Dosing & Uses
Dosage Forms & Strengths
capsule
- 50mg
- 75mg
Melanoma
Also see Administration
Mutations must be detected by an FDA-approved test
BRAF V600E mutation-positive unresectable or metastatic melanoma
- Indicated as a single agent
- 150 mg PO BID
- Continue until disease recurrence or unacceptable toxicity
BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma
- Indicated, in combination with trametinib
- 150 mg PO BID plus trametinib 2 mg PO qDay
- Continue until disease recurrence or unacceptable toxicity
Adjuvant treatment of BRAF V600E or V600K mutation-positive melanoma
- Indicated in combination with trametinib when lymph node(s) involved following complete resection
- 150 mg PO BID plus trametinib 2 mg PO qDay
- Continue until disease recurrence or unacceptable toxicity for up to 1 year
Non-Small Cell Lung Cancer
BRAF V600E mutation-positive
Indicated in combination with trametinib
150 mg PO BID plus trametinib 2 mg PO qDay
Continue until disease recurrence or unacceptable toxicity
Also see Administration
Thyroid Cancer, Locally Advanced or Metastatic
BRAF V600E mutation-positive
Indicated, in combination with trametinib, for locally advanced or metastatic anaplastic thyroid cancer (ATC) in adults with no satisfactory locoregional treatment options
150 mg PO BID plus trametinib 2 mg PO qDay
Continue until disease recurrence or unacceptable toxicity
Dosage Modifications
Dose reductions for dabrafenib (single agent or in combination with trametinib)
- First dose reduction: 100 mg PO BID
- Second dose reduction: 75 mg PO BID
- Third dose reduction: 50 mg PO BID
- If unable to tolerate 50 mg BID: Permanently discontinue
Dose reductions for trametinib when administered with dabrafenib
- First dose reduction: 1.5 mg PO qDay
- Second dose reduction: 1 mg PO qDay
- Subsequent modification: Permanently discontinue if unable to tolerate trametinib 1 mg/day
Noncutaneous RAS mutation-positive malignancies
- Dabrafenib: Permanently discontinue
Febrile drug reaction
- Fever of 101.3-104°F: Withhold dabrafenib until fever resolves, then resume at same or lower dose; do not modify trametinib
- Fever >104°F or fever complicated by rigors, hypotension, dehydration, or renal failure: Withhold trametinib until fever resolves, then resume at same or lower dose; withhold dabrafenib, then resume at lower dose (or permanently discontinue)
Dermatologic reactions
- Intolerable Grade 2, or Grades 3 or 4: Withhold for up to 3 weeks; if improved, resume at lower dose level
- If not improved after withholding 3 weeks, permanently discontinue
- Applies to both trametinib and dabrafenib
Asymptomatic LVEF
- Asymptomatic, absolute decrease in LVEF ≥10% from baseline, but is below LLN from pretreatment value:
- Trametinib: Withhold for up to 4 weeks; if improved to normal LVEF value, resume at a lower dose level; if not improved to normal, permanently discontinue
- Dabrafenib: Do not modify dose
Symptomatic CHF
- Symptomatic congestive heart failure or absolute decrease in LVEF >20% from baseline that is below LLN:
- Trametinib: Permanently discontinue
- Dabrafenib: Withhold, if improved, then resume at the same dose
Uncomplicated DVT or PE
- Trametinib: Withhold trametinib for up to 3 weeks; if improved to Grade 0-1, resume at a lower dose level, if not improved, permanently discontinue
- Dabrafenib: Do not modify dose
Life-threatening PE
- Trametinib: Permanently discontinue
- Dabrafenib: Permanently discontinue
Retinal pigment epithelia detachments (RPED)
- Grade 2-3 RPED:
- Trametinib: Withhold for up to 3 weeks; if improved to Grade 0-1, resume at a lower dose level, if not improved, permanently discontinue
- Dabrafenib: Do not modify dose
Retinal vein occlusion
- Trametinib: Permanently discontinue
- Dabrafenib: Do not modify dose
Uveitis and iritis
- Trametinib: Do not modify dose
-
Dabrafenib
- If mild or moderate uveitis does not respond to ocular therapy, or for severe uveitis, withhold dabrafenib for up to 6 weeks
- If improved to Grade 0-1, then resume at the same or at a lower dose level
- If not improved, permanently discontinue
Pulmonary reactions
- Interstitial lung disease/pneumonitis
- Trametinib: Permanently discontinue
- Dabrafenib: Do not modify dose
Renal impairment
