trametinib

trametinib

COMMON TRADE NAME(S):   Mekinist®

• Melanoma
• Non-small cell lung cancer (NSCLC)

Refer to the product monograph for a full list and details of approved indications.

Emetogenic Potential:  

Adverse events reported below were from a phase III melanoma monotherapy trial, unless otherwise indicated. Clinically important, severe or life-threatening adverse events from other trials or post-marketing may also be included. Consult the DABRTRAM regimen monograph when used in combination.

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for trametinib include rash, diarrhea, edema, fatigue, nausea, vomiting, alopecia, hypertension, constipation, headache, and abdominal pain.

In the phase III melanoma study comparing the combination of tramatenib and dabrafenib to dabrafenib monotherapy, there was a higher risk of the following in the combination arm: increased LFT’s, chills, pyrexia, diarrhea, peripheral edema, and hypertension.

Decreases in left ventricular ejection fraction (LVEF) and PR prolongation were observed during clinical trials; the median onset of left ventricular dysfunction or LVEF decrease was 58.5 days.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported with trametinib. Fatal VTE events have been reported when used in combination with dabrafenib.

Retinal pigment epithelial detachment (RPED) cases were often bilateral, multifocal, occurring in the macular region of the retina, and were associated with symptoms such as blurred vision and decreased visual acuity. Symptoms usually resolve (median 11.5 days) after withholding the drug, but abnormalities on retinal imaging may persist more than a month in some cases. Some patients who experienced ≥ grade 2 RPED had recurrences after restarting trametinib at reduced doses. Retinal vein occlusion (RVO) occurs rarely, but is more common in patients with hypertension, diabetes, hypercholesterolemia and glaucoma and may be irreversible. Trametinib increased the severity of dabrafenib associated uveitis when used in combination.

Skin toxicities can include rash, palmar-plantar erythrodysesthesia syndrome, erythema, and in some cases have led to secondary skin and nail infections.

A prophylactic skin regimen should be considered; one example is:

• avoidance of unnecessary exposure to sunlight
• an SPF ≥30 broad-spectrum sunscreen (containing titanium dioxide or zinc oxide)
• a thick, alcohol-free emollient cream applied on dry areas of the body daily

Also consider:

• a mild strength topical steroid (e.g. 1% hydrocortisone) applied daily
• doxycycline 100mg bid or minocycline 100mg bid or topical antibiotic for the first 2-3 weeks of treatment

Management of skin toxicity is symptomatic, including oral antihistamines and cold compresses for pruritus, a moderate strength steroid cream (e.g. hydrocortisone 2.5%) for moderate or severe rash, with PO steroid for severe cases. Oral antibiotics, antiseptic bath and local potent corticosteroids were used for paronychia.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and life-threatening or fatal drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported during combination therapy with dabrafenib. 

Sarcoidosis, mostly involving the skin, lung, eye and lymph nodes, has been reported during combination therapy. Consider appropriate treatment; it is important not to misinterpret sarcoidosis as disease progression.

Diarrhea should be aggressively managed. Follow recommendations below and start loperamide (4 mg at first loose stool then 2 mg q4h or after each loose stool until diarrhea-free for 12 hours; max 16mg/day). If persists for > 24 hours, increase dose to 2mg q2h; max 16 mg/day; consider adding oral antibiotics. If persists after 48 hours total treatment with loperamide, start second-line agents (e.g. octreotide, budesonide). Consider adding antibiotics if diarrhea persists or patient if febrile/neutropenic. IV fluid and electrolyte replacement should be administered as appropriate.

Colitis and GI perforation have been reported and may be fatal.

Rhabdomyolysis, including severe cases requiring hospitalization and treatment discontinuation, has been reported.

Trametinib increases the frequency and severity of dabrafenib-associated pyrexia and serious non-infectious febrile events as well as bleeding events, including major hemorrhagic events. Fatal cerebral hemorrhage has been reported in patients who developed brain metastases while on the combination treatment; the risk may be increased in patients on anti-platelet or anticoagulant drugs.

• Patients who have a hypersensitivity to this drug or any of its components
   

• BRAF mutation must be confirmed using a validated test before starting trametinib treatment.
• Trametinib should not be used in patients with BRAF V600 mutation who progressed on a prior BRAF inhibitor.
• Use of trametinib is not recommended in patients with decreased LVEF at baseline. Exercise caution in patients with conditions that can impair left ventricular function, with pre-existing conduction disorders, a history of syncope of unknown etiology and medications that can result in PR prolongation.
• Use of trametinib is not recommended in patients with a history of retinal vein occlusion. Exercise caution in patients with risk factors for retinal vein occlusion such as diabetes, hypertension, hypercholesterolemia and glaucoma.
• Use combination therapy with caution in patients at risk of bleeding as severe or fatal events have been reported. The risk may be increased with concomitant use of antiplatelet/anticoagulant therapy or in patients who develop brain metastases while on treatment.
• Use with caution in patients with a history of diverticulitis, metastases to the GI tract and concomitant use of other medications with a risk of GI perforation.

• Carcinogenicity: Unknown
  

  Secondary malignancies have occurred in patients receiving dabrafenib and trametinib combination therapy.
   

• Genotoxicity: No
  
• Embryotoxicity: Yes
  
• Fetotoxicity: Yes
  
  • Trametinib is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 16 weeks after the last dose. 
  • Efficacy of hormonal contraceptives is likely to be decreased when used in combination with dabrafenib; use effective alternative methods of contraception.
• Excretion into breast milk: Unknown
  Breastfeeding is not recommended.
• Fertility effects: Probable
  

Metabolism of trametinib by CYPs is minor and it is not a substrate for BCRP, OATP, OCGT1, MRP2, and MATE1. Trametinib is an in vitro substrate of Pgp, but it is unlikely to be significantly affected by Pgp inhibition in vivo. Trametinib is unlikely to have an effect on the kinetics of CYP3A4 substrates and drug transporters (OAT1, OAT3, OCT2, MATE1, OATP1B1, OATP1B3, Pgp and BCRP).

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
 

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Exceptional Access Program (EAP Website)

• trametinib - As monotherapy in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, according to specific criteria
• trametinib - In combination with dabrafenib for the treatment of BRAF V600 mutation-positive, unresectable or metastatic melanoma, according to specific clinical criteria
• trametinib - For the adjuvant treatment of resected Stage III cutaneous melanoma according to clinical criteria

June 2021 Updated indications and status, adverse effects, dosing, and pregnancy and lactation sections