Dabrafenib (Capsules) Instructions for Use

ATC Code

L01EC02 (Dabrafenib)

Active Substance

Dabrafenib

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents, protein kinase inhibitors, serine-threonine kinase B-Raf (BRAF) inhibitors

Pharmacological Action

Antitumor agent, a selective inhibitor of RAF kinases, competing with ATP; IC₅₀ values for the BRAF^V600E, BRAF^V600K, and BRAF^V600D isoforms are 0.65 nmol, 0.5 nmol, and 1.84 nmol, respectively.

Oncogenic amino acid variations at valine position 600 (V600) of BRAF lead to constitutive activation of the RAS/RAF/MEK/ERK pathway and stimulation of tumor cell growth. BRAF gene mutations are detected in specific neoplasms, including melanoma (about 50% of cases) and non-small cell lung cancer (1-3%).

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

In biochemical studies, Dabrafenib also inhibits CRAF and wild-type BRAF isoforms with IC₅₀ values of 5 nmol and 3.2 nmol, respectively.

Dabrafenib inhibits the growth of melanoma and non-small cell lung cancer cell lines carrying the BRAF V600 gene mutation in vitro and in melanoma xenograft models in vivo.

BRAF gene mutations are observed in 2% of non-small cell lung cancer cases and are most common in adenocarcinomas. The BRAF V600E mutation accounts for approximately half of all mutations of this gene in non-small cell lung cancer, in addition to which other BRAF V600 mutations also occur, for example, V600K, which also leads to constitutive BRAF activation and is sensitive to BRAF inhibitors.

Pharmacokinetics

C_max of dabrafenib in plasma after oral administration is reached on average after 2 hours. The mean absolute bioavailability of dabrafenib after oral administration is 95%.

Dabrafenib exposure (C_max and AUC) increases proportionally to the dose after a single oral administration in the dose range from 12 mg to 300 mg, however, with repeated administration twice a day, the increase in exposure is less than dose-proportional.

With multiple applications, 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 a day, the geometric mean C_max, AUC, 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), absorption is slowed compared to taking dabrafenib capsules on an empty stomach.

Dabrafenib binds to plasma proteins (binding degree 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 stage of dabrafenib metabolism is the formation of hydroxydabrafenib, catalyzed by CYP2C8 and CYP3A4 isoenzymes. Hydroxydabrafenib is then oxidized to carboxydabrafenib by the CYP3A4 isoenzyme. Further non-enzymatic decarboxylation of carboxydabrafenib to form 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 h), whereas the carboxy- and desmethyl metabolites of dabrafenib are characterized by a longer T_1/2 (21-22 h).

After repeated administration of the drug, the mean metabolite/parent compound 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 to be important in the realization of the clinical efficacy of dabrafenib; the activity of carboxydabrafenib is unlikely to play a significant role.

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 h (due to prolongation of the terminal phase). Plasma clearance after IV administration is 12 L/h.

When taken twice a day, the clearance of dabrafenib is 17.0 L/h after a single application and 34.4 L/h after 2 weeks. After oral administration, it is excreted mainly through the intestine (71% of the radioactively labeled dose), only 23% of the radioactively labeled dose is excreted by the kidneys.

Indications

Unresectable or metastatic melanoma; adjuvant therapy for melanoma; advanced non-small cell lung cancer.

ICD codes

Dosage Regimen

Capsules

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

Orally. No later than 1 hour before a meal or no earlier than 2 hours after a meal, observing a 12-hour interval between each dose. The recommended dose, both as monotherapy and in combination with trametinib, is 150 mg twice a day, which corresponds to a total daily dose of 300 mg.

If a dose is missed, the missed dose should not be taken if it is less than 6 hours until the next dose.

Therapy should continue as long as there is a positive effect or until unacceptable toxicity occurs.

Adverse Reactions

Benign, malignant, or unspecified neoplasms (including cysts and polyps): very common – papilloma; common – cutaneous squamous cell carcinoma, seborrheic keratosis, acrochordon, basal cell carcinoma; uncommon – new primary melanoma lesion.

From the immune system uncommon – hypersensitivity.

From metabolism and nutrition very common – decreased appetite; common – hypophosphatemia, hyperglycemia.

From the nervous system: very common – headache, dizziness.

From the organ of vision uncommon – uveitis.

