Alimta - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Pemetrexed

ALIMTA 100 mg powder for concentrate for solution for infusion
ALIMTA 500 mg powder for concentrate for solution for infusion

Why is Alimta used? What is it for?

ALIMTA is a medicine used in the treatment of cancer.

ALIMTA is given in combination with cisplatin, another anticancer medicine, as a treatment for malignant pleural mesothelioma, a form of cancer that affects the lining of the lungs, to patients who have not received prior chemotherapy.

Furthermore, ALIMTA, in combination with cisplatin, is given for first-line therapy in patients with advanced lung cancer.

ALIMTA can be prescribed for advanced lung cancer if the disease has responded to treatment or if it remains mostly unchanged after initial chemotherapy.

ALIMTA is also a treatment for advanced lung cancer patients whose disease has progressed after previous initial chemotherapy treatment.

Contraindications When Alimta should not be used

Do not take ALIMTA:

  • if you are allergic (hypersensitive) to pemetrexed or any of the other ingredients of this medicine (listed in section 6).
  • if you are breastfeeding; you must stop breast-feeding during treatment with ALIMTA.
  • if you have recently had or are about to be vaccinated for yellow fever.

Precautions for use What you need to know before you take Alimta

Talk to your doctor or hospital pharmacist before taking ALIMTA.

If you have or have had kidney problems, please tell your doctor or hospital pharmacist as you may not be able to receive ALIMTA.

Before each infusion, blood will be drawn to see if you have sufficient liver and kidney function and to check that you have enough blood cells to receive ALIMTA. Your doctor may decide to change the dose or delay treatment depending on your general condition and if your blood test (white blood cells and platelets) is found to be inadequate (too low). Also, if you are receiving cisplatin, your doctor will advise you. you must ensure that you are adequately hydrated and that you receive appropriate treatment before and after receiving cisplatin to prevent vomiting.

If you have had or will have to undergo radiation treatment, please tell your doctor, as an early or delayed reaction due to radiation treatment may occur with ALIMTA.

If you have recently been vaccinated, please tell your doctor, as this could cause harmful effects with ALIMTA.

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

If you have a buildup 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

Interactions Which drugs or foods may change the effect of Alimta

Tell your doctor if you are taking any medicines for pain or for an inflammatory process (swelling), such as medicines called 'non-steroidal anti-inflammatory drugs' (NSAIDs), including medicines bought without a prescription (such as' ibuprofen). There are many types of NSAIDs with different duration of activity. Based on the expected date of your ALIMTA infusion and / or your kidney function, your doctor will advise you on which medicines you can take and when you can take them. If you are not sure, ask your doctor or pharmacist if any of your medicines are NSAIDs.

Tell your doctor or hospital pharmacist if you are taking or have recently taken any other medicines, even those obtained without a prescription.

Warnings It is important to know that:

Pregnancy

If you are pregnant, think you may be pregnant or are planning to become pregnant, please tell your doctor. The use of ALIMTA during pregnancy should be avoided. Your doctor will talk with you about the potential risk of taking ALIMTA during pregnancy. Women should use effective birth control while taking ALIMTA.

Feeding time

If you are breastfeeding, please tell your doctor. Breastfeeding should be discontinued during treatment with ALIMTA.

Fertility

Men are advised not to conceive a child during treatment with ALIMTA for up to 6 months and then to use effective contraception during treatment with ALIMTA or for up to 6 months afterwards. If you want to conceive a child during treatment or within 6 months afterwards, ask your doctor or pharmacist for advice. It is advisable to ask for information on how to store sperm before starting therapy.

Driving and using machines

ALIMTA can induce fatigue. Be careful when driving a vehicle or using machinery.

ALIMTA contains sodium

ALIMTA 500 mg contains approximately 54 mg of sodium per vial. It should be taken into consideration by patients on a controlled sodium diet. ALIMTA 100 mg contains less than 1 mmol sodium (23 mg) per vial, ie it is essentially "sodium free".

Dose, Method and Time of Administration How to use Alimta: Posology

The dose of ALIMTA is 500 mg for each square meter of body surface. His height and weight are measured to calculate his body surface area. Your doctor will use this body surface to calculate the right dose for you. This dosage may be adjusted or treatment may be delayed depending on your blood test and general condition. A hospital pharmacist, nurse or doctor will have mixed ALIMTA powder with sodium chloride 9 mg / ml solution. (0.9%) for injections before giving it to you.

You will always receive ALIMTA by infusion into a vein. The infusion will last about 10 minutes.

When ALIMTA is used in combination with cisplatin: Your doctor or hospital pharmacist will calculate the dose you need based on your height and weight. Cisplatin is also given by infusion into a vein, approximately 30 minutes after the ALIMTA infusion is complete. The cisplatin infusion will last approximately 2 hours.

Usually you should receive the infusion once every 3 weeks.

Additional medicines:

Corticosteroids: Your doctor will prescribe you steroid tablets (equivalent to 4 milligrams of dexamethasone twice a day) which you will need to take the day before, the same day and the day after your ALIMTA treatment. This medicine is given to you to reduce the frequency and severity of skin reactions that may occur during anticancer treatment.

Vitamin supplement: your doctor will prescribe folic acid (vitamin) or an oral multivitamin product containing folic acid (350-1000 micrograms) which you must take once a day while on ALIMTA. You must take at least 5 doses during the seven days before the first dose of ALIMTA. You should continue taking folic acid for 21 days after the last dose of ALIMTA. You will also receive an injection of vitamin B12 (1000 micrograms) in the week before taking ALIMTA and then approximately every 9 weeks (corresponding to 3 courses of ALIMTA treatment). Vitamin B12 and folic acid are given to you to reduce the possible toxic effects of anticancer treatment.

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

Overdose What to do if you have taken too much Alimta

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

You should contact your doctor immediately if you notice any of the following side effects:

  • Fever or infection (common): if you have a body temperature of 38 ° C or higher, sweating or other signs of infection (as you may have fewer white blood cells than normal which is very common). The infection (sepsis) can be serious and could lead to death.
  • If you start to feel chest pain (common) or have a fast heart rate (uncommon).
  • If you have pain, redness, swelling or sores in your mouth (very common).
  • Allergic reaction: if you develop a rash (very common) / burning or tingling sensation (common) or fever (common). Rarely, skin reactions can be severe and could lead to death. Contact your doctor if you get a severe rash, itching, or blisters (Stevens-Johnson syndrome or toxic epidermal necrolysis).
  • If you feel tired, faint, take your breath easily or look pale (as you may have less hemoglobin than normal which is very common).
  • If you have bleeding from the gums, nose or mouth or any bleeding that does not stop, reddish or slightly pink urine, unexpected bruising (as you may have fewer platelets than normal which is very common).
  • If you experience sudden shortness of breath, severe chest pain or cough with blood in your sputum (uncommon) (this may indicate a blood clot in the blood vessels of the lungs).

Side effects with ALIMTA can include:

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

  • Low white blood cell count
  • Low hemoglobin level (anemia)
  • Low platelet count
  • Diarrhea
  • He retched
  • Pain, redness, swelling or sores in the mouth
  • Nausea
  • Loss of appetite
  • Fatigue (tiredness)
  • Rash
  • Hair loss
  • Constipation
  • Loss of sensation
  • Kidneys: abnormal blood tests

Common (may affect up to 1 in 10 patients)

  • Allergic reaction: rash / burning or tingling sensation Infection including sepsis
  • Fever
  • Dehydration
  • Kidney failure
  • Skin irritation and itching
  • Chest pain
  • Muscle weakness
  • Conjunctivitis (inflammation of the eyes)
  • Upset stomach
  • Pain in the abdomen
  • Disturbed taste Liver: abnormal blood tests
  • Increased lacrimation

Uncommon (may affect up to 1 in 100 patients)

  • Acute renal failure
  • Increased heart rate
  • Inflammation of the inner wall of the esophagus has been manifested with ALIMTA / radiation treatment
  • Colitis (inflammation of the inner wall of the colon which may be associated with intestinal or rectal bleeding)
  • Interstitial pneumonia (small scars around the lung alveoli)
  • Edema (excess fluid in the body tissue, causing swelling)
  • Some patients have had a heart attack, a cerebrovascular accident, even a minor one, during treatment with ALIMTA, usually in combination with "other anticancer therapy."
  • Pancytopenia - low combined counts of white blood cells, red blood cells and platelets.

Actinic pneumonia (small scars around the pulmonary alveoli, related to radiotherapy) may occur in patients receiving radiation treatment before, during or after the ALIMTA infusion.

Extremity pain, low body temperature and discoloration of the skin have been reported.Blood clots in the pulmonary blood vessels (pulmonary embolism).

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

  • Radiation recall phenomena (skin rash resembling severe sunburn), which may occur in areas of the skin previously exposed to radiation therapy for days to years after irradiation.
  • Blistering (skin diseases that cause blisters) - which include Stevens-Johnson syndrome and toxic epidermal necrolysis.
  • Immune-mediated haemolytic anemia (destruction of red blood cells by antibodies).
  • Hepatitis (inflammation of the liver).
  • Anaphylactic shock (severe allergic reaction).

Not known: frequency cannot be estimated from the available data

  • Swelling with pain and redness in the lower limbs

You may have any of these symptoms and / or conditions. You should tell your doctor as soon as possible when you start having any of these side effects.

If you have any questions about any side effects, please talk to your doctor.

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 this 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.

Side Effects What are the side effects of Alimta

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.

This medicinal product does not require any special storage conditions.

Reconstituted and Infusion Solutions: The product should be used immediately. When prepared as directed, chemical and physical in-use stability of reconstituted and infusion solutions of pemetrexed have been demonstrated for 24 hours at refrigerated temperature.

This medicine is for single use only, any unused solution must be disposed of in accordance with local legal requirements.

Expiry and Retention

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.

This medicinal product does not require any special storage conditions.

Reconstituted and Infusion Solutions: The product should be used immediately. When prepared as directed, chemical and physical in-use stability of reconstituted and infusion solutions of pemetrexed have been demonstrated for 24 hours at refrigerated temperature.

This medicine is for single use only, any unused solution must be disposed of in accordance with local legal requirements.

Other information

What ALIMTA contains

The active ingredient is pemetrexed.

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

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

After reconstitution, the solution contains 25 mg / ml of pemetrexed. Prior to administration, further dilution by healthcare personnel is required.

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

Description of what ALIMTA looks like and contents of the package

ALIMTA is a powder for concentrate for solution for infusion in a vial. It is a freeze-dried powder varying in color from white to light yellow or yellow-green

Each ALIMTA pack contains one vial of ALIMTA.

Not all pack sizes may be marketed.

The following information is intended for medical or healthcare professionals only

Instructions for use, handling and disposal

  1. Aseptic techniques should be used during reconstitution and further dilution of pemetrexed for intravenous infusion administration.
  2. Calculate the dose and the number of ALIMTA vials needed. Each vial contains an excess of pemetrexed to facilitate dispensing of the quantity indicated on the label.
  3. ALIMTA 100 mg: Reconstitute each 100 mg vial with 4.2 ml of sodium chloride 9 mg / ml (0.9%) solution for injections, without preservatives, to obtain a solution containing 25 mg / ml of pemetrexed. ALIMTA 500 mg: Reconstitute each 500 mg vial with 20 ml of sodium chloride 9 mg / ml (0.9%) solution for injections, without preservatives, to obtain a solution containing 25 mg / ml of pemetrexed. Gently shake each vial until the powder is completely dissolved. The solution thus obtained is clear and varies from colorless to yellow or yellow-green without adversely affecting the quality of the product. The pH of the reconstituted solution is between 6.6 and 7.8. Further dilution is required.
  4. The appropriate volume of pemetrexed reconstituted solution should be further diluted to 100 ml with sodium chloride 9 mg / ml (0.9%) solution for injection, without preservative, and administered by intravenous infusion over 10 minutes.
  5. Pemetrexed infusion solutions prepared as described above are compatible with polyvinyl chloride and polyolefin lined infusion bags and administration sets. Pemetrexed is incompatible with calcium-containing solvents, including lactated Ringer's for injections and Ringer's for injections.
  6. Prior to administration, parenteral medicinal products should be visually checked for the presence of particles and color changes. Do not administer if particles are observed.
  7. Pemetrexed solutions are for single use only. Unused product and waste derived from this medicine must be disposed of in accordance with local legal requirements.

Precautions for preparation and administration: As with other potentially toxic anticancer agents, caution should be exercised in handling and preparing pemetrexed infusion solutions. The use of gloves is recommended. If a pemetrexed solution comes into contact with the skin, wash immediately and thoroughly with soap and water. If solutions of pemetrexed come into contact with mucous membranes, wash thoroughly with water. Pemetrexed is not blistering. There is no specific antidote for pemetrexed extravasation. Some cases have been reported. extravasation of pemetrexed which were not considered serious by the investigator Extravasation should be managed according to standard procedures as with other non-blistering agents.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Alimta can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

FEED

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

ALIMTA 100 mg powder for concentrate for solution for infusion

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

Excipients with known effects

Each vial contains approximately 11 mg of sodium.

ALIMTA 500 mg powder for concentrate for solution for infusion

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

Excipients with known effects

Each vial contains approximately 54 mg of 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.

03.0 PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion.

Freeze-dried powder ranging in color from white to light yellow or yellow-green.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Malignant pleural mesothelioma

ALIMTA in combination with cisplatin is indicated in the chemotherapy treatment of non-pretreated patients with unresectable malignant pleural mesothelioma.

Non-Small Cell Lung Carcinoma

ALIMTA in combination with cisplatin is indicated as 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 after platinum-based chemotherapy (see paragraph 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).

04.2 Posology and method of administration

Dosage

ALIMTA should only be administered under the supervision of a physician qualified in the use of anticancer chemotherapy.

FEED in association with cisplatin

The recommended dose of ALIMTA is 500 mg / m2 body surface area to be administered by intravenous infusion over 10 minutes on the first day of each 21-day cycle. The recommended dose of cisplatin is 75 mg / m2 body surface area to be administered by infusion over 2 hours, approximately 30 minutes after completing the pemetrexed infusion on the first day of each 21-day cycle. Patients should receive adequate anti-emetic treatment. and appropriate hydration before and / or after receiving cisplatin (see also the Summary of Product Characteristics of cisplatin for specific administration recommendations).

ALIMTA in monotherapyIn patients treated for non-small cell lung cancer after previous chemotherapy, the recommended dose of ALIMTA is 500 mg / m2 body surface area, to be administered by intravenous infusion over 10 minutes on the first day of each 21-day cycle.

Pre-medication scheme

To reduce the incidence and severity of skin reactions, a corticosteroid should be administered the day before, the same day and the day after pemetrexed administration. The corticosteroid should be equivalent to 4 mg dexamethasone administered orally twice a day. day (see section 4.4).

To reduce toxicity, patients treated with pemetrexed should also receive vitamin supplementation (see section 4.4). Patients should take oral folic acid or a multivitamin product containing folic acid (350-1000 μg) daily. At least five doses folic acid should be taken in the seven days preceding the first dose of pemetrexed and supplementation should continue throughout the therapy period and for 21 days after the last dose of pemetrexed. Patients should also receive an intramuscular injection of vitamin B12 (1000 mcg) in the week before the first dose of pemetrexed and once every three cycles thereafter. Subsequent injections of vitamin B12 can be given on the same day as pemetrexed.

