Alimta

Each vial of powder for concentrate for solution for infusion contains 100 mg and 500 mg of pemetrexed as pemetrexed disodium.
Reconstituted solution contains premetexed 25 mg/mL.
It also contains the following excipients: Mannitol, hydrochloric acid and sodium hydroxide.

Pharmacotherapeutic Group: Folic acid analogues. ATC Code: L01BA04.
Pharmacology: Pharmacodynamics: Pemetrexed is a multi-targeted anticancer 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 multi-targeted 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 tumour 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.
Clinical Efficacy: Mesothelioma: EMPHACIS, a multicentre, randomised, single-blind phase 3 study of Alimta plus cisplatin versus cisplatin in chemo-naive patients with malignant pleural mesothelioma, has shown that patients treated with Alimta and cisplatin had a clinically meaningful 2.8-month median survival advantage over patients receiving cisplatin alone. During the study, low-dose folic acid and vitamin B₁₂ supplementation was introduced to patient therapy to reduce toxicity. The primary analysis of this study was performed on the population of all patients randomly assigned to a treatment arm who received the study drug (randomised and treated). A subgroup analysis was performed on patients who received folic acid and vitamin B₁₂ supplementation during the entire course of study therapy (fully supplemented). The results of these analyses of efficacy are summarised in Table 1. (See Table 1.)


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A statistically significant improvement of the clinically relevant symptoms (pain and dyspnoea) associated with malignant pleural mesothelioma in the Alimta/cisplatin arm (212 patients) versus the cisplatin arm alone (218 patients) was demonstrated using the lung cancer symptom scale. Statistically significant differences in pulmonary function tests were also observed. The separation between the treatment arms was achieved by improvement in lung function in the Alimta/cisplatin arm and deterioration of lung function over time in the control arm.
There are limited data in patients with malignant pleural mesothelioma treated with Alimta alone. Alimta at a dose of 500 mg/m² was studied as a single-agent in 64 chemo-naive patients with malignant pleural mesothelioma. The overall response rate was 14.1%.
Non-Small Cell Lung Cancer (NSCLC) 2nd-Line Treatment: A multicentre, randomised, open-label phase 3 study of Alimta versus docetaxel in patients with locally advanced or metastatic NSCLC after prior chemotherapy has shown median survival times of 8.3 months for patients treated with Alimta [intent to treat population (ITT) n=283] and 7.9 months for patients treated with docetaxel (ITT n=288). An analysis of the impact of NSCLC histology on the treatment effect on overall survival was in favour of Alimta versus docetaxel for other than predominantly squamous histologies (n=399, 9.3 versus 8 months, adjusted HR=0.78; 95% CI=0.61-1, p=0.047) and was in favour of docetaxel for squamous cell carcinoma histology (n=172, 6.2 versus 7.4 months, adjusted hazard ratio (HR)=1.56; 95% CI=1.08-2.26, p=0.018). There were no clinically relevant differences observed for the safety profile of Alimta within the histology subgroups.
Limited clinical data from a separate randomized, phase 3, controlled trial, suggest that efficacy data (overall survival, progression-free survival) for pemetrexed are similar between patients previously pre-treated with docetaxel (n=41) and patients who did not receive previous docetaxel treatment (n=540). (See Table 2.)


