dabrafenib

Dabrafenib is an anticancer (antineoplastic) medication used in the treatment of certain types of melanoma skin cancer, lung and thyroid cancers, and solid tumors. Dabrafenib is used as monotherapy or in combination with trametinib, another antineoplastic drug, to treat different types of metastatic cancers with BRAF V600E or V600K gene mutations, as confirmed by an FDA-approved test. In some cancers, the combination treatment is more effective than either of the drugs alone in controlling cancer growth as well as emergence of resistance to treatment.

Dabrafenib is a small molecule drug that enters into the cells and changes specific cell mechanisms. Dabrafenib is a BRAF kinase inhibitor that works by inhibiting mutated forms of proteins (kinases) encoded by BRAF genes. Dabrafenib inhibits BRAF V600E, BRAF V600K, and BRAF V600D enzymes. Dabrafenib also inhibits BRAF and CRAF normal (wild-type) genes and their expression and signaling. BRAF enzymes (kinases) promote cell proliferation, and BRAF mutations result in uncontrolled cell growth and proliferation in cancers.

Dabrafenib is used in combination with trametinib to treat multiple cancers. The two drugs inhibit two different kinases in the signaling cascade (RAS/RAF/MEK/ERK pathway) activated by the BRAF mutations. Lab studies showed that dabrafenib and trametinib combination resulted in greater antitumor activity as well as delay in emergence of resistance in the cancer cells, compared to either drug alone.

In BRAF-mutant colorectal cancers, cancer cells develop resistance to dabrafenib treatment by inducing another signaling pathway (MAPK) mediated by epidermal growth factor (EGF), a protein that promotes cell growth and differentiation. Dabrafenib is not approved for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition. Dabrafenib is not indicated for treatment of patients with wild-type BRAF solid tumors.

The FDA-approved uses of dabrafenib are:

Adult:

Monotherapy:

• Treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

In combination with trametinib:

• Treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.
• Adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection.
• Treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test.
• Treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options.

Adult and Pediatric:

In combination with trametinib:

• Treatment of adult and pediatric patients 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Pediatric:

In combination with trametinib:

• Treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy.

• Dabrafenib treatment as a single agent or with trametinib can promote growth of new primary malignancies, both skin (cutaneous) and non-cutaneous.
  • Evaluate patients for cutaneous malignancies before starting treatment with dabrafenib and monitor every 2 months during and for 6 months after discontinuation of treatment.
  • Monitor patients for non-cutaneous malignancies during treatment and discontinue treatment if the patient develops signs and symptoms of RAS mutation-positive non-cutaneous malignancies.
• Confirm evidence of BRAF V600E or V600K mutation with the FDA-approved test before starting treatment. Experiments show dabrafenib can cause paradoxical activation of MAP-kinase signaling and increase cell proliferation in BRAF wild-type cells promoting BRAF wild-type tumor growth.
• Dabrafenib/trametinib treatment can cause hemorrhage, fatal sometimes, including gastrointestinal, cerebral, uterine, post-procedural and nasal hemorrhage. Depending on severity, interrupt treatment and restart with a reduced dose when symptoms resolve or permanently discontinue treatment.
• Dabrafenib/trametinib combination treatment can cause heart muscle disease (cardiomyopathy) that can reduce the left ventricular ejection fraction (LVEF).
  • Assess LVEF in patients before starting treatment and 1 month after treatment initiation, and monitor every 2 to 3 months during treatment.
  • Withhold dabrafenib if the patient develops symptomatic cardiomyopathy or asymptomatic LV dysfunction of more than 20% from baseline that is below institutional lower limit of normal (LLN).
  • Resume treatment at the same dose upon recovery of cardiac function to at least the institutional LLN for LVEF and absolute decrease of 10% or less compared to baseline.
• Dabrafenib, with or without trametinib can cause inflammation in the uvea, the middle layer of the eye (uveitis) including in the iris (iritis) and the ciliary body (iridocyclitis).
  • Monitor patients for symptoms of uveitis such as eye pain, light sensitivity (photophobia) or changes in vision.
  • If the patient develops iritis, treat appropriately and continue dabrafenib without changing dosage.
  • If the patient develops severe uveitis (iridocyclitis) or mild/moderate uveitis that does not improve with treatment, institute ocular treatment and withhold dabrafenib until uveitis improves.
  • If Grade 2 or higher uveitis persists for longer than 6 weeks, permanently discontinue dabrafenib.
• Dabrafenib treatment is associated with fever (pyrexia) and severe febrile reactions with complications that can include rigors or chills, dehydration, low blood pressure (hypotension) and kidney failure. The incidence is higher with dabrafenib/trametinib combination treatment than dabrafenib monotherapy.
  • Withhold dabrafenib, or dabrafenib and trametinib in case of combination treatment, if the patient’s temperature goes to 100.4 F or higher. Monitor patient for complications and signs and symptoms of infection.
  • Treatment may be restarted at same or lower dose, if the patient recovers from febrile reactions for at least 24 hours.
  • Administer antipyretic prophylaxis when resuming treatment after febrile reactions.
  • Administer corticosteroids for at least 5 days if the patient develops subsequent pyrexia that doesn’t resolve within 3 days, or pyrexia with complications without evidence of any infection.
• Dabrafenib can cause severe skin reactions such as Stevens-Johnson syndrome (SJS) and drug reactions with eosinophilia and systemic symptoms (DRESS) that can be life-threatening or fatal.
• Monitor patient for new or worsening skin reactions, withhold dabrafenib for severe or intolerable skin toxicities and resume at a lower dose if the patient recovers within 3 weeks.
• Permanently discontinue dabrafenib if the patient does not improve within 3 weeks, or develops SJS or DRESS.
• Dabrafenib can increase blood glucose levels. Evaluate the patient’s glucose levels before starting treatment. Monitor glucose levels as clinically appropriate thereafter in patients with preexisting hyperglycemia or diabetes, and initiate or adjust dosage of antidiabetic medications as required.
• Dabrafenib can cause premature destruction of red blood cells and lead to hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Monitor patients with G6PD deficiency for signs and symptoms of hemolytic anemia.
• When using dabrafenib in combination with trametinib, review the prescribing information for trametinib for information on the serious risks of trametinib before treatment initiation.
• Dabrafenib can cause fetal harm if used during pregnancy.
  • Verify pregnancy status of women of pregnancy potential before initiating dabrafenib.
  • Inform women who are or may get pregnant of the hazard to the fetus.
  • Advise women to use effective non-hormonal contraception for the recommended period during and after treatment, because dabrafenib can render hormonal contraceptives ineffective.
• Avoid concurrent use of dabrafenib with drugs that are strong inducers or inhibitors of the liver enzymes CYP3A4 or CYP2C8.
• Dabrafenib can decrease the efficacy of drugs metabolized by liver enzymes CYP3A4, CYP2C9 and CYP1A2.
  • Avoid concurrent use with substrates of these enzymes and use substitutes where possible. If use of these medications is unavoidable, monitor patients for loss of efficacy.
  • Monitor international normalized ratio (INR) in patients taking warfarin during initiation and discontinuation of dabrafenib.

Common side effects of dabrafenib include:

