Dabrafenib Mesylate (Tafinlar) is a mutant BRAF-kinase inhibitor that is used as monotherapy or in combination with Trametinib (Mekinist) for the treatment of melanoma and other malignancies like anaplastic thyroid carcinoma and metastatic non-small cell lung cancer.

Dabrafenib (Tafinlar) Uses:

• Melanoma:

  • Used for the adjuvant treatment of melanoma (in combination with trametinib) in patients with a BRAF V600E or BRAF V600K mutation ( detected by an approved test), and lymph node involvement, following complete resection.
  • Used for the treatment of unresectable or metastatic melanoma in patients with a BRAF V600E mutation (single-agent therapy) or in patients with BRAF V600E or BRAF V600K mutations (in combination with trametinib);
  • confirm BRAF V600E or BRAF V600K mutation status with an approved test prior to treatment.

• Non-small cell lung cancer, metastatic:

  • Used for the treatment of metastatic non-small cell lung cancer (NSCLC) in patients with BRAF V600E mutation as detected by an approved test (in combination with trametinib).

• Thyroid cancer, anaplastic, locally advanced or metastatic:

  • Used for the treatment of locally advanced or metastatic anaplastic thyroid cancer (ATC) (in combination with trametinib) in patients with BRAF V600E mutation and with no satisfactory locoregional treatment options.
  • Limitations of use: for patients having wild-type BRAF melanoma, wild-type BRAF NSCLC, or wild-type BRAF ATC, Trametinib is not indicated for the treatment of those patients.

Dabrafenib (Tafinlar) Dose in Adults

Note: Confirm BRAF V600 mutation status prior to treatment initiation.

Dabrafenib (Tafinlar) Dose in the treatment of Melanoma, adjuvant treatment (with BRAF V600E or BRAF V600K mutation):

• Oral: 150 mg twice in a day, approximately every 12 hours (in combination with trametinib); continue for up to 1 year in the absence of disease progression or unacceptable toxicity.

Dabrafenib (Tafinlar) Dose in the treatment of metastatic or unresectable melanoma (with BRAF V600E mutation):

• Oral: 150 mg twice in a day, approximately every 12 hours (single-agent therapy); continue until disease progression or unacceptable toxicity.

Dabrafenib (Tafinlar) Dose in the treatment of metastatic or unresectable melanoma (with BRAF V600E or BRAF V600K mutation):

• Oral: 150 mg twice daily, approximately every 12 hours (in combination with trametinib); continue until disease progression or unacceptable toxicity.

Dabrafenib (Tafinlar) Dose in the treatment of metastatic non-small cell lung cancer (with BRAF V600E mutation):

• Oral: 150 mg twice in a day, approximately every 12 hours (in combination with trametinib);
• continue until disease progression or unacceptable toxicity.

Dabrafenib (Tafinlar) Dose in the treatment of locally advanced or metastatic anaplastic Thyroid cancer (with BRAF V600E mutation):

• Oral: 150 mg twice in a day, approximately every 12 hours (in combination with trametinib); continue until disease progression or unacceptable toxicity.

• Missed doses:

  • A missed dose may be administered up to 6 hours prior to the next dose;
  • Do not administer if less than 6 hours until the next dose (do not make up the missed dose).

Use in Children:

Not indicated.

Dabrafenib (Tafinlar) Pregnancy Category: N

• Its mechanism of action and animal reproduction research findings may determine if dabrafenib is safe for fetal harm.
• A highly effective non-hormonal contraceptive should be used by females with reproductive potential during treatment.
• It should be used for at least two weeks for single-agent therapy, or for 4 months for combination therapy. After treatment is completed, hormonal contraceptives may no longer work.
• Males may have impaired spermatogenesis (observed in animal research); before you consider therapy, it is important to think about family planning and fertility counseling.

Use of Dabrafenib while breastfeeding

• It is not known whether dabrafenib can be found in breast milk.
• The manufacturer does not recommend breastfeeding during treatment or for more than 2 weeks (single agent therapy) or for 4 months (combination Therapy with Trametinib).
• This is because there are serious adverse reactions that could occur in breastfed babies.

Dabrafenib (Tafinlar) Dose in Kidney Disease:

• GFR ≥30 mL/minute/1.73 m²:

  • No dosage adjustment required.

• GFR <30 mL/minute/1.73 m²:

  •  The manufacturer's labeling doesn't provide any dosage adjustments (has not been studied).

Dabrafenib (Tafinlar) Dose in Liver disease:

• Mild impairment:

  • No dosage adjustment required.

• Moderate to severe impairment:

  • Manufacturer's labeling doesn't provide any dosage adjustments (has not been studied); however, metabolism is primarily hepatic and exposure may be increased in patients with moderate to severe impairment.

