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daBRAFenib

( da-BRA-fe-nib )
Funding:
Exceptional Access Program
  • daBRAfenib - As monotherapy for the first-line and second-line 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
Other Name(s): Tafinlar®
Appearance: capsule In various strengths and colours
A - Drug Name

daBRAFenib

COMMON TRADE NAME(S):   Tafinlar®

 
B - Mechanism of Action and Pharmacokinetics

Dabrafenib is an inhibitor of RAF kinases, including BRAF. It acts on BRAF mutations which result in a constitutively active MAPK pathway (including RAS, RAF, MEK and ERK) and stimulated cell growth. 



Absorption

Decreased exposure was observed with repeat dosing (auto-induction of metabolism) and also with high fat foods. Food also delays dabrafenib absorption.  

Bioavailability 95%, decreased with food
Peak plasma levels achieved at 2 hours

Distribution
PPB 96.3 to 99.9% (dabrafenib and metabolites)
Metabolism
Main enzymes involved CYP3A4 and CYP2C8
Inducer of CYP3A4 (moderate to strong), CYP2B6, possibly CYP2C8, CYP 2C9 (weak), CYP2C19, UGTs, Pgp
Inhibitor of OATP1B1, OATP1B3, OAT1, OAT3 (low risk of interactions)
Active metabolites hydroxy-dabrafenib, desmethyl-dabrafenib
Inactive metabolites carboxy-dabrafenib (10-fold higher exposure compared to the parent drug and the other 2 metabolites)
Elimination
Feces 71% of dose (major route)
Urine 23% of dose
Half-life 8 h (unchanged drug); 10 h (hydroxy metabolite); 21-22 h (carboxy and desmethyl metabolites)
 
C - Indications and Status
Health Canada Approvals:

  • Monotherapy or in combination with trametinib for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation 
  • In combination with trametinib for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600 mutation

Notes:

  • For both indications, a validated test is required to confirm BRAF V600 mutation status. Dabrafenib should not be used in BRAF wild-type disease.

Melanoma:

  • Approval was based on overall response rate (ORR) and progression-free survival (PFS); improvements in overall survival (OS) and quality of life (QOL) have not been demonstrated.
  • Response rate may be lower in patients with BRAFV600K or less common mutations and in patients previously treated with BRAF inhibitors. 
  • Combination treatment is not recommended in patients who previously progressed on a BRAF inhibitor. 

 

 

 

 

NSCLC:

  • Approval was based on ORR from a single-arm phase 2 trial; improvements in PFS, OS and QOL have not been demonstrated. 
  • Clinical data supporting combination treatment are limited to patients with BRAF V600E mutations.


 
D - Adverse Effects

Emetogenic Potential:  

Minimal – No routine prophylaxis; PRN recommended

Extravasation Potential:   Not applicable

The following adverse events were mainly observed in the phase III monotherapy melanoma trial, unless otherwise indicated.  Consult the trametinib drug monograph when used in combination.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Atrial fibrillation (2%) E
Cardiotoxicity (NSCLC) E  D
Hypotension (<1%) E
Other (worsening valve disease <1%) E
QT interval prolonged (rare) E
Venous thromboembolism (3-4% when combined with trametinib) E
Dermatological Alopecia (29%) D
Erythema nodosum (1%) (or Panniculitis) E  D
Hand-foot syndrome (20%) E
Other (39%) (hyperkeratosis) E
Photosensitivity (3%) E
Rash (18%) E
Gastrointestinal Anorexia (12%) E
Constipation (13%) E
Diarrhea (14%) E
Nausea, vomiting (27%) I
General Edema (14%) E
Fatigue (22%) E
Fever (31%) (non-infection related, increased in combination; 5% severe with complications) E
Hematological Hemorrhage (5%) (severe, combined with trametinib) E
Myelosuppression (4%) (severe, combination with trametinib) E
Hepatobiliary ↑ LFTs (23%) E
Pancreatitis (1-2% when combined with trametinib) E  D
Hypersensitivity Hypersensitivity (1%) I
Metabolic / Endocrine Abnormal electrolyte(s) (41%) (severe 6%; mainly ↓PO4, also ↓Na) E
Hyperglycemia (56%) (severe 8%) E
Musculoskeletal Musculoskeletal pain (32%) E
Neoplastic Other (25%) skin papilloma D
Secondary malignancy (9%) (cuSCC, new primary melanoma, non-cutaneous malignancies) D  L
Nervous System Headache (34%) E
Ophthalmic Retinal detachment (2%) (when combined with trametinib) E  D
Uveitis (1%) (2% when combined with trametinib) E
Renal Nephritis (<1%) (2% when combined with trametinib) E
Renal failure (1%) E
Respiratory Cough (14%) E
Pharyngitis (16%) (nasopharyngitis) E


* "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 hyperglycemia, abnormal electrolyte(s), hyperkeratosis, headache, musculoskeletal pain, fever, alopecia, nausea/vomiting , cutaneous or non-cutaneous malignancies and ↑ LFTs. 

