Data Sheet

ALIMTA

Pemetrexed disodium, powder for solution for infusion, vial 500 mg.

Presentation

Each vial contains 500 mg of pemetrexed as pemetrexed disodium.
Each 500 mg vial must be reconstituted with 20 mL of 0.9 % Sodium Chloride Injection (preservative free). The reconstituted ALIMTA solution contains 25 mg/mL of pemetrexed.

Uses

Actions

ALIMTA (pemetrexed) is a multitarget 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 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 folyl polyglutamate synthase. 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.

Pharmacokinetics

The pharmacokinetics 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 to 838 mg/m² infused over a 10-minute period. Pemetrexed has a steady-state volume of distribution of 16.1 litres. 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. 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.

Clinical Efficacy

Malignant Pleural Mesothelioma - EMPHACIS, a multicentre, randomised, single-blind Phase 3 study of ALIMTA plus cisplatin versus cisplatin alone in chemonaive 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 were 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). The results of these analyses of efficacy are summarised in Table 1.

Table 1 Efficacy of ALIMTA plus Cisplatin vs. Cisplatin in Malignant Pleural Mesothelioma

Abbreviation: CI = confidence interval.
* p-value refers to comparison between arms.
** In the ALIMTA /cisplatin arm, randomised and treated (N = 225) and fully supplemented (N = 167).

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 alone arm (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 chemonaive patients with malignant pleural mesothelioma. The overall response rate was 14.1%.

Non-Small Cell Lung Cancer - The safety and efficacy of ALIMTA have been evaluated as a single agent in patients who have previously received chemotherapy treatment for Non-Small Cell Lung Cancer (NSCLC).

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 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 2, indicate comparable efficacy between pemetrexed and docetaxel.

Table 2. Efficacy of Alimta vs docetaxel in NSCLC - ITT Population

Abbreviations: CI = confidence interval; ITT = intent to treat; n = total population size.

* Based on Rothmann analysis.

Indications

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

ALIMTA is indicated for treatment of patients with locally advanced or metastatic non-small cell lung cancer, after prior platinum-based chemotherapy.

Dosage and Administration

ALIMTA should only be administered under the supervision of a physician qualified in the use of anticancer chemotherapy. The ALIMTA solution must be prepared according to the instructions provided (see Instructions for Use and Handling section).

Malignant Pleural Mesothelioma

Combination use with cisplatin:
In patients treated for malignant pleural mesothelioma, the recommended dose of ALIMTA is 500 mg/m² 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 infused over two hours approximately 30 minutes after completion of the pemetrexed infusion on the first day of each 21-day cycle. Patients should receive hydration consistent with local practice prior to and/or after receiving cisplatin. See cisplatin package insert for specific dosing advice.

Non-Small Cell Lung Cancer (NSCLC)

Single agent use:

The recommended dose of ALIMTA is 500 mg/m² 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 ALIMTA administration. The corticosteroid should be equivalent to 4 mg of dexamethasone administered orally twice a day (see Warnings and Precautions).
To reduce toxicity, patients treated with ALIMTA should also receive vitamin supplementation (see Warnings and Precautions). Patients must take oral folic acid or a multivitamin containing folic acid (350 to 1000 micrograms) on a daily basis. At least five doses of folic acid must be taken during the seven days preceding the first dose of ALIMTA, and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. Patients must also receive an intramuscular injection of vitamin B₁₂ (1000 micrograms) in the week preceding the first dose of ALIMTA and every three cycles thereafter. Subsequent vitamin B₁₂ injections may be given on the same day as ALIMTA.

Monitoring

Patients receiving ALIMTA should 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 greater than or equal to 1500 cells/mm³ and platelets should be greater than or equal to 100,000 cells/mm³ prior to the start of each cycle.

Dose Adjustments

Dose adjustments at the start of a subsequent cycle should be based on nadir haematologic counts or maximum nonhaematologic 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 3, 4 and 5, which are applicable for ALIMTA used as a single agent or in combination with cisplatin.

TABLE 3 - Dose Modification Table for ALIMTA (as Single Agent or in Combination) and Cisplatin - Haematologic Toxicities

If patients develop nonhaematologic toxicities (excluding neurotoxicity) greater than or equal to Grade 3 (with the exception of Grade 3 transaminase elevations), ALIMTA should be withheld until resolution to less than or equal to the patient's pretherapy value. Treatment should be resumed according to the guidelines in Table 4.

TABLE 4 - Dose Modification Table for ALIMTA (as Single Agent or in Combination) and Cisplatin- Nonhaematologic Toxicities^a,b

a National Cancer Institute Common Toxicity Criteria (CTC).
b Excluding neurotoxicity.
c Except Grade 3 transaminase elevation.

In the event of neurotoxicity, the recommended dose adjustment for ALIMTA and cisplatin is documented in Table 5. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is observed.

TABLE 5 - Dose Modification Table for ALIMTA (as Single Agent or in Combination) and Cisplatin - Neurotoxicity

*Common Toxicity Criteria (CTC).

