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TRAMETINIB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Trametinib dimethyl sulfoxide, a kinase inhibitor, is used in the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations. It is not indicated in patients that have received prior BRAF-inhibitor therapy.

Specific Substances

    1) Trametinib dimethyl sulfoxide
    2) C26H23FIN504.C2H6OS

Available Forms Sources

    A) FORMS
    1) Trametinib dimethyl sulfoxide is available in 0.5 mg, 1 mg and 2 mg film-coated tablets (Prod Info MEKINIST(TM) oral tablets, 2013).
    B) USES
    1) Trametinib dimethyl sulfoxide, a kinase inhibitor, is used in the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test (http://www.fda.gov/CompanionDiagnostics to confirm the presence of mutations). Treatment should be continued until disease progression or unacceptable toxicity occurs. It is not indicated in patients that have received prior BRAF-inhibitor therapy (Prod Info MEKINIST(TM) oral tablets, 2013).

Overview

Laboratory Monitoring

    A) Monitor vital signs.
    B) Monitor fluid and serum electrolyte status in patients with significant diarrhea. Monitor serial CBCs with differential following a significant exposure; bleeding has been observed with therapy.
    C) Monitor liver enzymes after a significant overdose.
    D) Serum trametinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    E) Due to the risk of fetal harm, a pregnancy test is recommended in women of childbearing age who have been exposed to trametinib.
    F) Monitor respiratory and cardiac function in symptomatic patients. Cardiomyopathy has been a late (ie, weeks to months after the initiation of therapy) complication of therapy.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) No overdose information. Treatment is symptomatic supportive. Monitor vital signs. Hypertension can develop. Monitor fluid status in patients that develop significant diarrhea; treat with IV fluids as necessary. Stomatitis may occur.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor vital signs. Monitor CBC, electrolytes and liver enzymes following a significant overdose. Treat severe hypertension with nitroprusside as the preferred agent; nitroglycerin or phentolamine as alternatives. Hemorrhagic events (gastrointestinal, genitourinary, and ocular) have been observed. Monitor for bleeding and transfuse as needed for severe bleeding. Cardiomyopathy (ie, cardiac failure, left ventricular dysfunction or decreased left ventricular ejection fraction) may be a late complication of exposure (time to onset: 63 days during clinical trials; range 16 to 156 days). Obtain an echocardiogram and/or MUGA scan to evaluate cardiac function in symptomatic patients. Retinal pigment epithelial detachment has occurred infrequently. An ophthalmic exam and consult is indicated in any patient with a new onset of vision loss or visual changes.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal after a potentially toxic ingestion in patients who are awake and able to maintain their airway.
    2) HOSPITAL: Consider activated charcoal after a potentially toxic ingestion in patients who are able to maintain their airway or if airway is protected.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following an acute exposure.
    E) ANTIDOTE
    1) None.
    F) STOMATITIS
    1) Stomatitis has been reported in patients receiving trametinib therapy; most cases were not severe. Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function.
    G) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be effective following a trametinib overdose because it is highly protein bound (97.4%).
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults with inadvertent ingestions (a single extra dose) can be monitored at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Patients demonstrating severe fluid and electrolyte imbalance, bleeding, or cardiac instability should be admitted.
    4) CONSULT CRITERIA: Contact a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Consult an ophthalmologist in any patient that develops a new onset of visual disturbances.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. The highest dose evaluated during clinical trials was 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. Of the 7 patients that received one of these treatment protocols, 2 developed retinal pigment epithelial detachment.
    B) THERAPEUTIC DOSE: ADULT: 2 mg orally once daily; treatment should be continued until disease progression or unacceptable toxicity occurs. PEDIATRIC: The safety and effectiveness of trametinib have not been established in pediatric patients.

