Consumer medicine information

PEMETREXED ACCORD

Pemetrexed

BRAND INFORMATION

Brand name

Pemetrexed Accord

Active ingredient

Pemetrexed

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using PEMETREXED ACCORD.

PEMETREXED ACCORD

PEMETREXED ACCORD

 Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

 1. Why am I being given Pemetrexed Accord?

Pemetrexed Accord contains the active ingredient pemetrexed. Pemetrexed Accord belongs to a group of medicines known as antineoplastic or cytotoxic agents. Pemetrexed Accord is used to treat mesothelioma, a rare cancer of the lungs often related to exposure to asbestos and non-small cell lung cancer, a type of lung cancer.

For more information, see Section 1. Why am I being given Pemetrexed Accord? in the full CMI.

 2. What should I know before I am given Pemetrexed Accord?

Do not use if you have ever had an allergic reaction to any medicine containing pemetrexed or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given Pemetrexed Accord? in the full CMI.

 3. What if I am taking other medicines?

Some medicines may interfere with Pemetrexed Accord and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

 4. How will I be given Pemetrexed Accord?

Pemetrexed Accord will be given to you by a doctor or a nurse.

More instructions can be found in Section 4. How will I be given Pemetrexed Accord? in the full CMI.

 5. What should I know while being given Pemetrexed Accord?

Things you should do
  • Be sure to keep all your doctor's appointments.
  • Tell any other doctors, dentists, and pharmacists who treat you that you are being given Pemetrexed Accord.
  • If you become pregnant while you are being given this medicine, tell your doctor immediately.
  • 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
Driving or using machinesBe careful driving or operating machinery until you know how Pemetrexed Accord 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.

For more information, see Section 5. What should I know while being given Pemetrexed Accord? in the full CMI.

 6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

Some of the serious side effects are:

  • Allergic reaction – some symptoms may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of body; rash, itching or hives on skin
  • chest pain or fast heart beat
  • fever or infection with a temperature sweating or other signs of infection
  • tiredness
  • feeling faint or breathless
  • looking pale
  • bleeding or bruising more easily than normal
  • bleeding from the gums, nose or mouth, any bleeding that will not stop, reddish or pinkish urine, unexpected bruising
  • mouth pain, redness, swelling, sores in the mouth

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

PEMETREXED ACCORD

Active ingredient(s): Pemetrexed (as disodium)

 Consumer Medicine Information (CMI)

This leaflet provides important information about using Pemetrexed Accord. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Pemetrexed Accord.

Where to find information in this leaflet:

1. Why am I being given Pemetrexed Accord?
2. What should I know before I am given Pemetrexed Accord?
3. What if I am taking other medicines?
4. How will I be given Pemetrexed Accord?
5. What should I know while being given Pemetrexed Accord?
6. Are there any side effects?
7. Product details

 1. Why am I being given Pemetrexed Accord?

Pemetrexed Accord contains the active ingredient pemetrexed. Pemetrexed Accord belongs to a group of medicines known as antineoplastic or cytotoxic agents. You may also hear of these being called chemotherapy medicines.

Pemetrexed Accord is used to treat mesothelioma, a rare cancer of the lungs often related to exposure to asbestos and non-small cell lung cancer, a type of lung cancer.

Pemetrexed Accord affects enzymes within cancer cells to kill the cancer cells or prevent them growing and multiplying.

Pemetrexed Accord may be used alone or in combination with other medicines to treat cancer.

Your doctor, however, may prescribe Pemetrexed Accord for another purpose.

 2. What should I know before I am given Pemetrexed Accord?

Warnings

You must not be given Pemetrexed Accord if:

  • you have an allergy to pemetrexed or any of the ingredients listed at the end of this leaflet.

Tell your doctor if you have or have had:

  • kidney problems

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor if you:

  • are pregnant, or intend to become pregnant
  • are breastfeeding or plan to breastfeed

Like most medicines used to treat cancer, Pemetrexed Accord is not recommended for use during pregnancy. Your doctor will discuss with you the risks and benefits of having Pemetrexed Accord during pregnancy.

You should not breast-feed your child during your treatment with Pemetrexed Accord.

