trametinib

General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Genetic Implications: Genetic Implications

Pronunciation:
tra-me-ti-nib


Trade Name(s)

  • Mekinist

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

  • Genetic implication Metastatic or unresectable melanoma with the BRAF V600E or V600K mutation (as monotherapy in patients who are BRAF-inhibitor treatment-naive or in combination with dabrafenib).
  • Genetic implication  Adjuvant treatment of melanoma with the BRAF V600E or V600K mutation (in combination with dabrafenib).
  • Genetic implication Metastatic non-small cell lung cancer (NSCLC) with the BRAF V600E mutation (in combination with dabrafenib).
  • Genetic implication Locally advanced or metastatic anaplastic thyroid cancer in patients with the BRAF V600E mutation who have no satisfactory locoregional treatment options (in combination with dabrafenib).
  • Genetic implication Metastatic or unresectable solid tumors with the BRAF V600E mutation in patients who have progressed following prior treatment and have no satisfactory alternative treatment options (in combination with dabrafenib).
  • Genetic implication  Low-grade glioma with the BRAF V600E mutation in patients who require systemic therapy (in combination with dabrafenib).

Action

Inhibits the activity of kinases, enzymes that promote cellular proliferation.

Therapeutic Effect(s):

  • Improved progression-free survival and overall survival in melanoma.
  • Decreased progression of NSCLC, anaplastic thyroid cancer, and solid tumors.
  • Decreased progression of and improved progression-free survival in low-grade glioma.

Pharmacokinetics

Absorption: Well absorbed following oral administration.

Distribution: Unknown.

Protein Binding: 97.4%.

Metabolism and Excretion: 50% metabolized, 80% eliminated in feces (metabolites and parent compound), 20% excreted in urine (mostly as metabolites).

Half-life: 3.9–4.8 days.

TIME/ACTION PROFILE (response)

ROUTEONSETPEAKDURATION
PO1 mo2 mo5–7 mo

Contraindication/Precautions

Contraindicated in:

  • OB:  Pregnancy;
  • Lactation: Lactation.

Use Cautiously in:

  • Severe renal impairment;
  • Moderate or severe hepatic impairment;
  • Rep:  Women of reproductive potential and men with female partners of reproductive potential;
  • Pedi:  Safety and effectiveness not established in children <18 yr (melanoma, NSCLC, anaplastic thyroid cancer) or <1 yr (solid tumors or glioma).

Adverse Reactions/Side Effects

CV: CARDIOMYOPATHY, hypertension, DEEP VEIN THROMBOSIS (DVT)

Derm: acneiform dermatitis, rash, cellulitis, DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), dry skin, erythema, folliculitis, palmar-plantar erythrodysesthesia syndrome, paronychia, photosensitivity, pruritus, STEVENS-JOHNSON SYNDROME

EENT: blurred vision, dry eye, retinal pigment epithelial detachment (RPED), retinal vein occlusion

Endo: hyperglycemia

GI: abdominal pain, diarrhea, ↑ liver enzymes, stomatitis, COLITIS, GI PERFORATION

GU: ↓ fertility (females)

Hemat: BLEEDING, hemophagocytic lymphohistiocytosis

MS: rhabdomyolysis

Neuro: dizziness, dysgeusia, INTRACRANIAL HEMORRHAGE, dizziness, dysgeusia

Resp: INTERSTITIAL LUNG DISEASE (ILD), PULMONARY EMBOLISM (PE)

Misc: fever (including serious febrile reactions) , lymphedema, MALIGNANCY

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

None reported.

Route/Dosage

Unresectable/Metastatic Melanoma, Non-Small Cell Lung Cancer, or Anaplastic Thyroid Cancer

PO (Adults): 2 mg once daily; continue until disease progression or unacceptable toxicity.

Adjuvant Treatment of Unresectable/Metastatic Melanoma

PO (Adults): 2 mg once daily; continue until disease recurrence or unacceptable toxicity for up to 1 yr.

Unresectable/Metastatic Solid Tumors

PO (Adults): 2 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and ≥51 kg): 2 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 38–50 kg): 1.5 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 26–37 kg): 1 mg once daily until disease progression or unacceptable toxicity.

Low-Grade Glioma

Oral Tablets

PO (Children ≥1 yr and ≥51 kg): 2 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 38–50 kg): 1.5 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 26–37 kg): 1 mg once daily until disease progression or unacceptable toxicity.

Oral Solution

PO (Children ≥1 yr and ≥51 kg): 2 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 46–50 kg): 1.6 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 42–45 kg): 1.4 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 38–41 kg): 1.25 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 34–47 kg): 1.15 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 30–33 kg): 1 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 26–29 kg): 0.9 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 22–25 kg): 0.85 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 18–21 kg): 0.7 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 14–17 kg): 0.55 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 12–13 kg): 0.45 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 11 kg): 0.4 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 9–10 kg): 0.35 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥1 yr and 8 kg): 0.3 mg once daily until disease progression or unacceptable toxicity.

Availability

Tablets: 0.5 mg, 2 mg

Oral solution (strawberry flavor): 0.05 mg/mL

Assessment

  • Assess left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition (MUGA) scan before starting, after 1 mo, and at 2–3-mo intervals during therapy.  If asymptomatic and absolute ↓ LVEF of ≥10% from baseline and below institutional lower limits of normal from pretreatment value,  withhold for up to 4 wk.  If LVEF improves to normal within 4 wk, resume at lower dose. If not improved to normal LVEF value after 4 wk,  permanently discontinue trametinib. If symptomatic cardiomyopathy or absolute ↓ LVEF >20% of baseline that is below institutional lower limits of normal,  permanently discontinue trametinib.
  • Perform ophthalmological evaluation at baseline.  If patient reports visual disturbance, within 24 hr, perform comparative evaluation.   If RPED occurs, withhold trametinib.  If RPED improves within 3 wk, resume trametinib at same or lower dose.  If no RPED improvement within 3 wk,  resume trametinib at lower dose or permanently discontinue. If retinal vein occlusion occurs,  permanently discontinue trametinib.
  • Assess for signs and symptoms of ILD (cough, dyspnea, hypoxia, pleural effusion, infiltrates).  If ILD or pneumonitis occur, permanently discontinue trametinib.
  • Monitor for serious or worsening skin reactions every 2 mo during and for 6 mo following therapy.  If severe cutaneous adverse reactions occur, permanently discontinue trametinib. If intolerable Grade 2, or if Grade 3 or 4 skin toxicity occurs,  withhold trametinib for up to 3 wk.  If intolerable Grade 2, or if Grade 3 or 4 skin toxicity improved within 3 wk,  resume trametinib at lower dose.  If intolerable Grade 2, or if Grade 3 or 4 skin toxicity not improved despite interruption of therapy for 3 wk, permanently discontinue trametinib.
  • Monitor BP periodically during therapy. May cause hypertension.
  • Monitor temperature during therapy. Also monitor for signs of infection and renal function during and following severe pyrexia. May cause serious febrile reactions.  If fever of 100.4°F–104°F, or first symptoms in case of recurrence,  withhold trametinib as monotherapy or both trametinib and dabrafenib until fever resolves; resume at same or lower dose, administering antipyretics as secondary prophylaxis.  If fever >104°F or complicated by rigors, hypotension, dehydration, or renal failure,  withhold trametinib as monotherapy or both trametinib and dabrafenib until fever resolves for ≥24 hr; resume at same or lower dose, administering antipyretics as secondary prophylaxis, or permanently discontinue trametinib.
  • Monitor for signs and symptoms of venous thromboembolism (shortness of breath, chest pain, arm or leg swelling).  If uncomplicated DVT or PE occur, withhold trametinib for up to 3 wk. If improved to Grade 0–1, trametinib may be resumed at lower dose.  If uncomplicated DVT or PE improved within 3 wk, or if life-threatening PE occurs, permanently discontinue trametinib.
  • Monitor for signs and symptoms of hemorrhage.  If Grade 3 hemorrhage occurs, withhold trametinib until hemorrhage improved; then resume at lower dose. If Grade 3 hemorrhage does not improve or Grade 4 hemorrhage occurs, permanently discontinue therapy.
  • Monitor for signs and symptoms of colitis and GI perforation.
  • Monitor for signs and symptoms of cytopenias.
  • Monitor patients receiving combination therapy with trametinib and dabrafenib closely for signs or symptoms of noncutaneous malignancies and hemophagocytic lymphohistiocytosis.  If hemophagocytic lymphohistiocytosis occurs, discontinue trametinib.