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Trametinib, a kinase inhibitor, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations.
    B) PHARMACOLOGY: Trametinib dimethyl sulfoxide is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and MEK2 kinase activity. It inhibits BRAF V6000 mutation-positive melanoma cell-growth in vitro and in vivo.
    C) EPIDEMIOLOGY: Exposure is uncommon.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects include rash, diarrhea and lymphedema. Elevated liver enzymes, anemia, and hypoalbuminemia are also likely to occur with therapeutic use.
    2) OTHER EVENTS: Other adverse effects that have occurred in greater than or equal to 10% of patients include: stomatitis, abdominal pain, hypertension, hemorrhage, dermatitis acneiform, pruritus and paronychia.
    3) INFREQUENT: Infrequent but serious effects that have occurred include: cardiomyopathy, interstitial lung disease, retinal pigment epithelial detachment, retinal vein occlusion and serious skin toxicity.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. In clinical trials, the highest doses evaluated (4 mg once daily and 10 mg administered once daily on 2 consecutive days followed by 3 mg daily) resulted in 2 (a total of 7 patients were treated) cases of retinal pigment epithelial detachment.
    0.2.20) REPRODUCTIVE
    A) Trametinib may cause fetal harm when given to a pregnant woman. Although there are no adequate and well-controlled studies of trametinib use in pregnant women, it was found to be embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended dose.
    0.2.21) CARCINOGENICITY
    A) Carcinogenicity studies with trametinib have not been conducted. However, an increased risk of cutaneous and non-cutaneous malignancies were observed in patients treated with trametinib in combination with dabrafenib during clinical trials.