Paediatric use

Pemetrexed Accord 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.

Taking Premedication

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

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

 3. What if I am taking other medicines?

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

Some medicines and Pemetrexed Accord may interfere with each other. These include:

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

These medicines and treatments may be affected by Pemetrexed Accord or may affect how well it works. You may need different amounts of your medicine, or you may need to have different medicines. Your doctor or pharmacist will advise you.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Pemetrexed Accord.

 4. How will I be given Pemetrexed Accord?

How much will be given

Your doctor will decide on what dose you will receive. This depends on your condition and other factors, such as your weight.

When will Pemetrexed Accord be given

Pemetrexed Accord 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.

Pemetrexed Accord 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 Accord. 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 receive too much Pemetrexed Accord

Since Pemetrexed Accord is usually given to you in hospital under the supervision of your doctor, it is very unlikely that you will be given too much of the medicine. If you think that you have been given too much Pemetrexed Accord.

You should immediately:

  • phone the Poisons Information Centre (13 11 26), or
  • contact your doctor, nurse or pharmacist.

You should do this even if there are no signs of discomfort or poisoning.

 5. What should I know while being given Pemetrexed Accord?

Things you must do

Be sure to keep all your doctor's appointments so that your progress can be checked.

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 Pemetrexed Accord.

Tell any other doctors, dentists, and pharmacists who treat you that you are being given Pemetrexed Accord.

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

Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

If you become pregnant while you are being given Pemetrexed Accord, tell your doctor immediately.

Driving or using machines

Be careful driving or operating machinery until you know how Pemetrexed Accord 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.

Looking after your medicine

The hospital will store Pemetrexed Accord under the correct conditions.

Getting rid of any unwanted medicine

Your doctor or pharmacist will dispose of any Pemetrexed Accord that may be left over.

Do not use this medicine after the expiry date.

 6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Common side effects

Common side effectsWhat to do
GENERAL BODY
  • fever or infection with a temperature, sweating or other signs of infection
  • fatigue
  • drowsiness
  • feeling dehydrated
  • muscle weakness
  • hair loss
  • abdominal, chest, back or leg pain
GASTROINTESTINAL
  • pain in stomach
  • upset stomach
  • nausea
  • loss of appetite
  • vomiting
  • diarrhoea
  • constipation
RESPIRATORY
  • coughing
  • difficulty breathing
  • wheezing caused by inflammation of the lung
KIDNEY
  • dark urine
EYES
  • conjunctivitis (red and itchy eyes with or without discharge and crusty eyelids)
SKIN
  • skin irritation
  • burning or prickling sensation
Additional side effects when used in combination with other chemotherapy agents.
GENERAL BODY
  • loss of feeling
MOUTH
  • taste change
KIDNEY
  • kidney problems – passing little or no urine
Speak to your doctor if you have any of these common side effects and they worry you

Serious side effects

Serious side effectsWhat to do
ALLERGY
Symptoms of allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of body; rash, itching or hives on skin
GENERAL BODY
  • chest pain or fast heart beat
  • fever or infection with a temperature sweating or other signs of infection
  • tiredness
  • feeling faint or breathless
  • looking pale
  • bleeding or bruising more easily than normal
  • bleeding from the gums, nose or mouth, any bleeding that will not stop, reddish or pinkish urine, unexpected bruising
MOUTH
  • pain
  • redness
  • swelling
  • sores in the mouth
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital

In rare cases Pemetrexed Accord 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

These side effects may differ when using Pemetrexed Accord in combination with another chemotherapy agent.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

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

The benefits and side effects of Pemetrexed Accord may take some time to occur. Therefore, even after you have finished your Pemetrexed Accord treatment you should tell your doctor or nurse immediately if you notice any of the side effects listed in this section.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

 7. Product details

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

What Pemetrexed Accord contains

Active ingredient
(main ingredient)		pemetrexed
Other ingredients
(inactive ingredients)		mannitol
hydrochloric acid, sodium hydroxide (pH adjustment)

Do not take this medicine if you are allergic to any of these ingredients.