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.

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.  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 and usually occurred in the first 2 to 3 months with monotherapy (longer 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 has been reported and is more common with combination treatment. 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.

 
E - Dosing

Refer to protocol by which patient is being treated.  A validated test is required to identify BRAF V600 mutation status. 

Prophylaxis with antipyretics +/- oral corticosteroids may be required if prior severe febrile reactions with dabrafenib. 

 

 

 



Adults:

 

Dose Level Dose
0 150 mg PO BID
-1 100 mg PO BID
-2 75 mg PO BID
-3 50 mg PO BID
unable to tolerate 50 mg PO BID discontinue

When given in combination, dabrafenib should be administered with a starting dose of trametinib 2 mg daily.

 


 

 


Dosage with Toxicity:

Refer to the regimen monograph DABRTRAM for dose modifications for combination therapy with trametinib.

Toxicity type

 Dabrafenib dose

 ↓ LVEF below LLN and > 20% decrease from baseline 

 Hold until resolution and then restart at the same or reduced dose level

 

Symptomatic cardiac failure

 Hold until resolution and then restart at the same or reduced dose level

 

Fever of 38.5-40°C without complications

Hold until resolution; monitor creatinine and for signs and symptoms of infection. Restart at same dose or ↓ 1 dose level.  Prophylaxis with antipyretics +/- oral corticosteroids may be required if prior severe febrile reactions

 

Fever > 40°C or any fever with complications due to rigors, hypotension, dehydration or renal failure

Monitor creatinine and for signs and symptoms of infection.

Discontinue
OR
Hold until ≤ grade 1 and ↓ 1 dose level.  Prophylaxis with antipyretics +/- oral corticosteroids may be required if prior severe febrile reactions.

Intolerable grade 2 or ≥ grade 3 rash Hold until ≤ grade 1 and then restart at ↓ 1 dose level
Intolerable grade 2 or ≥ grade 3 rash that does not improve wihtin 3 weeks of holding treatment Discontinue
Uveitis that responds to local ocular therapies Continue treatment without dose modifications and monitor
Uveitis that does not improve despite local ocular therapy Hold until resolved and ↓ 1 dose level
 RPED/RVO  Continue at same dose and monitor
 Pneumonitis  Continue at same dose and monitor

Pancreatitis

Hold until resolved.  Discontinue OR

If restart, ↓ 1 dose level and monitor carefully.

Cutaneous squamous cell carcinoma or new primary melanoma

No dose modification or interruptions recommended.

RAS associated malignancy Consider risk benefit before making decision to continue treatment

Other Grade 1 or tolerable Grade 2

No change; monitor.

Other intolerable Grade 2 or Grade 3

Hold until ≤ grade 1 and restart by ↓ 1 dose level

Other Grade 4 or Grade 3 that does not improve to ≤ grade 1

Discontinue OR hold until ≤ grade 1 and restart by ↓ 1 dose level



Dosage with Hepatic Impairment:

Hepatic metabolism and biliary secretion are the main routes of dabrafenib elimination; hepatic impairment may lead to increased exposure and toxicities.  Population pharmacokinetics in mild hepatic impairment suggest no dose adjustment is required, but no data are available for moderate to severe hepatic impairment.

Hepatic Impairment Dose
Mild No dose adjustment required.
Moderate No data
Severe No data


Dosage with Renal Impairment:

There are no clinical data in patients with severe renal impairment. With mild to moderate impairment, population pharmacokinetics suggest that no adjustments are required.

Creatinine clearance  Dose
30-89 mL/min No dose adjustment needed
 < 30 mL/min No data found. Use with caution.


Dosage in the elderly:

More adverse events were observed in elderly patients (≥ 65 years).  No dose adjustment required.  Peripheral edema and decreased appetite were reported more frequently in elderly patients (in combination with trametinib only).



Children:

Safety and efficacy have not been established in children and adolescents.  Adverse growth effects and renal toxicity have been observed in developing animals.



 
F - Administration Guidelines
  • Dabrafenib doses should be given approximately 12 hours apart on an empty stomach, at least 1 hour before or 2 hours after a meal.
  • When given in combination, trametinib should be administered once daily with either the morning or evening dose of dabrafenib.
  • Do not administer with high fat meals.
  • Avoid grapefruit, starfruit, Seville oranges, their juices or products during treatment.
  • If a dose is missed, it may be given if there are more than 6 hours before the next dose.  Otherwise, skip this dose and give the next one as scheduled.  Never give both doses at the same time.
  • Store at room temperature (15-30°C)
 
G - Special Precautions
Contraindications:

  • Patients who have a hypersensitivity to this drug or any of its components
  • Patients with BRAF wild-type or unknown disease.  BRAF mutation must be confirmed using a validated test before starting dabrafenib treatment.
     

