Tafinlar Combo (Tafinlar Combo)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Dosage form: & nbspcapsules and film-coated tablets
Composition:

Component 1:

Tafinlar (dabrafenib), capsules 50 mg / 75 mg

Each capsule contains:

Active substance: dabrafenib mesilate micronized - 59.25 / 88.88 mg (in terms of dabrafenib 50.00 / 75.00 mg); Excipients: cellulose microcrystalline - 1 18.50 / 177.70 mg, magnesium stearate - 1.80 / 2.70 mg, silicon dioxide colloid - 0.45 / 0.68 mg.

Composition of the capsule from hypromellose size № 2 Swedish Orange (Swedish orange) / size number 1, Opaque Pink (opaque pink): dye iron oxide red - 1.29 / 0.56%, titanium dioxide - 0.53 / 1.78%, hypromellose - q.s. to the South/q.s. up to 100%, ink S-1-17822/S-1-17823 (shellac 44.5 / 44.5%, ferric oxide black oxide 23.4 / 23.4%, propylene glycol 2.0 / 2.0%, ammonia water 1.0 / 1.0 %, butanol - 16.64 / 2.24%, isopropanol - 12.48 / 26.88%.

Component 2:

Mechinist (trametinib), tablets, coated film shell, 0.5 mg / 2.0 mg

Each film-coated tablet contains:

Active substance: tramethanib dimethylsulfoxide 0.5635 / 2.2540 mg (in terms of tramethanib 0.5 / 2.0 mg); Excipients: mannitol 95.47 / 106.95 mg, microcrystalline cellulose 36.25 / 41.25 mg, hypromellose 2910 - 7.25 / 8.25 mg, croscarmellose sodium - 4.35 / 4.95 mg, sodium lauryl sulfate - 0.017 / 0.068 mg, silicon dioxide colloid 0.010 / 0.040 mg, magnesium stearate - 1.09 / 1.24 mg;

film sheath (Opaprai yellow 03B120006 (hypromellose-63.00%, titanium dioxide 28.00%, macrogol-400 - 7.00%, iron oxide color yellow 2.00%)) - 4.35 mg / (Opadrai pink YS-1-14762-A (hypromellose - 59.00%.titanium dioxide - 31.04%, macrogol-400 - 8.00%, polysorbate-80 - 1.0%, iron dye oxide red 0.96%)) - 4.95 mg.

Description:

Component 1: Tafinlar (dubrafenib), capsules 50 mg, 75 mg

Capsules, 50 mg

Solid opaque capsules with a body and a lid of dark red color; on the cap of the capsule with black ink "GS TEW", on the capsule body - "50 mg". The contents of the capsules are white to almost white powder. The size of capsules number 2.

Capsules, 75 mg

Solid opaque capsules with a body and a lid of dark pink color; on the cap of the capsule with black ink "GS LHF", on the shell of the capsule - "75 mg". The contents of the capsules are white to almost white powder. The size of capsules number 1.

Component 2: Mechinist (trametinib), film-coated tablets, 0.5 mg, 2.0 mg

Tablets coated with a film coating, 0.5 mg: oval, biconvex tablets, covered with a film shell of yellow color, engraved "GS" on one side and "TFC" - another.

Film-coated tablets, 2.0 mg: round, biconvex tablets, covered with a film shell of pink color, with engraving "GS" on one side and "HMJ" - another.

Pharmacotherapeutic group:Antitumor agent, protein kinase inhibitor
ATX: & nbsp
  • Protein kinase inhibitors
    • Pharmacodynamics:

    Mechanism of action

    Dabrafenib

    Dabrafenib is a potent selective, competitor with ATP inhibitor of RAF-kinases; IC values50 for BRAF isoenzymesV600E, BRAFV600K and BRAFV600D are 0.65 nmol, 0.5 nmol and 1.84 nmol, respectively. Oncogenic mutations of the BRAF gene lead to constitutive activation of the RAS / RAF / MEK / ERK pathway and stimulation of growth of tumor cells. Mutations of the BRAF gene are detected with high frequency in specific neoplasms, including melanoma (about 50%).

    The most common mutations of V600E and V600K account for 95% of all BRAF mutations in patients with various malignancies. In rare cases, other mutations are detected, such as V600D, V600G and V600R.

    Dabrafenib also inhibits the CRAF and BRAF isoenzymes of the "wild" type, with the value

    IC50 5.0 nmol and 3.2 nmol, respectively. Dabrafenib inhibits the growth of melanoma cells bearing the mutation of the BRAFV600 gene. as in vitro, and in vivo.

    Trametinib

    Tramethinib is a highly selective allosteric inhibitor of the activation of mitogen-activated protein kinases 1 (MEK1) and 2 (MEK2), which are essential components of the ERK signal pathway (extracellular signal-regulated kinases).In melanoma and other cancers, this pathway often activates the mutated forms of the BRAF gene, which in turn activates the MEK and stimulates the growth of tumor cells. Trametinib inhibits the activation of MEK induced by the mutant BRAF gene, and also inhibits kinase activity of MEK. Trametinib inhibits the growth of melanoma cell lines with mutations in the BRAF V600 gene and demonstrates the antitumor effect in animals with melanoma with a mutation of the BRAFV600 gene.

    Dabrafenib + trametinib

    With combined use dubrafenib and trametinib inhibit two kinases in this signaling pathway, B-Raf and MEK. The use of these drugs in combination provides an effective inhibition of the proliferative signal. The combined use of dabrafenib and tramethinib has a synergistic effect in the melanoma cell lines with a BRAF mutation in vitro and delay the development of resistance in vivo in melanoma xenografts bearing a mutation BRAF V600.

    Pharmacodynamic properties

    Dabrafenib

    Dabrafenib inhibits the underlying pharmacodynamic marker (phosphorylated ERK kinase) in melanoma cells carrying the BRAF V600 mutation as in vitro, and in animals. In patients with melanoma with mutation BRAF V600 dubrafenib inhibits the activity of phosphorylated ERK kinase relative to baseline.

    Trametinib

    Tramethinib reduces the activity of phosphorylated ERK in melanoma tumor cell lines with a mutation of the BRAF gene and in melanoma xenograft models. In patients with melanoma with mutations in the BRAF and NRAS genes, the use of trametinib results in dose-dependent changes in tumor biomarkers, including inhibition of phosphorylated ERK, inhibition of Ki67 (tumor cell proliferation marker) and an increase in p27 (apoptosis marker). The mean values ​​of tramethinib concentration observed after repeated use of the drug at a dose of 2 mg once a day exceed the pre-clinical target concentration over the 24-hour interval between the drug applications, which ensures persistent inhibition of the MEK signaling pathway.