What Pemetrexed Accord looks like

Pemetrexed Accord is a white to off white powder and is available in a glass vial. (100 mg: AUST R 222420, 500 mg: AUST R 222415, 1000 mg: AUST R 222419)

Who distributes Pemetrexed Accord

Accord Healthcare Pty Ltd
Level 24, 570 Bourke Street
Melbourne, VIC, 3000
Australia

This leaflet was prepared in November 2023.

Published by MIMS February 2024

BRAND INFORMATION

Brand name

Pemetrexed Accord

Active ingredient

Pemetrexed

Schedule

S4

 

1 Name of Medicine

Pemetrexed disodium.

6.7 Physicochemical Properties

Pemetrexed disodium is a white to almost white solid.
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]-L-glutamic acid disodium salt. It has an empirical formula of C20H19N5Na2O6 and a molecular weight of 471.37.

Chemical structure.


CAS number.

150399-23-8.

2 Qualitative and Quantitative Composition

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

3 Pharmaceutical Form

Pemetrexed Accord pemetrexed (as disodium) powder for injection.
Pemetrexed Accord is supplied as a sterile lyophilised powder for intravenous infusion available in single dose clear glass vials. The product is a white to either light yellow or green-yellow lyophilised solid.

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 indicates that over-expression 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. 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 3 study of pemetrexed plus cisplatin versus cisplatin in chemonaive patients with malignant pleural mesothelioma, has shown that patients treated with pemetrexed and cisplatin had a clinically meaningful 2.8-month median survival advantage over patients receiving cisplatin alone. Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2 and cisplatin was administered intravenously over 2 hours at a dose of 75 mg/m2 beginning approximately 30 minutes after the end of administration of pemetrexed. Both drugs were given on Day 1 of each 21-day cycle. On this study, treatment was administered up to 6 cycles. Additional cycles were permitted for patients who were receiving benefit from therapy.
During the study, low-dose folic acid and vitamin B12 supplementation was introduced to patients' therapy to reduce toxicity. The primary analysis of this study was performed on the population of all patients randomly assigned to a treatment arm who received study drug (randomised and treated). A subgroup analysis was performed on patients who received folic acid and vitamin B12 supplementation during the entire course of study therapy (fully supplemented).
Table 8 summarises the efficacy results for all patients regardless of vitamin supplementation status and those patients receiving vitamin supplementation from the time of enrolment in the trial.
Table 9 summarises the number of cycles of treatment completed by randomised and treated patients and fully supplemented patients. Patients who never received folic acid and vitamin B12 during study therapy received a median of 2 cycles in both treatment arms.
A statistically significant improvement of the clinically relevant symptoms (pain and dyspnoea) associated with malignant pleural mesothelioma in the pemetrexed/cisplatin arm (212 patients) versus the cisplatin arm alone (218 patients) was demonstrated using the Lung Cancer Symptom Scale (LCCS). By the end of treatment (after 6 cycles), there was a statistically significant difference in favour of pemetrexed/cis for the symptoms of dyspnoea, pain, fatigue, symptom distress, interference with activity, and total LCSS. Statistically significant differences in pulmonary function tests were also observed. Differences favouring the pemetrexed/cis arm were seen in all pulmonary function tests early in therapy; these differences were occasionally significant in early cycles but uniformly became significant in later cycles. The separation between the treatment arms was achieved by improvement in lung function in the pemetrexed/cis 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 3 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) non-small cell lung cancer (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 as shown in Figure 2.
The analysis of the impact of NSCLC histology on overall survival demonstrated statistically significant superiority for pemetrexed + cisplatin in the adenocarcinoma (n=846, 12.6 versus 10.9 months, adjusted HR = 0.84; 95% CI =0.71-0.99, p =0.033) and large cell carcinoma subgroups (n=153, 10.4 versus 6.7, adjusted HR =0.67; 95% CI = 0.48-0.96, p =0.027) but not in patients with squamous cell carcinoma (n=473, 9.4 versus 10.8 months, adjusted HR=1.23; 95% CI =1.00-1.51, p =0.050) or patients with other histologies (n=250, 8.6 versus 9.2, adjusted HR=1.08; 95% CI =0.81-1.45, p =0.586). The results of the analysis of overall survival in patients with adenocarcinoma and large cell carcinoma are shown in Figure 3.
On this study, treatment was administered up to 6 cycles.
There were no clinically relevant differences observed for the safety profile of pemetrexed 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 pemetrexed plus best supportive care (BSC) (n = 441) with that of placebo plus BSC (n= 222) in patients with locally advanced (Stage IIIB) or metastatic (Stage IV) Non Small Cell Lung Cancer (NSCLC) who did not progress after 4 cycles of first line doublet therapy. All patients included in this study had an ECOG performance status 0 or 1. Patients received maintenance treatment until disease progression. Efficacy and safety were measured from the time of randomisation after completion of first line (induction) therapy. Patients received a median of 5 cycles of maintenance treatment with pemetrexed and 3.5 cycles of placebo. A total of 213 patients (48.3%) completed ≥ 6 cycles and a total of 103 patients (23.4%) completed ≥ 10 cycles of treatment with pemetrexed.
In the overall study population, pemetrexed was statistically superior to placebo in terms of overall survival (OS) (median 13.4 months versus 10.6 months, HR=0.79 (95% CI: 0.65-0.95), p-value=0.012) and PFS (median 4.0 months versus 2.0 months, HR=0.60 (95% CI: 0.49-0.73), p-value < 0.00001). Consistent with previous pemetrexed studies, a difference in treatment outcomes was observed according to histologic classification. For the indicated population i.e. patients with NSCLC other than predominantly squamous cell histology, pemetrexed was superior to placebo for OS (median 15.5 months versus 10.3 months, HR=0.70 (95% CI: 0.56-0.88)) and PFS (median 4.4 months versus 1.8 months, HR=0.47 (95% CI: 0.37-0.60)).
The PFS and OS results in patients with squamous cell histology suggested no advantage for pemetrexed over placebo.
There were no clinically relevant differences observed for the safety profile of pemetrexed within the histology subgroups. (See Figure 4.)
A multicentre, randomised, open label phase 3 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 (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 pemetrexed 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 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% to 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 3.5 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 tumor types from 10 single-agent Phase 2 studies, 70 patients from the Phase 3 malignant pleural mesothelioma EMPHACIS trial, and 47 patients from a Phase 1 renal study.

