Trametinib – Uses, Dosage, Side Effects, Interaction

Indications

  • Trametinib is indicated as a single agent for the treatment of BRAF-inhibitor treatment-naïve patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FD-approved test. It is used in combination with [dabrafenib] for the: – Treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations. – Adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. – Treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test. – Treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options.
  • Melanoma: Trametinib as monotherapy or in combination with dabrafenib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. Trametinib monotherapy has not demonstrated clinical activity in patients who have progressed on a prior BRAF inhibitor therapy.
  • Adjuvant treatment of melanoma: Trametinib in combination with dabrafenib is indicated for the adjuvant treatment of adult patients with Stage III melanoma with a BRAF V600 mutation, following complete resection.
  • Non-small cell lung cancer (NSCLC): Trametinib in combination with dabrafenib is indicated for the treatment of adult patients with advanced non-small cell lung cancer with a BRAF V600 mutation.
  • Trametinib is a dual-kinase inhibitor that is used in the treatment of advanced malignant melanoma, usually in combination with dabrafenib. Trametinib therapy is associated with transient elevations in serum aminotransferase and alkaline phosphatase levels during therapy but has yet to be linked to cases of clinically apparent acute liver injury.
  • Trametinib dimethyl sulfoxide is approved to be used alone or with dabrafenib mesylate to treat patients whose cancer has a certain mutation in the BRAF gene, including:

    • Anaplastic thyroid cancer that has spread and cannot be treated with local therapy. It is used with dabrafenib mesylate.

    • Glioma that is low grade in children aged 1 year and older who require systemic therapy. It is used with dabrafenib mesylate.

    • Melanoma. It is used:

    • With dabrafenib mesylate in patients who have had surgery to remove cancer that has spread to the lymph nodes.

    • Alone or with dabrafenib mesylate in patients whose cancer cannot be removed by surgery or has spread to other parts of the body.

    • Non-small cell lung cancer that has spread to other parts of the body. It is used with dabrafenib mesylate.

    • Solid tumors. It is used with dabrafenib mesylate in adults and children aged 6 years and older whose tumors cannot be removed by surgery or have spread to other parts of the body and have gotten worse after other treatments and cannot be treated with other therapies.

  • Advanced Non-Small Cell Lung Cancer (NSCLC)
  • Locally Advanced Anaplastic Thyroid Cancer
  • Melanoma
  • Metastatic Anaplastic Thyroid Cancer
  • Metastatic Melanoma
  • Metastatic Non-Small Cell Lung Cancer
  • Stage III Melanoma
  • Unresectable Melanoma
  • Unresectable or Metastatic Solid Tumors
  • This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, a confirmatory trial(s) must show that trametinib dimethyl sulfoxide provides a clinical benefit in these patients. Trametinib dimethyl sulfoxide is also being studied in the treatment of other types of cancer.

Use in Cancer

Trametinib dimethyl sulfoxide is approved to be used alone or with dabrafenib mesylate to treat patients whose cancer has a certain mutation in the BRAF gene, including:

  • Anaplastic thyroid cancer has spread and cannot be treated with local therapy. It is used with dabrafenib mesylate.
  • Glioma is low-grade in children aged 1 year and older who require systemic therapy. It is used with dabrafenib mesylate.
  • Melanoma. It is used:
    • With dabrafenib mesylate in patients who have had surgery to remove cancer that has spread to the lymph nodes.
    • Alone or with dabrafenib mesylate in patients whose cancer cannot be removed by surgery or has spread to other parts of the body.
  • Non-small cell lung cancer has spread to other parts of the body. It is used with dabrafenib mesylate.
  • Solid tumors. It is used with dabrafenib mesylate in adults and children aged 6 years and older whose tumors cannot be removed by surgery or have spread to other parts of the body and have gotten worse after other treatments and cannot be treated with other therapies.¹

This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, a confirmatory trial(s) must show that trametinib dimethyl sulfoxide provides a clinical benefit in these patients.

