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Folotyn

Last reviewed on RxList: 6/15/2020
Drug Description

What is Folotyn and how is it used?

Folotyn (pralatrexate injection) is an antineoplastic (anti-cancer) drug used to treat T-cell lymphoma that has spread throughout the body. Folotyn is given for relapsed T-cell lymphoma, or after other medications have been tried without successful treatment.

What are side effects of Folotyn?

Common side effects of Folotyn include:

Serious skin reactions can occur. Tell your doctor if you develop rash, peeling, sores or blisters on the skin while using Folotyn. Tell your doctor if you have unlikely but serious side effects of Folotyn including:

  • signs of infection (such as fever, cough, sore throat, chills),
  • easy bleeding or bruising,
  • dehydration,
  • feeling weak,
  • looking pale, or
  • shortness of breath.

DESCRIPTION

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:

FOLOTYN (pralatrexate) Structural Formula Illustration

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

The molecular formula is C23H23N7O5 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) singledose vials at a concentration of 20 mg/mL.

Indications & Dosage

INDICATIONS

FOLOTYN is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).

This indication is approved under accelerated approval based on overall response rate [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

DOSAGE AND ADMINISTRATION

Important Dosing Information

Pretreatment Vitamin Supplementation

Folic Acid

Instruct patients to take folic acid 1 to 1.25 mg orally once daily beginning 10 days before the first dose of FOLOTYN. Continue folic acid during treatment with FOLOTYN and for 30 days after the last dose [see WARNINGS AND PRECAUTIONS].

Vitamin B12

Administer vitamin B12 1 mg intramuscularly within 10 weeks prior to the first dose of FOLOTYN and every 8-10 weeks thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with FOLOTYN [see WARNINGS AND PRECAUTIONS].

Recommended Dosage

The recommended dosage of FOLOTYN is 30 mg/m² intravenously over 3-5 minutes once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity.

Dosage Modifications For Renal Impairment And End Stage Renal Disease

  • Severe renal impairment (eGFR 15 to 29 mL/min/1.73 m² by MDRD): Reduce the FOLOTYN dose to 15 mg/m² [see Use In Specific Populations].
  • End stage renal disease (ESRD: eGFR less than 15 mL/min/1.73 m² by MDRD) with or without dialysis: Avoid administration. If the potential benefit of administration justifies the potential risk, monitor renal function and reduce the FOLOTYN dose based on adverse reactions [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

Monitoring And Dosage Modifications For Adverse Reactions

Monitoring

Monitor complete blood cell counts and severity of mucositis at baseline and weekly. Perform serum chemistry tests, including renal and hepatic function, prior to the start of the first and fourth dose of each cycle.

Recommended Dosage Modifications

Do not administer FOLOTYN until:

  • Mucositis Grade 1 or less.
  • Platelet of 100,000/mcL or greater for first dose and 50,000/mcL or greater for all subsequent doses.
  • Absolute neutrophil count (ANC) of 1,000/mcL or greater. Dosage modifications for adverse reactions are provided in Tables 1, 2, and 3.

Table 1 : FOLOTYN Dosage Modifications for Mucositis

Mucositis Gradea on Day of TreatmentActionRecommended Dose upon Recovery to Grade 0 or 1
Patients Without Severe Renal ImpairmentPatients with Severe Renal Impairment
Grade 2Omit doseContinue prior doseContinue prior dose
Grade 2 recurrenceOmit dose20 mg/m²10 g/m²
Grade 3Omit dose20 mg/m²10 g/m²
Grade 4Stop therapy
a Based National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0)