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Non-Small Cell Lung Cancer, 1st-Line Treatment: A multicentre, randomised, open-label, phase 3 study of Alimta plus cisplatin versus gemcitabine plus cisplatin in chemonaive patients with locally advanced or metastatic (stage IIIb or IV) NSCLC showed that Alimta plus cisplatin (ITT population n=862) met its primary endpoint and showed similar clinical efficacy as gemcitabine plus cisplatin (ITT n=863) in overall survival (adjusted HR 0.94; 95% CI=0.84-1.05). All patients included in this study had an eastern cooperative oncology group (ECOG) performance status 0 or 1.
The primary efficacy analysis was based on the ITT population. Sensitivity analyses of main efficacy endpoints were also assessed on the protocol qualified (PQ) population. The efficacy analyses using PQ population are consistent with the analyses for the ITT population and support the non-inferiority of AC versus GC.
Progression free survival (PFS) and overall response rate were similar between treatment arms: Median PFS was 4.8 months for Alimta plus cisplatin versus 5.1 months for gemcitabine plus cisplatin (adjusted HR 1.04; 95% CI=0.94-1.15) and overall response rate was 30.6% (95% CI = 27.3-33.9) for Alimta plus cisplatin versus 28.2% (95% CI=25-31.4) for gemcitabine plus cisplatin. Progression free survival data were partially confirmed by an independent review (400/1725 patients were randomly selected for review).
The analysis of the impact of NSCLC histology on overall survival demonstrated clinically relevant differences in survival according to histology is shown on table 3 and figure 1. (See Table 3 and Figure 1.)


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There were no clinically relevant differences observed for the safety profile of Alimta plus cisplatin within the histology subgroups.
Patients treated with Alimta and cisplatin required fewer transfusions (16.4% vs 28.9%, p<0.001), red blood cell transfusions (16.1% vs 27.3%, p<0.001) and platelet transfusions (1.8% vs 4.5%, p=0.002). Patients also required lower administration of erythropoietin/darbopoietin (10.4% vs 18.1%, p<0.001), G-CSF/GM-CSF (3.1% vs 6.1%, p=0.004) and iron preparations (4.3% versus 7.0%, p=0.021).
Non-Small Lung Cell Cancer Maintenance Treatment: JMEN: A multicentre, randomised, double-blind, placebo-controlled phase 3 study (JMEN), compared the efficacy and safety of maintenance treatment with Alimta plus best supportive care (BSC) (n=441) with that of placebo plus BSC (n=222) in patients with locally advanced (stage IIIB) or metastatic (stage IV) NSCLC who did not progress after 4 cycles of first-line doublet therapy containing cisplatin or carboplatin in combination with gemcitabine, paclitaxel, or docetaxel. First-line doublet therapy containing Alimta was not included. All patients included in this study had an ECOG performance status 0 or 1. Patients received maintenance treatment until disease progression. Efficacy and safety were measured from the time of randomisation after completion of first-line (induction) therapy. Patients received a median of 5 cycles of maintenance treatment with Alimta and 3.5 cycles of placebo. A total of 213 patients (48.3%) completed ≥6 cycles and a total of 103 patients (23.4%) completed ≥10 cycles of treatment with Alimta.
The study met its primary endpoint and showed a statistically significant improvement in PFS in the Alimta arm over the placebo arm (n=581, independently reviewed population; median of 4 months and 2 months, respectively) (HR=0.6, 95% CI=0.49-0.73, p<0.00001). The independent review of patient scans confirmed the findings of the investigator assessment of PFS. The median OS for the overall population (n=663) was 13.4 months for the Alimta arm and 10.6 months for the placebo arm, HR=0.79 (95% CI=0.65-0.95, p=0.01192).
Consistent with other Alimta studies, a difference in efficacy according to NSCLC histology was observed in JMEN. For patients with NSCLC other than predominantly squamous cell histology (n=430, independently reviewed population) median PFS was 4.4 months for the Alimta arm and 1.8 months for the placebo arm, HR=0.47 (95% CI=0.37-0.60, p=0.00001). The median OS for patients with NSCLC other than predominantly squamous cell histology (n=481) was 15.5 months for the Alimta arm and 10.3 months for the placebo arm,  HR=0.70 (95% CI=0.56-0.88, p=0.002). Including the induction phase, the median OS for patients with NSCLC other than predominantly squamous cell histology was 18.6 months for the Alimta arm and 13.6 months for the placebo arm, HR=0.71 (95% CI=0.56-0.88, p=0.002).
The PFS and OS results in patients with squamous cell histology suggested no advantage for Alimta over placebo.
There were no clinically relevant differences observed for the safety profile of Alimta within the histology subgroups. (See Figure 2).


