Pemetrexed

Pemetrexed is a multitargeted antifolate antimetabolite. Cells take it up through folate transport systems and convert it to long-lived polyglutamate forms that block several folate-dependent enzymes, so dividing cells cannot make the building blocks of DNA and RNA. Because normal, rapidly dividing tissues such as bone marrow and the lining of the gut are affected as well, treatment is accompanied by folic acid and vitamin B12 supplementation to reduce toxicity.

Mechanism of Action

• Multitargeted enzyme inhibition: in vitro, pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT). These folate-dependent enzymes are central to the de novo synthesis of thymidine and purine nucleotides.
• Cell entry: pemetrexed is carried into cells by both the reduced folate carrier and membrane folate-binding protein transport systems.
• Polyglutamation: inside the cell, folylpolyglutamate synthetase rapidly converts pemetrexed to polyglutamate forms. These are retained in the cell, are even more potent inhibitors of TS and GARFT, and have a longer intracellular half-life, which prolongs the effect in malignant cells. The process depends on time and concentration and occurs in tumour cells and, to a lesser extent, in normal tissues.
• Combination with cisplatin: in laboratory studies pemetrexed inhibited the growth of mesothelioma cell lines and acted synergistically with cisplatin.
• Neutrophil nadir: population analyses show that the depth of the neutrophil nadir correlates with pemetrexed exposure and with folic acid and vitamin B12 supplementation, and that it does not worsen cumulatively over successive cycles.
• Evidence in mesothelioma: in the EMPHACIS phase 3 study of chemotherapy-naïve patients, pemetrexed plus cisplatin gave a median survival 2.8 months longer than cisplatin alone.

Pharmacokinetics

• Distribution: steady-state volume of distribution about 9 L/m²; about 81% bound to plasma proteins, which is not notably changed by varying degrees of renal impairment.
• Dose proportionality: total exposure (AUC) and peak concentration rise in proportion to dose. This was studied at 0.2 to 838 mg/m² as 10-minute infusions in 426 patients with solid tumours, and the kinetics were consistent over multiple cycles.
• Metabolism: limited hepatic metabolism.
• Elimination: mainly renal. 70–90% of a dose is recovered unchanged in urine within 24 hours, mostly through tubular secretion (active secretion by the transporter OAT3) and to a lesser extent glomerular filtration. In patients with normal renal function (creatinine clearance 90 mL/min), total systemic clearance is 91.8 mL/min and the plasma elimination half-life is 3.5 hours; between-patient variability in clearance is moderate (19.3%).
• Renal impairment: as renal function declines, clearance falls and exposure rises.
• Hepatic function: no relationship was found between AST, ALT or total bilirubin and pemetrexed pharmacokinetics.
• Co-treatment: concurrent cisplatin does not change the pharmacokinetics of pemetrexed, and neither oral folic acid nor intramuscular vitamin B12 supplementation affects them.

Alimta and Armisarte have the same indications.

• Malignant pleural mesothelioma: in combination with cisplatin, for chemotherapy-naïve patients with unresectable malignant pleural mesothelioma.
• Non-small cell lung cancer, first line: in combination with cisplatin, for locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology.
• Non-small cell lung cancer, maintenance: as monotherapy, for locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately after platinum-based chemotherapy.
• Non-small cell lung cancer, second line: as monotherapy, for locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology.

• Hypersensitivity to pemetrexed or to any of the excipients.
• Breastfeeding.
• Concomitant yellow fever vaccine.

The most common effects of pemetrexed, alone or with cisplatin, are bone marrow suppression (anaemia, neutropenia, leukopenia, thrombocytopenia) and gastrointestinal toxicity (anorexia, nausea, vomiting, diarrhoea, constipation, pharyngitis, mucositis, stomatitis). Others include renal toxicity, raised aminotransferases, alopecia, fatigue, dehydration, rash, infection or sepsis and neuropathy. The frequencies below come from the SmPC table, which covers all grades regardless of cause, from the pivotal studies and the post-marketing period.

Very common (≥1/10): infection (with or without neutropenia), pharyngitis, neutropenia, leukopenia, decreased haemoglobin, stomatitis, anorexia, vomiting, diarrhoea, nausea, rash, skin exfoliation, decreased creatinine clearance, increased blood creatinine (seen only with cisplatin), fatigue.

