Consumer medicine information

Alimta

Pemetrexed

BRAND INFORMATION

Brand name

Alimta

Active ingredient

Pemetrexed

Schedule

What is in this leaflet

This leaflet answers some common questions about ALIMTA. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date shown on the final page. More recent information on this medicine may be available. Make sure you speak to your pharmacist, nurse or doctor to obtain the most up to date information on this medicine. You can also download the most up to date leaflet from www.lilly.com.au. The updated leaflet may contain important information about ALIMTA and its use that you should be aware of.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking ALIMTA against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What ALIMTA is used for

ALIMTA is used to treat:

mesothelioma, a rare cancer of the lungs often related to exposure to asbestos
non-small cell lung cancer, a type of lung cancer.

It belongs to a group of medicines called cytotoxic or antineoplastic agents. They may also be called chemotherapy medicines.

It affects enzymes within cancer cells to kill cancer cells or prevent them growing and multiplying.

Your doctor may have prescribed it for another reason.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

This medicine is available only with a doctor's prescription.

ALIMTA may be used in combination with other chemotherapy drugs.

Before you are given ALIMTA

When you must not be given it

Do not take ALIMTA if you have an allergy to:

any medicine containing pemetrexed disodium heptahydrate
any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have or have had any of the following medical conditions:

kidney problems

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Pregnancy and breast-feeding should be avoided during ALIMTA treatment. Your doctor can discuss with you the risks and benefits involved.

This medicine is not recommended for use in children under the age of 18 years. Safety and effectiveness in children younger than 18 years have not been established.

If you have not told your doctor about any of the above, tell him/her before you take ALIMTA.

Taking Premedication

Your doctor should advise you to take certain medicines or vitamin while taking ALIMTA. These may help to minimise side effects.

Your doctor should advise you to take a folate supplement or a multivitamin containing folate once daily for at least five days in the week before your first ALIMTA dose. This should be continued throughout your therapy cycles and for at least three weeks following completion of ALIMTA treatment.

Your doctor should also advise you to have a vitamin B12 injection during the week before your first dose of ALIMTA. A vitamin B12 injection should be given once every three treatment cycles.

Your doctor may also advise you to take an oral corticosteroid such as dexamethasone to reduce the likelihood and severity of skin rashes.

Ask your doctor if you have any questions about why these other medicines have been prescribed for you.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines maybe affected by ALIMTA or may affect how it works. These include:

medicines used to treat arthritis or pain from inflammation such as ibuprofen or other non-steroidal anti-inflammatory medicines (NSAIDs).

You may need different amounts of your medicines or to stop taking them for a few days or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking ALIMTA.

How ALIMTA will be given

Follow all directions given to you by your doctor or pharmacist carefully.

How much is given

Your doctor will decide the dosage of ALIMTA you should take. This will depend on your condition and other factors, such as your weight.

How it is given

ALIMTA is given as an infusion (drip) into your veins over a 10 minute period.

When treating certain cancers, you may also be given other chemotherapy medicines.

Your doctor or nurse will inject ALIMTA for you.

Never inject ALIMTA yourself. Always let your doctor or nurse do this.

How often it is given

ALIMTA is given once every three weeks (1 treatment cycle). Your doctor will advise how many treatment cycles you need.

Before each infusion you will have samples of your blood taken to check that you have enough blood cells to receive ALIMTA. Your doctor may decide to change your dose or delay treating you depending on your general condition and if your blood cell counts are too low.

Overdose

As ALIMTA is given to you under the supervision of your doctor, it is unlikely that you will have too much

However, if you experience any side effects after being given ALIMTA, immediately tell your doctor or nurse or go to the Emergency Department at your nearest hospital. You may need urgent medical attention.

While you are taking ALIMTA

Things you must do

Always take your daily folate supplement until your doctor tells you to stop.

Always check with your doctor that your vitamin B12 injections are up to date.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are receiving ALIMTA.

Tell any other doctors, dentists and pharmacists who treat you that you are receiving this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are receiving this medicine. It may affect other medicines used during surgery.

If you become pregnant while receiving this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are receiving this medicine.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things to be careful of

Be careful driving or operating machinery until you know how ALIMTA affects you. This medicine may cause tiredness or drowsiness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ALIMTA. This medicine is to help people with mesothelioma or non-small cell lung cancer, but it may have unwanted side effects in some people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

fatigue, drowsiness, fainting
feeling dehydrated
pain in the stomach, upset stomach, nausea, loss of appetite, vomiting
diarrhoea, constipation, dark urine
muscle weakness
skin irritation, burning or prickling sensation
hair loss
conjunctivitis (red and itchy eyes with or without discharge and crusty eyelids)
coughing, difficulty breathing, wheezing caused by inflammation of the lung
abdominal, chest, back or leg pain.

Additional side effects when used in combination with other chemotherapy agents include:

taste change
loss of feeling
kidney problems where you pass little or no urine.

The above lists include the more common side effects of your medicine. When used in combination with other chemotherapy medicine, also refer to the other product's consumer medicine information leaflet for a list of other possible side effects.

Tell your doctor as soon as possible if you notice any of the following:

fever or infection with a temperature, sweating or other signs of infection
pain, redness, swelling or sores in your mouth
sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips or tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
tiredness, feeling faint or breathless, if you look pale
bleeding or bruising more easily than normal.

The above list includes serious side effects which may require medical attention.

In rare cases ALIMTA can cause inflammation of the colon (large bowel). Tell your doctor as soon as possible if you experience any of the following symptoms:

diarrhoea with blood and mucus
stomach pain
fever.

If any of the following happen, tell your doctor immediately or go to the Emergency Department at your nearest hospital:

chest pain or fast heart beat
bleeding from the gums, nose or mouth, any bleeding that will not stop, reddish or pinkish urine, unexpected bruising.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people. Some of these side effects (for example, abnormal blood tests showing low cell counts) can only be found when your doctor does tests to check your progress.

After having ALIMTA

Storage

This medicine will be stored in the hospital pharmacy or on the ward.

It will be kept in a cool dry place where the temperature stays below 25°C.

Product description

What it looks like

ALIMTA is a white to off white powder and is available in a glass vial container with a rubber stopper.

Ingredients

ALIMTA is supplied in 500 mg and 100 mg vials.

The 500 mg vial of ALIMTA contains pemetrexed disodium heptahydrate equivalent to 500 mg pemetrexed and 500 mg of mannitol.

The 100 mg vial of ALIMTA contains pemetrexed disodium heptahydrate equivalent to 100 mg pemetrexed and 106.4 mg of mannitol.

Hydrochloric acid and/or sodium hydroxide may be added to both presentations to adjust pH.

Supplier

ALIMTA is supplied by
Eli Lilly Australia Pty Ltd
Level 9, 60 Margaret Street
Sydney NSW 2000

Australian Registration Number:

ALIMTA 500 mg, AUST R 96731

ALIMTA 100 mg, AUST R 146828

This leaflet was revised in September 2023.

vA6

®= Registered Trademark

Published by MIMS November 2023

BRAND INFORMATION

Brand name

Alimta

Active ingredient

Pemetrexed

Schedule

1 Name of Medicine

Pemetrexed disodium heptahydrate.

2 Qualitative and Quantitative Composition

Alimta is supplied in 500 mg and 100 mg vials.
Each 500 mg vial of Alimta contains pemetrexed disodium heptahydrate equivalent to 500 mg pemetrexed. Each 100 mg vial of Alimta contains pemetrexed disodium heptahydrate equivalent to 100 mg pemetrexed.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Alimta is supplied as a sterile lyophilised powder for intravenous infusion available in single dose 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.

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

Non-small cell lung cancer.

Alimta 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.
Alimta 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

Alimta should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents.

Alimta in combination use with cisplatin.

Adults.

The recommended dose of Alimta 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 Alimta 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 Alimta 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. Pretreatment 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 Alimta administration.
To reduce toxicity, patients treated with Alimta 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 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 one intramuscular injection of vitamin B₁₂ during the week preceding the first dose of Alimta and every 3 cycles thereafter. Subsequent vitamin B₁₂ injections may be given the same day as Alimta. In clinical trials, the dose of folic acid studied ranged from 350 to 1,000 microgram, and the dose of vitamin B₁₂ received was 1,000 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 Alimta 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 ≥ 1,500 cells/mm³ and platelets ≥ 100,000 cells/mm³ prior to scheduled administration of any cycle.
Dose reduction recommendations. 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 1-3, which are suitable for using Alimta as a single agent or in combination with cisplatin.

If patients develop nonhaematologic toxicities (excluding neurotoxicity) ≥ grade 3, treatment 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 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.

Alimta therapy should be discontinued if a patient experiences any haematologic or nonhaematologic 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.

Renally impaired patients.

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 Alimta whose creatinine clearance is < 45 mL/min (using the standard Cockcroft and Gault formula or GFR measured by Tc99m-DPTA serum clearance method).

Preparation and administration instructions.

