Trametinib dimethyl sulfoxide: Difference between revisions

Revision as of 15:43, 3 February 2015

{{DrugProjectFormSinglePage |authorTag=Gloria Picoy [1] |genericName=Trametinib dimethyl sulfoxide |aOrAn=a |drugClass=kinase inhibitor |indicationType=treatment |indication=patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test in combination with dabrafenib |adverseReactions=fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, night sweats, decreased appetite, constipation, and myalgia |blackBoxWarningTitle=TITLE |blackBoxWarningBody=Condition Name: (Content) |fdaLIADAdult=Trametinib dimethyl sulfoxide as a single agent and in combination with dabrafenib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.

Dosage:

2 mg orally taken once daily as a single agent
2 mg orally taken once daily in combination with dabrafenib 150 mg orally taken twice daily

|offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Trametinib dimethyl sulfoxide in adult patients. |offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Trametinib dimethyl sulfoxide in adult patients. |fdaLIADPed=Safety and effectiveness not established in pediatric patients |offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Trametinib dimethyl sulfoxide in pediatric patients. |offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Trametinib dimethyl sulfoxide in pediatric patients. |contraindications=None |warnings======New Primary Malignancies===== New primary malignancies, cutaneous and non-cutaneous, can occur when trametinib dimethyl sulfoxide is used in combination with dabrafenib and with dabrafenib as a single agent.

Cutaneous Malignancies

In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving trametinib dimethyl sulfoxide in combination with dabrafenib, with an incidence of 9% (5/55) in patients receiving trametinib dimethyl sulfoxide in combination with dabrafenib compared with 2% (1/53) in patients receiving dabrafenib as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving trametinib dimethyl sulfoxide in combination with dabrafenib and was 197 days for the patient receiving dabrafenib as a single agent.

Cutaneous squamous cell carcinomas (SCC), including keratoacanthoma, occurred in 7% of patients receiving trametinib dimethyl sulfoxide in combination with dabrafenib and 19% of patients receiving dabrafenib as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving dabrafenib as a single agent.

New primary melanoma occurred in 2% (1/53) of patients receiving dabrafenib and in none of the 55 patients receiving trametinib dimethyl sulfoxide in combination with dabrafenib.

Perform dermatologic evaluations prior to initiation of trametinib dimethyl sulfoxide in combination with dabrafenib, every 2 months while on therapy, and for up to 6 months following discontinuation of the combination. No dose modifications of trametinib dimethyl sulfoxide or dabrafenib are recommended in patients who develop new primary cutaneous malignancies.

Non-Cutaneous Malignancies

Based on its mechanism of action, dabrafenib may promote growth and development of malignancies with activation of RAS through mutation or other mechanisms. In patients receiving trametinib dimethyl sulfoxide in combination with dabrafenib, four cases of non-cutaneous malignancies were identified: 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). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. If used in combination with dabrafenib, no dose modification is required for trametinib dimethyl sulfoxide in patients who develop non-cutaneous malignancies. Permanently discontinue dabrafenib in patients who develop RAS mutation-positive non-cutaneous malignancies.

Hemorrhage

Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when trametinib dimethyl sulfoxide is used in combination with dabrafenib.

In Trial 2, treatment with trametinib dimethyl sulfoxide in combination with dabrafenib resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with trametinib dimethyl sulfoxide in combination with dabrafenib compared with 2% (1/53) of patients treated with dabrafenib as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with trametinib dimethyl sulfoxide in combination with dabrafenib compared with none of the 53 patients treated with dabrafenib as a single agent. Intracranial hemorrhage was fatal in two (4%) patients receiving the combination of trametinib dimethyl sulfoxide and dabrafenib.

Permanently discontinue trametinib dimethyl sulfoxide, and also permanently discontinue dabrafenib if administered in combination, for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold trametinib dimethyl sulfoxide for up to 3 weeks for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold dabrafenib for Grade 3 hemorrhagic events; if improved resume at a lower dose level.

Venous Thromboembolism

Venous thromboembolism can occur when trametinib dimethyl sulfoxide is used in combination with dabrafenib.

In Trial 2, treatment with trametinib dimethyl sulfoxide in combination with dabrafenib resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with trametinib dimethyl sulfoxide in combination with dabrafenib compared with none of the 53 patients treated with dabrafenib as a single agent. Pulmonary embolism was fatal in one (2%) patient receiving the combination of trametinib dimethyl sulfoxide and dabrafenib.

Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue trametinib dimethyl sulfoxide and dabrafenib for life threatening PE. Withhold trametinib dimethyl sulfoxide for uncomplicated DVT and PE for up to 3 weeks; if improved, trametinib dimethyl sulfoxide may be resumed at a lower dose level. Do not modify the dose of dabrafenib.

Cardiomyopathy

Cardiomyopathy can occur when trametinib dimethyl sulfoxide is administered as a single agent or when used in combination with dabrafenib.

In Trial 1, cardiomyopathy (defined as cardiac failure, left ventricular dysfunction, or decreased left ventricular ejection fraction [LVEF]) occurred in 7% (14/211) of patients treated with trametinib dimethyl sulfoxide; no chemotherapy-treated patients in Trial 1 developed cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with trametinib dimethyl sulfoxide in combination with dabrafenib and in none of patients treated with dabrafenib as a single agent. The median time to onset of cardiomyopathy in patients treated with trametinib dimethyl sulfoxide was 63 days (range: 16 to 156 days) for Trial 1 and 86 days (range: 27 to 253 days) for Trial 2.

Cardiomyopathy was identified within the first month of treatment with trametinib dimethyl sulfoxide in 5 of 14 patients in Trial 1 and in 2 of 5 patients in Trial 2. Development of cardiomyopathy resulted in dose reduction (7/211) and/or discontinuation (4/211) of study drug in Trial 1, and resulted in dose reduction (4/55) and/or dose interruption (1/55) in Trial 2. Cardiomyopathy resolved in 10 of 14 (71%) patients in Trial 1 and in all 5 patients in Trial 2.

Across clinical trials of trametinib dimethyl sulfoxide administered either as a single agent (N = 329), or in combination with dabrafenib (N = 202), 11% and 8% of patients, respectively, developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Five percent and 2% in single-agent and in combination trials, respectively, demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of trametinib dimethyl sulfoxide as a single agent and in combination with dabrafenib, one month after initiation, and then at 2- to 3-month intervals while on treatment. Withhold treatment with trametinib dimethyl sulfoxide for up to 4 weeks if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue trametinib dimethyl sulfoxide and withhold dabrafenib. Resume dabrafenib at the same dose upon recovery of cardiac function.

Ocular Toxicities

Retinal Vein Occlusion (RVO)

Across all clinical trials of trametinib dimethyl sulfoxide, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue trametinib dimethyl sulfoxide in patients with documented RVO. If trametinib dimethyl sulfoxide is used in combination with dabrafenib, do not modify dabrafenib dose.

Retinal Pigment Epithelial Detachment (RPED)

Retinal pigment epithelial detachment (RPED) can occur when trametinib dimethyl sulfoxide is administered as a single agent or when used in combination with dabrafenib.

In Trial 1 and Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment.

In Trial 1, one patient (0.5%) receiving trametinib dimethyl sulfoxide developed RPED and no cases of RPED were identified in chemotherapy-treated patients. Across all clinical trials of trametinib dimethyl sulfoxide, the incidence of RPED was 0.8% (14/1,749). Retinal detachments were often bilateral and multifocal, occurring in the macular region of the retina. RPED led to reduction in visual acuity that resolved after a median of 11.5 days (range: 3 to 71 days) following the interruption of dosing with trametinib dimethyl sulfoxide, although Ocular Coherence Tomography (OCT) abnormalities persisted beyond a month in at least several cases.

In Trial 2, one patient (2%) receiving trametinib dimethyl sulfoxide in combination with dabrafenib developed RPED.

Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. Withhold trametinib dimethyl sulfoxide if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume trametinib dimethyl sulfoxide at a lower dose level. Discontinue trametinib dimethyl sulfoxide if no improvement after 3 weeks. If trametinib dimethyl sulfoxide is used in combination with dabrafenib, do not modify the dose of dabrafenib.

Uveitis and Iritis

Uveitis and iritis can occur when trametinib dimethyl sulfoxide is used in combination with dabrafenib and with dabrafenib as a single agent.

Uveitis occurred in 1% (2/202) of patients treated with trametinib dimethyl sulfoxide in combination with dabrafenib.

Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold dabrafenib for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If not improved, permanently discontinue dabrafenib. If trametinib dimethyl sulfoxide is used in combination with dabrafenib, do not modify the dose of trametinib dimethyl sulfoxide.

Interstitial Lung Disease

In clinical trials of trametinib dimethyl sulfoxide (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with trametinib dimethyl sulfoxide developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days).

Withhold trametinib dimethyl sulfoxide in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue trametinib dimethyl sulfoxide for patients diagnosed with treatment-related ILD or pneumonitis. If trametinib dimethyl sulfoxide is used in combination with dabrafenib, do not modify the dose of dabrafenib.

Serious Febrile Reactions

Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure, can occur when trametinib dimethyl sulfoxide is used in combination with dabrafenib and with dabrafenib as a single agent.

The incidence and severity of pyrexia are increased when trametinib dimethyl sulfoxide is used in combination with dabrafenib compared with dabrafenib as a single agent.

In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with trametinib dimethyl sulfoxide in combination with dabrafenib and 26% (14/53) in patients treated with dabrafenib as a single agent. Serious febrile reactions and fever of any severity accompanied by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with trametinib dimethyl sulfoxide in combination with dabrafenib compared with 2% (1/53) of patients treated with dabrafenib as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with trametinib dimethyl sulfoxide in combination with dabrafenib, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with dabrafenib as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with dabrafenib as a single agent.

Across clinical trials of trametinib dimethyl sulfoxide administered in combination with dabrafenib (N = 202), the incidence of pyrexia was 57% (116/202).

Withhold dabrafenib for fever of 101.3ºF or higher. Withhold trametinib dimethyl sulfoxide for fever higher than 104ºF. Withhold dabrafenib and trametinib dimethyl sulfoxide for any serious febrile reaction or fever accompanied by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming trametinib dimethyl sulfoxide or dabrafenib.

Serious Skin Toxicity

Serious skin toxicity can occur when trametinib dimethyl sulfoxide is administered as a single agent or when used in combination with dabrafenib. Serious skin toxicity can also occur with dabrafenib as a single agent.

In Trial 1, the overall incidence of any skin toxicity, the most common of which were rash, dermatitis acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema, was 87% in patients treated with trametinib dimethyl sulfoxide and 13% in chemotherapy-treated patients. Severe skin toxicity occurred in 12% of patients treated with trametinib dimethyl sulfoxide. Skin toxicity requiring hospitalization occurred in 6% of patients treated with trametinib dimethyl sulfoxide, most commonly for secondary infections of the skin requiring intravenous antibiotics or severe skin toxicity without secondary infection. In comparison, no patients treated with chemotherapy required hospitalization for severe skin toxicity or infections of the skin. The median time to onset of skin toxicity in patients treated with trametinib dimethyl sulfoxide was 15 days (range: 1 to 221 days) and median time to resolution of skin toxicity was 48 days (range: 1 to 282 days). Reductions in the dose of trametinib dimethyl sulfoxide were required in 12% and permanent discontinuation of trametinib dimethyl sulfoxide was required in 1% of patients with skin toxicity.

In Trial 2, the incidence of any skin toxicity was similar for patients receiving trametinib dimethyl sulfoxide in combination with dabrafenib (65% [36/55]) compared with patients receiving dabrafenib as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with trametinib dimethyl sulfoxide in combination with dabrafenib was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of trametinib dimethyl sulfoxide or dabrafenib for skin toxicity.

