Dabrafenib

Class: Antineoplastic Agents
Chemical Name: N-[3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluoro-benzenesulfonamide methanesulfonate (1:1)
Molecular Formula: C₂₃H₂₀F₃N₅O₂S₂•CH₄O₃S
CAS Number: 1195768-06-9
Brands: Tafinlar

Medically reviewed by Drugs.com on May 17, 2021. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of b-Raf serine-threonine kinase (BRAF) with V600E or V600K mutation.

Uses for Dabrafenib

Melanoma

Used in combination with trametinib as adjuvant therapy following complete resection of melanoma with BRAF V600E or V600K mutation and nodal involvement.

Used as a single agent for the treatment of unresectable or metastatic melanoma in patients with BRAF V600E mutation (designated an orphan drug by FDA as monotherapy for this use).

Used in combination with trametinib for treatment of unresectable or metastatic melanoma in patients with BRAF V600E or V600K mutation (designated an orphan drug by FDA when used in combination for this use).

FDA-approved diagnostic test (e.g., THxID BRAF kit) required to confirm presence of BRAF V600E mutation prior to initiation of monotherapy; also required to confirm presence of BRAF V600E or V600K prior to initiation of combination therapy.

Not recommended for use in patients with wild-type BRAF melanoma; safety and efficacy not established. (See Tumor Promotion in Wild-Type BRAF Tumors under Cautions.)

NSCLC

Used in combination with trametinib for treatment of metastatic non-small cell lung cancer (NSCLC) in patients with BRAF V600E mutation (designated an orphan drug by FDA when used in combination for this use).

FDA-approved diagnostic test (e.g., THxID BRAF kit) required to confirm presence of BRAF V600E mutation prior to initiation of therapy.

Not recommended for use in patients with wild-type BRAF NSCLC; safety and efficacy not established. (See Tumor Promotion in Wild-Type BRAF Tumors under Cautions.)

Anaplastic Thyroid Cancer

Used in combination with trametinib for treatment of locally advanced or metastatic anaplastic thyroid cancer in patients with BRAF V600E mutation when no satisfactory locoregional treatment options are available (designated an orphan drug by FDA when used in combination for this use).

FDA-approved diagnostic test (e.g., THxID BRAF kit) required to confirm presence of BRAF V600E mutation prior to initiation of therapy.

Not recommended for use in patients with wild-type BRAF anaplastic thyroid cancer; safety and efficacy not established. (See Tumor Promotion in Wild-Type BRAF Tumors under Cautions.)

Dabrafenib Dosage and Administration

General

• Confirm presence of BRAF V600E mutation prior to initiation of monotherapy for the treatment of unresectable or metastatic melanoma.

• Confirm presence of BRAF V600E mutation prior to initiation of dabrafenib/trametinib combination therapy for the treatment of metastatic NSCLC or locally advanced or metastatic anaplastic thyroid cancer.

• Confirm presence of BRAF V600E or V600K mutation prior to initiation of dabrafenib/trametinib combination therapy for the treatment of unresectable or metastatic melanoma or for the adjuvant treatment of melanoma.

Administration

Oral Administration

Administer orally twice daily, approximately every 12 hours, at least 1 hour before or 2 hours after a meal.

Do not open, crush, or break capsules.

Dosage

Available as dabrafenib mesylate; dosage expressed in terms of dabrafenib.

Adults

Melanoma

Adjuvant Therapy for Melanoma

Oral

150 mg twice daily (use in combination with trametinib). Continue therapy for up to 1 year or until disease progression or unacceptable toxicity occurs.

Monotherapy for Unresectable or Metastatic Melanoma

Oral

150 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Combination Therapy for Unresectable or Metastatic Melanoma

Oral

150 mg twice daily (use in combination with trametinib). Continue therapy until disease progression or unacceptable toxicity occurs.

NSCLC

Oral

150 mg twice daily (use in combination with trametinib). Continue therapy until disease progression or unacceptable toxicity occurs.

Anaplastic Thyroid Cancer

Oral

150 mg twice daily (use in combination with trametinib). Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Oral

Dosage may be reduced or therapy temporarily interrupted in patients who develop adverse effects. Up to 3 dosage reductions for toxicity may be made.

If necessary, initially reduce dosage to 100 mg twice daily. If further dosage reduction necessary, reduce dosage to 75 mg twice daily or subsequently to 50 mg twice daily. For patients unable to tolerate 50 mg twice daily, permanently discontinue the drug.

When used in combination with trametinib, dosage modification of trametinib for toxicity also may be required.

