Alimta 100 mg, 500 mg powder for concentrate for solution for infusion

ALIMTA®                                                     SUMMARY OF PRODUCT CHARACTERISTICS

(pemetrexed)                                                      Ireland, Malta, United Kingdom (Northern Ireland)

 

4.4         Special warnings and precautions for use

[…]

Method of administration

 

Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment and up to 36 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 and for 6 months following completion of treatment (see section 4.6).

[…]

 

4.6         Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in males and females

Pemetrexed can have genetically damaging effects. Women of childbearing potential must use effective contraception during treatment with pemetrexed and for 6 months following completion of treatment.

Pemetrexed can have genetically damaging effects. Sexually mature males are advised to use effective contraceptive measures and not to father a child during the treatment and up to 36 months thereafter. Contraceptive measures or abstinence are recommended.

 

 

4.8         Undesirable effects

Reporting of suspected adverse reactions

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Malta: ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal, Ireland: HPRA Pharmacovigilance, website: www.hpra.ie, United Kingdom (Northern Ireland): Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

 

 

10.         DATE OF REVISION OF THE TEXT

 

17 April 2020 22 April 2022

 

 

AT24M027

2. What you need to know before you use ALIMTA 

[…]

Pregnancy

If you are pregnant, think you may be pregnant or are planning to have a baby, 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 and for 6 months after receiving the last dose.

[…]

 

Fertility

Men are advised not to father a child during and up to 36 months following treatment with ALIMTA and should therefore use effective contraception during treatment with ALIMTA and for up to 36 months afterwards. If you would like to father a child during the treatment or in the 36 months following receipt of treatment, seek advice from your doctor or pharmacist. ALIMTA can affect your ability to have children. Talk to your doctor to seek advice about You may want to seek counselling on sperm storage before starting your therapy.

[…]

 

 

6.         DATE OF REVISION OF THE TEXT

 

January 2022 April 2022

 

 

AT0295

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

• Fever or infection (respectively, common or very 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 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).

 

Uncommon (may affect up to 1 in 100 people)

…..

Abnormal Increased heart rhythm

 

This leaflet was last revised in AprilSeptember 2020.

Added (underline) deleted (strikethrough)

Various minor grammar and format updates.  Some header standardisation and table re-numbering throughout.

4.2         Posology and method of administration

[…]

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

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

[…]

4.4         Special warnings and precautions for use

[…]

Excipients

ALIMTA 100 mg powder for concentrate for solution for infusion

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially, i.e. essentially ‘sodium- free’.

ALIMTA 500 mg powder for concentrate 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.

This medicinal product contains approximately 54 mg of sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

[…]

4.6         Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in males and females

[…]

Breast-feeding

It is not unknown whether pemetrexed is excreted in human milk and adverse reactions on the breast feeding suckling child […]

4.8         Undesirable effects

Tabulated list of adverse reactions

[Previous text and tables removed – previous text not included in this change summary]

[…]

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).

Table 4.               List of adverse reactions in clinical studies and postmarketing reports

[Reformatted table and in addition, some ADRs have been re-classified for frequencies and re-ordered]

Reporting of suspected adverse reactions

[Update HPRA reporting details]

10.         DATE OF REVISION OF THE TEXT

10 January 201917 April 2020

AT23MAT24M

Changes

Added (underline), deleted (strikethrough), additional notes:

4.8 Undesirable effects

…

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

Hyperpigmentation has been commonly reported.

Uncommon cases of acute renal failure have been reported with pemetrexed alone or in association with other chemotherapeutic agents (see section 4.4). Nephrogenic diabetes insipidus and renal tubular necrosis have been reported in post marketing setting with an unknown frequency.

…

Erythematous oedema mainly of the lower limbs has been reported with an unknown frequency. Infectious and non-infectious disorders of the dermis, the hypodermis and/or the subcutaneous tissue have been reported with an unknown frequency (e.g. acute bacterial dermo-hypodermitis, pseudocellulitis, dermatitis).

10. DATE OF REVISION OF THE TEXT

10 January 201902 February 2018

Added (underline)

 

4.4     Special warnings and precautions for use

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 monitored for acute tubular necrosis and decreased renal function and signs and symptoms of nephrogenic diabetes insipidus (e.g. hypernatraemia).

