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Tafinlar

Generic Name: Dabrafenib Mesylate
Class: Antineoplastic Agents
Chemical Name: N - [3 - [5 - (2 - amino - 4 - pyrimidinyl) - 2 - (1,1 - dimethylethyl) - 4 - thiazolyl] - 2 - fluorophenyl] - 2,6 - difluoro - benzenesulfonamide methanesulfonate (1:1)
Molecular Formula: C23H20F3N5O2S2•CH4O3S
CAS Number: 1195768-06-9

Introduction

Antineoplastic agent; an inhibitor of b-Raf serine-threonine kinase with V600E mutation (BRAF V600E).1 2 7

Uses for Tafinlar

Melanoma

Treatment of unresectable or metastatic melanoma with BRAF V600E mutation1 2 7 (designated an orphan drug by FDA for this use).3

Slideshow: Flashback: FDA Drug Approvals 2013

FDA-approved in vitro diagnostic test (e.g., THxID BRAF kit) required to confirm presence of BRAF V600E mutation prior to initiation of therapy.1 6

Not recommended for use in patients with wild-type BRAF melanoma; safety and efficacy not established.1

Tafinlar Dosage and Administration

Administration

Oral Administration

Administer orally twice daily, approximately 12 hours apart.1

Administer at least 1 hour before or 2 hours after a meal.1

Do not open, crush, or break capsules.1

Dosage

Available as dabrafenib mesylate; dosage expressed in terms of dabrafenib.1

Adults

Melanoma
Oral

150 mg twice daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Dosage Modification for Toxicity
Oral

Dosage may be reduced or therapy temporarily interrupted in patients who develop adverse effects.1 Up to 3 dosage reductions for toxicity may be made.1

If necessary, initially reduce dosage to 100 mg twice daily.1 If further dosage reduction necessary, reduce dosage to 75 mg twice daily or subsequently to 50 mg twice daily.1 For patients unable to tolerate 50 mg twice daily, permanently discontinue the drug.1

Dosage Modification for New Primary Cutaneous Malignancies
Oral

Dosage modification not necessary.1

Dosage Modification for Febrile Drug Reaction
Oral

Fever of 38.5–40°C: Interrupt therapy until fever resolves; resume therapy at same or reduced dosage.1

Fever >40°C or fever with complications (e.g., rigors, hypotension, dehydration, renal failure): Permanently discontinue dabrafenib.1 Alternatively, withhold drug until fever resolves; resume therapy with reduced dosage.1

Dosage Modification for Other Toxicity
Oral

Intolerable grade 2 or any grade 3 adverse reaction: Interrupt therapy until adverse reaction resolves to grade 1 or less; resume therapy at reduced dosage.1

First occurrence any grade 4 adverse reaction: Permanently discontinue dabrafenib.1 Alternatively, withhold drug until adverse reaction resolves to grade 1 or less; resume at reduced dosage.1

Intolerable grade 2 or any grade 3 or 4 adverse reaction in patients receiving 50 mg twice daily: Permanently discontinue dabrafenib.1

Recurrent grade 4 adverse reaction: Permanently discontinue dabrafenib.1

Special Populations

Hepatic Impairment

Mild hepatic impairment: Dosage adjustment not necessary.1

Moderate to severe hepatic impairment: Appropriate dosage not established.1

Renal Impairment

Mild or moderate renal impairment: Dosage adjustment not necessary.1

Severe renal impairment: Appropriate dosage not established.1

Cautions for Tafinlar

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenic and embryotoxic in animals.1

Advise female patients to use highly effective, nonhormonal contraception during treatment and for 4 weeks following drug discontinuance.1 (See Specific Drugs under Interactions.)

