PEMETREXED SUN

MIMS Revision Date: 01 January 2026

1 Name of Medicine

Pemetrexed disodium.

2 Qualitative and Quantitative Composition

One vial contains 100 mg, 500 mg or 1000 mg pemetrexed.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Pemetrexed SUN is supplied as a sterile lyophilised powder for intravenous infusion available in single dose clear vials. The product is a white to either light yellow or green-yellow lyophilised solid.

4 Clinical Particulars

4.1 Therapeutic Indications

Malignant pleural mesothelioma. Pemetrexed SUN, in combination with cisplatin, is indicated for the treatment of patients with malignant pleural mesothelioma.
Non-small cell lung cancer. Pemetrexed SUN in combination with cisplatin is indicated for initial treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology.
Pemetrexed SUN as monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology after prior platinum-based chemotherapy.

4.2 Dose and Method of Administration

Pemetrexed SUN should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Pemetrexed SUN should only be used in one patient on one occasion only and any residue should be discarded.
Pemetrexed SUN in combination use with cisplatin. Adults. The recommended dose of Pemetrexed SUN is 500 mg/m² as 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 2 hours approximately 30 minutes after completion of the Pemetrexed SUN 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. See cisplatin Product Information document for specific dosing advice.
Single agent use. Adults. The recommended dose of Pemetrexed SUN is 500 mg/m² BSA administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.
Premedication regimen. Skin rash has been reported in patients not pretreated with a corticosteroid. Pre-treatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after Pemetrexed SUN administration.
To reduce toxicity, patients treated with Pemetrexed SUN must be instructed to take a low-dose oral folic acid preparation or a multivitamin containing folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of Pemetrexed SUN, and dosing should continue during the full course of therapy and for 21 days after the last dose of Pemetrexed SUN. Patients must also receive one intramuscular injection of vitamin B₁₂ during the week preceding the first dose of Pemetrexed SUN and every 3 cycles thereafter. Subsequent vitamin B₁₂ injections may be given the same day as Pemetrexed SUN. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 microgram, and the dose of vitamin B₁₂ received was 1000 microgram. The most commonly used dose of oral folic acid was 400 microgram.
Laboratory monitoring and dose reduction recommendations. Monitoring. It is recommended that patients receiving Pemetrexed SUN be monitored before each dose with a complete blood count, including a differential and platelet count. Periodic blood chemistry tests should be collected to evaluate renal and hepatic function.
Absolute neutrophil count (ANC) should be ≥ 1500 cells/mm³ and platelets ≥ 100,000 cells/mm³ prior to scheduled administration of any cycle.
Dose adjustment. 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 1-3 which are suitable for using Pemetrexed SUN as a single agent or in combination with cisplatin.

If patients develop non-haematologic toxicities (excluding neurotoxicity) ≥ Grade 3, 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.
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.
Pemetrexed SUN therapy 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 patients. In clinical trials, there has been no indication that patients 65 years of age or older are at increased risk of adverse events compared with patients younger than 65. No dose reductions other than those recommended for all patients are necessary.
Renal insufficiency. In clinical studies, patients with creatinine clearance of at least 45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients. Therefore, patients should not receive Pemetrexed SUN whose creatinine clearance is < 45 mL/min [using the standard Cockcroft and Gault formula or GFR measured by Tc99m-DPTA serum clearance method].
Hepatic insufficiency. Pemetrexed SUN is not extensively metabolised by the liver. Pemetrexed SUN should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. The effect of third space fluid, such as pleural effusion and ascites, on Pemetrexed SUN is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to Pemetrexed SUN administration.
Preparation and administration instructions. Use aseptic technique.
Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection. Pemetrexed SUN is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection and Ringer's Injection. Co-administration of Pemetrexed SUN with other drugs and diluents has not been studied, and therefore is not recommended.
1. Use appropriate aseptic technique during the reconstitution and further dilution of Pemetrexed SUN for intravenous infusion administration.
2. Calculate the dose and the number of Pemetrexed SUN vials needed. A 1000 mg vial contains 1000 mg of pemetrexed. A 500 mg vial contains 500 mg of pemetrexed. A 100 mg vial contains 100 mg of pemetrexed. The vial contains an excess of pemetrexed to facilitate delivery of label amount.
3. Prior to administration, reconstitute 1000 mg vials with 40 mL of 0.9% Sodium Chloride Injection to give a solution containing 25 mg/mL pemetrexed. Reconstitute 500 mg vials with 20 mL of 0.9% Sodium Chloride Injection to give a solution containing 25 mg/mL pemetrexed. Reconstitute 100 mg vials with 4.2 mL of 0.9% Sodium Chloride Injection to give a solution containing 25 mg/mL pemetrexed.
4. 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 Pemetrexed SUN solution is between 6.6 and 7.8. Further dilution is required.
5. The appropriate volume of reconstituted Pemetrexed SUN solution should be further diluted to 100 mL with 0.9% Sodium Chloride Injection and administered as an intravenous infusion over 10 minutes.
6. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Chemical and physical stability of reconstituted and infusion solutions of Pemetrexed SUN was demonstrated for up to 24 hours after reconstitution of the original vial when refrigerated between 2 to 8°C. However, because Pemetrexed SUN and the recommended diluent contain no antimicrobial preservatives, to reduce antimicrobial hazard, reconstituted and infusion solutions should be used immediately. Discard any unused portion.

