Dabrafenib (Monograph)

Brand name: Tafinlar
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Nov 16, 2023. 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 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 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 solid tumors; safety and efficacy not established.

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 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 solid tumors; safety and efficacy not established.

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 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; no FDA-approved diagnostic test currently available for detection ofBRAF V600E in solid tumors other than melanoma and NSCLC.

Not recommended for use in patients with wild-type BRAF solid tumors; safety and efficacy not established.

Solid Tumors

Used in combination with trametinib for treatment of adult and pediatric patients ≥1 year of age with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment. Designated an orphan drug by FDA when used for malignant glioma.

Testing (e.g., THxID BRAF kit) required to confirm presence of BRAF V600E mutation prior to initiation of therapy; no FDA-approved diagnostic test currently available for detection of BRAF V600E in solid tumors other than melanoma and NSCLC.

Not indicated for use in patients with BRAF-mutant colorectal cancer because of intrinsic resistance to BRAF inhibition. Not recommended for use in patients with wild-type BRAF solid tumors; safety and efficacy not established.

Low-grade Glioma

Used in combination with trametinib for the treatment of pediatric patients ≥1 year of age with low-grade glioma with a BRAF V600E mutation who require systemic therapy.

Testing (e.g., THxID BRAF kit) required to confirm presence of BRAF V600E mutation prior to initiation of therapy; no FDA-approved diagnostic test currently available for detection of BRAF V600E in low-grade glioma.

Not recommended for use in patients with wild-type BRAF solid tumors; safety and efficacy not established.

Dabrafenib Dosage and Administration

General

Pretreatment Screening

• Melanoma: Confirm presence of the BRAF V600E mutation in tumor specimens prior to initiation of dabrafenib as a single agent and presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of combination therapy with dabrafenib and trametinib.

• Non-small cell lung cancer (NSCLC): Confirm presence of the BRAF V600E mutation in tumor specimens prior to initiation of combination therapy with dabrafenib and trametinib for the treatment of metastatic NSCLC.

• Anaplastic thyroid cancer: Confirm presence of the BRAF V600E mutation in tumor specimens prior to initiation of combination therapy with dabrafenib and trametinib for the treatment of locally advanced or metastatic anaplastic thyroid cancer.

• Solid tumors: Confirm presence of the BRAF V600E mutation in tumor specimens prior to initiation of combination therapy with dabrafenib and trametinib for the treatment of unresectable or metastatic solid tumors.

• Low-grade glioma: Confirm presence of the BRAF V600E mutation in tumor specimens prior to initiation of combination therapy with dabrafenib and trametinib for the treatment of low-grade glioma.

• Perform a dermatologic evaluation prior to initiation of therapy.

• Assess left ventricular ejection fraction (LVEF) by echocardiogram or multigated radionuclide angiography (MUGA) scan prior to the initiation of dabrafenib in combination with trametinib.

• Monitor serum glucose concentrations prior to initiation of therapy in patients with preexisting diabetes mellitus or hyperglycemia.

• Verify pregnancy status in females of reproductive potential prior to initiation of therapy.

Patient Monitoring

• Perform dermatologic evaluations every 2 months during therapy and for up to 6 months following discontinuance of dabrafenib.

• Monitor for signs and symptoms of new noncutaneous malignancies.

• In patients receiving combination therapy with dabrafenib and trametinib, assess LVEF by echocardiogram or MUGA scan 1 month after initiation of therapy, and then every 2–3 months during combination therapy.

• Monitor serum glucose concentrations as clinically appropriate in patients with preexisting diabetes mellitus or hyperglycemia.

• Monitor for signs and symptoms of uveitis (e.g., vision change, photophobia, eye pain).

• Monitor patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency for manifestations of hemolytic anemia.

• Monitor for signs and symptoms of bleeding due to the risk of hemorrhage.

• Monitor for new or worsening serious skin reactions during therapy, including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS).

Premedication and Prophylaxis

• Administer antipyretics as secondary prophylaxis when resuming dabrafenib therapy following resolution of a severe febrile reaction or fever associated with complications.

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), dabrafenib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Other General Considerations

• Clinicians should consult published protocols for information on the dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens with dabrafenib. When used in combination with trametinib, the usual cautions, precautions, and contraindications associated with trametinib must be considered in addition to those associated with dabrafenib.