Dosage Modification for New Primary Cutaneous Malignancies

Oral

If new primary cutaneous malignancies occur, dosage modification of dabrafenib not necessary.

Dosage Modification for New Primary Noncutaneous Malignancies

Oral

If new RAS mutation-positive, noncutaneous malignancies occur, permanently discontinue dabrafenib.

Dosage Modification for Febrile Drug Reactions

Oral

Fever of 38.5–40°C: Interrupt dabrafenib therapy until fever resolves; resume therapy at same or reduced dosage.

Fever >40°C or fever with complications (e.g., rigors, hypotension, dehydration, renal failure): Permanently discontinue dabrafenib. Alternatively, withhold drug until fever resolves; resume therapy with reduced dosage.

Dosage Modification for Dermatologic Effects

Oral

Intolerable grade 2 skin toxicity: Withhold dabrafenib for up to 3 weeks. If improvement observed within 3 weeks, resume therapy at reduced dosage. If no improvement observed within 3 weeks, permanently discontinue the drug.

Grade 3 or 4 skin toxicity: Withhold dabrafenib for up to 3 weeks. If improvement observed within 3 weeks, resume therapy at reduced dosage. If no improvement observed within 3 weeks, permanently discontinue the drug.

Dosage Modification for Cardiac Effects

Oral

Symptomatic CHF or asymptomatic decrease in LVEF from baseline >20% and to a level below lower limit of normal (LLN): Withhold dabrafenib therapy until LVEF is at or above the LLN and no more than 10% below baseline value, and then resume therapy at same dosage.

Dosage Modification for Hemorrhage

Oral

Grade 3 hemorrhagic events: Withhold dabrafenib therapy. If improvement observed, resume therapy at reduced dosage. If no improvement observed, permanently discontinue the drug.

Grade 4 hemorrhagic events: Permanently discontinue dabrafenib.

Dosage Modification for Venous Thromboembolism

Oral

Uncomplicated venous thromboembolism (VTE) with dabrafenib/trametinib combination therapy: Dosage modification of dabrafenib not recommended.

Dosage Modification for Ocular Effects

Oral

Retinal pigment epithelial detachment or retinal vein occlusion with dabrafenib/trametinib combination therapy: Dosage modification of dabrafenib not recommended.

Iritis: Continue therapy at same dosage and initiate ocular therapy.

Grade 2 or 3 uveitis unresponsive to ocular therapy: Interrupt dabrafenib therapy for up to 6 weeks. If improvement to grade 0 or 1 observed within 6 weeks, resume therapy at same or reduced dosage. If improvement not observed within 6 weeks, permanently discontinue the drug.

Severe uveitis or iridocyclitis: Interrupt dabrafenib therapy for up to 6 weeks and initiate ocular therapy as clinically indicated. If improvement to grade 0 or 1 observed within 6 weeks, resume therapy at same or reduced dosage. If no improvement observed within 6 weeks, permanently discontinue the drug.

Dosage Modification for Pulmonary Effects

Oral

Interstitial lung disease or pneumonitis with dabrafenib/trametinib combination therapy: Dosage modification of dabrafenib not needed.

Dosage Modification for Other Toxicity

Oral

Intolerable grade 2 or any grade 3 adverse reaction: Interrupt therapy until adverse reaction resolves to grade 1 or less; resume therapy at reduced dosage. If no improvement observed, permanently discontinue dabrafenib.

First occurrence any grade 4 adverse reaction: Permanently discontinue dabrafenib. Alternatively, withhold drug until adverse reaction resolves to grade 1 or less; resume at reduced dosage.

Recurrent grade 4 adverse reaction: Permanently discontinue dabrafenib.

Special Populations

Hepatic Impairment

Mild hepatic impairment: Dosage adjustment not necessary.

Moderate to severe hepatic impairment: Appropriate dosage not established.

Renal Impairment

Mild or moderate renal impairment: Dosage adjustment not necessary.

Severe renal impairment: Appropriate dosage not established.

Cautions for Dabrafenib

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Combination Therapy

When combination therapy with dabrafenib includes use of trametinib, cautions, precautions, and contraindications of trametinib also must be considered.

Development of New Primary Malignancies

New primary cutaneous or noncutaneous malignancies reported in patients receiving BRAF inhibitors, including dabrafenib.

Cutaneous squamous cell carcinoma and keratoacanthoma reported in patients receiving dabrafenib monotherapy in the BREAK-3 study.

Cutaneous squamous cell carcinoma, basal cell carcinoma, new primary melanoma, and noncutaneous malignancies reported in patients receiving dabrafenib in combination with trametinib in the COMBI-D, COMBI-AD, and BRF113928 studies.

