Tafinlar

TAFINLAR- dabrafenib mesylate capsule
Novartis Pharmaceuticals Corporation

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 [see Dosage and Administration (2.1)].

1.3 Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma

TAFINLAR is indicated, in combination with trametinib, for the 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 [see Dosage and Administration (2.1)].

1.4 BRAF V600E Mutation-Positive Metastatic NSCLC

TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test [see Dosage and Administration (2.1)].

1.5 BRAF V600E Mutation-Positive Locally Advanced or Metastatic Anaplastic Thyroid Cancer

TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options [see Dosage and Administration (2.1)].

1.6 BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors

TAFINLAR is indicated, in combination with trametinib, for the 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 [see Dosage and Administration (2.1)]. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.6)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

1.7 Limitations of Use

  • TAFINLAR is not indicated for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition [see Indications and Usage (1.6), Mechanism of Action (12.1)].
  • TAFINLAR is not indicated for treatment of patients with wild-type BRAF solid tumors [see Warnings and Precautions (5.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Melanoma

  • 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), Clinical Studies (14.1)].
  • Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Warnings and Precautions (5.2), Clinical Studies (14.2, 14.3)].
  • Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.

NSCLC

  • Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Clinical Studies (14.4)].
  • Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

ATC

  • Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Clinical Studies (14.5)]. An FDA-approved test for the detection of BRAF V600E mutation in ATC is not currently available.

Solid Tumors

  • Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Clinical Studies (14.6)]. An FDA-approved test for the detection of BRAF V600E mutation in solid tumors other than melanoma and NSCLC is not currently available.

2.2 Recommended Dosage

The recommended dosage for TAFINLAR in adult patients is 150 mg (two 75 mg capsules) orally taken twice daily.

The recommended dosage for TAFINLAR in pediatric patients who weigh at least 26 kg is based on body weight (Table 1). A recommended dose has not been established in patients who weigh less than 26 kg.

Table 1. Dosing in Pediatric Patients from 6 to 17 Years Old (Weight-Adjusted Dose)
Body Weight Recommended Dose
26 to 37 kg 75 mg orally twice daily
38 to 50 kg 100 mg (two 50 mg capsules) orally twice daily
51 kg or greater 150 mg (two 75 mg capsules) orally twice daily
  • The recommended duration of treatment for patients with unresectable or metastatic melanoma or solid tumors, metastatic NSCLC, or locally advanced or metastatic anaplastic thyroid cancer is until disease progression or unacceptable toxicity.
  • The recommended duration of treatment in the adjuvant melanoma setting is until disease recurrence or unacceptable toxicity for up to 1 year.>

Refer to the trametinib prescribing information for recommended trametinib dosing information.

2.3 Administration

  • Take TAFINLAR at doses approximately 12 hours apart.
  • 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.

2.4 Dosage Modifications for Adverse Reactions

Dose reductions for adverse reactions associated with TAFINLAR are presented in Tables 2 and 3.

Table 2. Recommended Dose Reductions for TAFINLAR for Adverse Reactions in Adult Patients
Action Recommended Dosage
First Dose Reduction 100 mg (two 50 mg capsules) orally twice daily
Second Dose Reduction 75 mg orally twice daily
Third Dose Reduction 50 mg orally twice daily
Subsequent Modification Permanently discontinue if unable to tolerate TAFINLAR 50 mg orally twice daily
Table 3. Recommended Dose Reductions for TAFINLAR for Adverse Reactions in Pediatric Patients (6 to 17 Years Old)
Action Recommended Dosage [see Dosage and Administration (2.2)]
75 mg orally twice daily 100 mg (two 50 mg capsules) orally twice daily 150 mg (two 75 mg capsules) orally twice daily
First Dose Reduction 50 mg orally twice daily 75 mg orally twice daily 100 mg (two 50 mg capsules) orally twice daily
Second Dose Reduction 50 mg orally twice daily 75 mg orally twice daily
Third Dose Reduction 50 mg orally twice daily
Subsequent Modification Permanently discontinue if unable to tolerate TAFINLAR 50 mg orally twice daily

Dosage modifications for adverse reactions associated with TAFINLAR are presented in Table 4.

Table 4. Recommended Dosage Modifications for TAFINLAR for Adverse Reactions
a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.b See Tables 2 and 3 for recommended dose reductions of TAFINLAR.c Dose modifications are not recommended for TAFINLAR when administered with trametinib for the following adverse reactions of trametinib: retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED), interstitial lung disease/pneumonitis, and uncomplicated venous thromboembolism. Dose modification of TAFINLAR is not required for new primary cutaneous malignancies.
Severity of Adverse Reactiona Dosage Modification for TAFINLAR b
New Primary Malignancies [see Warnings and Precautions (5.1)]
Non-Cutaneous RAS Mutation-positive Malignancies Permanently discontinue TAFINLAR.
Cardiomyopathy [see Warnings and Precautions (5.4)]
  • Symptomatic congestive heart failure
  • Absolute decrease in left ventricular ejection fraction (LVEF) of greater than 20% from baseline that is below lower limit of normal (LLN)
Withhold TAFINLAR until LVEF improves to at least the institutional LLN and absolute decrease to less than or equal to 10% compared to baseline, then resume at same dose.
Uveitis [see Warnings and Precautions (5.5)]
  • Uveitis, including iritis and iridocyclitis
For 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 TAFINLAR at same or lower dose.
  • If not improved, permanently discontinue TAFINLAR.
Febrile Reactions [see Warnings and Precautions (5.6)]
  • Fever of 100.4°F to 104°F (or first symptoms in case of recurrence)
Withhold TAFINLAR until fever resolves, then resume at same or lower dose.
  • Fever higher than 104°F
  • Fever complicated by rigors, hypotension, dehydration, or renal failure
  • Withhold TAFINLAR until febrile reactions resolve for at least 24 hours, then resume at lower dose.
Or
  • Permanently discontinue TAFINLAR.
Skin Toxicities [see Warnings and Precautions (5.7)]
  • Intolerable Grade 2
  • Grade 3 or 4
Withhold TAFINLAR for up to 3 weeks.
  • If improved, resume TAFINLAR at lower dose.
  • If not improved, permanently discontinue TAFINLAR.
  • Severe cutaneous adverse reactions (SCARs)
Permanently discontinue TAFINLAR.
Other Adverse Reactionsc , including Hemorrhage [see Warnings and Precautions (5.3)]
  • Intolerable Grade 2
  • Any Grade 3
Withhold TAFINLAR.
  • If improved to Grade 0-1, resume TAFINLAR at lower dose.
  • If not improved, permanently discontinue TAFINLAR.
  • First occurrence of any Grade 4
  • Withhold TAFINLAR until improves to Grade 0-1, then resume at a lower dose.
Or
  • Permanently discontinue TAFINLAR.
  • Recurrent Grade 4
Permanently discontinue TAFINLAR.

Refer to the trametinib prescribing information for dose modifications for adverse reactions associated with trametinib.

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