Monitoring

Patients receiving pemetrexed should undergo a check-up with a complete haematological test, including formula white blood cell count (WCC) and platelet count, prior to each administration. Prior to the administration of each chemotherapy, haematological chemistry tests should be performed to evaluate renal and hepatic function. Before starting a course of chemotherapy, patients should have the following values: Total neutrophil count (ANC) should be ≥ 1,500 cells / mm3 and platelets should be ≥ 100,000 cells / mm3. Creatinine clearance should be ≥ 45 mL / min.

Total bilirubin should be ≤ 1.5 times the upper limit of normal. Alkaline phosphatase (AP), aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) should be ≤ 3 times the upper limit of normal. Alkaline phosphatase, AST and ALT ≤ 5 times the upper limit of normal are acceptable if the liver is metastatic.

Dose adjustments

Dose adjustments at the start of a subsequent course should be made based on the nadir haematological count or the highest degree of non-haematological toxicity observed during the previous course of therapy. Treatment may be delayed to allow for a sufficient recovery period. Once patients have recovered, they should be re-treated according to the guidelines outlined in Tables 1, 2 and 3 which are applicable for ALIMTA used as a single drug or in combination with cisplatin.

TABLE 1 - Dose variation table for ALIMTA (as single drug or in combination) and cisplatin - Haematological toxicity ANC at nadir 3 and platelets at nadir ≥ 50,000 / mm3 75% of the previous dose (both ALIMTA and cisplatin). Platelets at nadir 3 regardless of ANC at nadir 75% of the previous dose (both ALIMTA and cisplatin). Platelets at nadir 3 associated with bleeding, regardless of ANC at nadir 50% of the previous dose (both ALIMTA and cisplatin).

a Bleeding ≥ Grade 2 according to the National Cancer Institute Common Toxicity Criteria (CTC) (v2.0; NCI 1998)

If patients develop non-haematological toxicities ≥ Grade 3 (excluding neurotoxicity), ALIMTA should be withheld until it returns to less than or equal to what the patient had before therapy. Treatment should be restarted according to the guidelines indicated in Table 2.

TABLE 2 - Dose variation table for ALIMTA (as single drug or in combination) and cisplatin - Non-haematological toxicity a, b ALIMTA dose (mg / m2) Dose of cisplatin (mg / m2) Any grade 3 or 4 toxicity except mucositis. 75% of the previous dose 75% of the previous dose Any diarrhea that required hospitalization (regardless of grade) or grade 3 or 4 diarrhea. 75% of the previous dose 75% of the previous dose Grade 3 or 4 mucositis. 50% of the previous dose 100% of the previous dose

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

b Neurotoxicity excluded

In case of neurotoxicity, the recommended dose adjustment for ALIMTA and cisplatin is described in Table 3. Patients should discontinue therapy if grade 3 or 4 neurotoxicity is observed.

TABLE 3 - Dose variation for ALIMTA (as single drug or in combination) and cisplatin - Neurotoxicity CTCa grade ALIMTA dose (mg / m2) Cisplatin dose (mg / m2) 0-1 100% of the previous dose 100% of the previous dose 2 100% of the previous dose 50% of the previous dose

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

Treatment with ALIMTA should be discontinued if a patient experiences any Grade 3 or 4 haematological or non-haematological toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Senior citizens

In clinical trials, there was no evidence that patients 65 years of age or older are at increased risk for adverse events compared to patients younger than 65 years. No dose reductions are required beyond those recommended for all patients.

Pediatric population

There is no indication for a specific use of ALIMTA in the pediatric population with malignant pleural mesothelioma and non-small cell lung cancer.

Patients with renal impairment (Cockcroft and Gault standard formula or Method for calculating glomerular filtration measured with Tc99m-DPTA)

Pemetrexed is primarily eliminated unchanged by renal excretion. In clinical studies, patients with creatinine clearance ≥ 45 mL / min required no dosage adjustments beyond 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 were identified between AST (SGOT), ALT (SGPT) or total bilirubin and pemetrexed pharmacokinetics.However, patients with hepatic impairment, such as those with bilirubin ≥ 1.5 times the upper limit of normal and / or with aminotransferases ≥ 3.0 times the upper limit of normal (in the absence of liver metastasis), or ≥ 5.0 times the upper limit of normal (in the presence of liver metastasis).

Method of administration

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

ALIMTA should be administered by intravenous infusion over 10 minutes on the first day of each 21 day cycle. For instructions on reconstitution and dilution of ALIMTA before administration, see section 6.6.

04.3 Contraindications

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

Breastfeeding (see section 4.6).

Simultaneous use of yellow fever vaccine (see section 4.5).

04.4 Special warnings and appropriate precautions for use

Pemetrexed may suppress bone marrow function as evidenced by neutropenia, thrombocytopenia and anemia (or pancytopenia) (see section 4.8). Myelosuppression is usually dose limiting toxicity. Patients should be monitored for myelosuppression during therapy and pemetrexed should not be given to patients until the total neutrophil count (ANC) returns to ≥ 1500 cells / mm3 and the platelet count to ≥ 100,000 cells / mm3. Dose reductions for subsequent courses are based on ANC to nadir, platelet count and the highest degree of non-haematological toxicity observed during the previous course of therapy (see section 4.2).

Lower toxicity and reduction of Grade 3/4 non-haematological and haematological toxicities such as neutropenia, febrile neutropenia and infection with Grade 3/4 neutropenia have been reported when pretreatment with folic acid and vitamin B12 was given . Therefore, all patients treated with pemetrexed should be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related toxicity (see section 4.2).

Skin reactions have been reported in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) may reduce the incidence and severity of skin reactions (see section 4.2).

An insufficient number of patients with creatinine clearance below 45 ml / min have been studied. Therefore the use of pemetrexed in patients with creatinine clearance

Patients with mild to moderate renal impairment (creatinine clearance 45 to 79 mL / min) should avoid taking non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and acetylsalicylic acid (> 1.3 g / day) within the previous 2 days, on the same day and within 2 days following the administration of pemetrexed (see section 4.5).

In patients with mild to moderate renal impairment eligible for pemetrexed therapy, NSAIDs with long elimination half-lives should be discontinued for at least 5 days prior to, on the same day 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 combination with other chemotherapeutic agents. Most patients in whom these events have occurred had risk factors for the development of renal events including dehydration, pre-existing hypertension or diabetes.

The effect on pemetrexed of fluid accumulation in the third space, such as pleural effusion or ascites, is not fully defined. A phase 2 study with pemetrexed in 31 solid tumor patients with stable third-space fluid accumulation showed no difference in dose-normalized plasma concentrations or clearances of pemetrexed when compared to patients without third-space fluid collections. . Consequently, drainage of the fluid collection in the third space should be considered prior to treatment with pemetrexed, although this may not be necessary.

Severe dehydration has been observed following the gastrointestinal toxicity of pemetrexed administered in combination with cisplatin. Therefore, patients should receive adequate antiemetic treatment and appropriate hydration before and / or after receiving treatment.

Serious cardiovascular events, including myocardial infarction, and cerebrovascular events have been reported infrequently in clinical trials with pemetrexed, usually when administered in combination with another cytotoxic agent. Most patients in whom these events have been observed had pre-existing cardiovascular risk factors (see section 4.8).

Immunosuppression is common in patients with cancer. Consequently, concomitant use of live attenuated vaccines is not recommended (see sections 4.3 and 4.5).

Pemetrexed can have harmful effects on a genetic level. Sexually mature males are advised not to procreate during treatment and for 6 months thereafter. Contraceptive measures or abstinence are recommended. Due to the possibility that treatment with pemetrexed causes irreversible infertility, men are advised to ask about how sperm is stored before starting treatment.

Women of childbearing potential should use effective contraception during treatment with pemetrexed (see section 4.6).

