Mekinist (Trametinib) 2 mg tablets 30 pcs - Instructions
Dosage form
Film-coated tablets, 30 pieces per package, 2 mg each.
Compound
Each film-coated tablet contains: active ingredient: trametinib dimethyl sulfoxide (in terms of trametinib) - 2.2540 mg (2.0 mg).
Excipients: mannitol - 106.95 mg, microcrystalline cellulose - 41.25 mg, hypromellose 2910 - 8.25 mg, croscarmellose sodium - 4.95 mg, sodium lauryl sulfate - 0.068 mg, colloidal silicon dioxide - 0.040 mg, magnesium stearate - 1.24 mg.
Film shell composition: Opadry yellow 03B120006 (hypromellose - 63.00%, titanium dioxide - 28.00%, macrogol-400 - 7.00%, yellow iron oxide dye - 2.00%) - 4.35/0 mg; Opadry pink YS-1-14762-A (hypromellose - 59.00%, titanium dioxide - 31.04%, macrogol-400 - 8.00%, polysorbate-80 - 1.00%, red iron oxide dye - 0, 96%) – 0/4.95 mg.
Pharmacological properties
Mechanism of action
Monotherapy
Trametinib is a highly selective allosteric inhibitor of the activation of mitogen-activated protein kinases 1 (MEK1) and 2 (MEK2), which are essential components of the ERK (extracellular signal-regulated kinase) signaling pathway. In melanoma and other cancers, this pathway is often activated by mutated forms of the BRAF gene, which in turn activates MEK and stimulates tumor cell growth. Trametinib inhibits MEK kinase activity and growth of BRAF V600 mutated melanoma and non-small cell lung cancer cell lines in vitro and demonstrates antitumor activity in xenograft models of BRAF V600 mutated melanoma. BRAF mutations occur in 2% of non-small cell lung cancers and are most common in adenocarcinomas. The BRAF V600E mutation accounts for approximately half of all mutations in this gene in non-small cell lung cancer, and there are also other BRAF V600 mutations, such as V600K, which also leads to constitutive activation of BRAF and is sensitive to BRAF inhibitors. Combination with Dabrafenib Dabrafenib is a potent, selective, ATP-competitive inhibitor of BRAF gene mutations (both wild-type and V600) and wild-type C-Raf kinases. Oncogenic mutations of the BRAF gene lead to constitutive activation of the RAS/RAF/MEK/ERK pathway and stimulation of tumor cell growth. Because the use of dabrafenib in combination with trametinib provides inhibition of two kinases in this signaling pathway, B-Raf and MEK, combination therapy provides more effective inhibition of proliferative signaling compared with monotherapy with either component. The combination of dabrafenib with trametinib was synergistic/additive in BRAF V600 mutated melanoma and non-small cell lung cancer cell lines in vitro and delayed the development of resistance in vivo in BRAF V600 mutated melanoma xenografts. Pharmacodynamics Trametinib reduces phosphorylated ERK activity in BRAF V600 mutated melanoma tumor cell lines and in xenograft models of melanoma and non-small cell lung cancer. In patients with melanoma with BRAF and NRAS gene mutations, the use of trametinib leads to dose-dependent changes in tumor biomarkers, including inhibition of phosphorylated ERK and Ki67 (a marker of tumor cell proliferation), as well as an increase in the concentration of p27 (a marker of apoptosis). Mean trametinib concentrations observed after multiple doses of 2 mg once daily exceed the preclinical target concentration over a 24-hour dosing interval, providing persistent inhibition of the MEK signaling pathway.
Pharmacokinetics
Suction
The median time to reach maximum concentration (Cmax) after oral administration is 1.5 hours. The average absolute bioavailability of trametinib after a single dose of 2 mg tablets is 72% compared with that after intravenous administration. The increase in trametinib exposure (Cmax and area under the concentration-time curve (AUC)) after repeated use is dose-proportional. After repeated dosing of trametinib at a dose of 2 mg per day, geometric mean Cmax, AUC, and predose concentrations were 22.2 ng/mL, 370 ng×h/mL, and 12.1 ng/mL, respectively, with a low Cmax to minimum concentration (1.8). Interindividual variability was low (less than 28%). Following administration of a single dose of trametinib with a high-calorie, high-fat meal, Cmax and AUC were reduced by 70% and 10%, respectively, compared with those administered in the fasted state.
Distribution
Trametinib is 97.4% bound to human plasma proteins. After intravenous administration of a microdose (5 μg), the volume of distribution of trametinib is 1060 L.