Clinical Effects

Summary Of Exposure

    A) USES: Trametinib, a kinase inhibitor, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations.
    B) PHARMACOLOGY: Trametinib dimethyl sulfoxide is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and MEK2 kinase activity. It inhibits BRAF V6000 mutation-positive melanoma cell-growth in vitro and in vivo.
    C) EPIDEMIOLOGY: Exposure is uncommon.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects include rash, diarrhea and lymphedema. Elevated liver enzymes, anemia, and hypoalbuminemia are also likely to occur with therapeutic use.
    2) OTHER EVENTS: Other adverse effects that have occurred in greater than or equal to 10% of patients include: stomatitis, abdominal pain, hypertension, hemorrhage, dermatitis acneiform, pruritus and paronychia.
    3) INFREQUENT: Infrequent but serious effects that have occurred include: cardiomyopathy, interstitial lung disease, retinal pigment epithelial detachment, retinal vein occlusion and serious skin toxicity.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. In clinical trials, the highest doses evaluated (4 mg once daily and 10 mg administered once daily on 2 consecutive days followed by 3 mg daily) resulted in 2 (a total of 7 patients were treated) cases of retinal pigment epithelial detachment.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) RETINAL PIGMENT EPITHELIAL DETACHMENT
    a) The incidence of retinal pigment epithelial detachment (RPED) was 0.8% (14 of 1749) in patients treated with trametinib across all clinical trials, including a report in 1 patient who received trametinib in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Occurring in the macular region of the retina, detachments were often bilateral and multifocal. After a median of 11.5 days (range, 3 to 71 days) of trametinib treatment interruption, visual acuity reduction resolved; although, ocular coherence tomography abnormalities lasted more than a month in several cases (Prod Info MEKINIST(TM) oral tablets, 2013).
    2) RETINAL VEIN OCCLUSION
    a) The incidence of retinal vein occlusion (RVO) was 0.2% (4 of 1749) in patients treated with trametinib across all clinical trials. Macular edema, decreased visual function, neovascularization, and glaucoma may result from an RVO. If a patient reports loss of vision or other visual disturbances, an ophthalmological evaluation should be performed within 24 hours. If RVO is documented, permanently discontinue treatment with trametinib (Prod Info MEKINIST(TM) oral tablets, 2013).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOMYOPATHY
    1) WITH THERAPEUTIC USE
    a) Cardiomyopathy, including cardiac failure, left ventricular dysfunction, or decreased left ventricular ejection fraction, was reported in 7% (14 of 211) of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily compared with none of the patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Median time to onset of cardiomyopathy in this study was 63 days (range, 16 to 156 days). Discontinuation and/or dose reduction due to cardiomyopathy occurred in 4% of patients in this study (Prod Info MEKINIST(TM) oral tablets, 2013).
    b) Cardiomyopathy (decrease in left ventricular ejection fraction (LVEF) below lower limits of normal with an absolute decrease in LVEF of 10% or more below baseline) was reported in 11% of patients with metastatic melanoma who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=329) in open-label, single-arm or active-controlled trials. A decrease in LVEF below lower limits of normal with an absolute decrease in LVEF of 20% or more below baseline occurred in 5% of the patients treated with trametinib in these studies (Prod Info MEKINIST(TM) oral tablets, 2013).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension (all grades) was reported in 15% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 7% of the patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma (Prod Info MEKINIST(TM) oral tablets, 2013).
    b) Grade 3 hypertension was reported in 12% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 3% of the patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma (Prod Info MEKINIST(TM) oral tablets, 2013).
    C) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Bradycardia was reported in 10% or less of patients with metastatic melanoma who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=329) in open-label, single-arm or active-controlled trials (Prod Info MEKINIST(TM) oral tablets, 2013).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash (all grades) was reported in 57% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 10% of patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma (Prod Info MEKINIST(TM) oral tablets, 2013).
    B) ACNEIFORM ERUPTION
    1) WITH THERAPEUTIC USE
    a) Acneiform dermatitis (all grades) was reported in 19% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 1% of patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma (Prod Info MEKINIST(TM) oral tablets, 2013).
    C) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus (all grades) was reported in 10% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 1% of the patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma (Prod Info MEKINIST(TM) oral tablets, 2013).
    D) PARONYCHIA
    1) WITH THERAPEUTIC USE
    a) Paronychia (all grades) was reported in 10% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 1% of the patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. No paronychia of grade 3 or 4 severity was reported in either arm of this study (Prod Info MEKINIST(TM) oral tablets, 2013).
    E) LYMPHEDEMA
    1) WITH THERAPEUTIC USE
    a) Lymphedema (all grades), including edema and peripheral edema, was reported in 32% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 4% of the patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma (Prod Info MEKINIST(TM) oral tablets, 2013).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) Rhabdomyolysis was reported in 10% or less of patients with metastatic melanoma who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=329) in open-label, single-arm or active-controlled trials (Prod Info MEKINIST(TM) oral tablets, 2013).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) INTERSTITIAL LUNG DISEASE
    1) WITH THERAPEUTIC USE
    a) Interstitial lung disease (ILD) or pneumonitis was reported in 2.4% (5 of 211) of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma; all 5 patients required hospitalization. Median time to onset of ILD or pneumonitis in this study was 160 days (range, 60 to 172 days). ILD or pneumonitis was reported in 1.8% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily in the treatment of metastatic melanoma in clinical trials (n=329) (Prod Info MEKINIST(TM) oral tablets, 2013).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness was reported in 10% or less of patients with metastatic melanoma who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=329) in open-label, single-arm or active-controlled trials (Prod Info MEKINIST(TM) oral tablets, 2013).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea (all grades) was reported in 43% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 16% of patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. No Grade 3 or 4 diarrhea was reported in the trametinib arm of this study compared with 2% of patients in the chemotherapy arm having grade 3 or 4 diarrhea (Prod Info MEKINIST(TM) oral tablets, 2013).
    B) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) Stomatitis (all grades), including aphthous stomatitis, mouth ulceration, and mucosal inflammation, was reported in 15% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 2% of patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma (Prod Info MEKINIST(TM) oral tablets, 2013).
    b) Grade 3 stomatitis, including aphthous stomatitis, mouth ulceration, and mucosal inflammation, was reported in 2% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with none of the patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma (Prod Info MEKINIST(TM) oral tablets, 2013).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain (all grades), including upper or lower abdominal pain and abdominal tenderness, was reported in 13% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 5% of patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Grade 3 abdominal pain was reported in 1% of each arm in this study (Prod Info MEKINIST(TM) oral tablets, 2013).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOALBUMINEMIA
    1) WITH THERAPEUTIC USE
    a) Hypoalbuminemia (all grades) was reported in 42% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 23% of patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma (Prod Info MEKINIST(TM) oral tablets, 2013).
    b) Grade 3 hypoalbuminemia was reported in 2% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 1% of patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. No Grade 4 hypoalbuminemia was reported in either arm of this study (Prod Info MEKINIST(TM) oral tablets, 2013).