Elderly.

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

Hepatic insufficiency.

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

Renal insufficiency.

Pharmacokinetic analyses included 127 patients with reduced renal function. Total plasma clearance and renal clearance of pemetrexed 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).

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.

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 other than predominantly squamous cell histology.
Pemetrexed 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.

4.3 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 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 nonhaematologic 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 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.

Pemetrexed is not extensively metabolised by the liver. However, patients with hepatic impairment such as bilirubin > 1.5 times the upper limit of normal (ULN) or aminotransferase > 3 times the ULN (hepatic metastases absent) or > 5 time the ULN (hepatic metastases present) have not been specifically studied.
Pemetrexed should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. Treatment-related adverse events of pemetrexed seen in clinical trials have been reversible. Skin rash has been reported in patients not pretreated with a corticosteroid in clinical trials. Pre-treatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction (see Section 4.2 Dose and Method of Administration).
The effect of third space fluid, such as pleural effusion and ascites, on pemetrexed is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to pemetrexed administration.

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 the elderly.

In clinical studies, there has been no indication that patients 65 years of age or older are at increased risk of adverse events compared to patients younger than 65 years old. No dose reductions other than those recommended for all patients are necessary.

Paediatric use.

Pemetrexed 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.

No data available.

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 is 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.
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 characterised 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.

4.8 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.
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).
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 2 results from three single agent pemetrexed studies (n=164) and the Phase 3 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 2 studies included chemonaive and heavily pre-treated breast cancer patients with pre-existing liver metastases and/or abnormal baseline liver function tests.

Combination with cisplatin (MPM).

Table 5 provides the frequency and severity of undesirable effects that have been reported in > 5% of 168 patients with mesothelioma who were randomly assigned to receive cisplatin and pemetrexed 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 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: increased AST (SGOT), ALT (SGPT), and GGT, infection, febrile neutropenia, renal failure, chest pain, pyrexia and urticaria.
Clinically relevant toxicity that was reported in < 1% (uncommon) of the patients that were randomly assigned to receive cisplatin and pemetrexed 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 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 (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 data.

