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Dabrafenib

Medically reviewed by Drugs.com. Last updated on Nov 11, 2020.

Pronunciation

(da BRAF e nib)

Index Terms

  • GSK2118436

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Tafinlar: 50 mg, 75 mg

Brand Names: U.S.

  • Tafinlar

Pharmacologic Category

  • Antineoplastic Agent, BRAF Kinase Inhibitor

Pharmacology

Dabrafenib selectively inhibits some mutated forms of the protein kinase B-raf (BRAF). BRAF V600 mutations result in constitutive activation of the BRAF pathway; through BRAF inhibition, dabrafenib inhibits tumor cell growth. The combination of dabrafenib and trametinib allows for greater inhibition of the MAPK pathway, resulting in BRAF V600 melanoma cell death (Flaherty 2012). Dabrafenib plus trametinib has been reported to synergistically inhibit cell growth in lung cancer cell lines which are BRAF V600E-mutant (Planchard 2016).

Absorption

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

Distribution

70.3 L

Metabolism

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

Excretion

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

Time to Peak

2 hours; delayed with a high-fat meal (~1,000 calories; 58 to 75 grams of fat)

Half-Life Elimination

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

Protein Binding

99.7% to plasma proteins

Special Populations: Hepatic Function Impairment

Patients with moderate (bilirubin >1.5 to 3 times ULN and any AST) or severe (bilirubin >3 to 10 times ULN and any AST) hepatic impairment may have increased dabrafenib exposure.

Use: Labeled Indications

Melanoma:

Adjuvant treatment of melanoma (in combination with trametinib) in patients with a BRAF V600E or BRAF V600K mutation (as detected by an approved test), and lymph node involvement, following complete resection.

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: 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: 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: Dabrafenib is not indicated for treatment of wild-type BRAF melanoma, wild-type BRAF NSCLC, or wild-type BRAF ATC.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to dabrafenib or any component of the formulation.

Dosing: Adult

Note: Confirm BRAF V600 mutation status (in tumor specimens) prior to treatment initiation.

Melanoma, adjuvant treatment (with BRAF V600E or BRAF V600K mutation): Oral: 150 mg twice daily, approximately every 12 hours (in combination with trametinib); continue for up to 1 year in the absence of disease recurrence or unacceptable toxicity (Long 2017).

Melanoma, metastatic or unresectable (with BRAF V600E mutation): Oral: 150 mg twice daily, approximately every 12 hours (single-agent therapy); continue until disease progression or unacceptable toxicity.

Melanoma, metastatic or unresectable (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.

Non-small cell lung cancer, metastatic (with BRAF V600E mutation): Oral: 150 mg twice daily, approximately every 12 hours (in combination with trametinib); continue until disease progression or unacceptable toxicity (Planchard 2016).

Thyroid cancer, anaplastic, locally advanced or metastatic (with BRAF V600E mutation): Oral: 150 mg twice daily, approximately every 12 hours (in combination with trametinib); continue until disease progression or unacceptable toxicity (Subbiah 2018).

Missed doses: A missed dose may be administered up to 6 hours prior to the next dose; do not administer if <6 hours until the next dose (do not make up the missed dose).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Recommended dabrafenib dose reductions for toxicity:

Usual initial dose: 150 mg twice daily.

First dose reduction: 100 mg twice daily.

Second dose reduction: 75 mg twice daily.

Third dose reduction: 50 mg twice daily.

Subsequent modifications (if unable to tolerate 50 mg twice daily): Permanently discontinue.

Note: If using combination therapy, refer to Trametinib monograph for recommended trametinib dose modifications.

Cardiotoxicity:

>20% absolute decrease in left ventricular ejection fraction (LVEF) from baseline and LVEF is below institutional lower limit of normal (LLN): Interrupt dabrafenib therapy until improved to at least the institutional LLN and absolute decrease to ≤10% (compared to baseline), then resume at the same dose.

Symptomatic heart failure: Interrupt dabrafenib therapy until improved to at least the institutional LLN and absolute decrease to ≤10% (compared to baseline), then resume at the same dose.