Across clinical trials of trametinib dimethyl sulfoxide administered in combination with dabrafenib (n = 202), severe skin toxicity and secondary infection of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with trametinib dimethyl sulfoxide in combination with dabrafenib.

Withhold trametinib dimethyl sulfoxide, and dabrafenib if used in combination, for intolerable or severe skin toxicity. trametinib dimethyl sulfoxide and dabrafenib may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

Hyperglycemia

Hyperglycemia can occur when trametinib dimethyl sulfoxide is used in combination with dabrafenib and with dabrafenib as a single agent. Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycemic agent therapy occurred with dabrafenib as a single agent.

In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with trametinib dimethyl sulfoxide in combination with dabrafenib compared with 2% (1/53) in patients treated with dabrafenib as a single agent.

Monitor serum glucose levels as clinically appropriate during treatment with trametinib dimethyl sulfoxide in combination with dabrafenib in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia.

Embryofetal Toxicity

Based on its mechanism of action, trametinib dimethyl sulfoxide can cause fetal harm when administered to a pregnant woman. trametinib dimethyl sulfoxide was 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 clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Advise female patients of reproductive potential to use highly effective contraception during treatment with trametinib dimethyl sulfoxide and for 4 months after treatment. Advise patients to use a highly effective non-hormonal method of contraception when trametinib dimethyl sulfoxide is administered in combination with dabrafenib, since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking trametinib dimethyl sulfoxide. |clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the Warnings and Precautions section and below reflect exposure to trametinib dimethyl sulfoxide as a single agent and in combination with dabrafenib. trametinib dimethyl sulfoxide as a single agent was evaluated in 329 patients including 107 (33%) exposed for greater than or equal to 6 months and 30 (9%) exposed for greater than or equal to one year. trametinib dimethyl sulfoxide as a single agent was studied in open-label, single-arm trials (N = 118) or in an open-label, randomized, active-controlled trial (N = 211). The median age was 54 years, 60% were male, >99% were white, and all patients had metastatic melanoma. All patients received 2 mg once-daily doses of trametinib dimethyl sulfoxide. The incidence of RPED and RVO are obtained from the 1,749 patients from all clinical trials with trametinib dimethyl sulfoxide.

The safety of trametinib dimethyl sulfoxide in combination with dabrafenib was evaluated in Trial 2 and other trials consisting of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received trametinib dimethyl sulfoxide 2 mg orally once daily in combination with dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. Among these 202 patients, 68 (34%) were exposed to trametinib dimethyl sulfoxide and 66 (33%) were exposed to dabrafenib for greater than 6 to 12 months while 36 (18%) were exposed to trametinib dimethyl sulfoxide and 40 (20%) were exposed to dabrafenib for greater than one year. The median age was 54 years, 57% were male and >99% were white.

Table 3 presents adverse reactions identified from analyses of Trial 1, a randomized, open-label trial of patients with BRAF V600E or V600K mutation-positive melanoma receiving trametinib dimethyl sulfoxide (N = 211) 2 mg orally once daily or chemotherapy (N = 99) (either dacarbazine 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks) [see Clinical Studies (14.1)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, or current evidence of Class II or greater congestive heart failure (New York Heart Association) were excluded from Trial 1. The median duration of treatment with trametinib dimethyl sulfoxide was 4.3 months. In Trial 1, 9% of patients receiving trametinib dimethyl sulfoxide experienced adverse reactions resulting in permanent discontinuation of trial medication. The most common adverse reactions resulting in permanent discontinuation of trametinib dimethyl sulfoxide were decreased left ventricular ejection fraction (LVEF), pneumonitis, renal failure, diarrhea, and rash. Adverse reactions led to dose reductions in 27% of patients treated with trametinib dimethyl sulfoxide. Rash and decreased LVEF were the most common reasons cited for dose reductions of trametinib dimethyl sulfoxide.

