trametinib (Rx)

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

BRAF V600E Mutation-Positive Solid Tumors

Indicated in combination with dabrafenib for unresectable or metastatic solid tumors with BRAF V600E mutation in patients who have progressed following prior treatment and have no satisfactory alternative treatment options

2 mg PO qDay plus dabrafenib 150 mg PO BID

Continue treatment until disease progression or unacceptable toxicity

Dosage Modifications

Refer to dabrafenib for recommending 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
• Unable to tolerate 1 mg qDay: Permanently discontinue

Febrile drug reaction

• Fever of 101.3-104°F: Withhold dabrafenib until fever resolves, then resume at same or lower dose; do not modify trametinib
• Fever >104°F or fever complicated by rigors, hypotension, dehydration, or renal failure: Withhold trametinib until febrile reactions resolve for ≥24 hr, then resume at lower dose; or permanently discontinue dabrafenib

Dermatologic reactions

• Intolerable Grade 2, or Grades 3 or 4: Withhold for up to 3 weeks; if improved, resume at lower dose level
• If unresolved after withholding 3 weeks, permanently discontinue
• Severe cutaneous adverse reactions (SCARs): Permanently discontinue
• Applies to both trametinib and dabrafenib

Cardiomyopathy

• Asymptomatic left ventricular ejection fraction (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 cardiomyopathy

  • Symptomatic cardiomyopathy or 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 deep vein thromboembolism (DVT) or pulmonary embolism (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

Retinal pigment epithelia detachments (RPED)

Grade 2-3 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

  • If mild or moderate uveitis does not respond to ocular therapy, or for severe uveitis, withhold dabrafenib for up to 6 weeks
  • If improved to Grade 0-1, then resume at the same or at a lower dose level
  • If not improved, permanently discontinue

Pulmonary reactions

• Interstitial lung disease/pneumonitis
• Trametinib: Permanently discontinue
• Dabrafenib: Do not modify dose

Other adverse reactions

• Includes hemorrhage
• Intolerable Grade 2 or any Grade 3: Withhold; if improved to Grade 0-1, then resume at the same or at a lower dose level; if unresolved, permanently discontinue
• First occurrence of any Grade 4: Withhold until improves to Grade 0-1, then resume at a lower dose; or permanently discontinue
• Recurrent Grade 4: Permanently discontinue
• Applies to both trametinib and dabrafenib

Renal impairment (trametinib only)

• eGFR 15-89 mL/min/1.73 m²: No dosage adjustment recommended; pharmacokinetic differences are not clinically relevant

Hepatic impairment (trametinib only)

• Mild (bilirubin >ULN or bilirubin >1-1.5x ULN and any AST): No dose adjustment necessary
• Moderate-to-severe (bilirubin 1.5-10x ULN and any AST): Dose not established; not studied

Dosing Considerations

Patient selection

• Confirm the presence of BRAF V600E or V600K mutation in tumor specimens before initiating
• Information on FDA-approved tests for melanoma is available at: http://www.fda.gov/CompanionDiagnostics

Limitations of use

• Not indicated for treatment of patients with wild-type BRAF solid tumors
• Not indicated for treatment of patients with colorectal cancer due to known intrinsic resistance to BRAF inhibition

BRAF V600E Mutation-Positive Solid Tumors

Indicated in combination with dabrafenib for unresectable or metastatic solid tumors with BRAF V600E mutation in children aged ≥1 years who have progressed following prior treatment and have no satisfactory alternative treatment options

<1 years: Safety and efficacy not established

≥1 year and ≥8 kg (oral solution)

• 8 kg: 6 mL (0.3 mg) PO qDay
• 9-10 kg: 7 mL (0.35 mg) PO qDay
• 11 kg: 8 mL (0.4 mg) PO qDay
• 12-13 kg: 9 mL (0.45 mg) PO qDay
• 14-17 kg: 11 mL (0.55 mg) PO qDay
• 18-21 kg: 14 mL (0.7 mg) PO qDay
• 22-25 kg: 17 mL (0.85 mg) PO qDay
• 26-29 kg: 18 mL (0.9 mg) PO qDay
• 30-33 kg: 20 mL (1 mg) PO qDay
• 34-37 kg: 23 mL (1.15 mg) PO qDay
• 38-41 kg: 25 mL (1.25 mg) PO qDay
• 42-45 kg: 28 mL (1.4 mg) PO qDay
• 46-50 kg: 32 mL (1.6 mg) PO qDay
• ≥51 kg: 40 mL (2 mg) PO qDay
• Continue until disease progression or until unacceptable toxicity
• Refer to dabrafenib prescribing information for recommended dosing information

≥1 years and ≥26 kg (tablets only)

• 26-37 kg: 1 mg PO qDay
• 38-50 kg: 1.5 mg PO qDay
• ≥51 kg: 2 mg PO qDay
• Continue until disease progression or unacceptable toxicity
• Refer to dabrafenib prescribing information for recommended dosing information

Low-Grade Glioma

Indicated, in combination with dabrafenib, in pediatric patients aged ≥1 year for low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy

<1 year: Safety and efficacy established

≥1 year and ≥8 kg (oral solution)

• 8 kg: 6 mL (0.3 mg) PO qDay
• 9-10 kg: 7 mL (0.35 mg) PO qDay
• 11 kg: 8 mL (0.4 mg) PO qDay
• 12-13 kg: 9 mL (0.45 mg) PO qDay
• 14-17 kg: 11 mL (0.55 mg) PO qDay
• 18-21 kg: 14 mL (0.7 mg) PO qDay
• 22-25 kg: 17 mL (0.85 mg) PO qDay
• 26-29 kg: 18 mL (0.9 mg) PO qDay
• 30-33 kg: 20 mL (1 mg) PO qDay
• 34-37 kg: 23 mL (1.15 mg) PO qDay
• 38-41 kg: 25 mL (1.25 mg) PO qDay
• 42-45 kg: 28 mL (1.4 mg) PO qDay
• 46-50 kg: 32 mL (1.6 mg) PO qDay
• ≥51 kg: 40 mL (2 mg) PO qDay
• Continue until disease progression or until unacceptable toxicity

≥1 year and ≥26 kg (tablets only)

• 26-37 kg: 1 mg PO qDay
• 38-50 kg: 1.5 mg PO qDay
• ≥51 kg: 2 mg PO qDay
• Continue until disease progression or until unacceptable toxicity
• Refer to dabrafenib prescribing information for recommended dosing information

Dosage Modifications

Dose reductions for adverse reactions for trametinib

Refer to dabrafenib for recommending dosage modifications

• Starting dose 1 mg qDay

  • First dose reduction: Reduce to 0.5 mg qDay
  • Unable to tolerate 0.5 mg qDay: Permanently discontinue

• Starting dose 1.5 mg PO qDay

  • First dose reduction: Reduce to 1 mg qDay
  • Second dose reduction: Reduce to 0.5 mg qDay
  • Unable to tolerate 0.5 mg qDay: Permanently discontinue

• Starting dose 2 mg PO qDay

  • First dose reduction: Reduce to 1.5 mg qDay
  • Second dose reduction: Reduce to 1 mg qDay
  • Third dose reduction: Reduce to 0.5 mg qDay
  • Unable to tolerate 0.5 mg qDay: Permanently discontinue

Dose reductions for trametinib oral solution

• Permanently discontinue if unable to tolerate a maximum of 2 dose reductions

• 8 kg

  • Recommended dose: 6 mL (0.3 mg)
  • First dose reduction: 5 mL
  • Second dose reduction: 3 mL

• 9-10 kg

  • Recommended dose: 7 mL (0.35 mg)
  • First dose reduction: 5 mL
  • Second dose reduction: 4 mL

• 11 kg

  • Recommended dose: 8 mL (0.4 mg)
  • First dose reduction: 6 mL
  • Second dose reduction: 4 mL

• 12-13 kg

  • Recommended dose: 9 mL (0.45 mg)
  • First dose reduction: 7 mL
  • Second dose reduction: 5 mL

• 14-17 kg

  • Recommended dose: 11 mL (0.55 mg)
  • First dose reduction: 8 mL
  • Second dose reduction: 6 mL

• 18-21 kg

  • Recommended dose: 14 mL (0.7 mg)
  • First dose reduction: 11 mL
  • Second dose reduction: 7 mL

• 22-25 kg

  • Recommended dose: 17 mL (0.85 mg)
  • First dose reduction: 13 mL
  • Second dose reduction: 9 mL

• 26-29 kg

  • Recommended dose: 18 mL (0.9 mg)
  • First dose reduction: 14 mL
  • Second dose reduction: 9 mL

• 30-33 kg

  • Recommended dose: 20 mL (1 mg)
  • First dose reduction: 15 mL
  • Second dose reduction: 10 mL

  • 34-37 kg

• Recommended dose: 23 mL (1.15 mg)
• First dose reduction: 17 mL
• Second dose reduction: 12 mL

• 38-41 kg

  • Recommended dose: 25 mL (1.25 mg)
  • First dose reduction: 19 mL
  • Second dose reduction: 13 mL

• 42-45 kg

  • Recommended dose: 28 mL (1.4 mg)
  • First dose reduction: 21 mL
  • Second dose reduction: 14 mL

• 46-50 kg

  • Recommended dose: 32 mL (1.6 mg)
  • First dose reduction: 24 mL
  • Second dose reduction: 16 mL

• ≥51 kg

  • Recommended dose: 40 mL (2 mg)
  • First dose reduction: 30 mL
  • Second dose reduction: 20 mL

Noncutaneous RAS mutation-positive malignancies

• Dabrafenib: Permanently discontinue

Febrile drug reaction

• Fever of 101.3-104ºF: Withhold until fever resolves, then resume at same or lower dose
• Fever >104ºF or fever complicated by rigors, hypotension, dehydration, or renal failure: Withhold until febrile reactions resolve for ≥24 hr, then resume at lower dose; or permanently discontinue
• Applies to both trametinib and dabrafenib

