Pemetra

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PEMETRO (PEMETRO)

Composition:

Active substance: pemetrexed;

1 vial contains 100 mg or 500 mg of pemetrexed (as pemetrexed disodium);

Excipients: mannitol (E 421), sodium hydroxide, hydrochloric acid.

Dosage form. Lyophilisate for solution for infusion.

Main physicochemical properties: lyophilisate ranging from white to light yellow or greenish-yellow in color.

Pharmacotherapeutic group. Antimetabolites. Structural analogues of folic acid.

ATC code L01B A04.

Pharmacological Properties

Pharmacodynamics

Pemetrexed is an antifolate antineoplastic agent with multi-targeted activity, disrupting key folate-dependent metabolic processes essential for cellular replication.

In vitro studies have demonstrated that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are critical folate-dependent enzymes for the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed enters cells via both the reduced folate carrier and folate-binding membrane protein transport systems. Once inside the cell, pemetrexed is rapidly converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. These polyglutamate forms accumulate within cells and are more potent inhibitors of TS and GARFT than the parent compound. Polyglutamation is a time- and concentration-dependent process that occurs more extensively in tumor cells than in healthy tissues. The polyglutamate metabolites have a prolonged intracellular half-life, resulting in prolonged drug action within malignant cells.

Studies using the mesothelioma cell line MSTO-211H have demonstrated synergistic effects when pemetrexed is combined with cisplatin.

Pharmacokinetics

The pharmacokinetic properties of pemetrexed have been studied in oncology patients with various solid tumors following administration as monotherapy via 10-minute infusion at doses ranging from 0.2 to 838 mg/m². Pemetrexed has a steady volume of distribution of 9 L/m². In vitro studies show that approximately 81% of pemetrexed is protein-bound in plasma. The extent of renal impairment does not affect protein binding. Pemetrexed undergoes limited hepatic metabolism; 70–90% of the administered dose is excreted unchanged in the urine within 24 hours after administration. In vitro studies indicate that pemetrexed is actively secreted by OAT3 (organic anion transporter 3).

The total plasma clearance of pemetrexed is 91.8 mL/min, and the plasma half-life is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min).

Inter-patient variability in clearance is moderate, at 19.3%. The overall systemic exposure to pemetrexed (AUC) and the maximum plasma concentration increase proportionally with dose escalation. The pharmacokinetics of pemetrexed remain consistent over multiple treatment cycles.

Concomitant administration of cisplatin does not affect the pharmacokinetic properties of pemetrexed. Oral supplementation with folic acid and intramuscular administration of vitamin B12 do not influence the pharmacokinetics of pemetrexed.

Clinical characteristics.

Indications.

Malignant pleural mesothelioma

Pemetrexed in combination with cisplatin is indicated for the treatment of patients with malignant unresectable pleural mesothelioma.

Non-small cell lung cancer

Pemetrexed in combination with cisplatin is indicated for the treatment of patients with locally advanced or metastatic non-squamous non-small cell lung cancer in first-line chemotherapy.

Pemetrexed as monotherapy is indicated for maintenance treatment of patients with locally advanced or metastatic non-squamous non-small cell lung cancer who have not experienced disease progression following platinum-based chemotherapy.

Pemetrexed as monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-squamous non-small cell lung cancer in second-line chemotherapy.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Breastfeeding period.

Concomitant administration of yellow fever vaccine.

Safety precautions.

As with handling other potentially toxic antineoplastic agents, great care should be taken in the preparation and administration of the pemetrexed infusion solution. Gloves are recommended. If pemetrexed solution comes into contact with the skin, the affected area should be immediately washed with soap and water. If pemetrexed solution comes into contact with mucous membranes, they should be rinsed thoroughly with water. Pemetrexed is not a vesicant. There is no specific antidote to reverse hemorrhage resulting from pemetrexed administration. Several cases of hemorrhage attributed to pemetrexed have been reported, which were not considered serious by investigators. Hemorrhage should be managed according to local standards.

Interaction with other medicinal products and other forms of interaction.

Pemetrexed is primarily excreted unchanged by the kidneys via tubular secretion, and less frequently via glomerular filtration. Concomitant use of nephrotoxic drugs (e.g., aminoglycosides, loop diuretics, platinum compounds, cyclosporine) may reduce pemetrexed clearance. Such combinations should be used with caution. If necessary, creatinine clearance should be closely monitored.

