trametinib (Rx)

Brand and Other Names:Mekinist
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 0.5mg
  • 2mg

Melanoma

Also see Administration

Mutations must be detected by an FDA-approved test

BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma

  • Indicated, as a single agent or in combination with dabrafenib
  • 2 mg PO qDay
  • May also be used in combination with dabrafenib 150 mg PO BID
  • Continue until disease recurrence or unacceptable toxicity

Adjuvant treatment of BRAF V600E or V600K mutation-positive melanoma

  • Indicated, in combination with dabrafenib, for mutation-positive and involvement of lymph node(s), following complete resection
  • 2 mg PO qDay plus dabrafenib 150 mg PO BID
  • Continue until disease recurrence or unacceptable toxicity for up to 1 year

Non-Small Cell Lung Cancer

Indicated in combination with dabrafenib for unresectable or metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation

2 mg PO qDay plus dabrafenib 150 mg PO BID

Continue treatment until disease progression or unacceptable toxicity

Thyroid Cancer

Indicated, in combination with dabrafenib, for locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation in adults with no satisfactory locoregional treatment options

2 mg PO qDay plus dabrafenib 150 mg PO BID

Continue treatment until disease progression or unacceptable toxicity

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 fever 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 lower dose or permanently discontinue

Dermatologic reactions

  • Intolerable Grade 2, or Grades 3 or 4
    • Withhold for ≤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 ≤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 ≤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

Ocular toxicities

  • Retinal pigment epithelial detachments (RPED)
    • Trametinib: Withhold for ≤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 ≤6 weeks; if improved to Grade 0-1, resume at same dose, if not improved, permanently discontinue

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 ≤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

Renal impairment

  • Mild-to-moderate: No dosage adjustment necessary
  • Severe: Safety and efficacy not established

Hepatic impairment

  • Mild: No dosage adjustment necessary
  • Moderate-to-severe: Safety and efficacy not established

Dosing Considerations

Patient selection

  • Confirm the presence of BRAF V600E (melanoma and NSCLC) or V600K (melanoma only) 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

Limitation of use

  • Not indicated for treatment of patients who have received prior BRAF-inhibitor therapy

Safety and efficacy not established

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Adverse Effects

Adverse effects listed are all grades of severity unless indicated otherwise

>10% (Monotherapy)

Increased AST (60%)

Rash (57%)

Hyperglycemia (50%)

Increase ALT (39%)

Leukopenia (38%)

Anemia (46%)

Neutropenia (44%)

Diarrhea (43%)

Hypoalbuminemia (42%)

Hyperphosphatemia (37%)

Hyperkeratosis (37%)

Headache (32%)

Lymphoedema (32%)

Pyrexia (28%)

Arthralgia (27%)

Papilloma (27%)

Increased alkaline phosphatase (24%)

Alopecia (22%)

Palmar-plantar erythrodysesthesia syndrome (20%)

Acneiform dermatitis (19%)

Stomatitis (15%)

Hypertension (15%)

Abdominal pain (13%)

Hemorrhage (13%)

Back pain (12%)

Cough (12%)

Myalgia (11%)

Dry skin (11%)

Constipation (11%)

>10% (Combination with trametinib)

Increased AST (57%)

Hyperglycemia (60-63%)

Pyrexia (54-63%)

Fatigue (59%)

Neutropenia (46-47%)

Increased ALT (48%)

Hypoalbuminemia (25-48%)

Anemia (25-43%)

Hypophosphatemia (38-42%)

Nausea (35-40%)

Headache (30-39%)

Increased alkaline phosphatase (38%)

Rash (32-37%)

Chills (31-37%)

Diarrhea (31-33%)

Lymphopenia (26-32%)

Vomiting (27-28%)

Arthralgia (25-28%)

Hypertension (26%)

Hyponatremia (25%)

Peripheral edema (21%)

Thrombocytopenia (21%)

Cough (20%)

Myalgia (15-20%)

Abdominal pain (18%)

Hemorrhage (18%)

Constipation (13%)

Nasopharyngitis (12%)

Dizziness (11%)

1-10%

Pruritus (10%)

Paronychia (10%)

Nasopharyngitis (10%)

Hyponatremia (8%)

Decreased LVEF (7%)

Cutaneous squamous cell carcinoma (7%)

Interstitial lung disease/pneumonitis (1.8-2.4%)

Grade 3-4

  • Rash (8%)
  • Hyponatremia (8%)
  • Hypophosphatemia (6-7%)
  • Increased AST/ALT (4.1-6%)
  • Neutropenia (6%)
  • Lymphopenia (5%)
  • Hyperglycemia (3-4.7%)
  • Cutaneous squamous cell carcinoma (4%)
  • Pyrexia (3%)
  • Back pain (3%)
  • Palmar-plantar erythrodysesthesia syndrome (2%)
  • Constipation (2%)
  • Hyponatremia (2%)
  • Pruritus and stomatitis (2%)
  • Hyperkeratosis and lymphedema (1%)