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Paramount: A multicenter, randomized, double-blind, placebo-controlled phase 3 study (Paramount), compared the efficacy and safety of continuation maintenance treatment with Alimta plus best supportive care (BSC) (n=359) with that of placebo plus BSC (n=180) in patients with locally advanced (stage IIIB) or metastatic (stage IV) NSCLC other than predominantly squamous cell histology which did not progress after 4 cycles of first-line doublet therapy of Alimta in combination with cisplatin. Of the 939 patients treated with Alimta plus cisplatin induction, 539 patients were randomized to maintenance treatment with pemetrexed or placebo. Of randomized patients, 44.9% had a complete/partial response and 51.9% had a response of stable disease to Alimta plus cisplatin induction. Patients randomized to maintenance treatment were required to have an ECOG performance status 0 or 1. The median time from the start of Alimta plus cisplatin induction therapy to the start of maintenance treatment was 2.96 months on both the pemetrexed arm and the placebo arm. Randomized patients received maintenance treatment until disease progression. Efficacy and safety were measured from the time of randomization after completion of first-line (induction) therapy. Patients received a median of 4 cycles of maintenance treatment with Alimta and 4 cycles of placebo. A total of 109 patients (30.4%) completed ≥ 6 cycles maintenance treatment with Alimta, representing at least 10 cycles of Alimta.
The study met its primary endpoint and showed a statistically significant improvement in PFS in the Alimta arm over the placebo arm (n=472, independently reviewed population; media of 3.9 months and 2.6 months, respectively) (HR=0.64, 95% CI=0.51-0.81, p=0.0002), the independent review of patient scans confirmed the findings of the investigator assessment of PFS. For randomized patients, as measured from the start of Alimta plus cisplatin first-line induction treatment, the median investigator-assessed PFS was 6.9 months for the Alimta arm and 5.59 months for the placebo arm (HR= 0.59, 95% CI=0.47-0.74). A preliminary survival analysis showed that the median survival on the Alimta continuation arm after induction therapy with Alimta/cisplatin (4 cycles) was 13.9 months versus 11.1 months for those on the placebo arm (HR=0.78, 95% CI=0.60-0.98, p=0.034) at the time of this preliminary survival analysis, 48% of patients were alive on the Alimta arm versus 38% on the placebo arm, with a median follow-up of 11.04 months. (See Figure 3).


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Pharmacokinetics: The pharmacokinetic properties of pemetrexed following single-agent administration have been evaluated in 426 cancer patients with a variety of solid tumours at doses ranging from 0.2-838 mg/m² infused over a 10-min 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 70-90% of the administered dose being recovered unchanged in urine within the first 24 hrs following administration. Pemetrexed total systemic clearance is 91.8 mL/min and the elimination half-life (t_1/2) from plasma is 3.5 hrs in patients with normal renal function [creatinine clearance (CrCl) of 90 mL/min]. Between patient variability in clearance is moderate at 19.3%. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (C_max) 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 vitamin B₁₂ IM supplementation do not affect the pharmacokinetics of pemetrexed.
Toxicology: Preclinical Safety Data: Administration of pemetrexed to pregnant mice resulted in decreased foetal viability and weight, incomplete ossification of some skeletal structures and cleft palate.
Administration of pemetrexed to male mice resulted in reproductive toxicity characterised by reduced fertility rates and testicular atrophy. In a study conducted in beagle dog by IV bolus injection for 9 months, testicular findings (degeneration/necrosis of the seminiferous epithelium) have been observed. 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.

Malignant Pleural Mesothelioma: Treatment of chemotherapy-naive patients with unresectable malignant pleural mesothelioma, in combination with cisplatin.
Non-Small Cell Lung Cancer: First-line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology (see Pharmacology: Pharmacodynamics under Actions), in combination with cisplatin.
As a 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. First-line treatment should be a platinum based with other cytotoxics chemotherapy (see Pharmacology: Pharmacodynamics under Actions).
As a single-agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy (as second line).
Alimta is not indicated for treatment of patients with squamous cell non-small cell lung cancer.

