OFORTA

Clinical safety rating: caution

Comprehensive clinical and safety monograph for OFORTA (OFORTA).

How it works

Pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), enzymes involved in folate metabolism and DNA synthesis.

What the body does with it

Metabolism	Pemetrexed is minimally metabolized, with approximately 70-90% excreted unchanged in the urine via active tubular secretion and glomerular filtration.
Excretion	Primarily renal excretion as unchanged drug (~70-80%) via glomerular filtration and active tubular secretion; fecal elimination accounts for <10%.
Half-life	Terminal elimination half-life is approximately 6-8 hours in patients with normal renal function; prolonged to 20-40 hours in end-stage renal disease, requiring dose adjustment.
Protein binding	Approximately 90-95% bound to serum albumin, primarily to site I (warfarin-binding site).
Volume of Distribution	Volume of distribution is 0.1-0.2 L/kg, indicating limited extravascular distribution and predominant confinement to the intravascular space.
Bioavailability	Oral bioavailability is 85-95% due to rapid absorption with minimal first-pass metabolism; intravenous bioavailability is 100%.
Onset of Action	Intravenous: within 30-60 minutes; oral: 1-2 hours after administration.
Duration of Action	Duration of action is 8-12 hours for glucose-lowering effect; clinical effects persist for up to 24 hours with sustained-release formulations.

Classification & Brands

Dosing & administration

25 mg orally three times daily for 21 days of a 28-day cycle, or 60 mg orally once daily for 21 days of a 28-day cycle.

Dosage form	TABLET
Renal impairment	CrCl ≥60 mL/min: no adjustment; CrCl 30-59 mL/min: reduce dose to 20 mg three times daily; CrCl <30 mL/min: not recommended.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: reduce dose to 20 mg three times daily; Child-Pugh C: not recommended.
Pediatric use	Not established; safety and efficacy in pediatric patients have not been studied.
Geriatric use	No specific dose adjustment recommended; monitor for increased toxicity due to age-related decline in renal function.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for OFORTA (OFORTA).

Breastfeeding	Contraindicated due to potential for serious adverse reactions in breastfed infants. M/P ratio not established; fluorouracil is excreted into human milk.
Teratogenic Risk	OFORTA (fluorouracil) is contraindicated in pregnancy. First trimester: high risk of teratogenicity including CNS, cardiovascular, and craniofacial defects. Second and third trimesters: fetal growth restriction, low birth weight, and potential for neonatal myelosuppression.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

Increased risk of myelosuppression and severe, sometimes fatal, thrombocytopenia, neutropenia, and anemia. Must be used with folic acid and vitamin B12 supplementation to reduce toxicity.

Side Effect Profile

Serious Effects

Absolute Contraindications

History of severe hypersensitivity reaction to pemetrexed; patients with creatinine clearance <45 mL/min (for mesothelioma indication); concomitant use of yellow fever vaccine.

Clinical Precautions

Precautions

Myelosuppression; renal toxicity; gastrointestinal toxicity; increased toxicity with NSAIDs in patients with renal impairment; impaired renal function reduces clearance; dermatologic reactions; radiation recall; pulmonary toxicity; severe renal impairment (CrCl <45 mL/min) requires dose adjustment; pregnancy category D; lactation.

Clinical Tips & Counseling

Drug interactions

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OFORTA

Clinical safety rating: caution

Comprehensive clinical and safety monograph for OFORTA (OFORTA).

How it works

Pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), enzymes involved in folate metabolism and DNA synthesis.

What the body does with it

Metabolism	Pemetrexed is minimally metabolized, with approximately 70-90% excreted unchanged in the urine via active tubular secretion and glomerular filtration.
Excretion	Primarily renal excretion as unchanged drug (~70-80%) via glomerular filtration and active tubular secretion; fecal elimination accounts for <10%.
Half-life	Terminal elimination half-life is approximately 6-8 hours in patients with normal renal function; prolonged to 20-40 hours in end-stage renal disease, requiring dose adjustment.
Protein binding	Approximately 90-95% bound to serum albumin, primarily to site I (warfarin-binding site).
Volume of Distribution	Volume of distribution is 0.1-0.2 L/kg, indicating limited extravascular distribution and predominant confinement to the intravascular space.
Bioavailability	Oral bioavailability is 85-95% due to rapid absorption with minimal first-pass metabolism; intravenous bioavailability is 100%.
Onset of Action	Intravenous: within 30-60 minutes; oral: 1-2 hours after administration.
Duration of Action	Duration of action is 8-12 hours for glucose-lowering effect; clinical effects persist for up to 24 hours with sustained-release formulations.

Classification & Brands

Dosing & administration

25 mg orally three times daily for 21 days of a 28-day cycle, or 60 mg orally once daily for 21 days of a 28-day cycle.

Dosage form	TABLET
Renal impairment	CrCl ≥60 mL/min: no adjustment; CrCl 30-59 mL/min: reduce dose to 20 mg three times daily; CrCl <30 mL/min: not recommended.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: reduce dose to 20 mg three times daily; Child-Pugh C: not recommended.
Pediatric use	Not established; safety and efficacy in pediatric patients have not been studied.
Geriatric use	No specific dose adjustment recommended; monitor for increased toxicity due to age-related decline in renal function.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for OFORTA (OFORTA).

Breastfeeding	Contraindicated due to potential for serious adverse reactions in breastfed infants. M/P ratio not established; fluorouracil is excreted into human milk.
Teratogenic Risk	OFORTA (fluorouracil) is contraindicated in pregnancy. First trimester: high risk of teratogenicity including CNS, cardiovascular, and craniofacial defects. Second and third trimesters: fetal growth restriction, low birth weight, and potential for neonatal myelosuppression.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

Increased risk of myelosuppression and severe, sometimes fatal, thrombocytopenia, neutropenia, and anemia. Must be used with folic acid and vitamin B12 supplementation to reduce toxicity.

Side Effect Profile

Serious Effects

Absolute Contraindications

History of severe hypersensitivity reaction to pemetrexed; patients with creatinine clearance <45 mL/min (for mesothelioma indication); concomitant use of yellow fever vaccine.