Table 2 : FOLOTYN Dosage Modifications for Myelosuppression

Blood Count on Day of TreatmentDuration of ToxicityActionRecommended Dose Upon Recovery
Patients Without Severe Renal ImpairmentPatients with Severe Renal Impairment
Platelet less than 50,000/mcL1 weekOmit doseContinue prior doseContinue prior dose
2 weeksOmit dose20 mg/m²10 mg/m²
3 weeksStop therapy
ANC 500 to 1,000/mcL and no fever1 weekOmit doseContinue prior doseContinue prior dose
ANC 500 to 1,000/mcL with fever or ANC less than 500/mcL1 weekOmit dose, give G-CSF or GM-CSFContinue prior dose with G-CSF or GM-CSFContinue prior dose with G-CSF or GM-CSF support
2 weeks or recurrenceOmit dose, give G-CSF or GM-CSF20 mg/m² with G-CSF or GM-CSF10 mg/m² with G-CSF or GM-CSF
3 weeks or nd 2 recurrenceStop therapy
G-CSF=granulocyte colony-stimulating factor; GM-CSF=granulocyte macrophage colony-stimulating factor

Table 3 : FOLOTYN Dosage Modifications for All Other Adverse Reactions

Toxicity Gradea on Day of TreatmentActionRecommended Dose upon Recovery to Grade 2 or Lower
Patients Without Severe Renal ImpairmentPatients with Severe Renal Impairment
Grade 3Omit dose20 mg/m²10 mg/m²
Grade 4Stop therapy
a Based on NCI CTCAE version 3.0

Preparation And Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use any vials exhibiting particulate matter or discoloration.

FOLOTYN is a hazardous drug. Follow applicable special handling and disposal procedures.1 If FOLOTYN comes in contact with the skin, immediately and thoroughly wash with soap and water. If FOLOTYN comes in contact with mucous membranes, flush thoroughlywith water.

Aseptically withdraw the calculated dose from the appropriate number of vial(s) into a syringe for immediate use. Do not dilute FOLOTYN. Administer undiluted FOLOTYN intravenously over 3-5 minutes via the side port of a free-flowing 0.9%

Sodium Chloride Injection. After withdrawal of dose, discard vial(s) including any unused portion.

HOW SUPPLIED

Dosage Forms And Strengths

Injection: 40 mg/2 mL (20 mg/mL) and 20 mg/mL clear yellow sterile solution in single-dose vial

Storage And Handling

FOLOTYN is available in clear glass single-dose vials containing pralatrexate at a concentration of 20 mg/mL as a preservative-free, sterile, clear yellow solution individually packaged for intravenous use in the following presentations:

NDC 72893-003-01: 20 mg of pralatrexate in 1 mL solution in a vial (20 mg / 1 mL)
NDC 72893-005-01: 40 mg of pralatrexate in 2 mL solution in a vial (40 mg / 2 mL)

Store refrigerated at 2-8°C (36-46°F) [see USP Controlled Cold Temperature] in original carton to protect from light.

FOLOTYN is a hazardous drug. Follow applicable special handling and disposal procedures.1

REFERENCES

1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

Manufactured for: Acrotech Biopharma LLC East Windsor, NJ 08520 1-888-255-6788. Revised: May 2020

SLIDESHOW

Skin Cancer Symptoms, Types, Images See Slideshow
Side Effects & Drug Interactions

SIDE EFFECTS

The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Myelosuppression [see WARNINGS AND PRECAUTIONS]
  • Mucositis [see WARNINGS AND PRECAUTIONS]
  • Dermatologic Reactions [see WARNINGS AND PRECAUTIONS]
  • Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
  • Hepatic Toxicity [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Peripheral T-cell Lymphoma

The safety of FOLOTYN was evaluated in Study PDX-008 [see Clinical Studies]. Patients received FOLOTYN 30 mg/m² once weekly for 6 weeks in 7-week cycles. The median duration of treatment was 70 days (range: 1 day to 1.5 years). The majority of patients (69%, n = 77) remained at the target dose for the duration of treatment. Overall, 85% of scheduled doses were administered.

Forty-four percent of patients (n = 49) experienced a serious adverse event while on study or within 30 days after their last dose of FOLOTYN. The most common serious adverse events (> 3%), regardless of causality, were pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. One death from cardiopulmonary arrest in a patient with mucositis and febrile neutropenia was reported in this trial. Across clinical trials, deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients who received doses ranging from 30 mg/m² to 325 mg/m².

Twenty-three percent of patients (n = 25) discontinued treatment with FOLOTYN due to adverse reactions. The most frequent adverse reactions reported as the reason for discontinuation of treatment were mucositis (6%) and thrombocytopenia (5%).

The most common adverse reactions (> 35%) were mucositis, thrombocytopenia, nausea, and fatigue.

Table 4 summarizes the adverse reactions in Study PDX-008.

Table 4 : Adverse Reactions in (≥ 10%) in Patients Who Received FOLOTYN in Study PDX-008

FOLOTYN
N=111
All Grades (%)Grade 3 (%)Grade 4 (%)
Any Adverse Reaction1004331
Mucositisa70174
Thrombocytopeniab411419b
Nausea4040
Fatigue3652
Anemia34152
Constipation3300
Pyrexia3211
Edema3010
Cough2810
Epistaxis2600
Vomiting2520
Neutropenia24137
Diarrhea2120
Dyspnea1970
Hypokalemia1541
Anorexia1530
Rash1500
Pruritus1420
Pharyngolaryngeal pain1410
Liver function test abnormalc1350
Abdominal pain1240
Pain in extremity1200
Leukopenia1134
Back pain1130
Night sweats1100
Asthenia1010
Upper respiratory tract infection1010
Tachycardia1000
a Mucositis includes stomatitis or mucosal inflammation of the gastrointestinal and genitourinary tracts.
b Five patients with platelets < 10,000/mcL.
c Liver function test abnormal includes increased ALT, increased AST, and increased transaminases

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of FOLOTYN. 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.

DRUG INTERACTIONS

Effects Of Other Drugs On FOLOTYN

Coadministration of FOLOTYN with probenecid increased pralatrexate plasma concentrations [see CLINICAL PHARMACOLOGY], which may increase the risk of adverse reactions. Avoid coadministration with probenecid or nonsteroidal anti-inflammatory drugs. If coadministration is unavoidable, monitor for increased risk of adverse reactions.

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Myelosuppression

FOLOTYN can cause myelosuppression, manifested by thrombocytopenia, neutropenia, and/or anemia.

Administer vitamin B12 and instruct patients to take folic acid to reduce the risk of treatment-related myelosuppression [see DOSAGE AND ADMINISTRATION].

Monitor complete blood counts and omit and/or reduce the dose based on ANC and platelet count prior to each dose [see DOSAGE AND ADMINISTRATION].

Mucositis

FOLOTYN can cause mucositis [see ADVERSE REACTIONS].

Administer vitamin B12 and instruct patients to take folic acid to reduce the risk of mucositis [see DOSAGE AND ADMINISTRATION]. Monitor for mucositis weekly and omit and/or reduce the dose for grade 2 or higher mucositis [see DOSAGE AND ADMINISTRATION].

Dermatologic Reactions

FOLOTYN can cause severe dermatologic reactions, which may result in death. These dermatologic reactions have been reported in clinical studies (2.1% of 663 patients) and post marketing experience, and have included skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN) [see ADVERSE REACTIONS]. They may be progressive and increase in severity with further treatment and may involve skin and subcutaneous sites of known lymphoma.

Monitor closely for dermatologic reactions. Withhold or discontinue FOLOTYN based on severity [see DOSAGE AND ADMINISTRATION].

Tumor Lysis Syndrome

FOLOTYN can cause tumor lysis syndrome (TLS). Monitor patients who are at increased risk of TLS and treat promptly.

Hepatic Toxicity

FOLOTYN can cause hepatic toxicity and liver function test abnormalities [see ADVERSE REACTIONS]. Persistent liver function test abnormalities may be indicators of hepatic toxicity and require dose modification or discontinuation.

Monitor liver function tests. Omit dose until recovery, adjust or discontinue therapy based on the severity of the hepatic toxicity [see DOSAGE AND ADMINISTRATION].

Risk Of Increased Toxicity With Renal Impairment

Patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m² based on MDRD) may be at greater risk for increased exposure and adverse reactions. Reduce FOLOTYN dosage in patients with severe renal impairment [see DOSAGE AND ADMINISTRATION].

Serious adverse reactions, including TEN and mucositis, were reported in patients with end stage renal disease (ESRD) undergoing dialysis who were administered FOLOTYN. Avoid FOLOTYN in patients with ESRD with or without dialysis. If the potential benefit of administration justifies the potential risk, monitor renal function and reduce the FOLOTYN dose based on adverse reactions [see DOSAGE AND ADMINISTRATION].

Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, FOLOTYN can cause fetal harm when administered to a pregnant woman. FOLOTYN was embryotoxic and fetotoxic in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with FOLOTYN and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with FOLOTYN and for 3 months after the last dose [see Use In Specific Populations].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Folic Acid And Vitamin B12 Supplementation

Advise patients treated with FOLOTYN to take folic acid and vitamin B12 to reduce the risk of possible side effects [see DOSAGE AND ADMINISTRATION].

Myelosuppression

Inform patients of the risk of myelosuppression and to immediately contact their healthcare provider should any signs of infection develop, including fever. Inform patients to contact their healthcare provider if bleeding or symptoms of anemiaoccur [see WARNINGS AND PRECAUTIONS].

Mucositis

Inform patients of the signs and symptoms of mucositis. Instruct patients on ways to reduce the risk of its development, and on ways to maintain nutrition and control discomfort from mucositis if it occurs [see WARNINGS AND PRECAUTIONS].

Dermatologic Reactions

Advise patients about the risks for and the signs and symptoms of dermatologic reactions. Instruct patients to immediately notify their healthcare provider if any skin reactions occur [see WARNINGS AND PRECAUTIONS].

Tumor Lysis Syndrome

Inform patients about the risk of and the signs and symptoms of tumor lysis syndrome. Patients should be instructed to notify their healthcare provider if they experience these symptoms [see WARNINGS AND PRECAUTIONS].

Concomitant Medications

Patients should be instructed to inform their healthcare provider if they are taking any concomitant medications including prescription drugs (such as trimethoprim/sulfamethoxazole and probenecid) and nonprescription drugs (such as nonsteroidal anti-inflammatory drugs) [see DRUG INTERACTIONS].

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females or reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Advise females patients of reproductive potential to use effective contraception during treatment with FOLOTYN and for 6 months after the final dose [see Use In Specific Populations].

Advise males with female partners of reproductive potential to use effective contraception during treatment with FOLOTYN and for at least 3 months after the final dose [see Use In Specific Populations]

Lactation

Advise females women not to breastfeed during treatment with FOLOTYN and for 1 week after the final dose [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Carcinogenicity studies have not been performed with pralatrexate.

Mutagenesis

Pralatrexate did not cause mutations in the Ames test or the Chinese hamster ovary cell chromosome aberration assay. Nevertheless, these tests do not reliably predict genotoxicity for this class of compounds. Pralatrexate did not cause mutations in the mouse micronucleus assay.

Impairment Of Fertility

No fertility studies have been performed.

Use In Specific Populations

Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action [see CLINICAL PHARMACOLOGY], FOLOTYN can cause fetal harm when administered to a pregnant woman. There are insufficient data on FOLOTYN use in pregnant women to evaluate for a drug-associated risk. FOLOTYN was embryotoxic and fetotoxic in rats and rabbits when administered during organogenesis at doses about 1.2% (0.012 times) of the clinical dose on a mg/m² basis. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Pralatrexate was embryotoxic and fetotoxic in rats at intravenous 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, intravenous 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.

Lactation

Risk Summary

There is no data on the presence of pralatrexate in human milk or its effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with FOLOTYN and for 1 week after the last dose.

Females And Males Of Reproductive Potential

FOLOTYN can cause fetal harm when administered to a pregnant woman [see Use In Specific Populations].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiation of FOLOTYN.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with FOLOTYN and for 6 months following the last dose.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with FOLOTYN and for 3 months following the last dose.

Pediatric Use

The safety and effectiveness of FOLOTYN in pediatric patients have not been established.

Geriatric Use

In the Study PDX-008, 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 adverse reactions [see DOSAGE AND ADMINISTRATION].

Renal Impairment

No dosage modification is recommended for patients with mild or moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m² based on MDRD). For patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m²), reduce the recommended dose of FOLOTYN [see DOSAGE AND ADMINISTRATION].

Serious adverse drug reactions, including TEN and mucositis, have been reported in patients with ESRD undergoing dialysis. Avoid the use of FOLOTYN in patients with ESRD with or without dialysis. If the potential benefit of administration justifies the potential risk, monitor renal function and reduce the FOLOTYN dose based on adverse reactions [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].

Overdosage & Contraindications

OVERDOSE

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 healthcare provider. Based on FOLOTYN's mechanism of action, consider the prompt administration of leucovorin.

CONTRAINDICATIONS

None.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

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.

Pharmacodynamics

Pralatrexate exposure-response relationship and the time course of pharmacodynamics responses are unknown.

Pharmacokinetics

Pralatrexate is a racemic mixture of S-and R-diastereomers. The pharmacokinetics of pralatrexate at the recommended dosage of 30 mg/m² once weekly have been evaluated in 10 patients with PTCL. Pralatrexate total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally over a dose range 30 to 325 mg/m² (10.8 times the approved recommended dosage). No accumulation of pralatrexate was observed.

Distribution

Steady-state volume of distribution of pralatrexate S-and R-diastereomers is 105 L and 37 L, respectively. Protein binding of pralatrexate is approximately 67% in vitro.

Elimination

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%).

Metabolism

Pralatrexate is not significantly metabolized by CYP450 isozymes or glucuronidases in vitro.

Excretion

Following a single dose of FOLOTYN 30 mg/m², approximately 34% of the pralatrexate dose was excreted unchanged into urine. Following a radiolabeled pralatrexate dose, 39% (CV = 28%) of the dosewas recovered in urine as unchanged pralatrexate and 34% (CV = 88%) in feces as unchanged pralatrexate and/or any metabolites. 10% (CV = 95%) of the dose was exhaled over 24 hours.

Specific Populations

No clinically meaningful effect on the pharmacokinetics of pralatrexate was observed based on sex. The effect of hepatic impairment on the pharmacokinetics of pralatrexate has not been studied.

Patients With Renal Impairment

Following administration of a single dose of FOLOTYN, mean exposures of the pralatrexate S-diastereomer and R-diastereomer were comparable in patients with mild to moderate (eGFR 30 to 59 mL/min/1.73 m² based on MDRD) renal impairment as compared with severe (eGFR 15 to 29 mL/min/1.73 m²) renal impairment.

The mean fraction of the administered dose excreted as unchanged diastereomers in urine (fe) decreased  with declining renal function [see Use In Specific Populations].

Drug Interaction Studies

Clinical Studies

Coadministration of probenecid (an inhibitor of multidrug resistance-associated protein 2 [MRP2] in vitro) resulted in delayed clearance of pralatrexate.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes

Pralatrexate does not induce or inhibit CYP enzymes.

Transporter Systems

Pralatrexate is a substrate for BCRP, MRP2, MRP3, and OATP1B3, but is not a substrate of P-gp, OATP1B1, OCT2, OAT1, or OAT3. Pralatrexate inhibits MRP2 and MRP3, but does not inhibit P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B1,or OATP1B3. MRP3 is a transporter that may affect the transport of etoposide and teniposide.

Clinical Studies

The efficacy of FOLOTYN was evaluated in Study PDX-008, an open-label, single-arm, multi-center, international trial that enrolled patients with relapsed or refractory PTCL. One hundred and eleven patients received FOLOTYN 30 mg/m² intravenously over 3 to 5 minutes once weekly by for 6 weeks in 7-week cycles until disease progression or unacceptable toxicity. Of the 111 patients treated, 109 patients were evaluable for efficacy. Evaluable patients had histologically confirmed PTCL by independent central review using the Revised European American Lymphoma (REAL) World Health Organization (WHO) disease classification, and relapsed or refractory disease after at least one prior treatment.

