Trametinib-Mekinist Tablets- @-(Jan 2013/Jan 2014)- Chemotherapeutic Agents
Drug Name:Trametinib-Mekinist Tablets- @-(Jan 2013/Jan 2014)- Chemotherapeutic Agents
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
Avoid concurrent administration of strong inhibitors of CYP3A4 or
CYP2C8 when MEKINIST is used in combination with dabrafenib.
Avoid concurrent administration of strong inducers of CYP3A4 or
CYP2C8 when MEKINIST is used in combination with dabrafenib.
Concomitant use with agents that are sensitive substrates of CYP3A4,
CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in loss of efficacy
of these agents when MEKINIST is used in combination with dabrafenib.
Indication:
MEKINIST (trametinib) tablets, for oral use
Initial U.S. Approval: 2013
RECENT MAJOR CHANGES
Indications and Usage (1) 01/2014
Dosage and Administration (2.2-2.3) 01/2014
Warnings and Precautions (5-5.10) 01/2014
Drug Name- Mekinist
Active Ingredient - Trametinib
To treat patients whose tumors express BRAF V600E OR V600K gene mutations
Indication-
Tumors
Approved by FDA on 29-5--2013 (Ref- FDA approved List- 2013)
Proprietary Name- MEKINIST TABLETS*
Established Name- Trametinib
Applicant- GLAXOSMITHKLINE LLC
Indication- Trametinib and Dabrafenib (Mekinist tablets and Tatlinar capsules)
for use in combination in the treatment of patients with unresectable
melaloma with BRAF V600E or V600K mutation as detected by an
FDA -approved test
Approval Date- 10/1/2013
Approved by US FDA (Ref- FDA approved list- 2013)
Proprietary Name- MEKINIST TABLETS-2*
Established Name- Trametinib
Applicant- GLAXOSMITHKLINE LLC
Indication- For the treatment of patients with unrescetable or metastatic melaloma
with BRAF V600ZE mutation as detected by an FDA approved test
Approval Date- May 29,2013
Approved by US FDA (Ref- FDA approved list- 2013)
Adverse Reaction:
Most common adverse reactions (.20%) for MEKINIST as a single
agent include rash, diarrhea, and lymphedema.
Most common adverse reactions (.20%) for MEKINIST in combination
with dabrafenib include pyrexia, chills, fatigue, rash, nausea, vomiting,
diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia,
night sweats, decreased appetite, constipation, and myalgia.
Contra-Indications:
CONTRAINDICATIONS
None.
WARNINGS and PRECAUTIONS
New primary malignancies, cutaneous and non-cutaneous, can occur
when MEKINIST is used in combination with dabrafenib. Monitor
patients for new malignancies prior to initiation of therapy while on
therapy, and following discontinuation of the combination treatment.
Hemorrhage: Major hemorrhagic events can occur in patients receiving
MEKINIST in combination with dabrafenib. Monitor for signs and
symptoms of bleeding
Venous Thromboembolism: Deep vein thrombosis and pulmonary
embolism can occur in patients receiving MEKINIST in combination
with dabrafenib.
Cardiomyopathy: Assess LVEF before treatment, after one month of
treatment, then every 2 to 3 months thereafter.
Ocular Toxicities: Perform ophthalmologic evaluation for any visual
disturbances. For Retinal Vein Occlusion (RVO), permanently
discontinue MEKINIST.
Interstitial Lung Disease (ILD): Withhold MEKINIST for new or
progressive unexplained pulmonary symptoms. Permanently discontinue
MEKINIST for treatment-related ILD or pneumonitis.
Serious Febrile Reactions can occur when MEKINIST is used in
combination with dabrafenib.
Serious Skin Toxicity: Monitor for skin toxicities and for secondary
infections. Discontinue for intolerable Grade 2, or Grade 3 or 4 rash not
improving within 3 weeks despite interruption of MEKINIST.
Hyperglycemia: Monitor serum glucose levels in patients with preexisting
diabetes or hyperglycemia.
Embryofetal Toxicity: Can cause fetal harm. Advise females of
reproductive potential of potential risk to the fetus.
Dosages/ Overdosage Etc:
Indication-
Tumors
INDICATIONS AND USAGE
MEKINIST is a kinase inhibitor indicated as a single agent and in
combination with dabrafenib for the treatment of patients with unresectable or
metastatic melanoma with BRAF V600E or V600K mutations as detected by
an FDA-approved test. The use in combination is based on the demonstration
of durable response rate. Improvement in disease-related symptoms or overall
survival has not been demonstrated for MEKINIST in combination with
dabrafenib.
Limitation of use: MEKINIST as a single agent is not indicated for treatment
of patients who have received prior BRAF-inhibitor therapy.
DOSAGE AND ADMINISTRATION
Confirm the presence of BRAF V600E or V600K mutation in tumor
specimens prior to initiation of treatment with MEKINIST.
The recommended dosage regimens of MEKINIST are 2 mg orally once
daily as a single agent or in combination with dabrafenib 150 mg orally
twice daily.Take MEKINIST at least 1 hour before or at least 2 hours
after a meal.
DOSAGE FORMS AND STRENGTHS
Tablets: 0.5 mg, 1 mg, and 2 mg.
Patient Information:
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information).
Inform patients of the following:
1. Evidence of BRAF V600E or V600K mutation within the tumor specimen is necessary
to identify patients for whom treatment with MEKINIST is indicated
2. MEKINIST 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 [see Warnings and Precautions
3. MEKINIST 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
4. MEKINIST 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
5. MEKINIST can cause cardiomyopathy. Advise patients to immediately report
any signs or symptoms of heart failure to their healthcare provider
6. MEKINIST 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 [see Warnings and Precautions
7. MEKINIST 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
8. MEKINIST can cause skin toxicities which may require hospitalization.
Advise patients to contact their healthcare provider for progressive
or intolerable rash
9. MEKINIST used in combination with dabrafenib can cause serious
febrile reactions. Instruct patients to contact their healthcare provider if they
develop fever while taking MEKINIST with dabrafenib
10. MEKINIST 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.
11.MEKINIST 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.
12, MEKINIST should be taken at least 1 hour before or at least 2 hours
after a meal.
13, MEKINIST 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 contra
Advise patients to contact their healthcare provider if they become pregnant,
or if pregnancy is suspected, while taking MEKINIST
14. Nursing infants may experience serious adverse reactions if the mother
is taking MEKINIST. Advise lactating mothers to discontinue nursing
while taking MEKINIST
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
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.
2. Pharmacokinetics
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 increas
in AUC was greater than dose proportional.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy
Pregnancy Category D
Risk Summary: MEKINIST 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
2. Nursing Mothers
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 MEKINIST, 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.
3. Pediatric Use
The safety and effectiveness of MEKINIST as a single agent or in combination
with dabrafenib have not been established in pediatric patients.
4. Geriatric Use
Clinical trials of MEKINIST 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 MEKINIST 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.