Other clinically important adverse reactions observed in ≤10% of patients (N = 329) treated with trametinib dimethyl sulfoxide were:

Cardiac Disorders: Bradycardia.
Gastrointestinal Disorders: Xerostomia.
Infections and Infestations: Folliculitis, rash pustular, cellulitis.
Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis.
Nervous System Disorders: Dizziness, dysgeusia.
Ocular Disorders: Vision blurred, dry eye.

Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving trametinib dimethyl sulfoxide 2 mg once daily in combination with dabrafenib 150 mg twice daily (N = 55), trametinib dimethyl sulfoxide 1 mg once daily in combination with dabrafenib 150 mg twice daily (N = 54), and dabrafenib as a single agent 150 mg twice daily (N = 53) [see Clinical Studies (14.1)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history of RVO, or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both trametinib dimethyl sulfoxide (2-mg once-daily treatment group) and dabrafenib when used in combination, 10.6 months for both trametinib dimethyl sulfoxide (1-mg once-daily treatment group) and dabrafenib when used in combination, and 6.1 months for dabrafenib as a single agent.

In Trial 2, 13% of patients receiving trametinib dimethyl sulfoxide in combination with dabrafenib at the recommended dose experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with trametinib dimethyl sulfoxide in combination with dabrafenib. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions, and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of trametinib dimethyl sulfoxide and dabrafenib when used in combination.

Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with trametinib dimethyl sulfoxide in combination with dabrafenib were:

Eye Disorders: Vision blurred, transient blindness.
Gastrointestinal Disorders: Stomatitis, pancreatitis.
General Disorders and Administration Site Conditions: Asthenia.
Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.
Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.
Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis.
Vascular Disorders: Hypertension.

QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with trametinib dimethyl sulfoxide in combination with dabrafenib and in 2% (1/53) of patients treated with dabrafenib as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with trametinib dimethyl sulfoxide in combination with dabrafenib and 2% (1/53) of patients treated with dabrafenib as a single agent. |drugInteractions=No formal clinical trials have been conducted to evaluate human cytochrome P450 (CYP) enzyme-mediated drug interactions with trametinib.

Dabrafenib

Coadministration of trametinib dimethyl sulfoxide 2 mg once daily and dabrafenib 150 mg twice daily resulted in no clinically relevant pharmacokinetic drug interactions.

Refer to the Full Prescribing Information for dabrafenib for further details on the drug interaction potential of dabrafenib. Avoid concurrent administration of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 with dabrafenib. If concomitant use of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers. Concomitant use of dabrafenib with agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in loss of efficacy of these agents. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable. |FDAPregCat=D |useInPregnancyFDA=======Risk Summary====== trametinib dimethyl sulfoxide can cause fetal harm when administered to a pregnant woman. Trametinib was 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 clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Animal Data

In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss.

In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals. |useInNursing=It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from trametinib dimethyl sulfoxide, a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother. |useInPed=The safety and effectiveness of trametinib dimethyl sulfoxide as a single agent or in combination with dabrafenib have not been established in pediatric patients.

Adequate juvenile animal studies using trametinib have not been completed. In a repeat-dose toxicity study in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose of dabrafenib based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC. |useInGeri=Clinical trials of trametinib dimethyl sulfoxide as a single agent did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In Trial 1, 49 patients (23%) were 65 years of age and older, and 9 patients (4%) were 75 years of age and older.

Across all clinical trials of trametinib dimethyl sulfoxide administered in combination with dabrafenib, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older. |useInRenalImpair=No formal clinical trial has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild or moderate renal impairment based on a population pharmacokinetic analysis. The appropriate dose of trametinib dimethyl sulfoxide has not been established in patients with severe renal impairment. |useInHepaticImpair=No formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis.

The appropriate dose of trametinib dimethyl sulfoxide has not been established in patients with moderate or severe hepatic impairment. |useInReproPotential=======Contraception====== Females: trametinib dimethyl sulfoxide can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of trametinib dimethyl sulfoxide. When trametinib dimethyl sulfoxide is used in combination with dabrafenib, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking trametinib dimethyl sulfoxide.

