Pralatrexate

Class: Antineoplastic Agents
VA Class: AN300
Chemical Name: (2S)-2[[4-[1RS)-1[2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid
Molecular Formula: C23H23N7O5
CAS Number: 146464-95-1
Brands: Folotyn

Introduction

Antineoplastic agent; a folic acid antagonist.1 3 4 5 6 7 8 9

Uses for Pralatrexate

Peripheral T-cell Lymphoma (PTCL)

Treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL).1 2 Efficacy determined based on overall response rate; clinical benefit (e.g., improvement in progression-free or overall survival) not established.1

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Designated an orphan drug by FDA for this condition.2

Pralatrexate Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

  • Monitor CBCs and severity of mucositis and other treatment-related toxicities (e.g., hepatotoxicity) weekly prior to each dose.1 Administer pralatrexate only when mucositis is grade 1 or lower, platelet count ≥100,000/mm3 (prior to first dose) or ≥50,000/mm3 (prior to subsequent doses), and ANC ≥1000/mm3.1 Perform serum chemistry tests, including hepatic and renal function tests, before administration of first and fourth pralatrexate doses of each treatment cycle.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Vitamin Supplementation

  • To reduce toxicity, all patients should take low-dose oral folic acid (1–1.25 mg daily) starting 10 days before the first dose of pralatrexate; continue folic acid during therapy and for 30 days after the last dose of pralatrexate.1

  • Administer one IM injection of vitamin B12 (1 mg) within 10 weeks of the first dose of pralatrexate and then once every 8–10 weeks; subsequent injections may be given on the same day as pralatrexate.1 (See Folate and Vitamin B12 Supplementation under Cautions.)

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer undiluted by rapid IV injection only.1

Administer into the side port of a free-flowing IV infusion of 0.9% sodium chloride.1

Prepare and handle cautiously; use protective gloves and other protective clothing. 1 If skin contact occurs, immediately wash affected area(s) throughly with soap and water; if mucosal contact occurs, flush throughly with water. 1

Using aseptic technique, withdraw appropriate volume of pralatrexate 20-mg/mL injection into a syringe for immediate use.1 Do not dilute.1

Pralatrexate injection contains no preservatives, and vials are intended for single-use only; discard any unused portions.1

Rate of Administration

Administer by rapid injection over 3–5 minutes.1

Dosage

Adults

Peripheral T-cell Lymphoma
IV

30 mg/m2 once weekly for 6 weeks, followed by 1 week of rest. 1 Continue this 7-week cycle until disease progression or toxicity occurs.1

Monitor CBCs and assess severity of mucositis and other treatment-related toxicities (e.g., hepatotoxicity) weekly just prior to each dose.1 Administer subsequent doses only when mucositis severity is grade 1 or lower, platelet count ≥50,000/mm3, and ANC ≥1000/mm3 on day of treatment.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Dosage Modification for Toxicity

Adjust subsequent doses based on severity of mucositis, hematologic counts (i.e., ANC, platelet count), and/or presence of other treatment-related toxicities (e.g., hepatotoxicity) determined on the day of treatment.1 Depending on severity of toxicity, may need to omit and/or reduce subsequent doses or discontinue pralatrexate permanently.1 11 (See Tables 1, 2, and 3.) Omitted doses should not be made up at the end of the treatment cycle; dosages reduced following drug-related adverse effects should not be re-escalated.1

Mucositis

Assess severity of mucositis weekly just prior to each dose. 1 Administer subsequent dose only if mucositis is grade 1 or lower on day of treatment.1 (See Table 1.)

Per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0).

Table 1: Recommended Dosage Modification for Mucositis

Mucositis Grade on Day of Treatment

Recommended Action

Grade 2

Omit dose; when mucositis improves (to grade 1 or lower), resume pralatrexate at prior dose1

Grade 2 recurrence

Omit dose; when mucositis improves (to grade 1 or lower), resume pralatrexate at a reduced dose of 20 mg/m21

Grade 3

Omit dose; when mucositis improves (to grade 1 or lower), resume pralatrexate at a reduced dose of 20 mg/m21

Grade 4

Discontinue pralatrexate permanently1 11

Hematologic Toxicity

Monitor CBCs weekly just prior to each dose.1 Administer subsequent doses only when platelet count ≥50,000/mm3 and ANC ≥1000/mm3 on day of treatment.1 (See Table 2.)