• Thickening of skin (hyperkeratosis)
• Hair loss (alopecia)
• Hand-foot syndrome (palmar-plantar erythrodysesthesia syndrome/PPES)
• Rash
• Dry skin
• Acneiform dermatitis
• High blood glucose levels (hyperglycemia)
• Electrolyte disturbances including:
  • Low serum phosphate level (hypophosphatemia)
  • Low blood sodium (hyponatremia)
  • Decrease in magnesium levels
  • Increase in magnesium levels
  • Low blood calcium (hypocalcemia)
  • Low blood potassium (hypokalemia)
  • Increase in potassium
• Low albumin levels in blood (hypoalbuminemia)
• Increase in alkaline phosphatase (ALK)
• Increase in alanine aminotransferase (ALT)
• Increase in aspartate aminotransferase (AST)
• Increase in total bilirubin
• Blood disorders including:
  • Low count of neutrophil immune cells (neutropenia)
  • Low count of lymphocyte immune cells (lymphopenia)
  • Increase in lymphocytes
  • Low white cell count (leukopenia)
  • Low red blood cell count (anemia)
  • Decrease in platelets
  • Decrease in hemoglobin
• Headache
• Fever (pyrexia)
• Fatigue
• Chills
• Dizziness
• Peripheral nerve disease (neuropathy)
• Swelling (edema)
• Peripheral edema
• Joint pain (arthralgia)
• Back pain
• Muscle pain (myalgia)
• Musculoskeletal pain
• Jaw pain
• Benign skin tumor (papilloma)
• Cutaneous squamous cell carcinoma (cuSCC)
• Cough
• Nose and throat inflammation (nasopharyngitis)
• Shortness of breath (dyspnea)
• Upper respiratory tract infection
• Pneumonia
• Sepsis
• Constipation
• Nausea
• Vomiting
• Inflammation of the pancreas (pancreatitis)
• Colon inflammation (colitis)
• Gastrointestinal perforation
• Decreased appetite
• Abdominal pain
• Oral inflammation (stomatitis)
• Mouth and throat (oropharyngeal) pain
• Increased weight
• Inflammation in the kidney (interstitial nephritis, tubulointerstitial nephritis)
• Increased creatinine levels
• Growth of clusters of inflammatory immune cells (sarcoidosis)
• Bleeding (hemorrhage)
• Decrease in left ventricular ejection fraction (LVEF)
• Inflammation of the eye’s uvea (uveitis)
• Anxiety
• Infusion related reaction
• Inflammation of the fat tissue beneath the skin (panniculitis)
• Infection of the fingernails or toenails (paronychia)
• Severe skin reactions including:
  • Stevens-Johnson syndrome (SJS)
  • Drug reaction with eosinophilia and systemic symptoms (DRESS)
• Hypersensitivity reactions
• Hypersensitivity reaction with blisters (bullous rash)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Capsule

• 50 mg
• 75 mg

Tablet for oral suspension

• 10 mg

Adult:

Melanoma

BRAF V600E mutation-positive unresectable or metastatic melanoma

• Indicated as a single agent
• 150 mg orally twice daily
• Continue until disease recurrence or unacceptable toxicity

BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma

• Indicated, in combination with trametinib
• 150 mg orally once daily plus trametinib 2 mg orally once daily
• 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 orally twice daily plus trametinib 2 mg orally once daily
• 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 orally twice daily plus trametinib 2 mg orally once daily
• Continue until disease recurrence or unacceptable toxicity

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 orally twice daily plus trametinib 2 mg orally once daily
• Continue until disease recurrence or unacceptable toxicity

BRAF V600E Mutation-Positive Solid Tumors

• Indicated in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation in patients who have progressed following prior treatment and have no satisfactory alternative treatment options
• 150 mg orally twice daily plus trametinib 2 mg orally once daily
• Continue until disease recurrence or unacceptable toxicity

Dosage Modifications

Dose reductions for dabrafenib (single agent or in combination with trametinib)

• Refer to trametinib for recommending dosage modifications
• First dose reduction: 100 mg orally twice daily
• Second dose reduction: 75 mg orally twice daily
• Third dose reduction: 50 mg orally twice daily
• If unable to tolerate 50 mg twice daily: Permanently discontinue

Dose reductions for trametinib when administered with dabrafenib

• First dose reduction: 1.5 mg orally once daily
• Second dose reduction: 1 mg orally once daily
• 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 101.3-104ºF: Withhold until fever resolves, then resume at same or lower dose
• Fever above 104ºF or fever complicated by rigors, hypotension, dehydration, or renal failure: Withhold until febrile reactions resolve for 24 hours or longer, then resume at lower dose; or permanently discontinue
• Applies to both trametinib and dabrafenib