Other Warnings/Precautions:

  • Dabrafenib monotherapy has not been studied in patients who have had previous treatment with BRAF inhibitors.
  • Use combination therapy with caution in patients at risk of bleeding as severe events have been reported.
  • 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
  • Fatal hemorrhage has occurred in patients on the combination of dabrafenib and trametinib.  The risk may be increased with concomitant use of antiplatelet/anticoagulant therapy or in patients who develop brain metastases while on treatment. 


Other Drug Properties:

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

Pregnancy and Lactation:
  • Embryotoxicity: Yes
  • Teratogenicity: Yes
  • Mutagenicity: No
  • Clastogenicity: No
  • Fertility effects: Yes

    Fertility effects may be irreversible.  Dabrafenib is not recommended for use in pregnancy.  Highly effective contraception (<1% pregnancy rate) should be used by both sexes during treatment, and for at least 4 weeks after treatment cessation of dabrafenib and for at least 4 months (for women) or 6 months (for men-general recommendation) following the last dose of trametinib when given in combination.  Efficacy of hormonal contraceptives can be decreased by dabrafenib (refer to Interactions); therefore effective non-hormonal contraception methods should be used.

     

  • Excretion into breast milk: Unknown
    Breastfeeding is not recommended.
 
H - Interactions

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, CYP2B6, CYP2C8, CYP2C19, UGTs and P-gp. The inhibitory effects of dabrafenib and its metabolites on OAT1 and OAT3 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.

AGENT EFFECT MECHANISM MANAGEMENT
CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) ↓ dabrafenib concentration and/or efficacy ↑ metabolism of dabrafenib into its metabolites Avoid strong CYP3A4 inducers if possible
CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) ↑ dabrafenib and metabolite exposure and/or toxicity (up to 61%↑) ↓ metabolism of dabrafenib Avoid strong CYP3A4 inhibitors if possible
CYP3A4 substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors) ↓ substrate exposure and/or efficacy (up to 74%↓) dabrafenib is a moderate to strong CYP3A4 inducer Caution; monitor for efficacy. Avoid hormonal contraceptives as dabrafenib can decrease their efficacy.
CYP 2C8 inducers (e.g. rifampin) ↓ dabrafenib concentration and/or efficacy ↑ metabolism of dabrafenib into its metabolites Avoid strong CYP2C8 inducers if possible
CYP 2C8 inhibitors (e.g. gemfibrozil) ↑ dabrafenib AUC up to 47% and metabolite exposure and/or toxicity ↓ metabolism of dabrafenib Avoid strong CYP2C8 inhibitors if possible
Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) ↑ risk of QT prolongation Additive Avoid if possible
OATP1B1 and 1B3 substrates (e.g. statins, angiotensin receptor blockers, SN-38) Potentially ↑ substrate concentration and/or toxicity ↓ metabolism of OATP1B1 or 1B3 substrates Caution
Substrates of CYP2B6, 2C8, 2C9, 2C19, UGTs and Pgp (e.g. warfarin, paclitaxel, amiodarone, bupropion, celecoxib, some PPIs, digoxin) Potentially ↓ substrate concentration and/or efficacy( ↓ warfarin AUC up to 37%) ↑ metabolism of substrates Use alternative medications if possible; if must use together, monitor for efficacy.
 
I - Recommended Clinical Monitoring

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

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

Skin examination for cutaneous squamous cell carcinoma and new primary melanoma

Non-cutaneous malignancies

Baseline, every 2 months during treatment, continue for 6 months after the last dose

Blood glucose

Baseline, every 1 to 2 months, more regularly (at each visit) in patients with diabetes or hyperglycemia

Liver function tests

Baseline, every 1 to 2 months

Renal function tests and electrolytes, including phosphate

Baseline, every 1 to 2 months, and during febrile events

Clinical toxicity assessment for febrile events, hypertension, pancreatitis, musculoskeletal pain, ocular and cardiac effects, hypersensitivity, bleeding and neurologic events (when combined with trametinib)

At each visit

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



Suggested Clinical Monitoring

Monitor Type Monitor Frequency

INR for patients receiving warfarin

Baseline and at each visit
 
J - Supplementary Public Funding

Exceptional Access Program (EAP Website)

  • daBRAfenib - As monotherapy for the first-line and second-line 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.

 
K - References

Product Monograph:  Tafinlar® (dabrafenib).  Novartis Pharmaceuticals Canada Inc., May 16, 2018.

Prescribing Information:  Tafinlar® (dabrafenib).  GlaxoSmithKline Inc. (US), May 2013.


January 2020 Added EAP funding info

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

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