Dermatologic toxicity:

Intolerable grade 2 toxicity or grade 3 or 4 toxicity: Interrupt dabrafenib therapy for up to 3 weeks. If toxicity improves within 3 weeks, resume dabrafenib at a lower dose. If toxicity does not improve within 3 weeks following therapy interruption, permanently discontinue dabrafenib.

New primary cutaneous malignancy: No dabrafenib dosage modification is necessary.

Severe cutaneous adverse reactions: Permanently discontinue dabrafenib.

Fever:

Fever of 38.5°C to 40°C (101.3°F to 104°F): Interrupt dabrafenib therapy until fever resolves and then resume at the same or lower dose.

Fever >40°C (104°F) and/or fever complicated by rigors, hypotension, dehydration, or renal failure: Interrupt dabrafenib therapy until fever resolves. Resume at a lower dose or permanently discontinue. May require prophylactic antipyretics (secondary prophylaxis) upon resumption. Administer corticosteroids (eg, prednisone 10 mg daily or equivalent) for at least 5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 days of onset of fever, or for fever associated with complications (eg, dehydration, renal failure, hypotension, or severe chills/rigors with no evidence of active infection).

Hemorrhage:

Grade 3 hemorrhage: Interrupt dabrafenib therapy. If hemorrhage improves, resume dabrafenib at a lower dose. If hemorrhage does not improve following therapy interruption, permanently discontinue dabrafenib.

Grade 4 hemorrhage: Permanently discontinue dabrafenib.

Ocular toxicity:

Uveitis including iritis and iridocyclitis: If mild or moderate uveitis does not respond to local ocular therapy (or for severe uveitis), interrupt dabrafenib therapy for up to 6 weeks. If improves to ≤ grade 1 within 6 weeks following therapy interruption, resume dabrafenib at the same or lower dose. If does not improve, or for persistent grade 2 or higher uveitis of >6 week duration, permanently discontinue dabrafenib.

Grade 2 or 3 retinal pigment epithelial detachments (RPED): No dabrafenib dosage modification is necessary.

Retinal vein occlusion: No dabrafenib dosage modification is necessary.

Pulmonary toxicity: Interstitial lung disease or pneumonitis: No dabrafenib dosage modification is necessary.

Venous thromboembolism: Uncomplicated: No dabrafenib dosage modification is necessary.

Other toxicity:

Intolerable grade 2 or any grade 3 toxicity: Interrupt dabrafenib therapy until resolution to ≤ grade 1; resume dabrafenib at a lower dose. If toxicity does not improve following therapy interruption, permanently discontinue dabrafenib.

Grade 4 toxicity (first occurrence): Interrupt dabrafenib therapy until resolution to ≤ grade 1; resume dabrafenib at a lower dose or permanently discontinue.

Grade 4 toxicity (recurrent after dosage reduction): Permanently discontinue dabrafenib.

New primary noncutaneous malignancy (RAS mutation-positive): Permanently discontinue dabrafenib.

Administration

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 once-daily dose of trametinib at the same time each day with either the morning or evening dose of dabrafenib.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Abametapir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Abemaciclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Abemaciclib. Avoid combination

Alfentanil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Alfentanil. Management: If concomitant use of alfentanil and moderate CYP3A4 inducers is necessary, consider dosage increase of alfentanil until stable drug effects are achieved. Monitor patients for signs of opioid withdrawal. Consider therapy modification

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Asunaprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Asunaprevir. Avoid combination

Avanafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Avanafil. Avoid combination

Avapritinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Avapritinib. Avoid combination

Axitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Axitinib. Avoid combination

Bedaquiline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline. Avoid combination

Bosutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib. Avoid combination

Brigatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inducers when possible. If combined, increase the daily dose of brigatinib in 30 mg increments after 7 days of treatment with the current brigatinib dose, up to maximum of twice the dose. Consider therapy modification

Capmatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Capmatinib. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CloZAPine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of CloZAPine. Monitor therapy

Cobimetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cobimetinib. Avoid combination

Codeine: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Codeine. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP2B6 Substrates (High risk with Inducers): Dabrafenib may decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Monitor therapy