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

Cardiomyopathy

• Asymptomatic left ventricular ejection fraction (LVEF)
  • Asymptomatic, absolute decrease in LVEF of 10% or more from baseline, but is below lower limit of normal (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 cardiomyopathy
  • Symptomatic cardiomyopathy or absolute decrease in LVEF of more than 20% from baseline that is below LLN:
  • Trametinib: Permanently discontinue
  • Dabrafenib: Withhold, if improved, then resume at the same dose

Uncomplicated deep venous thrombosis (DVT) or pulmonary embolism (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

Other adverse reactions

• Includes hemorrhage
• Intolerable Grade 2 or any Grade 3: Withhold dabrafenib; if improved to Grade 0-1, then resume at the same or at a lower dose level; if unresolved, permanently discontinue
• First occurrence of any Grade 4: Withhold dabrafenib until improves to Grade 0-1, then resume at a lower dose; or permanently discontinue dabrafenib
• Recurrent Grade 4: Permanently discontinue

Renal impairment (dabrafenib only)

• eGFR 15-89 mL/minute/1.73 m2: No dosage adjustment recommended; pharmacokinetic differences are not clinically relevant
• Hepatic impairment (dabrafenib only)
• Mild (bilirubin 1-1.5 times upper limit of normal [ULN] and any AST): No dose adjustment necessary
• Moderate-to-severe (bilirubin more than 1.5-10 times ULN and any AST): Dose not established; not studied

Dosing Considerations

Patient selection

• Confirm the presence of BRAF V600E or V600K mutation in tumor specimens before initiating
• Information on FDA-approved tests for melanoma is available at: https://www.fda.gov/CompanionDiagnostics

Limitations of use

• Not indicated for treatment of patients with wild-type BRAF solid tumors
• Not indicated for treatment of patients with colorectal cancer due to known intrinsic resistance to BRAF inhibition

Pediatric:

BRAF V600E Mutation-Positive Solid Tumors

• Indicated in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation in pediatric patients aged 6 years or above who have progressed following prior treatment and have no satisfactory alternative treatment options
• Children below 6 years: Safety and efficacy not established
• Children 6 years or above and weighing 8 kg or more (tablets for oral suspension only)
  • 8-9 kg: 20 mg orally twice daily
  • 10-13 kg: 30 mg orally twice daily
  • 14-17 kg: 40 mg orally twice daily
  • 18-21 kg: 50 mg orally twice daily
  • 22-25 kg: 60 mg orally twice daily
  • 26-29 kg: 70 mg orally twice daily
  • 30-33 kg: 80 mg orally twice daily
  • 34-37 kg: 90 mg orally twice daily
  • 38-41 kg: 100 mg orally twice daily
  • 42-45 kg: 110 mg orally twice daily
  • 46-50 kg: 130 mg orally twice daily
  • 51 kg or more: 150 mg orally twice daily
  • Continue until disease progression or until unacceptable toxicity
  • Refer to trametinib prescribing information for recommended dosing information
• Children 1 year or above and weighing 26 kg or more (capsules only)
• 26-37 kg: 75 mg orally twice daily
• 38-50 kg: 100 mg orally twice daily
• 51 kg or more: 150 mg orally twice daily
• Continue until disease progression or until unacceptable toxicity
• Refer to trametinib prescribing information for recommended dosing information

Low-Grade Glioma

• Indicated, in combination with trametinib, for low-grade glioma (LGG) with a BRAF V600E mutation in pediatric patients aged 1 year or above who require systemic therapy
• Children below 1 year: Safety and efficacy established
• Children 1 year or above and weighing 8 kg or more (tablets for oral suspension only)
  • 8-9 kg: 20 mg orally twice daily
  • 10-13 kg: 30 mg orally twice daily
  • 14-17 kg: 40 mg orally twice daily
  • 18-21 kg: 50 mg orally twice daily
  • 22-25 kg: 60 mg orally twice daily
  • 26-29 kg: 70 mg orally twice daily
  • 30-33 kg: 80 mg orally twice daily
  • 34-37 kg: 90 mg orally twice daily
  • 38-41 kg: 100 mg orally twice daily
  • 42-45 kg: 110 mg orally twice daily
  • 46-50 kg: 130 mg orally twice daily
  • 51 kg or more: 150 mg orally twice daily
  • Continue until disease progression or until unacceptable toxicity
• Children 1 year or above and weighing 26 kg or more (capsules only)
  • 26-37 kg: 75 mg orally twice daily
  • 38-50 kg: 100 mg orally twice daily
  • 51 kg or more: 150 mg orally twice daily
  • Continue until disease progression or until unacceptable toxicity
  • Refer to trametinib prescribing information for recommended dosing information

Dosage Modifications

Dose reductions for dabrafenib capsules

• Recommended dose 75 mg orally twice daily
  • First dose reduction: 50 mg orally twice daily
  • If unable to tolerate 50 mg orally twice daily: Permanently discontinue
• Recommended dose 100 mg
  • First dose reduction: 75 mg orally twice daily
  • Second dose reduction: 50 mg orally twice daily
  • If unable to tolerate 50 mg twice daily: Permanently discontinue
• Recommended dose 150 mg twice daily
  • First dose reduction: 100 mg orally twice daily
  • Second dose reduction: 75 mg orally twice daily
  • Third dose reduction: 50 mg orally twice daily
• If unable to tolerate 50 mg twice daily: Permanently discontinue

Dose reductions for dabrafenib tablets for oral suspension

• 8-9 kg
  • First dose reduction: 10 mg twice daily
  • Second dose reduction: N/A
  • Third dose reduction: N/A
• 10-13 kg
  • First dose reduction: 20 mg twice daily
  • Second dose reduction: 10 mg twice daily
  • Third dose reduction: N/A
• 14-21 kg
  • First dose reduction: 30 mg twice daily
  • Second dose reduction: 20 mg twice daily
  • Third dose reduction: 10 mg twice daily
• 22-25 kg
  • First dose reduction: 40 mg twice daily
  • Second dose reduction: 30 mg twice daily
  • Third dose reduction: 20 mg twice daily
• 26-29 kg
  • First dose reduction: 50 mg twice daily
  • Second dose reduction: 40 mg twice daily
  • Third dose reduction: 20 mg twice daily
• 30-33 kg
  • First dose reduction: 50 mg twice daily
  • Second dose reduction: 40 mg twice daily
  • Third dose reduction: 30 mg twice daily
• 34-37 kg
  • First dose reduction: 60 mg twice daily
  • Second dose reduction: 50 mg twice daily
  • Third dose reduction: 30 mg twice daily
• 38-41 kg
  • First dose reduction: 70 mg twice daily
  • Second dose reduction: 50 mg twice daily
  • Third dose reduction: 30 mg twice daily
• 42-45 kg
  • First dose reduction: 70 mg twice daily
  • Second dose reduction: 60 mg twice daily
  • Third dose reduction: 40 mg twice daily
• 46-50 kg
  • First dose reduction: 90 mg twice daily
  • Second dose reduction: 70 mg twice daily
  • Third dose reduction: 40 mg twice daily
• 51 kg or more
  • First dose reduction: 100 mg twice daily
  • Second dose reduction: 80 mg twice daily
  • Third dose reduction: 50 mg twice daily

Dose reductions for trametinib when administered with dabrafenib

• First dose reduction: 1.5 mg orally once daily
• 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 101.3-104ºF: Withhold until fever resolves, then resume at same or lower dose
• Fever above 104ºF or fever complicated by rigors, hypotension, dehydration, or renal failure: Withhold until febrile reactions resolve for 24 hours or longer, then resume at lower dose; or permanently discontinue
• Applies to both trametinib and dabrafenib

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

Cardiomyopathy

• Asymptomatic left ventricular ejection fraction (LVEF)
  • Asymptomatic, absolute decrease in LVEF 10% or more 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 cardiomyopathy
  • Symptomatic cardiomyopathy or absolute decrease in LVEF more than 20% from baseline that is below LLN:
  • Trametinib: Permanently discontinue
  • Dabrafenib: Withhold, if improved, then resume at the same dose

