ALIMTA 100 MG

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
PEMETREXED
Available from:
ELI LILLY ISRAEL LTD, ISRAEL
ATC code:
L01BA04
Pharmaceutical form:
POWDER FOR SOLUTION FOR INFUSION
Composition:
PEMETREXED 100 MG/VIAL
Administration route:
I.V
Prescription type:
Required
Manufactured by:
LILLY FRANCE S.A.S., FRANCE
Therapeutic group:
PEMETREXED
Therapeutic area:
PEMETREXED
Therapeutic indications:
Alimta in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curatible surgery. Alimta 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. Alimta 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.Alimta 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.
Authorization number:
138 86 31721 00
Authorization date:
2018-08-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Hebrew

05-10-2020

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PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS’

REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with a doctor’s prescription only

ALIMTA

500 mg

Powder for solution for infusion

ALIMTA

100 mg

Powder for solution for infusion

The active ingredient is pemetrexed.

Alimta 100 mg: Each vial contains 100 milligrams of pemetrexed (as pemetrexed disodium).

Alimta 500 mg: Each vial contains 500 milligrams of pemetrexed (as pemetrexed disodium).

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

healthcare provider is required prior to administration.

Inactive ingredients and allergens: See section 6 “Additional information” and section 2

“Important information about some of the ingredients of this medicine”.

Read this leaflet carefully in its entirety before using the medicine. This leaflet contains

concise information about the medicine. If you have any further questions, please contact your

doctor or pharmacist

This medicine has been prescribed for the treatment of your illness. Do not pass it on to others.

It may harm them, even if it seems to you that their illness is similar.

1. WHAT IS THIS MEDICINE INTENDED FOR?

Alimta is a medicine used in the treatment of cancer.

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

pleural mesothelioma, whose disease is unresectable or who are otherwise not candidates for

curatible surgery.

Alimta 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.

Alimta 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.

Alimta 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.

Therapeutic group: folic acid analogues.

2. BEFORE USING THIS MEDICINE

Do not use Alimta if:

you are sensitive (allergic) to pemetrexed or any of the other ingredients that this medicine

contains (listed in section 6).

you are breastfeeding; you must discontinue breastfeeding during treatment with Alimta.

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

Special warnings regarding the use of this medicine

Before starting treatment with Alimta, tell your doctor:

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 Alimta.

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 determine

the suitability of receiving the treatment of Alimta. 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 Alimta.

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

effects with Alimta

If you have a heart disease or a history of a 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 Alimta.

Children and adolescents:

There is no relevant use of Alimta in the pediatric population in malignant pleural mesothelioma

and non-small cell lung cancer.

Interactions/Drug interactions

If you are taking, or have recently taken, other medicines, including non-prescription

medicines and nutritional supplements, inform the doctor or pharmacist. Particularly if you

are taking

Any medicine 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 Alimta 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.

Pregnancy, breastfeeding and fertility

Pregnancy

If you are pregnant, think you may be pregnant or are planning a pregnancy, tell your doctor.

The use of Alimta should be avoided during pregnancy. Your doctor will discuss with you the

potential risk of taking Alimta during pregnancy. Women must use effective contraception

during treatment with Alimta.

Breastfeeding

If you are breastfeeding, tell your doctor

Breastfeeding must be discontinued during treatment with Alimta.

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Fertility

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

and should therefore use effective contraception during treatment with Alimta 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

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

Important information about some of the ingredients of this medicine

Alimta 100 mg contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium-free’

Alimta 500 mg contains 54 mg sodium (main component of cooking/table salt) in each vial. This

is equivalent to 2.7% of the recommended maximum daily dietary intake of sodium for an adult.

3. HOW SHOULD YOU USE THIS MEDICINE?

The dosage and manner of treatment will be determined by the doctor only. The usual dosage is:

The dose of Alimta is 500 milligrams for every square meter 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 Alimta powder with 9 mg/ml (0.9%) sodium

chloride solution for injection before it is given to you.

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

approximately 10 minutes.

When using Alimta 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 Alimta 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 milligrams of

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

day after Alimta 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 1,000 micrograms) that you must take once a day while you are

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

Alimta. You must continue taking the folic acid for 21 days after the last dose of Alimta. You will

also receive an injection of vitamin B

(1,000 micrograms) in the week before administration of

Alimta and then approximately every 9 weeks (corresponding to 3 courses of Alimta treatment).

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Vitamin B

and folic acid are given to you to reduce the possible toxic effects of the anticancer

treatment

Do not exceed the recommended dose.

