Prescription Drug Information: Tafinlar

TAFINLAR- dabrafenib mesylate capsule
GlaxoSmithKline LLC

1 INDICATIONS AND USAGE

1.1 BRAF V600E Mutation-Positive Unresectable or Metastatic Melanoma

TAFINLAR® is indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

1.2 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma

TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.

1.3 Limitation of Use

TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR as a single agent [see Warnings and Precautions (5.2)]. Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics .

2.2 Recommended Dosing

The recommended dosage regimen of TAFINLAR is 150 mg orally taken twice daily, approximately 12 hours apart as a single agent or with trametinib. Continue treatment until disease progression or unacceptable toxicity occurs.

Take TAFINLAR at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3)]. Do not take a missed dose of TAFINLAR within 6 hours of the next dose of TAFINLAR. Do not open, crush, or break TAFINLAR capsules.

2.3 Dose Modifications

Review the Full Prescribing Information for trametinib for recommended dose modifications. Dose modifications are not recommended for TAFINLAR when administered with trametinib for the following adverse reactions of trametinib: retinal vein occlusion, retinal pigment epithelial detachment, interstitial lung disease/pneumonitis, and uncomplicated venous thromboembolism.

For New Primary Cutaneous Malignancies

No dose modifications are required.

For New Primary Non-Cutaneous Malignancies

Permanently discontinue TAFINLAR in patients who develop RAS mutation-positive non-cutaneous malignancies.

Table 1. Recommended Dose Reductions
Dose Reductions for TAFINLAR
First Dose Reduction
100 mg orally twice daily
Second Dose Reduction
75 mg orally twice daily
Third Dose Reduction
50 mg orally twice daily
Subsequent Modification
Permanently discontinue TAFINLAR if unable to tolerate 50 mg orally twice daily
Table 2. Recommended Dose Modifications for TAFINLAR
Severity of Adverse
Reactiona
TAFINLARb

Febrile Drug Reaction

Fever of 101.3°F to 104°F

Withhold TAFINLAR until fever resolves. Then resume at same or lower dose level.

Fever higher than 104°F
Fever complicated by rigors, hypotension, dehydration, or renal failure
Withhold TAFINLAR until fever resolves. Then resume at a lower dose level.

Or

Permanently discontinue TAFINLAR.

Cutaneous

Intolerable Grade 2 skin toxicity
Grade 3 or 4 skin toxicity

Withhold TAFINLAR for up to 3 weeks.

If improved, resume at a lower dose level.
If not improved, permanently discontinue.

Cardiac

Symptomatic congestive heart failure
Absolute decrease in LVEF of greater than 20% from baseline that is below LLN

Withhold TAFINLAR, if improved, then resume at the same dose.

Uveitis

Uveitis including iritis and iridocyclitis

If mild or moderate uveitis does not respond to ocular therapy, or for severe uveitis, withhold TAFINLAR 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.

Other

Intolerable Grade 2 adverse reactions
Any Grade 3 adverse reaction

Withhold TAFINLAR.

If improved to Grade 0-1, resume at a lower dose level.
If not improved, permanently discontinue.
First occurrence of any Grade 4 adverse reaction
Withhold TAFINLAR until adverse reaction improves to Grade 0-1. Then resume at a lower dose level.

Or

Permanently discontinue TAFINLAR.
Recurrent Grade 4 adverse reaction

Permanently discontinue TAFINLAR.

a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.
b See Table 1 for recommended dose reductions of TAFINLAR.

3 DOSAGE FORMS AND STRENGTHS

50 mg capsules: Dark red capsule imprinted with ‘GS TEW’ and ‘50 mg’.

75 mg capsules: Dark pink capsule imprinted with ‘GS LHF’ and ‘75 mg’.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

Review the Full Prescribing Information for trametinib for information on the serious risks of trametinib prior to initiation of TAFINLAR in combination with trametinib.

5.1 New Primary Malignancies

New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used with trametinib.

Cutaneous Malignancies

TAFINLAR results in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma.

In Trial 1, cutaneous squamous cell carcinomas and keratoacanthomas (cuSCC) occurred in 7% (14/187) of patients receiving TAFINLAR and in none of the patients receiving dacarbazine.

Across clinical trials of TAFINLAR (N = 586), the incidence of cuSCC was 11%. The median time to first cuSCC was 2.1 months (range: 7 days to 12.2 months). Of those patients who developed new cuSCC, approximately 33% developed one or more cuSCC with continued administration of TAFINLAR. The median time between diagnosis of the first cuSCC and the second cuSCC was 6 weeks.

In Trial 2, the incidence of basal cell carcinoma in patients receiving TAFINLAR in combination with trametinib was 3.3% (7/209) compared with 6% (13/211) of patients receiving single-agent TAFINLAR. The median time to first diagnosis of basal cell carcinoma was 5.1 months (range: 2.8 to 23.9 months) in the TAFINLAR plus trametinib arm and was 4.4 months (range: 29 days to 16.5 months) in the single-agent TAFINLAR arm. Among the 7 patients receiving TAFINLAR with trametinib who developed basal cell carcinoma, 2 (29%) experienced more than one occurrence (range: 1 to 3).

Cutaneous squamous cell carcinoma and keratoacanthoma occurred in 3% of patients receiving TAFINLAR with trametinib and 10% of patients receiving single-agent TAFINLAR. The median time to first diagnosis of cuSCC was 7.3 months (range: 1.8 to 16.8 months) in the Tafinlar plus trametinib arm and was 2 months (range: 9 days to 20.9 months) in the single-agent TAFINLAR arm.

New primary melanoma occurred in 0.5% (1/209) of patients receiving TAFINLAR with trametinib and in 1.9% (4/211) of patients receiving single-agent TAFINLAR.

Perform dermatologic evaluations prior to initiation of TAFINLAR, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR are required in patients who develop new primary cutaneous malignancies [see Dosage and Administration (2.3)].

Non-cutaneous Malignancies

Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In Trial 2, non-cutaneous malignancies occurred in 1.4% (3/209) of patients receiving TAFINLAR with trametinib and in 2.8% (6/211) of patients receiving single-agent TAFINLAR.

Monitor patients receiving TAFINLAR for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies [see Dosage and Administration (2.3)].

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