Pemetrexed Kabi

Pemetrexed disodium.

Pemetrexed Kabi 100 mg and 500 mg, powder for concentrate for solution for infusion is a white to either light yellow or green yellow lyophilized powder or solid.
Pemetrexed Kabi 100 mg: Each vial contains Pemetrexed 100 mg (as Pemetrexed disodium).
Each 100 mg vial must be reconstituted with 4.2 ml of sodium chloride 9 mg/ml (0.9%) solution for injection resulting in 25 mg/ml of solution. The appropriate volume of required dose is removed from the vial and further diluted to 100 ml with sodium chloride 9 mg/ml (0.9%) solution for injection (see Instruction for use, handling and disposal under Cautions for Usage).
Pemetrexed Kabi 500 mg: Each vial contains Pemetrexed 500 mg (as Pemetrexed disodium).
Each 500 mg vial must be reconstituted with 20 ml of sodium chloride 9 mg/ml (0.9%) solution for injection resulting in 25 mg/ml of solution. The appropriate volume of required dose is removed from the vial and further diluted to 100 ml with sodium chloride 9 mg/ml (0.9%) solution for injection (see Instruction for use, handling and disposal under Cautions for Usage).
Excipients/Inactive Ingredients: Mannitol, Sodium hydroxide, Hydrochloric acid, Water for injection and Nitrogen.

Pharmacotherapeutic group: Folic acid analogues. ATC code: L01BA04.
Pharmacology: Pharmacodynamics: Pemetrexed is a multi-targeted anti-cancer antifolate agent that exerts its action by disrupting crucial folate-dependent metabolic processes essential for cell replication.
In vitro studies have shown that pemetrexed behaves as a multitargeted antifolate by inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are key folate-dependent enzymes for the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is rapidly and efficiently converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are even more potent inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.
Pharmacokinetics: The pharmacokinetic properties of pemetrexed following single-agent administration have been evaluated in 426 cancer patients with a variety of solid tumors at doses ranging from 0.2 to 838 mg/m² infused over a 10-minute period. Pemetrexed has a steady-state volume of distribution of 9 l/m². In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding was not notably affected by varying degrees of renal impairment. Pemetrexed undergoes limited hepatic metabolism. Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the administered dose being recovered unchanged in urine within the first 24 hours following administration. In vitro studies indicate that pemetrexed is actively secreted by OAT3 (organic anion transporter). Pemetrexed total systemic clearance is 91.8 ml/min and the elimination half-life from plasma is 3.5 hours in patients with normal renal function (creatinine clearance of 90 ml/min).
Between patient variability in clearance is moderate at 19.3%. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration increase proportionally with dose. The pharmacokinetics of pemetrexed are consistent over multiple treatment cycles.
The pharmacokinetic properties of pemetrexed are not influenced by concurrently administered cisplatin. Oral folic acid and intramuscular vitamin B₁₂ supplementation do not affect the pharmacokinetics of pemetrexed.
Toxicology: Preclinical safety data: Administration of pemetrexed to pregnant mice resulted in decreased foetal viability, decreased foetal weight, incomplete ossification of some skeletal structures and cleft palate.
Administration of pemetrexed to male mice resulted in reproductive toxicity characterized by reduced fertility rates and testicular atrophy. This suggests that pemetrexed may impair male fertility. Female fertility was not investigated.
Pemetrexed was not mutagenic in either the in vitro chromosome aberration test in Chinese hamster ovary cells, or the Ames test. Pemetrexed has been shown to be clastogenic in the in vivo micronucleus test in the mouse. Studies to assess the carcinogenic potential of pemetrexed have not been conducted.
Studies to assess the carcinogenicity potential of pemetrexed have not been conducted.

Malignant Pleural Mesothelioma: Pemetrexed Kabi in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma.
Non-small Cell Lung Cancer: Pemetrexed Kabi in combination with cisplatin is indicated for the first line treatment of patient with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology.
Pemetrexed Kabi is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy.
Pemetrexed Kabi is indicated as monotherapy for the second line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology.