Table 2. Recommended Dosage Modification for Hematologic Toxicity

Blood Count on Day of Treatment

Duration of Toxicity

Recommended Action

Platelet count <50,000/mm3

1 week

Omit dose; when platelet count ≥50,000/mm3, resume pralatrexate at prior dose1

 

2 weeks

Omit dose; when platelet count ≥50,000/mm3, resume pralatrexate at a reduced dose of 20 mg/m21

 

3 weeks

Discontinue pralatrexate permanently1 11

ANC of 500–1000/mm3 without fever

1 week

Omit dose; when ANC ≥1000/mm3, resume pralatrexate at prior dose1

ANC of 500–1000/mm3 with fever or ANC <500/mm3

1 week

Omit dose; initiate growth factor (e.g., filgrastim, sargramostim) support; when ANC ≥1000/mm3, resume pralatrexate at prior dose and continue growth factor support1

 

2 weeks or recurrence

Omit dose; initiate growth factor (e.g., filgrastim, sargramostim) support; when ANC ≥1000/mm3, resume treatment at a reduced dose of 20 mg/m2 and continue growth factor support1

 

3 weeks or second recurrence

Discontinue therapy permanently1 11

Other Treatment-related Toxicities

Per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0).

Table 3. Recommended Dosage Modification for Other Treatment-related Toxicities (e.g., Hepatotoxicity)

Toxicity Grade on Day of Treatment

Recommended Action

Grade 3

Omit dose; when toxicity improves (to grade 2 or lower), resume pralatrexate at a reduced dose of 20 mg/m21

Grade 4

Discontinue pralatrexate permanently1 11

Special Populations

Geriatric Patients

No dosage adjustments required in geriatric patients (≥65 years of age) with normal renal function except those recommended for all patients.1

Cautions for Pralatrexate

Contraindications

  • No known contraindications.1

Warnings/Precautions

Hematologic Toxicity

Risk of thrombocytopenia, anemia, and neutropenia.1

Monitor CBCs weekly just prior to each dose.1 Adjust dosage based on ANC and platelet count determined on day of treatment.1 (See Hematologic Toxicity under Dosage and Administration.)

Mucositis

Risk of mucositis (i.e., stomatitis or mucosal inflammation of the GI and GU tracts).1 3 4 5 Typically occurs within 2–5 days after initiation of pralatrexate.11

To reduce risk of mucositis, supplement with folic acid and vitamin B12 before and during pralatrexate therapy.1 (See General under Dosage and Administration.)

If mucositis is grade 2 or greater, may need to omit and/or reduce subsequent dose or discontinue pralatrexate permanently.1 11 (See Mucositis under Dosage and Administration.)

Consult manufacturer's labeling and/or other published guidelines (e.g., from National Comprehensive Cancer Network [NCCN]) for other strategies to prevent and manage mucositis.11 14

Folate and Vitamin B12 Supplementation

Folic acid and vitamin B12 needed to prevent treatment-related hematologic and GI toxicity (i.e., mucositis).1 5 (See General under Dosage and Administration.) Use of these supplements associated with reduction in severity of GI toxicity.5

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryotoxicity, fetotoxicity, and fetal lethality demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Hepatotoxicity

Elevated ALT/AST concentrations reported.1 Perform liver function tests prior to the first and fourth doses of each treatment cycle.1 If hepatotoxicity is grade 3 or greater, may need to omit and/or reduce subsequent dose or discontinue pralatrexate permanently.1 11 (See Table 3.)

