Pralatrexate

{{DrugProjectFormSinglePage |authorTag=Alberto Plate [1] |genericName=Pralatrexate |aOrAn=an |drugClass=antimetabolite, antineoplastic agent |indicationType=treatment |indication=patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) |adverseReactions=edema, constipation, nausea, anemia, neutropenia, thrombocytopenia, cough and fatigue |blackBoxWarningTitle=TITLE |blackBoxWarningBody=Condition Name: (Content) |fdaLIADAdult====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 Pralatrexate. Continue folic acid during the full course of therapy and for 30 days after the last dose of Pralatrexate.
• Vitamin B12: Administer vitamin B12 1 mg intramuscularly within 10 weeks prior to the first dose of Pralatrexate and every 8-10 weeks thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with Pralatrexate.

Dosing and Administration

• The recommended dose of Pralatrexate 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 The calculated dose of Pralatrexate should be aseptically withdrawn into a syringe for immediate use. Do not dilute Pralatrexate.
• Pralatrexate 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 Pralatrexate therapy.

Monitoring

• Monitor complete blood cell counts and severity of mucositis at baseline and weekly. Perform serum chemistry tests, including renal function 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 Pralatrexate:

• Mucositis should be ≤ Grade 1.
• Platelet count should be ≥ 100,000/mcL for first dose and ≥ 50,000/mcL for all subsequent doses.
• Absolute neutrophil count (ANC) should be ≥ 1,000/mcL.
• 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.

Special Handling Precautions

• Pralatrexate 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 Pralatrexate comes in contact with the skin, immediately and thoroughly wash with soap and water. If Pralatrexate comes in contact with mucous membranes, flush thoroughly with water.

• Several published guidelines for handling and disposal of anticancer agents are available:
• Pralatrexate vials should be refrigerated at 2-8°C (36-46°F) until use.
• Pralatrexate vials should be stored in original carton to protect from light until use.
• Pralatrexate vials contain no preservatives and are intended for single use only. After withdrawal of dose, discard vial including any unused portion.
• Unopened vial(s) of Pralatrexate 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.

|offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Pralatrexate in adult patients. |offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Pralatrexate in adult patients. |offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Pralatrexate in pediatric patients. |offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Pralatrexate in pediatric patients. |contraindications=None |warnings=====Bone Marrow Suppression====

• Pralatrexate can cause bone marrow suppression, manifested by thrombocytopenia, neutropenia, and/or anemia. Monitor complete blood counts and omit and/or reduce the dose based on ANC and platelet count prior to each dose as outlined in Section 2.2 TABLE 2. Administer vitamin B12 and instruct patients to take folic acid to reduce the risk of treatment-related hematological toxicity.

Mucositis

• Pralatrexate can cause mucositis. Monitor for mucositis weekly and if ≥ Grade 2 mucositis is observed, omit and/or reduce the dose as outlined in Section 2.2 TABLE 1. Administer vitamin B12 and instruct patients to take folic acid to reduce the risk of mucositis.

Dermatologic Reactions

• Pralatrexate can cause severe dermatologic reactions, which may result in death. These dermatologic reactions have been reported in clinical studies (14/663 patients [2.1%]) and post marketing experience, and have included skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN). They may be progressive and increase in severity with further treatment, and may involve skin and subcutaneous sites of known lymphoma. Monitor patients with dermatologic reactions closely, and if severe, withhold or discontinue Pralatrexate.

Tumor Lysis Syndrome

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

Hepatic Toxicity

• Pralatrexate can cause hepatic toxicity and liver function test abnormalities. 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.

Risk of Increased Toxicity in the Presence of Impaired Renal Function

• Patients with moderate to severe renal function impairment may be at greater risk for increased exposure and toxicity. Monitor patients for renal function and systemic toxicity and adjust dosing accordingly.
• Serious adverse drug reactions including toxic epidermal necrolysis and mucositis were reported in patients with end stage renal disease (ESRD) undergoing dialysis who were administered Pralatrexate therapy. Avoid Pralatrexate use in patients with end stage renal disease including those undergoing dialysis unless the potential benefit justifies the potential risk.

Embryo-Fetal Toxicity

• Pralatrexate can cause fetal harm when administered to a pregnant woman. Pralatrexate 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.

|clinicalTrials=The following serious adverse reactions are described below and elsewhere in the labeling:

• Bone Marrow Suppression
• Mucositis
• Dermatologic Reactions
• Tumor Lysis Syndrome
• Hepatic Toxicity

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

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 Pralatrexate 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 cyc

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).

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 Pralatrexate 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 Pralatrexate trials at doses ranging from 30 to 325 mg/m2.

Discontinuations

• Twenty-three percent of patients (n = 25) discontinued treatment with Pralatrexate 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 Pralatrexate 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.

|postmarketing=Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dermatologic Reactions

• Toxic epidermal necrolysis, sometimes fatal, has been reported during post-marketing use of Pralatrexate Fatal cases have been reported following the first dose of Pralatrexate including when a reduced dose is given, and have been reported in patients with end-stage renal disease undergoing dialysis.

