Consumer medicine information

Pemetrexed APOTEX Powder for Injection

Pemetrexed

BRAND INFORMATION

Brand name

Pemetrexed APOTEX

Active ingredient

Pemetrexed

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pemetrexed APOTEX Powder for Injection.

What is in this leaflet

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

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

What this medicine is used for

The name of your medicine is Pemetrexed APOTEX Powder for Injection, which is given as an intravenous infusion. It contains the active ingredient pemetrexed, as the disodium salt.

Pemetrexed 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.

Pemetrexed 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.

Pemetrexed may be used in combination with other chemotherapy drugs.

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

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

There is no evidence that this medicine is addictive.

This medicine should not be used in children under the age of 18.

Before you are given this medicine

When you must not be given it

Do not use this medicine if you have an allergy to:

  • any medicine containing pemetrexed
  • 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.

Do not use this medicine if you are pregnant. This medicine should not be given during pregnancy. You and your doctor should discuss the risks and benefits involved.

Do not breastfeed if you are using this medicine. This medicine should not be given whilst breastfeeding. You and your doctor should discuss the risks and benefits involved.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

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 breastfeeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start using this medicine.

Taking other medicines

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

Some medicines may interact with pemetrexed. These include:

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

If you are taking any of these, you may need a different dose, or you may need to take different medicines.

Other medicines not listed above may also interact with pemetrexed.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using this medicine.

Taking pre-medication

Your doctor should advise you to take certain medicines or vitamin while using pemetrexed. 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 pemetrexed dose. This should be continued throughout your therapy cycles and for at least three weeks following completion of pemetrexed treatment.

Your doctor should also advise you to have a vitamin B12 injection during the week before your first dose of pemetrexed. 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.

How this medicine will be given

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much will be given

Your doctor will decide the dosage of Pemetrexed APOTEX you will be given. This will depend on your condition and other factors, such as your weight.

How it is given

Pemetrexed 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 pemetrexed for you.

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

How often it is given

Pemetrexed 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 pemetrexed. 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.

If you are given too much (overdose)

As pemetrexed 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 pemetrexed, immediately tell your doctor or nurse or telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital. You may need urgent medical attention.

While you are being treated with this medicine

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 be treated with pemetrexed.

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

If you are going to have surgery, tell the surgeon or anaesthetist that you are being treated with 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 when driving or operating machinery until you know how this medicine 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 as soon as possible if you do not feel well while you are being treated with pemetrexed or if you have any questions or concerns.

All medicines can have side effects. Sometimes they are serious but most of the time they are not.

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

Tell your doctor if you notice any of the following:

  • fatigue, drowsiness, fainting
  • feeling dehydrated
  • pain in the stomach, upset stomach, nausea, loss of appetite, vomiting
  • diarrhoea, constipation or 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
  • swelling
  • abdominal, chest, back or leg pain.

The above lists include the more common side effects of your medicine.

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.

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.

These may be serious side effects and you may need medical attention.

In rare cases pemetrexed 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 you experience any of the following, contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital:

  • chest pain or fast heartbeat
  • bleeding from the gums, nose or mouth, any bleeding that will not stop, reddish or pinkish urine, unexpected bruising
  • symptoms of an allergic reaction including cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin

These are very serious side effects and you may need urgent medical attention or hospitalisation.

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

Other side effects not listed above may occur in some patients.

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.

Storage and disposal

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 will stay below 25°C.

Product description

What Pemetrexed APOTEX Powder for Injection looks like

500 mg strength

White to either light yellow or green-yellow powder. AUST R 210440.

Pack of 1 vial.

Ingredients

Each vial contains 500 mg of pemetrexed as the active ingredient.

Each vial also contains the following inactive ingredients:

  • mannitol.
  • hydrochloric acid and/or sodium hydroxide may have been added to both strengths to adjust pH.

This medicine is free from gluten, lactose, sucrose, tartrazine and other azo dyes.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO and APOTEX are registered trademarks of Apotex Inc.

This leaflet was last updated in June 2020.

Published by MIMS July 2020

BRAND INFORMATION

Brand name

Pemetrexed APOTEX

Active ingredient

Pemetrexed

Schedule

S4

 

1 Name of Medicine

Pemetrexed disodium hemipentahydrate.