    Pharmacokinetics:

    Dabrafenib

    Suction

    The maximum concentration of dabrafenib in the blood plasma (Cmax) after oral administration is achieved on average after 2 hours. The average absolute bioavailability of dabrafenib for oral administration is 95%.Exposition of dabrafenib (CmOh and the area under the pharmacokinetic curve "concentration-time" (AUC)) increases in proportion to the dose after a single oral intake in the dose range from 12 mg to 300 mg, but with repeated admission twice a day the exposure increases less than proportionally to the dose. With repeated use, the exposure of dabrafenib is somewhat reduced, possibly due to the induction of its own metabolism. The average cumulation ratio AUC day 18 / day 1 was 0.73. After taking dabrafenib in a dose of 150 mg 2 times a day the geometric mean CmOh, AUC(0-t) and concentration before taking the next dose (Ct) were 1478 ng / ml, 4341 ng / hr and 26 ng / ml, respectively.

    When taken during a meal, the bioavailability of dabrafenib decreases (CmOh and AUC decrease by 51% and 31%, respectively), the absorption slows down compared with the administration of dabrafenib in fasting capsules.

    Distribution

    Dabrafenib binds to blood plasma proteins (the degree of binding is 99.7%). The apparent volume of distribution is 70.3 liters. The volume of distribution in the equilibrium state after intravenous injection of the microdose is 46 liters.

    Metabolism

    The first stage of dabrafenib metabolism is the formation of hydroxydabrafenib catalyzed by isoenzymes CYP2C8 and CYP3A4. The hydroxydabrafenib is then oxidized to carboxy dibrafenib by isoenzyme CYP3A4. Further, non-enzymatic decarboxylation of carboxydabrafenib with the formation of desmethyldaborafenib is possible. Carboxidabrafenib is excreted with bile and through the kidneys. Desmethydabrafenib may also form in the intestine and be reabsorbed. Desmethyldabrafenib is oxidized by isoenzyme CYP3A4. End period half-life of hydroxydabrafenib corresponds to the half-life of the starting compound (10 hours), whereas the carboxy- and desmethyl metabolites of dabrafenib are characterized by a longer half-life (21-22 hours). After a second dose of dabrafenib, the mean AUC metabolite and parent compound were 0.9, 11, and 0.7 for hydroxy, carboxy, and desmethyl dibrafenib, respectively. Based on the exposure, relative effectiveness and pharmacokinetic properties, hydroxy- and desmethyldabrafenib probably have important the importance of implementing the clinical efficacy of dabrafenib; the activity of carboxydabrafenib probably does not play a significant role.

    Excretion

    The final half-life of dabrafenib after intravenous administration of the microdose is 2.6 hours. The final half-life of dabrafenib after oral administration is 8 hours (in connection with the lengthening of the terminal phase). The clearance from the blood plasma after intravenous administration is 12 l / h. The clearance of dabrafenib is 17.0 l / h after a single application and 34.4 l / h in 2 weeks when taken 2 times a day. The main way after oral administration is the excretion through the intestine (71% of the dose labeled with a radioactive label), only 23% of the dose labeled with a radioactive label is excreted by the kidneys.

    Trametinib

    Suction

    The median time to reach the maximum concentration of tramethinb after ingestion is 1.5 hours. The average absolute bioavailability of tramethinib after a single dose of 2 mg tablet is 72% compared to that after intravenous administration. Increased exposure trametinib (CmOh and AUC) after repeated application in proportion to the dose. After repeated application of trametinib at a dose of 2 mg per day, the geometric mean CmOh, AUC and the concentration before taking the next dose were 22.2 ng / ml, 370 ng / h and 12.1 ng / ml, respectively, with a low ratio of maximum to minimum concentration (1.8).Interindividual variability was low (<28%). After the use of tramethinib with a high-fat high-fat food, there was a decrease in CmOh and AUC on 70% and 10% accordingly in comparison with the given parameters after reception on an empty stomach.

    Distribution

    Tramethanib is 97.4% bound to human plasma proteins. After intravenous administration of the microdose (5 μg), the volume of distribution of tramethinib is 1060 liters.

    Metabolism

    According to in vitro and in vivo tramethanib is metabolized predominantly by deacetylation, deacetylation with monooxidation. The deacetylated metabolite is further metabolized by glucuronation. Deacetylation is mediated by carboxyl esterases (i.e., carboxyl esterase lb, 1c and 2), may also be mediated by other hydrolytic isoenzymes.

    After applying a single dose of labeled [14C] -tetramine, about 50% of the circulating radioactive material is represented by the starting compound. But, based on the profile of metabolites after repeated use of tramethinib, ≥75% of the drug-bound substance in the plasma is represented by the parent compound.

    Excretion

    Tramethinib is accumulated with an average accumulation ratio of 6.0 with repeated daily use at a dose of 2 mg once daily. The average end-point of half-life is 127 hours (5.3 days) after a single dose. The equilibrium concentration is reached by day 15. The plasma clearance of trametinib is 3.21 l / h.

    After ingestion of a single dose of trametinib. labeled solution as a solution, the total isolated dose after a 10-day collection period is low (<50%) due to a long half-life. Metamorphic products of trametinib are excreted mainly through the intestine (> 80% of radioactivity is found in feces) and to a small extent by kidneys (<19%). The initial compound was less than 0.1% of the dose excreted by the kidneys.

    Dabrafenib + trametinib

    Multiple re-application of dabrafenib 150 mg twice daily together with tramethanib at a dose of 2 mg once a day led to an increase in CmOh and AUC dabrafenib by 16% and 23%, respectively. According to the population pharmacokinetic analysis, a small decrease in the bioavailability of trametinib, corresponding to a decrease AUC on 12%.

    Special patient groups

    Dabrafenib

    Patients with impaired hepatic function

    The pharmacokinetics of dabrafenib have been described in clinical studies in 65 patients with mild liver function disorder (according to the classification of the National Cancer Institute, NCI) with the help of population analysis. In these patients, the clearance of dabrafenib after oral administration was slightly different from that of dabrafenib in individuals with normal liver function (4% difference). In addition, a mild liver function disorder did not have a significant effect on the concentration of dabrafenob metabolites in the blood plasma. Dabrafenib should be used with caution in patients with impaired liver function of medium and severe degree (see section "Method of administration and dose").

    Patients with impaired renal function

    The pharmacokinetics of dabrafenib have been described in clinical studies using a population analysis in 233 patients with mild renal dysfunction (GFR 60-89 mL / min / 1.73 m2) and 30 patients with impaired renal function of medium degree (GFR 30-59 ml / min / 1.73 m2). In these patients, impaired renal function had a weak and clinically insignificant effect on clearance of dabrafenib after oral administration (<6% in patients of both categories).Violation of the function of the kidneys of mild or moderate degree had no effect on the concentration of hydroxy-, carboxy- and desmethyldabrafenib in blood plasma. Data on the use of dabrafenib in patients with impaired renal function are not severe (see section "Method of administration and dose").