Common Side Effects of Dabrafenib (Tafinlar):

• Cardiovascular:

  • Hypertension
  • Peripheral Edema

• Central Nervous System:

  • Headache
  • Chills

• Dermatologic:

  • Hyperkeratosis
  • Skin Rash
  • Alopecia
  • Palmarplantar Erythrodysesthesia
  • Xeroderma

• Endocrine & Metabolic:

  • Hyperglycemia
  • Hypophosphatemia
  • Hypoalbuminemia
  • Hyponatremia

• Gastrointestinal:

  • Nausea
  • Diarrhea
  • Abdominal Pain
  • Vomiting
  • Constipation

• Hematologic & Oncologic:

  • Anemia
  • Lymphocytopenia
  • Papilloma
  • Neutropenia
  • Hemorrhage
  • Malignant Neoplasm Of Skin

• Hepatic:

  • Increased Serum Alanine Aminotransferase
  • Increased Serum Alkaline Phosphatase
  • Increased Serum Aspartate Aminotransferase

• Neuromuscular & Skeletal:

  • Arthralgia
  • Myalgia
  • Back Pain

• Respiratory:

  • Cough

• Miscellaneous:

  • Fever

Less Common Side Effects Of Dabrafenib (Tafinlar):

• Cardiovascular:

  • Cardiomyopathy

• Central Nervous System:

  • Dizziness

• Gastrointestinal:

  • Pancreatitis
  • Gastrointestinal Hemorrhage

• Hematologic & Oncologic:

  • Thrombocytopenia
  • Basal Cell Carcinoma
  • Malignant Neoplasm
  • Malignant Melanoma

• Hypersensitivity:

  • Hypersensitivity

• Ophthalmic:

  • Uveitis

• Renal:

  • Interstitial Nephritis

• Respiratory:

  • Nasopharyngitis

• Miscellaneous:

  • Febrile Reaction

Contraindications to Dabrafenib (Tafinlar):

The US labeling of the manufacturer doesn't contain any containdications.

Canadian labeling: Hypersensitivity of dabrafenib and any component of the formulation

Warnings and precautions

• Cardiomyopathy

  • Cardiac dysfunction can require interruption of dabrafenib therapy (see trametinib Monograph for trametinib dosage adjustments).
  • Some patients experience cardiomyopathy after treatment interruptions, dose adjustments or permanent discontinuation.
  • Cardiomyopathy can occur when trametinib is used alone or in combination.
  • Before starting combination therapy, assess LVEF by echocardiogram or MUGA scan at one month. Then, every 2 to 3 years, while on therapy.

• Dermatologic toxicities:

  • You should monitor for signs and symptoms of skin toxicity, and secondary infections.
  • It is possible to interrupt treatment, reduce dosage, or discontinue therapy.
  • Combining trametinib with trametinib can lead to serious dermatologic toxicities (eg, rash and acneiform rash as well as dermatitis and palmar-plantar syndrome).
  • This is a known complication of single agent trametinib therapy.
  • Some patients needed hospitalization due to severe toxicity or secondary skin infections.

• Febrile reactions

  • It is possible to reduce or discontinue dosage. In the event of a febrile reaction, it may be necessary to administer antipyretics as secondary prevention.
  • For pyrexia that is not accompanied by complications, such as hypotension, dehydration or severe chills/rigors, you should take prednisone 10mg daily or an equivalent for at least 5 days.
  • Serious febrile reactions, including severe fever, were seen in dabrafenib single agent therapy, and when it was used with trametinib.
  • For fevers >=38.5degC (101.3degF), or any other serious febrile reaction, stop dabrafenib treatment immediately.
  • Also, evaluate for signs/symptoms and monitor serum creatinine to determine if there is evidence of kidney function after severe fever.

• Hemorrhage

  • You may need to interrupt treatment and reduce dosage. Permanently discontinue trametinib and dabrafenib for all grade 4 hemorhagic events.
  • Dabrafenib may cause hemorhage or symptomatic bleeding in critical areas/organs.
  • Major bleeding events (some of which are fatal) include intracranial, retroperitoneal and subarachnoid hemorhages.

• Hyperglycemia

  • Patients with diabetes or hyperglycemia should monitor their serum glucose at baseline as well as any clinically indicated intervals.
  • Treatment may cause hyperglycemia (either with trametinib alone or with combination therapy).
  • If this happens, you may need to initiate insulin or oral hypoglycemic agents therapy (or a higher dose if you are already taking).

• Malignancy

  • CuSCC was less common when used with trametinib to treat melanoma.
  • Patients with NSCLC also had cases of cuSCC.
  • Although rare, basal cell carcinoma (BCC), can also be caused by combination or single-agent treatment. However, it is possible for patients to experience more than one BCC.
  • Before starting therapy, you should have a dermatology evaluation.
  • This can be done every 2 months, or for as long as 6 months after discontinuation.
  • Single-agent dabrafenib therapy was associated with an increase in the incidence of cutaneous squamous cells carcinoma (cuSCC), and new primary melanomas (cuSCC).
  • This increased incidence was compared to control therapy in clinical trials.
  • Studies of melanoma monotherapy showed that approximately one-third (or more) of patients with cuSCC developed multiple occurrences.
  • Combination therapy can cause noncutaneous malignancies. Monitor for any signs or symptoms.
  • If RAS mutation-positive, noncutaneous malignancies develop, Dabrafenib must be discontinued permanently (no trametinib dose reduction required).

