Mekinist (trametinib dimethyl sulfoxide)

Dosage of trametinib dimethyl sulfoxide is expressed in terms of trametinib.

If an asymptomatic decrease in left ventricular ejection fraction (LVEF) from baseline of 10% or more and to a level below institution-specific lower limit of normal occurs, interrupt trametinib for up to 4 weeks. If LVEF improves to normal values within 4 weeks of withholding trametinib, resume at a reduced dosage. If LVEF does not improve to normal values within 4 weeks of withholding trametinib, permanently discontinue trametinib.

If symptomatic cardiomyopathy or an absolute decrease in LVEF from baseline exceeding 20% and to a level below institution-specific lower limit of normal occurs, permanently discontinue.

If grade 2 skin toxicity develops and is intolerable, interrupt trametinib for up to 3 weeks. If grade 2 toxicity improves within 3 weeks of withholding trametinib, resume at a reduced dosage. If grade 2 skin toxicity does not improve within 3 weeks of withholding trametinib, permanently discontinue trametinib.

If grade 3 or 4 skin toxicity occurs, interrupt trametinib for up to 3 weeks. If grade 3 or 4 skin toxicity does not improve within 3 weeks of withholding trametinib, permanently discontinue trametinib. If grade 3 or 4 skin toxicity improves within 3 weeks of withholding trametinib, resume at a reduced dosage.

If severe cutaneous adverse reactions (SCARs) occur, permanently discontinue trametinib.

If fever (temperature of 38-40degreesC) or any initial symptom of fever recurrence occurs, interrupt trametinib therapy until the adverse reaction resolves. Once fever resolves, trametinib may be resumed at the same or a reduced dosage.

If fever (temperature exceeding 40degreesC) or fever complicated by rigors, hypotension, dehydration, or renal failure occurs, interrupt trametinib treatment until the adverse reaction resolves for at least 24 hours. Once fever has resolved, resume trametinib at the same or reduced dosage or permanently discontinue trametinib.

If grade 3 hemorrhagic events occur, interrupt trametinib treatment. If improvement is observed, resume trametinib at a lower dosage. If grade 3 hemorrhagic events do not improve, permanently discontinue trametinib.

If any grade 4 hemorrhagic events occur, permanently discontinue trametinib.

If new primary cutaneous malignancies occur, no dosage modification of trametinib is recommended.

If new noncutaneous malignancies occur during combination therapy with trametinib and dabrafenib, no dosage modification of trametinib is required.

If retinal pigment epithelial detachment occurs, interrupt trametinib for up to 3 weeks. If retinal pigment epithelial detachment improves within 3 weeks of withholding trametinib, resume at the same or a reduced dosage. If retinal pigment epithelial detachment does not improve within 3 weeks of withholding trametinib, resume at a reduced dosage or permanently discontinue trametinib.

If retinal vein occlusion occurs, permanently discontinue trametinib.

If uveitis occurs during combination therapy with trametinib and dabrafenib, no dosage modification of trametinib is necessary.

If an intolerable grade 2 or any grade 3 adverse reaction occurs, interrupt trametinib treatment. If the adverse reaction improves to grade 0 or 1, resume trametinib at a reduced dosage. If the adverse reaction does not improve to grade 0 or 1, permanently discontinue trametinib.

At the first occurrence of any grade 4 adverse reaction, interrupt trametinib until the adverse reaction improves to grade 0 or 1 and then resume at a reduced dosage. If the grade 4 adverse reaction does not improve to grade 0 or 1, permanently discontinue trametinib. If there is a recurrent grade 4 adverse reaction, permanently discontinue trametinib.

If treatment-related interstitial lung disease or pneumonitis occurs, permanently discontinue trametinib.

Dosage of trametinib may be reduced or therapy temporarily interrupted in patients who develop adverse effects. Up to 2 dosage reductions for toxicity may be made. Recommended dosage modifications for trametinib tablets and oral solutions are presented in Tables 3 and 4, respectively. Permanently discontinue trametinib if the patient is unable to tolerate a maximum of 2 dosage reductions.

Table 3. Trametinib Tablet Dosage Modifications for Toxicity

Recommended 1 mg orally once 1.5 mg orally 2 mg orally once Dosage daily once daily daily First dose 0.5 mg (one 1 mg (two 0.5-mg 1.5 mg (three reduction 0.5-mg tablet) tablets) orally 0.5-mg tablets) orally once daily once daily orally once daily Second dose N/A 0.5 mg (one 1 mg (two 0.5-mg reduction 0.5-mg tablet) tablets) orally orally once daily once daily

Permanently discontinue trametinib if unable to tolerate a maximum of 2 dosage reductions.

