Trametinib

Take the missed dose as soon as you remember it. However, if it is less than 12 hours until your next scheduled dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Trametinib may cause serious side effects, including:

• heart problems, including heart failure. Your healthcare provider should check your heart function before you start taking trametinib and during treatment. Signs and symptoms of heart problems may include:
  • feeling like your heart is pounding or racing
  • shortness of breath
  • swelling of your ankles and feet
  • feeling lightheaded
• eye problems. Trametinib can cause eye problems including blindness. Tell your healthcare provider right away if you get these symptoms of eye problems:
  • blurred vision, loss of vision, or other vision changes
  • see color dots
  • halo (seeing blurred outline around objects)
• lung or breathing problems. Tell your healthcare provider if you have any new or worsening symptoms of lung or breathing problems, including:
  • shortness of breath
  • cough
• serious skin reactions. Rash is a common side effect of trametinib and in some cases can be severe and can result in admission to the hospital if severe. Tell your healthcare provider if you get any of the following symptoms:
  • skin rash
  • acne
  • redness, swelling, peeling, or tenderness of hands or feet
  • skin redness
• increased blood sugar. Some people may develop high blood sugar or worsening diabetes during treatment with trametinib, alone or in combination with dabrafenib. If you have diabetes, your healthcare provider should check your blood sugar levels closely during treatment with trametinib alone or in combination with dabrafenib. Your diabetes medicine may need to be changed. Tell your healthcare provider if you have any of the following symptoms of severe high blood sugar:
  • increased thirst
  • urinating more often than normal, or urinating an increased amount of urine
• bleeding problems. This medication can cause serious bleeding problems, especially in your brain or stomach, and can lead to death. Call your healthcare provider and get medical help right away if you have any signs of bleeding, including:
  • headaches, dizziness, or feeling weak
  • cough up blood or blood clots
  • vomit blood or your vomit looks like “coffee grounds”
  • red or black stools that look like tar
• inflammation of the intestines, or tears (perforation) of the stomach or intestines. This medication can cause inflammation of your intestines, or tears in the stomach or intestines that can lead to death. Tell your healthcare provider immediately if you have any of the following symptoms:
  • bleeding
  • diarrhea (loose stools) or more bowel movements than usual
  • stomach-area pain or tenderness
  • fever
  • nausea
• blood clots. Trametinib can cause blood clots in your arms or legs, which can travel to your lungs and can lead to death. Get medical help right away if you have the following symptoms:
  • chest pain
  • sudden shortness of breath or trouble breathing
  • pain in your legs with or without swelling
  • swelling in your arms or legs
  • a cool pale arm or leg

When trametinib is given with dabrafenib, there is a chance for developing a type of skin cancer, called cutaneous squamous cell carcinoma (cuSCC) and new cancers including basal cell carcinoma. Talk to your healthcare provider about your risk for these cancers. Check your skin and tell your healthcare provider right away about any skin changes including a:

• new wart
• skin sore or reddish bump that bleeds or does not heal
• change in size or color of a mole

Do not take trametinib if you are allergic to it or to any of its inactive ingredients.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. Trametinib can harm your unborn baby. Women who may become pregnant should use effective birth control (contraception) during treatment with trametinib and for 4 months after stopping treatment. Talk to your healthcare provider about birth control methods that may be right for you. Tell your healthcare provider right away if you become pregnant during treatment with trametinib.

It is not known if trametinib passes into your breast milk. You and your healthcare provider should decide if you will take trametinib or breastfeed. You should not do both.

Do not breastfeed during treatment and for 4 months after your last dose of trametinib. Talk to your healthcare provider about the best way to feed your baby during this time.

You should not use trametinib if you are allergic to it.

To make sure trametinib is safe for you, tell your doctor if you have ever had:

• heart disease;

• high blood pressure;

• lung disease;

• liver or kidney disease;

• bleeding problems, or a blood clot;

• eye problems (especially a problem with your retina); or

• if you have ever been treated with dabrafenib or vemurafenib to treat your melanoma.

Using trametinib with dabrafenib may increase your risk of developing a certain type of skin cancer. Ask your doctor about your specific risk. Tell your doctor if you notice any new skin symptoms such as redness, warts, sores that will not heal, or a mole that has changed in size or color.

