daBRAFenib

daBRAFenib

COMMON TRADE NAME(S):   Tafinlar®

• Melanoma
• Non-small cell lung cancer (NSCLC)

Refer to the product monograph for a full list and details of approved indications.

Emetogenic Potential:  

The following table lists adverse events observed in the phase III monotherapy study of treatment-naïve patients with unresectable or metastatic melanoma, unless otherwise indicated. Clinically important, severe or life-threatening adverse events from other trials or post-marketing may also be included. Consult the DABRTRAM regimen monograph when used in combination.

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for dabrafenib include hyperkeratosis, headache, musculoskeletal pain, fever, alopecia, nausea, vomiting, skin papilloma, fatigue, hand-foot syndrome and rash.

Combination therapy with trametinib had higher incidences or greater severity of ↑ LFTs, chills, fever, diarrhea, peripheral edema, bleeding, neutropenia, uveitis, muscle spasms, panniculitis, renal failure and hypertension compared to monotherapy. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and life-threatening or fatal drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported during combination therapy.

Sarcoidosis, mostly involving the skin, lung, eye and lymph nodes, has been reported during combination therapy. Assess carefully as sarcoidosis may mimic signs of disease progression. If sarcoidosis diagnosis is confirmed, treatment should be considered.

Febrile events include severe febrile drug reactions with rigors/chills, dehydration, hypotension and renal failure. Median time to initial onset of febrile events was 2 to 4 weeks and the incidence is higher in combination with trametinib. The incidence and severity of pyrexia are increased when dabrafenib is used in combination therapy with trametinib. Dose modification is required (refer to Dosing section).

Interstitial/granulomatous nephritis has also been reported.

Paradoxical activation of MAP-3 kinase signalling has been reported in BRAF wild-type cells with exposure to BRAF inhibitors, which may promote growth of wild-type melanoma or non-cutaneous malignancies. Cutaneous Squamous Cell Carcinoma (cuSCC) has been reported in up to 11% of patients on monotherapy and usually occurred in the first 2 months of treatment (4 to 7 months with combination therapy). New primary melanoma (1%) has also been reported in the first 3 to 4 months. Management of cuSCC and new primary melanoma included excision without dose adjustment. RAS associated malignancies (eg colorectal or pancreatic adenocarcinoma) have been reported in the clinic; risk benefit should be considered before continuing with treatment. 

Initiation and changes in hyperglycemia management may be required in some patients. Decreases in systolic and diastolic blood pressure were reported in the phase III trial. The average decreases were -4 to -7.5 mmHg SBP and -2 to -3.6 mmHg DBP during the first 18 weeks of treatment.

Pancreatitis, generally occuring soon after treatment initation, has been reported during clinical trials (< 1% with monotherapy, 2% in combination) and post-marketing surveillance. Unexplained abdominal pain should be investigated appropriately.

Fatal venous thromboembolic events and major hemorrhagic events (including intracranial or gastric hemorrhage) have been reported when dabrafenib was given in combination with trametinib. 

Fatal cerebral hemorrhage has been reported in patients who developed brain metastases while on the combination treatment; the risk may be increased in patients on anti-platelet or anticoagulant drugs.

• Patients who have a hypersensitivity to this drug or any of its components
   

• Dabrafenib should not be used in patients with BRAF wild-type or unknown disease. BRAF mutation must be confirmed using a validated test before starting dabrafenib treatment.
• Dabrafenib monotherapy has not been studied in patients who have had previous treatment with BRAF inhibitors.
• Exercise caution in patients with risk factors for QT prolongation or Torsades de pointes (low potassium/magnesium, congenital QT prolongation, or history of arrhythmia, CHF, anti-arrhythmics, other QTc prolonging agents, prior anthracyclines), diabetes, autonomic neuropathy.
• Patients were excluded from clinical trials if they had abnormal heart valve morphology ≥ grade 2.
• Monitor for hemolytic anemia in patients with G6PD deficiency as dabrafenib contains a sulfonamide moiety.
• Use combination therapy with caution in patients at risk of bleeding as severe or fatal events have been reported. The risk may be increased with concomitant use of antiplatelet/anticoagulant therapy or in patients who develop brain metastases while on treatment.
   

• Carcinogenicity:

  Cutaneous squamous cell carcinoma, new primary melanoma and non-cutaneous malignancies have been observed in patients treated with dabrafenib. 

• Phototoxicity: Yes
  

• Mutagenicity: No
  
• Clastogenicity: No
  
• Embryotoxicity: Yes
  
• Fetotoxicity: Yes
  
• Teratogenicity: Yes
  
  • Dabrafenib is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 2 weeks after the last dose when given as monotherapy, or for at least 16 weeks after the last dose of trametinib when given in combination.
  • Efficacy of hormonal contraceptives is likely to be decreased; use effective alternative methods of contraception.
• Excretion into breast milk: Unknown
  Breastfeeding is not recommended.
• Fertility effects: Likely
  

  No fertility data in humans. Adverse effects on male reproductive organs have been seen in animals. Fertility effects may be irreversible.

Dabrafenib is primarily metabolized by CYP3A4 and CYP2C8; drug interactions are probable with inhibitors of these enzymes. Dabrafenib is a moderate to strong inducer of CYP3A4, and may also induce CYP2C9 (weak), CYP2B6, CYP2C8, CYP2C19, UGTs and P-gp. It is an in vitro inhibitor of OATP1B1 and OATP1B3. The inhibitory effects of dabrafenib and its metabolites on OAT1, OAT3 and BCRP do not contribute to significant drug-drug interactions.

Drugs that alter upper GI pH (e.g. PPIs, H2 receptor anagonists, antacids) are not expected to reduce dabrafenib bioavailability to a clinically significant level.

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
 

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Exceptional Access Program (EAP Website)

• daBRAfenib - As monotherapy for the treatment of patients with BRAF V600 mutation-positive unresectable melanoma or metastatic disease, according to specific criteria
• daBRAfenib - In combination with trametinib for the treatment of BRAF V600 mutation-positive, unresectable or metastatic melanoma, according to specific clinical criteria
• daBRAfenib - For the adjuvant treatment of resected Stage III cutaneous melanoma according to clinical criteria

June 2021 Updated indications and status, adverse effects, dosing and special precautions sections.