Pemetrexed

Pregnancy Category: D

Lactation: not safe

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Mechanism of Action

Antifolate antineoplastic agent

Disrupts folate-dependent metabolic processes essential for cell replication

Distribution

Vdss: 16.1 L

Protein Bound: 81%

Metabolism

Metabolites: polyglutamate forms

Enzymes inhibited

• Thymidylate synthase
• Dihydrofolate reductase
• Glycinamide ribonucleotide formyltransferase
• All folate-dependent enzymes involved in de novo biosynthesis of thymidine and purine nucleotides

Elimination

Total Body Clearance: 91.8 mL/min

Half-Life, Elimination: 3.5 hr

Excretion: urine

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

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) - 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

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.

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 that have been reported in > 5% of 438 patients with NSCLC who received ALIMTA and 218 patients with NSCLC who received placebo. 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

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.

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

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 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 6: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLCa

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.

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

Dermatology/Skin - erythema multiforme

Neurology - motor neuropathy, sensory neuropathy

Renal - increased creatinine

Cardiovascular - supraventricular arrhythmias

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 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 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPMa

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

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

Cardiovascular - arrhythmia

Neurology - motor neuropathy

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 ALIMTA plus cisplatin arm.

Table 8: 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%).

Post-Marketing 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 have occurred with ALIMTA when used as a single-agent and in combination therapies.

Gastrointestinal - colitis

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

Read the entire FDA prescribing information for Alimta (Pemetrexed)

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of pemetrexed there are no specific foods that you must exclude from your diet when receiving this medication.

Pemetrexed is usually administered by a healthcare provider in a medical setting making it unlikely for an overdose to occur. However, if overdose is suspected, seek emergency medical attention.

Pemetrexed is injected into a vein through an IV. A healthcare provider will give you this injection.

Pemetrexed is usually given every 3 weeks. Your doctor will determine how many treatment cycles you should receive.

To prevent certain side effects of pemetrexed, you will need to take folic acid supplements and receive vitamin B12 injections (starting 7 days before your first dose of pemetrexed). Take only the amount of folic acid that your doctor has prescribed.

Your doctor may also prescribe steroid medication to reduce certain side effects of pemetrexed. Follow your doctor's dosing instructions very carefully.

Pemetrexed can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests.

• LY231514
• Pemetrexed Disodium

Mesothelioma: Treatment of unresectable malignant pleural mesothelioma (in combination with cisplatin)

Non-small cell lung cancer (NSCLC), nonsquamous: Treatment of locally advanced or metastatic nonsquamous NSCLC (as initial treatment in combination with cisplatin; as maintenance treatment after 4 cycles of initial platinum-based first-line therapy; as single-agent treatment after prior chemotherapy)

Limitation of use: Not indicated for the treatment of squamous cell NSCLC

Note: Start vitamin supplements 1 week before initial pemetrexed dose: Folic acid 400 to 1000 mcg daily orally (begin 7 days prior to treatment initiation; continue daily during treatment and for 21 days after last pemetrexed dose) and vitamin B12 1000 mcg IM 7 days prior to treatment initiation and then every 3 cycles. Give dexamethasone 4 mg orally twice daily for 3 days, beginning the day before treatment to minimize cutaneous reactions. New treatment cycles should not begin unless ANC ≥1500/mm3, platelets ≥100,000/mm3, and CrCl ≥45 mL/minute.

Malignant pleural mesothelioma: IV: 500 mg/m2 on day 1 of each 21-day cycle (in combination with cisplatin) or (off-label) in combination with carboplatin (Castagneto 2008; Ceresoli 2006) or (off-label) as single-agent therapy (Taylor 2008)

Non-small cell lung cancer, nonsquamous: IV:

Initial treatment: 500 mg/m2 on day 1 of each 21-day cycle (in combination with cisplatin)

Maintenance or second-line treatment: 500 mg/m2 on day 1 of each 21-day cycle (as a single-agent)

Bladder cancer, metastatic (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle until disease progression or unacceptable toxicity (Sweeney 2006)

Cervical cancer, persistent or recurrent (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle until disease progression or unacceptable toxicity occurs (Lorusso 2010) or 900 mg/m2 on day 1 of each 21-day cycle (Miller 2008)

Ovarian cancer, platinum-resistant (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle (Vergote 2009)

Thymic malignancies, metastatic (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle for 6 cycles or until disease progression or unacceptable toxicity occurs (Loehrer 2006)

Refer to adult dosing.