Do not take medicines in the dark! Check the label and the dose each time you take your

medicine. Wear glasses if you need them.

If you have further questions regarding the use of this medicine, consult your doctor or

pharmacist.

4. SIDE EFFECTS

As with any medicine, the use of Alimta may cause side effects in some users. Do not be

alarmed when reading the list of side effects. You may not experience any of 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 a 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 hemoglobin 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).

Additional side effects

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

Infection

Pharyngitis (a sore throat)

Low number of neutrophil granulocytes (a type of white blood cell)

Low white blood cells

Low hemoglobin level

Pain, redness, swelling or sores in your mouth

Loss of appetite

Vomiting

Diarrhea

Nausea

Skin rash

Flaking skin

Abnormal blood tests showing reduced functionality of kidneys

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Fatigue (tiredness)

Common side effects (may affect up to 1 in 10 people)

Blood infection

Fever with low number of neutrophil granulocytes (a type of white blood cell)

Low platelet count

Allergic reaction

Loss of body fluids

Taste change

Damage to the motor nerves which may cause muscle weakness and atrophy (primary in the

arms and legs)

Damage to the sensory nerves that may cause loss of sensation, burning pain and unsteady

gait

Dizziness

Inflammation or swelling of the conjunctiva (the membrane that lines the eyelids and covers the

white of the eye)

Dry eyes

Watery eyes

Dryness of the conjunctiva (the membrane that lines the eyelids and covers the white of the

eye) and cornea (the clear layer in front of the iris and pupil)

Swelling of the eyelids

Eye disorder with dryness, tearing, irritation, and/or pain

Cardiac failure (condition that affects the pumping power of your heart muscles)

Irregular heart rhythm

Indigestion

Constipation

Abdominal pain

Liver: increases in the chemicals in the blood made by the liver

Increased skin pigmentation

Itchy skin

Rash on the body where each mark resembles a bullseye

Hair loss

Hives

Kidney stop working

Reduced functionality of kidney

Fever

Pain

Excess fluid in body tissue, causing swelling

Chest pain

Inflammation and ulceration of the mucous membranes lining the digestive tract

Uncommon side effects (may affect up to 1 in 100 people)

Reduction in the number of red, white blood cells and platelets

Stroke

Type of stroke when an artery to the brain is blocked

Bleeding inside the skull

Angina (chest pain caused by reduced blood flow to the heart)

Heart attack

Narrowing or blockage of the coronary arteries

Abnormal heart rhythm

Deficient blood distribution to the limbs

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Blockage in one of the pulmonary arteries in your lungs

Inflammation and scarring of the lining of the lungs with breathing problems

Passage of bright red blood from the anus

Bleeding in the gastrointestinal tract

Ruptured bowel

Inflammation of the lining of the oesophagus

Inflammation of the lining of the large bowel, which may be accompanied by intestinal or rectal

bleeding (seen only in combination with cisplatin)

Inflammation, edema, erythema, and erosion of the mucosal surface of the esophagus caused

by radiation therapy

Inflammation of the lung caused by radiation therapy

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

Destruction of red blood cells

Anaphylactic shock (severe allergic reaction)

Inflammatory condition of the liver

Redness of the skin

Skin rash that develops throughout a previously irradiated area

Very rare side effects (may affect up to 1 in 10,000 people)

Infections of skin and soft tissues

Stevens-Johnson syndrome (a type of severe skin and mucous membranes reaction that may

be life threatening)

Toxic epidermal necrolysis (a type of severe skin reaction that may be life threatening)

Autoimmune disorder that results in skin rashes and blistering on the legs, arms, and abdomen

Inflammation of the skin characterized by the presence of bullae which are filled with fluid

Skin fragility, blisters and erosions and skin scarring

Redness, pain and swelling mainly of the lower limbs

Inflammation of the skin and fat beneath the skin (pseudocellulitis)

Inflammation of the skin (dermatitis)

Skin to become inflamed, itchy, red, cracked, and rough

Intensely itchy spots

Not known: frequency cannot be estimated from the available data

Form of diabetes primarily due to pathology of the kidney

Disorder of the kidneys involving the death of tubular epithelial cells that form the renal tubules

If a side effect occurs, if any of the side effects worsen, or if you are suffering from a side

effect not mentioned in this leaflet, consult the doctor.