4.3 Contraindications

Pemetrexed SUN is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any excipients in this product.

4.4 Special Warnings and Precautions for Use

Pemetrexed disodium can suppress bone marrow function as manifested by anaemia, neutropenia, thrombocytopenia, or pancytopenia. (see Section 4.8 Adverse Effects (Undesirable Effects)). Myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy and Pemetrexed SUN should not be given to patients until absolute neutrophil count (ANC) returns to ≥ 1500 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 in the previous cycle (see Section 4.2 Dose and Method of Administration, Dose reduction recommendations).
Patients treated with pemetrexed disodium must be instructed to take folic acid and vitamin B₁₂ with pemetrexed disodium as a prophylactic measure to reduce treatment-related toxicity (see Section 4.2 Dose and Method of Administration). In the Phase 3 mesothelioma EMPHACIS trial, less overall toxicity and reductions in Grade 3/4 haematologic and non-haematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B₁₂ was administered.
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.
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 disodium, 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.
Immuno-depressed status is common in cancer patients. As a result, concomitant use of live attenuated vaccines is not recommended.
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 radio-sensitising agents. Cases of radiation recall have been reported in patients who received radiotherapy weeks or years previously.
Use in hepatic impairment. Pemetrexed SUN is not extensively metabolised by the liver. However, patients with hepatic impairment such as bilirubin > 1.5 times the upper limit of normal (ULN) or aminotransferase > 3 times the ULN (hepatic metastases absent) or > 5 time the ULN (hepatic metastases present) have not been specifically studied.
Pemetrexed SUN should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.
Treatment-related adverse events of pemetrexed seen in clinical trials have been reversible. Skin rash has been reported in patients not pretreated with a corticosteroid in clinical trials. Pre-treatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction (see Section 4.2 Dose and Method of Administration).
The effect of third space fluid, such as pleural effusion and ascites, on Pemetrexed SUN is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to Pemetrexed SUN administration.
Use in renal impairment. Pemetrexed SUN is primarily eliminated unchanged by renal excretion. Insufficient numbers of patients have been studied with creatinine clearance below 45 mL/min. Therefore, Pemetrexed SUN should not be administered to patients whose creatinine clearance is < 45 mL/min (see Section 4.2 Dose and Method of Administration, Dose reduction recommendations).
Use in the 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.
Paediatric use. Pemetrexed SUN is not recommended for use in patients under 18 years of age, as safety and efficacy have not been established in this group of patients.
Effects on laboratory tests. See Section 4.2 Dose and Method of Administration, Laboratory monitoring and dose reduction recommendations.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pemetrexed disodium is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. In vitro studies indicate that pemetrexed disodium is actively secreted by the organic anion transporter 3 (OAT3) in the kidney. In vitro work also indicates that pemetrexed disodium has affinity for OAT4 but the role of OAT4 in the renal elimination of molecules in not fully understood. Concomitant administration of nephrotoxic drugs and/or substances that are tubularly secreted could result in delayed clearance of pemetrexed disodium.
Concomitant administration of pemetrexed with OAT3 (organic anion transporter 3) inhibitors (e.g. probenecid, penicillin, proton pump inhibitors (PPIs)) results in delayed clearance of pemetrexed. Caution should be made when these drugs are combined with pemetrexed.
Results from in vitro studies with human liver microsomes suggest that pemetrexed disodium would not cause clinically significant interactions with drugs metabolised by CYP3A, CYP2D6, CYP2C9, and CYP1A2.
The pharmacokinetics of pemetrexed disodium 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 disodium administration.
Although NSAIDs in moderate doses can be administered with pemetrexed disodium in patients with normal renal function (creatinine clearance ≥ 80 mL/min), renal clearance was reduced by 16% when ibuprofen was concurrently administered with pemetrexed in patients with normal renal function. Caution should be used when administering NSAIDs concurrently with pemetrexed disodium to patients with mild to moderate renal insufficiency (creatinine clearance of 45-79 mL/min). It is recommended that patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of pemetrexed disodium.
In the absence of data regarding potential interaction between pemetrexed disodium and NSAIDs with longer half-lives in patients with mild to moderate renal insufficiency, patients with mild to moderate renal insufficiency taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following pemetrexed disodium administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression and gastrointestinal toxicity.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility. Administration of pemetrexed to male mice at intraperitoneal doses of ≥ 0.3 mg/m²/day resulted in reproductive toxicity characterised by reduced fertility, hypospermia, and testicular atrophy.
Use in pregnancy. (Category D)
The use of Pemetrexed SUN should be avoided in pregnant women because of the potential hazard to the foetus. Pemetrexed was teratogenic (causing cleft palate) in mice at intravenous doses of ≥ 15 mg/m²/day. Other embryofetal toxic effects (embryofetal deaths, reduced fetal weights and incomplete ossification) were also observed. Embryofetal toxicity was observed at the lowest dose tested (0.6 mg/m²/day).
Category D - Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
Use in lactation. It is not known whether pemetrexed is excreted in human milk. Therefore, breast-feeding should be discontinued during Pemetrexed SUN therapy.

