dabrafenib (Rx)

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

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS)

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

Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills reported

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 therapy for severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS) 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

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.

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)

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)