Reporting side effects

Side effects can be reported to the Ministry of Health by clicking on the link "Reporting side

effects due to drug treatment" that can be found on the Homepage of the Ministry of Health’s

website (

www.health.gov.il)

, which refers to the online form for reporting side effects, or by

entering the following link:

https://sideeffects.health.gov.il

5. HOW TO STORE THE MEDICINE?

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Avoid poisoning! This medicine and any other medicine must be kept in a closed place out

of the reach and sight of children and/or infants to avoid poisoning. Do not induce vomiting

without an explicit instruction from the doctor.

Do not use this medicine after the expiry date (exp. date) that appears on the vial and on the

package. The expiry date refers to the last day of that month.

Storage conditions

Store below 25

Reconstituted and Infusion Solutions: From a microbiological point of view, the product

should be used immediately. If not used immediately and when prepared as directed,

chemical and physical in-use stability of reconstituted and infusion solutions of pemetrexed

were demonstrated for 24 hours at refrigerated temperature (2

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

with local requirement.

6. ADDITIONAL INFORMATION

In addition to the active ingredient, Alimta also contains:

mannitol, hydrochloric acid, sodium hydroxide, water for injection, nitrogen.

What Alimta looks like and contents of the pack

Alimta is a powder for solution for infusion in a vial. It is a white to either light yellow or green-

yellow lyophilised powder

Each pack of Alimta consists of one Alimta vial

License Holder and address: Eli Lilly Israel Ltd., 4 HaSheizaf St., P.O.B 4246, Ra’anana

4366411.

Manufacturer and address: Lilly France S.A.S., Fegersheim, France.

Registration numbers of the medicine in the National Drug Registry of the Ministry of

Health:

Alimta 100 mg: 138-86-31721-00

Alimta 500 mg: 131-45-31049-00/1

Revised in September 2020.

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1.

NAME OF THE MEDICINAL PRODUCT

ALIMTA 100 mg

powder for solution for infusion

ALIMTA 500 mg

powder for solution for infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

ALIMTA 100 mg powder for solution for infusion

Each vial contains 100

of pemetrexed (as pemetrexed disodium).

Excipient with known effect:

Each vial contains approximately 11

mg sodium.

ALIMTA 500 mg powder for solution for infusion

Each vial contains 500

of pemetrexed (as pemetrexed disodium).

Excipient with known effect:

Each vial contains approximately 54 mg sodium.

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

For the full list of excipients see section 6.1.

3.

PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion.

White to either light yellow or green-yellow lyophilised powder.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Malignant pleural mesothelioma

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

mesothelioma whose disease is unresectable or who are otherwise not candidates for curatible surgery.

Non-small cell lung cancer

ALIMTA 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).

ALIMTA 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).

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ALIMTA 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

ALIMTA must only be administered under the supervision of a physician qualified in the use of

anti-cancer chemotherapy.

ALIMTA in combination with cisplatin

The recommended dose of ALIMTA 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).

ALIMTA as single agent

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

ALIMTA is 500 mg/m

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

each 21-day cycle.

Pre-medication 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

1,000 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

(1,000 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

1,500 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.

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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 ALIMTA used as a single agent or in combination with

cisplatin.

Table 1 - Dose modification table for ALIMTA (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 ALIMTA and

cisplatin)

Nadir platelets

<

50,000 /mm

regardless of

nadir ANC

75% of previous dose (both ALIMTA and

cisplatin)

Nadir platelets <50,000/mm

with bleeding

regardless of nadir ANC.

50% of previous dose (both ALIMTA 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), ALIMTA 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 ALIMTA (as single agent or in combination) and

cisplatin– Non-haematologic toxicities

a, b

Dose of ALIMTA

(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 ALIMTA and cisplatin is

documented in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is observed.

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

cisplatin – Neurotoxicity

CTC

a

Grade

Dose of ALIMTA (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 ALIMTA 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.

Special populations

Elderly

In clinical studies, there has been no indication that patients 65 years of age or older are at increased risk

of adverse reaction 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 ALIMTA in the paediatric population in malignant pleural mesothelioma and

non-small cell lung cancer.

Patients with renal impairment

(standard cockcroft and gault formula or glomerular filtration rate

measured Tc99m-DPTA serum clearance method)

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

creatinine clearance of

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).

Patients with hepatic impairment

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

pharmacokinetics were identified. However, patients with hepatic impairment such as bilirubin > 1.5

times the upper limit of normal and/or 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:

ALIMTA is for intravenous use. ALIMTA should be administered as an intravenous infusion over

10 minutes on the first day of each 21-day cycle.

