Tafinlar^® Combo (Tablet and capsule kit) Instructions for Use

ATC Code

L01XY (Antineoplastic drug combinations)

Active Substances

Dabrafenib (Rec.INN registered by WHO)

Trametinib (Rec.INN registered by WHO)

Pharmacotherapeutic Group

Antineoplastic agent – protein kinase inhibitor

Pharmacological Action

Combined medicinal product.

Dabrafenib is a potent selective ATP-competitive inhibitor of RAF kinases; IC₅₀ values for BRAF^V600E, BRAF^V600K, and BRAF^V600D isoforms are 0.65 nmol, 0.5 nmol, and 1.84 nmol, respectively. In biochemical studies, Dabrafenib also inhibits CRAF and wild-type BRAF isoforms with IC₅₀ values of 5.0 nmol and 3.2 nmol, respectively. Dabrafenib inhibits the growth of melanoma and non-small cell lung cancer cell lines harboring the BRAF V600 mutation in vitro and in melanoma xenograft models in vivo.

Dabrafenib suppresses the downstream pharmacodynamic marker (phosphorylated ERK) in BRAF V600 mutant melanoma cells, both in vitro and in animals. In patients with BRAF V600 mutant melanoma, Dabrafenib suppresses phosphorylated ERK kinase activity relative to baseline.

Trametinib is a highly selective allosteric inhibitor of mitogen-activated protein kinase 1 (MEK1) and 2 (MEK2) activation, which are key components of the ERK (extracellular signal-regulated kinase) signaling pathway. In melanoma and other cancers, this pathway is often activated by mutated forms of the BRAF gene, which in turn activates MEK and stimulates tumor cell growth. Trametinib inhibits MEK kinase activity and the growth of BRAF V600 mutant melanoma and non-small cell lung cancer cell lines in vitro and demonstrates antitumor activity in BRAF V600 mutant melanoma xenograft models.

Trametinib reduces phosphorylated ERK activity in BRAF V600 mutant melanoma tumor cell lines and in melanoma and non-small cell lung cancer xenograft models.

In patients with BRAF and NRAS mutant melanoma, trametinib administration leads to dose-dependent changes in tumor biomarkers, including inhibition of phosphorylated ERK and Ki67 (a marker of tumor cell proliferation), as well as an increase in p27 concentration (a marker of apoptosis). The mean trametinib concentrations observed after repeated administration of the drug at a dose of 2 mg once daily exceeded the preclinical target concentration over the 24-hour interval between drug administrations, providing sustained inhibition of the MEK signaling pathway.

Dabrafenib+Trametinib. Since the administration of dabrafenib in combination with trametinib provides inhibition of two kinases in this signaling pathway, B-Raf and MEK, combination therapy provides more effective inhibition of proliferative signal transduction compared to monotherapy with each component. The combination of dabrafenib with trametinib has a synergistic/additive effect in BRAF V600 mutant melanoma and non-small cell lung cancer cell lines in vitro and delays the development of resistance in vivo in BRAF V600 mutant melanoma xenografts.

Pharmacokinetics

Dabrafenib

C_max of dabrafenib in plasma after oral administration is reached on average after 2 hours. The mean absolute bioavailability of oral dabrafenib is 95%. Dabrafenib exposure (C_max and AUC) increases proportionally with dose after a single oral administration in the dose range from 12 mg to 300 mg, but with repeated twice-daily administration, the increase in exposure is less than dose-proportional. With multiple administrations, dabrafenib exposure decreases somewhat, possibly due to induction of its own metabolism. The mean AUC accumulation ratio day 18 / day 1 was 0.73. After administration of dabrafenib at a dose of 150 mg twice daily, the geometric mean C_max, AUC_0-t, and trough concentration were 1478 ng/ml, 4341 ng×h/ml, and 26 ng/ml, respectively. When taken with food, the bioavailability of dabrafenib decreases: C_max and AUC decrease by 51% and 31%, respectively, and absorption is delayed compared to taking dabrafenib capsules on an empty stomach.

Dabrafenib plasma protein binding is 99.7%. The apparent V_d is 70.3 L. The V_d at steady state after intravenous microdose administration is 46 L.

