trametinib

trametinib

(tra-me-ti-nib) ,

Mekinist

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: kinase inhibitors
Pregnancy Category: D

Indications

Treatment of metastatic/unresectable melanoma with the BRAF V660E or V600K mutation.

Action

Inhibits the activity of kinases, enzymes that promote cellular proliferation

Therapeutic effects

Decreased progression of melanoma.

Pharmacokinetics

Absorption: Well absorbed following oral administration
Distribution: Unk
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:

Time/action profile (response)

ROUTEONSETPEAKDURATION
PO1 mo2 mo5–7mos

Contraindications/Precautions

Contraindicated in: Obstetric: May cause fetal harm Lactation: Breastfeeding should be avoided
Use Cautiously in: Obstetric: Patients with child-bearing potential Pediatric: Safe and effective use in children has not been established

Adverse Reactions/Side Effects

Central nervous system

  • dizziness

Ear, Eye, Nose, Throat

  • blurred vision
  • dry eyes
  • retinal pigment epithelial detachment
  • retinal vein occlusion

Respiratory

  • interstitial lung disease/pneumonitis (life-threatening)

Cardiovascular

  • cardiomyopathy (life-threatening)
  • hypertension (most frequent)

Gastrointestinal

  • abdominal pain (most frequent)
  • diarrhea (most frequent)
  • ↑ liver enzymes (most frequent)
  • stomatitis (most frequent)
  • dysgeusia

Dermatologic

  • acneiform dermatitis (most frequent)
  • rash (most frequent)
  • skin toxicity (most frequent)
  • cellulitis
  • dry skin
  • folliculitis
  • palmar-plantar erythrodysesthesia syndrome
  • paranychia
  • pruritus

Hematologic

  • bleeding (most frequent)

Musculoskeletal

  • rhabdomyolysis

Miscellaneous

  • lymphedema (most frequent)

Interactions

Drug-Drug interaction

None noted

Route/Dosage

Oral (Adults) 2 mg daily continued until disease progression or unacceptable toxicity; dose modifications recommended for various levels of toxicity.

Availability

Tablets: 0.5 mg, 1 mg, 2 mg

Nursing implications

Nursing assessment

  • Assess left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition (MUGA) scan before starting, after 1 month, and at 2–3 month 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 Grade 2–3 retinal pigment epithelial detachment (RPED) occurs, withhold trametinib for up to 3 wks. If Grade 2–3 RPED improves to Grade 0–1 within 3 wks, resume trametinib 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 during therapy. If Grade 2 rash occurs, reduce dose by 0.5 mg or discontinue in patients taking 1 mg daily. 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 for up to 3 wks. If improved within 3 wks, resume trametinib at a lower dose (0.5 mg) or discontinue in patients taking 1 mg daily. If intolerable Grade 2 or Grade 3 or 4 rash that does not improve despite interruption of therapy for 3 wks, permanently discontinue trametinib.
  • Monitor blood pressure periodically during therapy. May cause hypertension.
  • Lab Test Considerations: May cause ↑ AST, ALT, and alkaline phosphatase.
    • May cause hypoalbumemia.
    • May cause anemia.

Potential Nursing Diagnoses

Impaired skin integrity (Indications)

Implementation

  • Evidence of BRAF V600E or V600K mutations must be confirmed prior to starting therapy with trametinib.
  • Oral: Administer twice daily about 12 hrs apart. Administer on an empty stomach at least 1 hr before or 2 hrs after a meal. 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. Take missed doses as soon as remembered unless within 12 hrs of next dose, then skip missed dose and take regularly scheduled dose.
  • 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.
  • 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) or severe diarrhea occur.
  • Advise female patient to use a highly effective form of contraception during and for at least 4 months 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. May impair fertility in females.

Evaluation/Desired Outcomes

  • Decrease in progression of malignant melanoma.
References in periodicals archive ?
In melanoma's G-361V600V/E model, BI 882370 was superior to VEM, marketed BRAF inhibitor dabrafenib, marketed MEK inhibitor trametinib and DAB-TRA combination.
Commenting on both the Checkmate 238 trial and a second trial reported at ESMO (COMBI-AD) looking at a combination of dabrafenib and trametinib for patients with stage III melanoma with a BRAF V600 mutation, Olivier Michielin, MD, PhD, of the Swiss Institute of Bioinformatics in Lausanne, said that "we now have, with the data, two fantastic new options.
Adjuvant dabrafenib plus trametinib for Stage III BRAF-mutated melanoma.
Treatment with the MEK inhibitor trametinib combined with dabrafenib has been shown to have an objective response of 76%, with a median progression free survival (PFS) of 9.
Phase 1-2 trial of the BRAF inhibitor dabrafenib (D) plus MEK inhibitor trametinib (T) in BRAF V600 mutant colorectal cancer (CRC): updated efficacy and biomarker analysis [ASCO meeting abstract 3517].
The updated edition contains information on the latest immunotherapy and genetically targeted treatments, including ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), vemurafenib (Zelboraf), dabrafenib (Tafinlar), and trametinib (Mekinist).
Current US Food and Drug Administration-approved targeted therapies include the RAF inhibitor sorafenib for treatment of kidney, liver, and thyroid cancer; the MEK inhibitor trametinib for treatment of melanoma; and the EGFR, ERK1/2, and Akt inhibitor lapatinib for treatment of breast cancer.
Now scientists have found that experimental drugs trametinib and palbociclib when used together make the resistant cancer cells susceptible to radiation.
Several medications, such as dacarbazine, vemurafenib, dabrafenib, and trametinib, are being used in the treatment of metastatic melanoma, but it seems that there is still a need for drugs with better long-term effects and less toxicity [25].
Several studies investigating such possibilities are ongoing; these include docetaxel + ADT; enzalutamide/abiraterone; enzalutamide/degarelix ± trametinib or dasatinib; and enzalutamide ± LHRH analogue.
The seven new antineoplastic agents are adotrastuzumab emtansine (Kadcyla) for HER2-positive breast cancer; afatinib (Gilotrif) for non-small cell lung cancer; dabrafenib (Tafinlar) for unresectable or metastatic melanoma; ibrutinib (Imbruvica) for mantle cell lymphoma or chronic lymphocytic leukemia; obinutuzumab (Gazyva) for chronic lymphocytic leukemia; pomalidomide (Pomalyst) for multiple myeloma; and trametinib (Mekinist) for unresectable or metastatic melanoma.