4.7 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 disodium may cause fatigue. Therefore, patients should be cautioned against driving or operating machinery if this event occurs.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects. Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.
Single agent pemetrexed disodium (NSCLC). Table 4 provides the frequency and severity of undesirable effects that have been reported in > 5% of 265 patients randomly assigned to receive single agent pemetrexed disodium 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.

Very common: ≥ 10%; Common: > 5% 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 disodium).
Clinically relevant CTC toxicity that was reported in ≥ 1% and ≤ 5% (common) of the patients that were randomly assigned to pemetrexed disodium include: sensory neuropathy, motor neuropathy, abdominal pain, increased creatinine, febrile neutropenia, infection without neutropenia, allergic reaction/hypersensitivity and erythema multiforme.
Clinically relevant CTC toxicity that was reported in < 1% (uncommon) of the patients that were randomly assigned to pemetrexed disodium include supraventricular arrhythmias.
Clinically relevant Grade 3 and Grade 4 laboratory toxicities were similar between integrated Phase 2 results from three single agent pemetrexed disodium studies (n = 164) and the Phase 3 single agent.
Pemetrexed disodium study described above, with the exception of neutropenia (12.8% versus 5.3%, respectively) and alanine aminotransferase elevation (15.2% versus 1.9%, respectively). These differences were likely due to differences in the patient population, since the phase 2 studies included chemo-naive and heavily pre-treated breast cancer patients with pre-existing liver metastases and/or abnormal baseline liver function tests.
Combination with cisplatin (MPM). Table 5 provides the frequency and severity of undesirable effects that have been reported in > 5% of 168 patients with mesothelioma who were randomly assigned to receive cisplatin and pemetrexed disodium and 163 patients with mesothelioma randomly assigned to receive single agent cisplatin. In both treatment arms, these chemo-naive patients were fully supplemented with folic acid and vitamin B₁₂.
Very common: ≥ 10%; Common: > 5% 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 disodium 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 disodium include: increased AST (SGOT), ALT (SGPT), and GGT, infection, febrile neutropenia, renal failure, chest pain, pyrexia and urticaria.
Clinically relevant toxicity that was reported in < 1% (uncommon) of the patients that were randomly assigned to receive cisplatin and pemetrexed disodium include arrhythmia and motor neuropathy.
Combination with cisplatin (NSCLC). Table 6 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 randomised to study and received cisplatin and pemetrexed disodium and 830 patients with NSCLC who were randomised to study and received 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.
Very common: ≥ 10%; Common: > 5% 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 disodium 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 disodium 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. Acute renal failure was observed more commonly in the pemetrexed/cisplatin arm (6 cases, 0.7%) than in the gemcitabine/cisplatin arm (0 cases).
Single agent pemetrexed disodium (NSCLC maintenance). Table 7 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 disodium and 402 patients randomly assigned to receive placebo in the single-agent maintenance pemetrexed study (JMEN: N = 663) and continuation pemetrexed maintenance study (PARAMOUNT: N = 539). 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.
Clinically relevant CTC toxicity of any grade that was reported in ≥ 1% and ≤ 5% (common) of the patients that were randomly assigned to pemetrexed disodium include: decreased platelets, decreased creatinine clearance, constipation, oedema, alopecia, increased creatinine, pruritus/itching, fever (in the absence of neutropenia), ocular surface disease (including conjunctivitis), increased lacrimation, and decreased glomerular filtration rate.
Clinically relevant CTC toxicity that was reported in < 1% (uncommon) of the patients that were randomly assigned to pemetrexed disodium include: febrile neutropenia, allergic reaction/hypersensitivity, motor neuropathy, erythema multiforme, renal failure, and supraventricular arrhythmia.
Safety was assessed for patients who were randomised to receive pemetrexed disodium (N = 800). The incidence of adverse reactions was evaluated for patients who received ≤ 6 cycles of pemetrexed disodium maintenance (N = 519), and compared to patients who received > 6 cycles of pemetrexed disodium (N = 281). Increases in adverse reactions (all grades) were observed with longer exposure. A significant increase in the incidence of possibly study drug-related Grade 3-4 neutropenia was observed with longer exposure to pemetrexed (≤ 6 cycles: 3.3%, > 6 cycles: 6.4%, p = 0.046). No statistically significant differences in any other individual Grade 3/4/5 adverse reactions were seen with longer exposure.