Infertility

Females: trametinib dimethyl sulfoxide may impair fertility in female patients.
Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with trametinib dimethyl sulfoxide in combination with dabrafenib.

|administration=Oral |overdose=There were no reported cases of overdosage with trametinib dimethyl sulfoxide. The highest doses of trametinib dimethyl sulfoxide evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with trametinib dimethyl sulfoxide. |drugBox={{Drugbox2 | drug_name = Trametinib | IUPAC_name = N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide | image = Trametinib dimethyl sulfoxide structure.png | alt = | caption =

| C=26 | H=23 | F=1 | I=1 | N=5 | O=4 | molecular_weight = 615.39 g/mol | smiles = Ic1ccc(c(F)c1)N\C3=C\2/C(=O)N(C(=O)N(C/2=C(\C(=O)N3C)C)c4cccc(NC(=O)C)c4)C5CC5 | StdInChI = 1S/C26H23FIN5O4/c1-13-22-21(23(31(3)24(13)35)30-20-10-7-15(28)11-19(20)27)25(36)33(17-8-9-17)26(37)32(22)18-6-4-5-16(12-18)29-14(2)34/h4-7,10-12,17,30H,8-9H2,1-3H3,(H,29,34) | StdInChIKey = LIRYPHYGHXZJBZ-UHFFFAOYSA-N }} |mechAction=Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E 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.

Trametinib and dabrafenib target two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive melanoma cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive melanoma xenografts compared with either drug alone. |structure=Trametinib dimethyl sulfoxide has the following chemical structure:

|PD=Administration of 1 mg and 2 mg trametinib to patients with BRAF V600 mutation-positive melanoma resulted in dose-dependent changes in tumor biomarkers including inhibition of phosphorylated ERK, inhibition of Ki67 (a marker of cell proliferation), and increases in p27 (a marker of apoptosis). |PK=The pharmacokinetics (PK) of trametinib were characterized following single- and repeat-oral administration in patients with solid tumors and BRAF V600 mutation-positive metastatic melanoma.

Absorption

After oral administration, the median time to achieve peak plasma concentrations (Tmax) is 1.5 hours post-dose. The mean absolute bioavailability of a single 2-mg oral dose of trametinib tablet is 72%. The increase in Cmax was dose proportional after a single dose of 0.125 to 10 mg while the increase in AUC was greater than dose proportional. After repeat doses of 0.125 to 4 mg daily, both Cmax and AUC increase proportionally with dose. Inter-subject variability in AUC and Cmax at steady state is 22% and 28%, respectively.

Administration of a single dose of trametinib with a high-fat, high-calorie meal decreased AUC by 24%, Cmax by 70%, and delayed Tmax by approximately 4 hours as compared with fasted conditions.

Distribution

Trametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 214 L.

Metabolism

Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases.

Following a single dose of [14C]-trametinib, approximately 50% of circulating radioactivity is represented as the parent compound. However, based on metabolite profiling after repeat dosing of trametinib, ≥75% of drug-related material in plasma is the parent compound.

Elimination

The estimated elimination half-life based on the population PK model is 3.9 to 4.8 days. The apparent clearance is 4.9 L/h.

Following oral administration of [14C]-trametinib, >80% of excreted radioactivity was recovered in the feces while <20% of excreted radioactivity was recovered in the urine with <0.1% of the excreted dose as parent. |nonClinToxic=======Carcinogenesis, Mutagenesis, Impairment of Fertility====== Carcinogenicity studies with trametinib have not been conducted. Trametinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, and micronuclei in the bone marrow of rats.