From the respiratory system: very common – cough; common – dyspnea; uncommon – pneumonitis.

From the gastrointestinal tract: very common – nausea, vomiting, diarrhea; common – constipation; uncommon – pancreatitis.

From the skin and subcutaneous tissues very common – hyperkeratosis, alopecia, skin rash, palmar-plantar erythrodysesthesia; common – dry skin, skin itching, actinic keratosis, skin lesion, erythema, photosensitivity reactions; uncommon – panniculitis.

From the musculoskeletal system: very common – arthralgia, myalgia, pain in extremities.

From the kidneys and urinary tract: uncommon – renal failure, acute renal failure, nephritis.

Systemic disorders: very common – fever, increased fatigue, chills, asthenia; common – influenza-like illness.

With combination therapy of dabrafenib with trametinib

Infectious and parasitic diseases: very common – nasopharyngitis; common – urinary tract infections, cellulitis, folliculitis, paronychia, pustular rash.

From the blood and lymphatic system: common – neutropenia, anemia, thrombocytopenia, leukopenia.

From the organ of vision common – blurred vision, visual impairment, uveitis; uncommon – chorioretinopathy, retinal detachment, periorbital edema.

From the cardiovascular system: very common – arterial hypertension, bleeding of various locations, including intracranial hemorrhages and fatal bleeding; common – arterial hypotension, lymphedema, decreased ejection fraction; uncommon – bradycardia; frequency unknown – myocarditis.

Laboratory and instrumental data very common – increased ALT activity, AST activity; common – increased blood alkaline phosphatase activity, GGT, CPK.

Contraindications

Pregnancy and breastfeeding; age under 18 years; melanoma or non-small cell lung cancer with wild-type BRAF gene (lack of data on efficacy and safety).

With caution

Moderate and severe hepatic impairment, severe renal impairment, concurrent use with potent inhibitors or inducers of CYP2C8 or CYP3A4, substrates of OATP1B1 or OATP1B3.

Use in Pregnancy and Lactation

Use during pregnancy and breastfeeding is contraindicated.

Use in Hepatic Impairment

Use with caution in moderate and severe hepatic impairment.

Use in Renal Impairment

Use with caution in severe renal impairment.

Pediatric Use

Use is contraindicated in children under 18 years of age.

Special Precautions

The occurrence of fever has been observed in patients receiving Dabrafenib, both as monotherapy and as part of combination therapy with trametinib.

The severity and frequency of this phenomenon increased somewhat when used as part of combination therapy with trametinib for unresectable or metastatic melanoma; when used in combination with trametinib for non-small cell lung cancer, the severity and frequency of fever increased to a lesser extent.

When using dabrafenib at a dose of 150 mg twice a day in combination with trametinib at a dose of 2 mg once a day in patients with melanoma, in half of the cases the first episodes of fever were noted in the first month of therapy, and approximately one third of patients receiving combination therapy had 3 or more episodes of fever.

This condition may be accompanied by severe shaking, dehydration, and arterial hypotension; in rare cases, acute renal failure may develop. 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. In clinical studies of the drug, these conditions were successfully managed by dose adjustment and/or treatment interruption with supportive care.

Cases of cutaneous squamous cell carcinoma (cuSCC) (including those classified as keratoacanthoma and mixed keratoacanthoma) have been reported in patients receiving Dabrafenib, both as monotherapy and as part of combination therapy with trametinib.

In monotherapy, the occurrence of cuSCC was noted in 10% of patients with unresectable or metastatic melanoma, with the median time to the first manifestation of cuSCC being 8 weeks.

In combination therapy with trametinib, the occurrence of cuSCC was noted in 3% of patients, with the median time to the first manifestation of cuSCC ranging from 20 to 32 weeks.

In a clinical study, the development of cuSCC was noted in 18% of patients with non-small cell lung cancer receiving drug monotherapy, with the median time to the first manifestation being 11 weeks. The occurrence of cuSCC during therapy in combination with trametinib was noted in 2% of patients.

When used in combination with trametinib in adjuvant therapy for melanoma, the development of cuSCC was noted in 1% of patients, compared with 1% of patients who received placebo. The median time to the first manifestation in combination therapy was 18 weeks.