Cases of actinic pneumonia have been reported in patients receiving radiation treatment before, during or after the pemetrexed infusion. Particular attention should be paid to these patients, as well as to the use of other radiosensitizing agents.

Cases of "radiation recall" have been reported in patients who have been treated with radiotherapy in the previous weeks or years.

Excipients

ALIMTA 100 mg powder for concentrate for solution for infusion

The medicine contains less than 1 mmol sodium (23 mg) per vial, ie it is essentially 'sodium-free'.

ALIMTA 500 mg powder for concentrate for solution for infusion

The medicine contains approximately 54 mg of sodium per vial. This should be taken into consideration by patients on a controlled sodium diet.

04.5 Interactions with other medicinal products and other forms of interaction

Pemetrexed is primarily eliminated unchanged renally by tubular secretion and to a lesser extent by glomerular filtration. Co-administration of nephrotoxic drugs (eg aminoglycosides, loop diuretics, platinum compounds, cyclosporine) could potentially lead to delayed clearance of pemetrexed. This combination should be used with caution. Creatinine clearance should be monitored if necessary. carefully.

Co-administration of substances that are also secreted tubularly (e.g. probenecid, penicillin) could potentially result in delayed clearance of pemetrexed. Caution is advised when using these drugs in combination 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 at doses> 1600 mg / day) and high dose acetylsalicylic acid (≥ 1.3 g / day). day) may reduce the elimination of pemetrexed and consequently increase the occurrence of adverse events of pemetrexed. Therefore, caution is advised in administering higher doses of NSAIDs or high-dose acetylsalicylic acid concomitantly with pemetrexed to patients with normal renal function (clearance creatinine ≥ 80 ml / min).

In patients with mild to moderate renal impairment (creatinine clearance 45 to 79 ml / min) co-administration of pemetrexed with NSAIDs (e.g. ibuprofen) or higher doses of acetylsalicylic acid should be avoided for the previous 2 days. same day and within 2 days following the administration of pemetrexed (see section 4.4).

In the absence of data on the potential interaction with longer half-life NSAIDs, such as piroxicam or rofecoxib, co-administration with pemetrexed in patients with moderate to severe renal impairment should be stopped for at least the previous 5 days, the same day and at least in the 2 days following the administration of pemetrexed (see section 4.4). If concomitant administration of NSAIDs is required, patients should be closely monitored for toxicity, especially myelosuppression and gastrointestinal toxicity.

Pemetrexed undergoes limited hepatic metabolism. The results of the studies in vitro with human liver microsomes indicated that pemetrexed would not cause a clinically significant inhibition of the metabolic clearance of drugs metabolised by cytochromes CYP3A, CYP2D6, CYP2C9 and CYP1A2.

Interactions common to all cytotoxics

Due to the increased risk of thrombosis in cancer patients, the use of anticoagulant therapy is common. If it is decided to treat the patient with oral anticoagulants, the high intra-individual variability of coagulation during the disease and the possibility of interaction between oral anticoagulants and anticancer chemotherapy require a greater frequency of monitoring of the INR (International Normalized Ratio ).

Concomitant use contraindicated: Yellow fever vaccine: risk of fatal generalized vaccine disease (see section 4.3).

Concomitant use not recommended: Live attenuated vaccines (except yellow fever vaccine, for which concomitant use is contraindicated): risk of systemic disease possibly with fatal outcome. The risk is greater in patients who are already immunosuppressed due to underlying disease Use an inactivated vaccine when it exists (poliomyelitis) (see section 4.4).

04.6 Pregnancy and breastfeeding

Contraception in men and women

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 procreate during treatment and for 6 months thereafter. Contraceptive measures or abstinence are recommended.

Pregnancy

There are no data on the use of pemetrexed in pregnant women, but pemetrexed like other anti-metabolites is thought to cause serious congenital anomalies when administered during pregnancy. Animal studies have shown reproductive toxicity (see section 5.3). Pemetrexed it should not be used during pregnancy unless absolutely necessary, after a "careful assessment of the needs of the mother and the risk to the fetus (see section 4.4).

Feeding time

It is unknown whether pemetrexed is excreted in human milk and adverse reactions in infants cannot be excluded. Breastfeeding should be discontinued during pemetrexed therapy (see section 4.3).

Fertility

Because of the possibility that treatment with pemetrexed causes irreversible infertility, men are advised to ask about how sperm is stored before starting treatment.

04.7 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, pemetrexed has been reported to cause fatigue. Therefore, if this event occurs, patients should be warned about driving and "use of machinery.

04.8 Undesirable effects

Summary of the safety profile

The most commonly reported undesirable effects related to pemetrexed, when used alone or in combination, are suppression of bone marrow function resulting in anemia, neutropenia, leukopenia, thrombocytopenia; and gastrointestinal toxicities manifesting as anorexia, nausea, vomiting, diarrhea, constipation, pharyngitis, mucositis and stomatitis. Other undesirable effects include renal toxicity, increased aminotransferases, alopecia, fatigue, dehydration, rash, infection / sepsis and neuropathy. Rarely observed events include Stevens-Johnson syndrome and toxic epidermal necrolysis.

Summary table of adverse reactions

The table below provides the frequency and severity of undesirable effects that were reported in more than 5% of the 168 mesothelioma patients who were randomized to receive cisplatin and pemetrexed and in 163 mesothelioma patients randomized to receive cisplatin as a single drug. In both treatment arms, these non-pretreated patients received folic acid and vitamin B12 supplementation for the duration of treatment.

Frequency definition: very common (≥ 1/10), common (≥ 1/100,

Within each frequency class, undesirable effects are reported in descending order of severity.

Organic system classification Frequency Event* Pemetrexed / cisplatin Cisplatin (N = 168) (N = 163) All degrees of toxicity (%) Degree of toxicity 3 - 4 (%) All degrees of toxicity (%) Degree of toxicity 3 - 4 (%) Disorders of the blood and lymphatic system Very common Reduction of neutrophils / granulocytes 56,0 23,2 13,5 3,1 Reduction of leukocytes 53,0 14,9 16,6 0,6 Reduction of hemoglobin 26,2 4,2 10,4 0,0 Reduction of platelets 23,2 5,4 8,6 0,0 Metabolism and nutrition disorders common Dehydration 6,5 4,2 0,6 0,6 Nervous system disorders Very common Sensory neuropathy 10,1 0,0 9,8 0,6 common Alteration of taste 7,7 0,0*** 6,1 0,0*** Eye disorders common Conjunctivitis 5,4 0,0 0,6 0,0 Gastrointestinal disorders Very common Diarrhea 16,7 3,6 8,0 0,0 He retched 56,5 10,7 49,7 4,3 Stomatitis / Pharyngitis 23,2 3,0 6,1 0,0 Nausea 82,1 11,9 76,7 5,5 Anorexia 20,2 1,2 14,1 0,6 Constipation 11,9 0,6 7,4 0,6 common Dyspepsia 5,4 0,6 0,6 0,0 Skin and subcutaneous tissue disorders Very common Rash 16,1 0,6 4,9 0,0 Alopecia 11,3 0,0*** 5,5 0,0*** Renal and urinary disorders Very common Increased creatinine 10,7 0,6 9,8 1,2 Decreased creatinine clearance ** 16,1 0,6 17,8 1,8 General disorders and administration site conditions Very common Fatigue 47,6 10,1 42,3 9,2

* Referring to version 2 of the National Cancer Institute CTC for any degree of toxicity except the term "decreased creatinine clearance"

** derived from the term "renal / genitourinary - other".

*** According to the National Cancer Institute CTC (v2.0; NCI 1998), the alteration of taste and

alopecia should only be reported as Grade 1 or 2.

A 5% cut-off was used for the function of this table for the inclusion of all events for which the reporter considered that there was a possible relationship to pemetrexed and cisplatin.

