function

    The pharmacokinetics of cobimetinib has not been studied in patients with severe and moderate hepatic insufficiency.

    Indications:

    Inoperable or metastatic melanoma with BRAF V600 mutation in adult patients in combination with vemurafenib.

    Contraindications:

    Hypersensitivity to cobimetib and to other components of the drug.

    Pregnancy and the period of breastfeeding.

    Children under 18 years of age (efficacy and safety of use not established).

    Simultaneous reception with powerful and moderate isoenzyme inducers CYP3A and potent inhibitors of isoenzyme CYP3A.

    Severe degree of renal failure.

    Severe and moderate hepatic impairment.

    Carefully:

    Simultaneous administration with moderate isoenzyme inhibitors CYP3A.

    Insufficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

    Pregnancy and lactation:

    Pregnancy

    There are no data on the use of Cotellic in pregnant women.Preclinical studies have shown that in animals cobimetinib leads to the death of embryos and causes malformations of the main vessels and skull in the fetus at clinically significant exposures (approximately 0.9-1.4 times the clinical exposure AUC in human blood plasma).

    Contraception in women and men

    It is necessary to use two effective methods of contraception during treatment with Cotellic and for at least three months after discontinuation of treatment.

    Breastfeeding period

    It is not known whether cobimetinib with breast milk. It is impossible to exclude the risk for newborns / infants. The decision to recommend breastfeeding or the appointment of a Cotellic drug should be taken depending on the need for treatment with the drug for the mother.

    Fertility

    The effect of cobimetinib on fertility in humans is unknown.

    Special preclinical studies to study the possible negative effects of Cotellic's drug on fertility have not been conducted.

    In toxicological studies in animals with repeated use of the drug, degenerative changes in the reproductive tissues were observed,including an increase in the level of apoptosis / necrosis of yellow bodies and seminal vesicles, epithelial cells of the epididymis and vagina, and epithelial cells of the epididymis.

    Dosing and Administration:

    Treatment with Cotellic should begin and monitor a doctor who has experience in treating patients with cancer.

    Before using Cotellic in combination with vemurafenib, a validated test should be performed BRAF V600 mutations.

    When using Cotellic in combination with vemurafenib, see also the instructions for the medical use of vemurafenib.

    Standard dosing regimen

    The recommended dose of Cotellik is 60 mg (three 20 mg tablets) inside, once a day.

    Cotellics should be taken with 28-day cycles.

    Each dose of Cotellic is composed of three 20 mg tablets (60 mg) and should be taken once a day for 21 days (treatment period 1 to 21 days) followed by a 7-day break in treatment with Cotellic (break in treatment from 22 to 28 days).

    Each dose (three 20 mg tablets at a time) can be taken regardless of food intake.

    Tablets of Cotellik should be swallowed whole, washed down with water.

    Duration of treatment

    Treatment with Cotellic should be continued as long as patient benefit continues or until intolerable toxicity develops.

    Delayed doses or missed doses

    If you have 12 or more hours left before taking the next dose, you should take Cotellic to keep the treatment schedule once a day. If there are less than 12 hours left before the next dose, the treatment should be continued the next day according to the prescribed schedule.

    Vomiting

    In case of vomiting after taking Cotellic, do not take an additional dose of the drug on the same day, but continue treatment according to the prescribed schedule the next day.

    Dose change

    Changing the dose of the drug Cotellik should be based on the assessment of the safety of the doctor and the tolerability of the drug in a particular patient.

    If the missed dose is associated with the appearance of toxicity, the missed dose should not be replenished.

    After reducing the dose of the drug in the future should not again increase the dose.

    Changing the dose of the drug Cotellic does not depend on the change in the dose of vemurafenib. The decision to reduce the dose of one or both drugs should be based on a clinical evaluation.

    Table 1 below shows general recommendations for changing the dose of the drug Cotellus.

    Table 1. General recommendations for reducing the dose of Cotellic.

    Severity of adverse events *

    The recommended dose of Cotellik

    Degree 1 or degree 2 (portable)

    Without dose reduction.

    Degree 2 (intolerable) or degree 3/4


    1 manifestation

    Interruption of treatment to ≤1 severity of adverse events, the resumption of therapy at a dose of 40 mg once daily

    2 manifestation

    Interruption of treatment to ≤1 severity of adverse events, resumption of therapy at a dose of 20 mg once daily

    3 manifestation

    Consider discontinuation of treatment

    * Severity of adverse events in accordance with the United States National Cancer Institute's General Unwanted Criteria for Toxicity, version 4.0

    Dose change in the development of individual adverse reactions

    Left ventricular dysfunction

    Consideration should be given to the need for a complete cessation of treatment with Cotellic,if the symptoms from the heart are associated with treatment with this drug, and if there has been no improvement after the temporary interruption of treatment.

    Table 2. Changes in the dose of Cotellic in patients with a reduction in the left ventricular ejection fraction (LVEF) compared with baseline.

    A patient

    Indicator LVEF

    Recommended dose change of Cotellic

    Index of LVEF after interruption in treatment

    The recommended daily dose of Cotellic

    Without symptoms

    ≥50%

    (or 40-49% and a decrease of <10% of the absolute value from the baseline)

    Continue treatment at the current dose

    -

    -

    <40%

    (or 40-49% and a decrease of ≥ 10% of the absolute value from the baseline)

    Interruption of treatment for 2 weeks

    a decrease of <10% of the absolute value from the baseline

    1 appearance: 40 mg

    2 appearance: 20 mg

    3 appearance: complete cancellation

    <40%

    (or a decrease of ≥10% of the absolute value from the baseline)

    Full cancellation

    With symptoms

    Not applicable

    Interruption of treatment for 4 weeks

    Without symptoms and a decrease of <10% of the absolute value from the baseline

    1 appearance: 40 mg

    2 appearance: 20 mg

    3 appearance: complete cancellation

    Without symptoms and <40%

    (or a decrease of ≥10% of the absolute value from the baseline)

    Full cancellation

    With symptoms, regardless of LVEF

    Full cancellation

    When changing the dose of Cotellik, treatment with vemurafenib can be continued (in the presence of clinical indications).

    Increase in activity of creatine phosphokinase

    In patients with an asymptomatic increase in the activity of creatine phosphokinase (CK), there is no need to change the dose of Cotellic or interrupt its administration.

    Changing the dose of Cotellic when used in combination with vemurafenib

    Deviations of laboratory parameters of liver function

    In the case of deviations in laboratory parameters of liver function 1 and 2 severity, treatment with Cotellic and vemurafenib should be continued at the prescribed dose.

    3 severity: continue treatment with Cotellic in the prescribed dose. The dose of vemurafenib can be reduced in accordance with clinical indications (see the instructions for the medical use of vemurafenib).

    4 severity: treatment with Cotellic and vemurafenib should be discontinued. If abnormalities in laboratory liver function indicators decreased to ≤1 degree of severity within 4 weeks, the use of Cotellic should be resumed at a dose reduced by 20 mg,The use of vemuraphhene should be resumed according to clinical indications according to the instructions for the medical use of vemurafenib.

    Treatment with Cotellic and vemurafenib should be discontinued if laboratory abnormalities of liver function did not decrease to ≤1 degree of severity within 4 weeks or laboratory abnormalities of liver function of 4 severity are resumed after initial improvement.

    Photosensitivity

    Management of patients with a photosensitivity ≤2 degree of severity (tolerable) should include maintenance therapy.

    In case of photosensitivity of grade 2 (intolerable) or ≥3 degrees, treatment with Cotellic and vemurafenib should be interrupted until the severity of symptoms is reduced to ≤1 degree. Treatment can be resumed without changing the dose of Cotellic.

    The dose of vemurafenib must be reduced according to the instructions for the use of vemurafenib (see the instructions for the medical use of vemurafenib).

    Rash

    The rash can occur both on the background of treatment with Cotellic and vemurafenib.With the development of rash, treatment with Cotellic and / or vemurafenib may be temporarily interrupted and / or a dose reduction of one of the drugs or both drugs may be reduced according to clinical indications.

    Additionally, with the development of the rash:

    - ≤2 degrees (tolerable) - management of patients should include maintenance therapy, treatment with Cotellic can be continued without changing the dose;

    - 2 degrees (intolerable) or ≥3 degrees:

    • acneiform rash: it is necessary to follow the general recommendations for changing the dose of Cotellic according to Table 1; treatment with vemurafenib can be continued with a change in the regimen of therapy with Cotellic (in the presence of clinical indications);
    • non-reactive or maculopapular rash: treatment with Cotellic can be continued without changing the dose (according to clinical indications); treatment with vemurafenib may be temporarily interrupted and / or its dose reduced (see instructions for the medical use of vemurafenib).

    Retinal vein occlusion

    In case of occlusion of retinal veins, therapy with Cotellic should be stopped.

    Dosing in special cases

    Elderly patients

    Correction of the dose of Cotellic in patients aged ≥65 years is not required.

    Patients of childhood and adolescents

    Safety and efficacy of Cotellic in children and adolescents (<18 years) have not been established.

    Patients with impaired renal function

    According to the population pharmacokinetic analysis data, in patients with impaired renal function of mild or moderate degree, dose adjustment is not required. The safety and efficacy of Cotellic in patients with severe renal dysfunction have not been established.

    Impaired liver function

    Safety and efficacy of Cotellic in patients with impaired liver function are not established. In patients with mild hepatic insufficiency, dose adjustment is not required based on the results of population pharmacokinetic analysis.

    Side effects:

    Clinical researches

    In patients with advanced stages of melanoma with BRAF V600 mutations with Cotellic in combination with vemurafenib, the median time before the onset of the first adverse events ≥3 degree was 0.5 months.

    To describe the frequency of undesirable 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%).

    Below are the undesirable reactions (of all degrees) registered with the use of Cotellic in combination with vemurafenib.

    Violations of the blood and lymphatic system: very often - anemia.

    Disturbances on the part of the organ of sight: very often - serous retinopathy (including the phenomena of chorioretinopathy and retinal detachment, as an indicator of serous retinopathy); often - reduced visual acuity, visual impairment.

    Disorders from the gastrointestinal tract: very often - diarrhea, nausea, vomiting, stomatitis.

    General disorders and disorders at the site of administration: very often pyrexia, often - chills.

    Disorders from the metabolism and nutrition: often - dehydration, hypophosphatemia, hyponatremia, hyperglycemia.

    Benign, malignant and unspecified neoplasms (including cysts and polyps): often - basal cell carcinoma, cutaneous squamous cell carcinoma *, keratoacanthoma *.

    Disturbances from the skin and subcutaneous tissues: very often photosensitivity (includes photosensitivity reactions, sunburn, sun dermatitis, actinic elastosis), rash, maculopapular rash, acneiform dermatitis,hyperkeratosis *.

    Vascular disorders: very often - increased blood pressure, bleeding **.

    Disturbances from the respiratory system, chest and mediastinal organs: often - pneumonitis.

    Laboratory and instrumental data: increased activity of creatine phosphokinase (CK), increased activity of alanine aminotransferase (ALT), increased activity of aspartate aminotransferase (ACT), increased activity of gamma glutamyltranspeptidase, increased activity of alkaline phosphatase (SHF), hypokalemia, hypoalbuminemia, hyperkalemia, hypocalcemia, increased creatinine concentration, lymphopenia , thrombocytopenia; often - reduction of ejection fraction, increase of bilirubin concentration.

    * See subsection "Skin squamous cell carcinoma, keratoacanthoma and hyperkeratosis".

    **Cm. subsection "Bleeding".

    Additional information on individual adverse reactions

    Bleeding

    The phenomena of bleeding (of all types and degrees of severity) were more often recorded with Cotellic in combination with vemurafenib compared to the control group receiving vemurafenib monotherapy (10% vs. 6%).When using the Cotellic drug in combination with vemurafenib, a higher incidence of intracerebral hemorrhage (1% vs. 0%), bleeding from the gastrointestinal tract (GI) (3% compared to 1%), bleeding from the reproductive system (2 % compared to 1%) and hematuria (2% compared with 1%). Most of the phenomena were 1 or 2 degrees and were not serious (9% compared with 5%). Phenomena of 3-5 degrees developed in 1% and 0.4% of patients, respectively.

    When using the Cotellic drug in combination with vemurafenib, the median time to the first appearance of the undesirable phenomenon was 2.8 months (range 0 to 12.7 months).

    Photosensitivity

    The photosensitivity reactions were observed at a higher frequency with the use of Cotellic in combination with vemurafenib compared to the control group receiving monotherapy with vemurafenib (41% compared to 31%). Most of the events were 1 or 2 degrees, and the ≥3 degree events occurred in 3% of patients with Cotellic in combination with vemurafenib and were not observed in the control group (0%).

    There were no regularities in time before occurrence of phenomena of ≥3 degree.When photosensitivity phenomena of grade 3 occurred, patients receiving the Cotellic preparation in combination with vemurafenib underwent predominantly local therapy in combination with interruption of therapy with both drugs.

    When carrying out monotherapy with cobimetinib, no signs of phototoxicity were observed.

    Skin squamous cell carcinoma, keratoacanthoma and hyperkeratosis

    When using Cotellic in combination with vemurafenib compared with the control group receiving monotherapy with vemurafenib, the following undesirable effects were less often recorded: skin squamous cell carcinoma (all degrees: 3% compared to 11%), keratoacanthoma (all degrees: 1% compared to 8%), hyperkeratosis (all degrees: 10% compared with 29%).

    Serous retinopathy

    Patients treated with Cotellic had serous retinopathies. Patients who first experienced or increased visual impairment are recommended to undergo ophthalmological examination. Management of patients with serous retinopathy includes interruption of treatment, a reduction in dose or discontinuation of therapy.

    Occlusion of retinal veins was noted in one patient in each treatment group (in the group of Cotellic in combination with vemurafenib and in the control group receiving vemurafenib monotherapy).

    Left ventricular dysfunction

    In patients receiving the preparation of Cotellic, there was a decrease in the left ventricular ejection fraction (LVEF) relative to the baseline.

    LVEF should be evaluated before treatment to determine baseline values, then after a month of treatment and at least every 3 months or clinically until treatment is discontinued. Management of patients with a decrease in LVEF relative to the baseline includes interruption of treatment, a reduction in dose, or discontinuation of therapy.

    Deviations of laboratory indicators

    Deviations of laboratory parameters of liver function

    Patients treated with Cotellic in combination with vemurafenib showed abnormalities in laboratory liver function, especially ALT, ACT, ЩФ. Laboratory indicators of liver function should be assessed before starting the combined treatment, monthly during treatment or more often (in the presence of clinical indications).

    Increased activity of CKF

    The asymptomatic increase in the activity of CKK of the blood was more frequent when using the Cotellic drug in combination with vemurafenib compared to the control group receiving vemurafenib monotherapy (all degrees: 65% compared to 13%, 3-4 degrees: 11% compared to <1%) . One case of rhabdomyolysis was noted with a simultaneous increase in the activity of CK of blood in each of the groups.

    Overdose:

    In clinical trials, there were no cases of overdose. In the event of an alleged overdose, treatment with Cotellic should be stopped and maintenance therapy initiated. Specific antidote, which could be used in cases of overdose with Cotellic, does not exist.

    Interaction:

    Effect of concomitant medications on cobimetib

    Inhibitor inhibitors CYP3A

    Cobimetib is metabolized with the participation of isoenzyme CYP3A. In healthy individuals in the presence of a potent inhibitor of isoenzyme CYP3A (itraconazole) AUC Cobimetinib increases approximately 7-fold. There is a possibility that the magnitude of the interaction will be lower.

    Powerful inhibitors of isoenzyme CYP3A

    Simultaneous use of potent inhibitors of isoenzyme should be avoided CYP3A when treated with cobimetib. Examples of potent inhibitors of isoenzyme CYP3A include but are not limited to ritonavir, cobicistat, telaprevir, lopinavir, itraconazole, voriconazole, clarithromycin, telithromycin, posaconazole, nefazodone and grapefruit juice. If simultaneous application with a potent inhibitor of isoenzyme CYP3A you can not avoid, you should carefully monitor the safety of patients. In the case of short-term (≤7 days) application of potent inhibitors of isoenzyme CYP3A should consider the possibility of suspension of treatment with cobimetinib during the application of such an inhibitor.

    Moderate inhibitors of isoenzyme CYP3A

    Caution should be exercised when using cobimetinib simultaneously with moderate isoenzyme inhibitors CYP3A. Examples of moderate isoenzyme inhibitors CYP3A include but are not limited to amiodarone, erythromycin, fluconazole, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, imatinib. With the simultaneous use of co-methinib with a moderate inhibitor of isoenzyme CYP3A carefully monitor the safety of patients.

    Weak isoenzyme inhibitors CYP3A

    Cobimetib can be used concomitantly with weak isoenzyme inhibitors CYP3A without dose adjustment.

    Inductors of isoenzyme CYP3A

    Simultaneous application of cobimetinib with a powerful isoenzyme inducer CYP3A was not evaluated in the course of the clinical trial, but it is likely that the exposure to co-methimibe will decrease. Thus, simultaneous application of moderate and powerful isoenzyme inducers CYP3A (eg, carbamazepine, rifampicin, phenytoin and St. John's wort pitted) should be avoided. It is necessary to consider the possibility of using drugs with missing or minimal isoenzyme induction CYP3A, as an alternative. Efficacy can be reduced, since there is a possibility of a significant decrease in the concentration of co-methinib with simultaneous application with moderate and powerful isoenzyme inducers CYP3A.

    P-glycoprotein inhibitors

    Cobimetib is the substrate of P-glycoprotein. When used simultaneously with P-glycoprotein inhibitors, such as ciclosporin and verapamil, there is a possibility of an increase in the concentration of cobimetinib in the blood plasma.

    Drugs that reduce acidity

    Simultaneous use of a proton pump inhibitor does not affect the pharmacokinetics of cobimetib. To determine the effect of increasing the pH of the stomach cobimetinib assigned to healthy individuals with rabeprazole (proton pump inhibitor). At the same time, an increase in the pH of the stomach did not affect the absorption of cobimetinib.

    Effect of co-methimnib on concomitant medications

    Substrates of isoenzymes CYP3A and CYP2D6

    A clinical study of drug interactions in patients with oncological disease showed that in the presence of co-methionib, the concentrations of midazolam (sensitive substrate CYP3A) and dextromethorphan (sensitive substrate CYP2D6) in the blood plasma did not change.

    Substrates of the isoenzyme CYP1A2

    Cobimetinib is a potential isoenzyme inducer CYP1A2 in vitro, thus, probably reducing the exposure of substrates of this enzyme, for example, theophylline. Clinical studies of drug interactions to assess the clinical significance of this phenomenon has not been conducted.

    Substrates BCRP (breast cancer resistance protein - protein resistance of breast cancer)

    Cobimetinib is a mild inhibitor BCRP in vitro. Clinical studies of drug interactions to evaluate this phenomenon have not been conducted. The clinical significance of inhibition of the intestinal BCRP can not be ruled out.

    Other antineoplastic agents

    Vemurafenib

    Patients with inoperable or metastatic melanoma did not have clinically significant drug interactions between the Cotellic and vemurafenib, so dose adjustment is not recommended.

    Influence of cobimetinib on transport systems of drugs

    In studies in vitro shown, that cobimetinib is not a substrate of transport proteins OATP1B1, OATP1B3 and OST1, being a weak inhibitor of these transport proteins.

    The clinical significance of this data is not established.

    Special instructions:

    When using Cotellic in combination with vemurafenib, you should also carefully read the instructions for the medical use of vemurafenib.

    Cotellus in combination with vemurafenib in patients with disease progression with the use of an inhibitor BRAF

    Data on the use of the Cotellic drug in combination with vemurafenib in patients with progression of the disease who had previously been treated with an inhibitor BRAF, are bounded. According to these data, the effectiveness of the combination in such patients will be lower. Therefore, alternative treatments should be considered before using the combination in this group of patients who previously used an inhibitor BRAF.

    The sequence of treatment after the progression of the disease with the use of an inhibitor BRAF not installed.

    Cotellic in combination with vemurafenib in patients with brain metastases

    Estimates of the safety and efficacy of treatment with Cotellic in combination with vemurafenib in patients with metastatic melanoma (if available BRAF V600 mutations) with metastases to the brain was not performed. The intracranial activity of cobimetinib is currently unknown.

    Serous retinopathy

    Patients who received MEK inhibitors, including Cotellic, experienced serous retinopathy (fluid accumulation within the retinal layers). Most of the events included chorioretinopathy or retinal detachment.

    The median time to the first appearance of serous retinopathy is 1 month (range 0-9 months). Most of the phenomena observed in clinical trials were resolved, or their severity decreased to asymptomatic course of 1 degree after interruption of treatment or dose reduction.