2 Qualitative and Quantitative Composition

Each 500 mg vial contains pemetrexed disodium, equivalent to 500 mg pemetrexed, and 500 mg mannitol. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

500 mg.

White to either light yellow or green-yellow powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Malignant pleural mesothelioma.

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

Non-small cell lung cancer.

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

4.2 Dose and Method of Administration

Pemetrexed APOTEX powder for injection is intended for intravenous infusion.
Pemetrexed should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents.

Pemetrexed in combination use with cisplatin.

Adults.

The recommended dose of pemetrexed 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 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. Refer to cisplatin Product Information document for specific dosing advice.

Single agent pemetrexed.

Adults.

The recommended dose of pemetrexed is 500 mg/m2 BSA administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.

Premedication regimen.

Skin rash has been reported in patients not pre-treated 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 administration.
To reduce toxicity, patients treated with pemetrexed 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 and dosing should continue during the full course of therapy and for 21 days after the last dose of pemetrexed. Patients must also receive one intramuscular injection of vitamin B12 during the week preceding the first dose of pemetrexed and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as pemetrexed. In clinical trials, the dose of folic acid studied ranged from 350-1000 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 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 reduction recommendations.

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 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 therapy should be discontinued if a patient experiences any haematologic or non-haematologic Grade 3 or 4 toxicity after two 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 ≥ 45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance < 45 mL/min have been treated to make dosage recommendations for this group of patients. Therefore, patients should not receive pemetrexed 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. Pemetrexed is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection and Ringer's Injection. Co-administration of pemetrexed 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 for intravenous infusion administration.
2. Calculate the dose and the number of pemetrexed vials needed. A 500 mg vial contains 500 mg 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 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 solution is between 6.6 and 7.8. Further dilution is required.
5. The appropriate volume of reconstituted pemetrexed 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 was demonstrated for up to 24 hours after reconstitution of the original vial when refrigerated between 2-8°C. However, because pemetrexed 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 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 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 should not be given to patients until their 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-haematological toxicity seen in the previous cycle (see Section 4.2 Dose and Method of Administration, Dose reduction recommendations).
Patients treated with pemetrexed must be instructed to take folic acid and vitamin B12 with pemetrexed as a prophylactic measure to reduce treatment-related toxicity (see Section 4.2 Dose and Method of Administration). In the Phase III 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 pre-treatment 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.

Paediatric use.

Pemetrexed is not recommended for use in patients less than 18 years of age, as safety and efficacy have not been established in this group of patients.

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.

Use in renal impairment.

Pemetrexed is primarily eliminated unchanged by renal excretion. Insufficient numbers of patients have been studied with creatinine clearance below 45 mL/min. Therefore, pemetrexed 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 hepatic impairment.

Pemetrexed is not extensively metabolised by the liver. However, patients with hepatic impairment such as bilirubin > 1.5 x 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.
Pemetrexed 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 pre-treated 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 is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to pemetrexed administration.

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

Pemetrexed 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 pemetrexed.
Results from in vitro studies with human liver microsomes suggest that pemetrexed would not cause clinically significant interactions with drugs metabolised by CYP3A, CYP2D6, CYP2C9 and CYP1A2.
The pharmacokinetics of pemetrexed are not influenced by oral folic acid and intramuscular vitamin B12 supplementation or by concurrently administered cisplatin. Total platinum clearance is not affected by pemetrexed administration.

Non-steroidal anti-inflammatory drugs (NSAIDs).