Clinically relevant CTC toxicities reported in ≥ 1% and ≤ 5% of patients who were randomly assigned to receive cisplatin and pemetrexed include: renal failure, infection, pyrexia, febrile neutropenia, increased AST, ALT and GGT, hives and chest pain.

Clinically relevant CTC toxicities reported in a percentage

randomly assigned to receive cisplatin and pemetrexed, they include arrhythmia and motor neuropathy.

The table below provides the frequency and severity of undesirable effects that were reported in more than 5% of the 265 patients who were randomly assigned to receive pemetrexed as a single drug with a "folic acid and vitamin B12 supplementation and in the 276 patients. patients who were randomly assigned to receive docetaxel as a single drug All patients were diagnosed with locally advanced or metastatic non-small cell lung cancer and received prior chemotherapy.

Organic system classification Frequency Event* Pemetrexed N = 265 Docetaxel N = 276 All degrees of toxicity (%) Degree of toxicity 3 - 4 (%) All degrees of toxicity (%) Degree of toxicity 3 - 4 (%) Disorders of the blood and lymphatic system Very common Decreased neutrophils / granulocytes 10,9 5,3 45,3 40,2 Decrease in leukocytes 12,1 4,2 34,1 27,2 Decrease in hemoglobin 19,2 4,2 22,1 4,3 common Decrease in platelets 8,3 1,9 1,1 0,4 Gastrointestinal disorders Very common Diarrhea 12,8 0,4 24,3 2,5 He retched 16,2 1,5 12,0 1,1 Stomatitis / Pharyngitis 14,7 1,1 17,4 1,1 Nausea 30,9 2,6 16,7 1,8 Anorexia 21,9 1,9 23,9 2,5 common Constipation 5,7 0,0 4,0 0,0 Hepatobiliary disorders common Increase in SGPT (ALT) 7,9 1,9 1,4 0,0 Increased SGOT (AST) 6,8 1,1 0,7 0,0 Skin and subcutaneous tissue disorders Very common Skin rash / peeling 14,0 0,0 6,2 0,0 common Itching 6,8 0,4 1,8 0,0 Alopecia 6,4 0,4** 37,7 2,2** General disorders and administration site conditions Very common Fatigue 34,0 5,3 35,9 5,4 common Fever 8,3 0,0 7,6 0,0

* With reference to version 2 of the National Cancer Institute CTC for each degree of toxicity.

** According to the National Cancer Institute CTC (v2.0; NCI 1998), alopecia should only be reported as Grade 1 or 2.

A 5% cut-off was used for the function of this table for the inclusion of all events for which the reporter considered that there was a possible relationship to pemetrexed.

Clinically relevant CTC toxicities reported in ≥ 1% and allergic / hypersensitivity reaction, increased serum creatinine, motor neuropathy, sensory neuropathy, erythema multiforme and abdominal pain.

Clinically relevant CTC toxicities reported in a percentage

Clinically relevant Grade 3 and Grade 4 laboratory toxicities were similar between the integrated Phase 2 results from three studies with pemetrexed as a single drug (n = 164) and the Phase 3 study with pemetrexed as a single drug described above, for exception of neutropenia (12.8% vs 5.3%, respectively) and "increase of" alanine aminotranferase (15.2% vs 1.9%, respectively).These differences were likely due to differences in the patient population, as the Phase 2 studies included both non-pretreated and heavily pretreated patients with breast cancer and pre-existing liver metastases and / or liver function tests with abnormal baseline values.

The table below provides the frequency and severity of undesirable effects considered possibly related to study drug that were reported in more than 5% of the 839 patients with non-small cell lung cancer, randomized to receive cisplatin and pemetrexed, and 830 patients with cancer. non-small cell lung disease, randomized to receive cisplatin and gemcitabine. All patients received the above therapies as the first treatment for locally advanced or metastatic non-small cell lung cancer and patients in both treatment arms received folic acid and vitamin B12 supplementation for the duration of the study.

Organic system classification Frequency Event** Pemetrexed / cisplatin (N = 839) Gemcitabine / cisplatin (N = 830) All degrees of toxicity (%) Degree of toxicity 3 - 4 (%) All degrees of toxicity (%) Degree of toxicity 3 - 4 (%) Disorders of the blood and lymphatic system Very common Decrease in hemoglobin 33,0* 5,6* 45,7* 9,9* Decreased neutrophils / granulocytes 29,0* 15,1* 38,4* 26,7* Decrease in leukocytes 17,8 4,8* 20,6 7,6* Decrease in platelets 10,1* 4,1* 26,6* 12,7* Nervous system disorders common Sensory neuropathy 8,5* 0,0* 12,4* 0,6* Alteration of taste 8,1 0,0*** 8,9 0,0*** Gastrointestinal disorders Very common Nausea 56,1 7,2* 53,4 3,9* He retched 39,7 6,1 35,5 6,1 Anorexia 26,6 2,4* 24,2 0,7* Constipation 21,0 0,8 19,5 0,4 Stomatitis / Pharyngitis 13,5 0,8 12,4 0,1 Diarrhea without colostomy 12,4 1,3 12,8 1,6 common Dyspepsia / Heartburn 5,2 0,1 5,9 0,0 Skin and subcutaneous tissue disorders Very common Alopecia 11,9* 0*** 21,4* 0,5*** common Skin rash / peeling 6,6 0,1 8,0 0,5 Renal and urinary disorders Very common Increased creatinine 10,1* 0,8 6,9* 0,5 General disorders and administration site conditions Very common Fatigue 42,7 6,7 44,9 4,9

* P-values

** With reference to the National Cancer Institute CTC (v2.0; NCI 1998) for each degree of toxicity.

*** According to the National Cancer Institute CTC (v2.0; NCI 1998), taste disturbance and alopecia should only be reported as Grade 1 or 2.

In this table, a 5% cut-off was used to include all events for which a possible relationship to pemetrexed and cisplatin was considered.

Clinically relevant toxicity, reported in ≥ 1% and ≤ 5% of patients who were randomly assigned to receive cisplatin and pemetrexed, includes: AST increased, ALT increased, infection, febrile neutropenia, renal failure, pyrexia , dehydration, conjunctivitis, and decreased creatinine clearance.

Clinically relevant toxicity, reported in a percentage of chest pain, arrhythmia, and motor neuropathy.

With regard to gender, clinically relevant toxicities were substantially overlapping in the whole population of patients treated with pemetrexed plus cisplatin.

The table below provides the frequency and severity of undesirable effects considered possibly related to study drug that were reported in more than 5% of the 800 patients randomized to pemetrexed as a single drug and 402 patients randomized to placebo in the pemetrexed studies. as a single maintenance drug (JMEN: N = 663) than continuation of pemetrexed in maintenance (PARAMOUNT: N = 539). All patients had been diagnosed with Stage IIIB or IV NSCLC and had received prior platinum-based chemotherapy. Patients in both treatment arms received complete folic acid and vitamin B12 supplementation.

Organic system classification Frequency* Event** Pemetrexed *** (N = 800) Placebo *** (N = 402) All degrees of toxicity (%) Degree of toxicity 3 - 4 (%) All degrees of toxicity (%) Degree of toxicity 3 - 4 (%) Disorders of the blood and lymphatic system Very common Decrease in hemoglobin 18,0 4,5 5,2 0,5 common Decrease in Leukocytes 5,8 1,9 0,7 0,2 Decrease in neutrophils 8,4 4,4 0,2 0,0 Nervous system disorders common Sensory neuropathy 7,4 0,6 5,0 0,2 Gastrointestinal disorders Very common Nausea 17,3 0,8 4,0 0,2 Anorexia 12,8 1,1 3,2 0,0 common He retched 8,4 0,3 1,5 0,0 Mucositis / stomatitis 6,8 0,8 1,7 0,0 Hepatobiliary disorders common Elevation of ALT (SGPT) 6,5 0,1 2,2 0,0 AST Increase (SGOT) 5,9 0,0 1,7 0,0 Skin and subcutaneous tissue disorders common Skin rash / peeling 8,1 0,1 3,7 0,0 General disorders and administration site conditions Very common Fatigue 24,1 5,3 10,9 0,7 common Ache 7,6 0,9 4,5 0,0 common Edema 5,6 0,0 1,5 0,0 Renal pathologies common Renal disorders **** 7,6 0,9 1,7 0,0

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Event; NCI = National Cancer Institute; SGOT = serum glutamic oxaloacetic aminotransferase; SGPT = pyruvic glutamic serum aminotransferase.