In clinical trials, sepsis which in some cases was fatal occurred in approximately 1% of patients.
Cases of oesophagitis have been reported uncommonly in clinical trials with pemetrexed.
Post-marketing data. Gastrointestinal disorders. Rare cases of colitis have been reported in patients treated with pemetrexed.
General disorders and administration site conditions. Rare cases of oedema have been reported in patients treated with pemetrexed disodium.
Injury, poisoning and procedural complications. Rare cases of radiation recall have been reported in patients who have previously received radiotherapy.
Respiratory disorders. Rare cases of interstitial pneumonitis have been reported in patients treated with pemetrexed disodium.
Skin. Rare cases of bullous conditions have been reported including Stevens-Johnson syndrome and toxic epidermal necrolysis which in some cases were fatal.
Blood and lymphatic system. Rare cases of immune-mediated haemolytic anaemia have been reported in patients treated with pemetrexed.
Hepatobiliary disorders. Rare cases of hepatitis, potentially serious, have been reported during clinical trials with pemetrexed disodium.
Rare - ≤ 0.1% of patients treated with pemetrexed disodium.

4.9 Overdose

Reported symptoms of pemetrexed disodium overdose include neutropenia, anaemia, thrombocytopenia, mucositis, 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 mucositis may be seen.
If overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. Management of Pemetrexed SUN overdose should include consideration of the use of folinic acid or thymidine rescue.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action. Pemetrexed disodium is an antifolate antineoplastic agent. In vitro studies have shown that pemetrexed disodium 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 that are essential for cell replication. Both the reduced folate carrier and membrane folate binding protein transport systems appear to be involved in transport of pemetrexed into cells. Once in the cell, pemetrexed disodium is converted to polyglutamate forms by the enzyme folyl polyglutamate synthetase. The polyglutamate forms are even more potent inhibitors of TS and GARFT than pemetrexed. Polyglutamation is a time and concentration dependent process that occurs in tumour cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have a longer intracellular half-life than the parent drug, resulting in prolonged drug action in malignant cells. Data indicates that overexpression of thymidylate synthase (TS) correlates with reduced sensitivity to pemetrexed in antifolate-resistant cell lines. Results in a study with specimens from chemo-naive patients with NSCLC demonstrated lower levels of TS expression in adenocarcinoma as compared to squamous cell carcinoma tumors. This data suggests that pemetrexed disodium may offer greater efficacy for patients with adenocarcinoma as compared to squamous carcinoma histology.
An in vitro study with the MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed disodium was combined with cisplatin.
Clinical trials. Malignant pleural mesothelioma. The safety and efficacy of pemetrexed have been evaluated in chemo-naive patients with malignant pleural mesothelioma (MPM) as a single-agent and in combination with platinum-based regimens.
EMPHACIS, a multi-centre, randomised, single-blind phase 3 study of pemetrexed plus cisplatin versus cisplatin in chemo-naive patients with malignant pleural mesothelioma, has shown that patients treated with pemetrexed and cisplatin had a clinically meaningful 2.8-month median survival advantage over patients receiving cisplatin alone. Pemetrexed disodium was administered intravenously over 10 minutes at a dose of 500 mg/m² and cisplatin was administered intravenously over 2 hours at a dose of 75 mg/m² beginning approximately 30 minutes after the end of administration of pemetrexed. Both drugs were given on Day 1 of each 21-day cycle. On this study, treatment was administered up to 6 cycles. Additional cycles were permitted for patients who were receiving benefit from therapy.
During the study, low-dose folic acid and vitamin B₁₂ supplementation was introduced to patients' 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 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).
Table 8 summarises the efficacy results for all patients regardless of vitamin supplementation status and those patients receiving vitamin supplementation from the time of enrolment in the trial.