 

4.8     Undesirable effects

 

 

Uncommon cases of acute renal failure have been reported with pemetrexed alone or in association with other chemotherapeutic agents (see section 4.4). Nephrogenic diabetes insipidus and renal tubular necrosis have been reported in post marketing setting with an unknown frequency.

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, website: www.hpra.ie, e-mail:  medsafety@hpra.ie, United Kingdom: Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

 

10.       DATE OF REVISION OF THE TEXT

02 February 2018

AT22M

In Section 4.4. Special warnings and precautions for use, the statement ‘100mg vial: This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium-free’.’ is added. ‘Aspirin’ is replaced by ‘acetylsalicylic acid’.

 

In Section 4.5. Interaction with other medicinal products and other forms of interaction, ‘aspirin’ is replaced by ‘acetylsalicylic acid’.

 

In Section 4.8. Undesirable effects the following text is added –

 

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

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, website: www.hpra.ie, e-mail:  medsafety@hpra.ie, United Kingdom: Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.

 

In Section 10. DATE OF REVISION OF THE TEXT, the date of revision is updated to 17 January 2017.

Changes

 

(New text bold.  Text struck-through removed.)

 

 

 

 

7.         MARKETING AUTHORISATION HOLDER

 

Eli Lilly Nederland B.V.

Papendorpseweg 83, 3528 BJ Utrecht Grootslag 1-5, NL-3991 RA, Houten
The Netherlands

 

 

 

10.       DATE OF REVISION OF THE TEXT

 

            19 November 201501 January 2016

New text bold.  Text struck-through removed.

 

Changes

 

 

4.1           Therapeutic indications

 

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 (NSCLC) other than predominantly squamous cell histology (see section 5.1).

 

4.8           Undesirable effects

 

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

 

 

                10.          DATE OF REVISION OF THE TEXT

 

                12 November 2012 19 November 2015

In Section 6.3, Shelf-life, the storage condition of reconstituted Alimta is update to remove storage at room temperature.

In Section 10, Date of revision of text, date of revision is updated.

Changes made throughout the SPC to replace ‘transaminase’ with ‘aminotransferase’

In Section 4.8, undesirable effects, the frequency table for maintenance tratment has been updated with PARAMOUNT overall survival data.

In Section 5.1, Pharmacodynamic properties, Paramount study data has been update with overall survival data.

In Section 10, Date of revision of the text, the date of revision is updated.

Sections 2, 4.3 and 6.3 are updated to comply with the QRD template.

In Section 4.5, Interaction with other medicinal products and other forms of interaction, the following statement is added - 'If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression and gastrointestinal toxicity'

In Section 4.8, Undesirable effects, the following statement is added - 'Rare cases of anaphylactic shock have been reported'

In Section 10, Date of revision of the text, the revision date is updated.

In Section 6.3, Shelf-life, the shelf life of Alimta 100mg has been changed to 3 years.

In Section 10, Date of revision of the text, the revision date is updated.

The following trademark information has been added at the end of the SPC -
'Detailed information on this product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu.
LEGAL CATEGORY
POM

*ALIMTA (pemetrexed) is a trademark of Eli Lilly and Company.'

In Section 4.1, Therapeutic indications, the following statement is removed – ‘First-line treatment should be a platinum doublet with gemcitabine, paclitaxel or docetaxel’

 

In Section 4.8, Undesirable effects, results from two studies JMEN, and PARAMOUNT have been added, and the frequencies of the updated accordingly.

 

In Section 5.1, Pharmacodynamic properties, details of the PARAMOUNT study are added.

 

In Section 10, Date of revision of the text, the revision date is updated.

New text highlighted.  Text struckthrough removed.

 

Changes

 

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.  …………………….

 

                                                                                 ………………………….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.

Children and adolescents: ALIMTA is not recommended for use in children below 18 years of age due to insufficient data on safety and efficacy.

 

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 ≥45ml/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 45ml/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 transaminase >3.0-times the upper limit of normal (hepatic metastases absent) or >5.0-times the upper limit of normal (hepatic metastases present), have not been specifically studied.

 

Method of administration:

 

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

 

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

The ALIMTA solution must be prepared according to the instructions provided in section 6.6.