The condition of the skin should be assessed before starting treatment, with subsequent monitoring every 2 months throughout the course of treatment. Skin condition should be monitored every 2-3 months for 6 months after the end of drug therapy or until the start of another antitumor therapy.

If cuSCC is diagnosed, surgical treatment of the affected area should be performed; drug therapy should be continued without dose adjustment. The patient should be instructed to report the occurrence of new skin lesions to the treating physician.

The occurrence of new primary melanoma lesions has been reported in patients taking Dabrafenib for unresectable or metastatic melanoma.

In vitro, paradoxical activation of the MAP kinase signaling cascade was observed in cells with wild-type BRAF with RAS mutation exposed to BRAF inhibitors, which may lead to an increased risk of developing malignant formations of other locations in patients receiving Dabrafenib.

Cases of development of malignant neoplasms carrying RAS mutation have been registered with the use of BRAF inhibitors.

In less than 1% of patients receiving Dabrafenib in clinical studies for unresectable or metastatic melanoma, the development of pancreatitis was noted; in clinical studies, acute pancreatitis developed in 1% of patients receiving the drug for non-small cell lung cancer.

The development of uveitis, including iritis (inflammation of the iris), has been observed during drug therapy. During therapy, monitoring of ophthalmological symptoms such as vision changes, photophobia, eye pain is necessary.

Serious cases of hemorrhagic phenomena have been registered during the use of dabrafenib both as monotherapy and in combination with trametinib. In clinical studies, 6 out of 559 patients (1%) receiving the drug in combination with trametinib for unresectable or metastatic melanoma developed fatal intracranial hemorrhage.

The development of uveitis, including iritis, has been observed during therapy. During therapy, monitoring of ophthalmological symptoms such as vision changes, photophobia, eye pain is necessary.

Serious cases of hemorrhagic phenomena have been registered during the use of the drug both as monotherapy and in combination with trametinib. In clinical studies, 6 out of 559 patients (1%) receiving Dabrafenib in combination with trametinib for unresectable or metastatic melanoma developed fatal intracranial hemorrhage. If symptoms of bleeding occur, the patient should immediately seek medical help.

The development of hyperglycemia has been observed with the use of dabrafenib. In a clinical study, 5 out of 12 patients with a history of diabetes mellitus required an increase in the intensity of hypoglycemic therapy when using dabrafenib.

Effect on ability to drive vehicles and mechanisms

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

Drug Interactions

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

In patients who are simultaneously receiving dabrafenib and strong inhibitors of CYP2C8 or CYP3A4 isoenzymes (e.g., ketoconazole, gemfibrozil, nefazodone, clarithromycin, ritonavir, saquinavir, telithromycin, itraconazole, voriconazole, posaconazole, atazanavir), caution should be exercised.

The use of dabrafenib simultaneously with potent inducers of CYP2C8 or CYP3A4 isoenzymes (including rifampicin, phenytoin, carbamazepine, phenobarbital or St. John’s wort preparations) should be avoided.

With simultaneous use of ketoconazole (CYP3A4 isoenzyme inhibitor) at a dose of 400 mg once a day and dabrafenib at a dose of 75 mg twice a day, the AUC of dabrafenib increased by 71%, and C_max by 33% (compared to the use of dabrafenib at a dose of 75 mg twice a day).

With simultaneous use of the specified drugs, the AUC of hydroxy- and desmethyldabrafenib increased by 82% and 68%, respectively. The AUC of carboxydabrafenib decreased by 16%.

With simultaneous use of gemfibrozil (CYP2C8 isoenzyme inhibitor) at a dose of 600 mg twice a day and dabrafenib at a dose of 75 mg twice a day, the AUC of dabrafenib increased by 47%, and C_max did not change (compared to the use of dabrafenib at a dose of 75 mg twice a day). Gemfibrozil did not have a clinically significant effect on the systemic exposure of dabrafenib metabolites (<13%).

When using rifampicin (CYP3A4/CYP2C8 isoenzyme inducer) at a dose of 600 mg once a day in patients repeatedly receiving Dabrafenib at a dose of 150 mg twice a day, the C_max of the latter decreased by 27%, and AUC by 34%.

No significant change in the AUC of hydroxydabrafenib was noted. The AUC of carboxydabrafenib increased by 73%, the AUC of desmethyldabrafenib decreased by 30%.