CYP2C19 Substrates (High risk with Inducers): Dabrafenib may decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Management: Avoid this concomitant therapy when possible. If concomitant therapy cannot be avoided, monitor for decreased clinical effects of the CYP2C19 substrate. Consider therapy modification

CYP2C8 Inhibitors (Moderate): May increase the serum concentration of Dabrafenib. Monitor therapy

CYP2C8 Inhibitors (Strong): May increase the serum concentration of Dabrafenib. Management: Consider alternatives to strong CYP2C8 inhibitors in patients being treated with dabrafenib. If such a combination cannot be avoided, monitor closely for evidence of dabrafenib-related adverse effects. Consider therapy modification

CYP3A4 Inducers (Strong): May decrease the serum concentration of Dabrafenib. Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Dabrafenib. Avoid combination

CYP3A4 Substrates (High risk with Inducers): Dabrafenib may decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to concomitant therapy when possible. If concomitant therapy cannot be avoided, monitor for reduced clinical effects of the CYP3A4 substrate. Consider therapy modification

Daclatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer. Consider therapy modification

Dasabuvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dasabuvir. Avoid combination

Deflazacort: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Deflazacort. Avoid combination

Elbasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elbasvir. Avoid combination

Encorafenib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Encorafenib. Avoid combination

Entrectinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Entrectinib. Avoid combination

Erdafitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Erdafitinib. Management: Dose modifications of erdafitinib may be required. See full monograph for details. Consider therapy modification

Estriol (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Systemic). Monitor therapy

Estriol (Topical): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Topical). Monitor therapy

Estrogen Derivatives (Contraceptive): Dabrafenib may decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Females of reproductive potential should use an alternative, highly effective, non-hormonal means of contraception during and at least 2 weeks (dabrafenib alone) or 4 months (dabrafenib + trametinib) after discontinuation of dabrafenib treatment. Consider therapy modification

Fedratinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Fedratinib. Avoid combination

FentaNYL: CYP3A4 Inducers (Moderate) may decrease the serum concentration of FentaNYL. Monitor therapy

Flibanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Flibanserin. Avoid combination

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Glasdegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Glasdegib. Management: Avoid use of glasdegib and moderate CYP3A4 inducers whenever possible. If combined, increase glasdegib dose from 100 mg daily to 200 mg daily or from 50 mg daily to 100 mg daily. Resume previous glasdegib dose 7 days after discontinuation of the inducer. Consider therapy modification

Glecaprevir and Pibrentasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy

Grazoprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Grazoprevir. Avoid combination

GuanFACINE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of GuanFACINE. Management: Increase extended-release guanfacine dose by up to double when initiating guanfacine in patients taking CYP3A4 inducers or if initiating a CYP3A4 inducer in a patient already taking extended-release guanfacine. Monitor for reduced guanfacine efficacy. Consider therapy modification

Hydrocortisone (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Hydrocortisone (Systemic). Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ifosfamide: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Lefamulin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with moderate CYP3A4 inducers unless the benefits outweigh the risks. Consider therapy modification

Lefamulin (Intravenous): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin (intravenous) with moderate CYP3A4 inducers unless the benefits outweigh the risks. Consider therapy modification

Lemborexant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lemborexant. Avoid combination

Lorlatinib: CYP3A4 Inducers (Moderate) may enhance the hepatotoxic effect of Lorlatinib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with moderate CYP3A4 inducers. If such a combination must be used, monitor AST, ALT, and bilirubin within 48 hours of starting the combination and at least three times within the first week of combined use. Consider therapy modification

Lumateperone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lumateperone. Avoid combination

Lurasidone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lurasidone. Management: Monitor for decreased lurasidone effects if combined with moderate CYP3A4 inducers and consider increasing the lurasidone dose if coadministered with a moderate CYP3A4 inducer for 7 or more days. Consider therapy modification

Lurbinectedin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lurbinectedin. Avoid combination

Meperidine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Meperidine. Monitor therapy

Neratinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Neratinib. Avoid combination

Nisoldipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nisoldipine. Avoid combination

Olaparib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olaparib. Avoid combination

Oliceridine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Oliceridine. Monitor therapy

Pemigatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pemigatinib. Avoid combination

Perampanel: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Perampanel. Management: Increase the perampanel starting dose to 4 mg/day when perampanel is used concurrently with moderate and strong CYP3A4 inducers. Monitor perampanel response closely, particularly with changes to CYP3A4 inducer therapy. Consider therapy modification

Pimavanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pimavanserin. Avoid combination

Pitolisant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pitolisant. Monitor therapy

PrednisoLONE (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of PrednisoLONE (Systemic). Monitor therapy

PredniSONE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of PredniSONE. Monitor therapy

Pretomanid: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pretomanid. Avoid combination

Progestins (Contraceptive): Dabrafenib may decrease the serum concentration of Progestins (Contraceptive). Management: Females of reproductive potential should use an alternative, highly effective, non-hormonal means of contraception during and at least 2 weeks (dabrafenib alone) or 4 months (dabrafenib + trametinib) after discontinuation of dabrafenib treatment. Consider therapy modification

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Ranolazine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ranolazine. Avoid combination

Rimegepant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rimegepant. Avoid combination

Selpercatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Selpercatinib. Avoid combination

Selumetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Selumetinib. Avoid combination

Simeprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simeprevir. Avoid combination

Sonidegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sonidegib. Avoid combination

St John's Wort: May decrease the serum concentration of Dabrafenib. Management: Seek alternatives to St. John's wort when possible. If concomitant therapy cannot be avoided, monitor closely for diminished therapeutic effects of dabrafenib. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tazemetostat: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tazemetostat. Avoid combination

Trametinib: May enhance the adverse/toxic effect of Dabrafenib. Monitor therapy

Ubrogepant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a moderate CYP3A4 inducer. Consider therapy modification

Velpatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Velpatasvir. Avoid combination

Venetoclax: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Venetoclax. Avoid combination

Vitamin K Antagonists (eg, warfarin): CYP2C9 Inducers (Weak) may decrease the serum concentration of Vitamin K Antagonists. Monitor therapy

Vorapaxar: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vorapaxar. Avoid combination

Vortioxetine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vortioxetine. Monitor therapy

Voxelotor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and moderate CYP3A4 inducers. If concomitant use is unavoidable, increase the voxelotor dose to 2,500 mg once daily. Consider therapy modification

Voxilaprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voxilaprevir. Avoid combination

Zaleplon: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zaleplon. Monitor therapy

Zanubrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zanubrutinib. Avoid combination

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Dermatologic: Alopecia (22%), hyperkeratosis (37%), palmar-plantar erythrodysesthesia (20%), skin rash (17% to 27%), xeroderma (16%)

Endocrine & metabolic: Hyperglycemia (50% to 57%), hyponatremia (8% to 14%), hypophosphatemia (35% to 37%)

Gastrointestinal: Constipation (10% to 11%)

Hematologic & oncologic: Papilloma (27%), squamous cell carcinoma of skin (7% to 11%; grade 3: 4%)

Hepatic: Increased serum alkaline phosphatase (19% to 25%)

Nervous system: Chills (17%), headache (30% to 32%)

Neuromuscular & skeletal: Arthralgia (27% to 31%), back pain (12%), myalgia (11% to 13%)

Respiratory: Cough (12% to 21%)

Miscellaneous: Fever (28% to 33%)

1% to 10%:

Dermatologic: Bullous rash (<10%)

Gastrointestinal: Pancreatitis (<10%)

Hematologic & oncologic: Basal cell carcinoma of skin (4%), keratoacanthoma (4%), malignant melanoma (new primary: 1%), malignant neoplasm (≤1%)

Nervous system: Dizziness (7%)

Ophthalmic: Uveitis (1%)

Renal: Interstitial nephritis (<10%)

Respiratory: Nasopharyngitis (10%)

Miscellaneous: Febrile reaction (serious: 6%)

Frequency not defined: Nervous system: Fatigue

Postmarketing: Hematologic & oncologic: Kaposi's sarcoma (Parakh 2016)