Common (≥1/100 to <1/10): sepsis (in some cases fatal), febrile neutropenia, decreased platelet count, hypersensitivity, dehydration, taste disorder, peripheral motor neuropathy, peripheral sensory neuropathy, dizziness, conjunctivitis, dry eye, increased lacrimation, keratoconjunctivitis sicca, eyelid oedema, ocular surface disease, cardiac failure, arrhythmia, dyspepsia, constipation, abdominal pain, increased alanine and aspartate aminotransferase, hyperpigmentation, pruritus, erythema multiforme, alopecia, urticaria, renal failure, decreased glomerular filtration rate, pyrexia, pain, oedema, chest pain, mucosal inflammation, increased gamma-glutamyltransferase.

Uncommon (≥1/1,000 to <1/100): pancytopenia, cerebrovascular accident, ischaemic stroke, intracranial haemorrhage, angina, myocardial infarction, coronary artery disease, supraventricular arrhythmia, peripheral ischaemia (sometimes leading to extremity necrosis), pulmonary embolism, interstitial pneumonitis (in some cases fatal, with respiratory failure), rectal haemorrhage, gastrointestinal haemorrhage, intestinal perforation, oesophagitis, colitis (seen only with cisplatin), radiation oesophagitis, radiation pneumonitis.

Rare (≥1/10,000 to <1/1,000): autoimmune haemolytic anaemia, anaphylactic shock, hepatitis, erythema, radiation recall phenomenon.

Very rare (<1/10,000): dermohypodermitis, Stevens-Johnson syndrome and toxic epidermal necrolysis (in some cases fatal), pemphigoid, bullous dermatitis, epidermolysis bullosa acquisita, erythematous oedema (mainly of the lower limbs), pseudocellulitis, dermatitis, eczema, prurigo.

Not known: nephrogenic diabetes insipidus, renal tubular necrosis.

Important serious reactions are febrile neutropenia and sepsis, acute renal failure, nephrogenic diabetes insipidus and renal tubular necrosis, interstitial pneumonitis, cardiac and cerebrovascular events, intestinal perforation and severe skin reactions.

Pemetrexed is cleared mainly unchanged by the kidneys, through tubular secretion and to a lesser extent glomerular filtration, so the interactions that matter are those that slow renal clearance.

• Nephrotoxic medicines (for example aminoglycosides, loop diuretics, platinum compounds, ciclosporin): may delay pemetrexed clearance. Use with caution and, if necessary, monitor creatinine clearance closely.
• OAT3 inhibitors (probenecid, penicillin, proton pump inhibitors): delay pemetrexed clearance; use with caution.
• NSAIDs and acetylsalicylic acid, normal renal function (creatinine clearance above 80 mL/min): high doses of NSAIDs (such as ibuprofen above 1,600 mg/day) and acetylsalicylic acid above 1.3 g daily may reduce pemetrexed elimination and increase its adverse reactions, so take care.
• NSAIDs and acetylsalicylic acid, mild to moderate renal impairment (creatinine clearance 45–79 mL/min): avoid NSAIDs such as ibuprofen, and higher-dose acetylsalicylic acid, for 2 days before, on the day of and 2 days after pemetrexed. NSAIDs with a long half-life, such as piroxicam, should be interrupted for at least 5 days before, on the day of and at least 2 days after pemetrexed.
• Yellow fever vaccine: contraindicated with pemetrexed. Other live attenuated vaccines are not recommended, because patients with cancer are often immunosuppressed.
• Cisplatin, folic acid and vitamin B12: none of them changes the pharmacokinetics of pemetrexed. Folic acid and vitamin B12 are required premedication, not interacting medicines (see Administration and Dosage).

Treatment must be given only under the supervision of a physician qualified in the use of anti-cancer chemotherapy. Pemetrexed is for intravenous use only, as an infusion over 10 minutes on the first day of each 21-day cycle. The concentrate (Armisarte) and the reconstituted powder (Alimta) are diluted before use; precautions for handling and instructions for dilution are in section 6.6 of the SmPC.

Recommended Dose

• With cisplatin (mesothelioma; first-line lung cancer): pemetrexed 500 mg/m² of body surface area as an intravenous infusion over 10 minutes on day 1 of each 21-day cycle. Cisplatin 75 mg/m² is infused over two hours, starting about 30 minutes after the pemetrexed infusion ends, on day 1 of each cycle. Adequate antiemetic treatment and hydration are needed before and/or after cisplatin (see the cisplatin SmPC).
• As a single agent (lung cancer after prior chemotherapy): pemetrexed 500 mg/m² over 10 minutes on day 1 of each 21-day cycle.