The first step of dabrafenib metabolism is the formation of hydroxydabrafenib, catalyzed by CYP2C8 and CYP3A4 isoenzymes. Hydroxydabrafenib is then oxidized to carboxydabrafenib by the CYP3A4 isoenzyme. Subsequent non-enzymatic decarboxylation of carboxydabrafenib to desmethyldabrafenib is possible. Carboxydabrafenib is excreted in bile and urine. Desmethyldabrafenib can also be formed in the intestine and reabsorbed. Desmethyldabrafenib is oxidized by the CYP3A4 isoenzyme. The terminal T_1/2 of hydroxydabrafenib corresponds to the T_1/2 of the parent compound (10 hours), whereas the carboxy- and desmethyl metabolites of dabrafenib are characterized by a longer T_1/2 (21-22 hours). After repeated administration of the drug, the mean metabolite-to-parent AUC ratios were 0.9, 11, and 0.7 for hydroxy-, carboxy-, and desmethyldabrafenib, respectively. Based on exposure, relative potency, and pharmacokinetic properties, hydroxy- and desmethyldabrafenib are likely important for the clinical efficacy of dabrafenib; the activity of carboxydabrafenib is most likely not significant.

The terminal T_1/2 of dabrafenib after intravenous microdose administration is 2.6 hours. The terminal T_1/2 of dabrafenib after oral administration is 8 hours (due to prolongation of the terminal phase). Plasma clearance after intravenous administration is 12 L/h. When taken twice daily, the clearance of dabrafenib is 17.0 L/h after a single dose and 34.4 L/h after 2 weeks. It is excreted primarily via the intestine – 71%, and by the kidneys – 23%.

Trametinib

The median time to reach C_max after oral administration is 1.5 hours. The mean absolute bioavailability of trametinib after a single 2 mg dose as tablets is 72% compared to that after intravenous administration. The increase in trametinib exposure (C_max and AUC) after repeated administration is dose-proportional. After repeated administration of trametinib at a dose of 2 mg/day, the geometric mean values of C_max, AUC, and trough concentration were 22.2 ng/ml, 370 ng×h/ml, and 12.1 ng/ml, respectively, with a low C_max to trough concentration ratio (1.8). Interindividual variability was low (<28%). After administration of a single dose of trametinib with a high-calorie, high-fat meal, a decrease in C_max and AUC of 70% and 10%, respectively, was observed compared to these parameters after administration on an empty stomach. Trametinib plasma protein binding is 97.4%. After intravenous microdose (5 mcg) administration, the V_d of trametinib is 1060 L.

According to in vitro and in vivo data, Trametinib is metabolized primarily via deacetylation alone or deacetylation with mono-oxidation. The deacetylated metabolite is further metabolized via glucuronidation. Deacetylation is mediated by carboxylesterases (i.e., carboxylesterase 1b, 1c, and 2), and may also be mediated by other hydrolytic isoenzymes.

Trametinib accumulates with a mean accumulation ratio of 6.0 with multiple daily administration at a dose of 2 mg once daily. The mean terminal T_1/2 is 127 hours (5.3 days) after a single dose administration. C_ss is reached by day 15. The plasma clearance of trametinib is 3.21 L/h.

After oral administration of a single dose of [¹⁴C]-labeled trametinib as a solution, the total excreted dose after a 10-day collection period is low (<50%) due to the long T_1/2. Trametinib metabolites are excreted primarily via the intestine (>80% of radioactivity found in feces) and to a lesser extent by the kidneys (<19%). The parent compound accounted for less than 0.1% of the renally excreted dose.

Dabrafenib+Trametinib

Multiple repeated administration of dabrafenib at a dose of 150 mg twice daily concurrently with trametinib at a dose of 2 mg once daily resulted in an increase in C_max and AUC of dabrafenib by 16% and 23%, respectively. According to population pharmacokinetic analysis, a slight decrease in the bioavailability of trametinib was calculated, corresponding to a 12% decrease in AUC. These changes in C_max and AUC are not clinically significant.

Indications

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

Treatment of patients with advanced non-small cell lung cancer with a BRAF V600 gene mutation.

ICD codes

Dosage Regimen

Tablet and capsule kit

Treatment with dabrafenib and trametinib should be carried out by a physician experienced in the use of anticancer drugs.

For oral administration.

Before starting dabrafenib and trametinib, confirmation of the BRAF V600 gene mutation using an approved or validated test must be obtained for each patient.

Dabrafenib the recommended dose is 150 mg twice daily.

Trametinib the recommended dose of trametinib is 2 mg orally once daily.