When using dabrafenib at a dose of 150 mg twice a day simultaneously with rabeprazole (a drug that increases pH) at a dose of 40 mg once a day, the AUC of dabrafenib increased by 3%, and C_max decreased by 12%.

Such changes in the AUC and C_max of dabrafenib are not considered clinically significant. A decrease in the bioavailability of dabrafenib in case of simultaneous use of drugs that change pH in the upper gastrointestinal tract (for example, proton pump inhibitors, H2 receptor blockers, antacids) is not expected.

In vitro, Dabrafenib caused a dose-dependent increase in the production of CYP2B6 and CYP3A4 isoenzymes. According to a drug interaction clinical study, C_max and AUC of midazolam (a CYP3A4 isoenzyme substrate) in case of its single administration to patients repeatedly receiving Dabrafenib decreased by 47% and 65%, respectively.

When using dabrafenib at a dose of 150 mg twice a day simultaneously with warfarin, the AUC of S- and R-warfarin decreased by 37% and 33%, respectively, compared with the use of warfarin alone. C_max of S- and R-warfarin increased by 18% and 19%, respectively.

Dabrafenib is likely to interact with many drugs that are eliminated by metabolism or active transport. If the therapeutic effect of such drugs is significant for the patient, and dose adjustment is difficult to perform based on monitoring of the effect or plasma concentration, the use of such drugs should be avoided or used with caution.

In patients simultaneously using enzyme inducers, the risk of liver damage after taking paracetamol is increased.

It is likely that due to drug interaction, Dabrafenib will affect many drugs, although the magnitude of the effect will vary.

Drugs that may be affected by Dabrafenib include, among others:

• analgesics (e.g., fentanyl, methadone);
• antibiotics (e.g., clarithromycin, doxycycline);
• antineoplastic agents (e.g., cabazitaxel);
• anticoagulants (e.g., acenocoumarol, warfarin);
• antiepileptic drugs (e.g., carbamazepine, phenytoin, primidone, valproic acid);
• antipsychotics (e.g., haloperidol);
• calcium channel blockers (e.g., diltiazem, felodipine, nicardipine, nifedipine, verapamil);
• cardiac glycosides (e.g., digoxin);
• corticosteroids (e.g., dexamethasone, methylprednisolone);
• antiviral drugs for HIV infection (e.g., amprenavir, atazanavir, darunavir, delavirdine, efavirenz, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir);
• hormonal contraceptives;
• hypnotics (e.g., diazepam, midazolam, zolpidem);
• immunosuppressants (e.g., cyclosporine, tacrolimus, sirolimus);
• statins metabolized by the CYP3A4 isoenzyme (e.g., atorvastatin, simvastatin ).

Enzyme induction occurs 3 days after starting Dabrafenib.

After discontinuation of Dabrafenib, enzyme induction gradually decreases; during this time, concentrations of sensitive substrates of the CYP3A4, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 isoenzymes, UDP-glucuronosyltransferase (UGT), and transporter proteins (e.g., P-gp or MRP2) may increase.

Patients should be monitored to prevent the development of toxic effects.

Dose adjustment of the aforementioned drugs may be required.

In vitro, Dabrafenib irreversibly inhibits the CYP3A4 isoenzyme.

Therefore, transient suppression of CYP3A4 isoenzyme activity may be observed during the first few days of treatment.

In vitro, Dabrafenib is an inhibitor of the organic anion transporter proteins OATP1B1 and OATP1B3, as well as BCRP.

When a single dose of rosuvastatin (a substrate of OATP1B1, OATP1B3, and BCRP) was administered concomitantly with multiple doses of Dabrafenib 150 mg twice daily in 16 patients, a slight change in AUC (7% increase) and a 2.6-fold increase in C_max of rosuvastatin were noted.

The clinical significance of the increase in rosuvastatin C_max is considered unlikely.

Possible adverse reactions should be monitored during concomitant use of the drug with OATP1B1 and OATP1B3 substrates with a narrow therapeutic index, taking into account the peak concentration of the co-administered drug.

Multiple concomitant administration of Dabrafenib 150 mg twice daily and trametinib 2 mg once daily resulted in a 16% and 23% increase in the C_max and AUC of Dabrafenib, respectively.

Since food affects the absorption of Dabrafenib, patients should take Dabrafenib alone or in combination with trametinib at least 1 hour before or 2 hours after a meal.

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.