    Children

    The use of dabrafenib in patients under the age of 18 years has not been studied (see section "Contraindications").

    Elderly patients

    According to population pharmacokinetic analysis, age has no significant effect on the pharmacokinetics of dabrafenib. Age over 75 years is a prognostic parameter of higher plasma concentrations of carboxy- and desmethyldabrafenib in blood plasma with a 40% increase in exposure compared to those in patients younger than 75 years.

    Body weight and sex

    According to population pharmacokinetic analysis, body weight and sex influence the clearance of dabrafenib when administered orally; body weight also affects the volume of distribution after ingestion and clearance distribution. These pharmacokinetic differences are not regarded as clinically significant.

    Race

    There is insufficient data to assess the possible influence of the race on the pharmacokinetics of dabrafenib.

    Trametinib

    Patients with impaired hepatic function

    The pharmacokinetics of trametinib has been described in clinical studies by a population analysis in 64 patients with mild liver function disorder (according to the classification NCI). In these patients, the clearance of tramethinib after oral administration was slightly different from the clearance of trametinib in individuals with normal liver function. There is no pharmacokinetics data available in patients with moderate or severe liver dysfunction.

    Patients with impaired renal function

    The clinically significant effect of renal dysfunction on the pharmacokinetics of tramethinib is unlikely in connection with the small involvement of the kidneys in excretion of trametinib. The pharmacokinetics of trametinib have been described in clinical studies using population analysis in 223 patients with mild renal dysfunction and 35 patients with impaired renal function of medium degree. Impaired renal function had no effect on the exposure of trametinib (<6% in both groups). There is no pharmacokinetic data in patients with impaired renal function of a serious degree.

    Children

    The use of trametinib in patients younger than 18 years of age has not been studied (see section "Contraindications").

    Elderly patients

    According to the population pharmacokinetic analysis, age does not significantly affect the pharmacokinetics of trametinib.

    Indications:

    Treatment of patients with unresectable or metastatic melanoma with a mutation of gene BRAF V600.

    Contraindications:

    - Hypersensitivity to dabrafenib, tramethanib or other substances that make up the drug.

    - Occlusion of retinal veins.

    - Melanoma with wild type of gene BRAF.

    - Pregnancy and the period of breastfeeding.

    - Children under 18 years.

    Carefully:

    It should be used with caution in patients with impaired liver function of moderate and severe severity, impaired renal function of a serious degree, in patients with diseases that may be accompanied by a violation of the function of the left ventricle.

    Pregnancy and lactation:

    Contraindicated the use of dabrafenib and tramethinib during pregnancy and the period of breastfeeding.

    In studies in animals, the reproductive toxicity of dabrafenib and trametinib was reported.Patients with preserved reproductive potential should use reliable contraceptive methods during treatment with the components of the Tafinlar Combo kit and at least 4 weeks after stopping treatment with dabrafenib, and for a minimum of 4 months after the last administration of tramethib.

    The simultaneous use of dabrafenib with hormonal contraceptives may reduce the effectiveness of the latter, and therefore, alternative contraceptive methods, such as barrier methods, should be used during drug therapy (see section "Interaction with other medicinal products").

    If dabrafenib and / or tramethinib are used during pregnancy, and if pregnancy occurs during this period, the patient should be informed of the potential risk to the fetus.

    Fertility

    Data on the effect of dabrafenib and trametinib on human fertility are not available.

    The animals noted undesirable reactions from the male reproductive system with the use of dabrafenib and unwanted reactions from the female reproductive system with the use of trametinib.Male patients should be informed about the possible risk of developing spermatogenesis disorders, which may be irreversible.

    Breastfeeding period

    It is not known whether dubrafenib and tramethanib into breast milk. Given that many drugs are excreted in breast milk, the risk for breastfeeding children can not be ruled out. It should be decided whether to stop breastfeeding or stop the drug therapy, based on the importance of treatment for the mother.

    Dosing and Administration:

    The Tafinlar Combo kit is intended for patients receiving combination therapy with dabrafenib and trametinib.

    Before starting the use of dabrafenib and tramethinib, it is necessary to obtain confirmation of the mutation of the gene BRAF V600 with the help of an approved or validated test for each patient.

    The efficacy and safety of dabrafenib for the treatment of patients with wild-type melanoma has not been established BRAF. In connection with the above, it is contraindicated the use of the drug Tafinlar Combo in patients with melanoma with a "wild" type BRAF (see section "Contraindications").

    Dabrafenib

    The recommended dose is 150 mg 2 times a day, which corresponds to a total daily dose of 300 mg. Capsules of dabrafenib should be taken orally at the same time, no later than 1 hour before meals, or no sooner than 2 hours after eating, observing the 12-hour interval between each dose. When missed intake of a regular dose of dabrafenib, the missed dose should not be taken if the intake of the next dose remains less than 6 hours.

    Trametinib

    The recommended dose of tramethanib is 2 mg orally once a day. A tablet of tramethinib should be taken orally, with a glass of water. A single dose of tramethinib is recommended to be taken every day at the same time with a morning or evening dose of dabrafenib.

    If you miss a regular dose of tramethinib, the missed dose should be taken only if there are more than 12 hours remaining until the next scheduled appointment.

    Correction of dose

    If unwanted reactions develop, patients receiving combination therapy may require interruption of treatment, a reduction in dose, or discontinuation of one or both of the components of the Tafinlar Combo kit.It is not recommended to adjust the dose or discontinue therapy when developing unwanted reactions such as squamous cell carcinoma (SCAD) or a new focus of primary melanoma (see section "Special instructions").

    Correction of the dose of both components of the Tafinlar Combo kit

    The recommended step-by-step dose reduction scheme, as well as a dose adjustment scheme for both components of the Tafinlar Combo kit, are presented in Table 1 and Table 2, respectively, depending on the severity of the adverse reactions.

    Table 1. The recommended step-by-step scheme for reducing the dose of both components of the Tafinlar Combo kit

    Dose change

    The dose of dubrafenib

    The dose of trametinib

    Initial dose

    150 mg twice daily

    2 mg once a day

    1st dose reduction

    100 mg twice daily

    1.5 mg once a day

    2nd dose reduction

    75 mg twice daily

    1 mg once a day

    3rd dose reduction

    50 mg twice a day


    Reduction of the dose of dabrafenib less than 50 mg twice a day is not recommended. A decrease in dose of tramethinib less than 1.0 mg per day is not recommended.