Premedication and Vitamin Supplementation

• Corticosteroid: given the day before, on the day of and the day after pemetrexed, equivalent to 4 mg of dexamethasone by mouth twice a day, to reduce the incidence and severity of skin reactions.
• Folic acid: oral folic acid, or a multivitamin containing folic acid (350 to 1,000 micrograms), every day. At least five doses must be taken in the seven days before the first pemetrexed dose, and daily dosing continues through the whole course and for 21 days after the last dose.
• Vitamin B12: an intramuscular injection of 1,000 micrograms in the week before the first pemetrexed dose and then once every three cycles. Later injections may be given on the same day as pemetrexed.

Monitoring Before Each Cycle

• A complete blood count with differential white cell count and platelet count before each dose, and blood chemistry for renal and hepatic function before each chemotherapy administration.
• Before the start of any cycle: absolute neutrophil count (ANC) of at least 1,500 cells/mm³, platelets of at least 100,000 cells/mm³ and creatinine clearance of at least 45 mL/min.
• Total bilirubin no more than 1.5 times the upper limit of normal (ULN); alkaline phosphatase, AST and ALT no more than 3 times ULN, or no more than 5 times ULN if the liver is involved by tumour.

Dose Adjustments

Doses at the start of each new cycle are based on the lowest (nadir) blood counts or the worst non-haematological toxicity of the previous cycle. Treatment may be delayed to allow recovery. The reductions below apply to pemetrexed alone or with cisplatin.

• Haematological toxicity: nadir ANC below 500/mm³ with nadir platelets of at least 50,000/mm³, or nadir platelets below 50,000/mm³ whatever the ANC: 75% of the previous dose of both pemetrexed and cisplatin. Nadir platelets below 50,000/mm³ with bleeding (grade 2 or higher), whatever the ANC: 50% of the previous dose of both.
• Non-haematological toxicity of grade 3 or higher (excluding neurotoxicity): withhold pemetrexed until the patient is back to the pre-treatment value or better, then resume. Any grade 3 or 4 toxicity except mucositis, and any diarrhoea needing hospital admission (any grade) or grade 3 or 4 diarrhoea: 75% of the previous dose of both medicines. Grade 3 or 4 mucositis: 50% of the previous pemetrexed dose and 100% of the cisplatin dose.
• Neurotoxicity: grade 0–1, 100% of both doses; grade 2, 100% of pemetrexed and 50% of cisplatin; grade 3 or 4, stop treatment.
• Stopping rule: stop pemetrexed if a patient has any grade 3 or 4 haematological or non-haematological toxicity after two dose reductions, or immediately for grade 3 or 4 neurotoxicity.

Special Populations

• Elderly: there is no indication that patients aged 65 or over are at higher risk of adverse reactions; no dose reductions other than those for all patients.
• Renal impairment: patients with creatinine clearance of at least 45 mL/min need no adjustment beyond those for all patients. Data are insufficient below 45 mL/min, so use is not recommended.
• Hepatic impairment: no relationship between AST, ALT or total bilirubin and pemetrexed pharmacokinetics was found. Patients with bilirubin above 1.5 times ULN and/or aminotransferases above 3.0 times ULN (no liver metastases) or above 5.0 times ULN (liver metastases present) have not been specifically studied.
• Children and adolescents: there is no relevant use of pemetrexed in children and adolescents in malignant pleural mesothelioma or non-small cell lung cancer. The European Medicines Agency has waived paediatric studies for the authorised indications.

Myelosuppression

Pemetrexed can suppress bone marrow function, causing neutropenia, thrombocytopenia and anaemia (or pancytopenia), and myelosuppression is usually the dose-limiting toxicity. Blood counts are monitored during treatment, and pemetrexed is not given until the neutrophil count is back to at least 1,500 cells/mm³ and platelets to at least 100,000 cells/mm³. Later doses are reduced according to the nadir counts and the worst non-haematological toxicity of the previous cycle.

Folic Acid and Vitamin B12

Pre-treatment with folic acid and vitamin B12 was associated with less toxicity and with fewer grade 3 or 4 haematological and non-haematological toxicities, such as neutropenia, febrile neutropenia and infection with grade 3 or 4 neutropenia. Every patient must therefore be instructed to take both vitamins as a preventive measure (see Administration and Dosage).

Skin Reactions

Skin reactions were reported in patients who had not been pre-treated with a corticosteroid. Pre-treatment with dexamethasone or an equivalent reduces their incidence and severity.