Concomitant administration of substances that are also excreted via tubular secretion (e.g., probenecid, penicillin) may potentially reduce pemetrexed clearance. These medicinal products should be used cautiously in combination with pemetrexed. If necessary, creatinine clearance should be closely monitored.

In patients with normal renal function (creatinine clearance ≥ 80 mL/min), high doses of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (> 1600 mg/day), and acetylsalicylic acid (≥ 1.3 g/day) may reduce pemetrexed elimination and thus increase the frequency of adverse reactions. Therefore, high doses of NSAIDs or acetylsalicylic acid should be used with caution when administered concomitantly with pemetrexed in patients with normal renal function (creatinine clearance ≥ 80 mL/min).

In patients with mild to moderate renal impairment (creatinine clearance 45–79 mL/min), concomitant use of pemetrexed with NSAIDs (e.g., ibuprofen) or high-dose acetylsalicylic acid should be avoided for 2 days before, on the day of, and for 2 days after pemetrexed administration.

In the absence of data on potential interactions with NSAIDs having a long half-life, such as piroxicam or rofecoxib, concomitant use of these agents in patients with mild to moderate renal impairment should be discontinued 5 days before, on the day of, and for 2 days after pemetrexed administration. If concomitant use of NSAIDs is necessary, patients should be closely monitored for signs of toxicity, particularly myelosuppression and gastrointestinal toxicity.

Pemetrexed undergoes minimal metabolism in the liver. In vitro studies with human liver microsomes suggest that pemetrexed does not clinically significantly inhibit the clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

Interactions common to all cytotoxic agents

Due to the increased risk of thrombosis in cancer patients, anticoagulant therapy is frequently used. High individual variability in coagulation status during the disease and the potential for interaction between oral anticoagulants and antineoplastic chemotherapy necessitate increased frequency of monitoring of the international normalized ratio (INR) if oral anticoagulants are prescribed to such patients.

Concomitant use is contraindicated: yellow fever vaccine – due to the risk of developing fatal generalized vaccine disease.

Concomitant use is not recommended: live attenuated vaccines (except yellow fever vaccine, for which concomitant use is contraindicated) – due to the risk of systemic, possibly fatal, disease. The risk is increased if the patient already has immunosuppression due to the underlying disease. In such cases, inactivated vaccines should be used if available (e.g., poliomyelitis).

Special precautions for use.

Pemetrexed may suppress bone marrow function, manifesting as neutropenia, thrombocytopenia, anemia (or pancytopenia); myelosuppression is usually the dose-limiting toxicity. Myelosuppression in patients should be monitored throughout treatment. Pemetrexed must not be administered to patients until the absolute neutrophil count (ANC) has recovered to ≥ 1500 cells/mm³ and platelet count has recovered to ≥ 100,000 cells/mm³. Dose reduction in subsequent cycles is based on the following parameters obtained from the previous treatment: the lowest ANC value, platelet count, and the most severe non-hematological toxicities.

Lower overall toxicity and reduced incidence of grade III–IV hematological and non-hematological toxicities, such as neutropenia, febrile neutropenia, and neutropenia-associated infection, have been observed when folic acid and vitamin B12 were administered prophylactically. Therefore, patients receiving pemetrexed therapy should be informed about the necessity of taking folic acid and vitamin B12 as a preventive measure to reduce therapy-related toxicity.

Skin reactions have been observed in patients who did not receive corticosteroids. Pre-treatment with dexamethasone (or equivalent) may reduce the frequency and severity of skin reactions.

Clinical experience with pemetrexed in patients with creatinine clearance below 45 mL/min is limited; therefore, pemetrexed should not be administered to such patients.

Patients with mild to moderate renal impairment should avoid taking NSAIDs, such as ibuprofen, and acetylsalicylic acid (> 1.3 g/day) for 2 days before, on the day of, and for 2 days after pemetrexed administration.

For patients with mild to moderate renal impairment receiving pemetrexed therapy, NSAIDs with a long elimination half-life should be discontinued 5 days before, on the day of, and for 2 days after pemetrexed administration.