* Definition of frequency: Very common - ≥ 10%; Common -> 5% e

** With reference to the NCI CTCAE criteria (Version 3.0; NCI 2003) for each degree of toxicity. The reported frequencies are in accordance with version 3.0 of the CTCAE.

*** The table of integrated adverse reactions combines the results of the studies of pemetrexed in maintenance according to the JMEN protocol (N = 663) and of pemetrexed in continuous maintenance according to the PARAMOUNT protocol (N = 539).

**** Combined term includes increased serum / blood creatinine, decreased glomerular filtration, renal and renal / genitourinary insufficiency - other.

Clinically relevant CTC toxicity of any grade which has been reported in ≥ 1% and lacrimation, dizziness and motor neuropathy.

Clinically relevant CTC toxicity which has been reported in an allergic / hypersensitivity rate, erythema multiforme, supraventricular arrhythmia and pulmonary embolism.

Safety was assessed for patients who were randomized to receive pemetrexed (N = 800). For patients who received ≤ 6 cycles of maintenance pemetrexed (N = 519), the incidence of adverse reactions was assessed, and compared to patients who received> 6 cycles of pemetrexed (N = 281). Increases in adverse reactions (all grades of toxicity) were observed with longer exposure. A significant increase in the incidence of Grade 3/4 neutropenia possibly related to study drug was observed with longer exposure to pemetrexed (≤6 cycles: 3.3 %,> 6 cycles: 6.4%: p = 0.046) No statistically significant differences were observed in any other individual Grade 3/4/5 adverse reactions with longer exposure.

Serious cardiovascular and cerebrovascular events including myocardial infarction, angina pectoris, cerebrovascular accident and transient ischemic attack have been reported infrequently during clinical trials with pemetrexed, usually when administered in combination with another cytotoxic agent. Most of the patients in whom these events were observed had pre-existing cardiovascular risk factors.

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

Pancytopenia has been reported infrequently in clinical trials with pemetrexed.

In clinical trials, cases of colitis (associated with sometimes fatal intestinal and rectal bleeding, intestinal perforation, intestinal necrosis and typhlitis) have been uncommonly reported in patients treated with pemetrexed.

In clinical trials, cases of interstitial pneumonia associated with respiratory failure, sometimes fatal, have been reported uncommonly in patients treated with pemetrexed.

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

Radiation esophagitis / oesophagitis has been reported infrequently in clinical studies with pemetrexed.

Sepsis, sometimes with a fatal outcome, has been commonly reported in clinical studies with pemetrexed.

During post-marketing surveillance, the following adverse reactions have been reported in patients treated with pemetrexed:

Uncommon cases of acute renal failure have been reported with pemetrexed alone or in combination with other chemotherapeutic agents (see section 4.4).

Uncommon cases of actinic pneumonia have been reported in patients receiving radiation treatment before, during or after the pemetrexed infusion (see section 4.4).

Rare cases of "radiation recall" have been reported in patients who have been treated with radiotherapy in the previous weeks or years (see section 4.4).

Uncommon cases of peripheral ischaemia, sometimes leading to necrosis of the extremities, have been reported.

There have been rare reports of bullous conditions including Stevens-Johnson syndrome and toxic epidermal necrolysis, which in some cases have been fatal.

Rarely, immune-mediated haemolytic anemia has been reported in patients treated with pemetrexed.

Rare cases of anaphylactic shock have been reported.

With unknown frequency, erythematous edema has been reported mainly in the lower limbs.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous 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. in Annex V.

04.9 Overdose

Overdose symptoms reported include neutropenia, anemia, thrombocytopenia, mucositis, sensory polyneuropathy and skin reaction. Expected complications of overdose include suppression of bone marrow function as evidenced by neutropenia, thrombocytopenia and anemia. In addition, infection with or without fever, diarrhea and / or mucositis may be observed. In the event of a suspected overdose, patients should be screened for blood counts and should receive supportive therapy as required. The use of calcium folinate / folinic acid should be considered in the treatment of pemetrexed overdose.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: folic acid analogues.

ATC code: L01BA04.

ALIMTA (pemetrexed) is a multi-target antitumor antifolate agent that exerts its action by interfering with the fundamental folate-dependent metabolic processes essential for cell replication.

Education in vitro have shown that pemetrexed acts as a multi-target antifolate agent by inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide-ribonucleotide-formyl transferase (GARFT) which are key folate-dependent enzymes for biosynthesis de novo of thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate carrier and the folate-binding membrane protein transport systems. Once inside the cell, pemetrexed is rapidly and effectively converted to polyglutamate forms via the cell. "enzyme foli-polyglutamate synthetase. 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 tumor cells and to a lesser extent in normal tissues.

The polyglutamate metabolites have a longer "intracellular half-life which determines a" prolonged action of the drug in malignant cells.

The European Medicines Agency has waived the obligation to submit the results of studies with ALIMTA in all subsets of the pediatric population in the authorized indications (see section 4.2).

Clinical efficacy

Mesothelioma

EMPHACIS, a blinded, multicentre, randomized phase 3 study of ALIMTA plus cisplatin versus cisplatin in non-pretreated patients with malignant pleural mesothelioma, demonstrated that patients treated with ALIMTA and cisplatin had a clinically significant 2.8 month benefit in median survival compared to patients who received cisplatin alone.

During the study, low doses of folic acid and vitamin B12 were added to patients' therapy to reduce toxicity. The primary analysis of this study was conducted on the population of all patients who were randomly assigned to a treatment arm receiving study drug (randomized and treated). A subgroup analysis was performed on patients who had received folic acid and vitamin B12 supplementation throughout the study therapy period (supplemented for the duration of treatment). The results of these efficacy analyzes are summarized in the following table:

Efficacy of ALIMTA plus cisplatin vs. cisplatin in malignant pleural mesothelioma Randomized and treated patients Patients integrated for the duration of the treatment Effectiveness parameter ALIMTA / cisplatin (N = 226) Cisplatin (N = 222) ALIMTA / cisplatin (N = 168) Cisplatin (N = 163) Median overall survival (months) 12,1 9,3 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 to tumor progression (months) 5,7 3,9 6,1 3,9 (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) 4,5 2,7 4,7 2,7 (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 *

Abbreviation: CI = confidence interval

* p-value referred to the comparison between the two arms.

** In the ALIMTA / cisplatin arm, randomized and treated (N = 225) and integrated for the duration of treatment (N = 167)

A statistically significant improvement in clinically specific symptoms (pain and dyspnoea) associated with malignant pleural mesothelioma was demonstrated in the ALIMTA / cisplatin arm (212 patients) versus the cisplatin alone arm (218 patients) using the Lung Cancer Symptom Scale. In addition, statistically significant differences were observed in lung function tests. The distinction between treatment arms was made by evaluating improvement in lung function in the ALIMTA / cisplatin arm and worsening of lung function over time in the control arm.

There is limited clinical data in patients with malignant pleural mesothelioma treated with ALIMTA alone. ALIMTA at a dose of 500 mg / m2 was studied as a single drug in 64 non-pretreated patients with malignant pleural mesothelioma. The overall response rate was 14.1%.