    Table 2. Scheme of dose adjustment for both components of the drug Tafinlar Combo at depending on the severity of the unwanted reactions

    Severity of unwanted reactions (on the CTC-AE scale) *

    Modification of the dose

    Degree 1 or degree 2 (transferable)

    Continuation of treatment and monitoring in accordance with clinical indications.

    Degree 2 (intolerable) or degree 3

    Break in treatment until the severity of the toxic reactions reaches 0-1 degree and when the treatment is resumed, the dose is reduced by one level.

    Degree 4

    Abolition of therapy or interruption of treatment until the severity of toxic reactions reaches 0-1 degree and with the resumption of treatment - a dose reduction at one level.

    * - the severity of unwanted reactions is assessed according to the Standard Criteria for the Evaluation of Unwanted Reactions (STS-AE), version 4.0.

    Once control over unwanted reactions has been achieved, it is possible to increase the dose, which is carried out step-by-step in the reverse order indicated in Tables 1 and 2.

    The dose of dabrafenib should not exceed 150 mg twice a day.

    Correction of the dose of only one of the components of the Tafinlar Combo kit

    Correction of the dose of only dabrafenib

    Correction of the dose of only dabrafenib is necessary in the case of the development of the following conditions on the background of combined therapy:

    - fever.

    - uveitis.

    Fever

    The intake of dabrafenib should be interrupted with an increase in body temperature ≥38.5 ° C, while tramethanib therapy should be continued at the same dose. Use antipyretic drugs, such as ibuprofen or acetaminophen / paracetamol and conduct a patient examination to identify possible signs and symptoms of infection (see section "Special instructions").

    The intake of dabrafenib can be resumed after normalization of body temperature in combination with appropriate prevention of antipyretic drugs.

    When resuming treatment, dabrafenib is recommended in the same dose. The dose of dabrafenib should be reduced by one level in case of repeated fever and / or if the fever is accompanied by other severe symptoms, including dehydration, arterial hypotension or renal insufficiency. In case of ineffectiveness of antipyretic drugs, the possibility of using oral glucocorticosteroids should be considered.

    Uveitis

    In the case of uveitis, combined with a dose-response therapy, dabrafenib is not required if the symptoms of the inflammatory process are well controlled by topical medications.If there is no response to treatment with ophthalmic drugs for topical use, dabrafenib should be discontinued and the local inflammatory process resumed after a cupping. Resume dabrafenib should be taken at a dose reduced by one level.

    With the development of the above conditions on the background of combined therapy with dabrafenib with trametinib, dose modification of trametinib is not required.

    Correction of dose only trametinib

    Correction of a dose only tramethanib is necessary in case of development of the following conditions on the background of combined therapy:

    - reduction of the left ventricular ejection fraction (LVEF);

    - retinal vein occlusion (SVS) and retinal pigment epithelial retinal detachment (OPES);

    - pneumonitis and interstitial lung disease (IBL).

    Decreased LVEF, left ventricular dysfunction

    Acceptance of tramethinib should be discontinued in the case of asymptomatic absolute reduction of LVEF by more than 10% of the baseline with an ejection fraction lower than the lower limit of the norm (see section "Special instructions"). Dabrafenib should be taken at the same dose.

    After the restoration of LVEF, resumption of tramethib in a dose reduced by 1 level is possible, with careful monitoring of the condition.

    It should be completely canceled the reception of tramethinib in case of development of a violation of the function of the left ventricle 3 or 4 degrees or with a repeated non-reducible decrease LVEF.

    Occlusion of retinal veins and detachment of retinal pigment epithelium In the case of developing such complaints and symptoms with tramethanib, like reduced visual acuity, blurred vision or loss of vision, an ophthalmological examination should be carried out immediately. When an OVS is detected, the drug should be stopped immediately (see section "Contraindications").

    In the case of OPES diagnosis, tramethanib treatment should be performed as described below (see Table 3).

    Table 3. Scheme correction of dose of trametinib in the development of OPES

    OPES 1 degree

    Continue treatment with a monthly evaluation of the retina before resolution. In case of progression of the OPES - follow the recommendations below, stop treatment with trametinib for up to 3 weeks.

    OPPP

    2-3 degrees

    Suspend treatment with trametinib for up to 3 weeks.

    OPPP

    2-3 degrees, which improves to 0-1 degree within 3 weeks

    To resume taking tramethinib at a lower dose (decrease by 0.5 mg).In patients taking tramethanib at a dose of 1 mg per day, treatment should be discontinued.

    OPES 2-3 degrees without improvement to a minimum of 1 degree for 3 weeks

    Completely stop treatment with trametinib.

    Pneumonitis and interstitial lung disease

    Trametinib treatment should be discontinued before a clinical examination in patients with suspected IBL or pneumonitis, including in patients with new or progressive symptoms and signs, including cough, dyspnea, hypoxia, pleural effusion, or infiltrates. When confirming the diagnosis of IBL or pneumonitis associated with taking the drug, treatment with tramethanib should be discontinued.

    With the development of the above conditions on the background of combined therapy with dabrafenib with trametinib, no modification of the dose of dabrafenib is required.

    Special patient groups

    Children and teens

    The efficacy and safety of dabrafenib and trametinib in children and adolescents under the age of 18 years is not established (see section "Contraindicated").

    Elderly patients

    Patients over 65 years of age do not require dose adjustment for both components of the Tafinlar Combo kit (see subsection "Pharmacokinetics"),

    Patients with impaired renal function

    Correction of the dose of dabrafenib and / or tramethinib in patients with mild and moderate renal dysfunction is not required. Due to the lack of clinical data on the use of dabrafenib and / or tramethinib in patients with severe renal dysfunction, treatment with this drug should be carried out with caution.

    Patients with impaired hepatic function

    Correction of the dose of dabrafenib and / or tramethinib in patients with mild liver dysfunction is not required. In patients with impaired liver function of medium and severe degree, the drug should be treated with caution.

    Side effects:

    Clinical Trials Data

    Evaluation of the safety of combination therapy dubrafenib + tramethanib was performed in two clinical trials involving patients with unresectable or metastatic melanoma with a gene mutation BRAF, who took in dubrafenib in a dose of 150 mg twice a day and tramethanib at a dose of 2 mg once a day. The most frequent HP (≥20%) with dabrafenib in combination with trametinib were fever, fatigue, nausea, headache, chills, diarrhea, rash, arthralgia, hypertension, vomiting and coughing.

    HP, registered with combined therapy with dabrafenib and tramethanib in the framework of clinical trials are given below.