Severe renal disorders, including acute renal failure, have been reported both with pemetrexed monotherapy and in combination with other chemotherapeutic agents. Most patients who developed such disorders had risk factors for renal impairment, including dehydration, arterial hypertension, or diabetes. Cases of nephrogenic diabetes insipidus and renal tubular necrosis have also been reported during post-marketing studies with pemetrexed, either alone or in combination with other chemotherapeutic agents. Most of these events resolve after discontinuation of pemetrexed. Acute tubular necrosis, decreased renal function, and symptoms of nephrogenic diabetes insipidus (e.g., hypernatremia) should be monitored regularly in patients.

The effect of pemetrexed on cavity fluids such as pleural effusion and ascites has not been fully established. In a phase 2 study involving 31 patients with solid tumors and stable levels of fluid in serous cavities, no differences were observed in dose-normalized plasma concentration or pemetrexed clearance compared to patients without serous cavity fluid. Therefore, drainage should be considered before administering pemetrexed to patients with significant volumes of cavity fluid.

Severe dehydration associated with gastrointestinal toxicity of pemetrexed in combination with cisplatin has been observed. Therefore, patients should receive adequate antiemetic therapy and appropriate hydration before and/or after treatment.

Serious cardiovascular events, including myocardial infarction, and cerebrovascular events have been infrequently observed in clinical trials of pemetrexed, usually when pemetrexed was administered in combination with other cytotoxic agents. Most patients in whom such events occurred had pre-existing cardiovascular risk factors.

Most cancer patients are immunocompromised; therefore, concomitant use of live attenuated vaccines is not recommended.

Pemetrexed may cause genetic damage. Sexually active men are advised not to father a child during pemetrexed therapy and for 3 months after treatment. Contraceptive measures should be used or sexual intercourse avoided. Due to the potential of pemetrexed to cause irreversible infertility, men are advised to consider sperm preservation before starting treatment.

Women of childbearing potential must use effective contraception during pemetrexed therapy and for 6 months after completion of treatment.

Cases of radiation pneumonitis have been reported in patients who received radiotherapy before, during, or after pemetrexed therapy. These patients require special attention and caution should be exercised when using other radiosensitizing agents.

Cases of "radiation recall" have been reported in patients who received treatment in previous weeks or years.

The 100 mg vial contains less than 1 mmol of sodium (approximately 11 mg), and the 500 mg vial contains approximately 2.3 mmol of sodium (approximately 54 mg), which should be taken into account for patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Contraception in men and women

Women of childbearing potential must use effective contraception during pemetrexed therapy and for 6 months after completion of treatment. Pemetrexed may cause genetic damage. Sexually active men are advised to use effective contraception and not to father a child during treatment and for up to 3 months thereafter.

Pregnancy

There are no data on the use of pemetrexed in pregnant women, but like other antimetabolites, pemetrexed may cause severe congenital malformations when administered during pregnancy. Animal studies have shown reproductive toxicity. Pemetrexed should not be used during pregnancy except in cases of critical necessity and only after careful assessment of benefit to the mother and risk to the fetus.

Breastfeeding period

It is unknown whether pemetrexed is excreted in human milk. Adverse reactions in breastfed infants cannot be excluded. Therefore, breastfeeding must be discontinued during pemetrexed therapy.

Fertility

Due to the potential of pemetrexed to cause irreversible infertility, men are advised to consider sperm preservation before starting treatment.

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect of the drug on the ability to drive or operate machinery have been conducted. However, fatigue has been reported with pemetrexed; therefore, patients should exercise caution when driving a car or operating machinery.

Administration and Dosage

The medicinal product should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents.

Combination therapy with cisplatin

The recommended dose of Pemetrexed is 500 mg/m² body surface area (BSA) as an intravenous infusion administered over 10 minutes on day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m² BSA as an infusion administered over 2 hours, approximately 30 minutes after completion of the pemetrexed infusion, on day 1 of each 21-day cycle. Patients should receive appropriate antiemetic therapy. Adequate hydration should be provided before and/or after cisplatin administration.

Monotherapy administration

For the treatment of non-small cell lung cancer (NSCLC) after prior chemotherapy, the recommended dose of Pemetrexed is 500 mg/m² BSA as an intravenous infusion administered over 10 minutes on day 1 of each 21-day cycle.

Premedication regimen

To reduce the frequency and severity of skin reactions, corticosteroids should be administered the day before, on the day of, and the day after pemetrexed administration. The corticosteroid dose should be equivalent to 4 mg dexamethasone, taken orally twice daily.