Trametinib may impair fertility in humans. In female rats given trametinib for up to 13 weeks, increased follicular cysts and decreased corpora lutea were observed at doses ≥0.016 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC). In rat and dog toxicity studies up to 13 weeks in duration, there were no treatment effects observed on male reproductive tissues. |clinicalStudies======BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma===== The safety and efficacy of trametinib dimethyl sulfoxide were evaluated in two clinical trials. Trial 1 was an international, multicenter, randomized (2:1), open-label, active-controlled trial in 322 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Trial 2 was a multicenter, randomized (1:1:1), open-label, dose-ranging trial designed to evaluate the clinical activity and safety of trametinib dimethyl sulfoxide (at two different doses) in combination with dabrafenib and to compare the safety with dabrafenib as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma.

In Trial 1, patients were not permitted to have more than one prior chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not permitted. The primary efficacy outcome measure was progression-free survival (PFS). Patients were randomized to receive trametinib dimethyl sulfoxide 2 mg orally once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine 1,000 mg/m2 intravenously every 3 weeks or paclitaxel 175 mg/m2 intravenously every 3 weeks. Treatment continued until disease progression or unacceptable toxicity. Randomization was stratified according to prior use of chemotherapy for advanced or metastatic disease (yes versus no) and lactate dehydrogenase level (normal versus greater than upper limit of normal). Tumor tissue was evaluated for BRAF mutations at a central testing site using a clinical trial assay. Tumor samples from 289 patients (196 patients treated with trametinib dimethyl sulfoxide and 93 chemotherapy-treated patients) were also tested retrospectively using an FDA-approved companion diagnostic test, THxID™-BRAF assay.

The median age for randomized patients was 54 years, 54% were male, >99% were white, and all patients had baseline ECOG performance status of 0 or 1. Most patients had metastatic disease (94%), were Stage M1c (64%), had elevated LDH (36%), no history of brain metastasis (97%), and received no prior chemotherapy for advanced or metastatic disease (66%). The distribution of BRAF V600 mutations was BRAF V600E (87%), V600K (12%), or both (<1%). The median durations of follow-up prior to initiation of alternative treatment were 4.9 months for patients treated with trametinib dimethyl sulfoxide and 3.1 months for patients treated with chemotherapy. Fifty-one (47%) patients crossed over from the chemotherapy arm at the time of disease progression to receive trametinib dimethyl sulfoxide.

Trial 1 demonstrated a statistically significant increase in progression-free survival in the patients treated with trametinib dimethyl sulfoxide. Table 7 and Figure 1 summarize the PFS results.

In supportive analyses based on independent radiologic review committee (IRRC) assessment, the PFS results were consistent with those of the primary efficacy analysis.

Trial 2 randomized (1:1:1) patients to trametinib dimethyl sulfoxide (at two different doses) in combination with dabrafenib compared with dabrafenib as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive trametinib dimethyl sulfoxide 2 mg orally once daily with dabrafenib 150 mg orally twice daily (n = 54), trametinib dimethyl sulfoxide 1 mg orally once daily with dabrafenib 150 mg orally twice daily (n = 54), or dabrafenib 150 mg orally twice daily (n = 54). Treatment continued until disease progression or unacceptable toxicity. Patients randomized to receive dabrafenib as a single agent were offered trametinib dimethyl sulfoxide 2 mg orally once daily with dabrafenib 150 mg orally twice daily at the time of investigator-assessed disease progression. The major efficacy outcome measure was investigator-assessed overall response rate (ORR). Additional efficacy outcome measures were investigator-assessed duration of response, independent radiology review committee (IRRC)-assessed ORR, and IRRC-assessed duration of response.

The median age of patients in Trial 2 was 53 years, 57% were male, >99% were white, 66% of patients had a pretreatment ECOG performance status of 0, 67% had M1c disease, 54% had a normal LDH at baseline, and 8% had a history of brain metastases. Most patients (81%) had not received prior anti-cancer therapy for unresectable or metastatic disease. All patients had tumor containing BRAF V600E or V600K mutations as determined by local laboratory or centralized testing, 85% with BRAF V600E mutations and 15% with BRAF V600K mutations.

The median duration of follow-up was 14 months. Efficacy outcomes for the arm receiving trametinib dimethyl sulfoxide 2 mg daily in combination with dabrafenib and the arm receiving dabrafenib as a single agent are summarized in Table 8.