Combination Use with Cisplatin: The recommended dose of Alimta is 500 mg/m² of body surface area (BSA) administered as an IV infusion over 10 min on the 1st day of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m² BSA infused over 2 hrs approximately 30 min after completion of the pemetrexed infusion on the 1st day of each 21-day cycle.
Patients must receive adequate antiemetic treatment and appropriate hydration prior to and/or after receiving cisplatin.
Single Agent Use: Non-Small Cell Lung Cancer (NSCLC): In patients treated for NSCLC after prior chemotherapy, the recommended dose of Alimta is 500 mg/m² BSA administered as an IV infusion over 10 min on the 1st 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 dexamethasone 4 mg administered orally twice daily (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 (350-1000 mcg) on a daily basis. At least 5 doses of folic acid must be taken during the 7 days preceding the 1st 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 IM injection of vitamin B₁₂ (1000 mcg) in the week preceding the 1st dose of pemetrexed and once every 3 cycles thereafter. Subsequent 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 ≥1,500 cells/mm³ and platelets should be ≥100,000 cells/mm³; CrCl 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 4, 5 and 6 (see Tables 4,5 and 6), which are applicable for Alimta used as a single agent or in combination with cisplatin. (See Tables 4.)


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If patients develop non-haematologic toxicities ≥Grade 3 (excluding neurotoxicity), Alimta should be withheld until resolution to less than equal to the patient's pre-therapy value. Treatment should be resumed according to the guidelines in Table 5. (See Table 5.)


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In the event of neurotoxicity, the recommended dose adjustment for Alimta and cisplatin is documented in Table 6. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is observed. (See Table 6.)


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Treatment with Alimta should be discontinued if a patient experiences any haematologic or non-haematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.
Elderly: In clinical studies, there has been no indication that patients ≥65 years are at increased risk of adverse events compared to patients <65 years. No dose reductions other than those recommended for all patients are necessary.
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 CrCl 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 CrCl <45 mL/min. Therefore the use of pemetrexed is not recommended (see Precautions).
Hepatic Impairment: No relationships between AST (SGOT), ALT (SGPT), or total bilirubin and pemetrexed pharmacokinetics were identified. However, patients with hepatic impairment eg, bilirubin >1.5 times the upper limit of normal and/or aminotransaminase >3 times the upper limit of normal (hepatic metastases absent) or >5 times the upper limit of normal (hepatic metastases present) have not been specifically studied.
Administration: Alimta should be administered as an IV infusion over 10 min on the 1st day of each 21-day cycle. For instructions on reconstitution and dilution, see Cautions for Usage. (See Cautions for Usage.)

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 should be considered.

Hypersensitivity to pemetrexed or to any of the excipients of Alimta.
Concomitant yellow fever vaccine (see Interactions).
Use in lactation: It is not known whether pemetrexed is excreted in human milk and adverse reactions on the suckling child cannot be excluded. Breastfeeding must be discontinued during pemetrexed therapy.