Perform dermatologic evaluations prior to initiation of dabrafenib monotherapy or dabrafenib/trametinib combination therapy, every 2 months during therapy, and for up to 6 months following discontinuance of dabrafenib. Monitor for signs and symptoms of new noncutaneous malignancies. If new primary RAS mutation-positive, noncutaneous malignancies develop, permanently discontinue drug. (See Dosage Modification For Toxicity under Dosage and Administration.)

Tumor Promotion in Wild-Type BRAF Tumors

In vitro evidence of increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors.

Confirm BRAF V600E mutation prior to initiating dabrafenib monotherapy for the treatment of unresectable or metastatic melanoma or dabrafenib/trametinib combination therapy for the treatment of metastatic NSCLC or locally advanced or metastatic anaplastic thyroid cancer; confirm BRAF V600E or V600K mutation prior to initiating dabrafenib/trametinib combination therapy for the treatment of unresectable or metastatic melanoma or for the adjuvant treatment of melanoma; not recommended in patients with wild-type BRAF melanoma.

Hemorrhage

Hemorrhage (sometimes fatal), including intracranial, retroperitoneal, subarachnoid, or GI hemorrhage, has occurred during dabrafenib/trametinib combination therapy.

Dosage modification or treatment discontinuance may be necessary if hemorrhagic events occur. (See Dosage Modification for Toxicity under Dosage and Administration.)

Cardiac Effects

Cardiomyopathy (defined as an absolute decrease in LVEF from baseline of >10% and to a level below the institution-specific LLN) reported. Cardiomyopathy resolved in 83–86 or 50% of patients with melanoma receiving dabrafenib in combination with trametinib or single-agent dabrafenib, respectively, following dosage interruption, dosage reduction, or discontinuance of dabrafenib. Cardiomyopathy resolved in 50% of patients with NSCLC receiving dabrafenib in combination with trametinib following dosage interruption or discontinuance of dabrafenib.

Assess LVEF by echocardiogram or multigated radionuclide angiography (MUGA) prior to and 1 month after initiation of therapy, then every 2–3 months during therapy. If left ventricular dysfunction occurs, therapy interruption may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)

Ocular Effects

Uveitis reported. If uveitis occurs, symptomatic treatment with ophthalmic corticosteroid or mydriatic preparations may be required.

Monitor patients for signs and symptoms of uveitis (e.g., vision change, photophobia, eye pain). If ocular toxicities occur, therapy interruption, dosage reduction, or discontinuance of the drug and/or initiation of ocular therapy may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)

Febrile Drug Reactions

Serious febrile drug reactions (including fever accompanied by hypotension, rigors/chills, dehydration, or renal failure) reported. Increased incidence and severity of pyrexia observed during dabrafenib/trametinib combination therapy compared with dabrafenib alone.

For any serious febrile reaction or fever complicated by hypotension, rigors/chills, dehydration, or renal failure, interrupt treatment and evaluate patient for manifestations of infection. Monitor renal function (e.g., S_cr) during and following severe pyrexia. Dosage modification or treatment discontinuance may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)

Use prophylactic antipyretics when resuming dabrafenib following serious febrile reactions or fever associated with complications. Use corticosteroids (e.g., prednisone 10 mg daily) for at least 5 days for second or subsequent occurrences of prolonged fever (lasting >3 days) or fever associated with complications (e.g., dehydration, hypotension, renal failure, severe chills/rigors) without evidence of active infection.

Dermatologic Effects

Serious dermatologic toxicity reported in patients receiving dabrafenib/trametinib combination therapy.

Dosage modification or treatment discontinuance may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)

Hyperglycemia

Hyperglycemia requiring increased dosage or initiation of insulin or oral hypoglycemic agents reported in patients receiving dabrafenib.

Monitor serum glucose concentrations in patients with preexisting diabetes mellitus or hyperglycemia prior to initiation of therapy and as clinically appropriate.

Hemolytic Anemia

Potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

Closely monitor patients with G-6-PD deficiency for hemolytic anemia.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenic and embryotoxic in animals.

Advise female patients of childbearing potential to use effective nonhormonal contraception during treatment and for 2 weeks after the last dose. (See Specific Drugs under Interactions.)

If used during pregnancy, inform patient of potential fetal hazard.

Impairment of Fertility

May reduce male and female fertility.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into human milk. Effects on nursing infants and milk production also unknown. Discontinue nursing during therapy and for 2 weeks after the last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No substantial differences in safety and efficacy of dabrafenib monotherapy in those ≥65 years of age relative to younger adults.