Gastrointestinal disorders.

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

General disorders and administration site conditions.

Rare cases of oedema have been reported in patients treated with pemetrexed.

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.

Blood and lymphatic system.

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

Hepatobiliary disorders.

Rare cases of hepatitis, potentially serious, have been reported during clinical trials with pemetrexed.
Rare: ≤ 0.1% of patients treated 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.

4.2 Dose and Method of Administration

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

Pemetrexed Accord in combination use with cisplatin.

Adults.

The recommended dose of Pemetrexed Accord 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 Accord infusion on the first day of each 21-day cycle. Patients must receive adequate anti-emetic treatment and appropriate hydration prior to and/or after receiving cisplatin. See cisplatin product information document for specific dosing advice.

Single agent use.

Adults.

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

Premedication regimen.

Skin rash has been reported in patients not pretreated with a corticosteroid. Pre-treatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after Pemetrexed Accord administration.
To reduce toxicity, patients treated with Pemetrexed Accord 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 Accord, and dosing should continue during the full course of therapy and for 21 days after the last dose of Pemetrexed Accord. Patients must also receive one intramuscular injection of vitamin B12 during the week preceding the first dose of Pemetrexed Accord and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as Pemetrexed Accord. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 microgram, and the dose of vitamin B12 received was 1000 microgram. The most commonly used dose of oral folic acid was 400 microgram.

Laboratory monitoring and dose reduction recommendations.

Monitoring.

It is recommended that patients receiving Pemetrexed Accord 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 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 Pemetrexed Accord as a single agent or in combination with cisplatin. See Table 1.
If patients develop nonhaematologic 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 Accord 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 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 Accord is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection and Ringer's Injection. Coadministration of Pemetrexed Accord 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 Accord for intravenous infusion administration.
2. Calculate the dose and the number of Pemetrexed Accord vials needed. A 1000 mg vial contains 1000 mg of pemetrexed. A 500 mg vial contains 500 mg of pemetrexed. A 100 mg vial contains 100 mg of pemetrexed. The vial contains an excess of pemetrexed to facilitate delivery of label amount.
3. Prior to administration, reconstitute 1000 mg vials with 40 mL of 0.9% sodium chloride injection to give a solution containing 25 mg/mL pemetrexed. Reconstitute 500 mg vials with 20 mL of 0.9% sodium chloride injection to give a solution containing 25 mg/mL pemetrexed. Reconstitute 100 mg vials with 4.2 mL of 0.9% sodium chloride injection to give a solution containing 25 mg/mL pemetrexed.
4. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in colour from colourless to yellow or green-yellow without adversely affecting product quality. The pH of the reconstituted Pemetrexed Accord solution is between 6.6 and 7.8. Further dilution is required.
5. The appropriate volume of reconstituted Pemetrexed Accord 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 Accord was demonstrated for up to 72 hours after reconstitution of the original vial when refrigerated between 2 to 8°C. However, because Pemetrexed Accord and the recommended diluent contain no antimicrobial preservatives, to reduce antimicrobial hazard, reconstituted and infusion solutions should be used immediately. The product is for single use in one patient on one occasion only. Discard any residue.

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.

4.9 Overdose

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.
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 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each 100 mg vial of Pemetrexed Accord contains 100 mg of mannitol.
Each 500 mg vial of Pemetrexed Accord contains 500 mg of mannitol.
Each 1000 mg vial of Pemetrexed Accord contains 1000 mg of mannitol.
Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.
The product contains no preservative and is for single use in one patient on one occasion only. Discard any residue.

6.2 Incompatibilities

See Section 4.2 Dose and Method of Administration, Preparation and administration instructions.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

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

6.5 Nature and Contents of Container

Pemetrexed Accord, pemetrexed disodium powder for injection is available in sterile single use glass vials containing: 100 mg, 500 mg or 1000 mg pemetrexed (pack size 1 vial).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes