FOLOTYN - pralatrexate injection 
Allos Therapeutics, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use FOLOTYN® safely and effectively. See full prescribing information for FOLOTYN.
FOLOTYN (pralatrexate injection)
Solution for intravenous injection
Initial U.S. Approval: 2009


INDICATIONS AND USAGE

FOLOTYN is a folate analog metabolic inhibitor indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is based on overall response rate. Clinical benefit such as improvement in progression-free survival or overall survival has not been demonstrated. (1)


DOSAGE AND ADMINISTRATION

  • The recommended dose of FOLOTYN is 30 mg/m2 administered as an intravenous push over 3 to 5 minutes once weekly for 6 weeks in 7-week cycles. (2.1)
  • Supplement patients with vitamin B12 1 mg intramuscularly every 8-10 weeks and folic acid 1.0-1.25 mg orally on a daily basis. (2.2)
  • Treatment interruption or dose reduction to 20 mg/m2 may be needed to manage adverse drug reactions. (2.5)

DOSAGE FORMS AND STRENGTHS

  • Sterile, single-use vials containing pralatrexate at a concentration of 20 mg/mL in the following presentations:
     
    - 20 mg of pralatrexate in 1 mL solution in a vial (20 mg / 1 mL)
     
    - 40 mg of pralatrexate in 2 mL solution in a vial (40 mg / 2 mL) (3)

CONTRAINDICATIONS

  • None. (4)

WARNINGS AND PRECAUTIONS

  • Thrombocytopenia, neutropenia, and anemia may occur. Monitor blood counts and omit or modify dose for hematologic toxicities. (2.5, 5.1)
  • Mucositis may occur. If ≥ Grade 2 mucositis is observed, omit or modify dose. (2.5, 5.2)
  • FOLOTYN can cause fetal harm. Women should avoid becoming pregnant while being treated with FOLOTYN, and pregnant women should be informed of the potential harm to the fetus. (5.4, 8.1)
  • Use caution in patients with moderate to severe renal function impairment. (5.5)
  • Elevated liver function test abnormalities may occur. If liver function test abnormalities are ≥ Grade 3, omit or modify dose. (2.5, 5.6)

ADVERSE REACTIONS

Most common adverse reactions are mucositis, thrombocytopenia, nausea, and fatigue. Most common serious adverse reactions are pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Allos Therapeutics, Inc at 1-888-ALLOS88 (1-888-255-6788) or www.FOLOTYN.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch


DRUG INTERACTIONS

  • Co-administration with probenecid, NSAIDs, and trimethoprim/sulfamethaxazole may result in delayed renal clearance. (7)

USE IN SPECIFIC POPULATIONS

  • Women should be advised against breastfeeding while being treated with FOLOTYN. (8.3)


See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

Revised: 05/2010

FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Peripheral T-cell Lymphoma

2.2 Vitamin Supplementation

2.3 Preparation and Administration Precautions

2.4 Preparation for Intravenous Push Administration

2.5 Monitoring and Dose Modifications

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Bone Marrow Suppression

5.2 Mucositis

5.3 Folic Acid and Vitamin B12 Supplementation

5.4 Pregnancy Category D

5.5 Decreased Renal Function

5.6 Elevated Liver Enzymes

5.7 Dermatologic Reactions

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Need for Folic Acid and Vitamin B12

17.2 Mucositis

17.3 Low Blood Cell Counts

17.4 Concomitant Medications

17.5 Pregnancy/Nursing

17.6 Dermatologic Reactions


FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

FOLOTYN is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is based on overall response rate. Clinical benefit such as improvement in progression-free survival or overall survival has not been demonstrated.

2 DOSAGE AND ADMINISTRATION

FOLOTYN should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

2.1 Peripheral T-cell Lymphoma

The recommended dose of FOLOTYN is 30 mg/m2 administered as an intravenous (IV) push over 3-5 minutes via the side port of a free-flowing 0.9% Sodium Chloride Injection, USP IV line once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity.

2.2 Vitamin Supplementation

Patients should take low-dose (1.0-1.25 mg) oral folic acid on a daily basis. Folic acid should be initiated during the 10-day period preceding the first dose of FOLOTYN, and dosing should continue during the full course of therapy and for 30 days after the last dose of FOLOTYN. Patients should also receive a vitamin B12 (1 mg) intramuscular injection no more than 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 (5.3)].

2.3 Preparation and Administration Precautions

FOLOTYN is a cytotoxic anticancer agent. Caution should be exercised in handling, preparing, and administering of the solution. The use of gloves and other protective clothing is recommended. 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 thoroughly with water.

