Trametinib - Indications, Side Effects, Contraindications, Dosage, and Precautions

Overview:

A drug called Trametinib is used to treat some cancers, including melanoma, with particular genetic abnormalities. It is a member of the class of medications known as MEK (mitogen-activated protein kinase kinase) inhibitors, which focus on a pathway connected to cell division and proliferation. The United States Food and Drug Administration (FDA) approved Trametinib for the management of melanoma on 29th May 2013.

Drug Group:

Trametinib is a member of the MEK inhibitor medication class. Inhibitors of MEK treat some cancers, especially those with BRAF gene mutations. By blocking MEK proteins, Trametinib contributes to the disruption of aberrant signaling pathways that encourage the proliferation of cancer cells.

Dosages:

• Single Agent: Taken once daily by mouth

• Combination Therapy: Two mg of Dabrafenib taken once a day.

• Duration of Therapy: Therapy will continue for as long as the disease progresses or toxicity becomes intolerable.

Adjuvant Melanoma Treatment:

• Combination Therapy: Two mg of Dabrafenib taken once a day

• Duration of Therapy: Therapy will be administered for a maximum of one year, or until the condition progresses or toxicity becomes intolerable.

For Patients:

What Is Melanoma?

Skin cancer called melanoma arises in the melanocytes, which are the cells that produce the pigment called melanin, which gives the skin its color. It might manifest as new pigmented growths on the skin or as moles. Since it can spread to other regions of the body if it is not discovered and treated promptly, melanoma is thought to be more hazardous than other forms of skin cancer. Prevention requires both sun protection and routine skin exams.

What Is the Management of Melanoma?

• Diagnosis: For verification, do a biopsy.Staging to assess the disease's severity.

• Surgery: Removal of the cancerous growth.Biopsy of a sentinel lymph node for staging.

• Immunotherapy: Checkpoint inhibitors, such as Nivolumab and Pembrolizumab.

• Interferon treatment.

• Personalized Medicine: BRAF inhibitors for melanomas with mutant BRAF, such as Vemurafenib.

• Radiation Treatment: Adjuvant treatment in some situations.

• Follow-Up: Regular monitoring for recurrence. Imaging studies as needed.

• Clinical Examinations: Involvement with investigations aimed at developing new medicines.

• Prevention and Education: Sun awareness and protection. Often, examine the texture of the skin.

• Multidisciplinary Method: Cooperation between dermatologists, surgeons, oncologists, and other experts.

How Does Trametinib Work?

MEK proteins are the target of Trametinib in the mitogen-activated protein kinase (MAPK) signaling pathway, which is essential for cell division and survival. Trametinib inhibits MEK, which stops abnormal signaling in cancer cells and prevents them from proliferating. More specifically, it prevents signals that encourage tumor growth from spreading. This interference facilitates apoptosis, the body's normal process of planned cell death, and aids in controlling cell division. Because of its ability to precisely target particular biochemical pathways, Trametinib is a useful treatment option, especially when cancer growth is caused by dysregulated MAPK signaling.

How Should the Drug Be Taken?

For oral use, Trametinib comes in tablet and liquid form. It is usually taken once a day, preferably on an empty stomach, at least one hour before or two hours after a meal. Following the recommended dosage and schedule listed on the prescription label is crucial. If the patient has trouble swallowing the tablets as a whole, let the doctor know. If the patient has vomiting after taking Trametinib, stick to the usual dosing schedule and do not take any more medication. The doctor may change the dosage in response to the patient's reaction to the treatment and any side effects that are experienced. Without first talking to the doctor, never stop taking Trametinib or change the dosage.

What Are the Benefits of Using Trametinib for Melanoma?

• Prevents the growth of cancer cells by inhibiting MEK protein, an essential part of the MAPK signaling cascade.

• Approved for treatment in patients with V600E or V600K genetic alterations in advanced melanoma.

• Improved progression-free survival in trials that were conducted.