Table 9 summarises the number of cycles of treatment completed by randomised and treated patients and fully supplemented patients. Patients who never received folic acid and vitamin B₁₂ during study therapy received a median of 2 cycles in both treatment arms.
A statistically significant improvement of the clinically relevant symptoms (pain and dyspnoea) associated with malignant pleural mesothelioma in the pemetrexed disodium/ cisplatin arm (212 patients) versus the cisplatin arm alone (218 patients) was demonstrated using the Lung Cancer Symptom Scale (LCCS). By the end of treatment (after 6 cycles), there was a statistically significant difference in favour of pemetrexed disodium/cis for the symptoms of dyspnoea, pain, fatigue, symptom distress, interference with activity, and total LCSS. Statistically significant differences in pulmonary function tests were also observed. Differences favouring the pemetrexed disodium/cis arm were seen in all pulmonary function tests early in therapy; these differences were occasionally significant in early cycles but uniformly became significant in later cycles. The separation between the treatment arms was achieved by improvement in lung function in the pemetrexed disodium/cis arm and deterioration of lung function over time in the control arm.
Non-small cell lung cancer. The safety and efficacy of pemetrexed disodium have been evaluated in combination with cisplatin as initial treatment for Non-Small Cell Lung Cancer (NSCLC) and as a single-agent in patients who have previously received chemotherapy treatment.
A multi-centre, randomised, open-label Phase 3 study of pemetrexed disodium plus cisplatin versus gemcitabine plus cisplatin (for up to 6 cycles) in chemo-naive patients with locally advanced or metastatic (Stage IIIb or IV) non-small cell lung cancer (NSCLC) showed that pemetrexed disodium plus cisplatin (Intent to Treat [ITT] population n = 862) met its primary endpoint and showed similar clinical efficacy as gemcitabine plus cisplatin (ITT n = 863) in overall survival (adjusted hazard ratio 0.94; 95% CI 0.84-1.05). See Figure 1 and Table 10.
A series of subsets of patients were examined in pre-specified adjusted analyses as shown in Figure 2.
The analysis of the impact of NSCLC histology on overall survival demonstrated statistically significant superiority for pemetrexed disodium + cisplatin in the adenocarcinoma (n = 846, 12.6 versus 10.9 months, adjusted HR = 0.84; 95% CI = 0.71-0.99, p = 0.033) and large cell carcinoma subgroups (n = 153, 10.4 versus 6.7, adjusted HR = 0.67; 95% CI = 0.48-0.96, p = 0.027) but not in patients with squamous cell carcinoma (n = 473, 9.4 versus 10.8 months, adjusted HR = 1.23; 95% CI = 1.00-1. 51, p = 0.050) or patients with other histologies (n = 250, 8.6 versus 9.2, adjusted HR = 1.08; 95% CI = 0.81-1.45, p = 0.586). The results of the analysis of overall survival in patients with adenocarcinoma and large cell carcinoma are shown in Figure 3.
On this study, treatment was administered up to 6 cycles.
There were no clinically relevant differences observed for the safety profile of pemetrexed disodium plus cisplatin within the histology subgroups.
A multi-centre, randomised, double-blind, placebo-controlled Phase 3 study (JMEN), compared the efficacy and safety of maintenance treatment with pemetrexed disodium 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) Non Small Cell Lung Cancer (NSCLC) who did not progress after 4 cycles of first line doublet therapy. 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 pemetrexed disodium 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 pemetrexed disodium.
In the overall study population, pemetrexed disodium was statistically superior to placebo in terms of overall survival (OS) (median 13.4 months versus 10.6 months, HR = 0.79 (95% CI: 0.65-0.95), p-value = 0.012) and PFS (median 4.0 months versus 2.0 months, HR = 0.60 (95% CI: 0.49-0.73), p-value < 0.00001). Consistent with previous pemetrexed disodium studies, a difference in treatment outcomes was observed according to histologic classification. For the indicated population i.e. patients with NSCLC other than predominantly squamous cell histology, pemetrexed disodium was superior to placebo for OS (median 15.5 months versus 10.3 months, HR = 0.70 (95% CI: 0.56-0.88)) and PFS (median 4.4 months versus 1.8 months, HR = 0.47 (95% CI: 0.37-0.60)).
The PFS and OS results in patients with squamous cell histology suggested no advantage for pemetrexed disodium over placebo.
There were no clinically relevant differences observed for the safety profile of pemetrexed disodium within the histology subgroups. See Figure 4.
