DECREASED RENAL FUNCTION
ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance >/=45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min (see Dose Reduction Recommendations under DOSAGE AND ADMINISTRATION).
One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.
BONE MARROW SUPPRESSION
ALIMTA can suppress bone marrow function, manifested by neutropenia, thrombocytopenia, and anemia (see ADVERSE REACTIONS); myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle (see Dose Reduction Recommendations under DOSAGE AND ADMINISTRATION).
NEED FOR FOLATE AND VITAMIN B12 SUPPLEMENTATION
Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity (see DOSAGE AND ADMINISTRATION). In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered.
PREGNANCY CATEGORY D
ALIMTA may cause fetal harm when administered to a pregnant woman. Pemetrexed was fetotoxic and teratogenic in mice at i.p. doses of 0.2 mg/kg (0.6 mg/m2) or 5 mg/kg (15 mg/m2) when given on gestation days 6 through 15. Pemetrexed caused fetal malformations (incomplete ossification of talus and skull bone) at 0.2 mg/kg (about 1/833 the recommended i.v. human dose on a mg/m2 basis), and cleft palate at 5 mg/kg (about 1/33 the recommended i.v. human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. There are no studies of ALIMTA in pregnant women. Patients should be advised to avoid becoming pregnant. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking ALIMTA, the patient should be apprised of the potential hazard to the fetus.
ALIMTA should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. Treatment-related adverse events of ALIMTA seen in clinical trials have been reversible. Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction (see DOSAGE AND ADMINISTRATION).
The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.
Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is >/=1500 cells/mm3, the platelet count is >/=100,000 cells/mm3, and creatinine clearance is >/=45 mL/min.
ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA.
Although ibuprofen (400 mg qid) can be administered with ALIMTA in patients with normal renal function (creatinine clearance >/=80 mL/min), caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA.
In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.
DRUG/LABORATORY TEST INTERACTIONS
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.
Pregnancy Category D (see WARNINGS).
It is not known whether ALIMTA or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ALIMTA, it is recommended that nursing be discontinued if the mother is treated with ALIMTA.
The safety and effectiveness of ALIMTA in pediatric patients have not been established.
Dose adjustments based on age other than those recommended for all patients have not been necessary (see Special Populations under CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Dose adjustments based on gender other than those recommended for all patients have not been necessary (see Special Populations under CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
PATIENTS WITH HEPATIC IMPAIRMENT
Patients with bilirubin >1.5 times the upper limit of normal were excluded from clinical trials of ALIMTA. Patients with transaminase >3.0 times the upper limit of normal were routinely excluded from clinical trials if they had no evidence of hepatic metastases. Patients with transaminase from 3 to 5 times the upper limit of normal were included in the clinical trial of ALIMTA if they had hepatic metastases.
Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 9 (see Special Populations under CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
PATIENTS WITH RENAL IMPAIRMENT
ALIMTA is known to be primarily excreted by the kidney. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment (see Special Populations under CLINICAL PHARMACOLOGY).
PREPARATION AND ADMINISTRATION PRECAUTIONS
As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions of ALIMTA. The use of gloves is recommended. If a solution of ALIMTA contacts the skin, wash the skin immediately and thoroughly with soap and water. If ALIMTA contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available. 1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
ALIMTA is not a vesicant. There is no specific antidote for extravasation of ALIMTA. To date, there have been few reported cases of ALIMTA extravasation, which were not assessed as serious by the investigator. ALIMTA extravasation should be managed with local standard practice for extravasation as with other non-vesicants.
PREPARATION FOR INTRAVENOUS INFUSION ADMINISTRATION
Use aseptic technique during the reconstitution and further dilution of ALIMTA for intravenous infusion administration.
Calculate the dose and the number of ALIMTA vials needed. Each vial contains 500 mg of ALIMTA. The vial contains an excess of ALIMTA to facilitate delivery of label amount.
Reconstitute 500-mg vials with 20 mL of 0.9% Sodium Chloride Injection (preservative free) to give a solution containing 25 mg/mL ALIMTA. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from colorless to yellow or green-yellow without adversely affecting product quality. The pH of the reconstituted ALIMTA solution is between 6.6 and 7.8. FURTHER DILUTION IS REQUIRED.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is observed, do not administer.
The appropriate volume of reconstituted ALIMTA solution should be further diluted to 100 mL with 0.9% Sodium Chloride Injection (preservative free) and administered as an intravenous infusion over 10 minutes.
Chemical and physical stability of reconstituted and infusion solutions of ALIMTA were demonstrated for up to 24 hours following initial reconstitution, when stored at refrigerated or ambient room temperature [see USP Controlled Room Temperature] and lighting. When prepared as directed, reconstitution and infusion solutions of ALIMTA contain no antimicrobial preservatives. Discard any unused portion.
Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection (preservative free). ALIMTA is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection, USP and Ringer's Injection, USP and therefore these should not be used. Coadministration of ALIMTA with other drugs and diluents has not been studied, and therefore is not recommended.