Reproductive

    3.20.1) SUMMARY
    A) Trametinib may cause fetal harm when given to a pregnant woman. Although there are no adequate and well-controlled studies of trametinib use in pregnant women, it was found to be embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended dose.
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) Do not give this drug to a pregnant woman. If pregnancy occurs, apprise the patient of the potential for fetal harm (Prod Info MEKINIST(R) oral tablets, 2015).
    B) CONTRACEPTION
    1) Use of adequate contraception required in female patients of reproductive potential during treatment and for at least 4 months after discontinuation (Prod Info MEKINIST(R) oral tablets, 2015).
    C) ANIMAL STUDIES
    1) During animal studies, administration of trametinib at doses approximately 0.3 times the recommended human AUC resulted in decreased fetal weights and postimplantation loss (including total loss of pregnancy). Maternal toxicity and increases in postimplantation loss were observed with trametinib doses 1.8-fold higher than the recommended human AUC. Trametinib doses approximately 0.08 times the recommended human AUC resulted in decreased fetal body weight and increased variations in ossification (Prod Info MEKINIST(R) oral tablets, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) Lactation studies have not been conducted and the effects on a nursing infant or milk production are unknown (Prod Info MEKINIST(R) oral tablets, 2015).
    B) BREAST MILK
    1) Because of the potential for serious adverse effects in the breastfed infant, breastfeeding is not recommended during therapy and for 4 months after discontinuation (Prod Info MEKINIST(R) oral tablets, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Increases in follicular cysts and decreased corpora lutea were reported in female animals administered trametinib for up to 13 weeks at doses equivalent to 0.3 times the recommended human AUC. No effects on male reproductive tissues were observed (Prod Info MEKINIST(R) oral tablets, 2015).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) Increased aspartate aminotransferase (AST) (all grades) was reported in 60% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 16% of patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma (Prod Info MEKINIST(TM) oral tablets, 2013).
    1) Grade 3 increased AST was reported in 2% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 1% of patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. No grade 4 increased AST was reported in either arm of this study (Prod Info MEKINIST(TM) oral tablets, 2013).
    b) Increased alanine aminotransferase (ALT) (all grades) was reported in 39% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 20% of patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Grade 3 increased ALT was reported in 3% of each arm in this study; no grade 4 increased ALT was reported in either arm (Prod Info MEKINIST(TM) oral tablets, 2013).
    c) Increased alkaline phosphatase (all grades) was reported in 24% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 18% of patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Grade 3 increased alkaline phosphatase was reported in 2% of the trametinib arm and 3% of the chemotherapy arm in this study; no grade 4 increased alkaline phosphatase was reported in either arm (Prod Info MEKINIST(TM) oral tablets, 2013).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLEEDING
    1) WITH THERAPEUTIC USE
    a) Hemorrhage (all grades), including epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage, hematuria, and conjunctival hemorrhage, was reported in 13% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with none of the patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma (Prod Info MEKINIST(TM) oral tablets, 2013).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia (all grades) was reported in 38% of patients who received oral trametinib dimethyl sulfoxide 2 mg once daily (n=211) compared with 26% of patients who received chemotherapy consisting of either IV dacarbazine 1000 mg/m(2) or paclitaxel 175 mg/m(2) every 3 weeks (n=99) in a randomized, open-label clinical study in patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Grade 3 anemia was reported in 2% of the trametinib arm and 3% of the chemotherapy arm in this study; no grade 4 anemia was reported in either arm (Prod Info MEKINIST(TM) oral tablets, 2013).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Carcinogenicity studies with trametinib have not been conducted. However, an increased risk of cutaneous and non-cutaneous malignancies were observed in patients treated with trametinib in combination with dabrafenib during clinical trials.
    3.21.3) HUMAN STUDIES
    A) NEW PRIMARY CUTANEOUS MALIGNANCIES
    1) BASAL CELL CARCINOMA: In a clinical study, 9% of patients with BRAF V600E or V600K mutation-positive melanoma treated with trametinib in combination with dabrafenib (n=55) developed basal cell carcinoma compared with 2% treated with dabrafenib monotherapy (n=53). The diagnoses were made within 28 to 249 days with trametinib combination therapy and 197 days with dabrafenib therapy alone (Prod Info MEKINIST oral tablets, 2014).
    2) CUTANEOUS SQUAMOUS CELL CARCINOMA OR KERATOACANTHOMA: In a clinical study, 7% of patients with BRAF V600E or V600K mutation-positive melanoma treated with trametinib in combination with dabrafenib (n=55) developed squamous cell carcinoma, including keratoacanthoma, compared with 19% of patients treated with dabrafenib monotherapy (n=53). The diagnosis was made within 136 to 197 days with trametinib combination therapy and 9 to 197 days with dabrafenib therapy alone (Prod Info MEKINIST oral tablets, 2014).
    B) NON-CUTANEOUS MALIGNANCIES
    1) In a clinical study, 4 cases of non-cutaneous malignancies, including KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1), developed in patients during treatment with trametinib in combination with dabrafenib for BRAF V600E or V600K mutation-positive melanoma. Dabrafenib, with activation of RAS through mutation or other mechanism, may promote growth and development of malignancies (Prod Info MEKINIST oral tablets, 2014).
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, carcinogenicity studies with trametinib have not been conducted (Prod Info MEKINIST(TM) oral tablets, 2013).