- Mild (GFR 60 to 89 mL/min/1.73 m2) or moderate (GFR 30 to 59 mL/min/1.73 m2) renal impairment: Dose adjustment not recommended
- Severe (GFR less than or equal to 30 mL/min/1.73 m2) renal impairment: Dose not established; not studied
Hepatic impairment
- Mild (bilirubin ULN and AST > ULN or bilirubin >1x to 1.5x ULN and any AST) hepatic impairment: Dose adjustment not recommended
- Moderate (bilirubin> 1.5x to 3x ULN and any AST) to severe (bilirubin >3x to 10x ULN and any AST): Dose not established; not studied
Other
- Applies to both trametinib and dabrafenib
- Intolerable Grade 2 or any Grade 3 adverse reactions: Withhold treatment; if improved to Grade 0-1, resume at lower dose level, if not improved, permanently discontinue
- First occurrence of any Grade 4 reaction: Withhold treatment until improves to Grade 0-1, then resume at lower dose level, or permanently discontinue
- Recurrent Grade 4 reactions: Permanently discontinue
Dosing Considerations
Patient selection
- Melanoma or NSCLC: Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment as a single agent (melanoma) or in combination therapy with trametinib (melanoma or NSCLC)
- ATC: Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with dabrafenib and trametinib
- Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics
Limitations of use
- Not indicated for treatment of patients with wild-type BRAF melanoma, wild-type BRAF NSCLC, or wild-type BRAF ATC
Glioma (Orphan)
Orphan designation for treatment of malignant glioma with BRAF V600 mutation
Sponsor
- Novartis Pharmaceuticals Corporation; 1 Health Plaza, Bldg 337; East Hanover, New Jersey 07936
Safety and efficacy not established
Interactions
Interaction Checker
No Results

Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor

Adverse Effects
Adverse effects listed are all grades of severity unless indicated otherwise
>10%
Hyperglycemia (50%)
Hypophosphatemia (37%)
Hyperkeratosis (37%)
Headache (28%)
Arthralgia (27%)
Papilloma (27%)
Alopecia (22%)
Palmar-planter erythrodysesthesia syndrome (20%)
Increased alkaline phosphatase (19%)
Rash (17%)
Back pain (12%)
Cough (12%)
Myalgia (11%)
Constipation (11%)
1-10%
Nasopharyngitis (10%)
Hyponatremia (8%)
Cutaneous squamous cell carcinoma (7%)
Pancreatitis (<10%)
Hypersensitivity manifesting as bullous rash (<10%)
Interstitial nephritis (<10%)
Grade 3 or 4
- Hyperglycemia (6%)
- Hyperphosphatemia (6%)
- Cutaneous squamous cell carcinoma (eg, squamous cell carcinoma of the skin, keratoacanthoma) (4%)
- Back pain (3%)
- Palmar-plantar erythrodysesthesia syndrome (2%)
- Constipation (2%)
- Hyponatremia (2%)
- Hyperkeratosis (1%)
- Arthralgia (1%)
Postmarketing Reports
Pyrexia and chills
Warnings
Contraindications
None
Cautions
Also see Dosage Modifications
Increases incidence of cutaneous squamous cell carcinoma, keratoacanthoma, and new incidence melanoma; perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy, and for up to 6 months following discontinuation
BRAF inhibitors may cause paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells; confirm evidence of BRAF V600E mutation status prior to initiation
Based on its mechanism of action, dabrafenib may promote growth and development of malignancies with activation of RAS through mutation or other mechanisms
Withhold if fever >101.3°F or complicated fever occurs; incidence and severity of pyrexia increased when used in combination with trametinib
Hemorrhage, including major hemorrhages, can occur when used in combination with trametinib; permanently discontinue therapy for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve; withhold therapy for Grade 3 hemorrhagic events; if improved, resume at next lower dose level
Venous thromboembolism can occur when used in combination with trametinib
Hyperglycemia reported; monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia; initiate or optimize anti-hyperglycemic medications as clinically indicated
Contains a sulfonamide moiety which increases the risk of hemolytic anemia in patients with G6PD deficiency
Based on its mechanism of action, dabrafenib can cause fetal harm; advise females of reproductive potential of potential risk to a fetus
Skin toxicity
- Risk of serious skin toxicity including rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema
- Withhold treatment for intolerable or severe skin toxicity
- Resume treatment at a lower dose in patients with improvement or recovery from skin toxicity within 3 weeks
- Permanently discontinue drug if skin toxicity not improved within 3 weeks
Uveitis
- Uveitis, iritis, and retinal pigment epithelial detachment (RPED) reported; monitor patients routinely for visual symptoms
- If iritis diagnosed, administer ocular therapy and continue therapy without dose modification
- If severe uveitis (i.e., iridocyclitis) or if mild or moderate uveitis does not respond to ocular therapy, withhold treatment and treat as clinically indicated
- Resume treatment at same or lower dose if improves to Grade 0 or 1
- Permanently discontinue therapy for persistent Grade 2 or greater uveitis of > 6 weeks
Cardiomyopathy
- Risk increases when used as a single agent or with trametinib
- Reassess LVEF after 1 month of treatment and then ~ every 2-3 months thereafter
- Withhold therapy for symptomatic cardiomyopathy or asymptomatic LV dysfunction of > 20% from baseline that is below institutional lower limit of normal (LLN)
- Resume treatment at the same dose level upon recovery of cardiac function to at least the institutional LLN for LVEF and absolute decrease 10% compared to baseline
Drug interaction overview
- Dabrafenib may render hormonal contraceptives less effective and an alternative method of contraception should be used
- Coadministration with strong inhibitors or inducers of CYP3A4 or CYP2C8 is not recommended
- Drugs that increase gastric pH may decrease dabrafenib concentrations
- Dabrafenib inhibits certain CYP isoenzymes; concomitant use with drugs that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in loss of efficacy of these drugs
Pregnancy & Lactation
Pregnancy
Verify pregnancy status in females of reproductive potential prior to initiating therapy
Based on data from animal studies and its mechanism of action, can cause fetal harm when administered to pregnant women
Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure
Contraception
- Advise female patients of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose
- Counsel patients to use a nonhormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective
- To avoid potential drug exposure to pregnant partners and female partners of reproductive potential, advise male patients (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment and for at least 2 weeks after last dose
Infertility
- Females: Advise female patients of reproductive potential that dabrafenib may impair fertility
- Males: Advise male patients of the potential risk for impaired spermatogenesis which may be irreversible
Lactation
Data are not available regarding presence in human milk, effects on breastfed infants, or effects on milk production
Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment and for 2 weeks after the last dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Inhibits some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively
Absorption
Bioavailability: 95%
Peak plasma time: 2 hr
High-calorie meal decreased AUC by 31%, Cmax by 51%, and delayed Tmax by 3.6 hr compared with fasted state
Distribution
Protein Bound: 99.7%
Vd: 70.3 L
Metabolism
Primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib
Hydroxy-dabrafenib is further oxidized via CYP3A4 to form carboxy-dabrafenib and subsequently excreted in bile and urine
Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsorbed from the gut
Desmethyl-dabrafenib is further metabolized by CYP3A4 to oxidative metabolites
Elimination
Half-life: 8 hr (parent); 10 hr (hydroxy-dabrafenib); 21-22 hr (carboxy- and desmethyl-dabrafenib)
Clearance: 17 L/hr (single dose); 34.4 L/hr (after 2 wk of BID dosing)
Excretion: 71% feces; 23% urine (as metabolites only)
Administration
Oral Administration
Administer dose BID ~12 hr apart
Take on empty stomach at least 1 hr before or 2 hr after meals
A missed dose can be taken up to 6 hr prior to the next dose
Swallow capsule whole; do not open, chew, crush, or break
Storage
Tablets: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
Images
Patient Handout
Formulary
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