Trametinib dimethyl sulfoxide is also being studied in the treatment of other types of cancer.

Contraindications

  • an increased risk of bleeding
  • detachment of the retina of the eye
  • a clot in the lung
  • cardiomyopathy, a disease of the heart muscle
  • chronic heart failure
  • blood clot in a deep vein of the extremities
  • a body temperature higher than 101 degrees Fahrenheit
  • high blood sugar
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • a rupture in the wall of the stomach or intestine
  • lung tissue problem

Dosage

Strengths: 0.5 mg; 2 mg

 Melanoma – Metastatic

Unresectable or Metastatic Melanoma:

  • Single agent: 2 mg orally once a day
  • Combination therapy: 2 mg orally once a day with dabrafenib (refer to the dabrafenib prescribing information for recommended dabrafenib dosing information)
  • Duration of therapy: Until disease progression or unacceptable toxicity occurs.

Adjuvant Treatment of Melanoma:

  • Combination therapy: 2 mg orally once a day with dabrafenib (refer to the dabrafenib prescribing information for recommended dabrafenib dosing information)
  • Duration of therapy: Until disease progression or unacceptable toxicity occurs for up to one year.
  • Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation.
  • As a single agent for the treatment of BRAF-inhibitor treatment-naive patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test
  • In combination with dabrafenib for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test
  • In combination with dabrafenib for patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection

Non-Small Cell Lung Cancer

  • 2 mg orally once a day with dabrafenib (refer to the dabrafenib prescribing information for recommended dabrafenib dosing information)
    Duration of therapy: Until disease progression or unacceptable toxicity occurs.
  • Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of therapy with this drug and dabrafenib.
  • In combination with dabrafenib for patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test

Thyroid Cancer

  • 2 mg orally once a day with dabrafenib (refer to the dabrafenib prescribing information for recommended dabrafenib dosing information)
    Duration of therapy: Until disease progression or unacceptable toxicity occurs.
  • Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of therapy with this drug and dabrafenib.
  • In combination with dabrafenib for patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options

Dose Adjustments

Recommended Dose Reductions for Adverse Reactions:

  • First dose reduction: 1.5 mg orally once a day
  • Second dose reduction: 1 mg orally once a day
  • Subsequent modification: Permanently discontinue therapy if unable to tolerate 1 mg orally once a day

Venous Thromboembolism:

  • Uncomplicated DVT or PE: Withhold therapy for up to 3 weeks; if improved to Grade 0 or 1, resume at a lower dose level; if not improved, permanently discontinue therapy.
  • Life threatening PE: Permanently discontinue therapy.

Cardiac Toxicity:

  • Asymptomatic, absolute decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline that is below institutional lower limits of normal (LLN) from pretreatment value: Withhold therapy for up to 4 weeks; if improved to normal LVEF value, resume therapy at a lower dose; if not improved to normal LVEF value, permanently discontinue therapy.
  • Symptomatic congestive heart failure or an absolute decrease in LVEF of greater than 20% from baseline that is below LLN: Permanently discontinue therapy.

Ocular Toxicity:

  • Retinal pigment epithelial detachments (RPED): Withhold therapy for up to 3 weeks; if improved, resume therapy at same or lower dose level; if not improved, discontinue therapy or resume at a lower dose.
  • Retinal vein occlusion: Permanently discontinue therapy.

Pulmonary Toxicity:
Interstitial lung disease/pneumonitis: Permanently discontinue therapy.

Febrile Drug Reactions:

  • Fever higher than 104F or fever complicated by rigors, hypotension, dehydration or renal failure: Withhold therapy until fever resolves, then resume at same or lower dose level.

Dermatologic Toxicity:

  • Grade 3 or 4 or intolerable Grade 2: Withhold therapy for up to 3 weeks; if improved, resume therapy at a lower dose level; if not improved, permanently discontinue therapy.