Several published guidelines for handling and disposal of anticancer agents are available [see References (15)].

2.4 Preparation for Intravenous Push Administration

  1. FOLOTYN vials should be refrigerated at 2-8°C (36-46°F) until use.
  2. FOLOTYN vials should be stored in original carton to protect from light until use.
  3. FOLOTYN is a clear, yellow solution. 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.
  4. The calculated dose of FOLOTYN should be aseptically withdrawn into a syringe for immediate use.
  5. Do not dilute FOLOTYN.
  6. FOLOTYN vials contain no preservatives and are intended for single use only. After withdrawal of dose, discard vial including any unused portion.
  7. Unopened vial(s) of FOLOTYN are stable if stored in the original carton at room temperature for 72 hours. Any vials left at room temperature for greater than 72 hours should be discarded.

2.5 Monitoring and Dose Modifications

Management of severe or intolerable adverse reactions may require dose omission, reduction, or interruption of FOLOTYN therapy.

Monitoring

Complete blood cell counts and severity of mucositis should be monitored weekly. Serum chemistry tests, including renal and hepatic function, should be performed prior to the start of the first and fourth dose of a given cycle.

Dose Modification Recommendations

Prior to administering any dose of FOLOTYN:

Doses may be omitted or reduced based on patient tolerance. Omitted doses will not be made up at the end of the cycle; once a dose reduction occurs for toxicity, do not re-escalate. For dose modifications and omissions, use the guidelines in Tables 1, 2, and 3.

Table 1 FOLOTYN Dose Modifications for Mucositis
Mucositis Gradea on Day of TreatmentActionDose upon Recovery to ≤ Grade 1

a Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 3.0)

Grade 2 Omit dose Continue prior dose
Grade 2 recurrence Omit dose 20 mg/m2
Grade 3 Omit dose 20 mg/m2
Grade 4 Stop therapy
Table 2 FOLOTYN Dose Modifications for Hematologic Toxicities
Blood Count on Day of TreatmentDuration of ToxicityActionDose upon Restart
Platelet < 50,000/μL 1 week Omit dose Continue prior dose
2 weeks Omit dose 20 mg/m2
3 weeks Stop therapy
ANC 500-1,000/μL and no fever 1 week Omit dose Continue prior dose
ANC 500-1,000/μL with fever
or
ANC < 500/μL
1 week Omit dose, give G‑CSF or GM‑CSF support Continue prior dose with G‑CSF or GM‑CSF support
2 weeks or recurrence Omit dose, give G‑CSF or GM‑CSF support 20 mg/m2 with G‑CSF or GM‑CSF support
3 weeks or 2nd recurrence Stop therapy
Table 3 FOLOTYN Dose Modifications for All Other Treatment-related Toxicities
Toxicity Grade a on Day of TreatmentActionDose upon Recovery to ≤ Grade 2

a Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 3.0)

Grade 3 Omit dose 20 mg/m2
Grade 4 Stop therapy

3 DOSAGE FORMS AND STRENGTHS

FOLOTYN is available in sterile, single-use vials containing pralatrexate at a concentration of 20 mg/mL in the following presentations:

20 mg of pralatrexate in 1 mL solution in a vial (20 mg / 1 mL)

40 mg of pralatrexate in 2 mL solution in a vial (40 mg / 2 mL)

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Bone Marrow Suppression

FOLOTYN can suppress bone marrow function, manifested by thrombocytopenia, neutropenia, and anemia. Dose modifications are based on ANC and platelet count prior to each dose [see Dosage and Administration (2.5) and Adverse Reactions (6)].

5.2 Mucositis

Treatment with FOLOTYN may cause mucositis. If ≥ Grade 2 mucositis is observed, omit dose and follow guidelines in Section 2.5, Table 1 [see Dosage and Administration (2.5)].

5.3 Folic Acid and Vitamin B12 Supplementation

Patients should be instructed to take folic acid and receive vitamin B12 to potentially reduce treatment-related hematological toxicity and mucositis [see Dosage and Administration (2.2)].

5.4 Pregnancy Category D

FOLOTYN can cause fetal harm when administered to a pregnant woman. FOLOTYN was embryotoxic and fetotoxic in rats and rabbits. 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 [see Use in Specific Populations (8.1)].