Metabolism
Based on in vitro and in vivo data, trametinib is metabolized predominantly through deacetylation alone or deacetylation with monooxidation. The deacytylated metabolite is further metabolized through glucuronidation. Deacetylation is mediated by carboxylesterases (i.e., carboxylesterase 1b, 1c and 2), and can also be mediated by other hydrolytic isoenzymes.
Removal
Trametinib accumulates with a mean accumulation ratio of 6.0 when administered multiple times daily at a dose of 2 mg once daily. The mean terminal half-life is 127 hours (5.3 days) after a single dose. Equilibrium concentration is achieved by day 15. Plasma clearance of trametinib is 3.21 l/h. Following oral administration of a single dose of [14C]-labeled trametinib solution, the total dose excreted after a 10-day collection period is low (<50%) due to its long half-life. Metabolic products of trametinib are eliminated primarily through the intestine (>80% of radioactivity found in feces) and to a small extent by the kidneys (<19%). The parent compound accounted for less than 0.1% of the renally excreted dose. Combination with dabrafenib Repeated administration of dabrafenib 150 mg twice daily concomitantly with trametinib 2 mg once daily increased dabrafenib Cmax and AUC by 16% and 23%, respectively. Based on population pharmacokinetic analysis, a slight decrease in the bioavailability of trametinib was calculated, corresponding to a 12% decrease in AUC. These changes in Cmax and AUC are not clinically significant.
Pharmacokinetics in special cases
Children
The use of trametinib in patients under 18 years of age has not been studied.
Elderly patients
According to population pharmacokinetic analysis, age does not have a significant effect on the pharmacokinetics of trametinib.
Gender/body weight
According to population pharmacokinetic analysis, the elimination of trametinib after oral administration does not depend on the gender and body weight of the patient. Although exposure to trametinib in patients with low body weight is higher than in patients with higher body weight, these differences are not clinically significant.
Race/Ethnicity
There are insufficient data to assess the effect of race on the pharmacokinetics of trametinib.
Patients with impaired renal function
A clinically significant effect of renal impairment on the pharmacokinetics of trametinib is unlikely due to the limited involvement of the kidneys in the elimination of trametinib. The pharmacokinetics of trametinib were described in clinical studies using a population-based analysis in 223 patients with mild renal impairment and 35 patients with moderate renal impairment. Renal impairment did not influence trametinib exposure (<6% in both groups). There are no data on pharmacokinetics in patients with severe renal impairment.
Patients with liver dysfunction
The pharmacokinetics of trametinib were described in clinical studies using a population-based analysis in 64 patients with mild hepatic impairment (NCI classification). In these patients, the clearance of trametinib after oral administration was not significantly different from the clearance of trametinib in subjects with normal liver function. There are no pharmacokinetic data available in patients with moderate to severe hepatic impairment.
Indications for use
- Unresectable or metastatic melanoma.
Mekinist®, alone and in combination with dabrafenib, is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
Mekinist® is not effective as monotherapy in patients who have progressed on prior BRAF inhibitor therapy.
- Adjuvant therapy for melanoma
Mekinist® in combination with dabrafenib is indicated for adjuvant therapy in patients after total resection of stage III melanoma with a BRAF V600 mutation.
- Advanced non-small cell lung cancer
Mekinist® in combination with dabrafenib is indicated for the treatment of patients with advanced non-small cell lung cancer with a BRAF V600 mutation.
Directions for use and doses
Inside. The drug is used in a dosage of 2 mg 1 time per day one hour before meals or two hours after meals, washed down with plenty of water. If you miss a dose of the drug, you should not take it if there are less than 12 hours left before the next dose. Treatment with Mekinist should be continued until disease progression or signs of unacceptable toxicity develop.
Contraindications
Pregnancy and breastfeeding period. Children under 18 years of age. Retinal vein occlusion (RVO). Hypersensitivity to trametinib or other components of the drug.
Carefully
Mekinist® should be used with caution in patients with severe renal impairment, moderate to severe hepatic impairment, as well as diseases that may be accompanied by impaired left ventricular function.
Use during pregnancy and breastfeeding
The use of trametinib is contraindicated during pregnancy and breastfeeding.
Adverse reactions
Infectious and parasitic diseases: often - folliculitis, paronychia, infection of the deep layers of the skin and subcutaneous tissue (cellulitis), pustular rash.
Disorders of the blood and lymphatic system: often - anemia.
Immune system disorders: uncommon - hypersensitivity. May present with symptoms such as fever, rash, elevated liver function tests, and visual disturbances.
Metabolic and nutritional disorders: often - dehydration.
Visual disturbances: often - blurred vision, periorbital edema, blurred vision; Uncommon: chorioretinopathy, retinal vein occlusion, papilledema, retinal detachment.