Pemetrexed Kabi must only be administered under the supervision of a physician qualified in the use of anti-cancer chemotherapy.
Method of administration: For precautions to be taken before handling or administering Pemetrexed Kabi, see Instruction for use, handling and disposal under Cautions for Usage.
Pemetrexed Kabi should be administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle. For instructions on reconstitution and dilution of Pemetrexed Kabi before administration, see Instruction for use, handling and disposal under Cautions for Usage.
Pemetrexed in combination with cisplatin: The recommended dose of pemetrexed is 500 mg/m² of body surface area (BSA) administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m² BSA infused over two hours approximately 30 minutes after completion of the pemetrexed infusion on the first day of each 21-day cycle. Patients must receive adequate anti-emetic treatment and appropriate hydration prior to and/or after receiving cisplatin.
Pemetrexed as single agent: In patients treated for non-small cell lung cancer, the recommended dose of pemetrexed is 500 mg/m² BSA administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.
Premedication regimen: To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day prior to, on the day of, and the day after pemetrexed administration. The corticosteroid should be equivalent to 4 mg of dexamethasone administered orally twice a day (see Precautions).
To reduce toxicity, patients treated with pemetrexed must also receive vitamin supplementation (see Precautions). Patients must take oral folic acid or a multivitamin containing folic acid (350 to 1000 micrograms) on a daily basis. The most commonly used dose of oral folic acid in clinical trials was 400 micrograms. At least five doses of folic acid must be taken during the seven days preceding the first dose of pemetrexed, and dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed. Patients must also receive an intramuscular injection of vitamin B₁₂ (1000 micrograms) in the week preceding the first dose of pemetrexed and once every three cycles thereafter. Subsequently vitamin B₁₂ injections may be given on the same day as pemetrexed.
Monitoring: Patients receiving pemetrexed should be monitored before each dose with a complete blood count, including a differential white cell count (WCC) and platelet count. Prior to each chemotherapy administration blood chemistry tests should be collected to evaluate renal and hepatic function. Before the start of any cycle of chemotherapy, patients are required to have the following: absolute neutrophil count (ANC) should be ≥1500 cells/mm³ and platelets should be ≥100,000 cells/mm³.
Creatinine clearance should be ≥45 ml/min.
The total bilirubin should be ≤1.5 times upper limit of normal. Alkaline phosphatase (AP), aspartate transaminase (AST or SGOT) and alanine transaminase (ALT or SGPT) should be ≤3 times upper limit of normal. Alkaline phosphatase, AST and ALT ≤5 times upper limit of normal is acceptable if liver has tumour involvement.
Dose adjustments: Dose adjustments at the start of a subsequent cycle should be based on nadir haematologic counts or maximum non-haematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery patients should be retreated using the guidelines in Tables 1, 2 and 3, which are applicable for pemetrexed used as a single agent or in combination with cisplatin. (See Table 1.)

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If patients develop non-haematologic toxicities ≥Grade 3 (excluding neurotoxicity), treatment should be withheld until resolution to less than or equal to the patient's pre-therapy value. Treatment should be resumed according to the guidelines in Table 2. (See Table 2.)

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In the event of neurotoxicity, the recommended dose adjustment for pemetrexed and cisplatin is documented in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is observed. (See Table 3.)

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Treatment with pemetrexed should be discontinued if a patient experiences any haematologic or non-haematologic Grade 3 or 4 toxicity after 2 doses reductions or immediately if Grade 3 or 4 neurotoxicity is observed.
Elderly: In clinical studies, there has been no indication that patients 65 years of age or older are at increased risk of adverse events compared to patients younger than 65 years old. No dose reductions other than those recommended for all patients are necessary.
Children and adolescents: Pemetrexed is not recommended for use in patients under 18 years of age, due to insufficient data on safety and efficacy.
Patients with renal impairment (Standard Cockcroft and Gault formula or Glomerular Filtration Rate measured Tc99m-DPTA serum clearance method): Pemetrexed is primarily eliminated unchanged by renal excretion. In clinical studies, patients with creatinine clearance of ≥45 ml/min required no dose adjustments other than those recommended for all patients. There are insufficient data on the use of pemetrexed in patients with creatinine clearance below 45 ml/min; therefore the use of pemetrexed is not recommended (see Precautions).
Patients with hepatic impairment: No relationships between AST (SGOT), ALT (SGPT), or total bilirubin and pemetrexed pharmacokinetics were identified. However patients with hepatic impairment such as bilirubin >1.5 times the upper limit of normal and/or transaminase >3.0 times the upper limit of normal (hepatic metastases absent) or >5.0 times the upper limit of normal (hepatic metastases present) have not been specifically studied.