5.5 Decreased Renal Function

Although FOLOTYN has not been formally tested in patients with renal impairment, caution is advised when administering FOLOTYN to patients with moderate to severe impairment. Monitor patients for renal function and systemic toxicity due to increased drug exposure [see Clinical Pharmacology (12.3)].

5.6 Elevated Liver Enzymes

Liver function test abnormalities have been observed after FOLOTYN administration. Persistent liver function test abnormalities may be indicators of liver toxicity and require dose modification. Monitor patients for liver function [see Dosage and Administration (2.5)].

5.7 Dermatologic Reactions

Dermatologic reactions have been reported in clinical studies and post-marketing safety reports in patients treated with FOLOTYN. Dermatologic reactions have included skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN). These reactions, as well as tumor lysis syndrome, may involve skin and subcutaneous sites of known lymphoma. Skin reactions may be progressive and increase in severity with further treatment. Severe skin reactions have been associated with fatal outcomes. Patients with skin reactions should be monitored closely, and if skin reactions are severe, FOLOTYN should be withheld or discontinued.

6 ADVERSE REACTIONS

The most common adverse reactions observed in patients with peripheral T-cell lymphoma (PTCL) treated with FOLOTYN were mucositis, thrombocytopenia, nausea, and fatigue.

6.1 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.

The safety of FOLOTYN was evaluated in 111 PTCL patients in a single-arm clinical study in which patients received a starting dose of 30 mg/m2 once weekly for 6 weeks in 7-week cycles. The median duration of treatment was 70 days (range 1-540 days).

Most Frequent Adverse Reactions

Table 4 summarizes the most frequent adverse reactions, regardless of causality, using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, version 3.0).

Table 4 Adverse Reactions Occurring in PTCL Patients (Incidence ≥ 10% of patients)
N=111
TotalGrade 3Grade 4
Preferred TermN%N%N%

aStomatitis or mucosal inflammation of the gastrointestinal and genitourinary tracts.

bFive patients with platelets < 10,000/μL

cAlanine aminotransferase, aspartate aminotransferase, and transaminases increased

Any Adverse Event 111 100 48 43 34 31
    Mucositisa78 70 19 17 4 4
    Thrombocytopeniab45 41 15 14 21 19b
    Nausea 44 40 4 4 0 0
    Fatigue 40 36 5 5 2 2
    Anemia 38 34 17 15 2 2
    Constipation 37 33 0 0 0 0
    Pyrexia 36 32 1 1 1 1
    Edema 33 30 1 1 0 0
    Cough 31 28 1 1 0 0
    Epistaxis 29 26 0 0 0 0
    Vomiting 28 25 2 2 0 0
    Neutropenia 27 24 14 13 8 7
    Diarrhea 23 21 2 2 0 0
    Dyspnea 21 19 8 7 0 0
    Anorexia 17 15 3 3 0 0
    Hypokalemia 17 15 4 4 1 1
    Rash 17 15 0 0 0 0
    Pruritus 16 14 2 2 0 0
    Pharyngolaryngeal pain 15 14 1 1 0 0
    Liver function test abnormalc14 13 6 5 0 0
    Abdominal pain 13 12 4 4 0 0
    Pain in extremity 13 12 0 0 0 0
    Back pain 12 11 3 3 0 0
    Leukopenia 12 11 3 3 4 4
    Night sweats 12 11 0 0 0 0
    Asthenia 11 10 1 1 0 0
    Tachycardia 11 10 0 0 0 0
    Upper respiratory tract infection 11 10 1 1 0 0

Serious Adverse Events

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. Deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients treated on all FOLOTYN trials at doses ranging from 30 to 325 mg/m2.

Discontinuations

Twenty-three percent of patients (n = 25) discontinued treatment with FOLOTYN due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment were mucositis (6%, n = 7) and thrombocytopenia (5%, n = 5).

Dose Modifications

The target dose of FOLOTYN was 30 mg/m2 once weekly for 6 weeks in 7-week cycles. The majority of patients (69%, n = 77) remained at the target dose for the duration of treatment. Overall, 85% of scheduled doses were administered.

7 DRUG INTERACTIONS

In vitro studies indicate that pralatrexate is not a substrate, inhibitor, or inducer of CYP450 isoenzymes and has low potential for drug-drug interactions at CYP450 isoenzymes [see 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 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.

Due to the contribution of renal excretion (approximately 34%) to the overall clearance of pralatrexate, concomitant administration of drugs that are subject to substantial renal clearance (eg, NSAIDs, trimethoprim/sulfamethoxazole) may result in delayed clearance of pralatrexate.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.4)].

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).