A multi-centre, randomised, double-blind, placebo-controlled Phase 3 study (PARAMOUNT), compared the efficacy and safety of continuation maintenance treatment with pemetrexed disodium plus 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 who did not progress after 4 cycles of first line doublet therapy of pemetrexed disodium in combination with cisplatin. Of the 939 patients treated with pemetrexed disodium plus cisplatin induction, 539 patients were randomised to maintenance treatment with pemetrexed disodium or placebo. Of the randomised patients, 44.9% had a complete/ partial response and 51.9% had a response of stable disease to pemetrexed disodium plus cisplatin induction. Patients randomised to treatment were required to have an ECOG performance status 0 or 1. The median time from the start of pemetrexed disodium plus cisplatin induction therapy to the start of maintenance treatment was 2.96 months on both the pemetrexed arm and the placebo arm. Randomised patients received maintenance treatment until disease progression. For statistical purposes, efficacy and safety were measured from the time of randomisation after completion of first line (induction) therapy. Patients received a median of 4 cycles of maintenance treatment with pemetrexed disodium and 4 cycles of placebo. A total of 169 patients (47.1%) completed ≥ 6 cycles maintenance treatment with pemetrexed disodium, representing at least 10 total cycles of pemetrexed disodium.
Independent review of the imaging of 472 of the 539 randomised patients showed that the study met its primary endpoint (PFS) and showed a statistically significant improvement in PFS in the pemetrexed disodium arm over the placebo arm - median of 3.9 months and 2.6 months respectively (hazard ratio = 0.64, 95% CI = 0.51-0.81, p = 0.0002). The independent review of patient scans showed consistent results to the findings of the investigator assessment of PFS. In addition, for randomised patients, as measured from the start of pemetrexed disodium plus cisplatin first line induction treatment, the median investigator-assessed PFS was 6.9 months for the pemetrexed arm and 5.6 months for the placebo arm (hazard ratio = 0.59, 95% CI = 0.47-0.74).
Following pemetrexed disodium plus cisplatin induction (4 cycles), treatment with pemetrexed disodium was statistically superior to placebo for OS (median 13.9 months versus 11.0 months, hazard ratio = 0.78, 95% CI = 0.64-0.96, p = 0.0195). At the time of final survival analysis, 28.7% of patients were alive or lost to follow up on the pemetrexed arm versus 21.7% on the placebo arm. The relative treatment effect of pemetrexed disodium was internally consistent across subgroups (including disease stage, induction response, ECOG PS, smoking status, gender, histology and age) and similar to that observed in the unadjusted OS and PFS analyses. The 1 year and 2 year survival rates for patients on pemetrexed disodium were 58% and 32% respectively, compared to 45% and 21% for patients on placebo. From the start of pemetrexed disodium plus cisplatin first line induction treatment, the median OS of patients was 16.9 months for the pemetrexed arm and 14.0 months for the placebo arm (hazard ratio = 0.78, 95% CI = 0.64-0.96). The percentage of patients that received post-discontinuation chemotherapy was 64.3% for pemetrexed disodium and 71.7% for placebo. See Figure 5.
The pemetrexed disodium maintenance safety profiles from the two studies JMEN and PARAMOUNT were similar.
A multi-centre, randomised, open label phase 3 study of pemetrexed disodium versus docetaxel (with treatment until progression) in patients with locally advanced or metastatic NSCLC after prior chemotherapy has shown median survival times of 8.3 months for patients treated with pemetrexed disodium (Intent To Treat population n = 283) and 7.9 months for patients treated with docetaxel (ITT n = 288) which is not statistically significantly different. These data, as outlined in Table 11, indicate comparable efficacy between pemetrexed disodium and docetaxel.
On this study, treatment was administered until disease progression.
An analysis of the impact of NSCLC histology on overall survival was in favour of pemetrexed disodium versus docetaxel for other than predominantly squamous histology (n = 399, 9.3 versus 8.0 months, adjusted HR = 0.78; 95% CI = 0.61-1.00, p = 0.047) and was in favour of docetaxel for squamous cell carcinoma histology (n = 172, 6.2 versus 7.4 months, adjusted HR = 1.56; 95% CI = 1.08-2.26, p = 0.018). There were no clinically relevant differences observed for the safety profile of pemetrexed disodium within the histology subgroups.