Grade 3-4 (Combination with trametinib)

  • Hyponatremia (6%)
  • Hyperglycemia (6%)
  • Pyrexia (5%)
  • Hypophosphatemia (3.8%)
  • Hemorrhage (2%)
  • Diarrhea (1.3%)
  • Rash (1.1%)
  • Vomiting (1.1%)
  • Increased alkaline phosphatase (1%)

<1%

Retinal pigment epithelial detachment (0.8%)

Retinal vein occlusion (0.2%)

Grade 3-4 (Combination with trametinib)

  • Headache (0.9%)
  • Arthralgia (0.9%)
  • Chills (0.5%)
  • Myalgia (0.2%)
  • Constipation (0.2%)
  • Dizziness (0.2%)

Postmarketing Reports

Colitis and gastrointestinal perforation

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Warnings

Contraindications

None

Cautions

See Dosage Modifications

New primary malignancies, cutaneous and noncutaneous, 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

Interstitial lung disease reported; withhold dose for patients with symptoms (eg, cough, dyspnea, hypoxia, pleural effusion, or infiltrates)

Colitis and gastrointestinal perforation can occur; monitor patients closely for colitis and gastrointestinal perforations

Serious febrile reactions can occur when trametinib is used in combination with dabrafenib and with dabrafenib as a single agent; upon resolution, resume at same or lower dose

May cause fetal harm when administered to a pregnant woman (see Pregnancy)

Hyperglycemia

  • Coadministration with dabrafenib: Hyperglycemia can occur when trametinib is used in combination with dabrafenib and with dabrafenib as a single agent
  • Monitor serum glucose levels upon initiation and as clinically appropriate when administered with dabrafenib in patients with pre-existing diabetes or hyperglycemia
  • Initiate or optimize anti-hyperglycemic medications as clinically indicated

Cardiomyopathy

  • 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

  • For an asymptomatic absolute decrease in LVEF of 10% or greater from baseline that is below the LLN, withhold drug for up to 4 weeks; if improved to normal LVEF value, resume at a lower dose; if no improvement to normal LVEF value within 4 weeks, permanently discontinue

Ocular toxicities

  • Risk (rare) for retinal pigment epithelial detachment (RPED); monitor for visual disturbances
  • Withhold therapy if RPED diagnosed; if resolution of RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume treatment at same or reduced dose; if no improvement after 3 weeks, resume at reduced dose or permanently discontinue therapy
  • Retinal vein occlusion reported; urgently (within 24 hr) perform ophthalmology evaluation for patient-reported vision loss

Skin toxicity

  • Risk of serious skin toxicity including rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema
  • Withhold treatment for intolerable or severe skin toxicity; resume treatment at a lower dose in patients with improvement or recovery from skin toxicity within 3 weeks
  • Permanently discontinue therapy if skin toxicity has not improved in 3 weeks

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Pregnancy & Lactation

Pregnancy

Based on its mechanism of action and findings from animal reproduction studies, trametinib can cause fetal harm when administered to a pregnant woman

Insufficient data are available in pregnant women exposed to trametinib to assess the risk

Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures ~0.3 times the human exposure at the recommended clinical dose

Advise patients of the potential risk to the fetus

Contraception

  • Advise female patients of reproductive potential to use effective contraception during treatment with trametinib and for 4 months after the last dose
  • Advise female patients of reproductive potential that trametinib may impair fertility; increased follicular cysts and decreased corpora lutea were observed in female rats at dose exposures equivalent to 0.3 times the human exposure at the recommended dose

Lactation

There are no data on the presence of trametinib in human milk, or the effects of trametinib on the breastfed infant, or on milk production

Advise women not to breastfeed during treatment with trametinib and for 4 months following the last dose

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 time: 1.5 hr

High-calorie meal decreased AUC by 24%, peak plasma concentration by 70%, and delayed peak plasma timeby ~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: Feces (>80%); urine (<20%)

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Administration

Oral Administration

Administer doses once daily, ~24 hours apart

Take on empty stomach at least 1 hr before or 2 hr after meals

Missed dose

  • >12 hr before your next scheduled dose: Take it as soon as possible
  • <12 hr before your next scheduled dose: Skip missed dose; administer next dose at regular schedule time

Storage

Tablets: Refrigerate at 2-8°C (36-46°F); protect from moisture and light

Dispense in original bottle; do not place tablets in pill boxes

Do not remove desiccant

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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.

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  • 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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Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.