Do not use trametinib if you are pregnant. It could harm the unborn baby. Tell your doctor if you become pregnant during treatment. Use effective birth control to prevent pregnancy while you are using this medicine and for at least 4 months after your last dose.

Trametinib can make birth control pills, patches, or injections less effective. Ask your doctor about using non hormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy while taking trametinib.

This medication may affect fertility (your ability to have children), whether you are a man or a woman.

It is not known whether trametinib passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine, and for at least 4 months after your last dose.

This medicine can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Usual Adult Dose for Melanoma - Metastatic:

Single agent: 2 mg orally once a day.
Combination therapy: 2 mg orally once daily with dabrafenib 150 mg orally twice a day.
Duration of therapy: Until disease progression or unacceptable toxicity occurs.

Comments:
-Take at least 1 hour before or 2 hours after a meal.
-Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation.
-Trametinib is not indicated for treatment of patients who have received prior BRAF-inhibitor therapy.
-Continue treatment until disease progression or unacceptable toxicity occurs.

Use:
-As a single agent and in combination with dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.
-Trametinib as a single agent is not indicated for treatment of patients who have received prior BRAF-inhibitor therapy.

Other drugs may interact with trametinib, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.

Medicines used to treat cancer are very strong and can have many side effects. Before using trametinib, make sure you understand all the risks and benefits. It is important for you to work closely with your doctor during your treatment.

Take trametinib exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

trametinib usually comes with a patient information leaflet. Read and follow the instructions carefully. Ask your doctor or pharmacist if you have any questions.

Take trametinib at least 1 hour before or 2 hours after a meal.

Dosing

The dose of trametinib will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of trametinib. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For melanoma and non-small cell lung cancer:
    • Adults—2 milligrams (mg) once a day. Your doctor may adjust your dose if needed.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of trametinib, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose and it is less than 12 hours until your next regular dose, skip the missed dose and take your next dose at the regular time. If you miss a dose and it is more than 12 hours until your next dose, take it as soon as possible and go back to your regular dosing schedule.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store in the refrigerator. Do not freeze.

Keep the medicine in its original bottle. Protect from moisture and light.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Sometimes, dabrafenib is taken with trametinib. If you are taking dabrafenib with trametinib, be sure you know the side effects that can happen with each drug. When these drugs are taken together, the chance of certain side effects may be raised. These side effects can be very bad and sometimes deadly. This includes bleeding, bleeding in the brain, blood clots, eye problems, fever, heart problems (like heart failure), high blood sugar, other cancers, and skin problems. Talk with your doctor about the chance of side effects with your drugs.
• High blood pressure has happened with trametinib. Have your blood pressure checked as you have been told by your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Have your eye pressure and eyesight checked as you have been told by the doctor.
• Blood clots have happened with this medicine. Tell your doctor if you have ever had a blood clot. Talk with your doctor.
• Call your doctor right away if you have signs of a blood clot like chest pain or pressure; coughing up blood; shortness of breath; swelling, warmth, numbness, change of color, or pain in a leg or arm; or trouble speaking or swallowing.
• It is common to get a rash with trametinib but other skin reactions may also happen. Sometimes, these rashes and skin reactions can be very bad and may need treatment in the hospital. Call your doctor right away if you have acne, skin redness, or a skin rash that bothers you or does not go away. Call your doctor right away if you have redness or irritation of the palms of hands or soles of feet.
• Very bad eye problems have happened with this medicine. Sometimes, this has led to loss of eyesight. Call your doctor right away if you have blurred eyesight, loss of eyesight, or other changes in eyesight. Call your doctor right away if you see color dots or halos or if bright lights bother you.
• A bowel problem (colitis) and holes in the bowel have happened with trametinib. Sometimes, these have been deadly. Call your doctor right away if you have diarrhea, stomach pain or cramps, fever, or very upset stomach.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• This medicine may cause fertility problems. This may affect being able to have children. Talk with the doctor.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• Use birth control that you can trust to prevent pregnancy while taking trametinib and for 4 months after your last dose.
• If you get pregnant while taking this medicine or within 4 months after your last dose, call your doctor right away.