Genotoxicity

    A) Trametinib was not found to be genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells and micronuclei in the bone marrow of rats (Prod Info MEKINIST(TM) oral tablets, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs.
    B) Monitor fluid and serum electrolyte status in patients with significant diarrhea. Monitor serial CBCs with differential following a significant exposure; bleeding has been observed with therapy.
    C) Monitor liver enzymes after a significant overdose.
    D) Serum trametinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    E) Due to the risk of fetal harm, a pregnancy test is recommended in women of childbearing age who have been exposed to trametinib.
    F) Monitor respiratory and cardiac function in symptomatic patients. Cardiomyopathy has been a late (ie, weeks to months after the initiation of therapy) complication of therapy.
    4.1.2) SERUM/BLOOD
    A) Monitor fluid and serum electrolyte status in patients with significant diarrhea. Monitor serial CBCs with differential following a significant exposure; bleeding has been observed with therapy.
    B) Monitor liver enzymes after a significant overdose.
    4.1.4) OTHER
    A) OTHER
    1) PREGNANCY TEST
    a) Due to the risk of fetal harm, a pregnancy test is recommended in women of childbearing age who have been exposed to trametinib.
    2) CARDIOMYOPATHY
    a) Cardiomyopathy (ie, cardiac failure, left ventricular dysfunction or decreased left ventricular ejection fraction) may be a late complication of exposure (time to onset: 63 days during clinical trials; range 16 to 156 days) (Prod Info MEKINIST(TM) oral tablets, 2013).
    b) Obtain an echocardiogram and/or MUGA scan to evaluate cardiac function in symptomatic patients.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients demonstrating severe fluid and electrolyte imbalance, bleeding, or cardiac instability should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults with inadvertent ingestions (a single extra dose) can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Consult an ophthalmologist in any patient that develops a new onset of visual disturbances.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.