In the COMBI-D, COMBI-V, and COMBI-AD studies in patients with melanoma, no overall differences in efficacy of dabrafenib/trametinib combination therapy relative to younger adults observed; some adverse effects (i.e., peripheral edema, anorexia) occurred more frequently in geriatric patients with metastatic melanoma.

Insufficient experience with dabrafenib/trametinib combination therapy in patients ≥65 years of age with NSCLC to determine whether geriatric patients respond differently than younger adults.

Hepatic Impairment

Mild hepatic impairment did not substantially affect systemic exposure of dabrafenib and its metabolites. (See Hepatic Impairment under Dosage and Administration.)

Not studied in patients with moderate or severe hepatic impairment. (See Special Populations under Pharmacokinetics.)

Renal Impairment

Mild to moderate renal impairment did not substantially affect systemic exposure of dabrafenib and its metabolites. (See Renal Impairment under Dosage and Administration.)

Not studied in patients with severe renal impairment.

Common Adverse Effects

Monotherapy in patients with unresectable or metastatic melanoma with BRAF V600E mutation: Hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), hyperglycemia, hypophosphatemia, elevated alkaline phosphatase concentrations.

Combination therapy with trametinib in patients with previously untreated unresectable or metastatic melanoma with BRAF V600E or V600K mutation: Pyrexia, diarrhea, fatigue, nausea, rash, chills, headache, vomiting, arthralgia, hypertension, cough, hyperglycemia, elevated alkaline phosphatase concentrations, hypophosphatemia, hyponatremia.

Combination therapy with trametinib for the adjuvant treatment of melanoma with BRAF V600E or V600K mutation: Pyrexia, fatigue, nausea, headache, chills, rash, diarrhea, arthralgia, vomiting, myalgia, hyperglycemia, elevated AST/ALT concentrations, neutropenia, hypophosphatemia, elevated alkaline phosphatase concentrations, lymphopenia, anemia, hypoalbuminemia.

Combination therapy with trametinib in patients with metastatic NSCLC with BRAF V600E mutation: Pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, dyspnea, hyperglycemia, elevated alkaline phosphatase concentrations, elevated AST/ALT concentrations, hyponatremia, leukopenia, anemia, neutropenia, lymphopenia, hypophosphatemia, elevated S_cr concentrations.

Combination therapy with trametinib in patients with locally advanced or metastatic anaplastic thyroid cancer: Adverse effects similar to those in patients with melanoma or NSCLC.

Interactions for Dabrafenib

Metabolized by CYP3A4 and 2C8; inducer of CYP3A4 and 2C9; in vitro data show dabrafenib as inducer of CYP3A4 and 2B6; possible inducer of other CYP2C isoenzymes.

Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); moderate inhibitor of BCRP in vitro.

Inhibits organic anion-transporting polypeptides (OATP) 1B1 and 1B3; also inhibits organic anion transporters (OAT) 1 and 3 in vitro.

May induce uridine diphosphate-glucuronosyltransferase (UGT).

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A4 or 2C8: Potential pharmacokinetic interaction (increased dabrafenib concentrations). Alternative therapy to potent inhibitors of CYP3A4 or 2C8 recommended. If concomitant use unavoidable, monitor patients closely for dabrafenib-associated adverse reactions.

Potent inducers of CYP3A4 or 2C8: Potential pharmacokinetic interaction (decreased dabrafenib concentrations).

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4, 1A2, 2B6, 2C8, 2C9: Potential pharmacokinetic interaction (decreased concentrations of substrate drug). Alternative therapy to substrate drug recommended. If concomitant use is unavoidable, monitor for reduced efficacy of substrate drug.

Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase

Substrates of UGT: Potential pharmacokinetic interaction (decreased concentrations of substrate drug). Consider alternative therapy to substrate drug. If concomitant use is unavoidable, monitor for reduced efficacy of substrate drug.

Drugs Transported by Organic Anion-Transporting Polypeptide and Organic Anion Transporters

Substrates of OATP1B1, OATP1B3, OAT1, OAT3: Potential pharmacokinetic interactions (increased concentrations of the substrate drug).

Specific Drugs

Dabrafenib Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability 95%.

Following oral administration, peak plasma concentrations attained after approximately 2 hours.

Desmethyl metabolite may be reabsorbed from the gut.

Food

High-fat meal decreased peak plasma concentrations and AUC by 51 and 31%, respectively; also delayed median time to peak plasma concentrations by 3.6 hours.