Cardiac disorders: often - left ventricular dysfunction, decreased ejection fraction; infrequently - heart failure.
Vascular disorders: very often - increased blood pressure; often - lymphedema.
Disorders of the respiratory system, chest and mediastinal organs: often - nosebleeds; uncommon - pneumonitis, interstitial lung disease.
Gastrointestinal disorders: very often - diarrhea, nausea, vomiting, constipation, abdominal pain, dry mouth; often - stomatitis.
Disorders of the liver and biliary tract: often - increased activity of aspartate aminotransferase, increased activity of alanine aminotransferase, increased activity of alkaline phosphatase.
Disorders of the skin and subcutaneous tissues: very often - rash, acneiform dermatitis, dry skin, itching, alopecia; often - peeling of the skin, erythema, palmoplantar erythrodysesthesia, cracks in the skin.
Musculoskeletal and connective tissue disorders: often - increased creatine phosphokinase activity; infrequently - rhabdomyolysis.
General disorders and disorders at the injection site: very often - fatigue, peripheral edema, hyperthermia; often - swelling of the face, inflammation of the mucous membranes, asthenia.
Post-marketing surveillance data are not available.
Overdose
Symptoms and signs
In clinical studies, there were no cases of use of the drug Mekinist® in doses exceeding 4 mg 1 time per day. Clinical studies examined the use of trametinib orally at a dose of up to 4 mg once daily and a loading dose of 10 mg once daily for 2 consecutive days.
Treatment
Further treatment should be carried out in accordance with clinical manifestations or recommendations of the national poison control center. There is no specific treatment for trametinib overdose. If necessary, maintenance treatment should be carried out with appropriate monitoring of the condition. Hemodialysis does not increase elimination due to the high binding of trametinib to plasma proteins.
Drug interactions
Because trametinib is metabolized primarily through deacetylation, likely mediated by hydrolytic esterase enzymes, it is unlikely that other drugs affect its pharmacokinetics through metabolic interactions. Concomitant use of inducers of the CYP3A4 isoenzyme did not affect the exposure of trametinib with repeated use (see section "Pharmacokinetics").
Based on data obtained in vitro and in vivo, trametinib does not significantly affect the pharmacokinetics of other drugs through interactions with cytochrome isoenzymes or transporters (see section "Pharmacokinetics").
Effect of trametinib on drug metabolizing enzymes and transporters
Data obtained in vitro and in vivo indicate that trametinib does not affect the pharmacokinetics of other drugs. Based on the results of in vitro studies, trametinib is not an inhibitor of the isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2D6 and CYP3A4. Trametinib was found to be an in vitro inhibitor of the CYP2C8, CYP2C9 and CYP2C19 isoenzymes, an inducer of the CYP3A4 isoenzyme and an inhibitor of the OATP1B1, OATP1B3, P-gp and BCRP transporters. However, based on the low clinical significance of trametinib systemic exposure (0.04 µmol/L) relative to in vitro inhibition or induction (>0.34 µmol/L), trametinib is not considered to be an inhibitor of these transporter enzymes in vivo. Repeated administration of trametinib 2 mg once daily had no effect on the Cmax and AUC of dabrafenib, a substrate for CYP2C8 or CYP3A4, after a single dose.
Effect of other drugs on trametinib
In vitro and in vivo data indicate that other drugs do not affect the pharmacokinetics of trametinib. Trametinib is not a substrate for the cytochrome isoenzymes or efflux transporters P-gp and BCRP. Trametinib is deacetylated by hydrolytic enzymes, which are generally not associated with a risk of drug interactions. Following concomitant use of trametinib and dabrafenib, a CYP3A4 inducer, the Cmax and AUC of trametinib after repeated dosing were consistent with the exposure observed when administered as monotherapy, indicating that the CYP3A4 inducer does not affect trametinib exposure.
special instructions
Women of reproductive age should use effective methods of contraception during treatment and for 4 months after discontinuation of therapy.
Mekinist may reduce the effectiveness of hormonal contraceptives, so it is recommended to use alternative methods of contraception (for example, barrier methods).
Validated test to confirm the presence of the BRAF V600 gene mutation
The safety and effectiveness of Mekinist have not been evaluated in patients who test negative for the BRAF V600 mutation in melanoma.
A clinical trial in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma did not compare ionotherapy trametinib with a BRAF inhibitor. Based on a cross-over comparison study, overall survival and progression-free survival data suggest similar efficacy between trametinib and a BRAF inhibitor. However, the overall response rate was lower in patients treated with trametinib compared with the response rate in patients treated with BRAF inhibitors.