Other Adverse Reactions (dose modifications are not recommended for this drug when administered with dabrafenib for the following adverse reactions of dabrafenib: non-cutaneous malignancies and uveitis; dose modification of this drug is not required for new primary cutaneous malignancies):

  • Any Grade 3 or intolerable Grade 2 adverse reaction: Withhold therapy; if improved to Grade 0 to 1, resume therapy at a lower dose level, if not improved, permanently discontinue therapy.
  • First occurrence of any Grade 4 adverse reaction: Withhold therapy until adverse reaction improves to Grade 0 to 1, then resume therapy at a lower dose level; if not improved, permanently discontinue therapy.
  • Recurrent Grade 4 adverse reaction: Permanently discontinue therapy.

Side Effects

The Most Common

  • dry skin
  • sores on the mouth and tongue
  • dry mouth
  • vomiting
  • loss of appetite
  • change in ability to taste food
  • tiredness
  • unusual bleeding or bruising
  • bloody or black, tarry stools
  • coughing up or vomiting blood or material that looks like coffee grounds
  • nosebleed
  • severe diarrhea
  • stomach pain
  • nausea
  • fever
  • chills
  • rapid, irregular, or pounding heartbeat
  • difficulty breathing
  • chest pain
  • swelling of the face, arms, legs, ankles, or feet
  • dizziness, lightheadedness, or weakness
  • shortness of breath
  • leg pain, swelling, tenderness, redness, or warmth
  • severe headache
  • cough
  • blurred vision
  • change in vision, including seeing halos (blurred outline around objects) or colored dots
  • loss of vision
  • eye pain
  • dry, red, or swollen eyes
  • rash, red skin, or pimples
  • wart
  • a reddish bump that bleeds or does not heal
  • change in size or color of a mole
  • itching
  • blisters, ulcers, or sores on the skin or nails
  • tingling, burning, redness, swelling, peeling or flaking, blisters, or sores on the palms of the hands or soles of the feet
  • frequent urination
  • increased thirst

More common

  • Acne, pimples
  • burning, itching, and pain in hairy areas, pus at the root of the hair
  • canker sores
  • change in taste
  • dark urine
  • dry eyes
  • dry mouth
  • dry skin
  • itching, pain, redness, swelling, tenderness, or warmth on the skin
  • loosening of the fingernails
  • loss of taste
  • redness or soreness around the fingernails
  • sores, ulcers, or white spots on the lips or tongue or inside the mouth
  • swelling or inflammation of the mouth
  • thirst
  • Bleeding from the rectum or bloody stools
  • bleeding gums
  • blemishes on the skin
  • blistering, crusting, irritation, itching, or reddening of the skin
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • bloody nose
  • blurred vision
  • chest discomfort, pain, or tightness
  • cracked, dry, or scaly skin
  • coughing up blood
  • decreased urine output
  • diarrhea
  • difficulty in moving
  • difficulty with breathing or swallowing
  • dilated neck veins
  • extreme tiredness or weakness
  • fast, slow, irregular, or pounding heartbeat
  • headache
  • increased menstrual flow or vaginal bleeding
  • irregular breathing
  • joint pain
  • lightheadedness, dizziness, or fainting
  • muscle aches, cramps, pain, or stiffness
  • nervousness
  • nosebleeds
  • paralysis
  • pimples
  • pounding in the ears
  • prolonged bleeding from cuts
  • rapid weight gain
  • rash
  • red or black, tarry stools
  • red or dark brown urine
  • redness, swelling, or pain of the skin
  • scaling of the skin on the hands and feet
  • swelling of the hands, ankles, feet, or lower legs
  • tingling of the hands and feet
  • ulceration of the skin
  • unusual tiredness or weakness
  • unusual weight gain or loss

Rare

  • Change in vision
  • seeing flashes or sparks of light
  • seeing floating spots before the eyes, or a veil or curtain across part of your vision
  • stomach cramps, pain, or tenderness
  • watery or bloody diarrhea
  • Blistering, peeling, loosening of the skin
  • chills
  • itching
  • red skin lesions, often with a purple center
  • sore throat
  • sores, ulcers, or white spots in the mouth or on lips
  • swollen glands
  • unusual bleeding or bruising

Drug interactions

Pregnancy and Lactation

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned.