For precautions to be taken before handling or administering ALIMTA and for instructions on

reconstitution and dilution of ALIMTA before administration, see section 6.6.

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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

1,500 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 have 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 insufficiency (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 insufficiency 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

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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.

Excipients

ALIMTA 100 mg powder for solution for infusion

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially

‘sodium- free’.

ALIMTA 500 mg powder for solution for infusion

This medicinal product contains 54 mg sodium per vial, equivalent to 2,7 % of the WHO recommended

maximum daily intake of 2 g sodium for an adult.

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.

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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 > 1,600 mg/day) and acetylsalicylic acid at a higher

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

pemetrexed adverse reactions. 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 insufficiency (creatinine clearance from 45 to 79 ml/min), the

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

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

Women of childbearing potential / 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

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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).

Breast-feeding

It is unknown whether pemetrexed is excreted in human milk and adverse reactions on the breast-feeding

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 4 lists the adverse drug events regardless of causality associated with pemetrexed used either as

a monotherapy treatment or in combination with cisplatin from the pivotal registration studies (JMCH,

JMEI, JMBD,

JMEN and PARAMOUNT) and from the post marketing period.

ADRs are listed by MedDRA body system organ class. The following convention has been used for

classification of frequency: 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

the available data).

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Table 4. Frequencies of all grades adverse drug events regardless of causality from the pivotal

registration studies: JMEI (ALIMTA vs Docetaxel), JMDB (ALIMTA and Cisplatin versus

GEMZAR and Cisplatin, JMCH (ALIMTA plus Cisplatin versus Cisplatin), JMEN and

PARAMOUNT (Pemetrexed plus Best Supportive Care versus Placebo plus Best Supportive Care)

and from post-marketing period.

System

Organ Class

(MedDRA)

Very common

Common

Uncommon

Rare

Very rare

Not

known

Infections and

infestations

Infection

Pharyngitis

Sepsis

Dermo-

hypodermitis

Blood and

lymphatic

system

disorders

Neutropenia

Leukopenia

Haemoglobin

decreased

Febrile

neutropenia

Platelet count

decreased

Pancytopenia

Autoimmune

haemolytic

anaemia

Immune

System

disorders

Hypersensiti-

vity

Anaphylac-tic

shock

Metabolism

and nutrition

disorders

Dehydration

Nervous

system

disorders

Taste disorder

Peripheral

motor

neuropathy

Peripheral

sensory

neuropathy

Dizziness

Cerebrovascul

ar accident

Ischaemic

stroke

Haemorrhage

intracranial

Eye disorders

Conjunctivitis

Dry eye

Lacrimation

increased

Keratoconjunc

tivitis sicca

Eyelid oedema

Ocular

surface

disease

Cardiac

disorders

Cardiac failure

Arrhythmia

Angina

Myocardial

infarction

Coronary

artery disease

Arrhythmia

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supraventricul

Vascular

disorders

Peripheral

ischaemia

Respiratory,

thoracic and

mediastinal

disorders

Pulmonary

embolism

Interstitial

pneumonitis

Gastrointes-

tinal disorders

Stomatitis

Anorexia

Vomiting

Diarrhoea

Nausea

Dyspepsia

Constipation

Abdominal

pain

Rectal

haemorrhage

Gastrointestina

l haemorrhage

Intestinal

perforation

Oesophagitis

Colitis

Hepatobiliary

disorders

Aalanine

aminotransfera

se increased

Aspartate

aminotransfera

se increased

Hepatitis

Skin and

subcutaneous

tissue

disorders

Rash

Skin

exfoliation

Hyperpigment

ation

Pruritus

Erythema

multiforme

Alopecia

Urticaria

Erythema

Stevens-

Johnson

syndrome

Toxic

epidermal

necrolysis

Pemphigoid

Dermatitis

bullous

Acquired

epidermolysis

bullosa

Erythema-tous

oedema

Pseudocellu-

litis

Dermatitis

Eczema

Prurigo

Renal and

urinary

disorders

Creatinine

clearance

decreased

Blood

creatinine

increased

Renal failure

Glomerular

filtration rate

decreased

Nephro

ge-nic

diabete

insipid

Renal

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tubular

necrosi

General

disorders and

administration

site conditions

Fatigue

Pyrexia

Pain

Oedema

Chest pain

Mucosal

inflammation

Investigations

Gamma-

glutamyltransf

erase increased

Injury,

poisoning and

procedural

complications

Radiation

oesophagitis

Radiation

pneumonitis

Recall pheno-

menon

with and without neutropenia

in some cases fatal

sometimes leading to extremity necrosis

with respiratory insufficiency

seen only in combination with cisplatin

mainly of the lower limbs

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form via the following link:

https://sideeffects.health.gov.il

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

ALIMTA (pemetrexed) is a multi-targeted anti-cancer antifolate agent that exerts its action by disrupting

crucial folate-dependent metabolic processes essential for cell replication.