Reported symptoms of overdose include neutropenia, anaemia, thrombocytopenia, mucositis, sensory polyneuropathy and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia and anaemia. In addition, infection with or without fever, diarrhoea, and/or mucositis may be seen. In the event of suspected overdose, patients should be monitored with blood counts and should receive supportive therapy as necessary. The use of calcium folinate/folinic acid in the management of pemetrexed overdose should be considered.

Hypersensitivity to the pemetrexed or to any of the excipients listed in Description.
Breast-feeding must be discontinued during pemetrexed therapy (see Use in Pregnancy & Lactation).
Concomitant yellow fever vaccine (see Interactions).

Pemetrexed can suppress bone marrow function as manifested by neutropenia, thrombocytopenia and anaemia (see Adverse Reactions). Myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy and pemetrexed should not be given to patients until absolute neutrophil count (ANC) returns to ≥1,500 cells/mm³ and platelet count returns to ≥100,000 cells/mm³. Dose reductions for subsequent cycles are based on nadir ANC, platelet count and maximum non-haematologic toxicity seen from the previous cycle (see Dosage & Administration).
In the phase 3 mesothelioma trial, overall less toxicity and reduction in Grade 3/4 haematologic and non-haematologic toxicities such as neutropenia, febrile neutropenia and infection with Grade 3/4 neutropenia were reported when pre-treatment with folic acid and vitamin B₁₂ was administered. Therefore patients treated with pemetrexed must be instructed to take folic acid and vitamin B₁₂ as a prophylactic measure to reduce treatment-related toxicity (see Dosage & Administration).
Skin reactions have been reported in patients not pre-treated with a corticosteroid. Pre-treatment with dexamethasone (or equivalent) can reduce the incidence and severity of skin reactions (see Dosage & Administration).
An insufficient number of patients has been studied with creatinine clearance of below 45 ml/min. Therefore, the use of pemetrexed in patients with creatinine clearance of <45 ml/min is not recommended (see Dosage & Administration).
Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min) should avoid taking non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, and aspirin (>1.3 g daily) for 2 days before, on the day of, and 2 days following pemetrexed administration (see Interactions).
In patients with mild to moderate renal insufficiency eligible for pemetrexed therapy NSAIDs with long elimination half-lives should be interrupted for at least 5 days prior to, on the day, and at least 2 days following pemetrexed administration (see Interactions).
Serious renal events, including acute renal failure, have been reported with pemetrexed alone or in association with other chemotherapeutic agents. Many of the patients in whom these occurred had underlying risk factors for the development of renal events including dehydration or pre-existing hypertension or diabetes.
The effect of third space fluid, such as pleural effusion or ascites, on pemetrexed is not fully defined. A phase 2 study of pemetrexed in 31 solid tumour patients with stable third space fluid demonstrated no difference in pemetrexed dose normalized plasma concentrations or clearance compared to patients without third space fluid collections. Thus, drainage of third space fluid collection prior to pemetrexed treatment should be considered, but may not be necessary.
Due to the gastrointestinal toxicity of pemetrexed given in combination with cisplatin, severe dehydration has been observed. Therefore, patients should receive adequate antiemetic treatment and appropriate hydration prior to and/or after receiving treatment.
Serious cardiovascular events, including myocardial infarction and cerebrovascular events have been uncommonly reported during clinical studies with pemetrexed, usually when given in combination with another cytotoxic agent. Most of the patients in whom these events have been observed had pre-existing cardiovascular risk factors (see Adverse Reactions).
Immunodepressed status is common in cancer patients. As a result, concomitant use of live attenuated vaccines (except yellow fever) is not recommended (see Interactions).
Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are recommended. Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment.
Cases of radiation pneumonitis have been reported in patients treated with radiation either prior, during or subsequent to their pemetrexed therapy. Particular attention should be paid to these patients and caution exercised with use of other radiosensitising agents.
Cases of radiation recall have been reported in patients who received radiotherapy weeks or years previously.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. However, it has been reported that pemetrexed may cause fatigue. Therefore, patients should be cautioned against driving or operating machines if this event occurs.
Use in Pregnancy: Women of childbearing potential must use effective contraception during treatment with pemetrexed (see Use in Pregnancy & Lactation).