• It can be applied both on its own and in conjunction with other focused treatments.

• Possibility of increased overall survival in specific patient demographics.

• Less severe side effects than with conventional chemotherapy.

• Provides patients with metastatic or incurable melanoma with an alternate course of treatment.

What Must the Patient Inform the Doctor Before Taking Trametinib?

• Any existing medical conditions, especially heart or liver problems.

• Current medications, including prescription and over-the-counter drugs, herbal supplements, and vitamins.

• History of eye problems, as Trametinib may cause retinal detachment.

• Pregnancy status or plans for pregnancy, as Trametinib can harm the unborn baby.

• Breastfeeding status, as it is not recommended to breastfeed while on Trametinib.

• Any allergic reactions to medications or previous treatments.

What Are the Side Effects of Using Trametinib?

• Nausea.

• Vomiting.

• Diarrhea.

• Rash.

• Fatigue.

• Swelling or fluid retention.

• Elevated liver enzymes.

• High blood pressure.

• Gastrointestinal perforations (rare but serious).

• Cardiomyopathy (rare but serious).

• Interstitial lung disease (group of diseases that cause scarring (fibrosis) of the lungs.

For Doctors:

Description:

Trametinib dimethyl sulfoxide is a kinase inhibitor known by its chemical name acetamide, N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]-, compound with 1,1’-sulfinylbis[methane] (1:1). It has a molecular formula C26H23FIN5O4•C2H6OS with a mass of 693.53 g/mol (grams per mole) and appears as a white to almost white powder. Trametinib tablets, available in 0.5 mg and 2 mg, consist of Trametinib dimethyl sulfoxide and specific inactive ingredients, including colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, and sodium lauryl sulfate in the core, and hypromellose, iron oxide red (2 mg tablets), iron oxide yellow (0.5 mg tablets), polyethylene glycol, polysorbate 80 (2 mg tablets), and titanium dioxide in the coating. The tablets are designed for oral administration, and Trametinib non-solvated parent content is specified for each tablet's strength. Additionally, the substance is practically insoluble in aqueous media within the pH range of 2 to 8.

Therapeutic Uses of Trametinib:

• Treatment for Melanoma: Patients with unresectable or metastatic melanoma with a particular mutation (BRAF V600E or V600K) are frequently treated with Trametinib as a targeted therapy.

• Combination Therapy: To increase its efficacy in treating melanoma with BRAF mutations, it is frequently administered in conjunction with Dabrafenib, another targeted therapy.

• Adjuvant Treatment: To lower the chance of recurrence following surgical melanoma excision, Tratinib may be used as adjuvant therapy.

• Non-Small Cell Lung Cancer (NSCLC): Trametinib is occasionally used to treat NSCLC that has certain mutations, like BRAF V600E.

• Pediatric Patients: Patients with neurofibromatosis type 1 (NF1) and plexiform neurofibromas that are symptomatic but incurable may also be treated with Trametinib.

Dosage Forms and Strengths:

• 0.5 mg Tablets: Yellow, modified oval shape, biconvex, film-coated. 'GS' on one side and 'TFC' on the other.

• 0.5 mg Tablets (Alternative): Yellow, ovoid shape, biconvex, unscored film-coated. Novartis logo on one side and 'TT' on the other.

• 2 mg Tablets: Pink, round shape, biconvex, film-coated. 'GS' on one side and 'HMJ' on the other.

• 2 mg Tablets (Alternative): Pink, round shape, biconvex, unscored film-coated. Novartis logo on one side and 'LL' on the other.

Dosage and Administration:

For adult patients, the recommended dosage of Trametinib is 2 mg taken orally once daily. In pediatric patients weighing at least 26 kg (kilograms), the dosage varies based on body weight: 1 mg for 26 to 37 kg, 1.5 mg for 38 to 50 kg, and 2 mg for 51 kg or greater. There is no established dose for patients weighing less than 26 kg. Treatment duration depends on the specific condition, such as until disease progression or unacceptable toxicity for unresectable or metastatic melanoma or metastatic NSCLC. In the adjuvant melanoma setting, treatment lasts until disease recurrence or unacceptable toxicity for up to 1 year. Trametinib should be taken approximately 24 hours apart, at least 1 hour before or 2 hours after a meal. Do not take a missed dose within 12 hours of the next scheduled dose.