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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.

Clinical efficacy:

Mesothelioma:

EMPHACIS, a multicentre, randomised, single-blind phase 3 study of ALIMTA plus cisplatin versus

cisplatin in chemonaive patients with malignant pleural mesothelioma

has shown that patients treated

with ALIMTA and cisplatin had a clinically meaningful 2.8-month median survival advantage over

patients receiving cisplatin alone.

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:

Table 5.

Efficacy of ALIMTA plus cisplatin vs. cisplatin in malignant pleural mesothelioma

Randomized and treated

Fully supplemented

patients

patients

Efficacy parameter

ALIMTA/

cisplatin

Cisplatin

ALIMTA/

cisplatin

Cisplatin

(N = 226)

(N = 222)

(N = 168)

(N = 163)

Median overall survival (months)

12.1

13.3

10.0

(95% CI)

(10.0 - 14.4)

(7.8 - 10.7)

(11.4 - 14.9)

(8.4 - 11.9)

Log Rank p-value

0.020

0.051

Median

time

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

41.3%

16.7%

45.5%

19.6%

(95% CI)

(34.8 - 48.1)

(12.0 - 22.2)

(37.8 - 53.4)

(13.8 - 26.6)

Fisher’s exact p-value

< 0.001

< 0.001

Abbreviation: CI = confidence interval

* p-value refers to comparison between arms.

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ALIMTA/cisplatin

arm,

randomized

treated

(N = 225)

fully

supplemented

(N = 167)

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

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

cisplatin 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 ALIMTA/cisplatin arm and

deterioration of lung function over time in the control arm.

There are limited data in patients with malignant pleural mesothelioma treated with ALIMTA alone.

ALIMTA at a dose of 500 mg/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 ALIMTA versus docetaxel in patients with locally

advanced or metastatic NSCLC after prior chemotherapy has shown median survival times of 8.3 months

for patients treated with ALIMTA (Intent To Treat population N = 283) and 7.9 months for patients

treated with docetaxel (ITT N = 288). Prior chemotherapy did not include ALIMTA.

An analysis of the

impact of NSCLC histology on the treatment effect on overall survival was in favour of ALIMTA 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 ALIMTA 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).

Table 6. Efficacy of ALIMTA vs. docetaxel in NSCLC - ITT population

ALIMTA

Docetaxel

Survival Time (months

Median (m)

95% CI for median

(N = 283)

(7.0 - 9.4)

(N = 288)

(6.3 - 9.2)

95% CI for HR

Non-inferiority p-value (HR)

0.99

82 - 1.20)

.226

Progression free survival (months)

Median

(N = 283)

(N = 288)

HR (95% CI)

0.97

82 – 1.16)

Time to treatment failure (TTTF – months)

Median

(N = 283)

(N = 288)

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.

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NSCLC, first-line treatment:

A multicentre, randomised, open-label, Phase 3 study of ALIMTA 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 ALIMTA plus cisplatin (Intent-To-Treat [ITT] population N = 862) met its

primary endpoint and showed similar clinical efficacy as gemcitabine plus cisplatin (ITT N = 863) in

overall survival (adjusted hazard ratio 0.94; 95% CI = 0.84-1.05). 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 ALIMTA 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 ALIMTA plus cisplatin versus 28.2% (95% CI = 25.0-31.4) for gemcitabine plus cisplatin. PFS

data were partially confirmed by an independent review (400/1,725 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.

Table 7. Efficacy of ALIMTA + cisplatin vs. gemcitabine + cisplatin in first-line non-small cell lung

cancer – ITT population and histology subgroups.

ITT population

and histology

subgroups

Median overall survival in months

(95% CI)

Adjusted

hazard

ratio

(HR)

(95% CI)

Superiority

p-value

ALIMTA + cisplatin

Gemcitabine + cisplatin

ITT population

(N = 1,725)

10.3

(9.8 – 11.2)

N=862

10.3

(9.6 – 10.9)

N=863

0.94

(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).