The ORR results were similar in subgroups defined by BRAF mutation subtype, i.e., in the 85% of patients with V600E mutation-positive melanoma and in the 15% of patients with V600K mutation-positive melanoma. In exploratory subgroup analyses of the patients with retrospectively confirmed BRAF V600E or V600K mutation-positive melanoma using the THxID™-BRAF assay, the ORR results were also similar to the intent-to-treat analysis.

Lack of Clinical Activity in Metastatic Melanoma Following BRAF-Inhibitor Therapy

The clinical activity of trametinib dimethyl sulfoxide as a single agent was evaluated in a single-arm, multicenter, international trial (Trial 3) in 40 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma who had received prior treatment with a BRAF inhibitor. All patients received trametinib dimethyl sulfoxide at a dose of 2 mg orally once daily until disease progression or unacceptable toxicity.

The median age was 58 years, 63% were male, all were white, 98% had baseline ECOG PS of 0 or 1, and the distribution of BRAF V600 mutations was V600E (83%), V600K (10%), and the remaining patients had multiple V600 mutations (5%), or unknown mutational status (2%). No patient in Trial 3 achieved a confirmed partial or complete response as determined by the clinical investigators. |howSupplied=* Trametinib dimethyl sulfoxide 0.5 mg Tablets

Bottles of 30 (NDC 0173-0849-13).

Trametinib dimethyl sulfoxide 1 mg Tablets

Bottles of 30 (NDC 0173-0858-13).

Trametinib dimethyl sulfoxide 2 mg Tablets

Bottles of 30 (NDC 0173-0848-13).

|storage=Store refrigerated at 2° to 8°C (36° to 46°F)

|packLabel=

|fdaPatientInfo=Inform patients of the following:

Evidence of BRAF V600E or V600K mutation within the tumor specimen is necessary to identify patients for whom treatment with trametinib dimethyl sulfoxide is indicated.
trametinib dimethyl sulfoxide administered in combination with dabrafenib can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies.
trametinib dimethyl sulfoxide administered in combination with dabrafenib increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage.
trametinib dimethyl sulfoxide administered in combination with dabrafenib increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling.
trametinib dimethyl sulfoxide can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider.
trametinib dimethyl sulfoxide can cause severe visual disturbances that can lead to blindness. Advise patients to contact their healthcare provider if they experience any changes in their vision.
trametinib dimethyl sulfoxide can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea.
trametinib dimethyl sulfoxide used in combination with dabrafenib can cause serious febrile reactions. Instruct patients to contact their healthcare provider if they develop fever while taking trametinib dimethyl sulfoxide with dabrafenib.
trametinib dimethyl sulfoxide can cause skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash.
trametinib dimethyl sulfoxide causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness.
trametinib dimethyl sulfoxide often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment.
trametinib dimethyl sulfoxide should be taken at least 1 hour before or at least 2 hours after a meal.
trametinib dimethyl sulfoxide can cause fetal harm if taken during pregnancy. Instruct female patients to use highly effective contraception during treatment and for 4 months after treatment. Advise patients to use a highly effective non-hormonal method of contraception when trametinib dimethyl sulfoxide is administered in combination with dabrafenib. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking trametinib dimethyl sulfoxide.
Nursing infants may experience serious adverse reactions if the mother is taking trametinib dimethyl sulfoxide. Advise lactating mothers to discontinue nursing while taking trametinib dimethyl sulfoxide.

|alcohol=Alcohol-Trametinib dimethyl sulfoxide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. |brandNames=* Mekinist ^[1] }} {{#subobject:

 |Label Page=Trametinib dimethyl sulfoxide
 |Label Name=Trametinib dimethyl sulfoxide 0.5 mg.png

}}

{{#subobject:

 |Label Page=Trametinib dimethyl sulfoxide
 |Label Name=Trametinib dimethyl sulfoxide 1 mg.png

}}