Contraception in males and females: Women of childbearing potential must use effective contraception during treatment with pemetrexed. Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are recommended.
Pregnancy: There are no data from the use of pemetrexed in pregnant women but pemetrexed, like other anti-metabolites, is suspected to cause serious birth defects when administered during pregnancy.
Animal studies have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). Pemetrexed should not be used during pregnancy unless clearly necessary, after a careful consideration of the needs of the mother and the risk for the foetus (see Precautions).
Breast-feeding: It is unknown whether pemetrexed is excreted in human milk and adverse effects on the sucking child cannot be excluded. Breast-feeding must be discontinued during pemetrexed therapy (see Contraindications).
Fertility: Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment.

Summary of the safety profile: The most commonly reported undesirable effects related to pemetrexed, whether used as monotherapy or in combination, are bone marrow suppression manifested as anaemia, neutropenia, leukopenia, thrombocytopenia; and gastrointestinal toxicities, manifested as anorexia, nausea, vomiting, diarrhoea, constipation, pharyngitis, mucositis, and stomatitis. Other undesirable effects include renal toxicities, increased transaminase, alopecia, fatigue, dehydration, rash, infection/sepsis and neuropathy. Rarely seen events include Stevens-Johnson syndrome and toxic epidermal necrolysis.
Tabulated list of adverse reactions: Combination with cisplatin: The table as follows provides the frequency and severity of undesirable effects that have been reported in >5% of 168 patients with mesothelioma who were randomized to receive cisplatin and pemetrexed and 163 patients with mesothelioma randomized to receive single agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B₁₂.
Adverse reactions: Frequency estimate: very common (≥1/10); common (≥1/100 and <1/10); uncommon (≥1/1,000 and <1/100); rare (≥1/10,000 and <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from available data-spontaneous reports). (See Table 4.)

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Very common ≥10%; common is normally defined as ≥1% and <10%. For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed and cisplatin.
Clinically relevant CTC toxicities that were reported in ≥1% and ≤5% (common) of the patients that were randomly assigned to receive cisplatin and pemetrexed include: Increased AST, ALT, and GGT, infection, pyrexia, febrile neutropenia, renal failure, chest pain, and urticaria.
Clinically relevant CTC toxicities that were reported in <1% (uncommon) of the patients that were randomly assigned to receive cisplatin and pemetrexed include arrhythmia and motor neuropathy.
Single agent Pemetrexed after prior chemotherapy (NSCLC): The table as follows provides the frequency and severity of undesirable effects that have been reported in >5% of 265 patients randomly assigned to receive single agent pemetrexed with folic acid and vitamin B₁₂ supplementation and 276 patients randomly assigned to receive single agent docetaxel. All patients were diagnosed with locally advanced or metastatic non-small cell lung cancer and received prior chemotherapy. (See Table 5.)

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Very common ≥10%; Common is normally defined as ≥1% and <10%. For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed.
Clinically relevant CTC toxicities that were reported in ≥1% and ≤5% (common) of the patients that were randomly assigned to pemetrexed include: sensory neuropathy, motor neuropathy, abdominal pain, increased creatinine, febrile neutropenia, infection without neutropenia, allergic reaction/hypersensitivity and erythema multiforme.
Clinically relevant CTC toxicities that were reported in <1% (uncommon) of the patients that were randomly assigned to pemetrexed include supraventricular arrhythmias.
Clinically relevant Grade 3 and Grade 4 laboratory toxicities were similar between integrated Phase 2 results from three single agent pemetrexed studies (n=164) and the Phase 3 single agent pemetrexed study described previously, with the exception of neutropenia (12.8% versus 5.3%, respectively) and alanine transaminase elevation (15.2% versus 1.9%, respectively). These differences were likely due to differences in the patient population, since the Phase 2 studies included both chemonaive and heavily pre-treated breast cancer patients with pre-existing liver metastases and/or abnormal baseline liver function tests.
Combination with Cisplatin (NSCLC): The table as follows provides the frequency and severity of undesirable effects considered possibly related to study drug that have been reported in >5% of 839 patients with NSCLC who were randomized to receive cisplatin and pemetrexed and 830 patients with NSCLC who were randomized to receive cisplatin and gemcitabine. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B₁₂. (See Table 6.)