Use aseptic technique.
Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% sodium chloride injection. Alimta is physically incompatible with diluents containing calcium, including lactated Ringer's injection and Ringer's injection. Coadministration of Alimta 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 Alimta for intravenous infusion administration.
2. Calculate the dose and the number of Alimta vials needed. 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 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 Alimta solution is between 6.6 and 7.8. Further dilution is required.
5. The appropriate volume of reconstituted Alimta 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 discolouration prior to administration.
Chemical and physical stability of reconstituted and infusion solutions of Alimta was demonstrated for up to 24 hours after reconstitution of the original vial when refrigerated between 2 to 8°C. However, because Alimta 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

Alimta 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

Alimta 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 Alimta 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 nonhaematologic toxicity seen in the previous cycle (see Section 4.2 Dose and Method of Administration, Dose reduction recommendations).
Patients treated with Alimta must be instructed to take folic acid and vitamin B₁₂ with Alimta 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 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.
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, 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.
Immunodepressed 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 radiosensitising agents. Cases of radiation recall have been reported in patients who received radiotherapy weeks or years previously.

Use in hepatic impairment.

Alimta 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 times the ULN (hepatic metastases present) have not been specifically studied.
Alimta 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 Alimta seen in clinical trials have been reversible. Skin rash has been reported in patients not pretreated with a corticosteroid in clinical trials. Pretreatment 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 Alimta is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to Alimta administration.

Use in renal impairment.

Alimta is primarily eliminated unchanged by renal excretion. Insufficient numbers of patients have been studied with creatinine clearance below 45 mL/minute. Therefore, Alimta 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.

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.

Effects on laboratory tests.

There are no data available that shows that pemetrexed has an effect on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Alimta is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. In vitro studies indicate that pemetrexed is actively secreted by the organic anion transporter 3 (OAT3) in the kidney. In vitro work also indicates that pemetrexed 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 Alimta.
Results from in vitro studies with human liver microsomes suggest that Alimta would not cause clinically significant interactions with drugs metabolised by CYP3A, CYP2D6, CYP2C9 and CYP1A2.
The pharmacokinetics of Alimta are not influenced by oral folic acid and intramuscular vitamin B₁₂ supplementation or by concurrently administered cisplatin. Total platinum clearance is not affected by Alimta administration.
Although NSAIDs in moderate doses can be administered with Alimta 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 Alimta 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 Alimta.
In the absence of data regarding potential interaction between Alimta 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 Alimta 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.
(Category D)
The use of Alimta 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).
It is not known whether pemetrexed is excreted in human milk. Therefore, breastfeeding should be discontinued during Alimta 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 Alimta may cause fatigue. Therefore, patients should be cautioned against driving or operating machinery if this event occurs.

4.8 Adverse Effects (Undesirable Effects)

Single agent Alimta (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 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.

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% (uncommon) 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 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 chemonaive and heavily pretreated 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 Alimta and 163 patients with mesothelioma randomly assigned to receive single agent cisplatin. In both treatment arms, these chemonaive 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 Alimta and cisplatin).
Clinically relevant toxicity that was reported in ≥ 1% and ≤ 5% (common) of the patients that were randomly assigned to receive cisplatin and Alimta 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 Alimta 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 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 and cisplatin.
Clinically relevant toxicity that was reported in ≥ 1% and ≤ 5% (common) of the patients that were randomly assigned to receive cisplatin and pemetrexed include: AST increase, ALT increase, infection, febrile neutropenia, renal failure, pyrexia, dehydration, conjunctivitis, and creatinine clearance decrease.
Clinically relevant toxicity that was reported in < 1% (uncommon) of the patients that were randomly assigned to receive cisplatin and pemetrexed include: GGT increase, chest pain, arrhythmia, and motor neuropathy. 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 Alimta (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 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 include: decreased platelets, decreased creatinine clearance, constipation, edema, 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 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 (N = 800). The incidence of adverse reactions was evaluated for patients who received ≤ 6 cycles of pemetrexed maintenance (N = 519), and compared to patients who received > 6 cycles of pemetrexed (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.

Postmarketing data.

Gastrointestinal disorders.

Rare cases of colitis have been reported in patients treated with Alimta.

General disorders and administration site conditions.

Rare cases of oedema 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 disorders.

Rare cases of interstitial pneumonitis have been reported in patients treated with Alimta.