If used during pregnancy, inform patient of potential fetal hazard.1

New Primary Cutaneous Malignancy

Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma reported.1 In clinical trials, median time to first cutaneous squamous cell carcinoma or keratoacanthoma 9 weeks.1

Perform dermatologic evaluations at baseline, every 2 months during therapy, and for up to 6 months following discontinuance of dabrafenib.1

Tumor Promotion in Wild-Type BRAF Melanoma

In vitro evidence of increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors.1

Confirm BRAF V600E mutation prior to initiating dabrafenib; not recommended in patients with wild-type BRAF melanoma.1

Febrile Drug Reactions

Serious febrile drug reactions (including fever accompanied by hypotension, rigors/chills, dehydration, or renal failure and not due to another identifiable cause) reported.1

For fever ≥38.5°C or other serious febrile reactions, interrupt treatment and evaluate patient for manifestations of infection.1 Dosage modification or treatment discontinuance may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

May use prophylactic antipyretics when resuming dabrafenib following adverse febrile reactions.1

Hyperglycemia

Hyperglycemia requiring increased dosage or initiation of insulin or oral hypoglycemic agents reported.1

Monitor serum glucose concentrations in patients with preexisting diabetes or hyperglycemia, as clinically appropriate.1 Also evaluate patients for manifestations of severe hyperglycemia (e.g., excessive thirst, increased volume/frequency of urination).1

Ocular Effects

Uveitis, including iritis, reported. 1 If uveitis occurs, symptomatic treatment with ophthalmic corticosteroid or mydriatic preparations may be required.1

Monitor patients for signs and symptoms of uveitis (e.g., vision change, photophobia, eye pain).1

Hemolytic Anemia

Potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.1

Closely monitor patients with G-6-PD deficiency for hemolytic anemia.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Fertility

Potential for impaired spermatogenesis.1 Advise male patients to seek counseling on fertility/family planning options prior to therapy initiation.1

Lactation

Not known whether distributed into milk; discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No substantial differences in safety and efficacy in those ≥65 years of age relative to younger adults.1

Hepatic Impairment

Not studied in patients with hepatic impairment; possible increased exposure in moderate to severe hepatic impairment.1

Renal Impairment

Not studied in patients with renal impairment.1

Common Adverse Effects

Hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), hyperglycemia, hypophosphatemia.1

Interactions for Tafinlar

Metabolized by CYP 3A4 and 2C8; moderate inducer of CYP3A4 and possible inducer of other CYP isoenzymes (e.g., 2B6, 2C8, 2C9, 2C19).1

Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); moderate inhibitor of BCRP in vitro.1

Inhibits organic anion-transporting polypeptides (OATP) 1B1 and 1B3; also inhibits organic anion transporters (OAT) 1 and 3 in vitro.1

May induce uridine diphosphate glucuronosyltransferase (UGT).1

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP 3A4 or 2C8: Potential pharmacokinetic interaction (increased dabrafenib concentrations).1 Alternative therapy to potent inhibitors of CYP 3A4 or 2C8 recommended.1 If concomitant use unavoidable, monitor patients closely for dabrafenib-associated adverse reactions.1

Potent inducers of CYP 3A4 or 2C8: Potential pharmacokinetic interaction (decreased dabrafenib concentrations).1 Alternative therapy to potent inducers of CYP 3A4 or 2C8 recommended.1 If concomitant use unavoidable, monitor patients closely for reduced dabrafenib efficacy.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP 3A4, 2B6, 2C8, 2C9, 2C19: Potential pharmacokinetic interaction (decreased concentrations of substrate drug).1 Alternative therapy to substrate drug recommended.1 If concomitant use is unavoidable, monitor for reduced efficacy of substrate drug.1

Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase

Substrates of UGT: Potential pharmacokinetic interaction (decreased concentrations of substrate drug).1 Consider alternative therapy to substrate drug.1 If concomitant use is unavoidable, monitor for reduced efficacy of substrate drug.1

Drugs Affecting Gastric pH

Potential pharmacokinetic interaction with drugs that alter pH of upper GI tract (possible reduced dabrafenib concentrations, unknown effect on dabrafenib efficacy).1

Specific Drugs

Drug

Interaction

Comments

Antacids

Possible decreased dabrafenib concentrations; effect on dabrafenib efficacy unknown1

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Possible decreased dabrafenib concentrations1

Monitor closely for reduced dabrafenib efficacy1

Clarithromycin

Possible increased dabrafenib concentrations1

Monitor closely for dabrafenib-associated adverse effects1

Dexamethasone

Possible decreased dexamethasone concentrations and reduced efficacy1

Alternative therapy to dexamethasone recommended; if concomitant use unavoidable, monitor closely for reduced dexamethasone efficacy1

Gemfibrozil

Possible increased dabrafenib concentrations1

Use alternative to gemfibrozil; if concomitant use unavoidable, monitor closely for dabrafenib-associated adverse effects1

Histamine H2-receptor antagonists

Possible decreased dabrafenib concentrations; effect on dabrafenib efficacy unknown1

Hormonal contraceptives

Possible decreased estrogen/progestin concentrations and reduced efficacy1

Advise females of childbearing potential to use alternative nonhormonal contraception during and for 4 weeks after discontinuing dabrafenib therapy1

If concomitant use unavoidable, monitor closely for reduced hormonal contraceptive efficacy1

Ketoconazole

Possible increased dabrafenib concentrations1

Use alternative to ketoconazole; if concomitant use unavoidable, monitor closely for dabrafenib-associated adverse effects1

Midazolam

Decreased midazolam concentrations1

Use alternative to midazolam; if concomitant use unavoidable, monitor closely for reduced midazolam efficacy1

Nefazodone

Possible increased dabrafenib concentrations1

Use alternative to nefazodone; if concomitant use unavoidable, monitor closely for dabrafenib-associated adverse effects1

Proton-pump inhibitors

Possible decreased dabrafenib concentrations; effect on dabrafenib efficacy unknown1

Rifampin

Possible decreased dabrafenib concentrations1

Use alternative to rifampin; if concomitant use unavoidable, monitor closely for reduced dabrafenib efficacy1

St. John’s wort (Hypericum perforatum)

Possible decreased dabrafenib concentrations1

Use alternative to St. John's wort; if concomitant use unavoidable, monitor closely for reduced dabrafenib efficacy1

Warfarin

Possible decreased warfarin concentrations1

Use alternative to warfarin; if concomitant use unavoidable, monitor closely for reduced warfarin efficacy1

Tafinlar Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability 95%.1

Following oral administration, peak plasma concentrations attained after approximately 2 hours.1 8

Desmethyl metabolite may be reabsorbed from the gut.1

Food

High-fat meal decreased peak plasma concentrations and AUC by 51 and 31%, respectively; also delayed median time to peak plasma concentrations by 3.6 hours.1 8

Distribution

Extent

Not known if distributed into milk.1

Plasma Protein Binding

99.7%.1

Elimination

Metabolism

Principally mediated by CYP3A4 and 2C8 to form hydroxy-dabrafenib.1 Hydroxy metabolite further metabolized via CYP3A4 to form carboxy-dabrafenib.1 Carboxy metabolite further metabolized to desmethyl-dabrafenib via decarboxylation.1 Hydroxy and desmethyl metabolites likely contribute to clinical activity.1

Elimination Route

Fecal (71%) and urinary (23%) excretion.1

Half-life

8 hours.1

Special Populations

Formal pharmacokinetic study not performed in patients with hepatic impairment; population analysis indicates no clinically important pharmacokinetic changes in patients with mild hepatic impairment.1 No data available in patients with moderate to severe hepatic impairment; systemic exposure may be increased in these patients.1

Formal pharmacokinetic study not performed in patients with renal impairment; population analysis indicates no clinically important pharmacokinetic changes in patients with mild or moderate renal impairment.1 No data available in patients with severe renal impairment.1

Clinically important pharmacokinetic differences based on age, gender, or weight not observed.1

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).1

Actions

  • Potent inhibitor of b-Raf serine-threonine kinase with V600E mutation (BRAF V600E);1 7 8 also shows some in vitro activity against kinases with BRAF mutations V600K and V600D.1 10

  • Approximately 50% of cutaneous melanomas carry a BRAF mutation; substitution of glutamic acid for valine at codon 600 (BRAF V600E) is the most common BRAF mutation.2 9

  • Mutation of BRAF V600E activates the mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) signal transduction pathway, which enhances cell proliferation and tumor progression (e.g., metastasis).1 9

  • Paradoxical activation of MAPK and increased cell proliferation observed in BRAF wild-type cells exposed to b-Raf serine-threonine kinase inhibitors.1

Advice to Patients

  • Importance of advising patient to read the manufacturer's medication guide before beginning treatment and each time the prescription is refilled.1

  • Importance of taking dabrafenib exactly as prescribed and of not altering the dosage or discontinuing therapy unless advised to do so by clinician.1

  • Importance of taking dabrafenib at least 1 hour before or 2 hours after a meal and of not opening, crushing, or breaking the capsules.1

  • Importance of taking a missed dose as soon as remembered, but only if it can be taken at least 6 hours prior to next scheduled dose.1

  • Importance of confirming that patient has melanoma testing positive for the BRAF V600E mutation using an FDA-approved diagnostic test prior to initiation of therapy.1 6

  • Risk of new primary cutaneous malignancies.1 Importance of contacting clinician promptly if dermatologic changes occur.1

  • Risk of serious febrile drug reactions.1 Importance of contacting clinician if fever occurs.1

  • Risk of impaired glucose control in patients with diabetes resulting in need for more intensive antidiabetic treatment.1 Importance of contacting clinician if symptoms of severe hyperglycemia occur.1

  • Risk of hemolytic anemia in patients with G-6-PD deficiency.1 Importance of patients with known G-6-PD deficiency contacting clinician if manifestations of anemia or hemolysis occur.1

  • Risk of fetal harm if taken during pregnancy.1 Importance of female patients using highly effective, nonhormonal contraception during treatment and for 4 weeks after drug discontinuance.1 Importance of contacting clinician if pregnancy is suspected or confirmed during treatment. 1

  • Risk of serious adverse reactions in nursing infants of women receiving dabrafenib.1 Importance of discontinuing breast-feeding during therapy.1

  • Risk of impaired spermatogenesis.1 Importance of counseling male patients on fertility/family planning options prior to therapy initiation.1

  • Risk of adverse ocular effects.1 Importance of monitoring and contacting clinician promptly if ocular pain, swelling, redness, or blurred vision occurs.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., diabetes).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Dabrafenib Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

50 mg (of dabrafenib)

Tafinlar

GlaxoSmithKline

75 mg (of dabrafenib)

Tafinlar

GlaxoSmithKline

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 30, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. GlaxoSmithKline. Tafinlar(dabrafenib) capsules prescribing information. Research Triangle Park, NC; 2013 May.

2. Hauschild A, Grob JJ, Demidov LV et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012; 380:358-65. [PubMed 22735384]

3. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD. From FDA web site.

6. bioMerieux. THxID BRAF kit package insert. Durham, NC. 2013 May.

7. Long GV, Trefzer U, Davies MA et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012; 13:1087-95. [PubMed 23051966]

8. Ouellet D, Grossmann KF, Limentani G et al. Effects of particle size, food, and capsule shell composition on the oral bioavailability of dabrafenib, a BRAF inhibitor, in patients with BRAF mutation-positive tumors. J Pharm Sci. 2013; :. [PubMed 23608920]

9. Jang S, Atkins MB. Which drug, and when, for patients with BRAF-mutant melanoma?. Lancet Oncol. 2013; 14:e60-9. [PubMed 23369684]

10. Gentilcore G, Madonna G, Mozzillo N et al. Effect of dabrafenib on melanoma cell lines harbouring the BRAF(V600D/R) mutations. BMC Cancer. 2013; 13:17. [PubMed 23317446]

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