Lab Test Considerations:

  • Verify negative pregnancy before starting therapy.

  • Genetic implication Confirm presence of BRAF V600E or V600K mutation in tumor specimens prior to starting therapy with trametinib. Information on FDA-approved tests for the detection of BRAF V600E mutations in melanoma or NSCLC is available at http://www.fda.gov/CompanionDiagnostics.

    • May cause ↑ AST, ALT, and alkaline phosphatase.
    • May cause hypoalbuminemia.
    • May cause cytopenia, neutropenia, lymphopenia, and anemia.
    • May cause hyperglycemia. Monitor blood sugar at baseline and periodically during therapy when administered with dabrafenib.

Implementation

  • Recommended Dose Reductions: 1st dose reduction (for tablets): ↓ by 0.5 mg/day. 2nd dose reduction (for tablets): , ↓ by 0.5 mg/day.  If unable to tolerate a maximum of 2 reductions (for tablets): Permanently discontinue trametinib. Refer to drug labeling for dose reductions for oral solution when adverse reactions occur.
  • PO Administer on an empty stomach at least 1 hr before or 2 hr after a meal approximately 24 hr apart.  DNC: Swallow tablets whole; do not break, crush, break, or chew. 

Patient/Family Teaching

  • Instruct patient to take trametinib as directed at least 1 hr before or 2 hr after meals approximately 24 hr apart. Take missed doses as soon as remembered unless within 12 hr of next dose; then skip missed dose and take regularly scheduled dose. Store in refrigerator in original bottle with dessicant; do not place in pill boxes. Oral solution is intended to be prepared and administered by a caregiver. Advise patient to read  Patient Information  before starting therapy and with each Rx refill in case of changes.
  • Inform patient of potential side effects. Advise patient to notify health care professional if signs and symptoms of heart failure (pounding or racing heart, shortness of breath, swelling of feet or ankles, dizziness), visual disturbances (blurred vision, loss of vision, seeing colored dots, seeing a blurred outline or halo around objects, other visual changes), dyspnea, progressive or intolerable rash (acne; redness, swelling, peeling, or tenderness of hands or feet), hypertension (severe headache, blurry vision, dizziness), hemorrhage (headache, dizziness, weakness, coughing or vomiting blood [or "coffee-ground" contents], red or black tarry stools, increased bruising), skin changes (new wart, sore or reddish bump that bleeds or does not heal, change in size or color of a mole), hyperglycemia (↑ thirst, urinating more often than normal or urinating an increased amount of urine), or severe diarrhea occur.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
  • Rep:   Advise female patients of reproductive potential and male patients with female partners of reproductive potential to use a highly effective form of contraception during and for at least 4 mo after treatment. Use a nonhormonal form of contraception; trametinib may ↓ effectiveness of hormonal contraceptives. Advise patient to notify health care professional if pregnancy is suspected and to avoid breastfeeding during and for 4 mo following therapy. May impair fertility in females.

Evaluation/Desired Outcomes

  • Improved progression-free survival and overall survival in melanoma.
  • Decreased progression of NSCLC, anaplastic thyroid cancer, and solid tumors.
  • Decreased progression of and improved progression-free survival in low-grade glioma.