Dabrafenib Chinese Package Insert: Indications, Dosage and Administration, Adverse Reactions, Precau

Dabrafenib is a selective BRAF serine-threonine kinase inhibitor that exerts antitumor effects by specifically targeting the BRAF V600E/V600K mutation site. Developed by Novartis Pharmaceuticals, it was first approved by the FDA on May 29, 2013.

Indications for Dabrafenib

1. Melanoma

(1) Dabrafenib in combination with trametinib is indicated for the adjuvant treatment of patients with completely resected melanoma with BRAF V600E or V600K mutation and lymph node involvement. As a single agent, it is indicated for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation (designated an orphan drug by the FDA).

(2) Dabrafenib in combination with trametinib is indicated for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation (designated an orphan drug by the FDA).

(3) An FDA-approved diagnostic test (e.g., THxID BRAF kit) is required prior to initiation of dabrafenib monotherapy to confirm the presence of BRAF V600E mutation; confirmation of BRAF V600E or V600K is also required prior to initiation of combination therapy.

(4) Dabrafenib is not recommended for patients with wild-type BRAF solid tumors; safety and efficacy have not been established.

2. Non-Small Cell Lung Cancer (NSCLC)

(1) Dabrafenib in combination with trametinib is indicated for the treatment of metastatic NSCLC with BRAF V600E mutation (designated an orphan drug by the FDA).

(2) An FDA-approved diagnostic test (e.g., THxID BRAF kit) is required prior to initiation of dabrafenib therapy to confirm the presence of BRAF V600E mutation.

(3) Dabrafenib is not recommended for patients with wild-type BRAF solid tumors; safety and efficacy have not been established.

3. Anaplastic Thyroid Cancer (ATC)

(1) Dabrafenib in combination with trametinib is indicated for the treatment of locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation when there is no satisfactory locoregional treatment option (designated an orphan drug by the FDA).

(2) An FDA-approved diagnostic test (e.g., THxID BRAF kit) is required prior to initiation of therapy to confirm the presence of BRAF V600E mutation; there are currently no FDA-approved diagnostic tests for detecting BRAF V600E in solid tumors other than melanoma and NSCLC.

(3) Not recommended for patients with wild-type BRAF solid tumors; safety and efficacy have not been established.

4. Solid Tumors

(1) Dabrafenib in combination with trametinib is indicated for the treatment of adult and pediatric patients aged ≥1 year with unresectable or metastatic solid tumors with BRAF V600E mutation that have progressed following prior therapy and for whom no satisfactory alternative treatment exists. Designated an orphan drug by the FDA for malignant gliomas.

(2) A test (e.g., THxID BRAF kit) is required prior to initiation of therapy to confirm the presence of BRAF V600E mutation; there are currently no FDA-approved diagnostic tests for detecting BRAF V600E in solid tumors other than melanoma and NSCLC.

(3) Not indicated for patients with BRAF-mutated colorectal cancer due to intrinsic resistance to BRAF inhibition. Not recommended for patients with wild-type BRAF solid tumors; safety and efficacy have not been established.

5. Low-Grade Glioma (LGG)

(1) Dabrafenib in combination with trametinib is indicated for the treatment of pediatric patients aged ≥1 year with BRAF V600E-mutant low-grade glioma requiring systemic therapy.

(2) A test (e.g., THxID BRAF kit) is required prior to initiation of therapy to confirm the presence of BRAF V600E mutation; there are currently no FDA-approved diagnostic tests for detecting BRAF V600E in low-grade glioma.

(3) Not recommended for patients with wild-type BRAF solid tumors; safety and efficacy have not been established.

Dosage and Administration of Dabrafenib

1. Recommended Dosage in Pediatric Patients

(1) Oral Capsules

For pediatric patients aged ≥1 year:

Body weight ≥51 kg: 150 mg dabrafenib (two 75 mg capsules) twice daily

Body weight 38–50 kg: 100 mg twice daily

Body weight 26–37 kg: 75 mg twice daily

Continue treatment until disease progression or unacceptable toxicity.

The recommended dose of dabrafenib capsules has not been established for patients <26 kg.

(2) Oral Suspension Tablets

8 to 9 kg: 20 mg dabrafenib suspension twice daily

10 to 13 kg: 30 mg dabrafenib suspension twice daily

14 to 17 kg: 40 mg dabrafenib suspension twice daily

18 to 21 kg: 50 mg dabrafenib suspension twice daily

22 to 25 kg: 60 mg dabrafenib suspension twice daily

26 to 29 kg: 70 mg dabrafenib suspension twice daily

30 to 33 kg: 80 mg dabrafenib suspension twice daily

34 to 37 kg: 90 mg dabrafenib suspension twice daily

38 to 41 kg: 100 mg dabrafenib suspension twice daily

42 to 45 kg: 110 mg dabrafenib suspension twice daily

46 to 50 kg: 130 mg dabrafenib suspension twice daily

≥51 kg: 150 mg dabrafenib suspension twice daily

2. Recommended Dosage in Adults

150 mg (two 75 mg capsules) orally twice daily. Continue treatment for up to 1 year or until disease progression or unacceptable toxicity.