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

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

|FDAPregCat=D |useInPregnancyFDA=*Pralatrexate 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. |useInNursing=*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 Pralatrexate taking into account the importance of Pralatrexate to the mother. |useInPed=*Pediatric patients were not included in clinical studies with Pralatrexate. The safety and effectiveness of Pralatrexate in pediatric patients have not been established. |useInGeri=*In the PTCL efficacy study, 36% of patients (n = 40) were 65 years of age and over. No overall differences in efficacy and safety were observed in patients based on age (< 65 years compared with ≥ 65 years). Due to the contribution of renal excretion to overall clearance of pralatrexate (approximately 34%), age-related decline in renal function may lead to a reduction in clearance and a commensurate increase in plasma exposure. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Since elderly patients may be at higher risk, monitor more closely. Omit dose and subsequently adjust or discontinue therapy for exposure related toxicity. |useInRenalImpair=*The safety, efficacy and pharmacokinetics of Pralatrexate have not been evaluated in patients with renal impairment.

• The risk for toxicity may be greater when administering Pralatrexate to patients with moderate-to-severe impairment due to the contribution of renal excretion (approximately 34%) to the overall clearance of pralatrexate. Serious adverse drug reactions, including TEN and mucositis have been reported in patients with ESRD undergoing dialysis. Monitor patients for renal function and for systemic toxicity due to increased drug exposure and adjust dosing accordingly. Avoid the use of Pralatrexate in patients with end stage renal disease undergoing dialysis unless the potential benefit justifies the potential risk.

|useInHepaticImpair=*The safety, efficacy and pharmacokinetics of Pralatrexate have not been evaluated in patients with hepatic impairment. Patients with the following laboratory values were excluded from the pralatrexate lymphoma clinical trials: total bilirubin > 1.5 mg/dL; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN); and AST or ALT > 5 × ULN if documented hepatic involvement with lymphoma. Treatment with Pralatrexate can cause hepatic toxicity and liver function test abnormalities. |overdose=*No specific information is available on the treatment of overdosage of Pralatrexate If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. Based on Pralatrexate's mechanism of action, consider the prompt administration of leucovorin. |drugBox={{Drugbox2 | Verifiedfields = changed | verifiedrevid = 461750802 | IUPAC_name = N-(4-{1-[(2,4-diaminopteridin-6-yl)methyl]but-3-yn-1-yl}benzoyl)-L-glutamic acid | image = Pralatrexate Structue.png | width = 300

| tradename = Pralatrexate | Drugs.com = Monograph | licence_US = Pralatrexate | pregnancy_AU = | pregnancy_US = | pregnancy_category = D | legal_AU = | legal_CA = | legal_UK = | legal_US = Rx-only | legal_status = | routes_of_administration = Intravenous

| bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion =

| CAS_number_Ref =  ^N | CAS_number = 146464-95-1 | ATC_prefix = L01 | ATC_suffix = BA05 | PubChem = 148121 | DrugBank_Ref =  ^Y | DrugBank = | ChEBI_Ref =  ^N | ChEBI = 71223 | ChemSpiderID_Ref =  ^Y | ChemSpiderID = 130578 | UNII_Ref =  ^Y | UNII = A8Q8I19Q20 | ChEMBL_Ref =  ^N | ChEMBL = 1201746

| C=23 | H=23 | N=7 | O=5 | molecular_weight = 477.47 g/mol | smiles = O=C(O)[C@@H](NC(=O)c1ccc(cc1)C(CC#C)Cc2nc3c(nc2)nc(nc3N)N)CCC(=O)O | InChI = 1/C23H23N7O5/c1-2-3-14(10-15-11-26-20-18(27-15)19(24)29-23(25)30-20)12-4-6-13(7-5-12)21(33)28-16(22(34)35)8-9-17(31)32/h1,4-7,11,14,16H,3,8-10H2,(H,28,33)(H,31,32)(H,34,35)(H4,24,25,26,29,30)/t14?,16-/m0/s1 | InChIKey = OGSBUKJUDHAQEA-WMCAAGNKBV | StdInChI_Ref =  ^Y | StdInChI = 1S/C23H23N7O5/c1-2-3-14(10-15-11-26-20-18(27-15)19(24)29-23(25)30-20)12-4-6-13(7-5-12)21(33)28-16(22(34)35)8-9-17(31)32/h1,4-7,11,14,16H,3,8-10H2,(H,28,33)(H,31,32)(H,34,35)(H4,24,25,26,29,30)/t14?,16-/m0/s1 | StdInChIKey_Ref =  ^Y | StdInChIKey = OGSBUKJUDHAQEA-WMCAAGNKSA-N }} |mechAction=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. |structure=Pralatrexate has the chemical name (2S)-2-4-(1RS)-1-(2, 4-diaminopteridin-6-yl)methylbut-3-ynylbenzoylaminopentanedioic acid. The structural formula is as follows:

The molecular formula is C23H23N7O5 and the molecular weight is 477.48 g/mol. |PK=====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.

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

• 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.

|nonClinToxic====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.

|clinicalStudies====Peripheral T-cell Lymphoma (PTCL)===

• The safety and efficacy of Pralatrexate 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 Pralatrexate 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 Pralatrexate, the response rate, as determined by independent central review by IWC, was 27% (n = 29) (TABLE 5).

|howSupplied=Pralatrexate 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)

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

|packLabel=

|alcohol=Alcohol-Pralatrexate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. |brandNames=*Folotyn }}