Warnings/Precautions

Concerns related to adverse effects:

• Cardiomyopathy: Cardiomyopathy (a decrease in left ventricular ejection fraction [LVEF] ≥10% from baseline and below the institutional lower limit of normal) has occurred when used in combination with trametinib. Assess LVEF (by echocardiogram or multigated acquisition scan [MUGA] scan) prior to combination therapy initiation, at 1 month, and then every 2 to 3 months while on therapy. Cardiac dysfunction may require dabrafenib treatment interruption (see trametinib monograph for trametinib dosage modifications). Cardiomyopathy resolved in most patients receiving dabrafenib in combination with trametinib following dose adjustments, treatment interruption, and/or permanent discontinuation.

• Dermatologic toxicity: Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms, may occur when dabrafenib is administered with trametinib and could be life-threatening or fatal. Other serious skin toxicities have also occurred (rare). Monitor for new or worsening serious skin toxicities. Treatment interruption, dose reduction, and/or therapy discontinuation may be necessary.

• Febrile reactions: Serious febrile reactions and fever (any severity) complicated by hypotension, rigors or chills, dehydration, or renal failure were observed during dabrafenib single-agent therapy and when used in combination with trametinib. Some patients experienced multiple discrete episodes. Interrupt dabrafenib therapy for fever ≥38.5°C (101.3°F) or for any other serious febrile reaction complicated by hypotension, rigors/chills, dehydration, or renal failure; evaluate promptly for signs/symptoms of infection (also monitor serum creatinine and other evidence of renal function during and after serious fever). Dosage reduction (or discontinuation) may be required; when resuming therapy after a febrile reaction, may require administration of antipyretics as secondary prophylaxis. Administer corticosteroids (eg, prednisone 10 mg daily or equivalent) for at least 5 days for second or subsequent episodes of pyrexia if temperature does not return to baseline within 3 days of fever onset, or for pyrexia associated with complications (eg, dehydration, hypotension, severe chills/rigors with no evidence of active infection).

• Hemorrhage: Hemorrhage, defined as symptomatic bleeding in a critical area/organ, may occur with dabrafenib in combination with trametinib. Major bleeding events (some fatal) included intracranial, cerebral, brainstem, or GI hemorrhage. May require treatment interruption and dosage reduction; permanently discontinue dabrafenib (and trametinib) for all grade 4 hemorrhagic events and any grade 3 event that does not improve with therapy interruption.

• Hyperglycemia: Hyperglycemia may occur in patients with a history of diabetes while on therapy (either as a single agent or in combination with trametinib); may require initiation or optimization of insulin or oral hypoglycemic agent therapy. Monitor serum glucose at baseline and as clinically necessary in patients with preexisting diabetes or hyperglycemia.

• Malignancy: Cutaneous squamous cell carcinoma (cuSCC) and keratoacanthoma and new primary melanoma were observed during single-agent dabrafenib therapy at an increased incidence compared with control therapy in clinical trials. When used in combination with trametinib, cuSCCs (including keratoacanthomas) were reported. Basal cell carcinoma (BCC) may also occur with combination or single-agent therapy. Dermatologic evaluations should be performed prior to initiating therapy, every 2 months during therapy, and for up to 6 months post discontinuation. There are case reports of noncutaneous malignancies with monotherapy and combination therapy; monitor for signs/symptoms of noncutaneous malignancies. Dabrafenib should be permanently discontinued if RAS mutation-positive noncutaneous malignancies develop (if used in combination, no trametinib dosage reduction is required).