    Frequency classification


    MEK1 15306

    (COMBI-d)

    n=209

    The combined data of MEK115306 and MEK116513 n=559

    Infectious and parasitic diseases

    Urinary tract infections

    Often

    often

    Nasopharyngitis

    Often

    Often

    Panniculitis

    often

    often

    Folliculitis

    often

    often

    Paronychia

    often

    often

    Pustular rash

    often

    often

    Benign, malignant and unspecified neoplasms (including cysts and polyps)

    Squamous cell carcinoma of the skin (SCRC), including the SCRC itself, cancer in situ (Bowen's disease) and keratoacantom

    often

    often

    Papilloma, including papilloma of the skin

    often

    often

    Seborrheic keratosis

    often

    often

    Acrochordon (soft wart)

    often

    infrequently

    New focus of primary melanoma

    infrequently

    infrequently

    Violations of the blood and lymphatic system

    Neutropenia

    Often

    often

    Anemia

    often

    often

    Thrombocytopenia

    often

    often

    Leukopenia

    often

    often

    Immune system disorders

    Hypersensitivity

    infrequently

    infrequently

    Disorders of metabolism and nutrition

    Decreased appetite

    Often

    Often

    Dehydration

    often

    often

    Hyperglycaemia

    often

    often

    Hyponatremia

    often

    often

    Hypophosphatemia

    often

    often

    Disturbances from the nervous system

    Headache

    Often

    Often

    Dizziness

    Often

    Often

    Disturbances on the part of the organ of sight

    Blurred vision

    often

    often

    Visual impairment

    often

    often

    Chorioretinopathy

    infrequently

    infrequently

    Uveitis

    infrequently

    infrequently

    Retinal disinsertion

    infrequently

    infrequently

    Periorbital edema

    infrequently

    infrequently

    Edema of the optic disc - infrequently with tramethib in monotherapy

    Heart Disease

    Reduction of the ejection fraction

    often

    often

    Left ventricular dysfunction

    not registered

    infrequently

    Heart failure

    not registered

    infrequently

    Bradycardia

    often

    often

    Vascular disorders

    Arterial hypertension

    Often

    Often

    Bleeding.

    In most cases, bleeding was mild, but extensive hemorrhage was reported, which was defined as symptomatic bleeding in the critical area and organ, as well as intracranial hemorrhage with a fatal outcome.


    Often

    Arterial hypotension

    often

    often

    Lymphatic edema

    infrequently

    infrequently

    Disturbances from the respiratory system, chest and mediastinal organs

    Cough

    Often

    Often

    Dyspnea

    often

    often

    Pneumonitis

    infrequently

    infrequently

    Interstitial lung disease

    not indicated

    infrequently

    Disorders from the gastrointestinal tract

    Abdominal pain

    Often

    Often

    Constipation

    Often

    Often

    Diarrhea

    Often

    Often

    Nausea

    Often

    Often

    Vomiting

    Often

    Often

    Dry mouth

    often

    often

    Stomatitis

    often

    often

    Pancreatitis

    infrequently

    infrequently

    Perforation of the organs of the gastrointestinal tract

    not registered

    infrequently

    Colitis

    infrequently

    infrequently

    Disturbances from the liver and bile ducts

    Increased activity of alanine aminotransferase

    Often

    Often

    Increase in activity of aspartate aminotransferase

    Often

    Often

    Increased activity of alkaline phosphatase in the blood

    often

    often

    Increase in activity of gamma-glutamyl transferase

    often

    often

    Disturbances from the skin and subcutaneous tissue

    Dryness of the skin

    Often

    Often

    Itchy skin

    Often

    Often

    Skin rash

    Often

    Often

    Acneiform dermatitis

    Often

    Often

    Erythema

    often

    often

    Actinic keratosis

    often

    often

    Night sweats

    often

    often

    Hyperkeratosis

    often

    often

    Alopecia

    often

    often

    Syndrome of palmar-plantar erythrodysesthesia

    often

    often

    Hyperhidrosis

    often

    often

    Damage to the skin

    often

    often

    Panniculitis

    often

    often

    Surface cracks in the skin

    often

    often

    Disturbances from the musculoskeletal system and connective tissue

    Arthralgia

    Often

    Often

    Myalgia

    Often

    Often

    Pain in the extremities

    Often

    Often

    Muscle spasm

    often

    often

    Increased activity of creatine phosphokinase in the blood

    often

    often

    Rhabdomyolysis

    not registered

    infrequently

    Renal impairment

    Renal insufficiency

    infrequently

    often

    Nephritis

    infrequently

    infrequently

    Acute kidney failure

    not registered

    infrequently

    General disorders and disorders at the site of administration

    Fatigability

    Often

    Often

    Peripheral edema

    Often

    Often

    Fever

    Often

    Often

    Chills

    Often

    Often

    Asthenia

    Often

    Often

    Inflammation of mucous membranes

    often

    often

    The flu-like syndrome

    often

    often

    Edema of the face

    often

    often

    If there is a deterioration in the clinical course of any of the side effects indicated in the manual or you notice any other side effects not listed in the instructions, inform the doctor about it.

    Overdose:

    Symptoms and signs

    Dabrafenib

    To date, data on the overdose of dabrafenib is extremely limited. The maximum dose of dabrafenib administered to patients in clinical trials was 600 mg (300 mg twice daily).

    Treatment

    The specific antidote of dabrafenib is unknown. If unwanted reactions develop, symptomatic therapy should be given. If you suspect an overdose, immediately cancel dubrafenib and begin supporting therapy. In the future, patient management should be adjusted in accordance with clinical manifestations

    or recommendations of the National Toxicology Center.

    Trametinib

    In clinical studies, the use of trametinib in doses exceeding 4 mg once a day was not recorded.In the framework of clinical studies, the use of tramethib inwards at a dose of up to 4 mg once a day and a loading dose of 10 mg once a day for 2 consecutive days is estimated.

    Treatment

    Further treatment should be carried out in accordance with the clinical manifestations or recommendations of the National Toxicology Center. There is no specific treatment for overdose with trametinib. If necessary, supportive care should be provided with appropriate condition monitoring. Hemodialysis does not increase excretion due to high binding of tramethinib to plasma proteins.
    Interaction:

    Dabrafenib

    The effect of other drugs on dubrafenib

    According to in vitro, main isoenzymes of the cytochrome system CYP, participating in the oxidative metabolism of dabrafenib, are isoenzymes CYP2C8 and CYP3A4, whereas hydroxydabrafenib and desmethyldabrafenib are substrates of the isoenzyme CYP3A4. According to the pharmacokinetic study, an increase in CmOh and AUC dabrafenib by 33% and 71%, respectively, with the simultaneous re-use of it with ketoconazole (an inhibitor of the isoenzyme CYP2C8). In addition, there is an increase AUC hydroxy- and desmethyldaborafenib, respectively, by 82% and 68%, with a decrease AUC carboxydabrafenib by 16%. The simultaneous use of gemfibrozil led to an increase AUC dabrafenib by 47% with repeated application of the latter without a corresponding change in the concentration of its metabolites.