Pregnancy

Based on its mechanism of action and findings from animal reproduction studies, MEKINIST can cause fetal harm when administered to a pregnant woman. There is insufficient data on pregnant women exposed to MEKINIST to assess the risks. 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. Advise pregnant women of the potential risk to the fetus.

Lactation

No information is available on the clinical use of trametinib during breastfeeding. Because trametinib is 97% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is 3.9 to 4.8 days and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during trametinib therapy and for 4 months after the last dose.

Why is this medication prescribed?

Trametinib is used alone or in combination with dabrafenib (Tafinlar) to treat a certain type of melanoma (a type of skin cancer) that cannot be treated with surgery or that has spread to other parts of the body. It is used in combination with dabrafenib to treat and prevent the return of a certain type of melanoma after surgery to remove it and any affected lymph nodes. Trametinib is also used in combination with dabrafenib to treat a certain type of non-small-cell lung cancer (NSCLC) that has spread to nearby tissues or to other parts of the body. It is used in combination with dabrafenib to treat a certain type of thyroid cancer that has spread to nearby tissues or to other parts of the body, which cannot be treated with other therapies. Trametinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps stop the spread of cancer cells.

How should this medicine be used?

Trametinib comes as a tablet to take by mouth. It is usually taken once a day on an empty stomach, at least 1 hour before or 2 hours after a meal. Take trametinib at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take trametinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. Do not stop taking trametinib without talking to your doctor.

Your doctor may adjust your dose of trametinib depending on your response to treatment and any side effects that you experience. Talk to your doctor about how you are feeling during your treatment.

Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

Other uses for this medicine

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before taking trametinib,

  • tell your doctor and pharmacist if you are allergic to trametinib, any other medications, or any of the ingredients in trametinib tablets. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take.
  • tell your doctor if you have or have ever had lung disease or breathing problems; diabetes; bleeding problems or blood clots; colitis (inflammation of the colon); stomach problems; high blood pressure; heart, eye, liver, or kidney disease; or any other medical conditions.
  • tell your doctor if you are pregnant or plan to become pregnant. You should not become pregnant while you are taking trametinib. You should use birth control to prevent pregnancy during your treatment with trametinib and for 4 months after your final dose. Talk to your doctor about birth control methods that will work for you. If you become pregnant while taking trametinib, call your doctor. Trametinib may harm the fetus.
  • tell your doctor if you are breastfeeding or plan to breastfeed. You should not breastfeed while taking trametinib and for 4 months after your final dose.
  • you should know that this medication may decrease fertility in women. Talk to your doctor about the risks of taking trametinib.

What should I know about storage and disposal of this medication?

Keep this medication in the container it came in, tightly closed, away from moisture and light, and out of the reach of children. Do not place the tablets in other containers, such as daily or weekly pill boxes. Store it in a refrigerator, but do not freeze it. Do not remove the desiccant (small packet included with medication to absorb moisture) from your bottle.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA’s Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

In case of emergency/overdose

In case of overdose, call the poison control helpline at 1-800-222-1222. Information is also available online at https://www.poisonhelp.org/help. If the victim has collapsed, had a seizure, has trouble breathing, or can’t be awakened, immediately call emergency services at 911.

Symptoms of overdose may include the following:

  • vision problems

What other information should I know?

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests before and during your treatment to see if it is safe for you to receive trametinib and to check your body’s response to trametinib. Your doctor will also check your skin for any changes before you begin treatment, every 2 months during your treatment, and for up to 6 months after treatment. Your doctor will also check your blood pressure from time to time as needed.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

References