NSCLC, second-line treatment

An open-label, multicentre, randomized phase 3 study of ALIMTA versus docetaxel in patients with locally advanced or metastatic NSCLC after previous chemotherapy demonstrated median survival times of 8.3 months for patients treated with ALIMTA (Intent To Treat Patients n = 283) and 7.9 months for docetaxel-treated patients (ITT n = 288). Previous chemotherapy did not include ALIMTA. An "analysis of the impact of histology of non-small cell lung cancer on the effect of treatment on overall survival was in favor of ALIMTA over docetaxel for predominantly non-squamous histology (n = 399, 9.3 versus 8). , 0 months, corrected HR = 0.78; 95% CI = 0.61 - 1.00, p = 0.047) and was in favor of docetaxel for squamous histology (n = 172, 6.2 versus 7.4 months, corrected HR = 1.56 ; 95% CI = 1.08 - 2.26, p = 0.018). Regarding the safety profile of ALIMTA, no clinically significant differences were observed between the histological subgroups.

Limited clinical data from a single, randomized, phase 3 controlled trial suggest that the efficacy data (overall survival, progression-free survival) of pemetrexed are similar between previously docetaxel pretreated patients (n = 41) and patients who have not previously been treated with docetaxel (n = 540).

Efficacy of ALIMTA vs docetaxel in NSCLC ITT population

ALIMTA Docetaxel Survival (months) (n = 283) (n = 288) • Median (m) 8,3 7,9 • 95% CI for median (7,0 - 9,4) (6,3 - 9,2) • HR 0,99 • 95% CI for HR (0,82 - 1,20) • p-value (HR) of non-inferiority 0,226 Progression-free survival (months) (n = 283) (n = 288) • Median 2,9 2,9 • HR (95% CI) 0,97 (0,82 - 1,16) Time to treatment failure (TTTF - months) (n = 283) (n = 288) • Median 2,3 2,1 • HR (95% CI) 0,84 (0,71 - 0,997) Answer (n: evaluable by answer) (n = 264) (n = 274) • Response rate (%) (95% CI) 9,1 (5,9 - 13,2) 8,8 (5,7 - 12,8) • Stability of disease (%) 45,8 46,4

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

NSCLC, first-line treatment

An open-label, multicentre, randomized Phase 3 study of ALIMTA plus cisplatin versus gemcitabine plus cisplatin in non-pretreated patients with locally advanced or metastatic non-small cell lung cancer (stage IIIb or IV) showed that ALIMTA plus cisplatin (Intent population) To-Treat [ITT] n = 862) met its primary endpoint and showed similar clinical efficacy to gemcitabine plus cisplatin (ITT n = 863) in overall survival (corrected hazard ratio 0.94; 95% CI 0.84 - 1.05) All patients included in this study had a performance status of 0 or 1 on the ECOG scale.

The primary efficacy analysis was based on the ITT population. Sensitivity analyzes of the main efficacy targets were also evaluated on the Protocol Qualified (PQ) population. The efficacy analyzes using the PQ population are consistent with the analyzes on the ITT population and support the non-inferiority of AC versus GC.

Progression-free survival (PFS) and objective response rate were similar between the two treatment arms: median PFS was 4.8 months for ALIMTA plus cisplatin versus 5.1 months for gemcitabine plus cisplatin (hazard ratio corrected 1.04; 95% CI 0.94 - 1.15), and the objective response rate was 30.6% (95% CI 27.3 - 33.9) for ALIMTA plus cisplatin compared to 28.2% (95% CI 25.0 - 31.4) for gemcitabine plus cisplatin. The PFS data were partially confirmed by an independent review (400 / 1,725 ​​patients were randomly selected for review).

In non-small cell lung cancer, analysis of the impact of histology on overall survival demonstrated clinically meaningful differences by histological type, see table below.

Efficacy of ALIMTA + cisplatin vs. gemcitabine + cisplatin as a treatment of

first line of non-small cell lung cancer

ITT population and histological subgroups

ITT population and histological subgroups Mean overall survival in months (95% CI) Hazard ratio (HR) corrected (95% CI) P-value superiority 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 0.94a (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 cells (N = 153) 10,4 (8,6 - 14,1) N = 76 6,7 (5,5 - 9,0) N = 77 0,67 (0,48 - 0,96) 0.027 Others (N = 252) 8,6 (6,8 - 10,2) N = 106 9,2 (8,1 - 10,6) N = 146 1,08 (0,81 - 1,45) 0.586 Squamous cells (N = 473) 9,4 (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 = size of the global population.

a Statistically significant for non-inferiority, with the full confidence interval for HR well below the non-inferiority margin of 1.17645 (p

No clinically significant differences in the safety profile of ALIMTA plus cisplatin were observed within the histological subgroups.

Patients treated with ALIMTA and cisplatin required fewer transfusions (16.4% vs 28.9%, p red blood cells (16.1% vs 27.3%, p erythropoietin / darbepoietin (10.4% vs 18 , 1%, p iron derivatives (4.3% vs 7.0%, p = 0.021).

NSCLC, maintenance treatment

JMEN

A Phase 3 (JMEN) placebo-controlled, double-blind, randomized, multicenter study compared the efficacy and safety of ALIMTA maintenance treatment combined with best supportive care (BSC) (n = 441) with "Efficacy and safety of BSC-associated placebo treatment (n = 222) in patients with locally advanced (Stage IIIB) or metastatic (Stage IV) non-small cell lung cancer (NSCLC) who have not progressed after 4 courses of therapy line containing Cisplatin or Carboplatin in combination with Gemcitabine, Paclitaxel, or Docetaxel. ALIMTA was not contained in the first line of dual drug therapy. All patients included in this study had a performance status of 0 or 1 on the ECOG scale. Patients received maintenance treatment until disease progression. Efficacy and safety were measured by time to randomization after completion of first-line (induction) therapy. Patients received a median of 5 courses of ALIMTA maintenance treatment and 3.5 courses of placebo. A total of 213 patients (48.3%) completed ≥ 6 cycles and a total of 103 patients (23.4%) completed ≥ 10 courses of ALIMTA treatment.

The study met its primary endpoint and showed an increase in PFS in the ALIMTA arm compared to 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 radiological examinations of the patients confirmed the findings of the investigators regarding the evaluation of PFS. The median overall survival (OS) of the whole population (n = 663) was of 13.4 months for the ALIMTA arm and 10.6 months for the placebo arm, hazard ratio = 0.79 (95% CI: 0.65 to 0.95; p = 0.01192).

A difference in efficacy according to the histology of NSCLC was observed in the JMEN study, consistent with other studies with ALIMTA. For patients with NSCLC other than predominantly squamous cell histology (n = 430, independently reviewed population) the 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). Also adding the induction phase, the median OS for NSCLC patients with the exception of 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 results of PFS and OS in patients with squamous histology did not suggest any advantage for ALIMTA over placebo.

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

PARAMOUNT

A Phase 3, multicentre, randomized, double-blind, placebo-controlled study (PARAMOUNT), compared the efficacy and safety of maintenance treatment with ALIMTA plus BSC (n = 359) with those of treatment with placebo plus BSC ( n = 180) in patients with locally advanced (Stage IIIB) or metastatic (Stage IV) NSCLC with the exception of predominantly squamous cell histology which has not progressed after 4 courses of first-line therapy with ALIMTA in combination with cisplatin. Of the 939 induction patients treated with ALIMTA plus cisplatin, 539 patients were randomized to maintenance treatment with pemetrexed or placebo. Of the randomized patients, 44.9% achieved complete / partial response and 51.9% disease stability after induction with ALIMTA plus cisplatin. All patients randomized to maintenance treatment were required to have a performance status of 0 or 1 on the ECOG scale. The median time from initiation of ALIMTA plus cisplatin induction therapy to initiation of maintenance was 2.96 months in both the pemetrexed and placebo arms. Randomized patients received maintenance treatment until disease progression. Efficacy and safety were measured from time of randomization after completion of first-line (induction) therapy. Patients received a median of 4 courses of ALIMTA maintenance treatment and 4 courses of placebo. A total of 169 patients (47.1%) completed ≥ 6 courses of ALIMTA maintenance treatment, representing at least 10 total courses of ALIMTA.