Administration

Oral Administration

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

Dabrafenib tablets for oral suspension: Do not chew or crush tablets and do not swallow whole. Prepare suspension by dissolving tablets with approximately 5 mL (1 to 4 tablets) or 10 mL (5 to 15 tablets) of water in provided cup. Fully dissolve tablets by gently stirring the tablets and water with the handle of a teaspoon; may take at least 3 minutes. Resulting suspension should be cloudy white. Administer suspension immediately after preparation from the cup, oral dosing syringe, or feeding tube. Discard suspension if not administered within 30 minutes after preparation.

If a dose of dabrafenib is missed, take the dose as soon as it is remembered, but only if it can be taken at least 6 hours prior to the next scheduled dose.

If vomiting occurs after administration, do not take an additional dose. Take the next dose at its scheduled time.

Dosage

Available as dabrafenib mesylate; dosage expressed in terms of dabrafenib. Refer to the trametinib prescribing information for recommended trametinib dosage regimens.

Pediatric Patients

Solid Tumors

Oral (Capsules)

Pediatric patients ≥1 year of age: 150 mg (two 75 mg capsules) twice daily for patients who weigh ≥51 kg; 100 mg twice daily for patients who weigh 38-50 kg; 75 mg twice daily for patients who weigh 26-37 kg. Continue therapy until disease progression or unacceptable toxicity occurs.

Recommended dosage of dabrafenib capsules not established for patients weighing <26 kg.

Oral (Tablets for Oral Suspension)

Pediatric patients ≥1 year of age: Recommended dosage based on body weight (see Table 1).

Low-grade Glioma

Oral (Capsules)

Pediatric patients ≥1 year of age: 150 mg (two 75 mg capsules) twice daily for patients who weigh ≥51 kg; 100 mg twice daily for patients who weigh 38-50 kg; 75 mg twice daily for patients who weigh 26-37 kg. Continue therapy until disease progression or unacceptable toxicity occurs.

Recommended dosage of dabrafenib capsules not established for patients weighing <26 kg.

Oral (Tablets for Oral Suspension)

Pediatric patients ≥1 year of age: Recommended dosage based on body weight (see Table 1).

Adults

Melanoma

Adjuvant Therapy for Melanoma

Oral

150 mg (two 75 mg capsules) 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 (two 75 mg capsules) twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Combination Therapy for Unresectable or Metastatic Melanoma

Oral

150 mg (two 75 mg capsules) twice daily (use in combination with trametinib). Continue therapy until disease progression or unacceptable toxicity occurs.

NSCLC

Oral

150 mg (two 75 mg capsules) twice daily (use in combination with trametinib). Continue therapy until disease progression or unacceptable toxicity occurs.

Solid Tumors

Oral

150 mg (two 75 mg capsules) 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 or discontinued in patients who develop adverse effects.

Dosage reductions for dabrafenib capsules and dabrafenib tablets for oral suspension for adverse reactions are presented in Tables 2 and 3. Permanently discontinue dabrafenib capsules if a patient is unable to tolerate the 50 mg twice daily dosage regimen.

New Primary Cutaneous Malignancies

Oral

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

New Primary Noncutaneous Malignancies

Oral

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

Febrile Drug Reactions

Oral

Fever of 38–40°C or any initial symptom of fever recurrence: 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 for ≥24 hours; once fever resolves, resume therapy with reduced dosage.

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.

Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS): Permanently discontinue dabrafenib.

Cardiac Effects

Oral

If symptomatic CHF occurs or LVEF decreases by >20% from baseline and to a level below the lower limit of normal (LLN), withhold dabrafenib therapy; therapy may be resumed at the same dosage when LVEF improves to at least the institutional LLN and absolute decrease to ≤10% compared to baseline.

Hemorrhage

Oral

Intolerable grade 2 or any grade 3 hemorrhagic events: Withhold dabrafenib therapy. If improvement to grade 0 or 1 observed, resume therapy at reduced dosage. If no improvement observed, permanently discontinue the drug.

Grade 4 hemorrhagic events: Permanently discontinue dabrafenib.

Venous Thromboembolism

Oral

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

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.

Mild or moderate 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: 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 or for persistent uveitis of grade 2 or greater, permanently discontinue the drug.