Pemetrexed can suppress bone marrow function as manifested by neutropenia, thrombocytopenia and anaemia (or pancytopenia) (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).
Less toxicity and reduction in Grade 3/4 haematologic and non-haematologic toxicities eg, neutropenia, febrile neutropenia and infection with Grade 3/4 neutropenia were reported when pre-treatment with folic acid and vitamin B₁₂ was administered. Therefore all 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 CrCl of <45 mL/min. Therefore, the use of pemetrexed in patients with CrCl of <45 mL/min is not recommended (see Dosage & Administration).
Patients with mild to moderate renal insufficiency (CrCl 45-79 mL/min) should avoid taking nonsteroidal anti-inflammatory drugs (NSAIDs) eg, ibuprofen, 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 t_½ should be interrupted for at least 5 days prior to, on the day of, 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 preexisting hypertension or diabetes.
The effect of third space fluid, eg pleural effusion or ascites, on pemetrexed is not fully defined. A phase 2 study of pemetrexed in 31 solid tumour patients with stable 3rd space fluid demonstrated no difference in pemetrexed dose normalized plasma concentrations or clearance compared to patients without 3rd space fluid collections. Thus, drainage of 3rd 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 preexisting cardiovascular risk factors (see Adverse Reactions).
Immunodepressed status is common in cancer patients. As a result, concomitant use of live attenuated vaccines is not recommended (see Contraindications and Interactions).
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 the Ability to Drive or Operate Machinery: 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.
Impairment of Fertility: 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 counseling on sperm storage before starting treatment.
Use in 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 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.
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.
Use in children and adolescents: Alimta is not recommended for use in children <18 years due to insufficient data on safety and efficacy.

Use in 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 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.
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.
Use in lactation: It is not known whether pemetrexed is excreted in human milk and adverse reactions on the suckling child cannot be excluded. Breastfeeding must be discontinued during pemetrexed therapy.

Summary of the Safety Profile: The most commonly reported adverse reactions 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 adverse reactions include renal toxicities, increased aminotransferase, alopecia, fatigue, dehydration, rash, infection/sepsis and neuropathy. Rarely seen events include Stevens-Johnson syndrome and toxic epidermal necrolysis.
Table 7 provides the frequency and severity of adverse reactions that have been reported in >5% of 168 patients with mesothelioma who were randomised to receive cisplatin and pemetrexed and 163 patients with mesothelioma randomised to receive the single agent cisplatin. In both treatment arms, these chemo-naive patients were fully supplemented with folic acid and vitamin B₁₂.
Frequency Estimate: Very common (≥1/10); common (≥1/100 and <1/10); uncommon (≥1/1000 and <1/100); rare (≥1/10,000 and <1/1000); very rare (<1/10,000) and not known (cannot be estimated from available data-spontaneous reports).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 7.)


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Clinically relevant circular tumor cell (CTC) toxicities that were reported in ≥1% and ≤5% (common) of the patients that were randomly assigned to receive cisplatin and pemetrexed include: Renal failure, infection, pyrexia, febrile neutropenia, increased AST, ALT and gamma-glutamyl transpeptidase (GGT), urticaria and chest pain.
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.
Table 8 provides the frequency and severity of adverse reactions 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 NSCLC and received prior chemotherapy. (See Table 8.)


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Clinically relevant CTC toxicities that were reported in ≥1% and ≤5% (common) of the patients that were randomly assigned to pemetrexed include: Infection without neutropenia, febrile neutropenia, allergic reaction/hypersensitivity, increased creatinine, motor neuropathy, sensory neuropathy, erythema multiforme and abdominal pain.
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 3 single agent pemetrexed studies (n=164) and the phase 3 single agent pemetrexed study described in the previous text, with the exception of neutropenia (12.8% vs 5.3%, respectively) and ALT elevation (15.2% vs 1.9%, respectively). These differences were likely due to differences in the patient population, since the phase 2 studies included both chemo-naive and heavily pre-treated breast cancer patients with preexisting liver metastases and/or abnormal baseline liver function tests.
The table as follows provides the frequency and severity of adverse reactions 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 9.)


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Clinically relevant toxicity that was reported in ≥1% and ≤5% of the patients that were randomly assigned to receive cisplatin and pemetrexed include: Increased AST and ALT, infection, febrile neutropenia, renal failure, pyrexia, dehydration, conjunctivitis and creatinine clearance decrease.
Clinically relevant toxicity that was reported in <1% of the patients that were randomly assigned to receive cisplatin and pemetrexed include: Increased GGT, 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.
Table 10 below provides the frequency and severity of adverse reactions 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 10.)