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Very common ≥10%; common is normally defined as ≥1% and <10%. For the purpose of this table, a cut-off of 5% was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed and cisplatin.
Clinically relevant toxicity that was reported in ≥1% and ≤5% (common) of the patients that were randomly assigned to receive cisplatin and pemetrexed include: AST increase, ALT increase, infection, febrile neutropenia, renal failure, pyrexia, dehydration, conjunctivitis, and creatinine clearance decrease.
Clinically relevant toxicity that was reported in <1% (uncommon) of the patients that were randomly assigned to receive cisplatin and pemetrexed include: GGT increase, chest pain, arrhythmia, and motor neuropathy.
Clinically relevant toxicities with respect to gender were similar to the overall population in patients receiving pemetrexed plus cisplatin.
Single agent pemetrexed for NSCLC immediately following initial chemotherapy (including pemetrexed continuation therapy): The following table provides the frequency and severity of undesirable effects considered possibly related to study drug that have been reported in >5% of 800 patients randomly assigned to receive single agent pemetrexed and 402 patients randomly assigned to receive placebo in the single agent pemetrexed maintenance (JMEN: N=663) and continuation pemetrexed maintenance (PARAMOUNT; N=539) studies. All patients were diagnosed with Stage IIIB or IV NSCLC and had received prior platinum-based chemotherapy. Patients in both study arms were fully supplemented with folic acid and vitamin B₁₂. (See Table 7.)

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Clinically relevant CTC toxicity of any grade that reported in ≥1% and ≤5% (common) of the patients that were randomly assigned to pemetrexed include: febrile neutropenia, infection, decreased platelets, decreased creatinine clearance, diarrhoea, constipation, edema, alopecia, increased creatinine, pruritis/itching, fever (in the absence of neutropenia), ocular surface disease (including conjunctivitis), increased lacrimation, decreased glomerular filtration rate, dizziness and motor neuropathy.
Clinically relevant CTC toxicity that was reported in <1% (uncommon) of the patients that were randomly assigned to pemetrexed include: allergic reaction/hypersensitivity, erythema multiforme, renal failure, supraventricular arrhythmia and pulmonary embolism.
Safety was assessed for patients who were randomized to receive pemetrexed (N=800). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of pemetrexed maintenance (N=568), and compared to patients who received >6 cycles of pemetrexed (N=232). Increases in adverse reactions (all grades) were observed with longer exposure; however, no statistically significant differences in any Individual Grade 3/4/5 adverse reactions were seen.
Serious cardiovascular and cerebrovascular events, including myocardial infarction, angina pectoris, cerebrovascular accident and transient ischaemic attack have been uncommonly reported during clinical studies with pemetrexed, usually when given in combination with another cytotoxic agent. Most of the patients in whom these events have been observed had pre-existing cardiovascular risk factors.
Rare cases of hepatitis, potentially serious, have been reported during clinical studies with pemetrexed.
Pancytopenia has been uncommonly reported during clinical trials with pemetrexed.
In clinical trials, cases of colitis (including intestinal and rectal bleeding, sometimes fatal, intestinal perforation, intestinal necrosis and typhlitis) have been reported uncommonly in patients treated with pemetrexed.
In clinical trials, cases of interstitial pneumonitis with respiratory insufficiency, sometimes fatal, have been reported uncommonly in patients treated with pemetrexed.
Oesophagitis has been uncommonly reported during clinical trials with pemetrexed.
Sepsis, sometimes fatal, has been commonly reported during clinical trials with pemetrexed.
During post-marketing surveillance, the following adverse reactions have been reported in patients treated with pemetrexed: Gastrointestinal: Rare cases (<0.1%) of colitis have been reported in patients treated with pemetrexed.
General disorders and administration site conditions: Rare cases (<0.1%) of edema have been reported in patients treated with pemetrexed.
Injury, poisoning and procedural complications: Rare cases (<0.1%) of radiation recall have been reported in patients who have previously received radiotherapy.
Respiratory: Rare cases (<0.1%) of interstitial pneumonitis have been reported in patients treated with pemetrexed.
Skin: Rare cases (<0.1%) of bullous conditions have been reported including Stevens-Johnson syndrome and Toxic epidermal necrolysis which in some cases were fatal.