• GSK1120212
• Trametinib Dimethyl Sulfoxide

Concerns related to adverse effects:

• Bone marrow suppression: Neutropenia (including grade 3 and 4 events) has been observed when used in combination with dabrafenib. Monitor complete blood counts at baseline and as clinically needed during therapy.

• Cardiac events: Cardiac events such as heart failure, left ventricular dysfunction, or decreased left ventricular ejection fraction (LVEF) were observed in clinical trials (for single-agent trametinib and when used in combination with dabrafenib). The median time to onset of cardiomyopathy in melanoma patients for single-agent trametinib was ~2 months (range: 16 to 156 days) and ~8 months (range: ~1 to 25 months) when used in combination with dabrafenib. The median time of onset of cardiomyopathy in patients with NSCLC was 6.7 months (range: 1.4 to 14.1 months). In some patients, cardiomyopathy developed within the first month of treatment. Assess LVEF (by echocardiogram or MUGA scan) prior to therapy initiation, at one month, and then at 2- to 3-month intervals while on therapy. Cardiac dysfunction may require treatment interruption, dosage reduction, or discontinuation; such measures resulted in resolution of cardiomyopathy in some patients.

• Dermatologic toxicity: Dermatologic toxicity (eg, rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema) was commonly observed in trametinib-treated patients (either as a single-agent or when used in combination with dabrafenib); some patients required hospitalization for severe toxicity or for secondary skin infections. In melanoma studies, the median time to onset and resolution of skin toxicity for single-agent trametinib was 15 days (range: 1 to 221 days) and 48 days (range: 1 to 282 days), respectively. The median time to onset and resolution of skin toxicity for combination therapy was 2 months (range: 1 day to 22 months) and 1.2 months (range: 1 day to ~24 months), respectively in melanoma studies. Monitor for dermatologic toxicity and signs/symptoms of secondary infections. Treatment interruption, dose reduction, and/or therapy discontinuation may be necessary.

• Febrile reactions: Serious febrile reactions and fever (any severity) accompanied by hypotension, rigors/chills, dehydration, or renal failure may occur when trametinib is used in combination with dabrafenib. The incidence and severity were higher with combination therapy than with single-agent dabrafenib; the median time to onset of fever was 1.2 months (range: 1 to 23 days) and duration was 3 days (range: 1 day to 1.7 months) for patients receiving combination therapy for the treatment of melanoma. Withhold trametinib for fever >104°F (if using in combination, withhold dabrafenib for fever ≥101.3°F) or for any fever with rigors/chills, hypotension, dehydration, or renal failure (evaluate for infection); may require prophylactic antipyretics as secondary prophylaxis upon therapy resumption. Administer corticosteroids (eg, prednisone 10 mg daily or equivalent) for at least 5 days for second or subsequent episodes of pyrexia if temperature does not return to baseline within 3 days of fever onset, or for pyrexia associated with complications (eg, dehydration, hypotension, severe chills/rigors with no evidence of active infection).

• Gastrointestinal events: Colitis and GI perforation, including fatal cases, have been reported with monotherapy and when administered concomitantly with dabrafenib; monitor closely for development of colitis and GI perforations.

• Hemorrhage: Hemorrhage, including symptomatic bleeding in a critical area/organ, may occur with trametinib, either as a single agent or in combination with dabrafenib. Major bleeding events (some fatal) included intracranial or gastrointestinal hemorrhage. May require treatment interruption and dosage reduction; permanently discontinue trametinib (and dabrafenib) for all grade 4 hemorrhagic events and any grade 3 event that does not improve with therapy interruption.

• Hepatotoxicity: Elevated liver function tests have been reported with trametinib, including grade 3 and 4 events. Monitor hepatic function as clinically necessary.

• Hyperglycemia: While not reported with single-agent trametinib, hyperglycemia may occur while on combination therapy with dabrafenib; may require initiation of insulin or oral hypoglycemic agent therapy (or an increased dose if already taking). Monitor serum glucose at baseline and as clinically necessary in patients with preexisting diabetes or hyperglycemia. Instruct patients to report symptoms of severe hyperglycemia (eg, polydipsia, polyuria).

• Hypertension: May cause hypertension; monitor blood pressure.