 

 

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/mm³ and platelet count returns to ≥100,000 cells/mm³.  Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum non-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 B₁₂ was administered.  Therefore, all patients treated with pemetrexed must 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 pre-treated with a corticosteroid.  Pre-treatment with dexamethasone (or equivalent) can reduce the incidence and severity of skin reactions (see section 4.2).

 

An insufficient number of patients has been studied with creatinine clearance of below 45ml/min.  Therefore, the use of pemetrexed in patients with creatinine clearance of <45ml/min is not recommended (see section 4.2).

 

Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79ml/min) should avoid taking non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, and aspirin (>1.3g daily) for 2 days before, on the day of, and 2 days following pemetrexed administration (see section 4.5). 

 

All In patients with mild to moderate renal insufficiency eligible for pemetrexed therapy should avoid taking , 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.

 

The effect of third-space fluid, such as pleural effusion or ascites, on pemetrexed is unknown.  In patients with clinically significant third-space fluid, consideration should be given to draining the effusion prior to pemetrexed administration 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 normalised plasma concentrations or clearance compared to patients without third-space fluid collections. Thus, drainage of third-space fluid collection prior to pemetrexed treatment should be considered, but may not be necessary.

 

Due to the gastrointestinal toxicity ……………..

 

4.5          Interaction with other medicinal products and other forms of interaction

 

Pemetrexed is mainly eliminated unchanged renally by tubular secretion and to a lesser extent by glomerular filtration.  Concomitant administration of nephrotoxic drugs (e.g., aminoglycoside, loop diuretics, platinum compounds, cyclosporin) could potentially result in delayed clearance of pemetrexed.  This combination should be used with caution.  If necessary, creatinine clearance should be closely monitored.

 

Concomitant administration of substances that are also tubularly secreted (e.g., probenecid, penicillin) could potentially result in delayed clearance of pemetrexed.  Caution should be made when these drugs are combined with pemetrexed.  If necessary, creatinine clearance should be closely monitored.

 

In patients with normal renal function (creatinine clearance >80ml/min), high doses of non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen >1600mg/day) and aspirin at higher doses (>1.3g daily)  may decrease pemetrexed elimination and, consequently, increase the occurrence of pemetrexed adverse events.  Therefore, caution should be made when administering higher doses of NSAIDs or aspirin at higher dose, concurrently with pemetrexed to patients with normal function (creatinine clearance >80ml/min).

 

In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79ml/min), the concomitant administration of pemetrexed with NSAIDs (e.g., ibuprofen) or aspirin at higher doses 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 avoided for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration (see section 4.4).

 

Pemetrexed undergoes limited hepatic metabolism.  …………………

 

4.6          Fertility, pregnancy and lactation

 

Contraception in males and females:

 

Women of childbearing potential must use effective contraception during treatment with pemetrexed.  Pemetrexed can have genetically damaging effects.  Sexually mature males are advised not to father a child during the treatment, and up to 6 months thereafter.  Contraceptive measures or abstinence are recommended.

 

Pregnancy:

 

There are no data from the use of pemetrexed in pregnant women; but pemetrexed, like other anti-metabolites, is suspected to cause serious birth defects when administered during pregnancy.  Animal studies have shown reproductive toxicity (see section 5.3).  Pemetrexed should not be used during pregnancy unless clearly necessary, after a careful consideration of the needs of the mother and the risk for the foetus (see section 4.4).

 

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.  Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment.

 

 

Breast-feeding:

 

It is not known whether pemetrexed is excreted in human milk, and adverse reactions on the suckling child cannot be excluded.  Breast-feeding must be discontinued during pemetrexed therapy (see section 4.3).

 

Fertility:

 

Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment.

 

 

4.8          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, leucopenia, thrombocytopenia; and gastrointestinal toxicities, manifested as anorexia, nausea, vomiting, diarrhoea, constipation, pharyngitis, mucositis, and stomatitis. Other undesirable effects include renal toxicities, increased transaminases, alopecia, fatigue, dehydration, rash, infection/sepsis and neuropathy. Rarely seen events include Stevens-Johnson syndrome and Toxic epidermal necrolysis.

 

Tabulated list of adverse reactions

 

The table below ……..

 

                                     ………………………………………………………………...with pemetrexed.

 

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

 

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

 

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

 

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

 

Uncommon cases of radiation pneumonitis have been reported in patients treated with radiation either prior, during or subsequent to their pemetrexed therapy (see section 4.4).

 

Rare cases of radiation recall have been reported in patients who have received radiotherapy previously (see section 4.4).

 

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

 

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

 

Rarely, haemolytic anaemia has been reported in patients treated with pemetrexed.

 

 

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.

 

In vitro studies have shown that pemetrexed behaves as a multi-targeted antifolate by inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are key folate-dependent enzymes for the de novo biosynthesis of thymidine and purine nucleotides.  Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems.  Once in the cell, pemetrexed is rapidly and efficiently converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase.  The polyglutamate forms are retained in cells and are even more potent inhibitors of TS and GARFT.  Polyglutamation is a time- and concentration-dependent process that occurs in tumour cells and, to a lesser extent, in normal tissues.  Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.

 

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

 

Clinical efficacy…………………………………………..

 

 

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 838mg/m² infused over a 10-minute period.  Pemetrexed has a steady-state volume of distribution of 9 l/m².  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 91.8ml/min and the elimination half-life from plasma is          3.5 hours in patients with normal renal function (creatinine clearance of 90ml/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 B₁₂ supplementation do not affect the pharmacokinetics of pemetrexed.

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date

 

27 January 2011

 

               

Changes

 

 

 

6.            PHARMACEUTICAL PARTICULARS

 

6.3          Shelf-life

 

Changes in bold and strikethrough

 

Unopened vial 100mg: 2 years

Unopened vial 500mg: 2 3 years

 

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date

 

24 February 2010

 

               



 

2.                     QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Changed:

 

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

 

Excipients: Each vial contains approximately 11 mg sodium.

 

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

 

Excipients: Each vial contains approximately 54 mg sodium.

 

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

 

For a full list of excipients see section 6.1.

 

 

 

4.            Clinical particulars

 

4.2          Posology and method of administration

 

Moved to end of section 4.2:

 

The ALIMTA solution must be prepared according to the instructions provided in section 6.6.

 

4.3          Contraindications

 

Deleted (strikethrough):

 

Breast‑feeding must be discontinued during pemetrexed therapy (see section 4.6).

 

4.4       Special warnings and precautions for use

 

Deleted (strikethrough):

 

Immunodepressed status is common in cancer patients. As a result, concomitant use of live attenuated vaccines (except yellow fever which is contraindicated) is not recommended (see section 4.3 and 4.5).

 

 

4.8          Undesirable effects

 

NOTE: Tables re-formatted throughout section 4.8.

 

Added:

 

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

 

 

 

6.            PHARMACEUTICAL PARTICULARS

 

6.3          Shelf-life

 

Added (italic):

 

Unopened vial: 2 years

 

6.5          Nature and contents of container

 

Changed:

 

Type I glass vial with rubber stopper containing 100 mg or 500 mg of pemetrexed.

 

 

 

9.            DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Added:

 

Date of latest renewal:    20 September 2009

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date

 

21 September 2009

 

               

Added:

 

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu.



4.                Clinical particulars

 

4.1              Therapeutic indications

 

Added:

 

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. First line treatment should be a platinum doublet with gemcitabine, paclitaxel or docetaxel (see Section 5.1).

 

4.8              Undesirable effects

 

Added:

 

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 B12.

System Organ Class	Frequencya	Eventb	Pemetrexed (N = 441)		Placebo (N = 222)
			All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)
Blood and Lymphatic   System Disorders	Very Common	Hemoglobin	15.2	2.7	5.4	0.5
	Common	Leukocytes	6.1	1.6	1.4	0.5
		Neutrophils	5.9	2.9	0.0	0.0
Gastrointestinal  Disorders	Very Common	Nausea	18.8	0.9	5.4	0.5
		Anorexia	18.6	1.8	5.0	0.0
	Common	Vomiting	8.6	0.2	1.4	0.0
		Mucositis/stomatitis	7.0	0.7	1.8	0.0
	Common	Diarrhoea	5.2	0.5	2.7	0.0
General	Very Common	Fatigue	24.5	5.0	10.4	0.5
Hepatobiliary Disorders	Common	ALT (SGPT)	9.5	0.2	3.6	0.0
		AST (SGOT)	8.2	0.0	3.6	0.0
Infections and Infestations	Common	Infection	5.2	1.6	1.8	0.0
Skin and Subcutaneous Tissue Disorders	Very Common	Rash/desquamation	10.0	0.0	3.2	0.0
Nervous System Disorders	Common	Neuropathy-sensory	8.8	0.7	4.1	0.0