Decreased LVEF, left ventricular dysfunction
There are reports of a decrease in LVEF when using the drug Mekinist (see section "Side effects"). In clinical studies, the mean time to onset of left ventricular dysfunction and decline in LVEF was 71 days. Mekinist should be used with caution in patients with diseases that may be accompanied by impaired left ventricular function. LVEF should be assessed in all patients before starting Mekinist. It is recommended to carry out periodic monitoring for 8 weeks after the start of treatment, depending on the clinical situation. LVEF should continue to be assessed during treatment depending on the clinical situation (see section "Dosage and Administration").
Arterial hypertension
When using the drug Mekinist in patients with or without pre-existing arterial hypertension, episodes of increased blood pressure were observed (see section "Side effects"). Blood pressure should be measured at baseline and monitored during treatment with Mekinist, and hypertension should be controlled with standard therapy as needed.
Interstitial lung disease (ILD)/pneumonitis
In the phase 3 study, 2.4% of patients treated with Mekinist developed IPD or pneumonia; all five patients required hospitalization. The median time to first onset of IPD or pneumonitis was 160 days (range: 60 to 172 days).
Mekinist should be avoided in patients with suspected IPD or pneumonitis, including patients who have new or worsening pulmonary symptoms and abnormalities, including cough, dyspnea, hypoxia, pleural effusion or infiltrates, until clinical examination. In patients diagnosed with ILD or treatment-related pneumonitis, treatment with Mekinist should be completely discontinued (see sections "Dosage and Administration" and "Side Effects").
Bleeding
Bleeding complications, including cases of major bleeding (defined as symptomatic bleeding in a critical area or organ), have been observed in patients taking Mekinist. The likelihood of these events occurring in patients with brain metastases or low platelet counts (<100,000) has not been determined because patients with such conditions were excluded from clinical studies. The risk of bleeding may increase when antiplatelet or anticoagulant therapy is administered concomitantly. If bleeding occurs, patients should be treated as clinically indicated (see Adverse Reactions section).
Rhabdomyolysis
Cases of rhabdomyolysis have been described in patients taking Mekinist. In some cases, patients were able to continue taking Mekinist. In more severe cases, hospitalization, interruption or complete cessation of use of the drug Mekinist was required. Signs and symptoms of rhabdomyolysis should prompt appropriate clinical evaluation and appropriate treatment (see section "Side effects").
Visual impairment
Visual disturbances, including chorioretinopathy or central serous retinopathy (CSR) and RVO, have been observed with the use of Mekinist. In clinical studies of Mekinist, symptoms such as blurred vision, decreased visual acuity, and other reactions were reported (see section "Side Effects").
Mekinist is not recommended for use in patients with RVO or risk of developing RVO.
At initial level and during treatment with Mekinist, a thorough ophthalmological examination should be carried out if clinically necessary. If the patient reports any visual disturbances that have occurred during treatment with Mekinist, an additional ophthalmological examination should be performed. If retinal disorders are detected, treatment with Mekinist should be immediately interrupted and contact a specialist in retinal diseases. When diagnosing CSR, you should adhere to the dose adjustment scheme indicated in Table 4 (intolerable adverse reactions) (see section “Method of administration and dosage”). In patients with RVO, treatment with Mekinist should be completely discontinued.
Rash
In clinical studies of Mekinist, rash was observed in approximately 60% of patients (see section "Side Effects"). In most cases, the rash was grade 1 or 2 and did not require treatment interruption or dose reduction. Instructions for the treatment of rash presented in Table 3 were used during clinical trials of the drug Mekinist (see section “Method of administration and dosage”).
Liver disorders
In clinical studies using the drug Mekinist, adverse reactions from the liver were noted. For patients receiving treatment with Mekinist, it is recommended that liver function be monitored every 4 weeks for 6 months after starting treatment with Mekinist. Subsequently, monitoring of liver function can be continued in accordance with clinical indications (see section "Side effects").
Patients with liver dysfunction
Since biotransformation and biliary excretion is the main route of elimination of trametinib, the use of Mekinist should be done with caution in patients with moderate or severe hepatic impairment (see sections "Dosage and Administration" and "Pharmacokinetics").
Impact on the ability to drive vehicles and machinery
Studies on the effect of trametinib on the ability to drive vehicles or operate machines have not been conducted. The pharmacological properties of trametinib indicate the absence of any negative impact on this type of activity. When assessing the ability to perform activities requiring rapid decision making, special motor and cognitive skills, it is necessary to take into account the general condition of the patient and the adverse reaction profile of trametinib.
