Alimta (Pemetrexed disodium) is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions of Alimta (Pemetrexed disodium) . The use of gloves is recommended. If a solution of Alimta (Pemetrexed disodium) contacts the skin, wash the skin immediately and thoroughly with soap and water. If Alimta (Pemetrexed disodium) contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available

Alimta (Pemetrexed disodium) is not a vesicant. There is no specific antidote for extravasation of Alimta (Pemetrexed disodium) . To date, there have been few reported cases of Alimta (Pemetrexed disodium) extravasation, which were not assessed as serious by the investigator. Alimta (Pemetrexed disodium) extravasation should be managed with local standard practice for extravasation as with other non-vesicants.

Alimta (Pemetrexed disodium) , pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

Alimta (Pemetrexed disodium) is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

Alimta (Pemetrexed disodium) 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
One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B died of drug-related toxicity following administration of Alimta (Pemetrexed disodium) alone.

Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with Alimta (Pemetrexed disodium) as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with Alimta (Pemetrexed disodium) when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

The following adverse reactions have been identified during post-approval use of Alimta (Pemetrexed disodium) . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These reactions have occurred with Alimta (Pemetrexed disodium) when used as a single-agent and in combination therapies.

Gastrointestinal
General Disorders and Administration Site Conditions
Injury, poisoning, and procedural complications
Respiratory
Skin

Efficacy of Alimta (Pemetrexed disodium) in pediatric patients has not been demonstrated. Alimta (Pemetrexed disodium) was administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All patients received pretreatment with vitamin B and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m and this dose (or 60 mg/kg for patients
The single dose pharmacokinetics of Alimta (Pemetrexed disodium) administered in doses ranging from 400 to 2480 mg/m were evaluated in the Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and C) appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m) and half-life (2.3 hours) in pediatric patients were comparable to values reported in adults.

Alimta (Pemetrexed disodium) is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Renal function monitoring is recommended with administration of Alimta (Pemetrexed disodium) . No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older

In the initial treatment non-small cell lung cancer clinical trial, 37.7% of patients treated with Alimta (Pemetrexed disodium) plus cisplatin were ≥65 years and Grade 3/4 neutropenia was greater as compared to patients
In the maintenance non-small cell lung cancer trial 33.3% of patients treated with Alimta (Pemetrexed disodium) were ≥65 years and no differences were seen in Grade 3/4 adverse reactions as compared to patients
In the non-small cell lung cancer trial after prior chemotherapy, 29.7% patients treated with Alimta (Pemetrexed disodium) were ≥65 years and Grade 3/4 hypertension was greater as compared to patients
The mesothelioma trial included 36.7% patients treated with Alimta (Pemetrexed disodium) plus cisplatin that were ≥65 years, and Grade 3/4 fatigue, leukopenia, neutropenia, and thrombocytopenia were greater as compared to patients
There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed

Dose adjustments based on hepatic impairment experienced during treatment with Alimta (Pemetrexed disodium) are provided in

In the initial treatment non-small cell lung cancer trial, 70% of patients were males and 30% females. For males the HR for overall survival was 0.97 (95% CI: 0.85, 1.10) and for females the HR was 0.86 (95% CI: 0.70, 1.06) in the intent to treat population.

In the maintenance non-small cell lung cancer trial, 73% of patients were males and 27% females. For males the HR for overall survival was 0.78 (95% CI: 0.63, 0.96) and for females the HR was 0.83 (95% CI: 0.56, 1.21) in the intent to treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 72% of patients were males and 28% females. For males the HR for overall survival was 0.95 (95% CI: 0.76, 1.19) and for females the HR was 1.28 (95% CI: 0.86, 1.91) in the intent to treat population.

In the mesothelioma trial, 82% of patients were males and 18% females. For males the HR for overall survival was 0.85 (95% CI: 0.66, 1.09) and for females the HR was 0.48 (95% CI: 0.27, 0.85) in the intent to treat population.

In the initial treatment non-small cell lung cancer trial, 78% of patients were Caucasians, 13% East/Southeast Asians, and 9% others. For Caucasians, the HR for overall survival was 0.92 (95% CI: 0.82, 1.04), for East/Southeast Asians the HR was 0.86 (95% CI: 0.61, 1.21), and for others the HR was 1.24 (95% CI: 0.84, 1.84) in the intent to treat population.

In the maintenance non-small cell lung cancer trial, 65% of patients were Caucasians, 23% East Asian, and 12% others. For Caucasians the HR for overall survival was 0.77 (95% CI: 0.62, 0.97), for East Asians was 1.05 (95% CI: 0.70, 1.59) and for others the HR was 0.46 (95% CI: 0.26, 0.79) in the intent to treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 71% of patients were Caucasians and 29% others. For Caucasians the HR for overall survival was 0.91 (95% CI: 0.73, 1.15) and for others the HR was 1.27 (95% CI: 0.87, 1.87) in the intent to treat population.

In the mesothelioma trial, 92% of patients were Caucasians and 8% others. For Caucasians, the HR for overall survival was 0.77 (95% CI: 0.61, 0.97) and for others the HR was 0.86 (95% CI: 0.39, 1.90) in the intent to treat population.

There have been few cases of Alimta (Pemetrexed disodium) overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m, intravenously once, followed by leucovorin, 50 mg/m, intravenously every 6 hours for 8 days.

The ability of Alimta (Pemetrexed disodium) to be dialyzed is unknown.

Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, -[4-[2-(2-amino-4,7-dihydro-4-oxo-1-pyrrolo[2,3-]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. It is a white to almost-white solid with a molecular formula of CHNNaO•7HO and a molecular weight of 597.49. The structural formula is as follows:

Alimta (Pemetrexed disodium) is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials. The product is a white to either light yellow or green-yellow lyophilized solid. Each 100-mg or 500-mg vial of Alimta (Pemetrexed disodium) contains pemetrexed disodium equivalent to 100 mg pemetrexed and 106 mg mannitol or 500 mg pemetrexed and 500 mg mannitol, respectively. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.

Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052). Studies with the MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin.

Absolute neutrophil counts (ANC) following single-agent administration of Alimta (Pemetrexed disodium) to patients not receiving folic acid and vitamin B supplementation were characterized using population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the depth of the ANC nadir, correlates with the systemic exposure, or area under the curve (AUC) of pemetrexed. It was also observed that lower ANC nadirs occurred in patients with elevated baseline cystathionine or homocysteine concentrations. The levels of these substances can be reduced by folic acid and vitamin B supplementation. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.

Time to ANC nadir with pemetrexed systemic exposure (AUC), varied between 8 to 9.6 days over a range of exposures from 38.3 to 316.8 mcg•hr/mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures.

A multi-center, randomized, open-label study in 1725 chemonaive patients with Stage IIIb/IV NSCLC was conducted to compare the overall survival following treatment with Alimta (Pemetrexed disodium) in combination with cisplatin (AC) versus gemcitabine in combination with cisplatin (GC). Alimta (Pemetrexed disodium) was administered intravenously over 10 minutes at a dose of 500 mg/m with cisplatin administered intravenously at a dose of 75 mg/m after Alimta (Pemetrexed disodium) administration, on Day 1 of each 21-day cycle. Gemcitabine was administered at a dose of 1250 mg/m on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m after administration of gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles, and patients in both treatment arms received folic acid, vitamin B, and dexamethasone

Patient demographics of the intent to treat (ITT) population are shown in . The demographics and disease characteristics were well balanced.

Patients received a median of 5 cycles of treatment in both study arms. Patients treated with Alimta (Pemetrexed disodium) plus cisplatin received a relative dose intensity of 94.8% of the protocol-specified Alimta (Pemetrexed disodium) dose intensity and 95.0% of the protocol-specified cisplatin dose intensity. Patients treated with gemcitabine plus cisplatin received a relative dose intensity of 85.8% of the protocol-specified gemcitabine dose intensity and 93.5% of the protocol-specified cisplatin dose intensity.

The primary endpoint in this study was overall survival. The median survival time was 10.3 months in the Alimta (Pemetrexed disodium) plus cisplatin treatment arm and 10.3 months in the gemcitabine plus cisplatin arm, with an adjusted hazard ratio of 0.94.

A pre-specified analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences in survival according to histology were observed and are shown in . This difference in treatment effect for Alimta (Pemetrexed disodium) based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in the single-agent, second-line study and the maintenance study

A multi-center, randomized, double-blind, placebo-controlled study was conducted in 663 patients with Stage IIIb/IV NSCLC who did not progress after four cycles of platinum-based chemotherapy. Patients who did not progress were randomized 2:1 to receive Alimta (Pemetrexed disodium) or placebo immediately following platinum-based chemotherapy. Alimta (Pemetrexed disodium) was administered intravenously over 10 minutes at a dose of 500 mg/m on Day 1 of each 21-day cycle, until disease progression. Patients in both study arms received folic acid, vitamin B , and dexamethasone .

The study was designed to demonstrate superior progression-free survival and overall survival of Alimta (Pemetrexed disodium) over placebo. Progression-free survival (PFS) was assessed by independent review. Patient characteristics of the intent to treat (ITT) population are shown in . The demographics and baseline disease characteristics were well balanced between study arms.

Patients received a median of 5 cycles of Alimta (Pemetrexed disodium) and 3.5 cycles of placebo. Patients randomized to Alimta (Pemetrexed disodium) received a relative dose intensity of 95.7%. A total of 213 patients (48.3%) completed ≥6 cycles and a total of 98 patients (22.6%) completed ≥10 cycles of treatment with Alimta (Pemetrexed disodium) .

In the overall study population, Alimta (Pemetrexed disodium) was statistically superior to placebo in terms of overall survival (OS) (median 13.4 months versus 10.6 months, HR=0.79 (95% CI: 0.65-0.95), p-value=0.012) and PFS (median 4.0 months versus 2.0 months, HR=0.60 (95% CI: 0.49-0.73), p-value
Efficacy results for the overall patient population are presented in and , and efficacy results by pre-specified histologic subgroups are presented in and , below.

A multi-center, randomized, open label study was conducted in patients with Stage III or IV NSCLC after prior chemotherapy to compare the overall survival following treatment with Alimta (Pemetrexed disodium) versus docetaxel. Alimta (Pemetrexed disodium) was administered intravenously over 10 minutes at a dose of 500 mg/m and docetaxel was administered at 75 mg/m as a 1-hour intravenous infusion. Both drugs were given on Day 1 of each 21-day cycle. All patients treated with Alimta (Pemetrexed disodium) received vitamin supplementation with folic acid and vitamin B . The study was intended to show either an overall survival superiority or non-inferiority of Alimta (Pemetrexed disodium) to docetaxel. Patient demographics of the intent to treat (ITT) population are shown in .

The primary endpoint in this study was overall survival. The median survival time was 8.3 months in the Alimta (Pemetrexed disodium) treatment arm and 7.9 months in the docetaxel arm, with a hazard ratio of 0.99 (see ). The study did not show an overall survival superiority of Alimta (Pemetrexed disodium) .

A retrospective analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences in survival according to histology were observed and are shown in Table 17. This difference in treatment effect for Alimta (Pemetrexed disodium) based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in the first-line combination study and in the maintenance study .

A multi-center, randomized, single-blind study in 448 chemonaive patients with malignant pleural mesothelioma (MPM) compared survival in patients treated with Alimta (Pemetrexed disodium) in combination with cisplatin to survival in patients receiving cisplatin alone. Alimta (Pemetrexed disodium) was administered intravenously over 10 minutes at a dose of 500 mg/m and cisplatin was administered intravenously over 2 hours at a dose of 75 mg/m beginning approximately 30 minutes after the end of administration of Alimta (Pemetrexed disodium) . Both drugs were given on Day 1 of each 21-day cycle. After 117 patients were treated, white cell and GI toxicity led to a change in protocol whereby all patients were given folic acid and vitamin B supplementation.

The primary analysis of this study was performed on the population of all patients randomly assigned to treatment who received study drug (randomized and treated). An analysis was also performed on patients who received folic acid and vitamin B supplementation during the entire course of study therapy (fully supplemented), as supplementation is recommended . Results in all patients and those fully supplemented were similar. Patient demographics are shown in .

Similar results were seen in the analysis of patients (N=303) with confirmed histologic diagnosis of malignant pleural mesothelioma. There were too few non-white patients to assess possible ethnic differences. The effect in women (median survival 15.7 months with the combination versus 7.5 months on cisplatin alone), however, was larger than the effect in males (median survival 11 versus 9.4 respectively). As with any exploratory analysis, it is not clear whether this difference is real or is a chance finding.

Objective tumor response for malignant pleural mesothelioma is difficult to measure and response criteria are not universally agreed upon. However, based upon prospectively defined criteria, the objective tumor response rate for Alimta (Pemetrexed disodium) plus cisplatin was greater than the objective tumor response rate for cisplatin alone. There was also improvement in lung function (forced vital capacity) in the Alimta (Pemetrexed disodium) plus cisplatin arm compared to the control arm.

Patients who received full supplementation with folic acid and vitamin B during study therapy received a median of 6 and 4 cycles in the Alimta (Pemetrexed disodium) /cisplatin (N=168) and cisplatin (N=163) arms, respectively. Patients who never received folic acid and vitamin B during study therapy received a median of 2 cycles in both treatment arms (N=32 and N=38 for the Alimta (Pemetrexed disodium) /cisplatin and cisplatin arm, respectively). Patients receiving Alimta (Pemetrexed disodium) in the fully supplemented group received a relative dose intensity of 93% of the protocol specified Alimta (Pemetrexed disodium) dose intensity; patients treated with cisplatin in the same group received 94% of the projected dose intensity. Patients treated with cisplatin alone had a dose intensity of 96%.

Alimta (Pemetrexed disodium) , pemetrexed for injection, is available in sterile single-use vials containing 100 mg pemetrexed.

   NDC 0002-7640-01 (VL7640): single-use vial with ivory flip-off cap individually packaged in a carton.

Alimta (Pemetrexed disodium) , pemetrexed for injection, is available in sterile single-use vials containing 500 mg pemetrexed.

   NDC 0002-7623-01 (VL7623): single-use vial with ivory flip-off cap individually packaged in a carton.

Alimta (Pemetrexed disodium) , pemetrexed for injection, should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Chemical and physical stability of reconstituted and infusion solutions of Alimta (Pemetrexed disodium) were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated, 2-8°C (36-46°F), or at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. When prepared as directed, reconstituted and infusion solutions of Alimta (Pemetrexed disodium) contain no antimicrobial preservatives. Discard unused portion

Alimta (Pemetrexed disodium) is not light sensitive.

See FDA-Approved Patient Labeling (PPI)

Patients should be instructed to read the patient package insert carefully.