To reduce toxicity, patients receiving pemetrexed therapy must be given folic acid supplements or multivitamins containing folic acid (350–1000 mcg) daily. At least 5 daily doses of folic acid should be taken during the 7-day period before the first dose of pemetrexed. Folic acid supplementation should continue throughout the treatment course and for 21 days after the last dose of pemetrexed. Patients should also receive intramuscular vitamin B12 injections once weekly starting one week before the first dose of pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be administered on the same day as pemetrexed administration.

Monitoring

In patients receiving pemetrexed, complete blood counts, including differential leukocyte counts and platelets, should be monitored before each administration. Biochemical blood tests to assess liver and kidney function should be performed prior to each chemotherapy cycle. Absolute neutrophil count (ANC) must be ≥1500 cells/mm³ and platelet count ≥100,000 cells/mm³ before initiating any chemotherapy cycle.

Creatinine clearance must be ≥45 mL/min.

Total bilirubin levels should not exceed 1.5 times the upper limit of normal. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels should not exceed the upper limit of normal by more than 3 times. Elevations in ALP, ALT, and AST up to 5 times the upper limit of normal are acceptable if liver metastases are present.

Dose modification

Dose adjustments prior to the start of the next cycle should be based on the lowest hematological values or the maximum non-hematological toxicity observed after the previous treatment cycle. Treatment may be withheld to allow sufficient time for recovery. After recovery, patients should resume therapy according to the recommendations in Tables 1–3, corresponding to the use of Pemetrexed as monotherapy or in combination with cisplatin.

Table 1

Dose modification of Pemetrexed (combination therapy or monotherapy) and cisplatin. Hematological toxicity

and Criteria according to the Common Toxicity Criteria (CTC) of the National Cancer Institute, USA (CTC v2.0; NCI 1998) correspond to the definition of bleeding ≥ CTC grade 2.

If a patient develops signs of nonhematological toxicity (except neurotoxicity) ≥ grade III, administration of pemetrexed should be discontinued until lower values are reached or values corresponding to the patient's baseline prior to initiation of therapy. Therapy should be continued according to the recommendations outlined in Table 2.

Table 2

Dose modification of pemetrexed (combination therapy or monotherapy) and cisplatin. Nonhematological toxicity a,b

a Grading based on the National Cancer Institute's Common Toxicity Criteria (CTC v2.0; NCI 1998).

b Excluding neurotoxicity.

Recommended dose modifications for Pemetrexed and Cisplatin in the event of neurotoxicity are provided in Table 3. In case of grade III or IV neurotoxicity, treatment should be discontinued.

Table 3

Dose modifications for Pemetrexed (combination therapy or monotherapy) and Cisplatin. Neurotoxicity

a Criteria according to the National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998).

Treatment with Pemetrexed should be discontinued if any hematological or non-hematological toxicity of grade III or IV occurs after two dose reductions, or immediately discontinued if neurotoxicity of grade III or IV occurs.

Elderly patients. During clinical studies, there was no evidence that patients aged 65 years or older had a higher risk of developing adverse reactions compared to patients under 65 years of age. No dose reduction is required other than those recommended for all patients.

Patients with renal impairment (using the standard Cockcroft-Gault formula or glomerular filtration rate (GFR) determined by plasma clearance of Tc99m-DPTA). Pemetrexed is primarily excreted unchanged by the kidneys. During clinical studies, dose adjustments were not required for patients with creatinine clearance ≥45 mL/min, apart from those recommended for all patients. The number of patients with creatinine clearance <45 mL/min was insufficient to make dosing recommendations specifically for this patient group. Therefore, the use of pemetrexed in patients with creatinine clearance <45 mL/min is not recommended.

Patients with hepatic impairment. No correlation has been established between levels of AST, ALT, total bilirubin, and the pharmacokinetics of pemetrexed. However, the effect of the drug in patients with hepatic dysfunction, such as bilirubin levels >1.5 times the upper limit of normal (ULN) or aminotransferases >3 times ULN (without liver metastases), or >5 times ULN (with liver metastases), has not been specifically studied.

Method of administration

Warnings regarding the preparation and administration of Pemetrexed are provided in the section "Special precautions for handling". Pemetrexed should be administered as an intravenous infusion over 10 minutes on day 1 of each 21-day cycle. Instructions for reconstitution and dilution of Pemetrexed are provided below.

