Clinical Trials Experience

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

Non-Small Cell Lung Cancer (NSCLC)

ALIMTA in Combination with Cisplatin

Table 4 provides the frequency and severity of adverse reactions that have been reported in > 5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. 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.

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLC^a

No clinically relevant differences in adverse reactions were seen in patients based on histology.

In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm.

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5%

Body as a Whole — febrile neutropenia, infection, pyrexia

General Disorders — dehydration

Metabolism and Nutrition — increased AST, increased ALT

Renal — creatinine clearance decrease, renal failure

Special Senses — conjunctivitis

Incidence Less than 1%

Cardiovascular — arrhythmia

General Disorders — chest pain

Metabolism and Nutrition — increased

GGT Neurology — motor neuropathy

Non-Small Cell Lung Cancer (NSCLC) – Maintenance

ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based Induction Therapy

Table 5 provides the frequency and severity of adverse reactions reported in > 5% of the 438 patients with NSCLC who received ALIMTA maintenance and the 218 patients with NSCLC who received placebo following a platinum-based induction therapy.

All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B₁₂.

Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLC^a Following Platinum-Based Induction Therapy

No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%).

Safety was assessed by exposure for patients who received at least one dose of ALIMTA (N=438). The incidence of adverse reactions was evaluated for patients who received ≤ 6 cycles of ALIMTA, and compared to patients who received > 6 cycles of ALIMTA. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences in Grade 3/4 adverse reactions were seen.

Consistent with the higher incidence of anemia (all grades) on the ALIMTA arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to the placebo arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).

The following additional adverse reactions were observed in patients with non-small cell lung cancer who received ALIMTA.

Incidence 1% to 5%

Dermatology/Skin — alopecia, pruritis/itching

Gastrointestinal — constipation

General Disorders — edema, fever (in the absence of neutropenia)

Hematologic — thrombocytopenia

Renal — decreased creatinine clearance, increased creatinine, decreased glomerular filtration rate

Special Senses — ocular surface disease (including conjunctivitis), increased lacrimation

Incidence Less than 1%

Cardiovascular — supraventricular arrhythmia

Dermatology/Skin — erythema multiforme

General Disorders — febrile neutropenia, allergic reaction/hypersensitivity

Neurology — motor neuropathy

Renal — renal failure

Continuation of ALIMTA as Maintenance Following ALIMTA Plus Platinum Induction Therapy

Table 6 provides the frequency and severity of adverse reactions reported in > 5% of the 500 patients with non-squamous NSCLC who received at least one cycle of ALIMTA maintenance (n=333) or placebo (n=167) on the continuation maintenance trial.

The median of maintenance cycles administered to patients receiving one or more doses of maintenance therapy was 4 on both the pemetrexed and placebo arms. Dose reductions for adverse events occurred in 3.3% of patients in the ALIMTA arm and 0.6% in the placebo arm. Dose delays for adverse events occurred in 22% of patients in the ALIMTA arm and 16% in the placebo arm. Patients in both study arms were supplemented with folic acid and vitamin B₁₂.

Table 6: Selected^a Adverse Reactions^b Occurring in ≥ 5% of Patients Receiving ALIMTA in Nonsquamous NSCLC Following ALIMTA Plus Cisplatin Induction Therapy

Administration of RBC (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0) were higher in the ALIMTA arm compared to the placebo arm.

The following additional Grade 3 or 4 adverse reactions were observed more frequently in the ALIMTA arm.

Incidence 1% to 5%

Blood/Bone Marrow — thrombocytopenia

General Disorders — febrile neutropenia

Incidence Less than 1%

Cardiovascular — ventricular tachycardia, syncope

General Disorders — pain

Gastrointestinal — gastrointestinal obstruction

Neurologic — depression

Renal — renal failure

Vascular — pulmonary embolism

Non-Small Cell Lung Cancer (NSCLC) – After Prior Chemotherapy

Table 7 provides the frequency and severity of adverse reactions that have been reported in > 5% of 265 patients randomly assigned to receive single-agent ALIMTA with folic acid and vitamin B₁₂ supplementation and 276 patients randomly assigned to receive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received prior chemotherapy.

Table 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLC^a

No clinically relevant differences in adverse reactions were seen in patients based on histology.

Clinically relevant adverse reactions occurring in < 5% of patients that received ALIMTA treatment but > 5% of patients that received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% ALIMTA, 12.7% docetaxel).

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA.

Incidence 1% to 5%

Body as a Whole — abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection

Dermatology/Skin — erythema multiforme

Neurology — motor neuropathy, sensory neuropathy

Renal — increased creatinine

Incidence Less than 1%

Cardiovascular — supraventricular arrhythmias Malignant Pleural Mesothelioma (MPM)

Table 8 provides the frequency and severity of adverse reactions that have been reported in > 5% of 168 patients with mesothelioma who were randomly assigned to receive cisplatin and ALIMTA and 163 patients with mesothelioma randomly assigned to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B₁₂.

Table 8: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPM^a

The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5%

Body as a Whole — febrile neutropenia, infection, pyrexia

Dermatology/Skin — urticaria

General Disorders — chest pain

Metabolism and Nutrition — increased AST, increased ALT, increased GGT

Renal — renal failure

Incidence Less than 1%

Cardiovascular — arrhythmia

Neurology — motor neuropathy

Effects of Vitamin Supplementations on Toxicity

Table 9 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients who received vitamin supplementation with daily folic acid and vitamin B₁₂ from the time of enrollment in the study (fully supplemented) with the incidence in patients who never received vitamin supplementation (never supplemented) during the study in the ALIMTA plus cisplatin arm.

Table 9: Selected Grade 3/4 Adverse Events Comparing Fully Supplemented versus Never Supplemented Patients in the ALIMTA plus Cisplatin arm (% incidence)

The following adverse events were greater in the fully supplemented group compared to the never supplemented group: hypertension (11%, 3%), chest pain (8%, 6%), and thrombosis/embolism (6%, 3%).

No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%).

Additional Experience Across Clinical Trials

Sepsis, which in some cases was fatal, occurred in approximately 1% of patients.

Esophagitis occurred in less than 1% of patients.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ALIMTA. 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 occurred with ALIMTA when used as a single-agent and in combination therapies.

Gastrointestinal — colitis, pancreatitis

General Disorders and Administration Site Conditions — edema

Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously received radiotherapy.

Respiratory — interstitial pneumonitis

Skin — Bullous conditions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Some cases were fatal.

Read the Alimta (pemetrexed) Side Effects Center for a complete guide to possible side effects »

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥ 80 mL/min). No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function [see CLINICAL PHARMACOLOGY].

Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min).

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided 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 (e.g., meloxicam, nabumetone), 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 NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.

Nephrotoxic Drugs

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.

Last reviewed on RxList: 10/25/2012
This monograph has been modified to include the generic and brand name in many instances.