Although NSAIDs in moderate doses can be administered with pemetrexed 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 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.
In the absence of data regarding potential interaction between pemetrexed 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 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 characterized by reduced fertility, hypospermia and testicular atrophy.
(Category D)
The use of pemetrexed 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 embryofoetal toxic effects (embryofoetal deaths, reduced foetal weights and incomplete ossification) were also observed. Embryofoetal 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, breast-feeding should be discontinued during pemetrexed 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 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 pemetrexed (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 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.
Clinically relevant CTC toxicity that was reported in ≥ 1% and ≤ 5% (common) of the patients that were randomly assigned to pemetrexed include sensory neuropathy, motor neuropathy, abdominal pain, increased creatinine, febrile neutropenia, infection without neutropenia, allergic reaction/ hypersensitivity and erythema multiforme.
Clinically relevant CTC toxicity that was reported in < 1% (uncommon) of the patients that were randomly assigned to pemetrexed include supraventricular arrhythmias.
Clinically relevant Grade 3 and Grade 4 laboratory toxicities were similar between integrated Phase II results from three single agent pemetrexed studies (n = 164) and the Phase III single agent pemetrexed 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 II 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 (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 pemetrexed and cisplatin 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.
Clinically relevant toxicity that was reported in ≥ 1% and ≤ 5% (common) of the patients that were randomly assigned to receive pemetrexed and cisplatin 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 pemetrexed and cisplatin 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 pemetrexed and cisplatin and 830 patients with NSCLC who were randomised to study and received gemcitabine and cisplatin. 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.
Clinically relevant toxicity that was reported in ≥ 1% and ≤ 5% (common) of the patients that were randomly assigned to pemetrexed plus cisplatin 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 pemetrexed and cisplatin include: GGT increase, chest pain, arrhythmia and motor neuropathy. Acute renal failure was observed more commonly in the pemetrexed and cisplatin arm (6 cases, 0.7%) than in the gemcitabine plus cisplatin arm (0 cases).

Single agent pemetrexed (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.

Post-marketing experience.

Rare: ≤ 0.1% of patients treated with pemetrexed.

Blood and lymphatic system.

Rare cases of immune-mediated haemolytic anaemia have been reported in patients treated with pemetrexed.

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.

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.

Skin.

Rare cases of bullous conditions have been reported including Stevens-Johnson syndrome and toxic epidermal necrolysis which in some cases were fatal.

Hepatobiliary disorders.

Rare cases of hepatitis, potentially serious, have been reported during clinical trials with pemetrexed.

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 and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms.

Reported symptoms of pemetrexed 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.

Treatment.

If overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. Management of pemetrexed 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 131126 (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 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 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 TS correlates with reduced sensitivity to pemetrexed in antifolate-resistant cell lines. Results in a study with specimens from chemonaive patients with non-small cell lung cancer (NSCLC) demonstrated lower levels of TS expression in adenocarcinoma as compared to squamous cell carcinoma tumours. This data suggests 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 pemetrexed 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 III study of pemetrexed plus cisplatin versus cisplatin in chemonaїve patients with MPM, 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 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. In 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 summarizes the number of cycles of treatment completed by randomized 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 MPM in the pemetrexed and cisplatin arm (n = 212 patients) versus the cisplatin arm alone (n = 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 and cisplatin 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 plus cisplatin 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 and cisplatin arm and deterioration of lung function over time in the control arm.

Non-small cell lung cancer.

