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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
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