Adequate Patient Evaluation and Monitoring

Administer under supervision of qualified clinicians experienced in the use of cytotoxic therapy.1

Monitor CBCs, including platelet counts and ANCs, prior to initiation of therapy and weekly during therapy (i.e., just prior to each dose).1

Assess for presence and severity of mucositis weekly during therapy (i.e., just prior to each dose).1

Perform chemistry tests, including hepatic and renal function tests, prior to the first and fourth doses of each treatment cycle.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether pralatrexate is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No overall differences in safety and efficacy relative to younger adults.1 However, possible increased incidence of mucositis in patients ≥65 years of age compared with younger adults.11

Age-related decline in renal function may result in reduced clearance of and increased exposure to pralatrexate.1

Hepatic Impairment

Safety and efficacy not established.1

Renal Impairment

Safety and efficacy not established.1 However, pralatrexate clearance shown to decrease with declining Clcr.1 Use with caution in patients with moderate or severe renal impairment.1

Common Adverse Effects

Mucositis,1 thrombocytopenia,1 3 4 nausea,1 fatigue,1 anemia,1 constipation,1 edema,1 pyrexia.1 cough,1 epistaxis,1 vomiting,1 neutropenia,1 diarrhea.1

Interactions for Pralatrexate

No formal drug interactions studies to date.1

Not a substrate, inhibitor, or inducer of CYP isoenzymes.1

Not a substrate or inhibitor of the P-glycoprotein transport system.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely with drugs affecting or metabolized by CYP isoenzymes.1

Drugs Eliminated by Renal Excretion

Possible pharmacokinetic interaction (delayed clearance of pralatrexate) with drugs that undergo substantial renal excretion.1

Specific Drugs

Drug

Interaction

Co-trimoxazole

Possible delayed renal clearance of pralatrexate1

NSAIAs

Possible delayed renal clearance of pralatrexate1

Probenecid

Possible delayed clearance of and increased exposure to pralatrexate1

Pralatrexate Pharmacokinetics

Absorption

Bioavailability

Following rapid IV injection (30 mg/m2 over 3–5 minutes) once weekly for 6 weeks in 7-week cycles, peak plasma concentration and AUC increased proportionally with dose.1

Pharmacokinetics did not change significantly over multiple treatment cycles, and no accumulation of pralatrexate observed.1

Distribution

Extent

Not known whether pralatrexate is distributed into milk.1 (See Lactation under Cautions.)

Plasma Protein Binding

Approximately 67%.1

Elimination

Metabolism

Not substantially metabolized by phase I CYP isoenzymes or phase II hepatic glucuronidases.1

Elimination Route

Approximately 34% eliminated in urine as unchanged drug.1

Half-life

12–18 hours.1

Special Populations

Pharmacokinetics not studied in patients with hepatic impairment.1

Clearance of pralatrexate decreases with decreasing Clcr.1

Pharmacokinetics not substantially affected by gender.1

Stability

Storage

Parenteral

Injection

2–8°C.1 Store unopened vials in original carton to protect from light until used.1 Once in syringe, use immediately.1

Unopened vials stored in original carton at room temperature are stable for 72 hours.1 Discard any vials stored at room temperature for >72 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility
Y-Site Compatibility

Compatible

Sodium chloride 0.9%1

Actions

  • Inhibits dihydrofolate reductase (DHFR); disrupts folate-dependent metabolic processes that are essential for cell replication, resulting in cytotoxicity against tumor cells.1 6 8 11

  • Structural modification in the 10-position allows pralatrexate to selectively and efficiently enter cells expressing reduced-folate carrier type 1 (RFC-1)4 5 6 7 8 10 11 and to undergo enhanced intracellular polyglutamylation by the enzyme folylpolyglutamate synthetase (FPGS).6 7 8 11 In preclinical studies, pralatrexate demonstrated enhanced intracellular transport (due to greater affinity for RFC-1),4 increased intracellular drug retention and accumulation (due to enhanced polyglutamylation), and improved cytotoxicity compared with other folic acid antagonists (e.g., methotrexate, pemetrexed).6 7 8 9 10 11 Down-regulation and/or inhibition of effective RFC-1 transport and/or polyglutamylation have been proposed as possible mechanisms of resistance to methotrexate and other folic acid antagonists.8 15

Advice to Patients

  • Importance of taking folic acid and vitamin B12 to reduce the risk of adverse effects.1 13

