Folotyn

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• bone marrow suppression--fever, chills, cold or flu symptoms, pale skin, easy bruising or bleeding, red or pink urine, painful mouth sores, cough, trouble breathing, feeling light-headed, rapid heart rate;
• dehydration--feeling very thirsty or hot, are unable to urinate, and have heavy sweating or hot and dry skin;
• low potassium--confusion, uneven heart rate, extreme thirst, increased urination, leg discomfort, muscle weakness or limp feeling);
• severe skin reaction -- fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• nausea, vomiting, loss of appetite, diarrhea, constipation;
• tired feeling;
• swelling; or
• mild rash or itching.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• Allos Therapeutics, Inc

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Folotyn crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Folotyn.

Pralatrexate is injected into a vein through an IV. A healthcare provider will give you this injection.

Pralatrexate is usually given once per week for up to 6 weeks at a time. Follow your doctor's instructions.

Your doctor may have you take folic acid supplements starting 10 days before your first dose of pralatrexate and ending 30 days after your last dose. Your may also receive vitamin B12 injections every 8 to 10 weeks during treatment. This can help protect your blood cells from some of the side effects of pralatrexate. Follow your doctor's medication instructions very closely.

Pralatrexate can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests.

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

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

Designated an orphan drug by FDA for this condition.2

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

Administer by rapid injection over 3–5 minutes.1

Dosage

Adults

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.)

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 notbe re-escalated.1

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).

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.)

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

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

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

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

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

Safety and efficacy not established.1

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

Safety and efficacy not established.1

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

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

Storage

Parenteral

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

• 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

General Dosing and Administration

Pretreatment Vitamin Supplementation

Folic Acid: Patients should take folic acid 1.0-1.25 mg orally once daily beginning 10 days before the first dose of Folotyn. Continue folic acid during the full course of therapy and for 30 days after the last dose of Folotyn [see Warnings and Precautions (5.1, 5.2)].

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 (5.1, 5.2)].

Dosing and Administration

The recommended dose of Folotyn is 30 mg/m2 administered as an intravenous push over 3-5 minutes via the side port of a free-flowing 0.9% Sodium Chloride Injection, intravenous line once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity. The calculated dose of Folotyn should be aseptically withdrawn into a syringe for immediate use. Do not dilute Folotyn.

For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m2), the recommended dose of Folotyn is 15 mg/m2.

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.

Monitoring and Dose Modifications

Management of severe or intolerable adverse reactions may require dose omission, reduction, or discontinuation of Folotyn therapy.

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.

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.

For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m2), the recommended starting dose of Folotyn is 15 mg/m2 with dose modification to 10 mg/m2 for the toxicities specified in Tables 1, 2, and 3.

Special Handling 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 available1-4.

Folotyn is available as a clear yellow solution in sterile, single-dose 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)

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.

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.

Elimination

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.

Excretion

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

Pharmacokinetics in Specific Populations

Renal Impairment

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

Hepatic Impairment

Pralatrexate has not been studied in patients with hepatic impairment.

Gender

There was no significant effect of gender on pharmacokinetics.

Drug Interactions

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

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

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

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

Folotyn (pralatrexate) is a cancer medication.

Folotyn is used to treat T-cell lymphoma that has spread throughout the body. It is given for relapsed T-cell lymphoma, or after other medications have been tried without successful treatment.

Folotyn may also be used for purposes not listed in this medication guide.