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dabrafenib (Rx)Brand and Other Names:Tafinlar

 
 
 

Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 50mg
  • 75mg
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Melanoma

BRAF protein kinase inhibitor indicated as a single agent for unresectable or metastatic melanoma with BRAF V600E mutation, or in combination with trametinib for BRAF V600E or V600K mutations

Single agent: 150 mg PO BID at least 1 hr ac or 2 hr pc

Combination regimen: 150 mg PO BID plus trametinib 2 mg PO qDay

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

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 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 same or lower dose (or permanently discontinue)

Cutaneous reactions

  • Intolerable Grade 2 skin toxicity, 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 (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

RPED

  • Grade 2-3 retinal pigment epithelia detachments (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: Withhold for up to 6 weeks; if improved to Grade 0-1, resume at same dose, if not improved, permanently discontinue

Pulmonary reactions

  • Interstitial lung disease/pneumonitis
  • Trametinib: Permanently discontinue
  • Dabrafenib: Do not modify dose

Other

  • Applies to both trametinib and dabrafenib
  • Intolerable Grade 2 or any Grade 3 adverse reactions: Withhold for up to 3 weeks; if improved to Grade 0-1, resume at lower dose level, if not improved, permanently discontinue
  • First occurrence of any Grade 4 reaction: Withhold until improves to Grade 0-1, then resume at lower dose level, or permanently discontinue
  • Recurrent Grade 4 reactions: Permanently discontinue

Dosing Considerations

Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with THxID BRAF Kit

Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at http://www.fda.gov/CompanionDiagnostics

Not indicated for treatment of patients with wild-type BRAF melanoma

Non-small Cell Lung Cancer (Orphan)

Orphan designation for treatment of patients with BRAF mutation positive non-small cell lung cancer

Sponsor

  • GlaxoSmithKline; 5 Crescent Drive; Phildelphia, PA 19112

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

dabrafenib and

No Results

     
     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            All grade toxicities reported

            >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%)

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            Warnings

            Contraindications

            None

            Cautions

            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

            Withhold if fever >101.3°F or complicated fever occurs (see Dosage Modifications)

            Hemorrhage, including major hemorrhages, can occur when used in combination with trametinib

            Venous thromboembolism can occur when used in combination with trametinib

            Hyperglycemia reported; monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia

            Risk of cardiomyopathy when used as a single agent or with trametinib; reassess LVEF after 1 month of treatment and then ~ every 2-3 months thereafter

            Uveitis, iritis, and retinal pigment epithelial detachment (RPED) reported; monitor patients routinely for visual symptoms

            Risk of serious skin toxicity including rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema

            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

            Dabrafenib may render hormonal contraceptives less effective and an alternative method of contraception should be used

            Concurrent administration of strong inhibitors or inducers of CYP3A4 or CYP2C8; coadministration with substrates of these isoenzymes 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

            Incidence and severity of pyrexia are increased with dabrafenib and trametinib

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            Pregnancy & Lactation

            Pregnancy Category: D

            Lactation: Unknown if distributed in human breast milk; a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

            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

            Instructions

            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

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            Images

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            Formulary

            FormularyPatient Discounts

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            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.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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