pemetrexed (Rx)

>10% (All Grades)

Nausea (31-82%)

Vomiting (16-57%)

Neutropenia (11-56%)

Fatigue (34-48%)

Anemia (19-26%)

Thrombocytopenia (8-23%)

Stomatitis/pharyngitis (15-23%)

Anorexia (20-22%)

Diarrhea (13-17%)

Rash (14-16%)

Decreased CrCl (16%)

Constipation (6-12%)

Alopecia (11%)

Elevated creatinine (11%)

>10% (Grade 3 or 4)

Neutropenia (5-23%)

Nausea (12%)

Vomiting (2-11%)

1-10% (All Grades)

Sensory neuropathy (10%)

Taste disturbance (8%)

Increased ALT (1-8%)

Fever (8%)

Pruritus (7%)

Increased AST (1-7%)

Dehydration (7%)

Alopecia (6%)

Dyspepsia (5%)

Conjunctivitis (5%)

Abdominal pain (1-5%)

Allergic reaction/hypersensitivity (1-5%)

Febrile neutropenia (1-5%)

Infection (1-5%)

Urticaria (1-5%)

Chest pain (1-5%)

Erythema multiforme (1-5%)

Renal failure (1-5%)

Motor or sensory neuropathy (1-5%)

Dyspepsia (1%)

1-10% (Grade 3 or 4)

Fatigue (5-10%)

Thrombocytopenia (2-5%)

Anemia (4%)

Dehydration (4%)

Diarrhea (4%)

Nausea (3%)

Stomatitis/pharyngitis (1-3%)

Increased ALT (2%)

Anorexia (2%)

Rash (1%)

Alopecia (1%)

Constipation (1%)

Anorexia (1%)

Increased AST (1%)

Decreased CrCl (1%)

<1%

Supraventricular arrhythmias

Renal failure

Motor neuropathy

Postmarketing Reports

Gastrointestinal: Colitis, pancreatitis

Blood and lymphatic system: Immune-mediated hemolytic anemia

General: Edema

Injury, poisoning, and procedural complications: Radiation recall

Respiratory: Interstitial pneumonitis

Skin: Serious and fatal bullous skin conditions, Stevens-Johnson syndrome, and toxic epidermal necrolysis

Contraindications

History of severe hypersensitivity reaction to pemetrexed

Cautions

Severe myelosuppression may occur, resulting in a requirement for transfusions and which may lead to neutropenic infection; risk of myelosuppression is increased in patients who do not receive vitamin supplementation; initiate supplementation with oral folic acid and intramuscular vitamin B-12 prior to first dose of therapy; continue vitamin supplementation during treatment and for 21 days after last dose to reduce severity of hematologic and gastrointestinal toxicity

Therapy can cause severe, and sometimes fatal, renal toxicity

Serious and sometimes fatal, bullous, blistering, and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, can occur; permanently discontinue for severe and life-threatening bullous, blistering or exfoliating skin toxicity

Serious interstitial pneumonitis can occur with treatment; withhold therapy for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation; if pneumonitis confirmed, permanently discontinue therapy

Radiation recall can occur with treatment in patients who have received radiation weeks to years previously; monitor for inflammation or blistering in areas of previous radiation treatment; permanently discontinue therapy for signs of radiation recall

Based on findings from animal studies and its mechanism of action, therapy can cause fetal harm when administered to a pregnant woman; avoid pregnancy (see Pregnancy)

Drug interactions overview

• Pemetrexed is a OAT3/OAT4 substrate; ibuprofen, an OAT3 inhibitor, inhibited the uptake of pemetrexed in OAT3-expressing cell cultures; data predict that at clinically relevant concentrations, other NSAIDs (naproxen, diclofenac, celecoxib) would not inhibit the uptake of pemetrexed

Pregnancy

Based on findings from animal studies and its mechanism of action, therapy can cause fetal harm when administered to a pregnant woman

There are no available data in pregnant women; in animal reproduction studies, IV administration of pemetrexed to pregnant mice during organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than recommended human dose of 500 mg/m²; advise pregnant women of the potential risk to a fetus

Contraception

• Females of reproductive potential: Use effective contraception during treatment for at least 6 months after final dose
• Males with female partners of reproductive potential: Use effective contraception during treatment and for 3 months after final dose

Infertility

• Therapy may impair fertility in males of reproductive potential; it is not known whether these effects on fertility are reversible

Lactation

There is no information regarding presence of drug or its metabolites in human milk, effects on breastfed infant, or on milk production; because of potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment and for 1 week after last dose

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

Vd (ss): 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: 3.5 hr

Excretion: Urine (70-90%)

IV Incompatibilities

Alimta

• Do not use calcium-containing solutions for reconstitution, including Lactated Ringer or Ringer solution

Pemfexy

• Do not use other diluents, such as Lactated Ringer or Ringer solution

IV Compatibilities

Alimta: 0.9% NaCl

Pemfexy: Dextrose 5%; compatible with polyolefin infusion bags with polyvinyl chloride (PVC) ports

IV Preparation

Pemetrexed a cytotoxic drug; follow applicable special handling and disposal procedures

Reconstitution

• Alimta: Reconstitute with 0.9% NaCl (preservative-free); add 4.2 mL to 100-mg vial and 20 mL to the 500-mg vial; final vial concentration is 25 mg/mL

Further dilution

• Gently swirl until completely dissolved; resulting solution is clear and ranges in color from colorless to yellow/green-yellow without adversely affecting quality
• Visually inspect particulate matter and discoloration prior to further dilution; if particulate matter is observed, discard vial
• Withdraw calculated dose from vial(s) and discard vial with any unused portion
• Further dilute reconstituted vial with 0.9% NaCl (Alimta) or Dextrose 5% (Pemfexy) to achieve a total volume of 100 mL for IV infusion

Premedication Regimen

Folic acid: 400-1000 mcg PO qDay beginning 7 days before first pemetrexed dose; continue until 21 days after last dose

Vitamin B-12: 1 mg IM beginning 1 week before first pemetrexed dose and repeat every 3 cycles thereafter; subsequent doses may be administered on the same day as pemetrexed

Do not substitute PO vitamin B-12 for IM (see Cautions)

Dexamethasone: 4 mg PO BID for 3 consecutive days starting the day before pemetrexed administration

IV Administration

Infuse over 10 min

For combination therapy: Administer after pembrolizumab and prior to carboplatin or cisplatin

Storage

Alimta

• Unused vials: Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF)
• Reconstituted vials: Refrigerate at 2-8°C (36-46°F) for no longer than 24 hr from the time of reconstitution; discard vial after 24 hr
• Diluted infusion: Refrigerate at 2-8°C (36-46°F) for no more than 24 hr from the time of reconstitution; discard after 24 hr

Pemfexy

• Unused vials: Refrigerate at 2-8°C (36-46°F)
• Reconstituted vials: Refrigerate at 2-8°C (36-46°F) or ambient room temperature for no longer than 48 hr from the time of reconstitution; discard vial after 48 hr
• Diluted infusion: Refrigerate at 2-8°C (36-46°F) for no more than 48 hr from the time of reconstitution; discard after 48 hr