Pemex Adverse Reactions

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 Pemetrexed as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with Pemetrexed when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.
Foreign Clinical Trials Experience: Non-Small Cell Lung Cancer (NSCLC) - Combination Use 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 pemetrexed 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. (See Table 4.)

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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 Pemetrexed and Cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the pemetrexed 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 pemetrexed 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: Table 5 provides the frequency and severity of adverse reactions reported in >5% of the 438 patients with NSCLC who received pemetrexed 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. (See Table 5.)

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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 pemetrexed (N=438). 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 clinically relevant differences in Grade 3/4 adverse reactions were seen.
Consistent with the higher incidence of anemia (all grades) on the pemetrexed arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the pemetrexed 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 pemetrexed.
Incidence 1% to 5%: Dermatology/Skin: alopecia, pruritus/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.
Non-Small Cell Lung Cancer (NSCLC) - After Prior Chemotherapy: Table 6 provides the frequency and severity of adverse reactions that have been reported in >5% of 265 patients randomly assigned to receive single-agent pemetrexed 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. (See Table 6.)

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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 pemetrexed treatment but >5% of patients that received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% pemetrexed, 12.7% docetaxel).
The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive pemetrexed.
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) - Combination Use with Cisplatin: Table 7 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 pemetrexed and 163 patients with mesothelioma randomly assigned to receive single-agent cisplatin. In both treatment arms, these chemo naive patients were fully supplemented with folic acid and vitamin B₁₂. (See Table 7.)

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The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive pemetrexed 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 8 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 pemetrexed plus cisplatin arm. (See Table 8.)

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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%).
Subpopulations: No relevant effect for pemetrexed 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 in Foreign Countries: The following adverse reactions have been identified during post-approval use of pemetrexed. 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 pemetrexed when used as a single-agent and in combination therapies.
Gastrointestinal: colitis.
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.
Experience of Chinese Patients: Table 9 provides Pemetrexed (ALIMTA) produced by LILLY did a research as second line drug for NSCLC (JMID). There were 106 Pemetrexed patients and 102 Docetaxel patients. The Incidence ≥2% may relate to patients in group is CTC Grade 3/4 toxic. (See Table 9.)

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Table 10 provides the frequency and severity of adverse reactions that have been reported in >5% of Chinese patients receiving pemetrexed (ALIMTA) for NSCLC maintain Globe clinical research for registering (JMEN) used CTCAE grades. (See Table 10.)

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