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 Alimta.
Rare: ≤ 0.1% of patients treated with Alimta.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Reported symptoms of Alimta 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 Alimta overdose should include consideration of the use of leucovorin 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 is an antifolate antineoplastic agent. 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 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 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 indicate that overexpression of thymidylate synthase (TS) correlates with reduced sensitivity to pemetrexed in antifolate resistant cell lines. Results in a study with specimens from chemonaive patients with NSCLC demonstrated lower levels of TS expression in adenocarcinoma as compared to squamous cell carcinoma tumors. These data suggest that pemetrexed 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 was combined with cisplatin.

Clinical trials.

Malignant pleural mesothelioma.

The safety and efficacy of Alimta have been evaluated in chemonaive patients with malignant pleural mesothelioma (MPM) as a single agent and in combination with platinum based regimens.
EMPHACIS, a multicentre, randomised, single blind phase 3 study of Alimta plus cisplatin versus cisplatin 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. Alimta 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 Alimta. 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 Alimta/ 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 Alimta/ 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 Alimta/ 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 Alimta/ cis arm and deterioration of lung function over time in the control arm.

Non-small cell lung cancer.

The safety and efficacy of Alimta 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 multicentre, randomised, open label phase 3 study of Alimta plus cisplatin versus gemcitabine plus cisplatin (for up to 6 cycles) in chemonaive patients with locally advanced or metastatic (stage IIIb or IV) non-small cell lung cancer (NSCLC) showed that Alimta 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 prespecified adjusted analyses as shown in Figure 2.

The analysis of the impact of NSCLC histology on overall survival demonstrated statistically significant superiority for Alimta + 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 Alimta plus cisplatin within the histology subgroups.
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) 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 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.
In the overall study population, Alimta 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 Alimta 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, Alimta 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 Alimta over placebo.
There were no clinically relevant differences observed for the safety profile of Alimta within the histology subgroups. See Figure 4.

A multicentre, randomised, double blind, placebo controlled phase 3 study (PARAMOUNT), compared the efficacy and safety of continuation maintenance treatment with Alimta 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 Alimta in combination with cisplatin. Of the 939 patients treated with Alimta plus cisplatin induction, 539 patients were randomised to maintenance treatment with Alimta or placebo. Of the randomised patients, 44.9% had a complete/ partial response and 51.9% had a response of stable disease to Alimta 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 Alimta plus cisplatin induction therapy to the start of maintenance treatment was 2.96 months on both the Alimta 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 Alimta and 4 cycles of placebo. A total of 169 patients (47.1%) completed ≥ 6 cycles maintenance treatment with Alimta, representing at least 10 total cycles of Alimta.
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 Alimta 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 Alimta plus cisplatin first line induction treatment, the median investigator assessed PFS was 6.9 months for the Alimta arm and 5.6 months for the placebo arm (hazard ratio = 0.59, 95% CI = 0.47-0.74).
Following Alimta plus cisplatin induction (4 cycles), treatment with Alimta 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 Alimta arm versus 21.7% on the placebo arm. The relative treatment effect of Alimta 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 Alimta were 58% and 32% respectively, compared to 45% and 21% for patients on placebo. From the start of Alimta plus cisplatin first line induction treatment, the median OS of patients was 16.9 months for the Alimta 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 postdiscontinuation chemotherapy was 64.3% for Alimta and 71.7% for placebo. See Figure 5.

The Alimta maintenance safety profiles from the two studies JMEN and PARAMOUNT were similar.
A multicentre, randomised, open label phase 3 study of Alimta 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 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 11, indicate comparable efficacy between pemetrexed and docetaxel.

On this study, treatment was administered until disease progression.
An analysis of the impact of NSCLC histology on overall survival was in favor of Alimta 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 favor 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 Alimta within the histology subgroups.

5.2 Pharmacokinetic Properties

Absorption.

Alimta is for intravenous administration only.

Distribution.

Alimta has a steady-state volume of distribution of 16.1 litres. In vitro studies indicate that Alimta is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment.

Metabolism.

Alimta undergoes limited hepatic metabolism.

Excretion.

Alimta 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 Alimta 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 Alimta 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 Alimta 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 Alimta 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 Alimta decrease as renal function decreases. On average, patients with creatinine clearance of 45 mL/min will have a 56% increase in Alimta 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 500 mg vial of Alimta contains 500 mg of mannitol. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.
Each 100 mg vial of Alimta contains 106.4 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. Alimta is not light sensitive.

6.5 Nature and Contents of Container

Alimta, pemetrexed disodium for injection is available in sterile single use vials containing 100 mg or 500 mg pemetrexed (pack size 1 vial).

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

Chemical structure.

The active ingredient in Alimta 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. Pemetrexed disodium is a white to almost white solid. The structural formula is as follows:

CAS number.

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

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only Medicine.

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