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Alimta (Pemetrexed Disodium) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

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 NSCLCa

a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.

b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity.

c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

Reactionb ALIMTA/cisplatin
(N=839)
Gemcitabine/cisplatin
(N=830)
All Grades
Toxicity (%)
Grade 3-4
Toxicity (%)
All Grades
Toxicity (%)
Grade 3-4
Toxicity (%)
All Adverse Reactions 90 37 91 53
 Laboratory
  Hematologic
   Anemia 33 6 46 10
   Neutropenia 29 15 38 27
   Leukopenia 18 5 21 8
   Thrombocytopenia 10 4 27 13
  Renal
   Creatinine elevation 10 1 7 1
 Clinical
  Constitutional Symptoms
   Fatigue 43 7 45 5
  Gastrointestinal
   Nausea 56 7 53 4
   Vomiting 40 6 36 6
   Anorexia 27 2 24 1
   Constipation 21 1 20 0
   Stomatitis/Pharyngitis 14 1 12 0
   Diarrhea 12 1 13 2
   Dyspepsia/Heartburn 5 0 6 0
  Neurology
   Neuropathy-sensory 9 0 12 1
   Taste disturbance 8 0c 9 0c
  Dermatology/Skin
   Alopecia 12 0c 21 1c
   Rash/Desquamation 7 0 8 1

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 NSCLCa Following Platinum-Based Induction Therapy

a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.

b Refer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity.

ALIMTA
(N=438)
Placebo
(N=218)
Reactionb All Grades
Toxicity (%)
Grade 3-4
Toxicity (%)
All Grades
Toxicity (%)
Grade 3-4
Toxicity (%)
All Adverse Reactions 66 16 37 4
 Laboratory
  Hematologic
  Anemia 15 3 6 1
  Neutropenia 6 3 0 0
  Leukopenia 6 2 1 1
 Hepatic
  Increased ALT 10 0 4 0
  Increased AST 8 0 4 0
 Clinical
 Constitutional Symptoms
  Fatigue 25 5 11 1
 Gastrointestinal
  Nausea 19 1 6 1
  Anorexia 19 2 5 0
  Vomiting 9 0 1 0
  Mucositis/stomatitis 7 1 2 0
  Diarrhea 5 1 3 0
 Infection 5 2 2 0
 Neurology
  Neuropathy-sensory 9 1 4 0
 Dermatology/Skin
  Rash/Desquamation 10 0 3 0

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: Selecteda Adverse Reactionsb Occurring in ≥5% of Patients Receiving ALIMTA in Nonsquamous NSCLC Following ALIMTA Plus Cisplatin Induction Therapy

a Adverse reactions of any severity (all grades) occurring more frequently (≥5%) or Grade 3-4 adverse reactions occurring more frequently (≥2%) in ALIMTA-treated patients compared to those receiving placebo.

b NCI CTCAE Criteria version 3.0

Adverse Reaction Organ System and Term ALIMTA
(N=333)
Placebo
(N=167)
All Gradesa
Toxicity (%)
Grade 3-4a
Toxicity (%)
All Gradesa
Toxicity (%)
Grades 3-4a
Toxicity (%)
All Adverse Reactions 53 17 34 4.8
 Laboratory
  Hematologic
   Anemia 15 4.8 4.8 0.6
   Neutropenia 9 3.9 0.6 0
 Clinical
  Constitutional Symptoms
   Fatigue 18 4.5 11 0.6
  Gastrointestinal
   Nausea 12 0.3 2.4 0
   Vomiting 6 0 1.8 0
   Mucositis/stomatitis 5 0.3 2.4 0
  General Disorders
   Edema 5 0 3.6 0

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 NSCLCa

a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.

b Refer to NCI CTC Criteria for lab values for each Grade of toxicity (version 2.0).

c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

ALIMTA
(N=265)
Docetaxel
(N=276)
Reactionb All Grades
Toxicity (%)
Grades 3-4
Toxicity (%)
All Grades
Toxicity (%)
Grades 3-4
Toxicity (%)
 Laboratory
  Hematologic
   Anemia 19 4 22 4
   Leukopenia 12 4 34 27
   Neutropenia 11 5 45 40
   Thrombocytopenia 8 2 1 0
  Hepatic
   Increased ALT 8 2 1 0
   Increased AST 7 1 1 0
 Clinical
  Gastrointestinal
   Nausea 31 3 17 2
   Anorexia 22 2 24 3
   Vomiting 16 2 12 1
   Stomatitis/Pharyngitis 15 1 17 1
   Diarrhea 13 0 24 3
   Constipation 6 0 4 0
  Constitutional Symptoms
   Fatigue 34 5 36 5
   Fever 8 0 8 0
  Dermatology/Skin
   Rash/Desquamation 14 0 6 0
   Pruritis 7 0 2 0
   Alopecia 6 1c 38 2c

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 MPMa

a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.

b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity except the term “creatinine clearance decreased” which is derived from the CTC term “renal/genitourinary-other”.

c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

ALIMTA/cisplatin
(N=168)
Cisplatin
(N=163)
Reactionb All Grades Toxicity (%) Grade 3-4 Toxicity (%) All Grades Toxicity (%) Grade 3-4 Toxicity (%)
 Laboratory
  Hematologic
   Neutropenia 56 23 13 3
   Leukopenia 53 15 17 1
   Anemia 26 4 10 0
   Thrombocytopenia 23 5 9 0
  Renal
   Creatinine elevation 11 1 10 1
   Creatinine clearance decreased 16 1 18 2
 Clinical
  Eye Disorder
   Conjunctivitis 5 0 1 0
  Gastrointestinal
   Nausea 82 12 77 6
   Vomiting 57 11 50 4
   Stomatitis/Pharyngitis 23 3 6 0
   Anorexia 20 1 14 1
   Diarrhea 17 4 8 0
   Constipation 12 1 7 1
   Dyspepsia 5 1 1 0
  Constitutional Symptoms
   Fatigue 48 10 42 9
  Metabolism and Nutrition
   Dehydration 7 4 1 1
  Neurology
   Neuropathy-sensory 10 0 10 1
   Taste Disturbance 8 0c 6 0c
  Dermatology/Skin
   Rash 16 1 5 0
   Alopecia 11 0c 6 0c

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)

a Refer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.0).

Adverse Eventa (%) Fully Supplemented Patients
(N=168)
Never Supplemented Patients
(N=32)
Neutropenia/granulocytopenia 23 38
Thrombocytopenia 5 9
Vomiting 11 31
Febrile neutropenia 1 9
Infection with Grade 3/4 neutropenia 0 6
Diarrhea 4 9

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.

Blood and Lymphatic System — immune-mediated hemolytic anemia

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.



REPORTS OF SUSPECTED ALIMTA SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Alimta. The information is not vetted and should not be considered as verified clinical evidence.

Possible Alimta side effects / adverse reactions in 70 year old male

Reported by a physician from China on 2011-10-05

Patient: 70 year old male

Reactions: White Blood Cell Count Decreased, Escherichia Test Positive, Counterfeit Drug Administered

Suspect drug(s):
Alimta

Other drugs received by patient: Dexamethasone; Folic Acid; Cisplatin; Vitamin B-12



Possible Alimta side effects / adverse reactions in 65 year old female

Reported by a consumer/non-health professional from Japan on 2011-10-07

Patient: 65 year old female

Reactions: Tympanic Membrane Perforation

Suspect drug(s):
Alimta

Other drugs received by patient: Cisplatin; Vitamin B-12; Folic Acid



Possible Alimta side effects / adverse reactions in 56 year old male

Reported by a physician from Japan on 2011-10-11

Patient: 56 year old male

Reactions: Death

Adverse event resulted in: death

Suspect drug(s):
Alimta
    Dosage: dosage is uncertain.
    Indication: non-Small Cell Lung Cancer

Avastin
    Indication: non-Small Cell Lung Cancer
    Start date: 2011-02-01
    End date: 2011-04-01

Cisplatin
    Dosage: dosage is uncertain.
    Indication: non-Small Cell Lung Cancer



See index of all Alimta side effect reports >>

Drug label data at the top of this Page last updated: 2013-09-12

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