Dosing and uses of Mekinist (trametinib)
Adult dosage forms and strengths
tablet
- 0.5mg
- 1mg
- 2mg
Melanoma
MEK inhibitor indicated as a single agent or in combination with dabrafenib for unresectable or metastatic melanoma with BRAF V600E or V600K mutations
Single agent regimen: 2 mg PO qDay
Combination regimen: 2 mg PO qDay plus dabrafenib 150 mg PO BId
Dosage modifications
Dose reductions for trametinib (single agent or in combination with dabrafenib)
- First dose reduction: 1.5 mg PO qDay
- Second dose reduction: 1 mg PO qDay
- Subsequent modification: Permanently discontinue if unable to tolerate trametinib 1 mg/day
Dose reductions for dabrafenib when administered with trametiniB
- First dose reduction: 100 mg PO BID
- Second dose reduction: 75 mg PO BID
- Third dose reduction: 50 mg PO BID
- Subsequent modification: Permanently discontinue if unable to tolerate dabrafenib 50 mg BID
Febrile drug reaction
- Fever of 101.3-104°F: Do not modify trametinib; withhold dabrafenib until fever resolves, then resume at same or lower dose
- Fever >104°F or complicated by rigors, hypotension, dehydration, or renal failure: Withhold trametinib until fever resolves, then resume at same or lower dose; withhold dabrafenib, then resume at same or lower dose (or permanently discontinue)
Cutaneous reactions
- Intolerable Grade 2 skin toxicity, or Grades 3 or 4:
- Withhold for up to 3 weeks; if improved, resume at lower dose level
- If not improved after withholding 3 weeks, permanently discontinue
- Applies to both trametinib and dabrafenib
Asymptomatic LVEF
- Asymptomatic, absolute decrease in LVEF ≥10% from baseline, but is below LLN from pretreatment value:
- Trametinib: Withhold for up to 4 weeks; if improved to normal LVEF value, resume at a lower dose level; if not improved to normal, permanently discontinue
- Dabrafenib: Do not modify dose
Symptomatic CHF
- Symptomatic congestive heart failure (absolute decrease in LVEF >20% from baseline that is below LLN:
- Trametinib: Permanently discontinue
- Dabrafenib: Withhold, if improved, then resume at the same dose
Uncomplicated DVT or Pe
- Trametinib: Withhold trametinib for up to 3 weeks; if improved to Grade 0-1, resume at a lower dose level, if not improved, permanently discontinue
- Dabrafenib: Do not modify dose
Life-threatening Pe
- Trametinib: Permanently discontinue
- Dabrafenib: Permanently discontinue
RPEd
- Grade 2-3 retinal pigment epithelia detachments (RPED):
- Trametinib: Withhold for up to 3 weeks; if improved to Grade 0-1, resume at a lower dose level, if not improved, permanently discontinue
- Dabrafenib: Do not modify dose
Retinal vein occlusion
- Trametinib: Permanently discontinue
- Dabrafenib: Do not modify dose
Uveitis and iritis
- Trametinib: Do not modify dose
- Dabrafenib: Withhold for up to 6 weeks; if improved to Grade 0-1, resume at same dose, if not improved, permanently discontinue
Pulmonary reactions
- Interstitial lung disease/pneumonitis
- Trametinib: Permanently discontinue
- Dabrafenib: Do not modify dose
Other
- Applies to both trametinib and dabrafenib
- Intolerable Grade 2 or any Grade 3 adverse reactions: Withhold for up to 3 weeks; if improved to Grade 0-1, resume at lower dose level, if not improved, permanently discontinue
- First occurrence of any Grade 4 reaction: Withhold until improves to Grade 0-1, then resume at lower dose level, or permanently discontinue
- Recurrent Grade 4 reactions: Permanently discontinue
Dosing Considerations
Confirm the presence of BRAF mutations in tumor specimens prior to initiation of treatment with THxID BRAF Kit
Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at https://www.fda.gov/CompanionDiagnostics
Not indicated for treatment of patients who have received prior BRAF-inhibitor therapy