The major efficacy outcome measure was overall response rate (complete response, complete response unconfirmed, and partial response) as assessed by International Workshop Criteria (IWC). An additional efficacy outcome measure was duration of response. Response assessments were scheduled at the end of cycle 1 and then every other cycle (every 14 weeks). Duration of response was measured from the first day of documented response to disease progression or death. Response and disease progression were evaluated by independent central review using the IWC.

The median age was 59 years (range: 21 to 85); 68% were male; 72% were White, 13% were Black, 8% were Hispanic and 5% were Asian. Patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (39%), 1 (44%), or 2 (17%). The median time from initial diagnosis to study entry was 1.3 years (range 24 days to 26.8 years). The median number of prior systemic therapies was 3 (range 1 to 12). Approximately 24% of patients (n = 27) did not have evidence of response to any previous therapy. Approximately 63% of patients (n = 70) did not have evidence of response to their most recent prior therapy before entering the study.

Efficacy results are provided in Table 5.

Table 5 : Efficacy Results for Study PDX-008 per Independent Central Review (IWC)

Evaluable Patients
(N=109)
N (%)95% CIMedian Duration of ResponseRange of Duration of Response
Overall Response
CR+CRu+PR29 (27)19, 36287 days (9.4 months)1-503 days
CR/CRu9 (8)
PR20 (18)
Responses ≥ 14 weeks
CR+CRu+PR13 (12)7, 20Not Reached98-503 days
CR/CRu7 (6)
PR6 (6)
Fourteen patients went off treatment in cycle 1; 2 patients were unevaluable for response by IWC due to insufficient materials provided to central review. CR = Complete Response, CRu = Complete Response unconfirmed, PR = Partial Response

The initial response assessment was scheduled at the end of cycle 1. Of the responders, 66% responded within cycle 1. The median time to first response was 45 days (range 37-349 days).

Medication Guide

PATIENT INFORMATION

FOLOTYN®
(FOH-loh-tin)
(pralatrexate) Injection

Read the Patient Information that comes with FOLOTYN before you start treatment and each time you get treated with FOLOTYN. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or treatment. Talk to your doctor if you have any questions about FOLOTYN.

What is FOLOTYN?

FOLOTYN is a prescription anti-cancer (chemotherapy) medicine. FOLOTYN is used to treat people with a type of cancer called Peripheral T-cell Lymphoma (PTCL) that does not go away, gets worse, or comes back after use of another cancer treatment.

What should I tell my doctor before receiving FOLOTYN?

Before you receive FOLOTYN, tell your doctor if you:

  • have liver problems.
  • have kidney problems.
  • have any other medical conditions.
  • are pregnant or plan to become pregnant. FOLOTYN can harm your unborn baby. Talk to your doctor about the best way to prevent pregnancy while taking FOLOTYN. Tell your doctor right away if you become pregnant while taking FOLOTYN.
  • are breast-feeding or plan to breast-feed. It is not known if FOLOTYN passes into breast milk. You and your doctor should decide if you will take FOLOTYN or breast-feed. You should not do both. Talk to your doctor about the best way to feed your baby while you are being treated with FOLOTYN.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how FOLOTYN works, and FOLOTYN may affect how other medicines work. Especially tell your doctor if you take:

  • sulfamethoxazole trimethoprim (Bactrim®, Septra®, Septra DS, Sulfatrim Pediatric, Sulfamethoprim, Sulfamethoprim-DS)
  • non-steroidal anti-inflammatory drugs (NSAIDs)
  • probenecid (Probalan, Col-Probenecid)

Ask your doctor or pharmacist if you are not sure if your medicine is listed above.

Know the medicines you take. Keep a list of them and show it to your doctor or pharmacist each time you start a new medicine.

How will I receive FOLOTYN?

  • FOLOTYN will be given to you as directed by your doctor, as an intravenous (IV) injection into your vein over 3 to 5 minutes.
  • FOLOTYN is usually given in cycles, one time each week for 6 weeks, with no treatment on the 7th  week. Treatment with FOLOTYN may be continued as long as it th is helpful to you.

To lower your chances of harmful side effects, it is important that you take folic acid and vitamin B during your treatment with FOLOTYN. Your doctor will give you specific instructions for vitamin supplementation.