The study met its primary endpoint and showed a statistically significant increase in PFS in the ALIMTA arm compared to 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 the patients' radiological examinations confirmed the findings of the investigators regarding the evaluation of PFS. For randomized patients, when measured from initiation of ALIMTA plus first-line cisplatin (induction) treatment, the median investigator-detected 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).

After induction with ALIMTA plus cisplatin (4 cycles), treatment with ALIMTA demonstrated a statistically significant increase in overall survival (OS) compared to treatment with placebo (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 the final survival analysis, 28.7% of patients in the ALIMTA arm were alive or lost to follow-up compared with 21.7% in the placebo arm. The relative effect of ALIMTA treatment was consistent across all patients. subgroups (including stage of disease, response to induction treatment, performance status according to the ECOG scale, smoking status, gender, histology and age), and similar to that observed in the overall survival (OS) and survival analysis progression-free (PFS). The 1 and 2-year survival rates for patients treated with ALIMTA were 58% and 32%, respectively, compared with 45% and 21% for patients treated with placebo. Since the initiation of first-line treatment with ALIMTA plus cisplatin (induction), the median overall survival (OS) was 16.9 months for patients in the ALIMTA arm and 14 months for patients in the placebo arm (hazard ratio = 0, 78, 95% CI = 0.64-0.96) The percentage of patients who received post-study treatment was 64.3% of those in the ALIMTA arm and 71.7% of those in the placebo arm.

The safety profiles of ALIMTA maintenance treatment in the two studies JMEN and PARAMOUNT were found to be similar.

05.2 Pharmacokinetic properties

The pharmacokinetic properties of pemetrexed as a single drug were evaluated in 426 cancer patients, with a diversity of solid tumors, at doses between 0.2 and 838 mg / m2 administered by infusion over a 10 minute period. Pemetrexed has a steady-state volume of distribution of 9 L / m2. Education in vitro indicate that pemetrexed is approximately 81% bound to plasma proteins. The binding is not particularly affected by varying degrees of renal insufficiency. Pemetrexed undergoes limited hepatic metabolism. Pemetrexed is mainly eliminated in the urine, with 70% - 90% of the administered dose which is recovered unchanged in the urine in the first 24 hours after administration in vitro indicate that pemetrexed is actively eliminated by the organic anion transporter OAT3. The total systemic clearance of pemetrexed is 91.8 ml / min and the plasma elimination half-life is 3.5 hours in patients with normal renal function (creatinine clearance of 90 ml / min). The variability of clearance between patients is modest being equal to 19.3%. The total systemic exposure (AUC) and the maximum plasma concentration of pemetrexed increase in a dose-proportional manner. The pharmacokinetics of pemetrexed are constant across multiple treatment courses.

The pharmacokinetic properties of pemetrexed are not affected by co-administration with cisplatin. Integration of oral folic acid and intramuscular vitamin B12 does not affect the pharmacokinetics of pemetrexed.

05.3 Preclinical safety data

Administration of pemetrexed to pregnant mice resulted in a reduction in fetal activity, a reduction in fetal weight, incomplete ossification of some skeletal structures and fissuring of the palate.

Administration of pemetrexed to male mice resulted in impairment of reproductive capacity characterized by a reduction in the degree of fertility and testicular atrophy. A study conducted in beagle dogs, administering intravenous boluses of pemetrexed for 9 months, revealed testicular changes (degeneration / necrosis of the seminiferous epithelium). This suggests that pemetrexed may alter male fertility. The effect on female fertility was not. studied.

Pemetrexed was not mutagenic in either the Chinese Hamster Ovary Cell Chromosome Aberration Test or the Ames Test. Pemetrexed was shown to be clastogenic in the test in vivo on the micronucleus in the mouse.

No studies have been performed to evaluate the carcinogenic potential of pemetrexed.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Mannitol.

Hydrochloric acid.

Sodium hydroxide.

06.2 Incompatibility

Pemetrexed is physically incompatible with calcium-containing solvents, including lactated Ringer's for injections and Ringer's for injections. In the absence of other compatibility studies this medicinal product must not be mixed with other medicinal products.

06.3 Period of validity

Closed vial

3 years.

Reconstituted and infusion solutions

When prepared as directed, reconstituted and infusion solutions of ALIMTA do not contain antimicrobial preservatives. Chemical and physical in-use stability of reconstituted and infusion solutions of pemetrexed have been demonstrated for 24 hours at refrigerated temperature. From a microbiological point of view, the product should be used immediately. storage of the product in use and the conditions prior to use are the responsibility of the user and should not exceed 24 hours at a temperature between 2 ° C and 8 ° C.

06.4 Special precautions for storage

Closed vial

No special storage precautions.

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

06.5 Nature of the immediate packaging and contents of the package

ALIMTA 100 mg powder for concentrate 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 concentrate 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.

06.6 Instructions for use and handling

1. Use aseptic techniques when reconstituting and further diluting pemetrexed for intravenous infusion administration.

2. Calculate the dose and number of ALIMTA vials needed. Each vial contains an excess of pemetrexed to facilitate dispensing of the quantity indicated on the label.

3. ALIMTA 100 mg

Reconstitute the 100 mg vials with 4.2 ml of sodium chloride 9 mg / ml (0.9%) solution for injections, without preservatives, to obtain a solution containing 25 mg / ml of pemetrexed.

ALIMTA 500 mg

Reconstitute the 500 mg vials with 20 ml of sodium chloride 9 mg / ml (0.9%) solution for injections, without preservatives, to obtain a solution containing 25 mg / ml of pemetrexed.

Gently shake each vial until the powder is completely dissolved. The solution thus obtained is clear and varies from colorless to yellow or yellow-green without adversely affecting the quality of the product. The pH of the reconstituted solution is between 6.6 and 7.8. Further dilution is required.

4. The appropriate volume of reconstituted pemetrexed solution should be further diluted to 100 ml with 9 mg / ml (0.9%) sodium chloride solution for injection, without preservative and administered by intravenous infusion over 10 minutes.

5. Pemetrexed infusion solutions prepared as described above are compatible with polyvinyl chloride and polyolefin lined infusion bags and administration sets.

6. Prior to administration, parenteral medicinal products should be visually checked for the presence of particles and color changes. Do not administer if particles are observed.

7. Pemetrexed solutions are for single use only. Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.

Precautions for preparation and administration

As with other potentially toxic anticancer agents, caution should be exercised in handling and preparing pemetrexed infusion solutions. The use of gloves is recommended. If a pemetrexed solution comes into contact with the skin, wash immediately and thoroughly with soap and water. If pemetrexed solutions come into contact with mucous membranes, wash thoroughly with water. Pemetrexed is not blistering. There is no specific antidote for pemetrexed extravasation. A few cases of pemetrexed extravasation have been reported which were not considered serious by the investigator. Extravasation should be managed according to standard procedures as with other non-blistering agents.

07.0 MARKETING AUTHORIZATION HOLDER

Eli Lilly Nederland B.V.

Papendorpseweg 83, 3528 BJ Utrecht

Netherlands

08.0 MARKETING AUTHORIZATION NUMBER

EU / 1/04/290/001

036587018

EU / 1/04/290/002

036587020

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 20 September 2004

Date of most recent renewal: 20 September 2009

10.0 DATE OF REVISION OF THE TEXT

D.CCE February 2017

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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