5.2 Pharmacokinetic Properties

Absorption. Pemetrexed disodium is for intravenous administration only.
Distribution. Pemetrexed disodium has a steady state volume of distribution of 16.1 litres. In vitro studies indicate that pemetrexed disodium is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment.
Metabolism. Pemetrexed disodium undergoes limited hepatic metabolism.
Excretion. Pemetrexed disodium is primarily eliminated in the urine with up to 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. Total plasma clearance of pemetrexed disodium is 92 mL/min, and the elimination half-life from plasma is 3.5 hours in patients with normal renal function.
Special populations. Analyses to evaluate the pharmacokinetics of pemetrexed disodium in special populations included 287 patients with a variety of advanced tumor types from 10 single agent Phase 2 studies, 70 patients from the Phase 3 malignant pleural mesothelioma EMPHACIS trial, and 47 patients from a Phase 1 renal study.
Elderly. No effect of age on the pharmacokinetics of pemetrexed disodium was observed over a range of 26 to 80 years.
Hepatic insufficiency. No effect of AST (SGOT), ALT (SGPT), or total bilirubin on the pharmacokinetics of pemetrexed disodium was observed. However, specific studies of hepatically impaired patients have not been conducted (see Section 4.4 Special Warnings and Precautions for Use).
Renal insufficiency. Pharmacokinetic analyses included 127 patients with reduced renal function. Total plasma clearance and renal clearance of pemetrexed disodium decrease as renal function decreases. On average, patients with creatinine clearance of 45 mL/min will have a 56% increase in pemetrexed disodium total systemic exposure (AUC) relative to patients with creatinine clearance of 90 mL/min (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity. Pemetrexed has been shown to be clastogenic in the in vivo micronucleus assay in the mouse, but was negative in the in vitro chromosome aberration test in Chinese hamster ovary cells. Pemetrexed was negative in assays for gene mutation (bacteria and mammalian cells in vitro).
Carcinogenicity. Studies to assess the carcinogenic potential of pemetrexed have not been conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each 1000 mg vial of Pemetrexed SUN contains pemetrexed disodium, equivalent to 1000 mg pemetrexed, and 1000 mg of mannitol. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH. Each 500 mg vial of Pemetrexed SUN contains pemetrexed disodium, equivalent to 500 mg pemetrexed, and 500 mg of mannitol. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH. Each 100 mg vial of Pemetrexed SUN contains pemetrexed disodium, equivalent to 100 mg pemetrexed, and 106 mg of mannitol. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Pemetrexed SUN is not light sensitive.

6.5 Nature and Contents of Container

Pemetrexed SUN, pemetrexed disodium for injection is available in sterile single-use (one patient one occasion) clear Type 1 glass vials containing: 100 mg, 500 mg or 1000 mg pemetrexed (pack size 1 vial).
Vial stopper not made with natural rubber latex.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Pemetrexed disodium is a white to almost white solid.
Chemical structure. The active ingredient in Pemetrexed SUN powder for injection is pemetrexed disodium.
Pemetrexed disodium has the chemical name L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. It has an empirical formula of C₂₀H₁₉N₅O₆.2Na.7H₂O and a molecular weight of 597.49. The structural formula is as follows:

CAS number. The CAS number for pemetrexed disodium is 357166-29-1.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Date of First Approval

17 June 2016

Date of Revision

18 November 2025

Summary Table of Changes