Dermatologic reactions

• Intolerable Grade 2, or Grades 3 or 4: Withhold for up to 3 weeks; if improved, resume at lower dose level
• If unresolved after withholding 3 weeks, permanently discontinue
• Severe cutaneous adverse reactions (SCARs): Permanently discontinue
• Applies to both trametinib and dabrafenib

Cardiomyopathy

• Asymptomatic left ventricular ejection fraction (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 cardiomyopathy

  • Symptomatic cardiomyopathy or 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 deep venous thrombosis (DVT) or pulmonary embolism (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

Retinal pigment epithelia detachments (RPED)

• Grade 2-3 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

  • If mild or moderate uveitis does not respond to ocular therapy, or for severe uveitis, withhold dabrafenib for up to 6 weeks
  • If improved to Grade 0-1, then resume at the same or at a lower dose level
  • If not improved, permanently discontinue

Pulmonary reactions

• Interstitial lung disease/pneumonitis
• Trametinib: Permanently discontinue
• Dabrafenib: Do not modify dose

Other adverse reactions

• Includes hemorrhage
• Intolerable Grade 2 or any Grade 3: Withhold dabrafenib; if improved to Grade 0-1, then resume at the same or at a lower dose level; if unresolved, permanently discontinue
• First occurrence of any Grade 4: Withhold dabrafenib until improves to Grade 0-1, then resume at a lower dose; or permanently discontinue dabrafenib
• Recurrent Grade 4: Permanently discontinue

Renal impairment (trametinib only)

• eGFR 15-89 mL/min/1.73 m²: No dosage adjustment recommended; pharmacokinetic differences are not clinically relevant

Hepatic impairment (trametinib only)

• Mild (bilirubin >ULN or bilirubin >1-1.5x ULN and any AST): No dose adjustment necessary
• Moderate (bilirubin 1.5-10x ULN and any AST): Dose not established; consider the risks versus benefits before prescribing

Dosing Considerations

Patient selection

• Confirm the presence of BRAF V600E mutation in tumor specimens before initiating
• Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics

Limitations of use

• Not indicated for treatment of patients with wild-type BRAF solid tumors

Contraindicated (0)

Serious - Use Alternative (1)

• palifermin

  palifermin increases toxicity of trametinib by Other (see comment). Avoid or Use Alternate Drug. Comment: Palifermin should not be administered within 24 hr before, during infusion of, or within 24 hr after administration of antineoplastic agents. Coadministration of palifermin within 24 hr of chemotherapy resulted in increased severity and duration of oral mucositis.

Monitor Closely (6)

• cholera vaccine

  trametinib decreases effects of cholera vaccine by immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to cholera vaccine.

• dengue vaccine

  trametinib decreases effects of dengue vaccine by immunosuppressive effects; risk of infection. Use Caution/Monitor. Immunosuppressive therapies (eg, irradiation, antimetabolites, alkylating agents, cytotoxic drugs, corticosteroids [greater than physiologic doses]) may reduce immune response to dengue vaccine.

• desmopressin

  desmopressin increases toxicity of trametinib by unknown mechanism. Use Caution/Monitor. Decreased desmopressin dose requirements were noted in 2 young patients with cranial diabetes insipidus in whom trametinib was used concurrently with desmopressin.

• dichlorphenamide

  dichlorphenamide and trametinib both decrease serum potassium. Use Caution/Monitor.

• ponesimod

  ponesimod and trametinib both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

• siponimod

  siponimod and trametinib both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

Minor (0)

• cholera vaccine

  Monitor Closely (1)trametinib decreases effects of cholera vaccine by immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to cholera vaccine.

• dengue vaccine

  Monitor Closely (1)trametinib decreases effects of dengue vaccine by immunosuppressive effects; risk of infection. Use Caution/Monitor. Immunosuppressive therapies (eg, irradiation, antimetabolites, alkylating agents, cytotoxic drugs, corticosteroids [greater than physiologic doses]) may reduce immune response to dengue vaccine.

• desmopressin

  Monitor Closely (1)desmopressin increases toxicity of trametinib by unknown mechanism. Use Caution/Monitor. Decreased desmopressin dose requirements were noted in 2 young patients with cranial diabetes insipidus in whom trametinib was used concurrently with desmopressin.

• dichlorphenamide

  Monitor Closely (1)dichlorphenamide and trametinib both decrease serum potassium. Use Caution/Monitor.

• palifermin

  Serious - Use Alternative (1)palifermin increases toxicity of trametinib by Other (see comment). Avoid or Use Alternate Drug. Comment: Palifermin should not be administered within 24 hr before, during infusion of, or within 24 hr after administration of antineoplastic agents. Coadministration of palifermin within 24 hr of chemotherapy resulted in increased severity and duration of oral mucositis.

• ponesimod

  Monitor Closely (1)ponesimod and trametinib both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

• siponimod

  Monitor Closely (1)siponimod and trametinib both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.