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Kaplan Meier plots of overall survival by histology

Adenocarcinoma

Survival Time (months)

Survival Probability

Large Cell Carcinoma

Survival Time (months)

Survival Probability

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

within the histology subgroups.

Patients treated with ALIMTA 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 ALIMTA plus best supportive care (BSC) (N = 441) with that

of placebo plus BSC (N = 222) in patients with locally advanced (Stage IIIB) or metastatic (Stage IV)

Non Small Cell Lung Cancer (NSCLC) who did not progress after 4 cycles of first line doublet therapy

containing Cisplatin or Carboplatin in combination with Gemcitabine, Paclitaxel, or Docetaxel. First line

doublet therapy containing ALIMTA 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 ALIMTA and 3.5 cycles of placebo.

A total of 213 patients (48.3%) completed ≥ 6 cycles and a total of 103 patients (23.4%) completed

≥ 10 cycles of treatment with ALIMTA.

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

ALIMTA 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 ALIMTA arm and 10.6 months for the placebo

arm, hazard ratio = 0.79 (95% CI = 0.65-0.95, p = 0.01192).

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Consistent with other ALIMTA 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 ALIMTA 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 ALIMTA 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 ALIMTA 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 ALIMTA

over placebo.

There were no clinically relevant differences observed for the safety profile of ALIMTA within the

histology subgroups.

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

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

Progression-Free Survival

Overall Survival

PFS Time (months)

PFS Probability

Pemetrexed

Placebo

Survival Time (months)

Survival Probability

Pemetrexed

Placebo

PARAMOUNT

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

the efficacy and safety of continuation maintenance treatment with ALIMTA plus BSC (N = 359) with

that of placebo plus BSC (N = 180) in patients with locally advanced (Stage IIIB) or metastatic (Stage IV)

NSCLC other than predominantly squamous cell histology who did not progress after 4 cycles of first line

doublet therapy of ALIMTA in combination with cisplatin. Of the 939 patients treated with ALIMTA

plus cisplatin induction, 539 patients were randomised to maintenance treatment with pemetrexed or

placebo. Of the randomised patients, 44.9% had a complete/partial response and 51.9% had a response of

stable disease to ALIMTA plus cisplatin induction. Patients randomised to maintenance treatment were

required to have an ECOG performance status 0 or 1. The median time from the start of ALIMTA plus

cisplatin induction therapy to the start of maintenance treatment was 2.96 months on both the 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 ALIMTA and

X ALIMVL F 15

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

ALIMTA, representing at least 10 total cycles of ALIMTA.

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

ALIMTA 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 ALIMTA plus cisplatin first line induction treatment, the median

investigator-assessed PFS was 6.9 months for the ALIMTA arm and 5.6 months for the placebo arm

(hazard ratio = 0.59 95% CI = 0.47-0.74).

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

superior to placebo for OS (median 13.9 months versus 11.0 months, hazard ratio = 0.78, 95% CI=0.64-

0.96, p=0.0195). At the time of this final survival analysis, 28.7% of patients were alive or lost to follow

up on the ALIMTA arm versus 21.7% on the placebo arm. The relative treatment effect of ALIMTA was

internally consistent across subgroups (including disease stage, induction response, ECOG PS, smoking

status, gender, histology and age) and similar to that observed in the unadjusted OS and PFS analyses.

The 1 year and 2 year survival rates for patients on ALIMTA were 58% and 32% respectively, compared

to 45% and 21% for patients on placebo. From the start of ALIMTA plus cisplatin first line induction

treatment, the median OS of patients was 16.9 months for the ALIMTA arm and 14.0 months for the

placebo arm (hazard ratio= 0.78, 95% CI= 0.64-0.96). The percentage of patients that received post study

treatment was 64.3% for ALIMTA and 71.7% for placebo.

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

for continuation ALIMTA maintenance versus placebo in patients with NSCLC other than

predominantly squamous cell histology (measured from randomisation)

Progression-Free Survival

Overall Survival

PFS Time (Months)

Time (Months)

Survival Probability

lity

0

3

6

9

12

15

18

21

24

27

30

33

36

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pemetrexed

Placebo

OS Time (Months)

OS Probability

The ALIMTA 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

X ALIMVL F 15

Page 18 of 20

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

Water for injection

Nitrogen

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.

X ALIMVL F 15

Page 19 of 20

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials.