No dosage adjustment is required in elderly patients with normal renal function [see Clinical Pharmacology (12.3)]

8.6 Hepatic Impairment

Formal studies have not been performed with FOLOTYN 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.

8.7 Renal Impairment

[see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

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 the prompt administration of leucovorin should be considered.

11 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:

Structural Formula

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-use 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-use vials at a concentration of 20 mg/mL.

12 CLINICAL PHARMACOLOGY

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

Absorption

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.

Distribution

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 in vitro studies using MDR1-MDCK and Caco-2 cell systems, pralatrexate was not a substrate for P-glycoprotein (Pgp)-mediated transport nor did it inhibit Pgp-mediated transport.

Metabolism

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. In vitro studies indicated that pralatrexate has low potential to induce or inhibit the activity of CYP450 isozymes.

Excretion

A mass balance study has not been performed. 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.

Patients with 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. In a population pharmacokinetic analysis drug clearance decreased with decreasing creatinine clearance [see Warnings and Precautions (5.5)].

Patients with Hepatic Impairment

Pralatrexate has not been studied in patients with hepatic impairment.

Effects of Age and Gender

Due to the contribution of renal excretion to overall clearance of pralatrexate, age-related decline in renal function may lead to a reduction in clearance and a commensurate increase in plasma exposure. There was no significant effect of gender on pharmacokinetics.

13 NONCLINICAL TOXICOLOGY

13.1 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.

14 CLINICAL STUDIES

Peripheral T-cell Lymphoma (PTCL)

The safety and efficacy of FOLOTYN was evaluated in an open-label, single-arm, multi-center, international trial that enrolled 115 patients with relapsed or refractory PTCL. One hundred and eleven patients were treated with FOLOTYN at 30 mg/m2 once weekly by IV push over 3-5 minutes 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 primary efficacy endpoint was overall response rate (complete response, complete response unconfirmed, and partial response) as assessed by International Workshop Criteria (IWC). The key secondary efficacy endpoint 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 of treated patients was 59.0 years (range 21-85); 68% were male and 32% were female. Most patients were White (72%) and other racial origins included: Black (13%), Hispanic (8%), Asian (5%), other and unknown (<1% each). Patients had an Eastern Cooperative Oncology Group (ECOG) performance status at study entry of 0 (39%), 1 (44%), or 2 (17%). The median time from initial diagnosis to study entry was 15.6 months (range 0.8 – 322.3).

The median number of prior systemic therapies was 3 (range 1-12). Approximately one-fourth of patients (24%, n = 27) did not have evidence of response to any previous therapy. Approximately two-thirds of patients (63%, n = 70) did not have evidence of response to their most recent prior therapy before entering the study.

In all evaluable patients (n = 109) treated with FOLOTYN, the response rate, as determined by independent central review by IWC, was 27% (n = 29) (Table 5).

Table 5 Response Analysis per Independent Central Review (IWC)
Evaluable Patients
(N=109)

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

N (%)95% CIMedian Duration of ResponseRange of Duration of Response
Overall Response
CR+CRu+PR 29 (27) 19, 36 287 days
(9.4 months)
1-503 days
CR/CRu 9 (8)
PR 20 (18)
Responses ≥ 14 weeks
CR+CRu+PR 13 (12) 7, 20 Not Reached 98-503 days
CR/CRu 7 (6)
PR 6 (6)

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).

15 REFERENCES

  1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165.
  2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/o tm/otm_vi/otm_vi_2.html
  3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
  4. Polovich, M., White, J. M., & Kelleher, L. O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

16 HOW SUPPLIED/STORAGE AND HANDLING

FOLOTYN is available in single-use clear glass 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 48818-001-01: 20 mg of pralatrexate in 1 mL solution in a vial (20 mg / 1 mL)

NDC 48818-001-02: 40 mg of pralatrexate in 2 mL solution in a vial (40 mg / 2 mL)

Vials must be stored refrigerated at 2-8°C (36-46°F) (see USP Controlled Cold Temperature) in original carton to protect from light.

Handle and dispose of FOLOTYN according to guidelines issued for cytotoxic drugs, including the use of gloves and other protective clothing to prevent skin contact [see References (15)].

Each vial of FOLOTYN is intended for single use only. Any unused drug remaining after injection must be discarded.

Rx only

17 PATIENT COUNSELING INFORMATION

See FDA-approved Patient Package Insert.

Patients should be instructed to read the Patient Package Insert carefully.