Treatment with ALIMTA should be discontinued if a patient experiences any haematologic or nonhaematologic Grade 3 or 4 toxicity after 2 dose reductions (except Grade 3 transaminase elevations) 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.

Paediatrics

ALIMTA 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.

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 greater than or equal to 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 ALIMTA is not recommended (see Warnings and 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.

Contraindications

ALIMTA is contraindicated in women of childbearing age unless adequate contraception is used. ALIMTA is contraindicated in patients with known hypersensitivity to pemetrexed or to any of the excipients.

Warnings and Precautions

Pemetrexed can suppress bone marrow function as manifested by anaemia, neutropenia, thrombocytopenia or pancytopenia. (see Adverse Effects). Myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy and ALIMTA should not be given to patients until absolute neutrophil count (ANC) returns to greater than or equal to 1500 cells/mm³ and platelet count returns to greater than or equal to 100,000 cells/mm³. Dose reductions for subsequent cycles are based on nadir ANC, platelet count and maximum nonhaematologic toxicity seen from the previous cycle (see Dosage and Administration).
In the Phase 3 mesothelioma EMPHACIS trial, overall less toxicity and reduction in Grade 3/4 haematologic and nonhaematologic 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. Therefore patients treated with ALIMTA must be instructed to take folic acid and vitamin B₁₂ as a prophylactic measure to reduce treatment-related toxicity (see Dosage and Administration).
Skin reactions have been reported in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) can reduce the incidence and severity of skin reactions (see Dosage and Administration).
Insufficient numbers of patients have been studied with creatinine clearance of below 45mL/min. Therefore, the use of ALIMTA in patients with creatinine clearance of <45mL/min is not recommended (see Dosage and Administration).
Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79mL/min) should avoid taking nonsteroidal anti-inflammatory drugs (NSAIDs) with short elimination half-lives for at least 2 days prior to, on the day of, and at least 2 days after administration of pemetrexed. All patients eligible for ALIMTA therapy should avoid taking NSAIDs with long elimination half-lives at least 5 days prior to, on the day of, and at least 2 days after pemetrexed administration (see Interactions).

The effect of third space fluid, such as pleural effusion or ascites, on pemetrexed is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to pemetrexed administration.

Carcinogenicity, Mutagenesis, Impairment of Fertility

Administration of pemetrexed to pregnant mice resulted in decreased foetal weight, incomplete ossification of some skeletal structures and cleft palate. The use of pemetrexed must therefore be avoided in pregnant women (see Contraindications; Pregnancy and Lactation).

Administration of pemetrexed to male mice resulted in reproductive toxicity characterised by slightly reduced fertility rates and testicular atrophy. This suggests that pemetrexed may impair male fertility.
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.

Pregnancy and Lactation

Pregnancy

ALIMTA is contraindicated in women of childbearing age unless adequate contraception is used. There are no data from the use of pemetrexed in pregnant women. Animal studies have shown reproductive toxicity such as birth defects and other effects on the development of the foetus, the course of gestation or peri- and postnatal development (see Carcinogenicity, Mutagenesis, Impairment of Fertility). The potential risk for humans is unknown. Therefore the use of pemetrexed must be avoided during pregnancy due to the potential hazard to the foetus. Women must be advised to avoid becoming pregnant while being treated with ALIMTA.

Lactation

It is not known whether pemetrexed is excreted in human milk. Therefore, it is recommended that breastfeeding be discontinued during ALIMTA therapy.

Effects on Ability to Drive and Use Machinery

No studies on the effects on the ability to drive and use machines have been performed. However, it has been reported that ALIMTA may cause fatigue. Therefore patients should be cautioned against driving or operating machinery if this event occurs.

Adverse Effects

Single agent ALIMTA (non-small cell lung cancer):

Table 6 provides the frequency and severity of undesirable effects that have been reported in >5% of 265 patients randomly assigned to receive single agent ALIMTA 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.

* Refer to NCI CTC Criteria for lab values for each Grade of toxicity (version 2.0).

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 ALIMTA)

Clinically relevant CTC toxicity that was reported in >1% and ≤5% (common) of the patients that were randomly assigned to ALIMTA 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% (rare) of the patients that were randomly assigned to ALIMTA include supraventricular arrhythmias.

Clinically relevant Grade 3 and Grade 4 laboratory toxicities were similar between integrated Phase 2 results from three single agent ALIMTA studies (n=164) and the Phase 3 single agent ALIMTA study described above, 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 chemonaive and heavily pre-treated breast cancer patients with pre-existing liver metastases and/or abnormal baseline liver function tests.

Combination with cisplatin (malignant pleural mesothelioma)

Table 7 provides the frequency and severity of adverse effects 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 single agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B₁₂.

Table 7

* Refer to National Cancer Institute CTC version 2 for each grade of toxicity.
Very common - greater than or equal to 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 and cisplatin).

Clinically relevant CTC toxicities that were reported in > 1 % and less than or equal to 5 % (common) of the patients who 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 less than or equal to 1% of the patients that were randomly assigned to receive cisplatin and pemetrexed include arrhythmia and motor neuropathy.

POST-MARKETING DATA:

Gastrointestinal Disorders - Rare cases of colitis have been reported in patients treated with ALIMTA.

