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Tafinlar

Last reviewed on RxList: 7/29/2019
Tafinlar Side Effects Center

Last reviewed on RxList 7/29/2019

Tafinlar (dabrafenib) is a kinase inhibitor used to treat patients with melanoma with BRAF V600E mutation that is metastatic or unable to be removed by surgery (unresectable). Common side effects of Tafinlar include:

The recommended dose for Tafinlar is 150 mg orally taken twice daily, approximately 12 hours apart. Take at least 1 hour before or at least 2 hours after a meal. Tafinlar may interact with ketoconazole, nefazodone, clarithromycin, gemfibrozil, rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort, proton pump inhibitors, H2-receptor antagonists, antacids, warfarin, dexamethasone, or hormonal contraceptives. Tell your doctor all medications and supplements you use. Tafinlar can cause fetal harm and is not recommended for use in pregnant women. Tell your doctor if you become pregnant during treatment. It is unknown if this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from Tafinlar in nursing infants, consult your doctor before breastfeeding.

Our Tafinlar (dabrafenib) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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Tafinlar Professional Information

SIDE EFFECTS

The following clinically significant adverse reactions are described elsewhere in the labeling:

There are additional adverse reactions associated with trametinib. Refer to the trametinib prescribing information for additional information.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the Warnings and Precautions section reflect exposure to TAFINLAR administered as a single agent in 586 patients with various solid tumors and exposure to TAFINLAR administered with trametinib in 559 patients with unresectable or metastatic melanoma and 93 patients with NSCLC. The safety of TAFINLAR as a single agent was evaluated in 586 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, previously treated or untreated, who received TAFINLAR 150 mg orally twice daily until disease progression or unacceptable toxicity, including 181 patients treated for at least 6 months and 86 additional patients treated for more than 12 months. TAFINLAR was studied in open-label, single-arm trials and in an open-label, randomized, active-controlled trial. The median daily dose of TAFINLAR was 300 mg (range: 118 to 300 mg).

Metastatic Or Unresectable Braf V600E Or V600K Mutation-Positive Melanoma

TAFINLAR as a Single Agent

The safety of TAFINLAR was evaluated in BREAK-3, a multicenter, international, open-label, randomized (3:1), controlled trial allocated 250 patients with unresectable or metastatic BRAF V600E mutation-positive melanoma to receive TAFINLAR 150 mg orally twice daily (n = 187) or dacarbazine 1,000 mg/m2 intravenously every 3 weeks (n = 63) [see Clinical Studies]. The trial excluded patients with abnormal left ventricular ejection fraction or cardiac valve morphology (≥ Grade 2), corrected QT interval ≥480 milliseconds on electrocardiogram, or a known history of glucose-6-phosphate dehydrogenase deficiency. The median duration on treatment was 4.9 months for patients treated with TAFINLAR and 2.8 months for dacarbazine-treated patients. The population exposed to TAFINLAR was 60% male, 99% White, and had a median age of 53 years.

The most common adverse reactions (≥ 20%) in patients treated with TAFINLAR were, in order of decreasing frequency: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES).

The incidence of adverse events resulting in permanent discontinuation of study medication in the BREAK-3 study was 3% for patients treated with TAFINLAR and 3% for patients treated with dacarbazine. The most frequent (≥ 2%) adverse reactions leading to dose reduction of TAFINLAR were pyrexia (9%), PPES (3%), chills (3%), fatigue (2%), and headache (2%). Table 3 and Table 4 present adverse reactions and laboratory abnormalities, respectively, of TAFINLAR as a single agent in the BREAK-3 study.