Uncomplicated deep venous thrombosis (DVT) or pulmonary embolism (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

Other adverse reactions

• Includes hemorrhage
• Intolerable Grade 2 or any Grade 3: Withhold dabrafenib; if improved to Grade 0-1, then resume at the same or at a lower dose level; if unresolved, permanently discontinue
• First occurrence of any Grade 4: Withhold dabrafenib until improves to Grade 0-1, then resume at a lower dose; or permanently discontinue dabrafenib
• Recurrent Grade 4: Permanently discontinue

Renal impairment (dabrafenib only)

• eGFR 15-89 mL/minute/1.73 m2: No dosage adjustment recommended; pharmacokinetic differences are not clinically relevant

Hepatic impairment (dabrafenib only)

• Mild (bilirubin 1-1.5 times ULN and any AST): No dose adjustment necessary
• Moderate-to-severe (bilirubin above 1.5-10 times ULN and any AST): Dose not established; not studied

Dosing Considerations

Patient selection

• Confirm the presence of BRAF V600E mutation in tumor specimens before initiating
• Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: https://www.fda.gov/CompanionDiagnostics

Limitations of use

• Not indicated for treatment of patients with wild-type BRAF solid tumors
• Not indicated for treatment of patients with colorectal cancer due to known intrinsic resistance to BRAF inhibition

Overdose

There is no information on dabrafenib overdose. Overdose treatment may include symptomatic and supportive care. Hemodialysis is unlikely to be effective in elimination of dabrafenib.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Severe interactions of dabrafenib include:
  • cariprazine
  • cobimetinib
  • doravirine
  • elbasvir/grazoprevir
  • fostemsavir
  • isavuconazonium sulfate
  • lefamulin
  • lonafarnib
  • lorlatinib
  • lumacaftor/ivacaftor
  • mavacamten
  • naloxegol
  • ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC)
  • panobinostat
  • regorafenib
  • tacrolimus ointment
• Dabrafenib has serious interactions with at least 160 different drugs.
• Dabrafenib has moderate interactions with at least 284 different drugs.
• Mild interactions of dabrafenib include:
  • acetazolamide
  • anastrozole
  • cyclophosphamide
  • danazol

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There is insufficient information on dabrafenib use in pregnant women to identify a drug-associated fetal risk. Based on its mechanism of action and animal reproductive studies, dabrafenib can cause fetal harm if used during pregnancy.
• Women of pregnancy potential should use effective nonhormonal contraception during treatment and for 2 weeks following the final dose of dabrafenib.
• Men with women partners who may get pregnant, including those who have had vasectomies, should use condoms during treatment and for 2 weeks after the last dose of dabrafenib.
• Dabrafenib may impair fertility in both men and women.
• There is no information on the presence of dabrafenib in breastmilk or its effects on milk production or the breastfed infant. Women should avoid breastfeeding during treatment and for two weeks following the final dose of dabrafenib because of the potential for serious adverse reactions in the breastfed infant.

• Take dabrafenib exactly as prescribed. Do not change dosage or discontinue dabrafenib unless directed by your physician.
• You will need medical tests before starting dabrafenib and periodically thereafter. Follow up with your physician and do not miss your appointments.
• Report to your physician immediately if you notice any new warts, bumps or sores that don’t heal or changes in color or size of a mole.
• During your treatment with dabrafenib, report to your physician immediately if you experience any of the following:
  • Heart-related symptoms such as fainting, shortness of breath with activity, fatigue and weakness
  • Symptoms of unusual bleeding
  • Fever, dehydration, low blood pressure symptoms, chills or rigors
  • Severe skin reactions
  • Symptoms of high blood sugar such as increased thirst and urination, tiredness and weight loss
  • Changes in vision
• If you have G6PD deficiency and you are receiving dabrafenib treatment, inform your physician if you develop symptoms of hemolytic anemia such as pale or yellowish skin, dark urine, fever, weakness and/or dizziness.
• Store dabrafenib safely out of reach of children.
• In case of overdose, seek medical help or contact Poison Control.