Dabrafenib

Dosage Forms

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

Capsule, Oral:

Tafinlar: 50 mg, 75 mg

Pharmacology

Mechanism of Action

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)

Pharmacokinetics/Pharmacodynamics

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

Protein Binding

99.7% to plasma proteins

Use in Specific Populations

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 patients with 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.

Dosage and Administration

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 progression 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).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Recommended dabrafenib dose reductions for toxicity:

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 reductions.

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:

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.

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:

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: 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 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

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

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

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

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: Seek alternatives to the CYP2C19 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). 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

CYP2C9 Substrates (High risk with Inducers): Dabrafenib may decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic 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 the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). 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

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 the guanfacine dose by up to double when initiating guanfacine in a patient taking a moderate CYP3A4 inducer. Increase guanfacine dose gradually over 1 to 2 weeks if initiating a moderate CYP3A4 inducer in a patient already taking guanfacine. Consider therapy modification

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

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

Palbociclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palbociclib. Management: The US label does not provide specific recommendations concerning use with moderate CYP3A4 inducers, but the Canadian label recommends avoiding use of moderate CYP3A4 inducers. Consider therapy modification

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. 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

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

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

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

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

Adverse Reactions

>10%:

Cardiovascular: Hypertension (16%), peripheral edema (11%)

Central nervous system: Headache (30% to 32%), chills (17%)

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

Endocrine & metabolic: Hyperglycemia (50% to 57%), hypophosphatemia (35% to 37%), hypoalbuminemia (27%), hyponatremia (8% to 14%)

Gastrointestinal: Nausea (27%), diarrhea (16%), abdominal pain (14%), vomiting (14%), constipation (10% to 11%)

Hematologic & oncologic: Anemia (38%, grades 3/4: 4%), lymphocytopenia (28%, grades 3/4: 7%), papilloma (27%), neutropenia (16%, grades 3/4: 2%), hemorrhage (15%), malignant neoplasm of skin (7% to 11%, grades 3/4: 4%; keratoacanthoma and squamous cell carcinoma)

Hepatic: Increased serum alanine aminotransferase (28%), increased serum alkaline phosphatase (19% to 25%), increased serum aspartate aminotransferase (21%)

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

Respiratory: Cough (12% to 21%)

Miscellaneous: Fever (28% to 33%)

1% to 10%:

Cardiovascular: Cardiomyopathy (3%)

Central nervous system: Dizziness (7%)

Gastrointestinal: Pancreatitis (<10%), gastrointestinal hemorrhage (3%)

Hematologic & oncologic: Thrombocytopenia (10%, grades 3/4: <1%), basal cell carcinoma of skin (6%), malignant neoplasm (3%), malignant melanoma (2%)

Hypersensitivity: Hypersensitivity reaction (<10%, bullous rash)

Ophthalmic: Uveitis (1%, including iritis)

Renal: Interstitial nephritis (<10%)

Respiratory: Nasopharyngitis (10%)

Miscellaneous: Febrile reaction (4%)

<1%, postmarketing, and/or case reports: Kaposi's sarcoma (Parakh 2016)

Warnings/Precautions

Concerns related to adverse effects:

• Cardiomyopathy: Cardiomyopathy may occur when used as a single agent or in combination with trametinib. Assess LVEF (by echocardiogram or 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 some patients following dose adjustments, treatment interruption or permanent discontinuation.
• Dermatologic toxicity: Serious dermatologic toxicity (eg, rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, erythema) may occur when used in combination with trametinib (known complication of single-agent trametinib therapy); some patients required hospitalization for severe toxicity or for secondary skin infections. Monitor for dermatologic toxicity and signs/symptoms of secondary infections. 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. 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, including symptomatic bleeding in a critical area/organ, may occur with dabrafenib either as a single agent or in combination with trametinib. Major bleeding events (some fatal) included intracranial, subarachnoid, retroperitoneal, or gastrointestinal 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 while on therapy (either as a single agent or in combination with trametinib); may require initiation of insulin or oral hypoglycemic agent therapy (or an increased dose if already taking). Monitor serum glucose at baseline and as clinically necessary in patients with preexisting diabetes or hyperglycemia.
• Malignancy: Cutaneous squamous cell carcinoma and keratoacanthoma (cuSCC) and new primary melanoma were observed during single-agent dabrafenib therapy at an increased incidence compared with control therapy in clinical trials. In melanoma monotherapy studies, approximately one-third of patients who developed cuSCC had more than one occurrence (with continued treatment). When used in combination with trametinib for the treatment of melanoma, cuSCC occurred less frequently than with single-agent dabrafenib therapy. Cases of cuSCC also occurred in patients with NSCLC. Basal cell carcinoma (BCC) may also occur with combination or single-agent therapy, although rare, some patients experienced more than one BCC occurrence. 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 combination therapy; monitor for signs/symptoms of noncutaneous malignancies. Dabrafenib should be permanently discontinued if RAS mutation-positive noncutaneous malignancies develop (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, 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 melanoma clinical trials when used in combination with trametinib (a known complication of trametinib single-agent therapy). Detachments were typically bilateral and multifocal and occurred in the central macular area of 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. Use with caution in patients who may be at increased risk for arrhythmias.
• Venous thromboembolism: Venous thromboembolism events (some fatal) may occur when dabrafenib is used in combination with trametinib. DVT and PE occurred at an increased incidence with combination therapy. 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 (retinal vein occlusion, interstitial lung disease) that occur with single-agent trametinib may also occur when dabrafenib is administered in combination with trametinib.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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 V600 E 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 secondary infections), and for noncutaneous malignancies.

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

Monitor adherence.

Pregnancy

Pregnancy Considerations

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

Verify pregnancy status in females of reproductive potential prior to treatment initiation. Dabrafenib may diminish efficacy of hormonal contraceptives. 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.

Patient Education

What is this drug used for?

• It is used to treat a type of skin cancer (melanoma).
• It is used to treat lung cancer.

Frequently reported side effects of this drug

• Hair loss
• Hard or thick skin
• Dry skin
• Headache
• Joint pain
• Muscle pain
• Back pain
• Constipation
• Cough
• Stuffy nose
• Sore throat

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• 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
• Severe cerebrovascular disease like 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
• 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 a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of 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 brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.