 

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

a 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.

b Refer to NCI CTCAE Criteria (Version 3.0; NCI 2003) for each grade of toxicity

 

Clinically relevant CTC toxicity of any grade that was reported in ≥1% and £5% (common) of the patients that were randomly assigned to pemetrexed include: decreased platelets, decreased creatinine clearance, constipation, edema, alopecia, increased creatinine, 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% (uncommon) of the patients that were randomly assigned to pemetrexed include: febrile neutropenia, allergic reaction/hypersensitivity, motor neuropathy, erythema multiforme, renal failure, and supraventricular arrhythmia.

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.

 

 

 

5.                PHARMACOLOGICAL PROPERTIES

 

5.1              Pharmacodynamic properties

 

Added:

 

Mesothelioma:

 

Added:

 

NSCLC, Second-Line Treatment:

Added (bold):

 

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.

 

Added:

 

NSCLC, First-Line Treatment:

 

Added:

 

NSCLC, Maintenance Treatment:

 

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 to 0.95; p = 0.01192).

 

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.

Kaplan Meier Plots of Progression-Free Survival (PFS) and Overall Survival ALIMTA versus Placebo in Patients with NSCLC other than Predominantly Squamous Cell Histology:

 

*NEW CHARTS ADDED HERE*

 

 

10.              DATE OF REVISION OF THE TEXT

 

New date

 

                02 July 2009

4.                Clinical particulars

 

4.8             Undesirable effects

 

Added:

 

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

 

Deleted:

 

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

 

Added:

Cases of peripheral ischemia leading sometimes to extremity necrosis have been reported.

 

 

 

10.              DATE OF REVISION OF THE TEXT

 

New date

 

                06 January 2009

4.       Clinical particulars

 

4.1              Therapeutic indications

 

Added (text in red):

 

Malignant Pleural Mesothelioma:

ALIMTA in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma.

 

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).

 

4.2              Posology and method of administration

 

Deleted (strikethrough) & Added (text in red):

 

Malignant pleural mesothelioma:

In patients treated for malignant pleural mesothelioma, tALIMTA in combination with cisplatin: The recommended dose of ALIMTA is 500 mg/m² 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/m² 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).

 

Non‑small cell lung cancer:

ALIMTA as single agent: In patients treated for non‑small cell lung cancer, after prior chemotherapy the recommended dose of ALIMTA is 500 mg/m² BSA administered as an intravenous infusion over 10 minutes on the first day of each 21‑day cycle.

 

Added text to table):

 

^a  These criteria meet the National Cancer Institute Common Toxicity Criteria (CTC)  (v2.0; NCI 1998) definition of ≥CTC Grade 2 bleeding

 

Added below table 2 (text in red):

 

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

 

Added below table 3 (text in red):

 

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

 

 

4.4              Special warnings and precautions for use

               

Deleted (strikethrough) & Added (text in red):

 

In the Phase 3 mesothelioma trial, overall lLess 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 B₁₂ was administered. Therefore all patients treated with pemetrexed must be instructed to take folic acid and vitamin B₁₂ as a prophylactic measure to reduce treatment‑related toxicity (see section 4.2).

 

4.5              Interaction with other medicinal products and other forms of interaction

 

Added (Text in red):

 

Concomitant use not recommended: Live attenuated vaccines (except yellow fever, for which concomitant use is contra-indicated): 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).

 

4.8                     Undesirable effects

 

Changed/Added (in red)

 

(Text in Table for Taste disturbance):

 

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

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

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

 

Very common - ≥ 10 %; Common is normally defined as - ≥ 1 % and < 10 %. For the purpose of this table a cut off of 5 % was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed and cisplatin.