Adverse Reactions

Infections and parasitic diseases: very common – nasopharyngitis; common – cellulitis, panniculitis, folliculitis, paronychia, pustular rash.

Neoplasms common – cutaneous squamous cell carcinoma, including carcinoma in situ (Bowen’s disease) and keratoacanthoma, papilloma (including skin papilloma), seborrheic keratosis; uncommon – acrochordon (skin tag), new primary melanoma lesion.

Blood and lymphatic system disorders very common – neutropenia; common – anemia, thrombocytopenia, leukopenia.

Immune system disorders uncommon – hypersensitivity.

Metabolism and nutrition disorders very common – decreased appetite; common – dehydration, hyperglycemia, hyponatremia, hypophosphatemia.

Nervous system disorders very common – headache, dizziness.

Eye disorders : common – blurred vision, visual impairment; uncommon – chorioretinopathy, uveitis, retinal detachment, periorbital edema.

Cardiac disorders very common – hypertension, hemorrhage; common – hypotension, lymphedema, decreased ejection fraction; uncommon – bradycardia; frequency unknown – myocarditis.

Respiratory, thoracic and mediastinal disorders very common – cough; common – dyspnea, pneumonitis.

Gastrointestinal disorders very common – abdominal pain, constipation, diarrhea, nausea, vomiting; common – dry mouth, stomatitis; uncommon – pancreatitis, gastrointestinal perforation, colitis.

Skin and subcutaneous tissue disorders: very common – dry skin, pruritus, skin rash, erythema, acneiform dermatitis; common – actinic keratosis, night sweats, hyperkeratosis, alopecia, palmar-plantar erythrodysesthesia syndrome, hyperhidrosis, skin lesions, panniculitis, photosensitivity reactions, superficial skin fissures.

Musculoskeletal and connective tissue disorders very common – arthralgia, myalgia, pain in extremity, muscle spasm.

Renal and urinary disorders common – renal failure; uncommon – nephritis.

General disorders and administration site conditions very common – fatigue, peripheral edema, pyrexia, chills, asthenia; common – mucosal inflammation, influenza-like illness, facial edema.

Investigations very common – increased ALT, AST, ALP, GGT, CPK.

Contraindications

Retinal vein occlusion; melanoma or non-small cell lung cancer with wild-type BRAF gene; pregnancy, lactation (breastfeeding); children under 18 years of age; hypersensitivity to dabrafenib, trametinib.

With caution

Moderate and severe hepatic impairment, severe renal impairment, in patients with conditions that may be accompanied by impaired left ventricular function, in patients with risk factors for gastrointestinal perforation (including history of diverticulitis; gastrointestinal metastases); when used with potent inhibitors of CYP2C8 or CYP3A4, substrates of OATP1B1 or OATP1B3.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Special Precautions

Safety and efficacy in patients without the BRAF V600 mutation have not been studied.

During and after severe episodes of fever, serum creatinine concentration and other renal function parameters should be monitored. Cases of severe non-infectious febrile fever have been reported.

The skin condition should be assessed before starting treatment and then monitored every 2 months throughout the course of treatment. Skin condition should be monitored every 2-3 months for 6 months after the end of therapy with the drug or until the start of another anticancer therapy. The patient should be instructed to report the occurrence of new skin lesions to the treating physician.

The patient should be monitored for the detection of secondary/recurrent RAS-positive malignant neoplasms of other locations for up to 6 months after discontinuation of dabrafenib therapy or until the start of other anticancer therapy.

Patients with complaints of abdominal pain of unknown etiology should be immediately examined with determination of serum amylase and lipase activity. The patient should be carefully monitored when resuming dabrafenib treatment after an episode of pancreatitis. If symptoms of colitis or gastrointestinal perforation occur, the patient should seek immediate medical attention.

Liver function monitoring is recommended every 4 weeks for the first 6 months after starting trametinib treatment. Subsequently, liver function monitoring may be continued as clinically indicated.

A thorough ophthalmological examination should be performed before starting treatment and repeated during therapy as clinically necessary. If visual impairment complaints occur in patients receiving therapy with this combination, an additional ophthalmological examination should be performed. If retinal damage is detected, treatment should be interrupted immediately and a retinal specialist should be consulted. During therapy, monitoring of ophthalmological symptoms such as visual changes, photophobia, eye pain is necessary.