Indications:

Trametinib is approved for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, either as a single agent in treatment-naïve patients or in combination with Dabrafenib. It is also indicated for adjuvant treatment in melanoma patients with these mutations following complete resection. Additionally, Trametinib in combination with Dabrafenib, is approved for metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation, locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation, and unresectable or metastatic solid tumors with BRAF V600E mutation in patients aged 6 years and older who have progressed after prior treatment with no satisfactory alternatives. However, it is not indicated for colorectal cancer due to intrinsic resistance to BRAF inhibition.

Contraindications:

Trametinib has contraindications that include hypersensitivity to the drug or its components, severe renal impairment, and certain heart conditions.

Warnings and Precautions:

Trametinib, when used with Dabrafenib, is associated with cutaneous malignancies, including keratoacanthomas, in two percent of patients. Non-cutaneous malignancies occurred in one percent of patients, warranting close monitoring. Hemorrhagic events, reported in 17 percent, include gastrointestinal and intracranial hemorrhage, with fatal cases. Colitis and gastrointestinal perforation (< one percent) have been reported, requiring vigilant monitoring. Venous thromboembolic events (two percent) call for immediate medical attention, with life-threatening cases leading to Trametinib discontinuation. Cardiomyopathy (six percent) necessitates Left ventricular ejection fraction (LVEF), which is the central measure of left ventricular systolic function. Assessment before and during treatment, with dose adjustments or discontinuation based on findings.

Adverse Reactions:

• New Primary Malignancies.

• Hemorrhage.

• Colitis and Gastrointestinal Perforation.

• Venous Thromboembolism.

• Cardiomyopathy.

• Ocular Toxicities.

• Interstitial Lung Disease/Pneumonitis.

• Serious Febrile Reactions.

• Serious Skin Toxicities.

• Hyperglycemia.

Pharmacological Aspects of Trametinib

Mechanism of Action:

Trametinib functions as a reversible inhibitor for MEK1 and MEK2, key components in the extracellular signal-related kinase (ERK) pathway that regulates cellular proliferation. Specifically designed for BRAF V600 mutation-positive tumors, it hinders cell growth both in vitro and in vivo. When combined with Dabrafenib, targeting different kinases in the RAS/RAF/MEK/ERK pathway, the synergistic effect demonstrates enhanced growth inhibition and prolonged suppression of tumor growth compared to individual use. Notably, in BRAF-mutant colorectal cancer, intrinsic resistance to BRAF inhibitors is associated with EGFR-mediated MAPK pathway reactivation.

Pharmacodynamics:

Treatment with one mg and two mg of Trametinib in patients with BRAF V600 mutation-positive melanoma led to dose-dependent alterations in tumor biomarkers. These changes included the inhibition of phosphorylated ERK, suppression of Ki67 (indicating reduced cell proliferation), and elevation of p27 (indicating increased apoptosis). In a specific study involving 32 patients, the heart rate-corrected QT (QTc) prolongation potential of Trametinib was evaluated. No clinically significant QTc prolongation was observed in patients receiving Trametinib. Clinical trials involving Trametinib and Dabrafenib revealed that QTc prolongation > 500 ms (millisecond) occurred in 0.8 percent of patients, while QTc increased by > 60 ms from baseline in 3.8 percent of patients.