• Ocular toxicities:

  • During treatment with combination therapy, it is important to have regular ophthalmic examinations (including retinal evaluation).
  • Uveitis can include iritis and iridocyclitis. This condition is treatable with dabrafenib single agent therapy or when combined with trametinib.
  • Combining trametinib with melanoma was shown to cause retina pigment epithelial dislocations (RPED). This is a known side effect of single-agent trametinib therapy.
  • The retina's central macular area was the most common location for detachments. They were usually bilateral and multifocal.
  • Refer patients to an ophthalmologist immediately (within 24hrs) if there is a loss of sight or other visual disturbances.
  • This may require dabrafenib treatment interruption (or permanent discontinuation) but not trametinib therapy alteration.
  • You should be looking out for any signs or symptoms of uveitis, such as eye pain, photophobia, vision problems, and so on.

• Extension of QT

  • Patients at higher risk of arrhythmias should be treated with caution.
  • QTcF prolongation of >60 msec above baseline, or to >500msec was reported (rarely), either as a single agent in combination with trametinib.

• Venous thromboembolism

  • Dabrafenib therapy can be continued for DVT or PE that is not complicated; for PE that is life-threatening, trametinib should be permanently discontinued.
  • Combining dabrafenib with trametinib can lead to fatal venous thromboembolism events (some even fatal).
  • Combination therapy was associated with a higher incidence of DVT and PE.
  • If symptoms such as DVT or PE are present, patients should immediately seek medical attention.

Dabrafenib: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• BRAFV600K or V600E mutation status (prior to treatment);
• serum glucose (particularly in patients with preexisting diabetes mellitus or hyperglycemia);
• electrolytes;
• renal function;
• dermatologic evaluations prior to initiation, every 2 months during therapy, and for up to 6 months following discontinuation to assess for new cutaneous malignancies;
• monitor for febrile drug reactions and signs/symptoms of infections;
• signs/symptoms of uveitis (eg, eye pain, photophobia, vision changes),
• monitor for signs/symptoms of hemolytic anemia, dermatologic toxicity (including secondary infections), and for noncutaneous malignancies.

For patients receiving combination therapy with trametinib:

• Hepatic function;
• CBC (baseline and periodically during therapy);
• assess LVEF (by echocardiogram or MUGA scan) at baseline, 1 month after therapy initiation, and then at 2- to 3-month intervals;
• monitor for signs/symptoms of hemorrhage, venous thromboembolism, interstitial lung disease, and RPED, or retinal vein occlusion.
• Monitor adherence.

How to administer Dabrafenib (Tafinlar)?

Oral:

• Administer orally at least 1 hour before or 2 hours after a meal; doses should be ~12 hours apart.
• Do not open, crush, or break capsules.
• When administered in combination with trametinib, take the one-time daily dose of trametinib at the same time every day with either the morning or evening dose of dabrafenib.

Mechanism of action of Dabrafenib (Tafinlar):

• Dabrafenib inhibits certain mutations in the protein kinase BRAF (BRAF) selectively. 
• BRAF V600 mutations cause constitutive activation (BRAF) of the BRAF pathway.
• Dabrafenib inhibits tumor growth by BRAF inhibition.
• Combining trametinib with dabrafenib results in greater inhibition of MAPK pathway activity, leading to BRAF V600 cell death.
• It has been shown that trametinib and dabrafenib can work together to inhibit cell growth in lung carcinoma cell lines that are BRAF V600E mutant.

Absorption:

• Decreased with a high-fat meal (~1,000 calories; 58 to 75 grams of fat)

Protein binding

•  99.7% to plasma proteins

Metabolism:

• Hepatic via CYP2C8 and CYP3A4 to hydroxy-dabrafenib (active) which is further metabolized via CYP3A4 oxidation to the active metabolite desmethyl-dabrafenib.

Bioavailability:

• 95%

Half-life elimination:

• Parent drug: 8 hours;
• Hydroxy-dabrafenib (active metabolite): 10 hours;
• Desmethyl-dabrafenib (active metabolite): 21 to 22 hours

Time to peak:

• 2 hours;
• The time to reach peak concentration is delayed with a high-fat meal (~1,000 calories; 58 to 75 grams of fat)

Excretion:

• Feces (71%);
• urine (23%; metabolites only)

International Brand Names of Dabrafenib:

• Tafinlar

Dabrafenib Brands Names in Pakistan: 

No brand is available in Pakistan.