Applies to pemetrexed: intravenous powder for injection

Cardiovascular

Uncommon (0.1% to 1%): Myocardial infarction, angina pectoris, cerebrovascular accident, transient ischemic attack, peripheral ischemia (sometimes leading to extremity necrosis), supraventricular arrhythmia, ventricular tachycardia, syncope, arrhythmia[Ref]

Dermatologic

Very common (10% or more): Rash/desquamation (up to 16%), alopecia (up to 11%)
Common (1% to 10%): Pruritus, urticaria
Rare (less than 0.1%): Radiation recall, bullous conditions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) which in some cases were fatal[Ref]

Gastrointestinal

Very common (10% or more): Nausea (up to 82%), vomiting (up to 57%), stomatitis/pharyngitis (up to 23%), anorexia (up to 20%), diarrhea (up to 17%), constipation (up to 12%)
Common (1% to 10%): Dyspepsia/heartburn
Uncommon (0.1% to 1%): Colitis (including intestinal and rectal bleeding, sometimes fatal, intestinal perforation, intestinal necrosis, neutropenic enterocolitis), esophagitis/radiation esophagitis, GI obstruction[Ref]

Hematologic

Very common (10% or more): Neutropenia (up to 56%), granulocytopenia (up to 56%), leukopenia (up to 53%), hemoglobinemia (up to 26%), platelets decreased (up to 23%), thrombocytopenia (up to 10%)
Common (1% to 10%):
Uncommon (0.1% to 1%): Pancytopenia
Rare (0.01% to 0.1%): Immune mediated hemolytic anemia[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Allergic reaction/hypersensitivity
Rare (0.01% to 0.1%): Anaphylactic shock[Ref]

Hepatic

Common (1% to 10%): SGPT (ALT) elevation, SGOT (AST) elevation[Ref]

Immunologic

Common (1% to 10%): Sepsis (sometimes fatal), infection[Ref]

Metabolic

Common (1% to 10%): Dehydration
Uncommon (0.1% to 1%): Edema, increased gamma-glutamyl transpeptidase (GGT)[Ref]

Nervous system

Very common (10% or more): Sensory neuropathy (up to 10%)
Common (1% to 10%): Taste disturbance
Uncommon (0.1% to 1%): Motor neuropathy[Ref]

Other

Very common (10% or more): Fatigue (up to 48%), pain
Common (1% to 10%): Fever, chest pain[Ref]

Psychiatric

Uncommon (0.1% to 1%): Depression[Ref]

Ocular

Common (1% to 10%): Conjunctivitis[Ref]

Renal

Common (1% to 10%): Renal disorders (including increased serum/blood creatinine, decreased glomerular filtration rate, renal failure, renal/genitourinary- other)
Uncommon (0.1% to 1%): Acute renal failure[Ref]

Respiratory

Uncommon (0.1% to 1%): Interstitial pneumonitis with respiratory insufficiency (sometimes fatal), radiation pneumonitis, pulmonary embolism[Ref]

Some side effects of pemetrexed may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Nonsquamous Non-Small Cell Lung Cancer – Combination with Cisplatin

Pemetrexed for Injection is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

Nonsquamous Non-Small Cell Lung Cancer – Maintenance

Pemetrexed for Injection 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.

Nonsquamous Non-Small Cell Lung Cancer – After Prior Chemotherapy

Pemetrexed for Injection is indicated as a single-agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.

Mesothelioma

Pemetrexed for Injection in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

Limitations of Use

Pemetrexed for Injection is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies (14.1, 14.2, 14.3)]

Pemetrexed for Injection is contraindicated in patients who have a history of severe hypersensitivity reaction to Pemetrexed.

There have been few cases of Pemetrexed for Injection 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/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.

The ability of Pemetrexed for Injection to be dialyzed is unknown.

Pemetrexed disodium hemipentahydrate has the chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, hemipentahydrate. It is a white to almost-white solid with a molecular formula of C20H19N5Na2O6•2.5H2O and a molecular weight of 516.41. The structural formula is as follows:

Pemetrexed for Injection 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 Pemetrexed for Injection 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.