TRAMEDNR DABRANDR Trametinib Dabrafenib capsule

Part I: Basic Drug Information

Generic Names: Trametinib / Dabrafenib (Dabrafenib Mesylate Capsules)

Brand Names: Mekinist / Tafinlar

Dosage Form: Oral Capsules

Specifications: Trametinib 2 mg × 30 capsules/box; Dabrafenib Mesylate Capsules 75 mg × 120 capsules/box

Manufacturer: INDAR Pharmaceuticals Pvt Ltd

Part II: Indications for Combination Therapy

This combination therapy is indicated for the treatment of:

1.  Unresectable or metastatic melanoma with a BRAF V600 mutation.

2.  Adjuvant treatment of Stage III melanoma with a BRAF V600 mutation, following complete resection.

3.  Metastatic non-small cell lung cancer (NSCLC) with a BRAF V600 mutation.

4.  Locally advanced or metastatic anaplastic thyroid cancer with a BRAF V600 mutation.

5.  Solid tumors with a BRAF V600 mutation (indicated for patients with no satisfactory alternative treatment options).

Key Prerequisite: Prior to treatment, the presence of a BRAF V600E or V600K mutation in tumor tissue must be confirmed using an approved diagnostic test.

Part III: Dosage and Administration

Recommended Dosage:

Dabrafenib: 150 mg, twice daily (approximately 12 hours apart).

Trametinib: 2 mg, once daily.

Administration: Both medications may be taken with or without food. Capsules/tablets should be swallowed whole; do not crush, chew, or dissolve.

Duration of Treatment: Continue treatment until disease progression or the occurrence of intolerable toxicity.

Dosage Adjustment: Complex dosage adjustment regimens exist for adverse reactions such as fever, dermatologic toxicity, cardiomyopathy, ocular toxicity, pulmonary toxicity, and hemorrhage (including temporary interruption, dose reduction [Trametinib may be reduced to 1.5 mg or 1 mg; Dabrafenib may be reduced to 100 mg or 75 mg twice daily], or permanent discontinuation). Adjustments or interruptions of both medications are typically required simultaneously. Part 4: Key Warnings and Precautions (Risks Specific to Combination Therapy)

1.  **New Primary Malignancies:** BRAF inhibitors used as monotherapy may promote the proliferation of RAS-mutant cells, leading to cutaneous squamous cell carcinoma. Combination with a MEK inhibitor significantly reduces this risk, but the risk remains. Monthly skin examinations are required, and vigilance for non-cutaneous malignancies is advised.

2.  **Hemorrhage:** Monitor for signs of gastrointestinal, respiratory, or intracranial hemorrhage.

3.  **Cardiomyopathy:** Assess Left Ventricular Ejection Fraction (LVEF) via echocardiogram or Multi-Gated Acquisition (MUGA) scan prior to treatment, one month after initiating treatment, and subsequently every 2–3 months.

4.  **Fever and Chills:** The incidence of fever associated with combination therapy exceeds 50%. It may be necessary to temporarily withhold the medication, administer antipyretics, and evaluate for potential infection.

5.  **Severe Cutaneous Reactions:** Monitor for the development of rashes. Permanent discontinuation of the drug is required in cases of Stevens-Johnson syndrome or Toxic Epidermal Necrolysis (TEN).

6.  **Hyperglycemia:** Monitor blood glucose levels prior to and during treatment, particularly in patients with diabetes.

7.  **Uveitis and Retinal Vein Occlusion:** Conduct periodic ophthalmologic examinations; immediate evaluation is required if new symptoms, such as visual disturbances, occur.

Part 5: Drug Interactions

**Strong CYP3A4/CYP2C8 Inducers or Inhibitors:** May alter the plasma concentrations of Dabrafenib (which is primarily metabolized via CYP3A4/CYP2C8); co-administration should be avoided.

**Strong CYP3A4/CYP2C8 Inducers:** May reduce the plasma concentrations of Trametinib; co-administration should be avoided.

**Gastric Acid Suppressants (e.g., PPIs):** May reduce the plasma concentrations and efficacy of Dabrafenib; consider switching to short-acting antacids and staggering the administration times.

**Hormonal Contraceptives:** Dabrafenib is a CYP3A4 inducer and may reduce the efficacy of hormonal contraceptives; non-hormonal or additional contraceptive methods should be used.

Part 6: Use in Specific Populations

**Hepatic Impairment:** No dose adjustment is required for mild or moderate hepatic impairment; data are limited for patients with severe impairment, and the drug should be used with caution. Renal Impairment: No dose adjustment is required for mild or moderate impairment; data are limited for patients with severe impairment, and the drug should be used with caution.

Pediatric Use: Approved for certain indications (e.g., specific solid tumors) in children aged 1 year and older; dosing is based on body surface area.

Geriatric Use: No specific dose adjustment is required; however, elderly patients may be more susceptible to certain adverse reactions.

Part 7: Storage

Store at room temperature (20°C–25°C); protect from moisture and light.

Keep out of reach of children.

Important Safety Warnings:

New Primary Malignancies: Combination therapy may increase the risk of cutaneous and non-cutaneous primary malignancies (including cutaneous squamous cell carcinoma, keratoacanthoma, new primary melanoma, *KRAS*-mutated pancreatic cancer, etc.). Dermatologic and systemic examinations should be performed regularly prior to and during treatment.

Hemorrhage: Major hemorrhagic events, including fatal intracranial or gastrointestinal hemorrhage, may occur.

Venous Thromboembolism: May increase the risk of deep vein thrombosis and pulmonary embolism.

Cardiomyopathy: May lead to a decrease in left ventricular ejection fraction, potentially resulting in heart failure.

Ocular Toxicity: Retinal vein occlusion, uveitis, and retinal pigment epithelial detachment may occur.

Interstitial Lung Disease (ILD): Severe, or even fatal, interstitial lung disease or pneumonitis may occur.

Fever: Fever (potentially accompanied by hypotension, chills, or dehydration) is a common and potentially serious adverse reaction.

Severe Cutaneous Reactions: Severe cutaneous reactions, such as Stevens-Johnson syndrome, may occur.

Hyperglycemia: May cause elevated blood glucose levels, particularly in patients with pre-existing diabetes or those at risk for diabetes.

Embryo-Fetal Toxicity: May cause harm to the fetus; patients of reproductive potential must use effective contraception.

Important Note:

This package insert is not a substitute for professional medical advice. Combination therapy with Trametinib and Dabrafenib must be administered under the supervision of an experienced oncologist. *BRAF* V600 mutation testing must be performed prior to initiating treatment. Patients must strictly adhere to their physician's instructions and undergo intensive monitoring and management for toxicity. Specifications

Product Name: Trametinib 2 mg × 30 Tablets + Dabrafenib Mesylate Capsules 75 mg × 120 Capsules (TRAMEDNR DABRANDR)