Table 3. Select Adverse Reactions Occurring in ≥ 10% (All Grades) or ≥ 2% (Grades 3 or 4) of Patients Treated with TAFINLAR in the BREAK-3 Studya

Adverse Reactions TAFINLAR
N = 187
Dacarbazine
N = 59
All Grades
(%)
Grades 3 and 4b
(%)
All Grades
(%)
Grades 3 and 4
(%)
Skin and subcutaneous tissue
  Hyperkeratosis 37 1 0 0
  Alopecia 22 NAf 2 NAf
  Palmar-plantar erythrodysesthesia syndrome 20 2 2 0
  Rash 17 0 0 0
Nervous system
  Headache 32 0 8 0
General
  Pyrexia 28 3 10 0
Musculoskeletal
  Arthralgia 27 1 2 0
  Back pain 12 3 7 0
  Myalgia 11 0 0 0
Neoplasms
  Papillomac 27 0 2 0
  cuSCCd, e 7 4 0 0
Respiratory
  Cough 12 0 5 0
Gastrointestinal
  Constipation 11 2 14 0
Infections
  Nasopharyngitis 10 0 3 0
a Adverse reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity.
b Grade 4 adverse reactions limited to hyperkeratosis (n = 1) and constipation (n = 1).
c Includes skin papilloma and papilloma.
d cuSCC = cutaneous squamous cell carcinoma, includes squamous cell carcinoma of the skin and keratoacanthoma.
e Cases of cuSCC were required to be reported as Grade 3 per protocol.
f NA = not applicable.

Table 4. Laboratory Abnormalities Worsening from Baseline Occurring at a Higher Incidence in Patients Treated with TAFINLAR in the BREAK-3 Study [Between-Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or 4)]a

Laboratory Abnormality TAFINLAR
N = 187
DTIC
N = 59
All Grades
(%)
Grades 3 and 4
(%)
All Grades
(%)
Grades 3 and 4
(%)
Hyperglycemia 50 6 43 0
Hypophosphatemia 37 6b 14 2
Increased alkaline phosphatase 19 0 14 2
Hyponatremia 8 2 3 0
a Adverse reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity.
b Grade 4 laboratory abnormality limited to hypophosphatemia (n = 1).

Other clinically important adverse reactions observed in less than 10% of patients (N = 586) treated with TAFINLAR were:

Gastrointestinal: Pancreatitis

Immune System: Hypersensitivity manifesting as bullous rash

Renal and Urinary: Interstitial nephritis

TAFINLAR with Trametinib

The safety of TAFINLAR when administered with trametinib was evaluated in 559 patients with previously untreated, unresectable or metastatic, BRAF V600E or V600K mutation-positive melanoma who received TAFINLAR in two trials, the COMBI-d study (n = 209) a multicenter, double-blind, randomized (1:1), active controlled trial and the COMBI-v study (n = 350) a multicenter, open-label, randomized (1:1), active controlled trial. In the COMBI-d and COMBI-v studies, patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. Both trials excluded patients with abnormal left ventricular ejection fraction, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), history of RVO or RPED, QTcB interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, or a known history of G6PD deficiency [see Clinical Studies].

Among these 559 patients, 199 (36%) were exposed to TAFINLAR for > 6 months to 12 months while 185 (33%) were exposed to TAFINLAR for ≥ 1 year. The median age was 55 years (range: 18 to 91), 57% were male, 98% were White, 72% had baseline ECOG performance status 0 and 28% had ECOG performance status 1, 64% had M1c stage disease, 35% had elevated LDH at baseline and 0.5% had a history of brain metastases.

The most common adverse reactions (≥ 20%) for TAFINLAR in patients receiving TAFINLAR plus trametinib in the COMBI-d and COMBI-v studies were: pyrexia, rash, chills, headache, arthralgia, and cough. The demographics and baseline tumor characteristics of patients enrolled in the COMBI-d study are summarized in Clinical Studies [see Clinical Studies]. Patients receiving TAFINLAR plus trametinib had a median duration of exposure of 11 months (range: 3 days to 30 months) to TAFINLAR. Among the 209 patients receiving TAFINLAR plus trametinib, 26% were exposed to TAFINLAR for > 6 months to 12 months while 46% were exposed to TAFINLAR for > 1 year.

In the COMBI-d study, adverse reactions resulting in discontinuation of TAFINLAR occurred in 11% of patients receiving TAFINLAR plus trametinib; the most frequent was pyrexia (1.9%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 26% of patients receiving TAFINLAR plus trametinib; the most frequent were pyrexia (14%), neutropenia (1.9%), rash (1.9%), and chills (1.9%). Adverse reactions leading to dose interruptions of TAFINLAR occurred in 56% of patients receiving TAFINLAR plus trametinib; the most frequent were pyrexia (35%), chills (11%), vomiting (7%), nausea (5%), and decreased ejection fraction (5%).