Pharmacokinetics:

Trametinib's pharmacokinetics were assessed in patients with solid tumors and BRAF V600 mutation-positive metastatic melanoma, revealing a median time of 1.5 hours to peak plasma concentrations after Trametinib oral administration. The mean absolute bioavailability for a single two mg dose is 72 percent, with a dose-proportional Cmax increase from 0.125 mg to 10 mg. Repeat doses of 0.125 mg to four mg show proportional increases in both Cmax and AUC (area under the curve), with inter-subject variability in AUC and Cmax at steady state. Food intake decreases AUC by 24 percent, Cmax by 70 percent, and delays Tmax by approximately 4 hours. Trametinib exhibits 97.4 percent plasma protein binding and a Vc/F of 214 L (liters). Its estimated elimination half-life is 3.9 to 4.8 days, with an apparent clearance of 4.9 L/h (liters per hour). Metabolism primarily involves deacetylation, mediated by carboxylesterases, with more than 75 percent of drug-related material in plasma as the parent compound after repeat dosing. Excretion analysis shows over 80 percent of radioactivity in feces and less than 20 percent in urine, with less than 0.1 percent as the parent compound.

Drug Interactions:

• Abrocitinib.

• Apalutamide.

• Brigatinib.

• Dabrafenib.

• Elacestrant.

• Elagolix.

• Encorafenib.

• Enzalutamide.

• Fostamatinib.

• Gilteritinib.

• Idelalisib.

• Isavuconazonium.

• Lasmiditan.

• Midostaurin.

• Pacritinib.

• Pirtobrutinib.

• Pralsetinib.

• Sarecycline.

• Tucatinib.

Use in Specific Populations:

• Pregnancy: Trametinib poses a risk of fetal harm when given to pregnant women, as indicated by its mechanism of action and animal reproduction studies. Limited data on pregnant women exposed to Trametinib makes it challenging to assess specific risks, but findings from animal studies highlight potential embryotoxic and abortifacient effects, particularly in rabbits. Pregnant women should be informed of the potential fetal risks associated with Trametinib. In the U.S. general population, the background risk of major birth defects and miscarriage is estimated to be two to four percent and 15 to 20 percent, respectively. The animal data indicates decreased fetal weights and increased post-implantation loss in rats, and in pregnant rabbits, there were variations in ossification and an elevated risk of pregnancy loss at certain doses.

• Lactation: Do not breastfeed while taking Trametinib and for four months after the last dose due to potential serious adverse effects on the infant, as there is no available data on Trametinib presence in human milk or its impact on the breastfed baby and milk production.

• Geriatrics: In the METRIC study, 27 percent of the 214 melanoma patients who received single-agent Trametinib were 65 years and older, with four percent over 75. However, the study lacked adequate geriatric representation to assess differential responses. For the COMBI-d, COMBI-v, and COMBI-AD studies with 994 melanoma patients on Trametinib plus Dabrafenib, 21 percent were 65 and older, with no observed differences in effectiveness for geriatric patients. Yet, peripheral edema and anorexia incidences increased in geriatric patients. In the NSCLC study (BRF113928), insufficient geriatric data were available. In the ATC study (BRF117019) with 93 patients, 77 percent were 65 and older, and 31 percent were over 75, but the study lacked younger adults for comparison of responses.

• Pediatrics: Trametinib, when combined with Dabrafenib, has been deemed safe and effective for pediatric patients aged six and above, weighing at least 26 kg. This conclusion is drawn from adult data and findings from the pediatric study X2101, where Parts C and D involved 48 patients (ages 1 to 17) with various tumor types. However, the safety and effectiveness of this combination for those under six years old remain undetermined. Additionally, Trametinib as a standalone treatment lacks established safety and effectiveness in pediatric patients.

Clinical Studies:

In a study for advanced skin cancer with a specific mutation (NRAS Q61R/K/L), using a high dose of a drug called Trametinib alone caused skin problems. However, when a low dose of another drug called Dabrafenib was added, it helped prevent these skin issues. The study found that combining these two drugs can reduce skin problems linked to Trametinib, but the general effectiveness was limited in this group of patients. The combination might still be useful for treating certain types of cancers sensitive to Trametinib.