Pulmonary Effects

Oral

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

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

In patients with mild hepatic impairment (bilirubin ≤ the upper limit of normal [ULN] and AST >ULN or bilirubin >1–1.5 times the ULN and any AST level), dosage adjustments are not necessary.

Patients with moderate hepatic impairment (bilirubin >1.5–3 times the ULN and any AST) or severe hepatic impairment (bilirubin >3–10 times the ULN and any AST) may have increased exposure to dabrafenib; however, an appropriate dosage has not been established for these patients.

Renal Impairment

No specific dosage recommendations.

Geriatric Use

No specific dosage recommendations.

Cautions for Dabrafenib

Contraindications

• None.

Warnings/Precautions

Combination Therapy

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

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 clinical trials.

Cutaneous squamous cell carcinoma, basal cell carcinoma, new primary melanoma, and noncutaneous malignancies reported in patients receiving dabrafenib in combination with trametinib in clinical trials.

Perform dermatologic evaluations prior to initiation of dabrafenib, every 2 months during therapy, and for up to 6 months following discontinuance of the drug.

Monitor for signs and symptoms of new noncutaneous malignancies.

If new primary RAS mutation-positive, noncutaneous malignancies develop, permanently discontinue drug.

Tumor Promotion in Wild-Type BRAF Tumors

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

Not recommended in patients with wild-type BRAF solid tumors.

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.

Cardiomyopathy

Cardiomyopathy (defined as an absolute decrease in LVEF from baseline of ≥10% and to a level below the institution-specific LLN) reported.

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.

Uveitis

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.

Serious Febrile 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.

Interrupt dabrafenib monotherapy and combination treatment with trametinib and evaluate the patient for manifestations of infection if the patient's temperature is ≥38ºC. Monitor renal function (e.g., S_cr) during and following severe pyrexia. Dosage modification or treatment discontinuance may be necessary.

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.

Serious Skin Toxicities

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS), reported during postmarketing experience with dabrafenib in combination with trametinib.

Monitor for new or worsening serious skin toxicities. Dosage modification or treatment discontinuance may be necessary. Permanently discontinue drug if SCARs occur. For other skin toxicities, withhold dabrafenib for intolerable or severe skin toxicity. Resume treatment at a lower dosage in patients with improvement or recovery from skin toxicity within 3 weeks; permanently discontinue therapy if skin toxicity has not improved within 3 weeks.

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. Initiate and optimize antihyperglycemic therapy as clinically indicated.

Glucose-6-Phosphate Dehydrogenase Deficiency

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.

Hemophagocytic Lymphohistiocytosis

Dabrafenib in combination with trametinib may result in hemophagocytic lymphohistiocytosis (HLH). Interrupt therapy if HLH suspected. If diagnosis confirmed, discontinue therapy and initiate appropriate HLH management.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and animal findings; teratogenic and embryotoxic in animals.

Verify pregnancy status in females of reproductive potential prior to initiation of therapy. Advise females of reproductive potential to use effective nonhormonal contraception during treatment and for 2 weeks after the last dose.

Advise females to contact their clinician if pregnancy is suspected or confirmed.

Specific Populations

Pregnancy

May cause fetal harm.

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

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.

Females and Males of Reproductive Potential

Verify pregnancy status in females of reproductive potential prior to initiation of therapy.

Since hormonal contraceptives may be ineffective when used concomitantly with dabrafenib, female patients of reproductive potential should use an effective nonhormonal method of contraception during treatment and for 2 weeks after the last dose.

Advise male patients (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with dabrafenib and for ≥2 weeks after the last dose.

May reduce male and female fertility.

Pediatric Use

Safety and efficacy of dabrafenib in combination with trametinib established in pediatric patients ≥1 year of age with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfatory alternative treatment options, or with low-grade glioma with BRAF V600E mutation who require systemic therapy. Safety and efficacy of dabrafenib in combination with trametinib not established in pediatric patients <1 year of age. Safety and efficacy of dabrafenib as monotherapy 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 clinical trials evaluating dabrafenib 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.

In clinical trials evaluating dabrafenib and trametinib combination therapy in patients with anaplastic thyroid cancer, insufficient data to determine whether geriatric patients respond differently than younger adults.

Hepatic Impairment

Moderate hepatic impairment (bilirubin >1.5–3 times the ULN and any AST) or severe hepatic impairment (bilirubin >3–10 times the ULN and any AST): possible increased exposure to dabrafenib.