• Ocular toxicity: Uveitis, including iritis and iridocyclitis, has been reported with dabrafenib single-agent therapy and when used in combination with trametinib; manage symptomatically with local ophthalmic steroid and mydriatic drops (while continuing dabrafenib). If not responsive to local ocular management or if severe, may require dabrafenib treatment interruption, dose reduction, and/or permanent discontinuation (does not require alteration in trametinib therapy). Monitor for signs/symptoms of uveitis (eg, eye pain, photophobia, vision changes). Retinal pigment epithelial detachments (RPED) were seen in clinical trials when used in combination with trametinib (a known complication of trametinib single-agent therapy). Detachments may be bilateral and multifocal, and occurred in the central macular area or elsewhere in the retina. Promptly (within 24 hours) refer patients for ophthalmological evaluations if loss of vision or other visual disturbances occur; dabrafenib dosage modification is not necessary for RPED (trametinib therapy modification may be required). Ophthalmic exams (including retinal evaluation) should be performed periodically during treatment with combination therapy.

• QT prolongation: QTcF prolongation >60 msec above baseline or to >500 msec was reported (rare), both as a single agent or when used in combination with trametinib.

• Venous thromboembolism: Venous thromboembolism events such as deep venous thrombosis (DVT) and pulmonary embolism (PE) (some fatal) may occur (rare) when dabrafenib is used in combination with trametinib. Patients should seek immediate medical attention with symptoms of DVT or PE (shortness of breath, chest pain, arm/leg swelling). Dabrafenib therapy may be continued for uncomplicated DVT or PE; permanently discontinue trametinib for life-threatening PE.

Concurrent drug therapy issues:

• Combination therapy with trametinib: Serious adverse reactions that occur with single-agent trametinib may also occur when dabrafenib is administered in combination with trametinib.

Special populations:

• Glucose-6-phosphate dehydrogenase deficiency: Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may be at risk for hemolytic anemia when administered dabrafenib; use with caution and closely observe for signs/symptoms of hemolytic anemia.

Other warnings/precautions:

• Appropriate use: Not indicated for treatment of patients with wild-type BRAF melanoma, NSCLC, or anaplastic thyroid cancer. Exposing wild-type cells to BRAF inhibitors such as dabrafenib may result in paradoxical activation of MAP-kinase signaling and increased cell proliferation. Prior to initiating therapy, confirm BRAF V600E or BRAF V600K mutation status (in tumor specimens) with an approved test. Information on approved tests for detection of BRAF V600 mutations is available at http://www.fda.gov/CompanionDiagnostics. An approved test for BRAF V600E mutation detection in anaplastic thyroid cancer is not available.

Monitoring Parameters

BRAFV600K or V600E mutation status (prior to treatment); serum glucose (particularly in patients with preexisting diabetes mellitus or hyperglycemia); electrolytes; renal function; verify pregnancy status prior to treatment initiation (in females of reproductive potential); 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 severe cutaneous adverse reactions), and for noncutaneous malignancies.

For patients receiving combination therapy with trametinib: Hepatic function; CBC (baseline and periodically during therapy); assess left ventricular ejection fraction (by echocardiogram or multigated acquisition scan [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.

Reproductive Considerations

Verify pregnancy status in females of reproductive potential prior to treatment initiation. Dabrafenib may cause hormonal contraceptives to be ineffective. Females of reproductive potential should use a highly effective nonhormonal contraceptive during dabrafenib therapy and for 2 weeks after the last dabrafenib dose. Males (including those with vasectomies) with pregnant partners or female partners of reproductive potential should use condoms during dabrafenib treatment and for ≥2 weeks after the last dabrafenib dose.

Pregnancy Considerations

Based on its mechanism of action and on findings in animal reproduction studies, in utero exposure to dabrafenib may cause fetal harm.

Patient Education

What is this drug used for?

• It is used to treat cancer.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Hair loss

• Hard or thick skin

• Dry skin

• Headache

• Joint pain

• Muscle pain

• Back pain

• Constipation

• Cough

• Nose irritation

• Throat irritation

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit

• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness or passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes

• Change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or vision changes

• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out

• Mole changes

• Skin changes like new wart, skin sore, or reddish bump that bleeds or does not heal

• Acne

• Persistent or bothersome rash

• Skin redness

• Redness or irritation of palms or soles of feet

• Chills

• Swollen glands

• Yellow skin or eyes

• Dark urine

• Blurred vision

• Blindness

• Vision changes

• Seeing halos or bright colors around lights

• Eye pain

• Sensitivity to lights

• Chest pain

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.