Non-small Cell Lung Cancer (Orphan)
Trametinib plus dabrafenib: Orphan designation for treatment of patients with BRAF mutation positive non-small cell lung cancer
Sponsor
- Novartis Pharmaceuticals Corp; One Health Plaza, Bldg 337; East Hanover, New Jersey 07936
Thyroid Cancer (Orphan)
Orphan designation for treatment of anaplastic thyroid cancer and locally advanced or metastatic papillary thyroid cancer with BRAF V600 mutation in combination with dabrafeniB
Sponsor
- Novartis Pharmaceuticals Corp; One Health Plaza; East Hanover, New Jersey 07936
Pediatric dosage forms and strengths
Safety and efficacy not established
Mekinist (trametinib) adverse (side) effects
>10%
Increased AST (60%)
Rash (57%)
Diarrhea (43%)
Hypoalbuminemia (42%)
Increased ALT (39%)
Anemia (38%)
Lymphedema (32%)
Increased alkaline phosphatase (24%)
Dermatitis acneiform (19%)
Stomatitis (15%)
Hypertension (15%)
Hemorrhage (13%)
Abdominal pain (13%)
Dry skin (11%)
1-10%
Pruritus (10%)
Paronychia (10%)
Decreased LVEF (7%)
Interstitial lung disease/pneumonitis (1.8-2.4%)
<1%
Retinal pigment epithelial detachment (0.8%)
Retinal vein occlusion (0.2%)
Warnings
Contraindications
None
Cautions
New primary malignancies, cutaneous and non-cutaneous, can occur when trametinib is used in combination with dabrafenib, and with dabrafenib as a single agent
Hemorrhage, including major hemorrhages, can occur when used in combination with dabrafeniB
Venous thromboembolism can occur when used in combination with dabrafeniB
Risk of cardiomyopathy when used as a single agent or with dabrafenib; reassess LVEF after 1 month of treatment and then ~ every 2-3 months thereafter
Risk for retinal pigment epithelial detachment (rare); monitor for visual disturbances
Retinal vein occlusion reported; urgently (within 24 hr) perform ophthalmology evaluation for patient-reported vision loss
Interstitial lung disease reported; withhold dose for patients with symptoms (eg, cough, dyspnea, hypoxia, pleural effusion, or infiltrates)
Risk of serious skin toxicity including rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema
Caution with moderate-to-severe hepatic impairment
Serious febrile reactions can occur when trametinib is used in combination with dabrafenib and with dabrafenib as a single agent
Hyperglycemia can occur when trametinib is used in combination with dabrafenib and with dabrafenib as a single agent
Based on its mechanism of action, can cause fetal harm; advise females of reproductive potential of potential risk to a fetus; women with reproductive potential should use highly effective birth control during and at least 4 months following treatment
Pregnancy and lactation
Pregnancy category: d
Lactation: Unknown if distributed in human breast milk; a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Mekinist (trametinib)
Mechanism of action
Reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity
Inhibits mutant BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo
BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2
Absorption
Bioavailability: 72%
Peak plasma concentration: 1.5 hr
High-calorie meal decreased AUC by 24%, Cmax by 70%, and delayed Tmax by ~4 hr compared with fasted state
Distribution
Protein bound: 97.4%
Vd: 214 L
Metabolism
Metabolized predominantly via deacetylation alone or with monooxygenation, or in combination with glucuronidation biotransformation pathways in vitro
Deacetylation is likely mediated by hydrolytic enzymes (eg, carboxyl-esterases, amidases)
Elimination
Half-life: 3.9-4.8 days
Clearance 4.9 L/hr
Excretion: >80% feces; <20% urine
Administration
Instructions
Take on empty stomach at least 1 hr before or 2 hr after meals
Do not take a missed dose within 12 hr prior to the next dose