Renal Impairment

Clinically relevant pharmacokinetic differences not observed in patients with renal impairment (eGFR 15–89 mL/minute per 1.73 m²).

Common Adverse Effects

Adverse effects (≥20%) with dabrafenib monotherapy in adults: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome).

Adverse effects (≥20%) with dabrafenib in combination with trametinib for treatment of previously untreated unresectable or metastatic melanoma in adults: pyrexia, rash, chills, headache, arthralgia, cough.

Adverse effects (≥20%) with dabrafenib in combination with trametinib for adjuvant treatment of melanoma in adults: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, myalgia.

Adverse effects (≥20%) with dabrafenib in combination with trametinib for treatment of metastatic NSCLC in adults: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, dyspnea.

Adverse effects (≥20%) with dabrafenib in combination with trametinib for treatment of adults with solid tumors: pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, edema.

Adverse effects (≥20%) with dabrafenib in combination with trametinib for treatment of pediatric patients with solid tumors: pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, paronychia.

Adverse effects (≥20%) with dabrafenib in combination with trametinib for treatment of pediatric patients with low-grade glioma: pyrexia, rash, headache, vomiting, musculokeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, dermatitis acneiform.

Drug Interactions

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.

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 Affected by Transport Proteins

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.

Pharmacokinetics in pediatric patients (1 to 18 years of age) with glioma and other solid tumors following single or multiple doses are within range observed in adults given the same dose based on weight. Weight (6 to 156 kg) had a statistically significant effect on dabrafenib oral clearance in this population.

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

Stability

Storage

Oral

Capsules

Store in original bottle with dessicant at 20–25°C (excursions permitted to 15–30°C).

Oral

Tablets for oral suspension

Store in original bottle with dessicant at 20–25°C (excursions permitted 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

• Take dabrafenib exactly as prescribed and do not alter the dosage or discontinue therapy unless advised to do so by a clinician.

• Advise patient or caregiver to read instructions for use for dabrafenib tablets for oral suspension for directions on preparing and administering the drug.

• Advise patients to take dabrafenib at least 1 hour before or 2 hours after a meal.

• Advise patients to take a missed dose as soon as remembered, but only if it can be taken at least 6 hours prior to the next scheduled dose.

• Inform patients of the risk of new primary cutaneous and noncutaneous malignancies. Advise patients to inform their clinician promptly if dermatologic changes (i.e., new lesions, changes to existing lesions) or signs and/or symptoms of other malignancies occur.

• Inform patients of the risk of intracranial and GI hemorrhage. Advise patients to inform their clinician promptly if signs and/or symptoms of unusual bleeding or hemorrhage occur.

• Inform patients of the risk of cardiomyopathy. Advise patients to inform their clinician promptly if signs and/or symptoms of heart failure occur.

• Inform patients of the risk of serious febrile drug reactions and the increased incidence and severity of pyrexia with dabrafenib/trametinib combination therapy. Advise patients to inform their clinician if fever occurs.

• Inform patients of the risk of serious skin toxicities. Advise patients to inform their clinician if progressive or intolerable rash occurs.

• Inform patients of the risk of impaired glucose control in patients with diabetes mellitus resulting in need for more intensive antidiabetic treatment. Advise patients to inform their clinician if symptoms of severe hyperglycemia occur.

• Inform patients of the risk of hemolytic anemia in patients with G-6-PD deficiency. Advise patients with known G-6-PD deficiency to contact their clinician if manifestations of anemia or hemolysis occur.

• Inform females of the risk of fetal harm if taken during pregnancy. Advise females of reproductive potential to use effective nonhormonal contraception during treatment and for 2 weeks after the last dose. Advise males (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment and for at least 2 weeks after the last dose. Advise patients to contact their clinician if pregnancy is suspected or confirmed during treatment.

• Advise females to avoid breast-feeding while receiving dabrafenib and for 2 weeks after the last dose.

• Advise males and females of reproductive potential that dabrafenib may reduce male and female fertility.

• Inform patients of the risk of uveitis, iritis, and iridocyclitis. Advise patients to contact their clinician promptly if any vision changes or other ocular effects (e.g., ocular pain, swelling, redness, blurred vision) occur.

• Advise patients to inform their clinician 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).

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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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