Table 5 and Table 6 present adverse reactions and laboratory abnormalities, respectively, observed in the COMBI-d study.

Table 5. Select Adverse Reactions Occurring in ≥ 10% (All Grades) of Patients Treated with TAFINLAR in Combination with Trametinib in the COMBI-d Studya

Adverse Reactions Pooled TAFINLAR plus Trametinib
N = 559
COMBI-d Study
TAFINLAR plus Trametinib N = 209 TAFINLAR
N = 211
All Grades
(%)
Grades 3 and 4b
(%)
All Grades
(%)
Grades 3 and 4
(%)
All Grades
(%)
Grades 3 and 4
(%)
General
  Pyrexia 54 5 57 7 33 1.9
  Chills 31 0.5 31 0 17 0.5
Skin
  Rashc 32 1.1 42 0 27 1.4
  Dry skin 10 0 12 0 16 0
Nervous system
  Headache 30 0.9 33 0.5 30 1.4
  Dizziness 11 0.2 14 0 7 0
Musculoskeletal
  Arthralgia 25 0.9 26 0.9 31 0
  Myalgia 15 0.2 13 0.5 13 0
Respiratory
  Cough 20 0 21 0 21 0
Gastrointestinal
  Constipation 13 0.2 13 0.5 10 0
Infections
  Nasopharyngitis 12 0 12 0 10 0
a NCI CTCAE version 4.0.
b Grade 4 adverse reactions limited to headache (n = 1).
c Includes rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, rash maculo-papular, and rash folliculitis.

Other clinically important adverse reactions for TAFINLAR across the COMBI-d and COMBI-v studies (N = 559) observed in less than 10% of patients receiving TAFINLAR in combination with trametinib were:

Gastrointestinal: Colitis, Gastrointestinal perforation, Pancreatitis

Subcutaneous Tissue: Panniculitis

Table 6. Select Laboratory Abnormalities Worsening from Baseline Occurring at ≥ 10% (All Grades) of Patients Receiving TAFINLAR with Trametinib in the COMBI-d Study

Laboratory Abnormality Pooled TAFINLAR plus Trametinib
N = 559a
COMBI-d Study
TAFINLAR plus Trametinib
N = 209b
TAFINLAR
N = 211b
All Grades
(%)
Grades 3 and 4c
(%)
All Grades
(%)
Grades 3 and 4c
(%)
All Grades
(%)
Grades 3 and 4c
(%)
Chemistry
  Hyperglycemia 60 4.7 65 6 57 4.3
  Hypophosphatemia 38 6 38 3.8 35 7
  Hyponatremia 25 8 24 6 14 2.9
Hepatic
  Increased blood alkaline phosphatase 49 2.7 50 1.0 25 0.5
a For these laboratory tests the denominator is 556.
b For these laboratory tests the denominator is 208 for the combination arm, 208-209 for the TAFINLAR arm.
c Grade 4 adverse reactions limited to hyperglycemia (n = 4), hyponatremia and hypophosphatemia (each n = 1), in the pooled combination arm; hyperglycemia (n = 1) in the COMBI-d study combination arm; hypophosphatemia (n = 1) in the TAFINLAR arm.

Adjuvant Treatment Of Braf V600E Or V600K Mutation-Positive Melanoma

The safety of TAFINLAR when administered with trametinib was evaluated in 435 patients with Stage III melanoma with BRAF V600E or V600K mutations following complete resection who received at least one dose of study therapy in the COMBI-AD study [see Clinical Studies]. Patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily for 12 months. The trial excluded patients with abnormal left ventricular ejection fraction; history of acute coronary syndromes, coronary angioplasty, or stenting within 6 months; Class II or greater congestive heart failure (New York Heart Association); QTc interval ≥ 480 msec; treatment-refractory hypertension; uncontrolled arrhythmias; or history of retinal vein occlusion. The median age of patients who received TAFINLAR in combination with trametinib was 50 years (range: 18 to 89), 56% were male, 99% were White, 92% had baseline ECOG performance status 0, and 8% had baseline ECOG performance status of 1. Patients receiving TAFINLAR in combination with trametinib had a median duration of exposure of 11 months (range: 0 to 12) to TAFINLAR. Among the 435 patients receiving TAFINLAR in combination with trametinib, 71% were exposed to TAFINLAR for > 6 months.

The most common adverse reactions (≥ 20%) in patients receiving TAFINLAR in combination with trametinib were: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.

Adverse reactions resulting in discontinuation, dose reduction, or dose interruption of TAFINLAR occurred in 25%, 35%, and 66% of patients, respectively; the most frequent for each were pyrexia and chills.

Table 7 summarizes adverse reactions that occurred in at least 20% of patients receiving TAFINLAR in combination with trametinib.

Table 7. Adverse Reactions Occurring in ≥ 20% of Patients in the COMBI-AD Studya

Adverse Reactions TAFINLAR plus Trametinib
N = 435
Placebo
N = 432
All Grades
(%)
Grades 3 and 4
(%)
All Grades
(%)
Grades 3 and 4
(%)
General
  Pyrexiab 63 5 11 <1
  Fatiguec 59 5 37 <1
  Chills 37 1 4 0
Gastrointestinal
  Nausea 40 <1 20 0
  Diarrhea 33 <1 15 <1
  Vomiting 28 <1 10 0
Nervous system
  Headached 39 1 24 0
Skin
  Rashe 37 <1 16 <1
Musculoskeletal
  Arthralgia 28 <1 14 0
  Myalgiaf 20 <1 14 0
a NCI CTCAE version 4.0
b Includes pyrexia and hyperpyrexia
c Includes fatigue, asthenia, and malaise
d Includes headache and tension headache
e Includes rash, rash maculo-papular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic, nodular rash, rash vesicular, and rash pustular
f Includes myalgia, musculoskeletal pain, and musculoskeletal chest pain

Other clinically important adverse reactions observed in less than 20% of patients in the COMBI-AD study receiving TAFINLAR in combination with trametinib were blurred vision (6%), ejection fraction decreased (5%), and rhabdomyolysis (< 1%).

The laboratory abnormalities are summarized in Table 8.

Table 8. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the COMBI-AD Study

Laboratory Abnormality TAFINLAR plus Trametiniba
N = 435
Placeboa
N = 432
All Grades
(%)
Grades 3 and 4
(%)
All Grades
(%)
Grades 3 and 4
(%)
Chemistry
  Hyperglycemia 63 3 47 2
  Hypophosphatemia 42 7 10 <1
  Hypoalbuminemia 25 <1 <1 0
Hepatic
  Increased AST 57 6 11 <1
  Increased ALT 48 5 18 <1
  Increased blood alkaline phosphatase 38 1 6 <1
Hematology
  Neutropenia 47 6 12 <1
  Lymphopenia 26 5 6 <1
  Anemia 25 <1 6 <1
a The incidence is based on the number of patients who had both a baseline and at least one on-study laboratory measurement: TAFINLAR plus Trametinib (range 429 to 431) and placebo arm (range 426 to 428)

Metastatic, Braf V600E-Mutation Positive Non-Small Cell Lung Cancer

The safety of TAFINLAR when administered with trametinib was evaluated in 93 patients with previously untreated (n = 36) and previously treated (n = 57) metastatic BRAF V600E mutation-positive NSCLC in a multicenter, multi-cohort, non-randomized, open-label trial (Study BRF113928). Patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. The trial excluded patients with abnormal left ventricular ejection fraction, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), QTc interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, history of interstitial lung disease or pneumonitis, or history or current retinal vein occlusion [see Clinical Studies].

Among these 93 patients, 53 (57%) were exposed to TAFINLAR and trametinib for > 6 months and 27 (29%) were exposed to TAFINLAR and trametinib for ≥ 1 year. The median age was 65 years (range: 41 to 91); 46% were male; 85% were White; 32% had baseline ECOG performance status 0 and 61% had ECOG performance status 1; 98% had non-squamous histology; and 12% were current smokers, 60% were former smokers, and 28% had never smoked.