Pemetrexed is mainly eliminated unchanged renally by tubular secretion and to a lesser extent by glomerular filtration. Concomitant administration of nephrotoxic drugs (e.g. aminoglycoside, loop diuretics, platinum compounds, cyclosporin) could potentially result in delayed clearance of pemetrexed. This combination should be used with caution. If necessary, creatinine clearance should be closely monitored.
Concomitant administration of substances that are also tubularly secreted (e.g. probenecid, penicillin) could potentially result in delayed clearance of pemetrexed. Caution should be made when these drugs are combined 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 aspirin at higher dosage (≥1.3 g daily) may decrease pemetrexed elimination and, consequently, increase the occurrence of pemetrexed adverse events. Therefore, caution should be made when administering higher doses of NSAIDs or aspirin at higher dosage, concurrently with pemetrexed to patients with normal function (creatinine clearance ≥80 ml/min).
In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min), the concomitant administration of pemetrexed with NSAIDs (e.g. ibuprofen) or aspirin at higher dosage should be avoided for 2 days before, on the day of, and 2 days following pemetrexed administration (see Precautions).
In the absence of data regarding potential interaction with NSAIDs having longer half-lives such as piroxicam or rofecoxib, the concomitant administration with pemetrexed in patients with mild to moderate renal insufficiency should be interrupted for at least 5 days prior to, on the day, and at least 2 days following pemetrexed administration (see Precautions).
Pemetrexed undergoes limited hepatic metabolism. Results from in vitro studies with human liver microsomes indicated that pemetrexed would not be predicted to cause clinically significant inhibition of the metabolic clearance of drugs metabolised by CYP3A, CYP2D6, CYP2C9, and CYP1A2.
The pharmacokinetics of pemetrexed are not influenced by oral folic acid and intramuscular vitamin B₁₂ supplementation or by concurrently administered cisplatin. Total platinum clearance is not affected by pemetrexed administration.
Interactions common to all cytotoxics: Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation treatment is frequent. The high intra-individual variability of the coagulation status during diseases and the possibility of interaction between oral anticoagulants and anticancer chemotherapy require increased frequency of INR (International Normalised Ratio) monitoring, if it is decided to treat the patient with oral anticoagulants.
Concomitant use contraindicated: Yellow fever vaccine: risk of fatal generalised vaccinate disease (see Contraindications).
Concomitant use not recommended: Live attenuated vaccines (except yellow fever for which concomitant use is contraindicated): risk of systemic, possibly fatal disease. The risk is increased in subjects who are already immunosuppressed by their underlying disease. Use an inactivated vaccine where it exists (poliomyelitis) (see Precautions).

Incompatibilities: Pemetrexed is physically incompatible with diluents containing calcium, including lactated Ringer's injection and Ringer's injection. In the absence of compatibility studies (with other drugs and diluents), this medicinal product must not be mixed with other medicinal products.
Instruction for use, handling and disposal: 1. Use aseptic technique during the reconstitution and further dilution of pemetrexed for intravenous infusion administration.
2. Calculate the dose and the number of Pemetrexed Kabi vials needed. Each vial contains an excess of pemetrexed to facilitate delivery of label amount.
3. Pemetrexed Kabi 500 mg: Reconstitute 500-mg vials with 20 ml of sodium chloride 9 mg/ml (0.9%) solution for injection, without preservative, resulting in a solution containing 25 mg/ml pemetrexed.
Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from colorless to yellow or green-yellow without adversely affecting product quality. The pH of the reconstituted solution is between 6.6 and 7.8. Further dilution is required.
4. The appropriate volume of reconstituted pemetrexed solution must be further diluted to 100 ml with sodium chloride 9 mg/ml (0.9%) solution for injection, without preservative, and administered as an intravenous infusion over 10 minutes.
5. Pemetrexed infusion solutions prepared as directed previously are compatible with polyvinyl chloride and polyolefin lined administration sets and infusion bags.
6. Parenteral medicinal products must be inspected visually for particulate matter and discoloration prior to administration. If particulate matter or discoloration is observed, do not administer.
7. Pemetrexed solutions are for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Preparation and administration precautions: As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of pemetrexed infusion solutions. The use of gloves is recommended. If a pemetrexed solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If pemetrexed solutions contact the mucous membranes, flush thoroughly with water. Pemetrexed is not a vesicant. There is not a specific antidote for extravasation of pemetrexed. There have been few reported cases of pemetrexed extravasation, which were not assessed as serious by the investigator.
Extravasation should be managed by local standard practice as with other non-vesicants.

Unopened vial: Do not store above 30°C.
Reconstituted and infusion solutions: When prepared as directed, reconstituted and infusion solutions of Pemetrexed Kabi contain no antimicrobial preservatives. Chemical and physical in-use stability of reconstituted and infusion solutions of pemetrexed were demonstrated for 24 hours at refrigerated temperature (2-8°C). From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not be longer than 24 hours at 2°C to 8°C.

Cytotoxic Chemotherapy

L01BA04 - pemetrexed ; Belongs to the class of antimetabolites, folic acid analogues. Used in the treatment of cancer.

S