Reconstituted and infusion solutions

When prepared as directed, reconstituted and infusion solutions of ALIMTA contain no antimicrobial

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

pemetrexed were demonstrated for 24 hours at refrigerated temperature. 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

6.4

Special precautions for storage

Store below 25°C

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

6.5

Nature and contents of container

ALIMTA 100 mg powder for solution for infusion

Type I glass vial with rubber stopper containing 100 mg of pemetrexed.

Pack of 1 vial.

Not all pack sizes may be marketed.

ALIMTA 500 mg powder for solution for infusion

Type I glass vial with rubber stopper containing 500 mg of pemetrexed.

Pack of 1 vial.

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 ALIMTA vials needed. Each vial contains an excess of

pemetrexed to facilitate delivery of label amount.

ALIMTA 100 mg

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

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

ALIMTA 500 mg

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

X ALIMVL F 15

Page 20 of 20

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.

Manufacturer

: Lilly France S.A.S., Fegersheim, France

License Holder

: Eli Lilly Israel Ltd., 4 HaSheizaf St., P.O.B. 4246, Ra’anana 4366411, Israel

Revised on Aug 2020

X ALIMVL F 15

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

)תוחיטב )תוחיטב :ךיראת

02.05.2012

םש

רישכת

Alimta 100mg, 500mg

רפסמ

:םושיר

138

86

31721

,

131

45

31049

םש

לעב

:םושירה

Eli Lilly Israel Ltd

.

םייונישה

ןולעב

םינמוסמ

לע

עקר

בוהצ ןולעב ןולעב

אפור אפור םיטרפ

לע

םי/יונישה

םי/שקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

4.1THERAPEUTIC

INDICATIONS

Malignant pleural mesothelioma

ALIMTA in combination with cisplatin is indicated

for the treatment of patients with malignant

pleural mesothelioma whose disease is

unresectable or who are otherwise not

candidates for curatible surgery.

Non-small cell lung cancer:

ALIMTA 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).

ALIMTA 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).

Malignant pleural mesothelioma

ALIMTA in combination with cisplatin is indicated

for the treatment of patients with malignant

pleural mesothelioma whose disease is

unresectable or who are otherwise not

candidates for curatible surgery.

Non-small cell lung cancer:

ALIMTA 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).

LIMTA 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)

ALIMTA 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).

UNDESIRABLE

EFFECTS

Tabulated list of adverse reactions (page 13)

The table below provides the frequency and

severity of undesirable effects considered

possibly related to study drug that have been

reported in > 5% of 441 patients randomly

assigned to receive single agent pemetrexed and

222 patients randomly assigned to receive

placebo in the single-agent maintenance

pemetrexed study (Study JMEN). 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

Tabulated list of adverse reactions (page 13)

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

4. 8 UNDESIRABLE

EFFECTS

**See below attached current Table on page 14:

**See below attached revised (New) Table on

page 14 in which the adverse events, “Infection”

and “Diarrhea” were removed and the frequency

of many of the Adverse Events was updated.

4. 8 UNDESIRABLE

EFFECTS

Foot notes of Table on page 14

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.

Foot notes of Table on page 14

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

4. 8 UNDESIRABLE

EFFECTS

Page 14-15

Clinically relevant CTC toxicity of any grade that

was reported in ≥ 1% and

5% of the patients

that were randomly assigned to pemetrexed

include: decreased platelets, decreased creatinine

clearance, constipation, edema, alopecia,

increased creatinine, pruritis/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% of the patients that were randomly

assigned to pemetrexed include: febrile

neutropenia, allergic reaction/hypersensitivity,

motor neuropathy, erythema multiforme, renal

failure, and supraventricular arrhythmia.

The incidence of adverse reactions was evaluated

for patients who received ≤ 6 cycles of

pemetrexed, and compared to patients who

received > 6 cycles of pemetrexed. Increases in

adverse reactions (all grades) were observed with

longer exposure; however, no statistically

significant differences in Grade 3/4 adverse

reactions were seen.

Page 14-15

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, decreased creatinine,

clearancediarrhoea constipation, edema,

alopecia, increased creatinine, pruritis/itching,

fever (in the absence of neutropenia), ocular

surface disease (including conjunctivitis),

increased lacrimation, decreased glomerular

filtration rate, 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,

renal failure, 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=568), and compared to patients

who received > 6 cycles of pemetrexed (N=232).

Increases in adverse reactions (all grades) were

observed with longer exposure; however, no

statistically significant differences in any

individual Grade 3/4/5 adverse reactions were

seen.

5.1PHARMACODY

NAMIC

PROPERTIES

דומעב תפסות

ינילק יוסנ טרפמה

PARAMOUNT

PARAMOUNT

A multicentre, randomised, double-blind,

placebo-controlled Phase 3 study

(PARAMOUNT), compared the efficacy and

safety of continuation maintenance treatment

with ALIMTA plus BSC (n = 359) with that

of placebo plus BSC (n = 180) in patients

with locally advanced (Stage IIIB) or

metastatic (Stage IV) NSCLC other than

predominantly squamous cell histology who

did not progress after 4 cycles of first line

doublet therapy of ALIMTA in combination

with cisplatin. Of the 939 patients treated

with ALIMTA plus cisplatin induction, 539

patients were randomised to maintenance

treatment with pemetrexed or placebo. Of

randomised patients, 44.9% had a

complete/partial response and 51.9% had a

response of stable disease to ALIMTA plus

cisplatin induction. Patients randomised to

maintenance treatment were required to

havean ECOG performance status 0 or 1. The

median time from the start of ALIMTA plus

cisplatin induction therapy to the start of

maintenance treatment was 2.96 months on

both the 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

ALIMTA and 4 cycles of placebo. A total of

109 patients (30.4%) completed ≥ 6 cycles

maintenance treatment with ALIMTA,

representing at least 10 total cycles of

ALIMTA.

The study met its primary endpoint and

showed a statistically significant

improvement in PFS in the ALIMTA 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 ALIMTA plus cisplatin first line

induction treatment, the median investigator-

assessed PFS was 6.9 months for the

ALIMTA arm and 5.59 months for the

placebo arm (hazard ratio = 0.59

95% CI = 0.47-0.74). A preliminary survival

analysis showed that the median survival on

the ALIMTA continuation arm after

induction therapy with ALIMTA/cisplatin (4

cycles) was 13.9 months versus 11.1 months

for those on the placebo arm (hazard

ratio = 0.78, 95% CI = 0.61-0.98, p = 0.034).

At the time of this preliminary survival

analysis, 48% of patients were alive on the

ALIMTA arm versus 38% on the placebo

arm, with a median follow-up of

11.04 months.

PARAMOUNT:Kaplan Meier plot of

progression-free survival (PFS) for

continuation ALIMTA maintenance

versus placebo in patients with NSCLC

other than predominantly squamous cell

histology (independent review, measured

from randomisation)

The ALIMTA maintenance safety profiles

from the two studies JMEN and

PARAMOUNT were similar

4.8

Undesirable Effects

Current Table on page 14:

System organ

class

Frequency

*

Event

**

Pemetrexed

(N = 441)

Placebo

(N = 222)

All

grades

toxicity

(%)

Grade

3 - 4

toxicit

y

(%)

All

grades

toxicit

y

(%)

Grade

3 - 4

toxicit

y

(%)

Infections and

infestations

Common

Infection

Blood and

lymphatic system

disorders

Very

common

Hemoglobin

15.2

Common

Leukocytes

Neutrophils

Nervous system

disorders

Common

Neuropathy-

sensory

Gastrointestinal

disorders

Very

common

Nausea

18.8

Anorexia

18.6

Common

Vomiting

Mucositis/

stomatitis

Common

Diarrhoea

Hepatobiliary

disorders

Common

ALT (SGPT)

AST (SGOT)

Skin and

subcutaneous

tissue disorders

Very

common

Rash/

desquamation

10.0

General disorders

and administration

site conditions

Very

common

Fatigue

24.5

10.4

Revised (New) Table on page 14

System organ

class

Frequency

*

Event

**

Pemetrexed

***

(N =

800

)

Placebo

***

(N =

402

)

All grades

toxicity

(%)

Grade

3 - 4

toxicity

(%)

All

grades

toxicit

y

(%)

Grade

3 - 4

toxicity

(%)

Blood and

lymphatic system

disorders

Very

common

Hemoglobin

decreased

14.6

Common

Leukocytes

decreased

Neutrophils

decreased

Nervous system

disorders

Common

Neuropathy-

sensory

Gastrointestinal

disorders

Very

common

Nausea

15.1

Anorexia

11.9

Common

Vomiting

Mucositis/

stomatitis

Hepatobiliary

disorders

Common

ALT (SGPT)

elevation

AST (SGOT)

elevation

Skin and

subcutaneous

tissue disorders

common

Rash/

desquamation

General disorders

administration

site conditions

Very

common

Fatigue

20.8

10.4

Common

Pain

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