3. Dosage Modifications for Toxicity

Dose reduction, temporary interruption, or discontinuation may be required for patients who experience adverse reactions. Permanently discontinue dabrafenib capsules if a patient cannot tolerate the 50 mg twice daily regimen.

Due to space limitations, please refer to the original drug package insert for detailed information. Administer only under the guidance of a physician.

Adverse Reactions of Dabrafenib

Adverse reactions (≥20%) in adults receiving dabrafenib monotherapy: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome).

Adverse reactions (≥20%) in adults with unresectable or metastatic melanoma treated with dabrafenib plus trametinib (previously untreated): pyrexia, rash, chills, headache, arthralgia, cough.

Adverse reactions (≥20%) in adults receiving dabrafenib plus trametinib for adjuvant treatment of melanoma: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, myalgia.

Adverse reactions (≥20%) in adults with metastatic NSCLC treated with dabrafenib plus trametinib: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, dyspnea.

Adverse reactions (≥20%) in adults with solid tumors treated with dabrafenib plus trametinib: pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, edema.

Adverse reactions (≥20%) in pediatric patients with solid tumors treated with dabrafenib plus trametinib: pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, acneiform dermatitis, headache, abdominal pain, nausea, hemorrhage, constipation, paronychia.

Adverse reactions (≥20%) in pediatric patients with low-grade glioma treated with dabrafenib plus trametinib: pyrexia, rash, headache, vomiting, myalgia, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, acneiform dermatitis.

Due to space limitations, please refer to the original drug package insert for detailed information. Administer only under the guidance of a physician.

Precautions for Dabrafenib

1. New Primary Malignancies

New primary cutaneous and non-cutaneous malignancies have been reported in patients receiving BRAF inhibitors, including dabrafenib. Perform dermatologic evaluations prior to initiation of dabrafenib, every 2 months during therapy, and for up to 6 months following discontinuation. Monitor for signs and symptoms of new non-cutaneous malignancies. Permanently discontinue if a new primary RAS mutation-positive non-cutaneous malignancy occurs.

2. Tumor Promotion in Wild-Type BRAF Tumors

In vitro evidence of increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors. Not recommended for patients with wild-type BRAF solid tumors.

3. Hemorrhage

Hemorrhage, sometimes fatal, including intracranial hemorrhage, retroperitoneal hemorrhage, subarachnoid hemorrhage, or gastrointestinal hemorrhage, has occurred during combination therapy with dabrafenib/trametinib. Dose modification or discontinuation may be required if a hemorrhagic event occurs.

4. Cardiomyopathy

Cardiomyopathy, defined as an absolute decrease in LVEF of ≥10% from baseline and below the institution-specific lower limit of normal (LLN), has been reported. Assess LVEF by echocardiogram or multigated radionuclide angiography (MUGA) prior to initiation and at 1 month after initiation, then every 2–3 months during treatment. Interruption may be required if left ventricular dysfunction occurs.

5. Uveitis

Uveitis has been reported. Symptomatic treatment with ophthalmic corticosteroids or mydriatic agents may be required if uveitis develops. Monitor patients for signs and symptoms of uveitis (e.g., changes in vision, photophobia, eye pain). Interruption, dose reduction, discontinuation, and/or initiation of ocular therapy may be required if ocular toxicity occurs.

6. Severe Febrile Reactions

Severe febrile drug reactions, including pyrexia complicated by hypotension, chills, dehydration, or renal failure, have been reported. Increased incidence and severity of pyrexia were observed during combination therapy with dabrafenib/trametinib compared with dabrafenib alone.

7. Severe Skin Toxicity

Severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in post-marketing experience with dabrafenib plus trametinib. Monitor for new or worsening severe skin toxicity. Dose modification or discontinuation may be required. Permanently discontinue if SCAR occurs. For other skin toxicities, interrupt dabrafenib for intolerable or severe skin toxicity. Resume at a lower dose in patients with improvement or recovery from skin toxicity within 3 weeks; permanently discontinue if skin toxicity does not improve within 3 weeks.

8. Hyperglycemia

Hyperglycemia requiring dose increase or initiation of insulin or oral anti-diabetic medication has been reported in patients treated with dabrafenib. Monitor serum glucose concentrations in patients with pre-existing diabetes or hyperglycemia prior to initiation of therapy, as clinically appropriate. Initiate and optimize anti-hyperglycemic therapy as clinically indicated.

9. Glucose-6-Phosphate Dehydrogenase Deficiency

Potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely monitor patients with G6PD deficiency for hemolytic anemia.

10. Hemophagocytic Lymphohistiocytosis

Dabrafenib in combination with trametinib can cause hemophagocytic lymphohistiocytosis (HLH). Interrupt therapy if HLH is suspected. Discontinue therapy and initiate appropriate management if HLH is confirmed.

11. Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on its mechanism of action and animal data; teratogenicity and embryotoxicity in animals. Verify pregnancy status in females of reproductive potential prior to initiation of therapy. Advise females of reproductive potential to use effective non-hormonal contraception during treatment and for 2 weeks after the last dose. Advise females to contact their healthcare provider if pregnancy is suspected or confirmed.