The most common adverse reactions (≥ 20%) in these 93 patients were: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.

Adverse reactions resulting in discontinuation of TAFINLAR occurred in 18% of patients; the most frequent were pyrexia (2.2%), decreased ejection fraction (2.2%), and respiratory distress (2.2%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 35% of patients; the most frequent were pyrexia (10%), diarrhea (4.3%), nausea (4.3%), vomiting (4.3%), and neutropenia (3.2%). Adverse reactions leading to dose interruptions of TAFINLAR occurred in 62% of patients; the most frequent were pyrexia (27%), vomiting (11%), neutropenia (8%), and chills (6%).

Table 9 and Table 10 present adverse reactions and laboratory abnormalities, respectively, of TAFINLAR in combination with trametinib in Study BRF113928.

Table 9. Adverse Reactions Occurring in ≥ 20% (All Grades) of Patients Treated with TAFINLAR in Combination with Trametinib in Study BRF113928a

Adverse Reactions TAFINLAR plus Trametinib
N = 93
All Grades
(%)
Grades 3 and 4b
(%)
General
  Pyrexia 55 5
  Fatigueb 51 5
  Edemac 28 0
  Chills 23 1.1
Gastrointestinal
  Nausea 45 0
  Vomiting 33 3.2
  Diarrhea 32 2.2
  Decreased appetite 29 0
Skin
  Dry skin 31 11
  Rashd 28 3.2
Vascular
  Hemorrhagee 23 3.2
Respiratory system
  Cough 22 0
  Dyspnea 20 5
a NCI CTCAE version 4.0.
b Includes fatigue, malaise, and asthenia
c Includes peripheral edema, edema, and generalized edema.
d Includes rash, rash generalized, rash papular, rash macular, rash maculo-papular, and rash pustular.
e Includes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage.

Other clinically important adverse reactions for TAFINLAR observed in less than 10% of patients with NSCLC receiving TAFINLAR in combination with trametinib were:

Gastrointestinal: Pancreatitis

Renal and Urinary: Tubulointerstitial nephritis

Table 10. Treatment-Emergent Laboratory Abnormalities Occurring in ≥ 20% (All Grades) of Patients Receiving TAFINLAR with Trametinib in Study BRF113928

Laboratory Abnormality TAFINLAR plus Trametinib
N = 93
All Grades
(%)
Grades 3 and 4
(%)
Chemistrya
  Hyperglycemia 71 9
  Hyponatremia 57 17
  Hypophosphatemia 36 7
  Increased creatinine 21 1.1
Hepatica
  Increased blood alkaline phosphatase 64 0
  Increased AST 61 4.4
  Increased ALT 32 6
Hematologyb
  Leukopenia 48 8
  Anemia 46 10
  Neutropenia 44 8
  Lymphopenia 42 14
a For these laboratory tests the denominator is 90.
b For these laboratory tests the denominator is 91.

Locally Advanced Or Metastatic, Braf V600E-Mutation Positive Anaplastic Thyroid Cancer

The safety of TAFINLAR when administered with trametinib was evaluated in a nine-cohort, multicenter, non-randomized, open-label study in patients with rare cancers with the BRAF V600E mutation, including locally advanced or metastatic ATC (Study BRF117019). At the time of the safety analysis, a total of 100 patients were enrolled in the trial, 16 of whom were enrolled in the ATC cohort. The primary safety population included all patients who received at least one dose of TAFINLAR or trametinib. Patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity.

Among these 100 patients, 46 (46%) were exposed to TAFINLAR and trametinib for > 6 months and 23 (23%) were exposed to TAFINLAR and trametinib for ≥ 1 year. The median age was 59.5 years (range: 18 to 85); 62% were male; 85% were White; and 31% had baseline ECOG performance status 0 and 59% had ECOG performance status 1.

The adverse reaction profile among all patients and among patients in the ATC cohort was similar to that observed in other approved indications.

Read the entire FDA prescribing information for Tafinlar (Dabrafenib Capsules)

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