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TAFINLAR® (dabrafenib) capsule

DESCRIPTION CLINICAL PHARMACOLOGY INDICATIONS AND USAGE
CONTRAINDICATIONS PRECAUTIONS ADVERSE REACTIONS
DOSAGE AND ADMINISTRATION HOW SUPPLIED WARNINGS
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Drug updates TAFINLAR (dabrafenib) capsules, for oral use
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2013

Mechanism of Action: Dabrafenib is an inhibitor of some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. Dabrafenib also inhibits wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM, respectively, and other kinases such as SIK1, NEK11, and LIMK1 at higher concentrations. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth [see Indications and Usage (1)]. Dabrafenib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo.

Dabrafenib and trametinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of dabrafenib and trametinib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive melanoma cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive melanoma xenografts compared with either drug alone.


WARNINGS  top of page

See warnings and precautions below.

DESCRIPTION  top of page

Dabrafenib mesylate is a kinase inhibitor. The chemical name for dabrafenib mesylate is N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt. It has the molecular formula C23H20F3N5O2S2•CH4O3S and a molecular weight of 615.68.

Dabrafenib mesylate is a white to slightly colored solid with three pKas: 6.6, 2.2, and -1.5. It is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media.

TAFINLAR (dabrafenib) capsules are supplied as 50-mg and 75-mg capsules for oral administration. Each 50-mg capsule contains 59.25 mg dabrafenib mesylate equivalent to 50 mg of dabrafenib free base. Each 75-mg capsule contains 88.88 mg dabrafenib mesylate equivalent to 75 mg of dabrafenib free base.

The inactive ingredients of TAFINLAR are colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose. Capsule shells contain hypromellose, red iron oxide (E172), and titanium dioxide (E171).

CLINICAL PHARMACOLOGY: top of page

Mechanism of Action:
Dabrafenib is an inhibitor of some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. Dabrafenib also inhibits wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM, respectively, and other kinases such as SIK1, NEK11, and LIMK1 at higher concentrations. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth [see Indications and Usage below]. Dabrafenib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo.

Dabrafenib and trametinib target two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway. Use of dabrafenib and trametinib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive melanoma cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive melanoma xenografts compared with either drug alone.

INDICATIONS AND USAGE  top of page

INDICATIONS AND USAGE:
TAFINLAR is a kinase inhibitor indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

TAFINLAR in combination with trametinib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. The use in combination is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with trametinib.

Limitation of Use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.  [see Warnings and Precautions]

CONTRAINDICATIONS top of page

None.

PRECAUTIONS top of page

WARNINGS AND PRECAUTIONS:

  1. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or in combination with trametinib. Monitor patients for new malignancies prior to initiation of therapy, while on therapy, and following discontinuation of TAFINLAR or the combination therapy.
  2. Tumor Promotion in BRAF Wild-Type Melanoma: Increased cell proliferation can occur with BRAF inhibitors.
  3. Hemorrhage: Major hemorrhagic events can occur in patients receiving TAFINLAR in combination with trametinib. Monitor for signs and symptoms of bleeding.
  4. Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur in patients receiving TAFINLAR in combination with trametinib.
  5. Cardiomyopathy: Assess LVEF before treatment with TAFINLAR in combination with trametinib, after one month of treatment, then every 2 to 3 months thereafter.
  6. Ocular Toxicities: Perform ophthalmologic evaluation for any visual disturbances.
  7. Serious Febrile Reactions: Incidence and severity of pyrexia are increased with TAFINLAR in combination with trametinib.
  8. Serious Skin Toxicity: Monitor for skin toxicities and for secondary infections. Discontinue for intolerable Grade 2, or Grade 3 or 4 rash not improving within 3 weeks despite interruption of TAFINLAR.
  9. Hyperglycemia: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia.
  10. Glucose-6-Phosphate Dehydrogenase Deficiency: Closely monitor for hemolytic anemia.
  11. Embryofetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus. TAFINLAR may render hormonal contraceptives less effective and an alternative method of contraception should be used.

ADVERSE REACTIONS top of page

ADVERSE REACTIONS
  1. Most common adverse reactions (geq20%) for TAFINLAR as a single agent are hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome.
  2. Most common adverse reactions (geq20%) for TAFINLAR in combination with trametinib are pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia.

To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS:
>Avoid concurrent administration of strong inhibitors of CYP3A4 or CYP2C8.

>Avoid concurrent administration of strong inducers of CYP3A4 or CYP2C8.

>Concomitant use with agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in loss of efficacy of these agents.

USE IN SPECIFIC POPULATIONS:
>Nursing Mothers: Discontinue drug or nursing.

>Females and Males of Reproductive Potential: Advise female patients to use highly effective contraception during treatment and for 2 weeks following discontinuation of treatment. Advise male patients of potential risk for impaired spermatogenesis.

See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide.

DOSAGE AND ADMINISTRATION  top of page

DOSAGE AND ADMINISTRATION:
Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR as a single agent. Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with TAFINLAR in combination with trametinib.

The recommended dose of TAFINLAR is 150 mg orally twice daily as a single agent or in combination with trametinib 2 mg orally once daily. Take TAFINLAR at least 1 hour before or at least 2 hours after a meal.

HOW SUPPLIED top of page

DOSAGE FORMS AND STRENGTHS:
Capsules: 50 mg, 75 mg.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F)

REFERENCE

Package insert data:   [Accessed: Jan 2014]
GlaxoSmithKline
Research Triangle Park, NC 27709
Revised: January 2014

Principal Display Panel
NDC 0173-0846-08
Tafinlar®
(Dabrafenib) Capsules
50 mg
Rx only
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