Kidney Function

• Use is not recommended when creatinine clearance is below 45 mL/min, because too few such patients have been studied.
• With mild to moderate renal insufficiency (creatinine clearance 45–79 mL/min), avoid NSAIDs such as ibuprofen and acetylsalicylic acid above 1.3 g daily for 2 days before, on the day of and 2 days after pemetrexed. NSAIDs with a long half-life should be interrupted for at least 5 days before, on the day of and at least 2 days after.
• Serious kidney events, including acute renal failure, have been reported with pemetrexed alone or with other chemotherapy. Many of these patients had risk factors such as dehydration, pre-existing hypertension or diabetes. Nephrogenic diabetes insipidus and renal tubular necrosis have been reported after marketing, and most cases resolved when pemetrexed was stopped. Patients should be monitored regularly for acute tubular necrosis, falling renal function and signs of nephrogenic diabetes insipidus, such as raised sodium in the blood (hypernatraemia).

Pleural Effusion and Ascites

The effect of fluid collections such as pleural effusion or ascites (third-space fluid) on pemetrexed is not fully defined. A phase 2 study of 31 patients with solid tumours and stable third-space fluid found no difference in dose-normalised plasma concentrations or clearance compared with patients without it. Draining the fluid before treatment should be considered but may not be necessary.

Dehydration With Cisplatin

Severe dehydration has been seen because of the gastrointestinal toxicity of pemetrexed given with cisplatin. Adequate antiemetic treatment and hydration are therefore required (see Administration and Dosage).

Further Warnings in the SmPC

The SmPC also covers serious cardiovascular and cerebrovascular events, radiation pneumonitis and radiation recall in patients who had radiotherapy before, during or after pemetrexed, and the use of live attenuated vaccines in immunosuppressed patients. The prescriber should consult the full text.

Pregnancy, Contraception, Breastfeeding and Fertility

• Contraception: pemetrexed can have genetically damaging effects. Women of childbearing potential must use effective contraception during treatment and for 6 months after it ends. Sexually mature men are advised to use effective contraception and not to father a child during treatment and for up to 3 months afterwards.
• Pregnancy: there are no data in pregnant women. Like other antimetabolites, pemetrexed is suspected to cause serious birth defects, and animal studies showed reproductive toxicity. It should not be used in pregnancy unless clearly necessary, after careful consideration of the mother’s needs and the risk to the foetus.
• Breastfeeding: it is unknown whether pemetrexed passes into human milk. Breastfeeding must be stopped during treatment, and it is a contraindication.
• Fertility: pemetrexed may cause irreversible infertility, so men are advised to seek counselling on sperm storage before starting treatment.

Sodium in Alimta

Alimta powder contains sodium: about 11 mg per 100 mg vial and about 54 mg per 500 mg vial. This matters for patients on a controlled sodium diet.

Effect on Driving

Pemetrexed has no or negligible influence on the ability to drive and use machines. Fatigue has been reported, so patients who are affected should not drive or operate machines.

• Armisarte (concentrate): store and transport refrigerated at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. It is a cold-chain product from dispatch to the hospital pharmacy.
• Alimta (powder): no special storage conditions are required.
• For storage after reconstitution or dilution, see Shelf Life.

• Armisarte, unopened vial: 18 months.
• Armisarte, after first opening: in-use stability has been shown for 7 days at 2–8 °C for the 4 mL vial (100 mg/4 mL) and for 14 days at 2–8 °C for the 20 mL, 34 mL and 40 mL vials. The rubber stopper may be punctured, and the contents withdrawn, a maximum of two times.
• Armisarte, diluted solution: chemical and physical stability in 5% glucose or 0.9% sodium chloride has been shown for 24 hours at room temperature and 7 days refrigerated. For microbiological reasons it should be used immediately; section 6.3 of the SmPC sets out the conditions if it is not.
• Alimta, unopened vial: 3 years.
• Alimta, reconstituted and infusion solutions: they contain no antimicrobial preservative. Chemical and physical stability has been shown for 24 hours refrigerated. For microbiological reasons the product should be used immediately; if it is not, storage times are the responsibility of the user and would not be longer than 24 hours at 2–8 °C.

Prescription only (Rx), for use under the supervision of a physician qualified in the use of anti-cancer chemotherapy. Pemetrexed is given as an intravenous infusion in a hospital or oncology clinic, so it is supplied to the hospital or clinic that administers it. Armisarte vials are kept and transported refrigerated at 2–8 °C (cold-chain delivery); Alimta powder needs no special storage conditions.