• Malignancy: New primary cutaneous malignancies (which are associated with dabrafenib as single-agent therapy) may occur when trametinib is given in combination with dabrafenib. The incidence of basal cell carcinoma (BCC) in melanoma patients is ~3% for combination therapy versus 6% for single-agent dabrafenib. The median time to BCC diagnosis ranged from ~3 to 24 months for patients receiving combination therapy for the treatment of melanoma. Cutaneous squamous cell carcinomas (cuSCC), including keratoacanthoma, occurred at a lower rate for combination therapy in melanoma patients compared to single-agent dabrafenib (3% vs 10%, respectively), with a median time to diagnosis ranging from ~2 to 17 months for combination therapy. Cases of cuSCC also occurred in patients with NSCLC, with a first occurrence onset ranging from 25 days to ~12 months. New primary melanoma occurred rarely in patients receiving trametinib. Dermatologic exams should be performed prior to initiation of combination therapy, every 2 months while receiving combination treatment, and for up to 6 months following discontinuation. There are case reports of noncutaneous malignancies, including pancreatic cancer (KRAS mutation-positive), colorectal cancer (recurrent NRAS mutation-positive), hand and neck cancer, and glioblastoma, with combination therapy; monitor for signs/symptoms of noncutaneous malignancies. No trametinib dosage modification is necessary for new primary cutaneous and noncutaneous malignancies; dabrafenib should be permanently discontinued if RAS mutation-positive noncutaneous malignancies develop.

• Ocular toxicity: Retinal pigment epithelial detachments (RPED) and retinal vein occlusion were seen in clinical trials (rare). Detachments were typically bilateral and multifocal and occurred in the central macular area of the retina. Retinal vein occlusion may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Promptly (within 24 hours) refer patients for ophthalmological evaluations if loss of vision or other visual disturbances occur. Ophthalmic exams (including retinal evaluation) should be performed periodically during treatment and with visual disturbances. Interrupt trametinib therapy for RPED; may resume if resolves within 3 weeks; reduce the dose or discontinue if not resolved within 3 weeks. Permanently discontinue if retinal vein occlusion develops. Uveitis and iritis have been reported when trametinib is used in combination with dabrafenib and are managed symptomatically with ophthalmic steroid and mydriatic drops (does not require alteration in trametinib therapy).

• Pulmonary toxicity: Interstitial lung disease (ILD) and pneumonitis were observed in clinical trials. The median time to initial presentation in melanoma patients was ~5 months (range: 2 to ~6 months). Monitor for new or progressive pulmonary symptoms (eg, cough, dyspnea, hypoxia, pleural effusion, infiltrates); withhold treatment if symptoms occur; permanently discontinue with diagnosis of ILD or pneumonitis.

• Venous thromboembolism: Venous thromboembolic events (some fatal) may occur (was observed when used in combination with dabrafenib). DVT and PE occurred at an increased incidence with combination therapy. Patients should seek immediate medical attention with symptoms of DVT or PE (shortness of breath, chest pain, arm/leg swelling). Withhold trametinib for uncomplicated DVT or PE; may resume at a lower dose if improves within 3 weeks; permanently discontinue trametinib for life-threatening PE.

Concurrent drug therapy issues:

• Combination therapy with dabrafenib: Serious adverse reactions (tumor promotion, hemolytic anemia), which occur with single-agent dabrafenib, may also occur when trametinib is administered in combination with dabrafenib.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Trametinib is not indicated for treatment of patients with melanoma who have progressed on prior BRAF-inhibitor therapy. Prior to initiating therapy, confirm BRAF mutation status with an approved test; approved for use in melanoma patients with BRAF V600K and BRAF V600E mutations and NSCLC patients with BRAF V600E mutation. Data regarding use in melanoma patients with BRAF V600K mutation is limited; compared to BRAF V600E mutation, lower response rates have been observed with BRAF V600K mutation. Data regarding other less common BRAF V600 mutations in melanoma is lacking.

Commonly reported side effects of trametinib include: acneiform eruption, cardiomyopathy, decreased left ventricular ejection fraction, dermatitis, palmar-plantar erythrodysesthesia, skin rash, and erythema. Other side effects include: cardiac failure. See below for a comprehensive list of adverse effects.

Mild to moderate renal dysfunction: No adjustment recommended
Severe renal impairment: An appropriate dose has not been established.