 

Clinically relevant CTC toxicities that were reported in - ≥ 1 % and < 5 % (common) of the patients that were randomly assigned to receive cisplatin and pemetrexed include: renal failure, infection, pyrexia, febrile neutropenia, increased AST, ALT, and GGT, urticaria and chest pain.

Clinically relevant CTC toxicities that were reported in < 1 % (uncommon) of the patients that were randomly assigned to receive cisplatin and pemetrexed include arrhythmia and motor neuropathy.

 

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

Very common - ≥ 10 %; Common is normally defined as - ≥ 1 % and < 10 %. For the purpose of this table a cut off of 5 % was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed.

 

Clinically relevant CTC toxicities that were reported in - ≥ 1 % and < 5 % (common) of the patients that were randomly assigned to pemetrexed include: infection without neutropenia, febrile neutropenia, allergic reaction/hypersensitivity, increased creatinine, motor neuropathy, sensory neuropathy, erythema multiforme, and abdominal pain.

Clinically relevant CTC toxicities that were reported in < 1 % (uncommon) of the patients that were randomly assigned to pemetrexed include supraventricular arrhythmias.

 

Added:

 

The table below provides the frequency and severity of undesirable effects considered possibly related to study drug that have been reported in >5% of 839 patients with NSCLC who were randomized to receive cisplatin and pemetrexed and 830 patients with NSCLC who were randomized to receive cisplatin and gemcitabine. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12. 

 

NEW TABLE ADDED HERE             

 

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

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

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

 

 

Very common - ≥10%; common is normally defined as ≥ 1 % and < 10 %. For the purpose of this table, a cut-off of 5% was used for inclusion of all events where the reporter considered a possible relationship to pemetrexed and cisplatin).

Clinically relevant toxicity that was reported in ≥1% and ≤5% (common) of the patients that were randomly assigned to receive cisplatin and pemetrexed include: AST increase, ALT increase, infection, febrile neutropenia, renal failure, pyrexia, dehydration, conjunctivitis, and creatinine clearance decrease.

Clinically relevant toxicity that was reported in <1% (uncommon) of the patients that were randomly assigned to receive cisplatin and pemetrexed include: GGT increase, chest pain, arrhythmia, and motor neuropathy.

Clinically relevant toxicities with respect to gender were similar to the overall population in patients receiving pemetrexed plus cisplatin.

 

5.                                PHARMACOLOGICAL PROPERTIES

 

5.1                     Pharmacodynamic properties

 

Added (text in red):

 

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). 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).

 

Added:

 

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

 

The analysis of the impact of NSCLC histology on overall survival demonstrated clinically relevant differences in survival according to histology, see table below.

Efficacy of ALIMTA + Cisplatin vs. Gemcitabine + Cisplatin in First-Line Non-Small Cell Lung Cancer – ITT Population and Histology Subgroups.

NEW TABLE ADDED HERE

 

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

a Statistically significant for noninferiority, with the entire confidence interval for HR well below the 1.17645 noninferiority margin (p <.001).

 

Kaplan Meier Plots of Overall Survival by Histology

NEW GRAPHS ADDED HERE

 

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<.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<.001), G-CSF/GM-CSF (3.1% versus 6.1%, p=0.004), and iron preparations (4.3% versus 7.0%, p=0.021).

 

 

6.                                PHARMACEUTICAL PARTICULARS

 

6.5              Nature and contents of container

 

Added:

 

Not all pack sizes may be marketed.

 

 

10.              DATE OF REVISION OF THE TEXT

 

New date

 

08 April 2008

 

4.       Clinical particulars

 

4.4       Special warnings and precautions for use

               

Added:

 

Cases of radiation recall have been reported in patients who received radiotherapy weeks or years previously.

 

4.8               Undesirable effects

 

Added:

 

Cases of radiation recall have been reported in patients who have received radiotherapy previously (see section 4.4).

 

 

6.       PHARMACEUTICAL PARTICULARS

 

6.6       Special precautions for disposal and other handling

 

Formatted:

 

1.             Use aseptic technique during the 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 delivery of label amount.

 

3.             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.

 

4.             The appropriate volume of reconstituted pemetrexed solution should 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.

