trametinib (Rx)

Brand and Other Names:Mekinist
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 0.5mg
  • 1mg
  • 2mg
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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 http://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

Safety and efficacy not established

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Adverse 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%)

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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

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Pregnancy & 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.

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Pharmacology

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

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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

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Formulary

FormularyPatient Discounts

Adding plans allows you to compare formulary status to other drugs in the same class.

To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

Adding plans allows you to:

  • View the formulary and any restrictions for each plan.
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The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

Tier Description
1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
NC NOT COVERED – Drugs that are not covered by the plan.
Code Definition
PA Prior Authorization
Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
QL Quantity Limits
Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
ST Step Therapy
Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
OR Other Restrictions
Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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