If symptoms of bleeding occur, the patient should seek immediate medical attention.

During treatment with dabrafenib, patients with previously diagnosed diabetes mellitus or hyperglycemia should undergo routine monitoring of serum glucose concentration. Patients are advised to report symptoms of severe hyperglycemia, such as excessive thirst or increased volume and frequency of urination, to their treating physician.

Dabrafenib, containing a sulfonamide group, increases the risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency. Such patients should be carefully monitored for signs of hemolytic anemia.

LVEF should be assessed in all patients before starting therapy, and periodic monitoring should be performed within 8 weeks after starting treatment, and thereafter during treatment as clinically indicated.

Blood pressure should be monitored before starting therapy and during treatment; antihypertensive therapy should be prescribed if necessary.

If a diagnosis of interstitial lung disease or pneumonitis associated with the use of this combination is confirmed, treatment should be discontinued.

Effect on ability to drive and operate machinery

When assessing the ability to perform activities requiring quick decision-making, special motor and cognitive skills, the patient’s general condition and the toxicity profile of dabrafenib and trametinib should be taken into account.

Drug Interactions

Dabrafenib

According to in vitro data, the main cytochrome P450 isoenzymes involved in the oxidative metabolism of dabrafenib are CYP2C8 and CYP3A4 isoenzymes, while hydroxydabrafenib and desmethyldabrafenib are substrates of the CYP3A4 isoenzyme.

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

According to a pharmacokinetic study, an increase in C_max and AUC of dabrafenib by 33% and 71%, respectively, was observed with its concurrent repeated administration with ketoconazole (a CYP2C8 isoenzyme inhibitor). Furthermore, an increase in the AUC of hydroxy- and desmethyldabrafenib by 82% and 68%, respectively, was observed, while the AUC of carboxydabrafenib decreased by 16%. Concurrent administration of gemfibrozil led to a 47% increase in the AUC of dabrafenib upon its repeated administration without a corresponding change in the concentration of its metabolites. With concurrent repeated administration with rifampicin (an inducer of CYP3A4/CYP2C8 isoenzymes), a decrease in the pharmacokinetic parameters of dabrafenib, C_max (27%) and AUC (34%), was observed. At the same time, no significant changes in the AUC of hydroxydabrafenib were observed, an increase in the AUC of carboxydabrafenib by 73% and a decrease in the AUC of desmethyldabrafenib by 30% were recorded.

Caution should be exercised when using potent inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, ritonavir, gemfibrozil) or inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort) of CYP2C8 or CYP3A4 isoenzymes concurrently with dabrafenib.

Dabrafenib enhances CYP3A4- and CYP2C9-mediated metabolism and may increase the activity of other cytochrome isoenzymes, including CYP2B6, CYP2C8, and CYP2C19 isoenzymes and UDP-glucuronosyltransferase (UGT), and may also increase the activity of transporter proteins (e.g., P-gp).

Concomitant use of dabrafenib with drugs that are sensitive to induction of CYP3A4 or CYP2C9 isoenzymes (for example, hormonal contraceptives, warfarin, or dexamethasone) may lead to a decrease in their concentration and loss of efficacy. When the use of such drugs with dabrafenib is necessary, the patient’s condition should be monitored to detect loss of efficacy of these drugs or an alternative drug therapy should be considered.

A large number of drugs with which drug interactions may develop when used concomitantly with dabrafenib is expected; however, the intensity of the interaction may vary.

The groups of the aforementioned drugs may include, among others: analgesics (for example, fentanyl, methadone); antibiotics (for example, clarithromycin, doxycycline); antineoplastic drugs (for example, cabazitaxel); anticoagulants (for example, acenocoumarol, warfarin); antiepileptic drugs (for example, carbamazepine, phenytoin, primidone, valproic acid); antipsychotics (for example, haloperidol); calcium channel blockers (for example, 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; hypnotic drugs (for example, diazepam, midazolam, zolpidem); immunosuppressants (for example, cyclosporine, tacrolimus, sirolimus); statins metabolized with the participation of the CYP3A4 isoenzyme (for example, atorvastatin, simvastatin).

Trametinib

Since Trametinib is metabolized primarily by deacetylation, most likely mediated by hydrolytic esterase enzymes (for example, carboxylesterases), it is unlikely that other drugs affect its pharmacokinetics through metabolic interaction.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.