trametinib

General

Genetic Implications: Genetic Implications

Pronunciation:
tra-me-ti-nib


Trade Name(s)

  • Mekinist

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

  • Genetic implication Metastatic/unresectable melanoma with the BRAF V600E or V600K mutation (as monotherapy in patients who are BRAF-inhibitor treatment-naïve 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).

Action

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

Therapeutic Effect(s):

  • Improvement in progression-free survival and overall survival in patients with melanoma.
  • Decreased progression of NSCLC and anaplastic thyroid cancer.

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 (may cause fetal harm);
  • 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.

Adverse Reactions/Side Effects

CNS: INTRACRANIAL HEMORRHAGE, dizziness, dysgeusia

CV: CARDIOMYOPATHY, VENOUS THROMBOEMBOLISM, hypertension

Derm: acneiform dermatitis, rash, skin toxicity, basal cell carcinoma, cellulitis, cutaneous squamous cell carcinoma, dry skin, erythema, folliculitis, palmar-plantar erythrodysesthesia syndrome, melanoma, paronychia, pruritus

EENT: blurred vision, dry eyes, retinal pigment epithelial detachment, retinal vein occlusion

Endo: hyperglycemia

GI: GI HEMORRHAGE, GI PERFORATION, abdominal pain, diarrhea, ↑ liver enzymes, stomatitis, colitis

GU: ↓ fertility (females)

Hemat: BLEEDING

MS: rhabdomyolysis

Resp: INTERSTITIAL LUNG DISEASE

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

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

Interactions

Drug-Drug

None noted

Route/Dosage

Treatment of Unresectable/Metastatic Melanoma, NSCLC, 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 progression or unacceptable toxicity for up to 1 yr.

Availability

Tablets: 0.5 mg, 2 mg

Assessment

  • Assess left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition (MUGA) scan before starting, after 1 month, 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 wks.  If LVEF improves to normal within 4 wks, resume trametinib at lower dose, ↓ by 0.5 mg, or discontinue in patients taking 1 mg daily.  If symptomatic HF, absolute ↓ LVEF >20% of baseline that is below institutional lower limits of normal, or absolute ↓ LVEF ≥10% of baseline that is below institutional lower limits of normal that does not improve to normal within 4 wks following interruption of therapy,  permanently discontinue trametinib.
  • Perform ophthalmalogic evaluation at baseline; compare if patient reports visual disturbance.  If retinal pigment epithelial detachment (RPED) occurs, withhold trametinib for up to 3 wks.  If RPED improves within 3 wks, resume trametinib at same or at a lower dose (0.5 mg) or discontinue in patients taking 1 mg daily.  If retinal vein occlusion occurs or if Grade 2–3 RPED does not improve to at least Grade 1 within 3 wks,  permanently discontinue trametinib.
  • Assess for signs and symptoms of interstitial lung disease (cough, dyspnea, hypoxia, pleural effusion, infiltrates). Permanently discontinue trametinib if these occur.
  • Monitor for skin toxicities and secondary infections every 2 mo during and for 6 mo following therapy.  If intolerable Grade 2 rash that does not improve within 3 wks following dose reduction or if Grade 3 or 4 rash occurs,  withhold trametinib (single-agent) or dabrafenib (combination therapy) for up to 3 wks.  If improved within 3 wks,  resume trametinib at a lower dose.  If intolerable Grade 2 or Grade 3 or 4 rash that does not improve despite interruption of therapy for 3 wks, permanently discontinue trametinib (single-agent) or dabrafenib (combination therapy).
  • Monitor BP periodically during therapy. May cause hypertension.
  • Monitor temperature during therapy. May cause serious febrile reactions.  If fever >104°F,  do not modify dose of trametinib; withhold dabrafenib until fever resolves. Then resume at same or lower dose.  If fever >104°F or complicated by rigors, hypotension, dehydration, or renal failure,  withhold trametinib (single-agent) or dabrafenib (combination therapy) until fever resolves. Then resume at same or lower dose.
  • Monitor for signs and symptoms venous thromboembolism (shortness of breath, chest pain, arm or leg swelling). Permanently discontinue trametinib and dabrafenib for life threatening pulmonary embolism. Withhold trametinib for uncomplicated deep vein thrombosis or pulmonary embolism for up to 3 wks; if improved to Grade 0–1, trametinib may be resumed at lower dose level. Do not modify dose of dabrafenib.
  • Monitor for signs and symptoms of hemorrhage. Withhold trametinib for Grade 3 hemorrhagic events; if improved, resume at next lower dose level. Permanently discontinue therapy for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve.
  • Monitor for signs and symptoms of colitis and GI perforation.
  • Monitor patients receiving trametinib and dabrafenib closely for signs or symptoms of non-cutaneous malignancies.

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 hypoalbumemia.
    • May cause anemia.
    • Monitor blood sugar at baseline and periodically during therapy when administered with dabrafenib. May cause hyperglycemia.

Potential Diagnoses

Implementation

  • Recommended Dose Reductions: 1st dose reduction: 1.5 mg daily.  2nd dose reduction:  1 mg daily.  Subsequent modification: Permanently discontinue.
  • PO Administer on an empty stomach at least 1 hr before or 2 hrs after a meal approximately 24 hr apart. 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 hrs after meals approximately 24 hr apart. Take missed doses as soon as remembered unless within 12 hrs 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. 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, lightheadedness), 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, lightheadedness, dizziness), bleeding problems (headaches, dizziness, or feeling weak, coughing up blood or blood clots, vomit blood or vomit looks like "coffee grounds", red or black stools that look like tar), skin changes (new wart, sore or reddish bump that bleeds or does not heal, change in size or color of a mole), hyperglycemia (increased 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 non-hormonal form of contraception; trametinib may decrease 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

  • Decrease in progression of malignant melanoma.
  • Decreased progression of NSCLC and anaplastic thyroid cancer.