Folotyn (Page 3 of 5)

6.2 Post Marketing Experience

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.

Dermatologic Reactions

Toxic epidermal necrolysis, sometimes fatal, has been reported during post-marketing use of FOLOTYN. Fatal cases have been reported following the first dose of FOLOTYN, including when a reduced dose is given, and have been reported in patients with end-stage renal disease undergoing dialysis [see Warnings and Precautions (5.3), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].


No formal clinical assessments of pharmacokinetic drug-drug interactions between FOLOTYN and other drugs have been conducted. The effect of co-administration of the uricosuric drug probenecid (an inhibitor of multiple transporter systems including the multidrug resistance-associated protein 2 (MRP2) efflux transporter) on pralatrexate pharmacokinetics was investigated in a Phase 1 clinical study. Co-administration of increasing doses of probenecid resulted in delayed clearance of pralatrexate and a commensurate increase in exposure [see Clinical Pharmacology (12.3) ].

When administering FOLOTYN to patients receiving probenecid or other drugs that may affect relevant transporter systems (eg, NSAIDs), monitor patients closely for signs of systemic toxicity due to increased drug exposure.


8.1 Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.7) ]

Embryo-Fetal Toxicity

FOLOTYN can cause fetal harm when administered to a pregnant woman. Pralatrexate was embryotoxic and fetotoxic in rats at IV doses of 0.06 mg/kg/day (0.36 mg/m2 /day or about 1.2% of the clinical dose on a mg/m2 basis) given on gestation days 7 through 20. Treatment with pralatrexate caused a dose-dependent decrease in fetal viability manifested as an increase in late, early, and total resorptions. There was also a dose-dependent increase in post-implantation loss. In rabbits, IV doses of 0.03 mg/kg/day (0.36 mg/m2 /day) or greater given on gestation days 8 through 21 also caused abortion and fetal lethality. This toxicity manifested as early and total resorptions, post-implantation loss, and a decrease in the total number of live fetuses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

8.3 Nursing Mothers

It is not known whether pralatrexate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from this drug, a decision should be made whether to discontinue nursing or to discontinue FOLOTYN, taking into account the importance of FOLOTYN to the mother.

8.4 Pediatric Use

Pediatric patients were not included in clinical studies with FOLOTYN. The safety and effectiveness of FOLOTYN in pediatric patients have not been established.

8.5 Geriatric Use

In the PTCL efficacy study, 36% of patients (n = 40) were 65 years of age and over. No overall differences in efficacy and safety were observed in patients based on age (< 65 years compared with ≥ 65 years). Due to the contribution of renal excretion to overall clearance of pralatrexate (approximately 34%), age-related decline in renal function may lead to a reduction in clearance and a commensurate increase in plasma exposure. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Since elderly patients may be at higher risk, monitor more closely. Omit dose and subsequently adjust or discontinue therapy for exposure related toxicity [see Dosage and Administration (2.2), Warnings and Precautions (5.5, 5.6), Use in Specific Populations (8.6, 8.7), and Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

The safety, efficacy and pharmacokinetics of FOLOTYN have not been evaluated in patients with hepatic impairment. Patients with the following laboratory values were excluded from the pralatrexate lymphoma clinical trials: total bilirubin > 1.5 mg/dL; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN); and AST or ALT > 5 × ULN if documented hepatic involvement with lymphoma. Treatment with FOLOTYN can cause hepatic toxicity and liver function test abnormalities [see Dosage and Administration (2.2) and Warnings and Precautions (5.6)].

8.7 Renal Impairment

For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m2), the recommended dose of FOLOTYN is 15 mg/m2. For patients with mild to moderate renal impairment, dose reduction is not necessary.

Serious adverse drug reactions, including TEN and mucositis have been reported in patients with ESRD undergoing dialysis. Monitor patients for renal function and for systemic toxicity due to increased drug exposure and adjust dosing accordingly. Avoid the use of FOLOTYN in patients with end stage renal disease undergoing dialysis unless the potential benefit justifies the potential risk [see Dosage and Administration (2.1, 2.2), Warnings and Precautions (5.3, 5.6), Adverse Reactions (6.2), and Clinical Pharmacology (12.3)].


No specific information is available on the treatment of overdosage of FOLOTYN. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. Based on FOLOTYN’s mechanism of action, consider the prompt administration of leucovorin.


FOLOTYN (pralatrexate injection) contains pralatrexate, which is an antineoplastic folate analog. Pralatrexate has the chemical name (2S)-2-[[4-[(1RS)-1-[(2, 4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid. The structural formula is as follows:

Structural Formula
(click image for full-size original)

Pralatrexate is a 1:1 racemic mixture of S — and R — diastereomers at the C10 position (indicated with *).

The molecular formula is C23 H23 N7 O5 and the molecular weight is 477.48 g/mol.

Pralatrexate is an off-white to yellow solid. It is soluble in aqueous solutions at pH 6.5 or higher. Pralatrexate is practically insoluble in chloroform and ethanol. The pKa values are 3.25, 4.76, and 6.17.