The safety and efficacy of pemetrexed 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 III study of pemetrexed plus cisplatin versus gemcitabine plus cisplatin (for up to 6 cycles) in chemonaive patients with locally advanced or metastatic (Stage IIIb or IV) NSCLC showed that pemetrexed 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 - see Figure 2.
The analysis of the impact of NSCLC histology on overall survival demonstrated statistically significant superiority for pemetrexed plus cisplatin in the adenocarcinoma (n = 846, 12.6 versus 10.9 months, adjusted Hazard Ratio = 0.84; 95% CI = 0.71-0.99, p = 0.033) and large cell carcinoma subgroups (n = 153, 10.4 versus 6.7, adjusted Hazard Ratio = 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 Hazard Ratio = 1.23; 95% CI = 1.00-1.51, p = 0.050) or patients with other histologies (n = 250, 8.6 versus 9.2, adjusted Hazard Ratio = 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.
In this study, treatment was administered up to 6 cycles.
There were no clinically relevant differences observed for the safety profile of pemetrexed plus cisplatin within the histology subgroups.
A multicentre, randomized, double-blind, placebo-controlled Phase III study (JMEN), compared the efficacy and safety of maintenance treatment with pemetrexed plus best supportive care (BSC) (n = 441) with that of placebo plus best supportive care (n = 222) in patients with locally advanced (Stage IIIB) or metastatic (Stage IV) NSCLC who did not progress after 4 cycles of first-line doublet therapy. All patients included in this study had an ECOG PS 0 or 1. Patients received maintenance treatment until disease progression. Efficacy and safety were measured from the time of randomization after completion of first line (induction) therapy. Patients received a median of 5 cycles of maintenance treatment with pemetrexed and 3½ 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.
In the overall study population, pemetrexed was statistically superior to placebo in terms of overall survival (median 13.4 months versus 10.6 months, Hazard Ratio = 0.79 (95% CI: 0.65-0.95), p-value = 0.012) and progression-free survival (median 4.0 months versus 2.0 months, Hazard Ratio = 0.60 (95% CI: 0.49-0.73), p-value < 0.00001). Consistent with previous pemetrexed studies, a difference in treatment outcomes was observed according to histological classification. For the indicated population i.e. patients with NSCLC other than predominantly squamous cell histology, pemetrexed was superior to placebo for overall survival (median 15.5 months versus 10.3 months, Hazard Ratio = 0.70 (95% CI: 0.56-0.88)) and progression-free survival (median 4.4 months versus 1.8 months, Hazard Ratio = 0.47 (95% CI: 0.37-0.60)).
The progression-free survival and overall survival results in patients with squamous cell histology suggested no advantage for pemetrexed over placebo. See Figure 4.
There were no clinically relevant differences observed for the safety profile of pemetrexed within the histology subgroups.
A multicentre, randomized, open-label Phase III study of pemetrexed 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 (ITT population n = 283) and 7.9 months for patients treated with docetaxel (ITT population n = 288) which is not statistically significantly different. These data, as outlined in Table 11, indicate comparable efficacy between pemetrexed and docetaxel.
In this study, treatment was administered until disease progression.
An analysis of the impact of NSCLC histology on overall survival was in favour of pemetrexed versus docetaxel for other than predominantly squamous histology (n = 399, 9.3 versus 8.0 months, adjusted Hazard Ratio = 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 Hazard Ratio = 1.56; 95% CI = 1.08-2.26, p = 0.018). There were no clinically relevant differences observed for the safety profile of pemetrexed within the histology subgroups.

5.2 Pharmacokinetic Properties

Absorption.

Pemetrexed is for intravenous administration only.

Distribution.

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 is not affected by degree of renal impairment.

Metabolism.

Pemetrexed undergoes limited hepatic metabolism.

Excretion.

Pemetrexed is primarily eliminated in the urine with up to 70%-90% of the dose recovered unchanged within the first 24 hours following administration. Total plasma clearance of pemetrexed is 92 mL/min and the elimination half-life from plasma is 3½ hours in patients with normal renal function.

Special populations.

Analyses to evaluate the pharmacokinetics of pemetrexed in special populations included 287 patients with a variety of advanced tumour types from 10 single-agent Phase II studies, 70 patients from the Phase III malignant pleural mesothelioma (MPM) EMPHACIS trial and 47 patients from a Phase I renal study.

Elderly.

No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26-80 years.

Renal impairment.

Pharmacokinetic analyses included 127 patients with reduced renal function. Total plasma clearance and renal clearance of pemetrexed decrease as renal function decreases. On average, patients with creatinine clearance of 45 mL/min will have a 56% increase in pemetrexed 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).

Hepatic impairment.

No effect of aspartate transaminase [(AST), (SGOT)], alanine transaminase [(ALT), (SGPT)], or total bilirubin on the pharmacokinetics of pemetrexed was observed. However, specific studies in hepatically-impaired patients have not been conducted (see Section 4.4 Special Warnings and Precautions for Use).

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

Hydrochloric acid, mannitol, sodium hydroxide.

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.

6.5 Nature and Contents of Container

Pemetrexed APOTEX powder for injection.

500 mg.

Pack size: 1 vial, single use.
AUST R 210440.
APO and APOTEX are registered trademarks of Apotex Inc.
* Not all strengths and/or pack sizes may be available.

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.
This medicine is supplied as a sterile lyophilized powder for intravenous infusion in single dose vials; the product is a white to either light yellow or green-yellow lyophilized solid in 500 mg vials.

Chemical structure.


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, hemipentahydrate.
Molecular Formula: C20H24N5Na2O8½.
Molecular Weight: 516.412.

CAS number.

357166-30-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes