Pemetrexed Actavis 100 mg Pulver till koncentrat till infusionsvätska, lösning

Švedska - švedski - Läkemedelsverket (Medical Products Agency)

Uputa o lijeku Uputa o lijeku (PIL)

22-05-2018

Svojstava lijeka Svojstava lijeka (SPC)

22-04-2018

Aktivni sastojci:
pemetrexeddinatrium-2,5-hydrat
Dostupno od:
Actavis Group PTC ehf.
ATC koda:
L01BA04
INN (International ime):
pemetrexeddinatrium-2,5-hydrat
Doziranje:
100 mg
Farmaceutski oblik:
Pulver till koncentrat till infusionsvätska, lösning
Sastav:
pemetrexeddinatrium-2,5-hydrat 120,82 mg Aktiv substans; mannitol Hjälpämne
Tip recepta:
Receptbelagt
Proizvod sažetak:
Förpacknings: Injektionsflaska, 1 st (100 mg)
Status autorizacije:
Avregistrerad
Broj odobrenja:
51899
Datum autorizacije:
2016-08-18

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Package leaflet: Information for the user

Pemetrexed Actavis 100 mg powder for concentrate for solution for infusion

Pemetrexed Actavis 500 mg powder for concentrate for solution for infusion

Pemetrexed Actavis 1000 mg powder for concentrate for solution for infusion

pemetrexed

Read all of this leaflet carefully before you start receiving this medicine because it contains

important information for you.

-

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

If you have any further questions, ask your doctor or pharmacist.

If you get any side effects, talk to your doctor or nurse or pharmacist. This includes any

possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

What Pemetrexed Actavis is and what it is used for

What you need to know before you use Pemetrexed Actavis

How to use Pemetrexed Actavis

Possible side effects

How to store Pemetrexed Actavis

Contents of the pack and other information

1.

What Pemetrexed Actavis is and what it is used for

Pemetrexed Actavis is a medicine used in the treatment of cancer. It contains the active substance

pemetrexed. Pemetrexed belongs to a group of medicines known as folic acid analogues and disrupts

processes that are essential for cell replication.

Pemetrexed Actavis is given in combination with cisplatin, another anti-cancer medicine, as treatment

for malignant pleural mesothelioma, a form of cancer that affects the lining of the lung, to patients who

have not received prior chemotherapy.

Pemetrexed Actavis is also given in combination with cisplatin for the initial treatment of patients with

advanced stage of lung cancer.

Pemetrexed Actavis can be prescribed to you if you have lung cancer at an advanced stage if your

disease has responded to treatment or it remains largely unchanged after initial chemotherapy.

Pemetrexed Actavis is also a treatment for patients with advanced stage of lung cancer whose disease

has progressed after other initial chemotherapy has been used.

2.

What you need to know before you use Pemetrexed Actavis

Do not use Pemetrexed Actavis

if you are allergic to pemetrexed or any of the other ingredients of this medicine (listed in

section 6).

if you are breast-feeding; you must discontinue breast-feeding during treatment with Pemetrexed

Actavis.

if you have recently received or are about to receive a vaccine against yellow fever.

Warnings and precautions

Talk to your doctor or hospital pharmacist before receiving Pemetrexed Actavis.

If you currently have or have previously had problems with your kidneys, talk to your doctor or

hospital pharmacist as you may not be able to receive Pemetrexed Actavis.

Before each infusion you will have samples of your blood taken to evaluate if you have sufficient

kidney and liver function and to check that you have enough blood cells to receive Pemetrexed

Actavis. Your doctor may decide to change the dose or delay treating you depending on your general

condition and if your blood cell counts are too low. If you are also receiving cisplatin, your doctor will

make sure that you are properly hydrated and receive appropriate treatment before and after receiving

cisplatin to prevent vomiting.

If you have had or are going to have radiation therapy, please tell your doctor, as there may be an early

or late radiation reaction with Pemetrexed Actavis.

If you have been recently vaccinated, please tell your doctor, as this can possibly cause bad effects

with Pemetrexed Actavis.

If you have heart disease or a history of heart disease, please tell your doctor.

If you have an accumulation of fluid around your lungs, your doctor may decide to remove the fluid

before giving you Pemetrexed Actavis.

Children and adolescents

There is no relevant use of Pemetrexed Actavis in the paediatric population.

Other medicines and Pemetrexed Actavis

Please tell your doctor if you are taking any medicines for pain or inflammation (swelling), such as

medicines called “nonsteroidal anti-inflammatory drugs” (NSAIDs), including medicines purchased

without a doctor’s prescription (such as ibuprofen). There are many sorts of NSAIDs with different

durations of activity. Based on the planned date of your infusion of Pemetrexed Actavis and/or on the

status of your kidney function, your doctor needs to advise you on which medicines you can take and

when you can take them. If you are unsure, ask your doctor or pharmacist if any of your medicines are

NSAIDs.

Like other chemotherapy medicines Pemetrexed ActavisPemetrexed Actavis is not recommended with

live attenuated vaccines. Inactive vaccines should be used where possible.

Tell your doctor or hospital pharmacist if you are taking, have recently taken or might take any other

medicines, including medicines obtained without a prescription.

Pregnancy, breast-feeding and fertility

Pregnancy

If you are pregnant, think you may be pregnant or are planning to have a baby,

tell your doctor

and ask

for advice before taking this medicine. The use of Pemetrexed Actavis should be avoided during

pregnancy. Your doctor will discuss with you the potential risk of taking Pemetrexed Actavis during

pregnancy. Women must use effective contraception during treatment with Pemetrexed Actavis.

Breast-feeding

If you are breast-feeding, tell your doctor.

Breast-feeding must be discontinued during Pemetrexed Actavis treatment.

Fertility

Men are advised not to father a child during and up to 6 months following treatment with Pemetrexed

Actavis and should therefore use effective contraception during treatment with Pemetrexed Actavis and

for up to 6 months afterwards. If you would like to father a child during the treatment or in the

6 months following receipt of treatment, seek advice from your doctor or pharmacist. You may want to

seek counselling on sperm storage before starting your therapy.

Driving and using machines

Pemetrexed Actavis may make you feel tired. Be careful when driving a car or using machines.

Pemetrexed Actavis contains sodium

One vial of 100 mg contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ´sodium-free`.

However, before Pemetrexed Actavis is given to you, it is mixed with a solution that contains sodium.

Talk to your doctor if you are on a controlled sodium diet.

One vial of 500 mg contains approximately 53.77 mg sodium per vial. Before Pemetrexed Actavis is

given to you, it is also mixed with a solution that contains sodium. Talk to your doctor if you are on a

controlled sodium diet.

One vial of 1000 mg contains approximately 107.54 mg sodium per vial. Before Pemetrexed Actavis

is given to you, it is also mixed with a solution that contains sodium. Talk to your doctor if you are on

a controlled sodium diet.

3.

How to use Pemetrexed Actavis

Pemetrexed Actavis powder for concentrate for solution for infusion will always be given to you by

a healthcare professional. The dose of Pemetrexed Actavis is 500 milligrams for every square metre of

your body’s surface area. Your height and weight are measured to work out the surface area of your

body. Your doctor will use this body surface area to work out the right dose for you. This dose may be

adjusted, or treatment may be delayed depending on your blood cell counts and on your general

condition. A hospital pharmacist, nurse or doctor will have mixed the Pemetrexed Actavis powder with

9 mg/ml (0.9 %) sodium chloride solution for injection before it is given to you.

You will always receive Pemetrexed Actavis by infusion into one of your veins. The infusion will last

approximately 10 minutes.

When using Pemetrexed Actavis in combination with cisplatin:

The doctor or hospital pharmacist will work out the dose you need based on your height and weight.

Cisplatin is also given by infusion into one of your veins, and is given approximately 30 minutes after

the infusion of Pemetrexed Actavis has finished. The infusion of cisplatin will last approximately

2 hours.

You should usually receive your infusion once every 3 weeks.

Additional medicines:

Corticosteriods: your doctor will prescribe you steroid tablets (equivalent to 4 milligram of

dexamethasone twice a day) that you will need to take on the day before, on the day of, and the day

after Pemetrexed Actavis treatment. This medicine is given to you to reduce the frequency and

severity of skin reactions that you may experience during your anticancer treatment.

Vitamin supplementation: your doctor will prescribe you oral folic acid (vitamin) or a multivitamin

containing folic acid (350 to 1000 micrograms) that you must take once a day while you are taking

Pemetrexed Actavis. You must take at least 5 doses during the seven days before the first dose of

Pemetrexed Actavis. You must continue taking the folic acid for 21 days after the last dose of

Pemetrexed Actavis. You will also receive an injection of vitamin B

(1000 micrograms) in the week

before administration of Pemetrexed Actavis and then approximately every 9 weeks (corresponding to

3 courses of Pemetrexed Actavis treatment). Vitamin B

and folic acid are given to you to reduce the

possible toxic effects of the anticancer treatment.

Your condition will be closely monitored during treatment. This routinely involves blood tests,

including checks on your liver and kidney function. Your dose may be changed or treatment delayed

depending on results from these tests.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

You must contact your doctor immediately if you notice any of the following:

Fever or infection (common): if you have a temperature of 38ºC or greater, sweating or other

signs of infection(since you might have less white blood cells than normal which is very

common). Infection (sepsis) may be severe and could lead to death.

If you start feeling chest pain (common) or having a fast heart rate (uncommon).

If you have pain, redness, swelling or sores in your mouth (very common).

Allergic reaction: if you develop skin rash (very common) / burning or prickling sensation

(common), or fever (common). Rarely, skin reactions may be severe and could lead to death.

Contact your doctor if you get a severe rash, or itching, or blistering (Stevens-Johnson

Syndrome or Toxic epidermal necrolysis).

If you experience tiredness, feeling faint, becoming easily breathless or if you look pale (since

you might have less haemoglobin than normal which is very common).

If you experience bleeding from the gums, nose or mouth or any bleeding that would not stop,

reddish or pinkish urine, unexpected bruising (since you might have less platelets than normal

which is very common).

If you experience sudden breathlessness, intense chest pain or cough with bloody sputum

(uncommon)(may indicate a blood clot in the blood vessels of the lungs)

Other side effects with Pemetrexed Actavis may include:

Very common (may affect more than 1 in 10 people)

Low white blood cells

Low haemoglobin level (anaemia)

Low platelet count

Diarrhoea

Vomiting

Pain, redness, swelling or sores in your mouth

Nausea

Loss of appetite

Fatigue (tiredness)

Skin rash, peeling of the skin

Hair loss

Constipation

Loss of sensation

Kidney: abnormal blood tests

Common (may affect up to 1 in 10 people)

Allergic reaction: skin rash / burning or prickling sensation

Infection including sepsis

Fever

Dehydration

Kidney failure

Irritation of the skin and itching

Hives

Chest pain

Muscle weakness

Conjunctivitis (inflamed eye)

Upset stomach

Pain in the abdomen

Taste change

Liver: abnormal blood tests

Watery eyes

Dizziness

Oedema (excess fluid in body tissue, causing swelling)

Increased skin pigmentation

Uncommon (may affect up to 1 in 100 people)

Acute renal failure

Fast or irregular heart rate

Inflammation of the lining of the oesophagus (gullet) has been experienced with Pemetrexed Actavis/

radiation therapy

Colitis (inflammation of the lining of the large bowel, which may be accompanied by intestinal or

rectal bleeding)

Interstitial pneumonitis (scarring of the air sacs of the lung)

Some patients have experienced a heart attack, stroke or “mini-stroke” while receiving Pemetrexed

Actavis usually in combination with another anticancer therapy

Pancytopenia- combined low counts of white cells, red cells and platelets

Radiation pneumonitis (scarring of the air sacs of the lung associated with radiation therapy) may

occur in patients who are also treated with radiation either before, during or after their Pemetrexed

Actavis therapy.

Extremity pain, low temperature and discolouration have been reported.

Blood clots in the lung blood vessels (pulmonary embolism)

Rare (may affect up to 1 in 1,000 people)

Radiation recall (a skin rash like severe sunburn) which can occur on skin that has previously been

exposed to radiotherapy, from days to years after the radiation.

Bullous conditions (blistering skin diseases)-including Stevens-Johnson syndrome and Toxic

epidermal necrolysis

Immune mediated haemolytic anaemia (antibody-mediated destruction of red blood cells)

Hepatitis (inflammation of the liver)

Anaphylactic shock (severe allergic reaction)

Not known (frequency cannot be estimated from the available data)

Lower limb swelling with pain and redness

Increased urine output

Thirst and increased water consumption

Hypernatraemia – increased sodium in blood

Inflammation of the skin, mainly of the lower limb with swelling, pain and redness

You might have any of these symptoms and/or conditions. You must tell your doctor as soon as

possible when you start experiencing any of these side effects.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in the leaflet. You can also report side effects directly via the national reporting system listed

in Appendix V. By reporting side effects you can help provide more information on the safety of this

medicine.

5.

How to store Pemetrexed Actavis

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton after ‘EXP’. The

expiry date refers to the last day of that month.

Keep the vial in the outer carton in order to protect from light.

This medicinal product does not require any special temperature storage conditions.

Reconstituted and infusion solutions

When prepared as directed, reconstituted and infusion solutions of Pemetrexed Actavis contain no

antimicrobial preservatives. Chemical and physical in-use stability of reconstituted and infusion

solutions of pemetrexed were demonstrated for 3 days at room temperature at normal lighting

conditions and 14 days at refrigerated temperature (2-8°C). From a microbiological point of view, the

product should be used immediately. If not used immediately, in-use storage times and conditions prior

to use are the responsibility of the user and would not be longer than 24 hours at 2°C to 8°C, unless

reconstitution / dilution has taken place in controlled and validated aseptic conditions.

Pemetrexed Actavis should not been used if there are any signs of particles.

This medicine is for single use only; any unused solution must be disposed of in accordance with local

requirement.

6.

Contents of the pack and other information

What Pemetrexed Actavis contains

The active substance is pemetrexed.

Pemetrexed Actavis 100 mg: Each vial contains 100 milligrams of pemetrexed (as pemetrexed

disodium hemipentahydrate).

Pemetrexed Actavis 500 mg: Each vial contains 500 milligrams of pemetrexed (as pemetrexed

disodium hemipentahydrate).

Pemetrexed Actavis 1000 mg: Each vial contains 1000 milligram of pemetrexed (as pemetrexed

disodium hemipentahydrate).

After reconstitution, the solution contains 25 mg/ml of pemetrexed. Further dilution by a healthcare

provider is required prior to administration.

The other ingredients are mannitol, hydrochloric acid and sodium hydroxide.

What Pemetrexed Actavis looks like and contents of the pack

Pemetrexed Actavis is a powder for concentrate for solution for infusion in a vial. It is a white to either

yellow or greenish-yellow lyophilisate powder.

Pemetrexed Actavis is in colourless glass vials (type I) with type I rubber (bromobutyl) lyo-stopper

and an aluminium cap with polypropylene disk. Vials are sheathed in protective sleeve.

Each pack of Pemetrexed Actavis consists of one Pemetrexed Actavis vial.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

[To be completed nationally]

Manufacturer

S.C. SINDAN-PHARMA S.R.L.

Ion Mihalache Boulevard

011171, Bucharest 1

Romania

This medicinal product is authorised in the Member States of the EEA under the following

names:

[To be completed nationally]

This leaflet was last revised in 2019-03-25

[To be completed nationally]

---------------------------------------------------------------------------------------------------------------------------

-------

The following information is intended for medical or healthcare professionals only:

Instructions for use, handling and disposal.

Use aseptic techniques during the reconstitution and further dilution of pemetrexed for

intravenous infusion administration.

Calculate the dose and the number of Pemetrexed Actavis vials needed. Each vial contains an

excess of pemetrexed to facilitate delivery of the label amount.

Reconstitute 100 mg vials with 4.2 ml of 9 mg/ml (0.9 %) sodium chloride solution for

injection, without preservative, resulting in a solution containing 25 mg/ml pemetrexed.

Reconstitute 500 mg vials with 20 ml of 9 mg/ml (0.9 %) sodium chloride solution for injection,

without preservative, resulting in a solution containing 25 mg/ml pemetrexed.

Reconstitute 1000 mg vials with 40 ml of 9 mg/ml (0.9 %) sodium chloride solution for

injection, without preservative, resulting in a solution containing 25 mg/ml pemetrexed.

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 solution is between 6.6 and 7.8.

Further dilution is

required

The appropriate volume of reconstituted pemetrexed solution must be further diluted to 100 ml

with 9 mg/ml (0.9 %) sodium chloride solution for injection, without preservative, and

administered as an intravenous infusion over 10 minutes.

Pemetrexed infusion solutions prepared as directed above are compatible with polyvinyl

chloride and polyolefin lined administration sets and infusion bags. Pemetrexed is incompatible

with diluents containing calcium, including lactated Ringer’s Injection and Ringer’s Injection.

Parenteral medicinal products must be inspected visually for particulate matter and

discolouration prior to administration. If particulate matter is observed, do not administer.

Pemetrexed solutions are for single use only. Any unused product or waste material should be

disposed of in accordance with local requirements.

Preparation and administration precautions:

As with other potentially toxic anticancer agents, care

should be exercised in the handling and preparation of pemetrexed infusion solutions. The use of

gloves is recommended. If a pemetrexed solution contacts the skin, wash the skin immediately and

thoroughly with soap and water. If pemetrexed solutions contact the mucous membranes, flush

thoroughly with water. Pemetrexed is not a vesicant. There is not a specific antidote for extravasation

of pemetrexed. There have been a few reported cases of pemetrexed extravasation, which were not

assessed as serious by the investigator. Extravasation should be managed by local standard practice as

with other non-vesicants.

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Pemetrexed Actavis 100 mg powder for concentrate for solution for infusion

Pemetrexed Actavis 500 mg powder for concentrate for solution for infusion

Pemetrexed Actavis 1000 mg powder for concentrate for solution for infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 100 mg of pemetrexed (as pemetrexed disodium hemipentahydrate).

Each vial contains 500 mg of pemetrexed (as pemetrexed disodium hemipentahydrate).

Each vial contains 1000 mg of pemetrexed (as pemetrexed disodium hemipentahydrate).

After reconstitution (see section 6.6), each vial contains 25 mg/ml of pemetrexed.

Excipient with known effect:

Each 100 mg vial contains approximately 11.29 mg sodium.

Each 500 mg vial contains approximately 53.77 mg sodium.

Each 1000 mg vial contains approximately 107.54 mg sodium.

For the full list of excipients see section 6.1.

3.

PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion.

White to yellow or greenish-yellow lyophilisate powder

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Malignant pleural mesothelioma

Pemetrexed in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients

with unresectable malignant pleural mesothelioma.

Non-small cell lung cancer

Pemetrexed in combination with cisplatin is indicated for the first line treatment of patients with

locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell

histology (see section 5.1).

Pemetrexed is indicated as monotherapy for the maintenance treatment of locally advanced or

metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients

whose disease has not progressed immediately following platinum-based chemotherapy (see section

5.1).

Pemetrexed is indicated as monotherapy for the second line treatment of patients with locally advanced

or metastatic non-small cell lung cancer other than predominantly squamous cell histology (see section

5.1).

4.2

Posology and method of administration

Posology

Pemetrexed must only be administered under the supervision of a physician qualified in the use of anti-

cancer chemotherapy.

Pemetrexed in combination with cisplatin

The recommended dose of pemetrexed is 500 mg/m

of 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/m

BSA infused over two 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 (see also cisplatin

Summary of Product Characteristics for specific dosing advice).

Pemetrexed as single agent

In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of

pemetrexed is 500 mg/m

BSA administered as an intravenous infusion over 10 minutes on the first

day of each 21-day cycle.

Premedication regimen

To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day prior

to, on the day of, and the day after pemetrexed administration. The corticosteroid should be equivalent

to 4 mg of dexamethasone administered orally twice a day (see section 4.4).

To reduce toxicity, patients treated with pemetrexed must also receive vitamin supplementation (see

section 4.4). Patients must take oral folic acid or a multivitamin containing folic acid (350 to

1000 micrograms) on a daily basis. At least five doses of folic acid must be taken during the seven

days preceding the first dose of pemetrexed, and dosing must continue during the full course of therapy

and for 21 days after the last dose of pemetrexed. Patients must also receive an intramuscular injection

of vitamin B

(1000 micrograms) in the week preceding the first dose of pemetrexed and once every

three cycles thereafter. Subsequent vitamin B

injections may be given on the same day as

pemetrexed.

Monitoring

Patients receiving pemetrexed should be monitored before each dose with a complete blood count,

including a differential white cell count (WCC) and platelet count. Prior to each chemotherapy

administration blood chemistry tests should be collected to evaluate renal and hepatic function. Before

the start of any cycle of chemotherapy, patients are required to have the following: absolute neutrophil

count (ANC) should be ≥ 1500 cells/mm

and platelets should be ≥ 100,000 cells/mm

Creatinine clearance should be ≥ 45 ml/min.

The total bilirubin should be ≤ 1.5 times upper limit of normal. Alkaline phosphatase (AP), aspartate

aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) should be ≤ 3 times

upper limit of normal. Alkaline phosphatase, AST and ALT ≤ 5 times upper limit of normal is

acceptable if liver has tumour involvement.

Dose adjustments

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, 2 and 3, which are applicable for pemetrexed used as a single agent or in combination with

cisplatin.

Table 1 - Dose modification table for pemetrexed (as single agent or in combination)

and cisplatin – Haematologic toxicities

Nadir ANC < 500 /mm

and nadir platelets

≥ 50,000 /mm

75 % of previous dose (both pemetrexed

and cisplatin)

Nadir platelets < 50,000 /mm

regardless of

nadir ANC

75 % of previous dose (both pemetrexed

and cisplatin)

Nadir platelets < 50,000/mm

with

bleeding

, regardless of nadir ANC

50 % of previous dose (both pemetrexed

and cisplatin)

These criteria meet the National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998)

definition of ≥CTC Grade 2 bleeding.

If patients develop non-haematologic toxicities ≥ Grade 3 (excluding neurotoxicity), pemetrexed

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.

Table 2 - Dose modification table for pemetrexed (as single agent or in combination)

and cisplatin– Non-haematologic toxicities

a,b

Dose of pemetrexed

(mg/m

2

)

Dose for cisplatin (mg/m

2

)

Any Grade 3 or 4 toxicities except

mucositis

75 % of previous dose

75 % of previous dose

Any diarrhoea requiring

hospitalisation (irrespective of

grade) or grade 3 or 4 diarrhoea.

75 % of previous dose

75 % of previous dose

Grade 3 or 4 mucositis

50 % of previous dose

100 % of previous dose

National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998)

Excluding neurotoxicity

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.

Table 3 - Dose modification table for pemetrexed (as single agent or in combination)

and cisplatin – Neurotoxicity

CTC

a

Grade

Dose of pemetrexed (mg/m

2

)

Dose for cisplatin (mg/m

2

)

0 – 1

100 % of previous dose

100 % of previous dose

100 % of previous dose

50 % of previous dose

National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998)

Treatment with pemetrexed should be discontinued if a patient experiences any haematologic or non-

haematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4

neurotoxicity is observed.

Elderly

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 population

There is no relevant use of pemetrexed in the paediatric population in malignant pleural mesothelioma

and non-small cell lung cancer.

Renal impairment

(Standard Cockcroft and Gault formula or Glomerular Filtration Rate measured

Tc99m-DPTA serum clearance method)

Pemetrexed is primarily eliminated unchanged by renal excretion. In clinical studies, patients with

creatinine clearance of ≥ 45 ml/min required no dose adjustments other than those recommended for

all patients. There are insufficient data on the use of pemetrexed in patients with creatinine clearance

below 45 ml/min; therefore the use of pemetrexed is not recommended (see section 4.4).

Hepatic impairment

No relationships between AST (SGOT), ALT (SGPT), or total bilirubin and pemetrexed

pharmacokinetics were identified. However patients with hepatic impairment such as bilirubin

> 1.5 times the upper limit of normal and/or aminotransferase > 3.0 times the upper limit of normal

(hepatic metastases absent) or > 5.0 times the upper limit of normal (hepatic metastases present) have

not been specifically studied.

Method of administration:

For precautions to be taken before handling or administering pemetrexed, see section 6.6.

Pemetrexed Actavis should be administered as an intravenous infusion over 10 minutes on the first day

of each 21-day cycle. For instructions on reconstitution and dilution of Pemetrexed Actavis before

administration, see section 6.6.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Breast-feeding (see section 4.6)

.

Concomitant yellow fever vaccine (see section 4.5).

4.4

Special warnings and precautions for use

Pemetrexed can suppress bone marrow function as manifested by neutropenia, thrombocytopenia and

anaemia (or pancytopenia) (see section 4.8). 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/mm

and platelet count

returns to ≥ 100,000 cells/mm

. Dose reductions for subsequent cycles are based on nadir ANC,

platelet count and maximum non-haematologic toxicity seen from the previous cycle (see section 4.2).

Less toxicity and reduction 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 B

was administered. Therefore, all patients treated with

pemetrexed must be instructed to take folic acid and vitamin B

as a prophylactic measure to reduce

treatment-related toxicity (see section 4.2).

Skin reactions have been reported in patients not pre-treated with a corticosteroid. Pre-treatment with

dexamethasone (or equivalent) can reduce the incidence and severity of skin reactions (see section

4.2).

An insufficient number of patients has been studied with creatinine clearance of below 45 ml/min.

Therefore, the use of pemetrexed in patients with creatinine clearance of < 45 ml/min is not

recommended (see section 4.2).

Patients with mild to moderate renal impairment (creatinine clearance from 45 to 79 ml/min) should

avoid taking non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, and acetylsalicylic

acid (> 1.3 g daily) for 2 days before, on the day of, and 2 days following pemetrexed

administration (see section 4.5).

In patients with mild to moderate renal impairment eligible for pemetrexed therapy NSAIDs with long

elimination half-lives should be interrupted for at least 5 days prior to, on the day of, and at least

2 days following pemetrexed administration (see section 4.5).

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.

Nephrogenic diabetes insipidus and renal tubular necrosis were also reported

in post marketing setting with pemetrexed alone or with other chemotherapeutic agents. Most of these

events resolved after pemetrexed withdrawal. Patients should be regularly monitored for acute tubular

necrosis, decreased renal function and signs and symptoms of nephrogenic diabetes insipidus (e.g.

hypernatraemia).

The effect of third space fluid, such as pleural effusion or ascites, on pemetrexed is not fully defined. A

phase 2 study of pemetrexed in 31 solid tumour patients with stable third space fluid demonstrated no

difference in pemetrexed dose normalized plasma concentrations or clearance compared to patients

without third space fluid collections. Thus, drainage of third space fluid collection prior to pemetrexed

treatment should be considered, but may not be necessary.

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 (see section 4.8).

Immunodepressed status is common in cancer patients. As a result, concomitant use of live attenuated

vaccines is not recommended (see section 4.3 and 4.5).

Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a

child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are

recommended. Owing to the possibility of pemetrexed treatment causing irreversible infertility, men

are advised to seek counselling on sperm storage before starting treatment.

Women of childbearing potential must use effective contraception during treatment with pemetrexed

(see section 4.6).

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.

One vial of 100 mg contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ´sodium free`.

Pemetrexed Actavis is however diluted in sodium chloride 9 mg/ml (0.9%) solution for injection (see

section 6.6). To be taken into consideration for patients on a controlled sodium diet.

One vial of 500 mg contains approximately 53.77 mg of sodium per vial. In addition, Pemetrexed

Actavis is diluted in sodium chloride 9 mg/ml (0.9%) solution for injection (see section 6.6). To be

taken into consideration for patients on a controlled sodium diet.

One vial of 1000 mg contains approximately 107.54 mg of sodium per vial. In addition, Pemetrexed

Actavis is diluted in sodium chloride 9 mg/ml (0.9%) solution for injection (see section 6.6). To be

taken into consideration for patients on a controlled sodium diet.

4.5

Interaction with other medicinal products and other forms of interaction

Pemetrexed is mainly eliminated unchanged renally by tubular secretion and to a lesser extent by

glomerular filtration. Concomitant administration of nephrotoxic drugs (e.g. aminoglycoside, loop

diuretics, platinum compounds, cyclosporin) could potentially result in delayed clearance of

pemetrexed. This combination should be used with caution. If necessary, creatinine clearance should

be closely monitored.

Concomitant administration of substances that are also tubularly secreted (e.g. probenecid, penicillin)

could potentially result in delayed clearance of pemetrexed. Caution should be made when these drugs

are combined with pemetrexed. If necessary, creatinine clearance should be closely monitored.

In patients with normal renal function (creatinine clearance > 80 ml/min), high doses of non-steroidal

anti-inflammatory drugs (NSAIDs, such as ibuprofen > 1600 mg/day) and acetylsalicylic acid at higher

dose (> 1.3 g daily) may decrease pemetrexed elimination and, consequently, increase the occurrence

of pemetrexed adverse events. Therefore, caution should be made when administering higher doses of

NSAIDs or acetylsalicylic acid, concurrently with pemetrexed to patients with normal function

(creatinine clearance > 80 ml/min).

In patients with mild to moderate renal impairment (creatinine clearance from 45 to 79 ml/min), the

concomitant administration of pemetrexed with NSAIDs (e.g. ibuprofen) or acetylsalicylic acid at

higher dose should be avoided for 2 days before, on the day of, and 2 days following pemetrexed

administration (see section 4.4).

In the absence of data regarding potential interaction with NSAIDs having longer half-lives such as

piroxicam or rofecoxib, the concomitant administration with pemetrexed in patients with mild to

moderate renal insufficiency should be interrupted for at least 5 days prior to, on the day of, and at

least 2 days following pemetrexed administration (see section 4.4). If concomitant administration of

NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression

and gastrointestinal toxicity.

Pemetrexed undergoes limited hepatic metabolism. Results from

in vitro

studies with human liver

microsomes indicated that pemetrexed would not be predicted to cause clinically significant inhibition

of the metabolic clearance of drugs metabolised by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

Interactions common to all cytotoxics

Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation treatment is

frequent. The high intra-individual variability of the coagulation status during diseases and the

possibility of interaction between oral anticoagulants and anticancer chemotherapy require increased

frequency of INR (International Normalised Ratio) monitoring, if it is decided to treat the patient with

oral anticoagulants.

Concomitant use contraindicated: Yellow fever vaccine: risk of fatal generalised vaccinale disease

(see section 4.3).

Concomitant use not recommended: Live attenuated vaccines (except yellow fever, for which

concomitant use is contraindicated): risk of systemic, possibly fatal, disease. The risk is increased in

subjects who are already immunosuppressed by their underlying disease. Use an inactivated vaccine

where it exists (poliomyelitis) (see section 4.4).

4.6

Fertility, pregnancy and lactation

Contraception in males and females

Women of childbearing potential must use effective contraception during treatment with pemetrexed.

Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a

child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are

recommended.

Pregnancy

There are no data from the use of pemetrexed in pregnant women but pemetrexed, like other anti-

metabolites, is suspected to cause serious birth defects when administered during pregnancy. Animal

studies have shown reproductive toxicity (see section 5.3). Pemetrexed should not be used during

pregnancy unless clearly necessary, after a careful consideration of the needs of the mother and the risk

for the foetus (see section 4.4).

Breastfeeding

It is not known whether pemetrexed is excreted in human milk and adverse reactions on the suckling

child cannot be excluded. Breast-feeding must be discontinued during pemetrexed therapy (see

section 4.3)

.

Fertility

Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to

seek counselling on sperm storage before starting treatment.

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 machines if this event occurs.

4.8

Undesirable effects

Summary of the safety profile

The most commonly reported undesirable effects related to pemetrexed, whether used as monotherapy

or in combination, are bone marrow suppression manifested as anaemia, neutropenia, leukopenia,

thrombocytopenia; and gastrointestinal toxicities, manifested as anorexia, nausea, vomiting, diarrhoea,

constipation, pharyngitis, mucositis, and stomatitis. Other undesirable effects include renal toxicities,

increased aminotransferases, alopecia, fatigue, dehydration, rash, infection/sepsis and neuropathy.

Rarely seen events include Stevens-Johnson syndrome and Toxic epidermal necrolysis.

Tabulated list of adverse reactions

The table below provides the frequency and severity of undesirable effects that have been reported in

> 5 % of 168 patients with mesothelioma who were randomised to receive cisplatin and pemetrexed

and 163 patients with mesothelioma randomised to receive single agent cisplatin. In both treatment

arms, these chemonaive patients were fully supplemented with folic acid and vitamin B

Frequency estimate: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000 to

< 1/100), Rare (≥ 1/10,000 to < 1/1,000), Very rare (< 1/10,000) and not known (cannot be estimated

from available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Pemetrexed/cisplatin

Cisplatin

(N = 168)

(N = 163)

System

organ

class

Frequency

Event*

All

grades

toxicity

(%)

Grade

3 - 4

toxicity

(%)

All

grades

toxicity

(%)

Grade

3 - 4

toxicity

(%)

Neutrophils/

Granulocytes

decreased

56.0

23.2

13.5

Blood and

lymphatic

system

disorders

Very

common

Leukocytes

decreased

53.0

14.9

16.6

Pemetrexed/cisplatin

Cisplatin

(N = 168)

(N = 163)

System

organ

class

Frequency

Event*

All

grades

toxicity

(%)

Grade

3 - 4

toxicity

(%)

All

grades

toxicity

(%)

Grade

3 - 4

toxicity

(%)

Haemoglobin

decreased

26.2

10.4

Platelets

decreased

23.2

Metabolism

and nutrition

disorders

Common

Dehydration

Very

common

Neuropathy-

Sensory

10.1

Nervous

system

disorders

Common

Taste

disturbance

0.0***

0.0***

Eye disorders

Common

Conjunctivitis

Diarrhoea

16.7

Vomiting

56.5

10.7

49.7

Stomatitis/

Pharyngitis

23.2

Nausea

82.1

11.9

76.7

Anorexia

20.2

14.1

Very

common

Constipation

11.9

Gastrointestinal

disorders

Common

Dyspepsia

Rash

16.1

Skin and

subcutaneous

tissue disorders

Very

common

Alopecia

11.3

0.0***

0.0***

Creatinine

elevation

10.7

Renal and

urinary

disorders

Very

common

Creatinine

clearance

decreased**

16.1

17.8

General

disorders and

administration

site conditions

Very

common

Fatigue

47.6

10.1

42.3

*Refer to National Cancer Institute CTC version 2 for each grade of toxicity except the term “creatinine

clearance decreased”

** which is derived from the term “renal/genitourinary other”.

*** According to National Cancer Institute CTC (v2.0; NCI 1998), taste disturbance and alopecia should only

be reported as Grade 1 or 2.

For the purpose of this table a cut off of 5 % was used for inclusion of all events where the reporter

considered a possible relationship to pemetrexed and cisplatin.

Clinically relevant CTC toxicities that were reported in ≥ 1 % and < 5 % of the patients that were

randomly assigned to receive cisplatin and pemetrexed include: renal failure, infection, pyrexia, febrile

neutropenia, increased AST, ALT, and GGT, urticaria and chest pain.

Clinically relevant CTC toxicities that were reported in < 1 % of the patients that were randomly

assigned to receive cisplatin and pemetrexed include arrhythmia and motor neuropathy.

The table below 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 B

supplementation and 276 patients randomly assigned to receive single agent docetaxel. All

patients were diagnosed with locally advanced or metastatic non-small cell lung cancer and received

prior chemotherapy.

Pemetrexed

N = 265

Docetaxel

N = 276

System organ

class

Frequency

Event*

All grades

toxicity

(%)

Grade 3 –

4 toxicity

(%)

All Grades

toxicity

(%)

Grade 3 –

4 toxicity

(%)

Neutrophils/

Granulocytes

decreased

10.9

45.3

40.2

Leukocytes

decreased

12.1

34.1

27.2

Very

common

Haemoglobin

decreased

19.2

22.1

Blood and

lymphatic

system disorders

Common

Platelets

decreased

Diarrhoea

12.8

24.3

Vomiting

16.2

12.0

Stomatitis/

Pharyngitis

14.7

17.4

Nausea

30.9

16.7

Very

common

Anorexia

21.9

23.9

Gastrointestinal

disorders

Common

Constipation

SGPT (ALT)

elevation

Hepatobiliary

disorders

Common

SGOT (AST)

elevation

Very

common

Rash/

desquamation

14.0

Pruritus

Skin and sub-

cutaneous tissue

disorders

Common

Alopecia

0.4**

37.7

2.2**

Very

common

Fatigue

34.0

35.9

General

disorders and

administration

site conditions

Common

Fever

*Refer to National Cancer Institute CTC version 2 for each grade of toxicity.

**According to National Cancer Institute CTC (v2.0; NCI 1998), alopecia should only be reported as

Grade 1 or 2.

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 toxicities that were reported in ≥ 1 % and < 5 % of the patients that were

randomly assigned to pemetrexed include: infection without neutropenia, febrile neutropenia, allergic

reaction/hypersensitivity, increased creatinine, motor neuropathy, sensory neuropathy, erythema

multiforme, and abdominal pain.

Clinically relevant CTC toxicities that were reported in < 1 % 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 both chemonaive and

heavily pre-treated breast cancer patients with pre-existing liver metastases and/or abnormal baseline

liver function tests.

The table below 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 randomized to

receive cisplatin and pemetrexed and 830 patients with NSCLC who were randomized to receive

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 B

Pemetrexed/

cisplatin

(N = 839)

Gemcitabine/

cisplatin

(N = 830)

System organ

class

Frequency

Event**

All

grades

toxicity

(%)

Grade

3 - 4

toxicity

(%)

All

grades

toxicity

(%)

Grade

3 - 4

toxicity

(%)

Hemoglobin

decreased

33.0*

5.6*

45.7*

9.9*

Neutrophils/

Granulocytes

decreased

29.0*

15.1*

38.4*

26.7*

Leukocytes

Decreased

17.8

4.8*

20.6

7.6*

Blood and

lymphatic

system

disorders

Very

common

Platelets

Decreased

10.1*

4.1*

26.6*

12.7*

Neuropathy-

sensory

8.5*

0.0*

12.4*

0.6*

Nervous

system

disorders

Common

Taste disturbance

0.0***

0.0***

Nausea

56.1

7.2*

53.4

3.9*

Vomiting

39.7

35.5

Anorexia

26.6

2.4*

24.2

0.7*

Constipation

21.0

19.5

Stomatitis/

Pharyngitis

13.5

12.4

Very

common

Diarrhoea without

colostomy

12.4

12.8

Gastrointestinal

disorders

Common

Dyspepsia/

Heartburn

Very

common

Alopecia

11.9*

0***

21.4*

0.5***

Skin and

subcutaneous

tissue disorders

Common

Rash/desquamation

Renal and

urinary

disorders

Very

common

Creatinine

elevation

10.1*

6.9*

General

disorders and

administration

site conditions

Very

common

Fatigue

42.7

44.9

*P-values <0.05 comparing pemetrexed/cisplatin to gemcitabine/cisplatin, using Fisher Exact test.

**Refer to National Cancer Institute CTC (v2.0; NCI 1998) for each Grade of Toxicity.

***According to National Cancer Institute CTC (v2.0; NCI 1998), taste disturbance and alopecia should

only be reported as Grade 1 or 2.

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 % 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 % of the patients that were randomly assigned to

receive cisplatin and pemetrexed include: GGT increase, chest pain, arrhythmia, and motor

neuropathy.

Clinically relevant toxicities with respect to gender were similar to the overall population in patients

receiving pemetrexed plus cisplatin.

The table below 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

pemetrexed maintenance (JMEN: N= 663) and continuation pemetrexed maintenance

(PARAMOUNT: N=539) studies. 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 B

Pemetrexed***

(N =800)

Placebo***

(N =402)

System organ

class

Frequency

*

Event

**

All grades

toxicity

(%)

Grade

3 - 4

toxicity

(%)

All

grades

toxicity

(%)

Grade

3 - 4

toxicity

(%)

Very

common

Hemoglobin

decreased

18.0

Leukocytes

decreased

Blood and

lymphatic

system disorders

Common

Neutrophils

decreased

Nervous system

disorders

Common

Neuropathy-

sensory

Nausea

17.3

Very

common

Anorexia

12.8

Vomiting

Gastrointestinal

disorders

Common

Mucositis/

stomatitis

ALT (SGPT)

elevation

Hepatobiliary

disorders

Common

AST (SGOT)

elevation

Skin and

subcutaneous

tissue disorders

Common

Rash/

desquamation

Very

common

Fatigue

24.1

10.9

General

disorders and

administration

site disorders

Common

Pain

Oedema

Renal Disorders

Common

Renal

disorders****

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common

Terminology Criteria for Adverse Event; NCI = National Cancer Institute; SGOT = serum glutamic

oxaloacectic aminotransferase; SGPT = serum glutamic pyruvic aminotransferase.

Definition of frequency terms: Very common - ≥ 10 %; Common - > 5 % and < 10 %. For the purpose of this

table, a cutoff of 5 % was used for inclusion of all events where the reporter considered a possible relationship

to pemetrexed.

Refer to NCI CTCAE Criteria (Version 3.0; NCI 2003) for each grade of toxicity. The reporting rates shown

are according to CTCAE version 3.0.

***Integrated adverse reactions table combines the results of the JMEN pemetrexed maintenance (N=663) and

PARAMOUNT continuation pemetrexed maintenance (N=539) studies.

****Combined term includes increased serum/blood creatinine, decreased glomerular filtration rate,

renal failure and renal/genitourinary- other.

Clinically relevant CTC toxicity of any grade that was reported in ≥ 1 % and ≤ 5 % of the patients

that were randomly assigned to pemetrexed include: febrile neutropenia, infection, decreased

platelets, diarrhoea, constipation, alopecia, pruritis/itching, fever (in the absence of neutropenia),

ocular surface disease (including conjunctivitis), increased lacrimation, dizziness and motor

neuropathy.

Clinically relevant CTC toxicity that was reported in < 1 % of the patients that were randomly

assigned to pemetrexed include: allergic reaction/hypersensitivity, erythema multiforme,

supraventricular arrhythmia and pulmonary embolism.

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.

Serious cardiovascular and cerebrovascular events, including myocardial infarction, angina pectoris,

cerebrovascular accident and transient ischaemic attack 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.

Rare cases of hepatitis, potentially serious, have been reported during clinical studies with

pemetrexed.

Pancytopenia has been uncommonly reported during clinical trials with pemetrexed.

In clinical trials, cases of colitis (including intestinal and rectal bleeding, sometimes fatal, intestinal

perforation, intestinal necrosis and typhlitis) have been reported uncommonly in patients treated

with pemetrexed.

In clinical trials, cases of interstitial pneumonitis with respiratory insufficiency, sometimes fatal,

have been reported uncommonly in patients treated with pemetrexed.

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

Oesophagitis/ radiation oesophagitis has been uncommonly reported during clinical trials with

pemetrexed.

Sepsis, sometimes fatal, has been commonly reported during clinical trials with pemetrexed.

During post marketing surveillance, the following adverse reactions have been reported in patients

treated with pemetrexed:

Hyperpigmentation has been commonly reported.

Uncommon cases of acute renal failure have been reported with pemetrexed alone or in association

with other chemotherapeutic agents (see section 4.4). Nephrogenic diabetes insipidus and renal

tubular necrosis have been reported in post marketing setting with an unknown frequency.

Uncommon cases of radiation pneumonitis have been reported in patients treated with radiation

either prior, during or subsequent to their pemetrexed therapy (see section 4.4).

Rare cases of radiation recall have been reported in patients who have received radiotherapy

previously (see section 4.4).

Uncommon cases of peripheral ischaemia leading sometimes to extremity necrosis have been

reported.

Rare cases of bullous conditions have been reported including Stevens-Johnson syndrome and Toxic

epidermal necrolysis which in some cases were fatal.

Rarely, immune mediated haemolytic anaemia has been reported in patients treated with

pemetrexed.

Rare cases of anaphylactic shock have been reported.

Erythematous oedema mainly of the lower limbs has been reported with an unknown frequency.

Infectious and non-infectious disorders of the dermis, the hypodermis and/or the subcutaneous tissue

have been reported with an unknown frequency (e.g. acute bacterial dermo-hypodermitis,

pseudocellulitis, dermatitis).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system

listed in Appendix V.

4.9

Overdose

Reported symptoms of overdose include neutropenia, anaemia, thrombocytopenia, mucositis,

sensory polyneuropathy 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/or mucositis may be seen. In the event of suspected overdose,

patients should be monitored with blood counts and should receive supportive therapy as necessary.

The use of calcium folinate / folinic acid in the management of pemetrexed overdose should be

considered.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Folic acid analogues, ATC code: L01BA04.

Pemetrexed is a multi-targeted anti-cancer antifolate agent that exerts its action by disrupting crucial

folate-dependent metabolic processes essential for cell replication.

In vitro

studies have shown that pemetrexed behaves as a multitargeted antifolate by inhibiting

thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide

formyltransferase (GARFT), which are key folate-dependent enzymes for the

de novo

biosynthesis

of thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate

carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is

rapidly and efficiently converted to polyglutamate forms by the enzyme folylpolyglutamate

synthetase. The polyglutamate forms are retained in cells and are even more potent inhibitors of TS

and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumour

cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased

intracellular half-life resulting in prolonged drug action in malignant cells.

The European Medicines Agency has waived the obligation to submit the results of studies with

pemetrexed in all subsets of the paediatric population in the granted indications (see section 4.2).

Clinical efficacy

Mesothelioma

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.

During the study, low-dose folic acid and vitamin B

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 B

supplementation during the entire course of study therapy (fully supplemented). The results of these

analyses of efficacy are summarised in the table below:

Efficacy of pemetrexed plus cisplatin vs. cisplatin

in malignant pleural mesothelioma

Randomized and treated

patients

Fully supplemented

Patients

Efficacy parameter

Pemetrexed/

cisplatin

(N = 226)

Cisplatin

(N = 222)

Pemetrexed/

cisplatin

(N = 168)

Cisplatin

(N = 163)

Median overall survival (months)

(95% CI)

12.1

(10.0 - 14.4)

(7.8 - 10.7)

13.3

(11.4 - 14.9)

10.0

(8.4 - 11.9)

Log Rank p-value*

0.020

0.051

Median time to tumour progression

(months)

(95% CI)

(4.9 - 6.5)

(2.8 - 4.4)

(5.3 - 7.0)

(2.8 - 4.5)

Log Rank p-value*

0.001

0.008

Time to treatment failure (months)

(95% CI)

(3.9 - 4.9)

(2.1 - 2.9)

(4.3 - 5.6)

(2.2 - 3.1)

Log Rank p-value*

0.001

0.001

Overall response rate**

(95% CI)

41.3%

(34.8 - 48.1)

16.7%

(12.0 - 22.2)

45.5%

(37.8 - 53.4)

19.6%

(13.8 - 26.6)

Fisher’s exact p-value*

< 0.001

< 0.001

Abbreviation: CI = confidence interval

*p-value refers to comparison between arms.

**In the pemetrexed/cisplatin arm, randomized and treated (N = 225) and fully supplemented (N = 167)

A statistically significant improvement of the clinically relevant symptoms (pain and dyspnoea)

associated with malignant pleural mesothelioma in the pemetrexed /cisplatin arm (212 patients)

versus the cisplatin arm alone (218 patients) was demonstrated using the Lung Cancer Symptom

Scale. Statistically significant differences in pulmonary function tests were also observed. The

separation between the treatment arms was achieved by improvement in lung function in the

pemetrexed/cisplatin arm and deterioration of lung function over time in the control arm.

There are limited data in patients with malignant pleural mesothelioma treated with pemetrexed

alone. Pemetrexed at a dose of 500 mg/m

was studied as a single-agent in 64 chemonaive patients

with malignant pleural mesothelioma. The overall response rate was 14.1 %.

NSCLC, second-line treatment

A multicentre, randomised, open label phase 3 study of pemetrexed versus docetaxel in patients with

locally advanced or metastatic NSCLC after prior chemotherapy has shown median survival times

of 8.3 months for patients treated with pemetrexed (Intent To Treat population n = 283) and

7.9 months for patients treated with docetaxel (ITT n = 288). Prior chemotherapy did not include

pemetrexed. An analysis of the impact of NSCLC histology on the treatment effect on overall

survival was in favour of pemetrexed versus docetaxel for other than predominantly squamous

histologies (n = 399, 9.3 versus 8.0 months, adjusted HR = 0.78; 95 % CI = 0 .61-1.00, p = 0.047)

and was in favour of docetaxel for squamous cell carcinoma histology (n = 172, 6.2 versus

7.4 months, adjusted HR = 1.56; 95 % CI = 1.08-2.26, p = 0.018). There were no clinically relevant

differences observed for the safety profile of pemetrexed within the histology subgroups.

Limited clinical data from a separate randomized, Phase 3, controlled trial, suggest that efficacy data

(overall survival, progression free survival) for pemetrexed are similar between patients previously

pre-treated with docetaxel (n = 41) and patients who did not receive previous docetaxel treatment

(n = 540).

Efficacy of pemetrexed vs docetaxel in NSCLC - ITT population

Pemetrexed

Docetaxel

(n = 283)

(7.0 - 9.4)

(n = 288)

(6.3 - 9.2)

Survival Time (months)

Median (m)

95 % CI for median

95 % CI for HR

Non-inferiority p-value (HR)

0.99

(.82 - 1.20)

.226

(n = 283)

(n = 288)

Progression free survival (months)

Median

HR (95 % CI)

0.97 (.82 – 1.16)

(n = 283)

(n = 288)

Time to treatment failure (TTTF – months)

Median

HR (95 % CI)

0.84 (.71 - .997)

Response (n: qualified for response)

Response rate (%) (95 % CI)

Stable disease (%)

(n = 264)

9.1 (5.9 - 13.2)

45.8

(n = 274)

8.8 (5.7 - 12.8)

46.4

Abbreviations: CI = confidence interval; HR = hazard ratio; ITT = intent to treat; n = total population size

NSCLC, first-line treatment

A multicentre, randomised, open-label, Phase 3 study of pemetrexed plus cisplatin versus

gemcitabine plus cisplatin 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). All patients included in this study had an ECOG performance status 0 or 1.

The primary efficacy analysis was based on the ITT population. Sensitivity analyses of main

efficacy endpoints were also assessed on the Protocol Qualified (PQ) population. The efficacy

analyses using PQ population are consistent with the analyses for the ITT population and support

the non-inferiority of AC versus GC.

Progression free survival (PFS) and overall response rate were similar between treatment arms:

median PFS was 4.8 months for pemetrexed plus cisplatin versus 5.1 months for gemcitabine plus

cisplatin (adjusted hazard ratio 1.04; 95 % CI = 0.94-1.15), and overall response rate was 30.6 %

(95 % CI = 27.3-33.9) for pemetrexed plus cisplatin versus 28.2 % (95 % CI = 25.0-31.4) for

gemcitabine plus cisplatin. PFS data were partially confirmed by an independent review

(400/1725 patients were randomly selected for review).

The analysis of the impact of NSCLC histology on overall survival demonstrated clinically relevant

differences in survival according to histology, see table below.

Efficacy of pemetrexed + cisplatin vs. gemcitabine + cisplatin in first-line non-small cell lung

cancer – ITT population and histology subgroups.

Median overall survival in months

(95 % CI)

ITT population

and histology

subgroups

Pemetrexed + cisplatin

Gemcitabine +

cisplatin

Adjusted

hazard ratio

(HR)

(95% CI)

Superiority

p-value

ITT population

(N = 1725)

10.3

(9.8 – 11.2)

N=862

10.3

(9.6 – 10.9)

N=863

0.94a

(0.84 – 1.05)

(0.84 – 1.05)

0.259

Adenocarcinoma

(N=847)

12.6 (10.7 –

13.6)

N=436

10.9

(10.2 – 11.9)

N=411

0.84

(0.71–0.99)

0.033

Large cell

(N=153)

10.4

(8.6 – 14.1)

N=76

(5.5 – 9.0)

N=77

0.67

(0.48–0.96)

0.027

Other

(N=252)

(6.8 – 10.2)

N=106

(8.1 – 10.6)

N=146

1.08

(0.81–1.45)

0.586

Squamous cell

(N=473)

(8.4 – 10.2)

N=244

10.8

(9.5 – 12.1)

N=229

1.23

(1.00–1.51)

0.050

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

Statistically significant for noninferiority, with the entire confidence interval for HR well below the

1.17645 noninferiority margin (p <0.001).

Kaplan Meier plots of overall survival by histology

There were no clinically relevant differences observed for the safety profile of pemetrexed plus

cisplatin within the histology subgroups.

Patients treated with pemetrexed and cisplatin required fewer transfusions (16.4 % versus 28.9 %,

p<0.001), red blood cell transfusions (16.1 % versus 27.3 %, p<0.001) and platelet transfusions (1.8 %

versus 4.5 %, p=0.002). Patients also required lower administration of erythropoietin/darbopoietin

(10.4 % versus 18.1 %, p<0.001), G-CSF/GM-CSF (3.1 % versus 6.1 %, p=0.004), and iron

preparations (4.3 % versus 7.0 %, p=0.021)

.

NSCLC, maintenance treatment

JMEN

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 containing Cisplatin or Carboplatin in combination with Gemcitabine,

Paclitaxel, or Docetaxel. First line doublet therapy containing pemetrexed was not included. 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.

The study met its primary endpoint and showed a statistically significant improvement in PFS in the

pemetrexed arm over the placebo arm (n = 581, independently reviewed population; median of

4.0 months and 2.0 months, respectively) (hazard ratio = 0.60, 95 % CI = 0.49-0.73, p < 0.00001). The

independent review of patient scans confirmed the findings of the investigator assessment of PFS. The

median OS for the overall population (n = 663) was 13.4 months for the pemetrexed arm and

10.6 months for the placebo arm, hazard ratio = 0.79 (95 % CI = 0.65-0.95, p = 0.01192).

Consistent with other pemetrexed studies, a difference in efficacy according to NSCLC histology was

observed in JMEN. For patients with NSCLC other than predominantly squamous cell histology

(n = 430, independently reviewed population) median PFS was 4.4 months for the pemetrexed arm and

1.8 months for the placebo arm, hazard ratio = 0.47 (95 % CI = 0.37-0.60, p = 0.00001). The median

OS for patients with NSCLC other than predominantly squamous cell histology (n = 481) was

15.5 months for the pemetrexed arm and 10.3 months for the placebo arm, hazard

ratio = 0.70 (95 % CI = 0.56-0.88, p = 0.002). Including the induction phase the median OS for

patients with NSCLC other than predominantly squamous cell histology was 18.6 months for the

pemetrexed arm and 13.6 months for the placebo arm, hazard ratio = 0.71 (95 % CI = 0.56-0.88,

p = 0.002).

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.

JMEN: Kaplan Meier plots of progression-free survival (PFS) and overall survival pemetrexed

versus placebo in patients with NSCLC other than predominantly squamous cell histology:

PARAMOUNT

A multicentre, randomised, double-blind, placebo-controlled Phase 3 study (PARAMOUNT),

compared the efficacy and safety of continuation maintenance treatment with pemetrexed plus BSC

(n = 359) with that of placebo plus BSC (n = 180) in patients with locally advanced (Stage IIIB) or

metastatic (Stage IV) NSCLC other than predominantly squamous cell histology who did not progress

after 4 cycles of first line doublet therapy of pemetrexed in combination with cisplatin. Of the

939 patients treated with pemetrexed plus cisplatin induction, 539 patients were randomised to

maintenance treatment with pemetrexed or placebo. Of the randomised patients, 44.9 % had a

complete/partial response and 51.9 % had a response of stable disease to pemetrexed plus cisplatin

induction. Patients randomised to maintenance treatment were required to have an ECOG performance

status 0 or 1. The median time from the start of pemetrexed plus cisplatin induction therapy to the start

of maintenance treatment was 2.96 months on both the pemetrexed arm and the placebo arm.

Randomised patients received maintenance treatment until disease progression. Efficacy and safety

were measured from the time of randomisation after completion of first line (induction) therapy.

Patients received a median of 4 cycles of maintenance treatment with pemetrexed and 4 cycles of

placebo. A total of 169 patients (47.1 %) completed ≥ 6 cycles maintenance treatment with

pemetrexed, representing at least 10 total cycles of pemetrexed.

The study met its primary endpoint and showed a statistically significant improvement in PFS in the

pemetrexed arm over the placebo arm (n = 472, independently reviewed population; median of

3.9 months and 2.6 months, respectively) (hazard ratio = 0.64, 95 % CI = 0.51-0.81, p = 0.0002). The

independent review of patient scans confirmed the findings of the investigator assessment of PFS. For

randomised patients, as measured from the start of pemetrexed plus cisplatin first line induction

treatment, the median investigator-assessed PFS was 6.9 months for the pemetrexed arm and

5.6 months for the placebo arm (hazard ratio = 0.59 95 % CI = 0.47-0.74).

Following pemetrexed plus cisplatin induction (4 cycles), treatment with pemetrexed was statistically

superior to placebo for OS (median 13.9 months versus 11.0 months, hazard ratio = 0.78,

95 %CI = 0.64-0.96, p = 0.0195). At the time of this final survival analysis, 28.7 % of patients were

alive or lost to follow up on the pemetrexed arm versus 21.7 % on the placebo arm. The relative

treatment effect of pemetrexed was internally consistent across subgroups (including disease stage,

induction response, ECOG PS, smoking status, gender, histology and age) and similar to that observed

in the unadjusted OS and PFS analyses. The 1 year and 2 year survival rates for patients on

pemetrexed were 58 % and 32 % respectively, compared to 45 % and 21 % for patients on placebo.

From the start of pemetrexed plus cisplatin first line induction treatment, the median OS of patients

was 16.9 months for the pemetrexed arm and 14.0 months for the placebo arm (hazard ratio= 0.78,

95 % CI = 0.64-0.96). The percentage of patients that received post study treatment was 64.3 % for

pemetrexed and 71.7 % for placebo.

PARAMOUNT:Kaplan Meier plot of progression-free survival (PFS) and Overall Survival

(OS) for continuation pemetrexed maintenance versus placebo in patients with NSCLC other

than predominantly squamous cell histology (measured from randomisation)

The pemetrexed maintenance safety profiles from the two studies JMEN and PARAMOUNT were

similar.

5.2

Pharmacokinetic properties

The pharmacokinetic properties of pemetrexed following single-agent administration have been

evaluated in 426 cancer patients with a variety of solid tumours at doses ranging from 0.2 to

838 mg/m

infused over a 10-minute period. Pemetrexed has a steady-state volume of distribution of

9 l/m

In vitro

studies indicate that pemetrexed is approximately 81 % bound to plasma proteins.

Binding was not notably affected by varying degrees of renal impairment. Pemetrexed undergoes

limited hepatic metabolism. Pemetrexed is primarily eliminated in the urine, with 70 % to 90 % of the

administered dose being recovered unchanged in urine within the first 24 hours following

administration.

In Vitro

studies indicate that pemetrexed is actively secreted by OAT3 (organic anion

transporter. Pemetrexed total systemic clearance is 91.8 ml/min and the elimination half-life from

plasma is 3.5 hours in patients with normal renal function (creatinine clearance of 90 ml/min).

Between patient variability in clearance is moderate at 19.3 %. Pemetrexed total systemic exposure

(AUC) and maximum plasma concentration increase proportionally with dose. The pharmacokinetics

of pemetrexed are consistent over multiple treatment cycles.

The pharmacokinetic properties of pemetrexed are not influenced by concurrently administered

cisplatin. Oral folic acid and intramuscular vitamin B

supplementation do not affect the

pharmacokinetics of pemetrexed.

5.3

Preclinical safety data

Administration of pemetrexed to pregnant mice resulted in decreased foetal viability, decreased foetal

weight, incomplete ossification of some skeletal structures and cleft palate.

Administration of pemetrexed to male mice resulted in reproductive toxicity characterised by reduced

fertility rates and testicular atrophy. In a study conducted in beagle dog by intravenous bolus injection

for 9 months, testicular findings (degeneration/necrosis of the seminiferous epithelium) have been

observed. This suggests that pemetrexed may impair male fertility. Female fertility was not

investigated.

Pemetrexed was not mutagenic in either the

in vitro

chromosome aberration test in Chinese hamster

ovary cells, or the Ames test. Pemetrexed has been shown to be clastogenic in the

in vivo

micronucleus

test in the mouse.

Studies to assess the carcinogenic potential of pemetrexed have not been conducted.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Mannitol

Hydrochloric acid

Sodium hydroxide

6.2

Incompatibilities

Pemetrexed is physically incompatible with diluents containing calcium, including lactated Ringer’s

injection and Ringer’s injection. In the absence of other compatibility studies this medicinal product

must not be mixed with other medicinal products.

6.3

Shelf life

Unopened vial

3 years

Reconstituted and infusion solutions

When prepared as directed, reconstituted and infusion solutions of Pemetrexed Actavis contain no

antimicrobial preservatives. Chemical and physical in-use stability of reconstituted and infusion

solutions of pemetrexed were demonstrated for 3 days at room temperature at normal lighting

conditions and 14 days at refrigerated temperature (2-8°C). From a microbiological point of view, the

product should be used immediately. If not used immediately, in-use storage times and conditions prior

to use are the responsibility of the user and would not be longer than 24 hours at 2°C to 8°C, unless

reconstitution / dilution has taken place in controlled and validated aseptic conditions.

6.4

Special precautions for storage

Unopened vial

Keep the vial in the outer carton in order to protect from light.

This medicinal product does not require any special temperature storage conditions.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5

Nature and contents of container

Pemetrexed Actavis is packed in colourless glass vials (type I) with type I rubber (bromobutyl) lyo-

stopper and an aluminium cap with polypropylene disk. <Vials are sheathed in protective sleeve.>

Pack sizes

One 10 ml vial containing 100 mg pemetrexed.

One 50 ml vial containing 500 mg pemetrexed.

One 50 ml vial containing 1000 mg pemetrexed.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal <and other handling>

Use aseptic technique during the reconstitution and further dilution of pemetrexed for

intravenous infusion administration.

Calculate the dose and the number of Pemetrexed Actavis vials needed. Each vial contains an

excess of pemetrexed to facilitate delivery of label amount.

Reconstitute 100 mg vials with 4.2 ml of 9 mg/ml (0.9 %) sodium chloride solution for

injection, without preservative, resulting in a solution containing 25 mg/ml pemetrexed.

Reconstitute 500 mg vials with 20 ml of 9 mg/ml (0.9 %) sodium chloride solution for injection,

without preservative, resulting in a solution containing 25 mg/ml pemetrexed.

Reconstitute 1000 mg vials with 40 ml of 9 mg/ml (0.9 %) sodium chloride solution for

injection, without preservative, resulting in a solution containing 25 mg/ml pemetrexed.

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 solution is between 6.6 and 7.8.

Further dilution is

required

The appropriate volume of reconstituted pemetrexed solution must be further diluted to 100 ml

with sodium chloride 9 mg/ml (0.9 %) solution for injection, without preservative, and

administered as an intravenous infusion over 10 minutes.

Pemetrexed infusion solutions prepared as directed above are compatible with polyvinyl

chloride and polyolefin lined administration sets and infusion bags.

Parenteral medicinal products must be inspected visually for particulate matter and

discolouration prior to administration. If particulate matter is observed, do not administer.

Pemetrexed solutions are for single use only. Any unused medicinal product or waste material

must be disposed of in accordance with local requirements.

Preparation and administration precautions:

As with other potentially toxic anticancer agents, care

should be exercised in the handling and preparation of pemetrexed infusion solutions. The use of

gloves is recommended. If a pemetrexed solution contacts the skin, wash the skin immediately and

thoroughly with soap and water. If pemetrexed solutions contact the mucous membranes, flush

thoroughly with water. Pemetrexed is not a vesicant. There is not a specific antidote for extravasation

of pemetrexed. There have been few reported cases of pemetrexed extravasation, which were not

assessed as serious by the investigator. Extravasation should be managed by local standard practice as

with other non-vesicants.

7.

MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<Date of first authorisation: {DD month YYYY}>

<Date of latest renewal: {DD month YYYY}>

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

2019-03-25

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