    Drugs that are potent inhibitors or inducers of isoenzymes CYP2C8 or CYP3A4, can accordingly increase or decrease the concentration of dabrafenib. During therapy with dabrafenib, alternative drugs should be used, if possible.

    Simultaneous use of ketoconazole (inhibitor CYP3A4) or gemfibrozil (inhibitor CYP2C8) increases the AUC dabrafenib by 71% and 47% respectively. Care should be taken when using powerful inhibitors (for example, ketoconazole, nefazodone, clarithromycin, ritonavir, gemfibrozil), or inducers (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John 's wort puffed) isoenzymes CYP2C8 or CYP3A4 simultaneously with dubrafenib.

    Effect of dabrafenib on transport system substances

    In vitro dabrafenib is an inhibitor of the proteins of the carriers of organic anions OATP1B1 and OATP1B3, the clinical significance of this phenomenon can not be ruled out. For this reason, caution should be exercised when using dabrafenib and OABB1B1 or OATP1B3 substrates simultaneously, such as statins.

    Although in vitro dabrafenib and its metabolites (hydroxydabrafenib, carboxydabrafenib and desmethydabrafenib) showed the properties of inhibitors of the proteins of the carriers of organic anatomins OAT1 and OAT3, the data of clinical studies suggest that the risk of drug interaction is minimal.

    It was also shown that dubrafenib and desmethodabrafenib are moderate inhibitors of the human breast cancer resistance protein, however, given the clinical exposition, the risk of drug interaction is minimal.

    Preparations, which affect the pH of gastric juice

    Drugs that alter the pH in the upper gastrointestinal tract (eg, proton pump inhibitors, antagonists H2-receptors, antacids), can change the solubility of dabrafenib and reduce its bioavailability, however, no clinical studies of the interaction of these drugs with dabrafenib have been conducted.Based on the foregoing, with the simultaneous use of dabrafenib with proton pump inhibitors, H antagonists2receptors or antacids, the systemic exposure of dabrafenib may decrease, the effect of this phenomenon on the efficacy of dabrafenib has not been established.

    Effect of dabrafenib on other drugs

    Dabrafenib strengthens CYP3A4- and CYP2C9-mediated metabolism and may increase the activity of other isoenzymes of the cytochrome system, including isozymes CYP2B6, CYP2C8 and CYP2C19 and UDP-glucuronosyltransferase (CGT), and may also increase the activity of the carrier proteins (eg, P-glycoprotein (P-gp)). In a clinical study in 12 patients who received a single dose of midazolam (substrate isoenzyme CYP3A4) a decrease in its CmOh and AUC 61% and 74%, respectively, with the repeated use of dabrafenib 150 mg twice daily. In a separate study, 14 patients had a decrease AUC S-varfarin (substrate isoenzyme CYP2C9) and R-warfarin (substrate isoenzymes CYP3A4/CYP1A2) by 37% and 33%, respectively, after simultaneous re-application of dabrafenib. Neither dubrafenib, nor its three metabolites do not exert inhibitory effect on Pgp in vitro.

    The simultaneous use of dabrafenib with drugs that are sensitive to the induction of these enzymes (eg, hormonal contraceptives, warfarin or dexamethasone), can lead to a decrease in their concentration and loss of efficacy. In the case where the use of such drugs with dabrafenib is necessary, the patient should be monitored to determine the loss of efficacy of these drugs or consider the possibility of using alternative drug therapy.

    A large number of drugs with which it is possible to develop a drug interaction with simultaneous application with dabrafenib is expected, however, the intensity of such interaction may be different.

    Groups of such medications can include, including:

    - analgesics (for example, fentanyl, methadone);

    - antibiotics (for example, clarithromycin, doxycycline);

    - antineoplastic agents (eg, cabazitaxel);

    - anticoagulants (for example, acenocoumarol, warfarin);

    - antiepileptic drugs (for example, carbamazepine, phenytoin, primidon, valproic acid);

    - antipsychotics (eg, haloperidol);

    - calcium channel blockers (eg, diltiazem, felodipine, nicardipine, verapamil);

    - cardiac glycosides (for example, digoxin);

    - glucocorticosteroids (for example, dexamethasone, methylprednisolone);

    - antiviral drugs for the treatment of HIV infection (for example, amprenavir, atazanavir, darunavir, delavirdine, efavirenz, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir);

    - hormonal contraceptives /

    - hypnotics (for example, diazepam, midazolam, zolpidem);

    - immunosuppressants (eg, ciclosporin, tacrolimus, sirolimus);

    - statins metabolized by isoenzyme CYP3A4 (eg, atorvastatin, simvastatin).

    Trametinib

    Since tramethanib is metabolized predominantly by deacetylation mediated by hydrolytic enzymes with esterases (eg, carboxyl esterases), it is unlikely that other drugs affect its pharmacokinetics through metabolic interactions.

    Effect of trametinib on enzymes that metabolize drugs, and carrier proteins

    Based on the data in vitro and in vivo. tramethanib does not significantly affect the pharmacokinetics of other drugs through interactions with cytochrome isoenzymes orcarrier proteins.

    In vitro tramethanib is not an inhibitor of isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2D6 and CYP3A4. In vitro tramethanib is an inhibitor of isoenzymes CYP2C8. CYP2C9 and CYP2C19, inducer of isoenzyme CYP3A4 and an inhibitor of OAT1, OAT3, OST2, MATE1, OATP1B1, OATP1B3, Pgp and BCRP. However, starting from a low dose and a small systemic exposure of tramethinib in clinical practice in comparison with in vitro, it is considered that tramethanib is not an inhibitor or inducer of these isoenzymes or carrier proteins in vivo. The repeated use of tramethinib in a dose of 2 mg once a day did not have a clinically significant effect on CmOh and AUC dabrafenib, a substrate for CYP2C8 or CYP3A4, after its single application.

    The effect of other drugs on tramethanib

    Data, in vitro and in vivo, indicate that other drugs probably do not affect the pharmacokinetics of trametinib. Trametinib is deacetylated with carboxyl esterases and possibly other hydrolytic enzymes. According to clinical studies, the development of drug interaction mediated by carboxyl esterases is unlikely. Isozymes of the cytochrome system (CYP) play an insignificant role in excretion of trametinib.Trametinib is not a substrate for carrier proteins BCRP, OATP1B1, OATP1B3, OATP2B1, OST1, MRP2 and MATE1. In vitro tramethanib is a substrate Pgp, However, the probability of a clinically significant effect of inhibition Pgp on trametinib is unlikely, given the expressed ability of the latter to passive penetration and its high bioavailability. Simultaneous application of isoenzyme inducers CYP3A4 did not affect the exposure of trametinib with repeated application. After repeated simultaneous application of trametinib with dabrafenib, isoenzyme inducer CYP3A4, FROMmOh and AUC tramethinib corresponded to the exposure when applied in monotherapy, which indicates that the isoenzyme inducer CYP3A4 does not affect the exposure of trametinib. Multiple simultaneous use of dabrafenib in a dose of 150 mg twice a day and tramethinib at a dose of 2 mg once a day resulted in an increase in CmOh and AUC dabrafenib by 16% and 23%, respectively. According to the population pharmacokinetic analysis, tramethib with dabrafenib showed a slight decrease in the bioavailability of trametinib, corresponding to a decrease AUC the latter by 12%.

    The indicated changes in CmOh and AUC dabrafenib and tramethinib are not clinically relevant.

    Food interaction

    Because with simultaneous admission with food, the absorption of trametinib varies, tramethanib should be taken at least 1 hour before or 2 hours after ingestion.

    Special instructions:

    Validated test for confirmation of the presence of a mutation ВRAF V600

    Safety and efficacy of trametinib in patients with no mutation BRAF

    V600 not studied.

    Dabrafenib

    Fever

    In patients who received dubrafenib both in monotherapy and in combination therapy with tramethanib, fever was noted, while this HP was observed more often with combined treatment. When dabrafenib was used at a dose of 150 mg twice a day in combination with trametinib at a dose of 2 mg once a day, half the time, the first episodes of fever were noted in the first month of combined therapy, with approximately one third of patients receiving combination therapy 3 or more episodes of fever. This condition can be accompanied by severe tremor, dehydration and arterial hypotension, in rare cases, it is possible to develop acute renal failure.During and after severe episodes of fever, serum creatinine and other renal function should be monitored. There have been cases of severe non-infectious febrile fever. When the drug was used in clinical trials, these conditions were successfully corrected by correcting the dose of dabrafenib and / or stopping therapy with maintenance therapy (see section "Method of administration and dose"). Squamous cell carcinoma of the skin (SCRC)

    In patients who received dubrafenib, both in monotherapy and in combination therapy with trametinib. reported cases of SCRC (including those classified as keratoacanthoma and mixed keratoacanthoma). With monotherapy with dabrafenib, the emergence of SCRC was noted in 10% of patients, with the median time before the onset of the first manifestation of the SCRC was 8 weeks. With combined therapy (dubrafenib + tramethanib), the appearance of the SCRC was noted in 3% of patients, while the median time before the onset of the first manifestation of the SCRC was 20 to 32 weeks. More than 90% of patients with the SCRC, which appeared against the background of dabrafenib, the treatment with the drug was continued without dose adjustment.You should evaluate the state skin integument before beginning treatment with the drug followed by monitoring every 2 months throughout the course of treatment. It is necessary to continue the control of the skin condition every 2-3 months for 6 months after the end of therapy with the drug or before the beginning of other antitumor therapy.

    When confirming the diagnosis of SCRC, surgical treatment of the affected area should be performed, the drug should be continued without dose adjustment. It should be instructed the patient about the need to inform the attending physician about the occurrence of new lesions on the skin.

    New foci of primary melanoma

    There were reports of new foci of primary melanoma in patients taking dubrafenib. In clinical trials, these cases were detected during the first 5 months of therapy and did not require correction of treatment, except resection of the affected area. It is necessary to regularly monitor the skin condition (according to the scheme described for the SCRC).

    Secondary / recurrent malignant tumors of non-localization

    In vitro there was a paradoxical activation MAP-kinase signaling cascade in cells with a "wild" type BRAF from RAS mutations exposed to inhibitors BRAF, which can lead to an increased risk of developing malignant formations of other localization in patients receiving dubrafenib. When using inhibitors BRAF cases of development of malignant tumors bearing a mutation RAS. Patients receiving drug therapy should be provided clinically appropriate observation. When a malignant new formations of other localization, carrying RASmutation, in a patient receiving dabrafenib therapy, treatment with the drug should be continued, based on an assessment of the benefit / risk ratio. Correction of a dose of tramethinib in the case of combination therapy is not required. Continue monitoring of the patient's condition in order to identify secondary / recurrent RAS positive malignant neoplasms of other localization for a period up to 6 months after the abolition of dabrafenib or until the beginning of other antitumor therapy.

    Pancreatitis

    Less than 1% of patients receiving dubrafenib in clinical studies, noted the development of pancreatitis.In one of the cases, the condition occurred when the first dose of dabrafenib was used, with repeated occurrence with repeated use of dabrafenib in a reduced dose. It is necessary to immediately examine the patient with complaints of abdominal pain of unknown etiology with the determination of the activity of amylase and lipase in the blood serum. You should carefully observe the patient when you resume therapy with dabrafenib after an episode of pancreatitis on the background of drug treatment.

    Uveitis

    There was a development of uveitis, including iritis (inflammation of the iris of the eye) against the background of drug therapy. It is necessary to control ophthalmic symptoms, such as changes in vision, photophobia, eye pain in patients receiving the drug (see section "Method of administration and dose").

    Interval lengthening QT

    The maximum recorded elongation interval QTc, exceeding 60 msec was observed in 3% of patients treated with dabrafenib (one case of lengthening of the interval was noted QTc > 500 msec). It is not recommended to use dabrafenib in patients with a violation of the water-electrolyte balance (including the magnesium content) that can not be corrected, the lengthening interval syndrome QT, as well as in patients receiving drugs that can lengthen the interval QT.

    An electrocardiographic study (ECG) should be performed, as well as the electrolyte content (including the magnesium content) before the beginning of therapy with the drug, and also 1 month after its beginning and after any dose adjustment of dabrafenib.

    Further monitoring is recommended, in particular, in patients with a moderate or severe liver function disorder every month for the first 3 months of treatment, and then every 3 months or more, according to clinical indications. In patients with an interval length QTc > 500 msec should not begin therapy with the drug. With increasing interval QTc > 500 msec on the background of therapy with dabrafenib, the treatment should be temporarily suspended, the water-electrolyte balance should be corrected (including the magnesium content), and the risk factors for lengthening the interval should be adjusted QT from the heart (for example, congestive heart failure, bradycardia). Treatment with dabrafenib should be resumed in a reduced dose (see Table 2) after shortening the interval QTc to a value of <500 ms. It is necessary to completely stop treatment with the drug with increasing interval QTc > 500 msec with an increase of more than 60 msec, from the initial value.

    Hyperglycaemia

    With the use of dabrafenib, the development of hyperglycemia was noted. In a clinical study in 5 out of 12 patients with diabetes mellitus in the history of dabrafenib, there was a need to increase the intensity of hypoglycemic therapy. The incidence of hyperglycemia of grade 3, according to laboratory data, was 6% in patients who received dubrafenib, in contrast to patients who received dacarbazine, in which such cases are not registered.

    When treating dabrafenib in patients with previously diagnosed diabetes mellitus or hyperglycemia, routine monitoring of serum glucose concentration should be performed. Patients should be informed to the treating physician about symptoms of hyperglycemia, such as excessive thirst or increased volume and frequency of urination.

    Deficiency of glucose-6-phosphate dehydrohease

    Dabrafenib containing a sulfonamide group increases the risk of hemolytic anemia in patients with deficiency of glucose-6-phosphate dehydrogenase (G6PDG). It is necessary to carefully monitor the condition of patients with G6PDH deficiency for signs of hemolytic anemia.

    Trametinib

    Decreased LVEF, left ventricular dysfunction

    In clinical studies in patients treated with tramethanib, there was a decrease in LVEF. The median time to development of left ventricular dysfunction, heart failure, or LVEF reduction, in patients treated with trametinib alone or in combination with dabrafenib, was 2 to 4-5 months. In patients with diseases that may be accompanied by a violation of the function of the left ventricle, apply trametinib with caution. In all patients, LVEF should be evaluated before starting therapy with the drug, and periodic monitoring for 8 weeks after initiation of treatment, and further during treatment with the drug according to clinical indications.

    Arterial hypertension

    When tramethinib was used, episodes of increasing blood pressure were noted in patients with or without previous arterial hypertension. Blood pressure should be measured before starting therapy with the drug and monitored further during treatment, if necessary, hypertension should be controlled by standard therapy.

    Interstitial lung disease (IBL) / pneumonitis

    In clinical trials, 2.4% of patients treated with tramethinib developed IBL or pneumonitis; all patients required hospitalization. The median time to the first manifestations of IBL or pneumonitis was 160 days (from 60 to 172 days). It is necessary to cancel the treatment with the drug until the results of the clinical examination are obtained from patients with suspected IBL or pneumonitis, including in patients with new or progressive symptoms and signs, including cough, dyspnea, hypoxia, pleural effusion, or infiltrates. When confirming the diagnosis of IBL or pneumonitis associated with taking tramethinib, treatment with the drug should be discontinued.

    Rhabdomyolysis

    Patients treated with tramethanib had cases of rhabdomyolysis, in some cases patients could continue taking the drug. In more severe cases, hospitalization, interruption or complete cessation of drug treatment was required. When signs and symptoms of rhabdomyolysis appear, an appropriate examination and treatment should be performed.

    Visual impairment

    With the use of trametinib, the development of visual impairment was noted, including chorioretinopathy, OPES, and OVS.In clinical studies, such symptoms as blurred vision, reduced visual acuity, and other phenomena from the side of the organ of vision are noted. The drug is not recommended for use in patients with OVS in the anamnesis. Before starting treatment with the drug, a thorough ophthalmological examination should be carried out and, if clinically necessary, it should be repeated during therapy. If there are complaints of visual impairment, an additional ophthalmological examination should be performed in patients receiving the drug. If a lesion of the retina is detected, the treatment with the drug should be immediately discontinued and the eye retina specialist should be consulted. In patients with OVS, the drug should be completely discontinued. If OPES is identified, the dose adjustment scheme specified in Table 3 should be followed (see section "Method of administration and dose").

    Skin rash

    In clinical studies, skin rash was observed in approximately 60% of patients who received monotherapy with tramethanib and in 30% of patients who received combined treatment with dabrafenib. In most cases, the skin rash had a severity of 1 or 2 and did not require interruption of treatment or dose reduction.

    Deep vein thrombosis (DVT) / pulmonary embolism (pulmonary embolism)

    DVT and PE can develop with monotherapy with tramethanib or combined treatment with dabrafenib. If symptoms of pulmonary embolism or DVT occur, seek medical help immediately.

    Disorders from the side of the liver

    In clinical trials with the use of trametinib, HP from the side of the liver. It is recommended to monitor liver function every 4 weeks for 6 months after starting treatment with the drug. Subsequently, control of liver function can be continued according to clinical indications.

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

    Studies on the effect of dabrafenib and trametinib on the ability of to operate vehicles and mechanisms, was not carried out. Based on the pharmacological properties of dabrafenib and trametinib, any negative effect on this kind of activity is unlikely. Assessing the ability to perform actions that require rapid decision making, special motor and cognitive skills, it is necessary to take into account the general condition of the patient and the toxicity profile of dabrafenib and trametinib.

    Form release / dosage:

    A set of capsules and film-coated tablets, 50 mg and 0.5 mg, 50 mg and 2.0 mg, 75 mg and 0.5 mg, 75 mg and 2.0 mg.

    Packaging:

    A set of capsules and film-coated tablets, 50 mg and 0.5 mg, 50 mg and 2.0 mg, 75 mg and 0.5 mg, 75 mg and 2.0 mg:

    Component 1 - Tafinlar (dabrafenib), capsules 50 mg, 75 mg: for 28 or 120 capsules in a bottle of high-density opaque white polyethylene with a desiccant, closed with a polypropylene lid with a device for opening against children and equipped with a membrane.

    Component 2 - Mechinist (trametinib), tablets, coated with a film coating, 0.5 mg, 2.0 mg: for 7 or 30 tablets in a vial of HDPE, closed with a polypropylene screw cap with a thermo-sealable foil film covered with polyethylene containing a desiccant, with an anti-opening device for children.

    1 bottle with Tafinlar (component 1) and 1 bottle with Mequinist (component 2) together with instructions for use in a cardboard pack.

    Storage conditions:

    Component 1 - Tafinlar:

    At a temperature of no higher than 30 ° C.

    Component 2 - Meqinist:

    At a temperature of 2 to 8 ° C, in a place protected from light and moisture. Do not freeze.

    Tafinlar Combo, a set of capsules and tablets coated with a film sheath:

    At a temperature of 2 to 8 ° C, in a place protected from light and moisture. Do not freeze. Keep out of the reach of children.

    Shelf life:

    Component 1 - Tafinlar:

    2 of the year.

    Component 2 - Meqinist:

    18 months

    Tafinlar Combo, a set of capsules and tablets coated with a film sheath:

    18 months

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

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004295
    Date of registration:17.05.2017
    Expiration Date:17.05.2022
    The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland
    Manufacturer: & nbsp
    Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC
    Information update date: & nbsp19.06.2017
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