    It is necessary to evaluate new symptoms or increase visual impairment in patients at each visit. Patients who developed or developed eye disorders for the first time were advised to undergo ophthalmological examination. In the case of diagnosis of serous retinopathy, treatment with Cotellic should be stopped until the severity of visual symptoms is reduced to <1 degree. Management of patients with serous retinopathy includes interruption of treatment, a reduction in dose or discontinuation of therapy.

    Left ventricular dysfunction

    In patients receiving Cotellic, there was a decrease in the left ventricular ejection fraction (LVEF) relative to the baseline. The median time before the first appearance of the phenomena is 4 months (1-7 months).

    LVEF should be evaluated before treatment to determine baseline values, then after a month of treatment and at least every 3 months or clinically until treatment is discontinued.Management of patients with a decrease in LVEF relative to the baseline includes interruption of treatment, a reduction in dose, or discontinuation of therapy.

    In all patients who were restarted with a lower dose of Cotellic, measurement of LVEF should be made as possible after 2 weeks, 4 weeks, 10 weeks and 16 weeks, and then according to clinical indications.

    Patients with baseline LVEF values ​​below the institution's lower limit or below 50% have not been studied.

    Deviations of laboratory parameters of liver function

    When using Cotellic in combination with vemurafenib, as well as with monotherapy with vemurafenib (see instructions for the medical use of vemurafenib), there may be deviations in laboratory parameters of liver function.

    Patients treated with Cotellic in combination with vemurafenib showed abnormalities in laboratory liver function, especially ALT, ACT, ЩФ. Deviations in liver function parameters should be assessed according to the results of laboratory tests before starting the combined treatment, monthly during treatment or more often (in the presence of clinical indications).

    Management of patients with laboratory abnormalities in liver function of grade 3 severity includes interrupting treatment or reducing the dose of vemurafenib. Management of patients with laboratory abnormalities of liver function of the 4th degree of severity includes interruption of treatment, a reduction in dose or discontinuation of therapy with both Cotellic and vemurafenib.

    Diarrhea

    In patients treated with Cotellic, cases of severe diarrhea and diarrhea ≥3 degrees of severity were noted. Management of patients with diarrhea includes the use of antidiarrheal agents and maintenance therapy. For diarrhea ≥3 degrees of severity that has occurred, despite the use of maintenance therapy, it is necessary to suspend treatment with Cotellic and vemurafenib until a decrease in the severity of the phenomenon to ≤1 degree is noted. When the diarrhea is restored ≥3 degrees of severity, it is necessary to reduce the dose of Cotellic and vemurafenib.

    Lactose intolerance

    The preparation contains lactose. Patients with a rare hereditary intolerance to galactose, congenital insufficiency of lactase or glucose-galactose malabsorption should consult with the attending physician for an individualDiscussing cases where the benefits exceed the risks.

    Interaction with inhibitors of isoenzyme CYP3A

    It is necessary to avoid simultaneous application of Cotellic with powerful inhibitors of isoenzyme CYP3A. Caution should be exercised when using cobimetinib simultaneously with moderate isoenzyme inhibitors CYP3A. If simultaneous application with a potent or moderate isoenzyme inhibitor CYP3A can not be avoided, care should be taken to ensure the safety of patients, and if necessary, reduce the dose as recommended in Table 1.

    Destruction of an unused preparation or product with expired shelf life must be carried out in accordance with local requirements.

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

    Studies of the effect of Cotellic on the ability to drive vehicles and work with machines and mechanisms have not been carried out.

    During clinical trials, visual impairment was reported in patients receiving the Cotellic drug. Patients in the event of visual impairment should not drive vehicles and work with machines and mechanisms without consultingdoctor.

    Form release / dosage:

    Tablets, film-coated, 20 mg.

    Packaging:

    For 21 tablets in a blister of duplex (PVC / PVDC) and aluminum foil.

    3 blisters together with instructions for use are placed in a cardboard box. In order to control the first opening, a protective holographic sticker is applied to the packaging.

    Storage conditions:

    Store at a temperature not exceeding 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003464
    Date of registration:17.02.2016
    Expiration Date:17.02.2021
    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: & nbsp31.07.2016
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