Injury, poisoning and procedural complications - Rare cases of radiation recall have been reported in patients who have previously received radiotherapy.

Respiratory - Rare cases of interstitial pneumonitis have been reported in patients treated with ALIMTA

Rare: ≤0.1% of patients treated with ALIMTA

Interactions

Nephrotoxic drugs: Pemetrexed is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of pemetrexed. Concomitant administration of substances that are also tubularly secreted (e.g. probenecid) could potentially result in delayed clearance of pemetrexed.
Ibuprofen: Although ibuprofen (400 mg four times daily) can be administered with pemetrexed in patients with normal renal function (creatinine clearance greater than or equal to 80 mL/min), caution should be used when administering ibuprofen concurrently with pemetrexed to patients with renal insufficiency (creatinine clearance 45 - 79 mL/min). Clinical trials have shown a decrease in pemetrexed clearance following coadministration of ibuprofen. It is recommended that patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives at least 2 days prior to, on the day of, and at least 2 days after administration of pemetrexed.
Other NSAIDs: In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, on the day of, and at least 2 days after pemetrexed administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression and gastrointestinal toxicity.
Aspirin: Acetylsalicylic acid, administered in low to moderate doses (325 mg orally every 6 hours) does not affect the pharmacokinetics of pemetrexed.
Concomitant cytotoxic therapy: The pharmacokinetics of pemetrexed are not influenced by concurrently administered cisplatin or carboplatin. Similarly, the pharmacokinetics of total platinum are unaltered by pemetrexed. Oral folic acid and intramuscular vitamin B₁₂ supplementation do not affect the pharmacokinetics of pemetrexed.
Cytochrome P450: 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.

Overdosage

Reported symptoms of 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. In the event of suspected overdose, patients should be monitored with blood counts and should receive supportive therapy as necessary. The use of leucovorin in the management of pemetrexed overdose should be considered.

Pharmaceutical Precautions

ALIMTA is an anticancer medicine. Appropriate handling and disposal procedures should be used.

Precautions for Storage

Store below 25°C. Store in the original packaging.

Shelf Life

24 months.

Reconstituted Solution

ALIMTA contains no antibacterial preservative. For the reconstituted solution, chemical and physical in-use stability has been demonstrated for 24 hours at 25°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 normally not be longer than 24 hours at 2 to 8°C, unless reconstitution / dilution has taken place in controlled and validated aseptic conditions.
Parenteral medicines should be inspected visually for particulate matter and discolouration prior to administration, whenever solution or container permits.
Any unused contents of the vial should be discarded in an appropriate manner.

Instructions for Use and Handling

1. Use appropriate aseptic technique during the reconstitution and further dilution of pemetrexed for intravenous infusion administration.
2. Calculate the dose and number of ALIMTA vials needed. The vial contains an excess of pemetrexed to facilitate delivery of the label amount.
3. Prior to administration, each 500 mg vial must be reconstituted with 20 mL of 0.9 % Sodium Chloride Injection (preservative free), resulting in a solution with a concentration of approximately 25 mg/mL pemetrexed. Slowly add the 0.9 % Sodium Chloride Injection (preservative free) to the vial and gently swirl until the powder is completely dissolved.
4. The reconstituted ALIMTA solution must be further diluted with 0.9 % Sodium Chloride Injection (preservative free) prior to intravenous infusion. Further dilute the appropriate volume of the reconstituted ALIMTA solution to 100 mL with 0.9 % Sodium Chloride Injection (preservative free). The bag should be inverted gently to mix the solution to obtain a homogeneous solution.
5. ALIMTA contains no antibacterial preservative. For the reconstituted solution, chemical and physical in-use stability has been demonstrated for 24 hours at 25°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 normally not be longer than 24 hours at 2 to 8°C, unless reconstitution / dilution has taken place in controlled and validated aseptic conditions.
6. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration.
7. ALIMTA solution should then be given by intravenous infusion over 10 minutes.
8. Procedures for proper handling and disposal should be observed. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions of pemetrexed. Any unused contents of the vial should be discarded in an appropriate manner.

Major Incompatibilities

ALIMTA should ONLY be reconstituted and diluted with 0.9 % Sodium Chloride Injection (preservative free) (see Instructions for Use and Handling). ALIMTA is compatible with standard polyvinyl chloride administration sets and intravenous solution bags. Pemetrexed is physically incompatible with lactated Ringer's Injection and Ringer's Injection.
Co-administration of pemetrexed with other medicines and diluents has not been studied, and therefore is not recommended.

Medicine Classification

Prescription Medicine.

Package Quantities

Lyophilised powder in vial (Type I glass). Each carton contains one 500 mg vial of ALIMTA.

Further Information

Excipients

Mannitol, hydrochloric acid, sodium hydroxide.

Name and Address

Eli Lilly and Company (NZ) Limited
Level 3, Axon House
414-422 Khyber Pass Road, Newmarket
PO Box 109 197, Newmarket
Auckland 1031
NEW ZEALAND

Telephone (09) 523 9300.

Date of Preparation

04 January 2008