Monitoring

    A) Monitor vital signs.
    B) Monitor fluid and serum electrolyte status in patients with significant diarrhea. Monitor serial CBCs with differential following a significant exposure; bleeding has been observed with therapy.
    C) Monitor liver enzymes after a significant overdose.
    D) Serum trametinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    E) Due to the risk of fetal harm, a pregnancy test is recommended in women of childbearing age who have been exposed to trametinib.
    F) Monitor respiratory and cardiac function in symptomatic patients. Cardiomyopathy has been a late (ie, weeks to months after the initiation of therapy) complication of therapy.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Overdose has not been reported. Treatment is symptomatic supportive. Monitor vital signs. Hypertension may develop.
    2) Monitor fluid status in patients that develop significant diarrhea; treat with IV fluids as necessary.
    3) Monitor CBC, electrolytes and liver enzymes following a significant overdose.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and liver enzymes after a significant overdose. Monitor fluid and electrolyte status in patients with significant gastrointestinal loss (eg, diarrhea, vomiting). Monitor serial CBC with differential following a significant exposure.
    C) HYPERTENSIVE DISORDER
    1) Treat severe hypertension with nitroprusside as the preferred agent; nitroglycerin or phentolamine as alternatives.
    2) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    3) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    4) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    5) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    6) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    9) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    10) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    11) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    12) PHENTOLAMINE/INDICATIONS
    a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    13) PHENTOLAMINE/ADULT DOSE
    a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    14) PHENTOLAMINE/PEDIATRIC DOSE
    a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    15) PHENTOLAMINE/ADVERSE EFFECTS
    a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    16) CAUTION
    a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    D) BLEEDING
    1) Hemorrhagic events (gastrointestinal, genitourinary, and ocular) and anemia have been observed with therapy (Prod Info MEKINIST(TM) oral tablets, 2013). Monitor for bleeding and obtain serial CBCs. Transfuse as needed for severe bleeding.
    E) STOMATITIS
    1) Stomatitis has been reported in patients receiving trametinib therapy; most cases were not severe (Prod Info MEKINIST(TM) oral tablets, 2013)
    2) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics (eg, morphine, hydrocodone, oxycodone, fentanyl). Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function (Bensinger et al, 2008).
    3) Total parenteral nutrition may provide nutritional requirements during the healing phase of drug-induced oral ulceration, mucositis, and esophagitis.
    F) CARDIOMYOPATHY
    1) Cardiomyopathy (ie, cardiac failure, left ventricular dysfunction or decreased left ventricular ejection fraction) may be a late complication of exposure (time to onset: 63 days during clinical trials; range 16 to 156 days) (Prod Info MEKINIST(TM) oral tablets, 2013).
    2) Obtain an echocardiogram and/or MUGA scan to evaluate cardiac function in symptomatic patients.
    G) RETINAL PIGMENT EPITHELIAL DETACHMENT
    1) Retinal pigment epithelial detachment has occurred (Prod Info MEKINIST(TM) oral tablets, 2013). An ophthalmic exam and consult is indicated in any patient with a new onset of vision loss or visual changes.

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis is unlikely to be effective following a trametinib overdose because it is highly protein bound (97.4%).

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. The highest dose evaluated during clinical trials was 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. Of the 7 patients that received one of these treatment protocols, 2 developed retinal pigment epithelial detachment.
    B) THERAPEUTIC DOSE: ADULT: 2 mg orally once daily; treatment should be continued until disease progression or unacceptable toxicity occurs. PEDIATRIC: The safety and effectiveness of trametinib have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose is 2 mg orally once daily as a single agent or in combination with dabrafenib (150 mg given orally twice daily) for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by a US Food and Drug Administration-approved test (http://www.fda.gov/CompanionDiagnostics to confirm the presence of mutations). Treatment should be continued until disease progression or unacceptable toxicity occurs (Prod Info MEKINIST oral tablets, 2014).
    7.2.2) PEDIATRIC
    A) The safety and effectiveness of trametinib as a single agent or in combination with dabrafenib have not been established in pediatric patients (Prod Info MEKINIST oral tablets, 2014).

Minimum Lethal Exposure

    A) A toxic dose has not been established (Prod Info MEKINIST(TM) oral tablets, 2013).

Maximum Tolerated Exposure

    A) The highest dose evaluated during clinical trials was 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. Of the 7 patients that received one of these treatment protocols, 2 developed retinal pigment epithelial detachment (Prod Info MEKINIST(TM) oral tablets, 2013).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Following oral administration of multiple doses of trametinib, 0.125 to 4 mg once daily, to patients with solid tumors or BRAF V600 mutation-positive melanoma, AUC and Cmax increased in a dose-proportional manner (Prod Info MEKINIST(TM) oral tablets, 2013).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 activity. MEK proteins promote cellular proliferation. BRAF V600E tumor mutations result in constitutive activation of the BRAF pathway, which includes MEK1 and MEK2. Trametinib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo (Prod Info MEKINIST(TM) oral tablets, 2013).

References

General Bibliography

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