  • Risk of mucositis.1 Importance of immediately informing clinicians of redness and/or soreness in the mucous membranes, including the mouth, lips, throat, and other areas along the GI tract and genital areas.11 13 Importance of understanding measures to prevent mucositis and to minimize discomfort should it occur.1 13

  • Risk of thrombocytopenia, anemia, and neutropenia.1 Importance of reporting any unusual bleeding (e.g., nosebleed), bruising, weakness, fatigue, pallor, shortness of breath, or fever or other manifestations of infection (e.g., chills, cough, pain or burning upon urination).13

  • Necessity of obtaining CBCs as well as renal and liver function tests periodically.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 13 Apprise patient of potential hazard to the fetus if used during pregnancy; women of childbearing potential should avoid becoming pregnant.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., co-trimoxazole, probenecid) and OTC drugs (e.g., NSAIAs), as well as any concomitant illnesses.1 13

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Pralatrexate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV use only

20 mg/mL

Folotyn (available in single-dose vials)

Allos

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 1, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Allos Therapeutics, Inc. Folotyn (pralatrexate) injection prescribing information. Westminster, CO; 2009 Sep.

2. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act. (P.L. 97-414). Rockville, MD; From FDA website; accessed 2009 Nov 3.

3. O'Connor O, Pro B, Pinter-Brown L et al. PROPEL; Results of the pivotal, multicenter, phase II study of pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). J Clin Oncol. 2009; 17(suppl): Abstract 8561 (presented at the 45th Annual ASCO meeting. Orlando, FL: 2009 May 29.

4. O'Connor OA, Horwitz S, Hamlin P et al. Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies. J Clin Oncol. 2009; 27:4357-64. [PubMed 19652067]

5. Mould DR, Sweeney K, Duffull SB et al. A population pharmacokinetic and pharmacodynamic evaluation of pralatrexate in patients with relapsed or refractory non-Hodgkin's or Hodgkin's lymphoma. Clin Pharmacol Ther. 2009; 86:190-6. [PubMed 19474785]

6. Molina JR. Pralatrexate, a dihydrofolate reductase inhibitor for the potential treatment of several malignancies. IDrugs. 2008; 11:508-21. [PubMed 18600598]

7. Kisliuk RL. Deaza analogs of folic acid as antitumor agents. Curr Pharm Des. 2003; 9:2615-25. [PubMed 14529545]

8. Izbicka E, Diaz A, Streeper R et al. Distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers. Cancer Chemother Pharmacol. 2009; 64:993-9. [PubMed 19221750]

9. Wang ES, O'Connor O, She Y et al. Activity of a novel anti-folate (PDX, 10-propargyl 10-deazaaminopterin) against human lymphoma is superior to methotrexate and correlates with tumor RFC-1 gene expression. Leuk Lymphoma. 2003; 44:1027-35. Abstract. [PubMed 12854905]

10. O'Connor OA, Hamlin PA, Portlock C et al. Pralatrexate, a novel class of antifol with high affinity for the reduced folate carrier-type 1, produces marked complete and durable remissions in a diversity of chemotherapy refractory cases of T-cell lymphoma. Br J Haematol. 2007; 139:425-8. [PubMed 17910632]

11. Allos Therapeutics, Inc., Westminster, CO: Personal communication.

12. Justice RL. Pralatrexate: FDA approval package. NDA number: 22-468. Rockville, MD: US Food and Drug Administration. From FDA website. Accessed 2010 Jan 28.

13. Allos Therapeutics, Inc. Folotyn (pralatrexate) injection patient information. Westminster, CO. Accessed 2010 Feb 4.

14. Bensinger W, Schubert M, Ang KK et al. NCCN Task Force Report. prevention and management of mucositis in cancer care. J Natl Compr Canc Netw. 2008; 6 Suppl 1:S1-21. [PubMed 18289497]

15. Mauritz R, Peters GJ, Priest DG et al. Multiple mechanisms of resistance to methotrexate and novel antifolates in human CCRF-CEM leukemia cells and their implications for folate homeostasis. Biochem Pharmacol. 2002; 63:105-15. [PubMed 11841783]

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