Use in childhood
The use of the drug in children and adolescents under 18 years of age is contraindicated.
For impaired renal function
Patients with mild or moderate renal impairment do not require dose adjustment. In mild to moderate renal impairment, the effect on the pharmacokinetics of trametinib is negligible.
Mekinist should be used with caution in patients with severe renal impairment. There are no data on the use of Mekinist in patients with severe renal impairment; therefore, the potential need for adjustment of the initial dose cannot be established.
For liver dysfunction
Patients with mild liver dysfunction do not require dose adjustment. Based on a population pharmacokinetic analysis, the oral clearance of trametinib and, therefore, its exposure did not differ significantly between patients with mild hepatic impairment and patients with normal hepatic function (see section "Pharmacokinetics").
There are no clinical data on the use of Mekinist in patients with moderate to severe liver dysfunction; therefore, the potential need for initial dose adjustment cannot be determined. Mekinist should be used with caution in patients with moderate to severe liver dysfunction.
Use in old age
Patients over 65 years of age do not require dose adjustment.
Conditions for dispensing from pharmacies
The drug is available with a prescription.
Storage conditions and periods
The drug should be stored in a place protected from light and moisture, out of reach of children, at a temperature of 2 to 8 ° C. Do not freeze. Shelf life: 18 months.
Do not use after the expiration date stated on the package.
Release form, composition and packaging
The tablets are yellow, oval, biconvex, film-coated, debossed with “GS” on one side and “TFC” on the other.
One tablet contains:
active substance: trametinib dimethyl sulfoxide - 0.5635 mg, which corresponds to the content of trametinib - 0.5 mg.
excipients: mannitol - 95.47 mg, microcrystalline cellulose - 36.25 mg, hypromellose 2910 - 7.25 mg, croscarmellose sodium - 4.35 mg, sodium lauryl sulfate - 0.017 mg, colloidal silicon dioxide - 0.01 mg, magnesium stearate - 1.09 mg;
shell composition: opadry yellow 03B120006 - 4.35 mg (hypromellose - 63%, titanium dioxide - 28%, macrogol-400 - 7%, iron dye yellow oxide - 2%).
The total weight of the dosage unit is 149.35 mg.
7 pcs. — polyethylene bottles (1) — cardboard packs. 30 pcs. — polyethylene bottles (1) — cardboard packs.
White, round, biconvex, film-coated tablets, debossed with “GS” on one side and “LHE” on the other.
One tablet contains:
active substance: trametinib dimethyl sulfoxide - 1.1270 mg, which corresponds to the content of trametinib - 1 mg;
excipients: mannitol - 101.51 mg, microcrystalline cellulose - 36.75 mg, hypromellose 2910 - 7.75 mg, croscarmellose sodium - 4.65 mg, sodium lauryl sulfate - 0.034 mg, colloidal silicon dioxide - 0.02 mg, magnesium stearate - 1.16 mg;
shell composition: opadry white OY-S-28876 - 4.65 mg (hypromellose - 63%, titanium dioxide - 30%, macrogol-400 - 7%).
The total weight of the dosage unit is 159.65 mg.
7 pcs. — polyethylene bottles (1) — cardboard packs. 30 pcs. — polyethylene bottles (1) — cardboard packs.
The tablets are pink, round, biconvex, film-coated, debossed with “GS” on one side and “HMJ” on the other.
One tablet contains:
active substance: trametinib dimethyl sulfoxide - 2.2540 mg, which corresponds to the content of trametinib - 2 mg;
excipients: mannitol - 106.95 mg, microcrystalline cellulose - 41.25 mg, hypromellose 2910 - 8.25 mg, croscarmellose sodium - 4.95 mg, sodium lauryl sulfate - 0.068 mg, colloidal silicon dioxide - 0.04 mg, magnesium stearate - 1.24 mg;
shell composition: opadry pink YS-1-14762-A - 4.95 mg (hypromellose - 59%, titanium dioxide - 31.04%, macrogol-400 - 8%, polysorbate-80 - 1%, red iron oxide dye - 0.06%).
The total weight of the dosage unit is 169.95 mg.
7 pcs. — polyethylene bottles (1) — cardboard packs. 30 pcs. — polyethylene bottles (1) — cardboard packs.
Contraindications
- pregnancy and breastfeeding;
- children under 18 years of age;
— retinal vein occlusion (RVO) or the risk of developing RVO;
- hypersensitivity to trametinib or other components of the drug.
Carefully
Mekinist should be used with caution in patients with severe renal impairment, moderate to severe hepatic impairment, and diseases that may be accompanied by impaired left ventricular function.
