dabrafenib (Rx)

Brand and Other Names:Tafinlar
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Dosing & Uses

AdultPediatric

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

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Interactions

Interaction Checker

and dabrafenib

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            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

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            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
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            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.

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            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)

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            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)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
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