  • You will take folic acid by mouth for 10 days before your first dose of FOLOTYN. Do not take more or less folic acid than your doctor tells you to take. Continue taking folic acid every day until your doctor tells you to stop.
  • Your doctor will give you a vitamin B injection into your muscle (intramuscular) before your first dose of FOLOTYN and about every 8 to 10 weeks during treatment with FOLOTYN.

You should have regular blood tests before and during your treatment with FOLOTYN. Your doctor may change your dose of FOLOTYN or delay treatment based on the results of your blood tests and on your general condition.

What are the possible side effects of FOLOTYN?

FOLOTYN may cause serious side effects, including:

  • Low Blood Cell Counts : FOLOTYN can affect your bone marrow and cause you to have low blood cell counts. Your doctor will do blood tests as needed to check your blood cell counts.
  • Low Platelet Count (thrombocytopenia): Tell your doctor right away if you have any unusual bleeding, such as nosebleeds, or bruising under your skin.
  • Low White Blood Cell Count (neutropenia): A low white blood cell count can cause you to get infections, which may be serious. Serious illness or death can happen if an infection is not treated right away when white blood cell counts are very low. Tell your doctor right away if you have any of the following signs or symptoms of an infection:
    • fever
    • chills
    • cough
    • shortness of breath
    • pain or burning on urination
  • Low Red Blood Cell Count (anemia): Tell your doctor if you have any of these symptoms of anemia during treatment with FOLOTYN:
    • feeling weak, tired, or you get tired easily
    • you look pale
    • you feel short of breath
  • Redness and sores of the mucous membrane lining of the mouth, lips, throat, digestivetract, and genitals (mucositis ). Discomfort or pain due to mucositis may happen as early as a few days after treatment with FOLOTYN. Your doctor should tell you about ways to reduce your risk of getting mucositis, and how to maintain nutrition and control the discomfort from mucositis.
  • Severe skin reactions. Severe skin reactions may happen after treatment with FOLOTYN, especially if you have lymphoma in or under your skin. If your skin reactions are severe, they may lead to serious illness or death. Tell your doctor right away if you have any of the following skin reactions:
    • rash
    • peeling and loss of skin
    • sores
    • blisters
  • Tumor Lys is Syndrome (TLS). FOLOTYN can cause the fast breakdown of certain types of cancer cells. This can lead to TLS. Your doctor may do blood tests to check you for TLS and treat you for TLS if needed.
  • Harm to an unborn baby. Females should avoid becoming pregnant while being treated with FOLOTYN. Talk to your doctor about how to avoid pregnancy while taking FOLOTYN.
  • Fever. Fever is often one of the most common and earliest signs of infection. Follow your doctor's instructions about how often to take your temperature, especially during the days after treatment with FOLOTYN. If you have a fever, tell your doctor or nurse right away.
  • Loss of too much fluid from the body (dehydration). If you feel tired and weak this could be a sign of dehydration. Follow your doctor's instructions for what to do to help prevent or treat dehydration.
  • Shortness of breath. Tell your doctor if this is a problem for you.

Common side effects of FOLOTYN include:

  • nausea
  • vomiting
  • tiredness
  • constipation
  • swelling
  • cough
  • nosebleed
  • diarrhea

Tell your doctor about any side effect that bothers you or that does not go away.

These are not all the possible side effects of FOLOTYN. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You can report side effects to FDA at 1-800-FDA-1088.

General information about FOLOTYN

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. This patient information leaflet summarizes the most important information about FOLOTYN. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about FOLOTYN that is written for health professionals.

For more information, go to www.FOLOTYN.com or call 1-888-255-6788.

What are the ingredients in FOLOTYN?

Active ingredient: pralatrexate

Inactive ingredients : sodium chloride, sodium hydroxide, and hydrochloric acid

What is PTCL?

PTCL is a rare type of non-Hodgkin's lymphoma, a cancer of the lymphatic system. It happens when a type of T-cell (a kind of white blood cell) grows too much. PTCL may be found in different parts of the body, such as the lymph nodes, skin, bone marrow, liver, or spleen.

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Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

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