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Clinically relevant CTC toxicity of any grade that was reported in ≥1% and ≤5% 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% 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 randomised 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 preexisting 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.
Uncommon cases of oedema have been reported in patients treated with pemetrexed.
Oesophagitis/radiation 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: Blood and Lymphatic System: Rare cases of immune-mediated hemolytic anemia have been reported in patients treated with pemetrexed.
Uncommon cases of acute renal failure have been reported with pemetrexed alone or in association with other chemotherapeutic agents (see Precautions).
Uncommon cases of radiation pneumonitis have been reported in patients treated with radiation either prior, during or subsequent to their pemetrexed therapy (see Precautions).
Rare cases of radiation recall have been reported in patients who have received radiotherapy previously (see Precautions).
Uncommon cases of peripheral ischemia sometimes leading to extremity necrosis have been reported.
Rare cases of bullous conditions have been reported including Stevens-Johnson syndrome and toxic epidermal necrolysis which in some cases were fatal.
Rarely, haemolytic anaemia has been reported in patients treated with pemetrexed.

Pemetrexed is mainly eliminated unchanged renally by tubular secretion and to a lesser extent by glomerular filtration. Concomitant administration of nephrotoxic drugs (eg, 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 (eg, 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 (CrCl ≥80 mL/min), high doses of nonsteroidal anti-inflammatory drugs (NSAIDs eg, ibuprofen >1,600 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 (CrCl ≥80 mL/min).
In patients with mild to moderate renal insufficiency (CrCl 45-79 mL/min), the concomitant administration of pemetrexed with NSAIDs (eg, 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 t_1/2 as piroxicam or rofecoxib, the concomitant administration with pemetrexed should be avoided 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.
Interactions Common to All Cytotoxics: Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation treatment is frequent. The high intraindividual variability of the coagulation status during diseases and the possibility of interaction between oral anticoagulants and anticancer chemotherapy require increased frequency of international normalised ratio (INR) monitoring, if it is decided to treat the patient with oral anticoagulants.
Concomitant Use Contraindicated: Yellow Fever Vaccine: Risk of fatal generalised vaccinale 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, Alimta must not be mixed with other drugs.

Special Precautions for Disposal and Other Handling: Use aseptic technique during the reconstitution and further dilution of pemetrexed for IV infusion administration. Calculate the dose and the number of Alimta vials needed. Each vial contains an excess of pemetrexed to facilitate delivery of label amount.
Alimta 100 mg: Reconstitute 100 mg vials with 4.2 mL of sodium chloride 9 mg/mL (0.9 %) solution for injection, without preservative, resulting in a solution containing pemetrexed 25 mg/mL. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in colour from colourless to yellow or green-yellow without adversely affecting product quality. The pH of the reconstituted solution is between 6.6-7.8. Further dilution is required.
Alimta 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 pemetrexed 25 mg/mL. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in colour from colourless to yellow or green-yellow without adversely affecting product quality. The pH of the reconstituted solution is between 6.6-7.8. Further dilution is required.
The appropriate volume of reconstituted pemetrexed solution should be further diluted to 100 mL with sodium chloride 9 mg/mL (0.9%) solution for injection, without preservative and administered as an IV infusion over 10 min.
Pemetrexed infusion solutions prepared as directed are compatible with polyvinyl chloride and polyolefin lined administration sets and infusion bags. Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration. If particulate matter is observed, do not administer. Pemetrexed solutions are for single use only. Any unused 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 no 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: Store below 25°C. Excursion permitted up to 30°C.
Shelf-Life: 2 years.
Reconstituted and Infusion Solutions: When prepared as directed, reconstituted and infusion solutions of Alimta contain no antimicrobial preservatives. Chemical and physical in-use stability of reconstituted and infusion solutions of pemetrexed were demonstrated for 24 hrs at refrigerated temperature. From a microbiological point of view, Alimta 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 normally not be longer than 24 hrs at 2°-8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

Cytotoxic Chemotherapy

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

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