Administration recommendations

1. Appropriate aseptic techniques should be used during reconstitution and subsequent dilution of pemetrexed for intravenous infusion.
2. Calculate the required dose and number of vials of Pemetrexed. Each vial contains an excess of pemetrexed to ensure the labeled dose can be withdrawn.
3. Contents of the 100 mg vial should be reconstituted with 4.2 mL, contents of the 500 mg vial with 20 mL of 0.9% sodium chloride injection solution (without preservatives) to obtain a solution containing 25 mg/mL of pemetrexed. Gently shake the vial until the lyophilized powder is completely dissolved. The resulting solution should be clear, colorless to yellow or greenish-yellow, and free from particulate matter. The pH of the reconstituted solution is 6.6–7.8.

FURTHER DILUTION REQUIRED

1. The required volume of the reconstituted pemetrexed solution should be further diluted to a total volume of 100 mL with 0.9% sodium chloride solution (without preservatives) and administered as an intravenous infusion over 10 minutes.
2. The pemetrexed infusion solution prepared as described above is compatible with infusion bags and administration sets made of polyvinyl chloride and polyolefin.
3. Parenteral preparations should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present, the solution must not be used.
4. Pemetrexed solution is intended for single use only. Any unused medicinal product or waste material should be disposed of in accordance with applicable regulations.

Children.

There are no relevant data on the use of Pemetrexed in pediatric practice for the treatment of malignant pleural mesothelioma and non-small cell lung cancer.

Overdose.

Symptoms. The following symptoms have been reported: neutropenia, anemia, thrombocytopenia, mucositis, sensory polyneuropathy, and rash. Expected complications of overdose include bone marrow suppression manifesting as neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and/or mucositis may occur.

Treatment. If overdose is suspected, the patient should be monitored, appropriate blood tests performed, and symptomatic therapy administered as needed. Consideration should be given to the use of calcium folinate/folic acid.

Adverse Reactions

The most commonly reported adverse reactions associated with the use of pemetrexed, either as monotherapy or in combination therapy, include bone marrow suppression manifested as anemia, neutropenia, leukopenia, and thrombocytopenia, as well as gastrointestinal toxicity presenting as anorexia, nausea, vomiting, diarrhea, constipation, pharyngitis, mucositis, and stomatitis. Other adverse reactions include renal toxicity, increased levels of aminotransferases, alopecia, asthenia, dehydration, rash, infection/sepsis, and neuropathy. Stevens–Johnson syndrome and toxic epidermal necrolysis have been reported rarely.

Table 4 lists adverse reactions regardless of causal relationship, observed during pivotal registration trials (JMCH, JMEI, JMBD, JMEN, and PARAMOUNT) and the post-marketing period, associated with the use of pemetrexed as monotherapy or in combination with cisplatin.

Adverse reactions listed below are categorized by MedDRA system organ classes. The following terminology was used to classify frequency:

Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

Table 4

aWith and without neutropenia.

bFatal in some cases.

cSometimes leads to limb necrosis.

dWith respiratory failure.

eObserved only in combination with cisplatin.

fMostly lower limbs.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after registration of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Reconstituted solution and infusion solution

If preparation recommendations are followed, the reconstituted solution and infusion solution do not contain antimicrobial preservatives.

The reconstituted solution and infusion solution maintain physicochemical stability for 24 hours at a temperature of 25 ± 2 °C. From a microbiological standpoint, the product should be used immediately. If the medicinal product is not used immediately, the responsibility for storage time and conditions prior to use lies with the user; storage time must not exceed 24 hours at a temperature not exceeding 25 °C.

Storage conditions.

The medicinal product does not require special storage conditions. Keep out of reach of children.

The prepared solution should be stored at a temperature not exceeding 25 °C for no more than 24 hours.

Incompatibilities.

Pemetrexed is incompatible with solvents containing calcium, such as Ringer's solution. Studies on pemetrexed incompatibility are lacking; therefore, it must not be mixed with any other medicinal product.

Packaging. One vial of lyophilisate per cardboard box.

Prescription status. Prescription only.

Manufacturer. Hetero Labs Limited, India.

Manufacturer's address and location of operations.

Unit-VI, TSIIC, Formulation SEZ, Sy No. 410 & 411, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.