Table 4. Trametinib Oral Solution Dosage Modifications for Toxicity

Body Weight and First Dose Reduction Second Dose Reduction Recommended Dosage 8 kg 0.3 mg (6 mL) once 5 mL once daily 3 mL once daily daily 9 kg 0.35 mg (7 mL) once 5 mL once daily 4 mL once daily daily 10 kg 0.35 mg (7 mL) 5 mL once daily 4 mL once daily once daily 11 kg 0.4 mg (8 mL) once 6 mL once daily 4 mL once daily daily 12--13 kg 0.45 mg (9 mL) 7 mL once daily 5 mL once daily once daily 14--17 kg 0.55 mg (11 8 mL once daily 6 mL once daily mL) once daily 18--21 kg 0.7 mg (14 mL) 11 mL once daily 7 mL once daily once daily 22--25 kg 0.85 mg (17 13 mL once daily 9 mL once daily mL) once daily 26--29 kg 0.9 mg (18 mL) 14 mL once daily 9 mL once daily once daily 30--33 kg 1 mg (20 mL) 15 mL once daily 10 mL once daily once daily 34--37 kg 1.15 mg (23 17 mL once daily 12 mL once daily mL) once daily 38--41 kg 1.25 mg (25 19 mL once daily 13 mL once daily mL) once daily 42--45 kg 1.4 mg (28 mL) 21 mL once daily 14 mL once daily once daily 46--50 kg 1.6 mg (32 mL) 24 mL once daily 16 mL once daily once daily >=51 kg 2 mg (40 mL) 30 mL once daily 20 mL once daily once daily

Concentration of trametinib oral solution: 0.05 mg/mL.

Permanently discontinue trametinib if unable to tolerate a maximum of 2 dosage reductions.

If uncomplicated deep-vein thrombosis (DVT) or pulmonary embolism (PE) occurs, interrupt trametinib for up to 3 weeks. If improvement to grade 0 or 1 is observed within 3 weeks, resume trametinib at a lower dosage. If no improvement is observed within 3 weeks, permanently discontinue trametinib.

If life-threatening PE occurs, permanently discontinue trametinib.

Trametinib is administered orally once daily (approximately every 24 hours).

Do not take a missed dose of trametinib within 12 hours of the next dose of trametinib.

If a dose of trametinib is vomited, do not take an additional dose; take the next dose at the regularly scheduled time.

No dosing information is available for this tab.

No dosing information is available for this tab.

In vitro studies have indicated that trametinib is an inhibitor of cytochrome P-450 (CYP) isoenzyme 2C8.

Trametinib is a substrate of P-glycoprotein (P-gp) and bile salt export pump (BSEP). Pharmacokinetic interactions are unlikely with drugs that inhibit the P-gp transport system since trametinib exhibits high passive permeability and bioavailability.

Trametinib is not a substrate for CYP isoenzymes, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, OATP1B3, OATP2B1, organic cation transporter (OCT) 1, multidrug resistance-associated protein (MRP) 2, or multidrug and toxic compound extrusion 1 (MATE1). Trametinib is not an inhibitor of CYP 1A2, 2A6, 2B6, 2C9, 2C19, or 2D6, and also is not an inhibitor of OATP1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, OCT2, P-gp, BCRP, BSEP, MRP2, or MATE1.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

*None.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

The most common adverse reactions (>=20%) in adults with unresectable or metastatic melanoma receiving trametinib monotherapy are rash, diarrhea, and lymphedema.

The most common adverse reactions (>= 20%) in adults receiving trametinib in combination with dabrafenib for adjuvant treatment of melanoma include pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.

The most common adverse reactions (>= 20%) in adults receiving trametinib in combination with dabrafenib for unresectable or metastatic melanoma include pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema.

The most common adverse reactions (>= 20%) in adults receiving trametinib in combination with dabrafenib for metastatic NSCLC include pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.

The most common adverse reactions (>= 20%) in adults receiving trametinib in combination with dabrafenib for other solid tumors include pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, and edema.

The most common adverse reactions (>= 20%) in pediatric patients receiving trametinib in combination with dabrafenib for solid tumors include pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, and paronychia.

The most common adverse reactions (>= 20%) in pediatric patients receiving trametinib in combination with dabrafenib for low-grade glioma (LGG) include pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

Safety and efficacy of trametinib monotherapy have not been established in pediatric patients.

Safety and efficacy of trametinib in combination with dabrafenib have been established in pediatric patients >=1 year of age with BRAF V600E mutation-positive unresectable or metastatic solid tumors who progressed on prior therapy (with no satisfactory treatment options) and BRAF V600E mutation-positive low-grade glioma requiring systemic therapy. The use of trametinib for these indications is supported by evidence from a study in pediatric patients with refractory or recurrent solid tumors (CTMT212X2101), and a study in pediatric patients with low-grade glioma (CDRB436G2201).

Safety and efficacy of trametinib in combination with dabrafenib have not been established for these indications in pediatric patients <1 year of age.

Trametinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings. Verify pregnancy status in females of reproductive potential prior to initiating trametinib.

There are no data on the presence of trametinib in human milk, the effects on the breast-fed infant, or the effects on milk production. Because of the potential for serious adverse reactions to trametinib in breast-fed infants, advise women not to breast-feed while receiving the drug and for 4 months after the last dose.

The manufacturer does not make any specific dosage recommendations for geriatric patients.

Clinical experience with trametinib monotherapy in patients 65 years of age or older with melanoma is insufficient to determine whether geriatric patients respond differently than younger adults.

In clinical studies evaluating trametinib in combination with dabrafenib in patients with melanoma, 21% of patients were 65 years of age or older and 5% were 75 years of age or older. No overall differences in efficacy were observed between geriatric patients and younger adults, but some adverse effects (i.e., peripheral edema, anorexia) occurred more frequently in geriatric patients with metastatic melanoma.

Clinical experience with trametinib in patients 65 years of age or older with NSCLC is insufficient to determine whether geriatric patients respond differently than younger adults.

In clinical studies evaluating trametinib in combination with dabrafenib in anaplastic thyroid cancer, 77% of patients were 65 years of age and older and 31% were 75 years of age or older. An insufficient number of younger adults were included in the study to determine if there are differences in response to trametinib.