 

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

 

6.             Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration. If particulate matter is observed, do not administer.

 

7.             Pemetrexed solutions are for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date

 

22 January 2008

4.       Clinical particulars

 

4.4       Special warnings and precautions for use

               

Added

 

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.

 

4.8       Undesirable effects

 

Added

 

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

 

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

 

Deleted

 

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

 

Added

 

Cases of radiation pneumonitis have been reported in patients treated with radiation either prior, during or subsequent to their pemetrexed therapy (see section 4.4).

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date

 

31 October 2007

5.             PHARMACOLOGICAL PROPERTIES

 

5.3          Preclinical safety data

               

Added

 

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.

 

10.          DATE OF REVISION OF THE TEXT

 

New date

2.             QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Added:

 

Excipients: For a full list of excipients see section 6.1.

 

Removed:

 

For excipients, see section 6.1.

 

4.             CLINICAL PARTICULARS

 

4.2          Posology and method of administration

 

Table 1 (second line) amended.

 

From:

 

Nadir platelets £50,000/mm3 regardless of nadir ANC

50% of previous dose (both Alimta and cisplatin)

 

To:

 

Nadir platelets <50,000/mm3 regardless of nadir ANC

50% of previous dose (both Alimta and cisplatin)

 

Added (new text in bold):

 

Children and adolescents: Alimta is not recommended for use in children below 18 years of age due to insufficient data on safety and efficacy.

 

Removed:

 

Children and adolescents: Alimta is not recommended for use in patients under 18 years of age, as safety and efficacy have not been established in this group of patients.

 

4.3          Contra-indications

 

Added (new text in bold):

 

Hypersensitivity to the active substance or to any of the excipients.

 

Removed:

 

Hypersensitivity to pemetrexed or to any of the excipients.

 

4.4          Special warnings and precautions for use

 

Added:

 

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.

 

Added (new text in bold):

 

Immunodepressed status is common in cancer patients.  As a result, concomitant use of live attenuated vaccines (except yellow fever, which is contra-indicated) is not recommended (see section 4.3 and section 4.5).

 

4.6          Pregnancy and lactation

 

Added (new text in bold):

 

It is not known whether pemetrexed is excreted in human milk and adverse reactions on the suckling child cannot be excluded.  Breast-feeding must be discontinued during pemetrexed therapy (see section 4.3).

 

Removed:

 

It is not known whether pemetrexed is excreted in human milk and adverse effects on the suckling child cannot be excluded.  Breast-feeding must be discontinued during pemetrexed therapy (see section 4.3).

 

4.8          Undesirable effects

 

Added:

 

Adverse Reactions

 

Frequency estimate: Very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1,000 and <1/100), rare (≥1/10,000 and <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from available data – spontaneous reports).

 

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

 

Re-ordered tables (actual data unchanged).

 

Re-ordered text in following sentence (changes in bold):

 

Clinically relevant CTC toxicities that were reported in >1% and <5% (common) of the patients that were randomly assigned to receive cisplatin and pemetrexed include: renal failure, infection, pyrexia, febrile neutropenia, increased AST, ALT, and GGT, urticaria, and chest pain.

 

Re-ordered text in following sentence (changes in bold):

 

Clinically relevant CTC toxicities that were reported in >1% and <5% (common) of the patients that were randomly assigned to pemetrexed include: infection without neutropenia, febrile neutropenia, allergic reaction/hypersensitivity, increased creatinine, motor neuropathy, sensory neuropathy, erythema multiforme, and abdominal pain.

 

Added:

 

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

 

6.             PHARMACEUTICAL PARTICULARS

 

6.3          Shelf-life

 

Added:

 

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 or 25°C.  From a microbiological point of view, the product should be used immediately.  If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

 

6.4                Special precautions for storage

 

Added:

 

For storage conditions of the reconstituted medicinal product see section 6.3.

 

Removed:

 

Reconstituted and infusion solutions: When prepared as directed, reconstitution 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 or 25°C.  From a microbiological point of view, the product should be used immediately.  If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

 

6.6          Special precautions for disposal and other handling (change of title)

 

10.          DATE OF REVISION OF THE TEXT

 

New date:

 

26 January 2007