FOLOTYN is supplied as a preservative-free, sterile, isotonic, non-pyrogenic clear yellow aqueous parenteral solution contained in a single-dose clear glass vial (Type I) for intravenous administration. Each 1 mL of solution contains 20 mg of pralatrexate, sufficient sodium chloride to achieve an isotonic (280-300 mOsm) solution, and sufficient sodium hydroxide, and hydrochloric acid if needed, to adjust and maintain the pH at 7.5-8.5. FOLOTYN is supplied as either 20 mg (1 mL) or 40 mg (2 mL) single-dose vials at a concentration of 20 mg/mL.


12.1 Mechanism of Action

Pralatrexate is a folate analog metabolic inhibitor that competitively inhibits dihydrofolate reductase. It is also a competitive inhibitor for polyglutamylation by the enzyme folylpolyglutamyl synthetase. This inhibition results in the depletion of thymidine and other biological molecules the synthesis of which depends on single carbon transfer.

12.3 Pharmacokinetics


The pharmacokinetics of pralatrexate administered as a single agent at a dose of 30 mg/m2 administered as an intravenous push over 3-5 minutes once weekly for 6 weeks in 7-week cycles have been evaluated in 10 patients with PTCL. The total systemic clearance of pralatrexate diastereomers was 417 mL/min (S -diastereomer) and 191 mL/min (R -diastereomer). The terminal elimination half-life of pralatrexate was 12-18 hours (coefficient of variance [CV] = 62-120%). Pralatrexate total systemic exposure (AUC) and maximum plasma concentration (Cmax ) increased proportionally with dose (dose range 30-325 mg/m2 , including pharmacokinetics data from high-dose solid tumor clinical studies). The pharmacokinetics of pralatrexate did not change significantly over multiple treatment cycles, and no accumulation of pralatrexate was observed.


Pralatrexate diastereomers showed a steady-state volume of distribution of 105 L (S- diastereomer) and 37 L (R -diastereomer). In vitro studies indicate that pralatrexate is approximately 67% bound to plasma proteins.



In vitro studies using human hepatocytes, liver microsomes and S9 fractions, and recombinant human CYP450 isozymes showed that pralatrexate is not significantly metabolized by the phase I hepatic CYP450 isozymes or phase II hepatic glucuronidases.


The mean fraction of unchanged pralatrexate diastereomers excreted in urine following a pralatrexate dose of 30 mg/m2 administered as an intravenous push over 3‑5 minutes was 31% (S ‑diastereomer) (CV = 47%) and 38% (R -diastereomer) (CV = 45%), respectively. In a mass balance study conducted in patients with advanced cancer, an average of 39% (CV = 28%) of the administered radiolabeled pralatrexate dose was excreted in urine as parent, racemic pralatrexate (fe ). An average of 34% (CV = 88%) of the administered dose was recovered in feces as total radiation (fe TR) which included both parent pralatrexate and/or any metabolites. An average of 10% (CV = 95%) of total dose was exhaled as total radioactivity over 24 hours.

Pharmacokinetics in Specific Populations

Renal Impairment

In patients with cancer without renal impairment, approximately 34% of pralatrexate was excreted unchanged into urine following a single dose of 30 mg/m2 administered as an intravenous push over 3-5 minutes. The pharmacokinetics of FOLOTYN was studied in patients with varying degrees of renal impairment. In patients with severe renal impairment (eGFR 15 to <30 mL/min/1.73 m2), the FOLOTYN dose was 15 mg/m2. Patients with normal renal clearance, mild renal impairment, and moderate renal impairment were all dosed with 30 mg/m2. Mean exposures of the pralatrexate S-diastereomer and R-diastereomer were comparable across cohorts. The mean fraction of the administered dose excreted as unchanged diastereomers in urine (fe ) decreased with declining renal function. The non-renal clearance and volume of distribution of pralatrexate were unaffected by renal impairment [see Use in Specific Populations (8.7) ].

Hepatic Impairment

Pralatrexate has not been studied in patients with hepatic impairment.


There was no significant effect of gender on pharmacokinetics.

Drug Interactions

In vitro studies indicated that pralatrexate does not induce or inhibit the activity of CYP450 isozymes at concentrations of pralatrexate that can be reasonably expected clinically.

In vitro , pralatrexate is a substrate for the breast cancer resistance protein (BCRP), MRP2, multidrug resistance-associated protein 3 (MRP3), and organic anion transport protein 1B3 (OATP1B3) transporter systems at concentrations of pralatrexate that can be reasonably expected clinically. Pralatrexate is not a substrate of the P glycoprotein (P-gp), organic anion transport protein 1B1 (OATP1B1), organic cation transporter 2 (OCT2), organic anion transporter 1 (OAT1), and organic anion transporter 3 (OAT3) transporter systems.

In vitro , pralatrexate inhibits MRP2 and MRP3 transporter systems ([I]/IC50 > 0.1) at concentrations of pralatrexate that can be reasonably expected clinically. MRP3 is a transporter that may affect the transport of etoposide and teniposide.

In vitro , pralatrexate did not significantly inhibit the P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B1, and OATP1B3 transporter systems at concentrations of pralatrexate that can be reasonably expected clinically.

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