17.1 Need for Folic Acid and Vitamin B12

Patients treated with FOLOTYN must be instructed to take folic acid and vitamin B12 as a prophylactic measure to potentially reduce possible side effects [see Dosage and Administration (2.2)].

17.2 Mucositis

Physicians should discuss with patients the signs and symptoms of mucositis. Patients should be instructed on ways to reduce the risk of its development, and/or ways to maintain nutrition and control discomfort from mucositis if it occurs.

17.3 Low Blood Cell Counts

Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any signs of infection develop, including fever. Patients should also be instructed to contact their physician if bleeding or symptoms of anemia occur.

17.4 Concomitant Medications

Patients should be instructed to inform their physician if they are taking any concomitant medications including prescription drugs (such as trimethoprim/sulfamethoxazole) and nonprescription drugs (such as nonsteroidal anti-inflammatory drugs) [see Drug Interactions (7)].

17.5 Pregnancy/Nursing

Patients should be instructed to tell their physician if they are pregnant or plan to become pregnant due to the risk of fetal harm. Patients should be instructed to tell their physician if they are nursing.

17.6 Dermatologic Reactions

Physicians should discuss with patients the signs and symptoms of dermatologic reactions. Patients should be made aware to immediately notify their physician if any untoward skin reactions occur [see Warnings and Precautions (5.7)].

ALLOS Therapeutics

Manufactured for:
Allos Therapeutics, Inc.
Westminster, CO 80020
1-888-ALLOS88 (1-888-255-6788)

FOLOTYN is a registered trademark of Allos Therapeutics, Inc.

U.S. Patents: 6,028,071 and 7,622,470

Rev. 2: May 2010
© 2010 Allos Therapeutics, Inc. All rights reserved.

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:

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 works. Especially tell your doctor if you take:

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?

To lower your chances of harmful side effects, it is important that you take folic acid and vitamin B12 during your treatment with FOLOTYN. Your doctor will give you specific instructions for vitamin supplementation.

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.

Redness and sores of the mucous membrane lining of the mouth, lips, throat, digestive tract, 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.

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 of any of the following skin reactions:

 
  • Rash
  • Peeling and loss of skin
  • Sores
  • Blisters

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.

ALLOS™
THERAPEUTICS

Allos Therapeutics, Inc.
Westminster, CO 80020
Issued: May 2010

FOLOTYN®
(pralatrexate injection)

FOLOTYN is a trademark of Allos Therapeutics, Inc.

© 2010 Allos Therapeutics, Inc. All rights reserved.

PACKAGE CARTON - FOLOTYN 20 mg/1 mL Vial

NDC 48818-001-01

FOLOTYN™

(pralatrexate injection)

20 mg/mL

For intravenous use

Rx only

1 mL

PACKAGE CARTON - FOLOTYN 20 mg/1 mL Vial

PACKAGE CARTON - FOLOTYN 40 mg/2 mL Vial

NDC 48818-001-02

FOLOTYN™

(pralatrexate injection)

40 mg/2 mL

(20 mg/mL)

For intravenous use

Rx only

2 mL

PACKAGE CARTON - FOLOTYN 40 mg/2 mL Vial

VIAL – FOLOTYN 20 mg/1 ml

NDC 48818-001-01

FOLOTYN™

(pralatrexate injection)

20 mg/mL

Rx only

1 mL

VIAL – FOLOTYN 20 mg/1 ml

VIAL – FOLOTYN 40 mg/2 ml

NDC 48818-001-02

FOLOTYN™

(pralatrexate injection)

40 mg/2 mL
(20 mg/mL)

Rx only

2 mL

VIAL – FOLOTYN 40 mg/1 ml

FOLOTYN 
pralatrexate   injection
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)48818-001
Route of AdministrationINTRAVENOUSDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
pralatrexate (pralatrexate) pralatrexate20 mg  in 1 mL
Inactive Ingredients
Ingredient NameStrength
sodium chloride 
sodium hydroxide 
hydrochloric acid 
water 
Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
148818-001-011 VIAL In 1 CARTONcontains a VIAL, SINGLE-USE
11 mL In 1 VIAL, SINGLE-USEThis package is contained within the CARTON (48818-001-01)
248818-001-021 VIAL In 1 CARTONcontains a VIAL, SINGLE-USE
22 mL In 1 VIAL, SINGLE-USEThis package is contained within the CARTON (48818-001-02)

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02246809/24/2009

Labeler - Allos Therapeutics, Inc. (835393869)
Revised: 05/2010Allos Therapeutics, Inc.