Distribution

Extent

Not known if distributed into milk.

Plasma Protein Binding

99.7%.

Elimination

Metabolism

Principally mediated by CYP3A4 and 2C8 to form hydroxy-dabrafenib. Hydroxy metabolite further metabolized via CYP3A4 to form carboxy-dabrafenib. Carboxy metabolite further metabolized to desmethyl-dabrafenib via decarboxylation. Hydroxy and desmethyl metabolites likely contribute to clinical activity.

Elimination Route

Fecal (71%) and urinary (23%) excretion.

Half-life

8 hours.

Special Populations

Formal pharmacokinetic study not performed in patients with hepatic impairment; population analysis indicates no clinically important pharmacokinetic changes in patients with mild hepatic impairment. No data available in patients with moderate to severe hepatic impairment; systemic exposure may be increased in these patients.

Formal pharmacokinetic study not performed in patients with renal impairment; population analysis indicates no clinically important pharmacokinetic changes in patients with mild or moderate renal impairment. No data available in patients with severe renal impairment.

Clinically important pharmacokinetic differences based on age, gender, or weight not observed.

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).

Actions

• Potent inhibitor of BRAF with V600E or V600K mutation; also shows some in vitro activity against kinases with BRAF V600D mutation.

• Approximately 50% of cutaneous melanomas carry a BRAF mutation. Most common BRAF mutation is the substitution of glutamic acid for valine at codon 600 in exon 15 (BRAF V600E); mutation involving substitution of lysine for valine at codon 600 in exon 15 (BRAF V600K) occurs less frequently.

• Mutation of BRAF V600E activates the mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) signal transduction pathway, which enhances cell proliferation and tumor progression (e.g., metastasis).

• Paradoxical activation of MAPK and increased cell proliferation observed in BRAF wild-type cells exposed to b-Raf serine-threonine kinase inhibitors.

• Combination therapy with a BRAF inhibitor (i.e., dabrafenib, encorafenib, vemurafenib) and an MEK inhibitor (i.e., binimetinib, cobimetinib, trametinib) results in complete inhibition of the MAPK/ERK pathway.

  Combination therapy with dabrafenib and trametinib resulted in greater growth inhibition of melanoma cell lines and prolonged inhibition of tumor growth in melanoma xenografts testing positive for BRAF V600 mutations in vitro.

Advice to Patients

• Importance of advising patient to read the manufacturer's medication guide before beginning treatment and each time the prescription is refilled.

• Importance of taking dabrafenib exactly as prescribed and of not altering the dosage or discontinuing therapy unless advised to do so by clinician.

• Importance of taking dabrafenib at least 1 hour before or 2 hours after a meal and of not opening, crushing, or breaking the capsules.

• Importance of taking a missed dose as soon as remembered, but only if it can be taken at least 6 hours prior to next scheduled dose.

• Risk of new primary cutaneous and noncutaneous malignancies. Importance of contacting clinician promptly if dermatologic changes (i.e., new lesions, changes to existing lesions) or signs and/or symptoms of other malignancies occur.

• Risk of intracranial and GI hemorrhage. Importance of contacting clinician promptly if signs and/or symptoms of unusual bleeding or hemorrhage occur.

• Risk of cardiomyopathy. Importance of contacting clinician promptly if signs and/or symptoms of heart failure occur.

• Risk of serious febrile drug reactions. Increased incidence and severity of pyrexia with dabrafenib/trametinib combination therapy. Importance of contacting clinician if fever occurs.

• Risk of serious skin toxicities. Importance of contacting clinician if progressive or intolerable rash occurs.

• Risk of impaired glucose control in patients with diabetes mellitus resulting in need for more intensive antidiabetic treatment. Importance of contacting clinician if symptoms of severe hyperglycemia occur.

• Risk of hemolytic anemia in patients with G-6-PD deficiency. Importance of patients with known G-6-PD deficiency contacting clinician if manifestations of anemia or hemolysis occur.

• Risk of fetal harm if taken during pregnancy. Importance of female patients using effective nonhormonal contraception during treatment and for 2 weeks after the last dose. Importance of contacting clinician if pregnancy is suspected or confirmed during treatment.

• Importance of advising women to avoid breast-feeding while receiving encorafenib and for 2 weeks after the last dose.

• Importance of advising men and women of reproductive potential that dabrafenib may reduce male and female fertility.

• Risk of uveitis, iritis, and iridocyclitis. Importance of contacting clinician promptly if any vision changes or other ocular effects (e.g., ocular pain, swelling, redness, blurred vision) occur.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., diabetes).

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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