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PRALAtrexate
Pralatrexate is a folate analog metabolic inhibitor that competitively inhibits dihydrofolate reductase (DHFR) and polyglutamylation by the enzyme folylpolyglutamyl synthetase (FPGS) in cells expressing reduced folate carrier type 1 (RFC-1). This inhibition results in the inhibition of RNA synthesis, DNA replication and cancer growth and apoptosis.
Following IV injection (30 mg/m2 over 3–5 minutes) once weekly for 6 weeks in 7-week cycles, Cmax and AUC increased proportionally with dose. PK was stable over multiple cycles and no accumulation of pralatrexate was observed.
| PPB | 67% - 84% |
Pralatrexate is not significantly metabolized by the phase I hepatic CYP450 isozymes or phase II hepatic glucuronidases.
| Half-life |
12-18 hours |
| Feces |
34% |
| Urine |
39% parent drug (racemic pralatrexate) |
- Peripheral T-cell lymphoma (PTCL)
(Includes conditional approvals)
Refer to the product monograph for a full list of approved indications.
Emetogenic Potential:
The following table lists adverse effects that occurred in ≥10% of patients in the single arm phase II trial in relapsed or refractory peripheral T-cell lymphoma (PTCL). Severe, life-threatening or post-marketing adverse events are also included.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Cardiotoxicity (<1%) | E | |||
| Tachycardia (10%) | E | ||||
| Dermatological | Other (11%) - night sweats | E | |||
| Rash, pruritus (15%) (may be severe - TEN) | I E | ||||
| Gastrointestinal | Abdominal pain (12%) | E | |||
| Anorexia, weight loss (15%) | E | ||||
| Constipation (33%) | E | ||||
| Dehydration (4%) (severe) | E D | ||||
| Diarrhea (21%) | E | ||||
| Dyspepsia (10%) | E | ||||
| Mucositis (70%) (may be severe) | E | ||||
| Nausea, vomiting (40%) | E | ||||
| General | Edema (30%) | E | |||
| Fatigue (36%) | E | ||||
| Fever, chills (32%) | E | ||||
| Hematological | Anemia (34%) | E | |||
| Myelosuppression (41%) (including bleeding; may be severe) | E | ||||
| Hepatobiliary | ↑ LFTs (13%) (may be severe) | E | |||
| Hypersensitivity | Infusion related reaction (<10%) | E | |||
| Infection | Infection (54%) (may be severe) | E | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (15%) (↓ K) | E | |||
| Tumor lysis syndrome (1%) | E | ||||
| Musculoskeletal | Musculoskeletal pain (14%) (including pharyngolaryngeal pain) | E | |||
| Nervous System | Headache (12%) | E | |||
| Renal | Renal failure (<10%) | E | |||
| Respiratory | Cough, dyspnea (28%) | E | |||
| Epistaxis (26%) | E | ||||
| Pneumonitis (1%) (including ARDS) | E | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for pralatrexate include mucositis, infection, myelosuppression, nausea, vomiting, fatigue, anemia, constipation, fever, chills, edema, cough and dyspnea.
Pralatrexate may cause severe and life-threatening mucositis including stomatitis or mucosal inflammation of gastrointestinal and genitourinary tracts. The median time to onset for ≥ grade 3 mucosal inflammation was 15 days with a median duration of 13 days.
Fatal cases of hematologic toxicity (thrombocytopenia, neutropenia and/or anemia) have been reported. The median time to onset of ≥ grade 3 thrombocytopenia was 15 days with a median duration of 16 days. None of the thrombocytopenic events were associated with ≥ grade 3 bleeding events. The median time to onset of ≥ grade 3 neutropenia was 22 days with a median duration of 8 days.
Severe infections including pneumonia, sepsis, septic shock, and herpes zoster have been reported and may be fatal.
Severe and potentially life-threatening dermatologic reactions, including skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN), have been reported. Skin reaction may be progressive and increase in severity with continued treatment and may also involve skin and subcutaneous tissues which are affected by lymphoma.
Severe and potentially life-threatening cases of pulmonary toxicity have been reported.
Refer to protocol by which patient is being treated.
Premedications:
-
Folic acid 1 to 1.25 mg PO daily: start 10 days prior to first pralatrexate dose; continue during treatment and for 30 days after last pralatrexate dose.
-
Vitamin B12 1 mg IM: administer within 10 weeks prior to first pralatrexate dose and every 8 to 10 weeks thereafter (after first dose, subsequent B12 doses may be administered on the same day as pralatrexate)
Prior to administering any pralatrexate dose:
-
Mucositis should be ≤ grade 1.
-
Absolute neutrophil count (ANC) should be ≥ 1×109/L.
-
Platelet count should be ≥ 100×109/L for first dose and ≥ 50×109/L for all subsequent doses.
Continue until disease progression or unacceptable toxicity.
Refer to the PRAL regimen monograph for details on an alternate schedule (doses given weekly x 3, with 1 week rest).
Do not make up omitted doses at the end of a cycle.
Refer to the PRAL regimen monograph for dose modifications of doses given in the alternate schedule.
Standard Schedule (6 weeks on, 1 week off):
Dose Levels:
| Dose Level | Pralatrexate dose (mg/m2) | Pralatrexate dose in Patients with Severe Renal Impairment (mg/m2) |
| 0 | 30 | 15 |
| -1 | 20 | 10 |
| -2 | Discontinue | |
Non-Hematologic toxicities:
| Toxicity on Day of Treatment | Grade | Action† |
| Mucositis | 2 | Hold until recovery to ≤ grade 1; restart at same dose |
| 2 recurrence or grade 3 | Hold until recovery to ≤ grade 1; restart at 1 dose level ↓ | |
| 4 | Discontinue | |
| All other non-Hematologic toxicities | 3 | Hold until recovery to ≤ grade 2; restart at 1 dose level ↓ |
| 4 | Discontinue |
† Do not re-escalate dose after a reduction due to toxicity.
Hematologic Toxicities
| Toxicity on Day of Treatment | Duration of toxicity | Action*† |
| Platelet < 50 x 109/L | 1 week | Hold; restart at same dose |
| 2 weeks | Hold; restart at 1 dose level ↓ | |
| 3 weeks | Discontinue | |
| ANC 0.5-1 x 109/L and no fever | 1 week | Hold; restart at same dose |
|
ANC 0.5-1 x 109/L with fever or ANC < 0.5 x 109/L |
1 week | Hold, give G-CSF support; restart at same dose |
| 2 weeks or recurrence | Hold, give G-CSF support; restart at 1 dose level ↓ | |
| 3 weeks or 2nd recurrence | Discontinue | |
|
*Administer subsequent doses only when platelet count ≥ 50×109/L and ANC ≥ 1×109/L on day of treatment. |
||
The safety, efficacy and pharmacokinetics of pralatrexate have not been evaluated in patients with hepatic impairment. Patients with total bilirubin > ULN, AST or ALT > 2.5 x ULN or AST or ALT > 5 x ULN if documented hepatic lymphoma involvement were excluded from clinical trials.
| Renal Impairment | Pralatrexate Dose (% of Usual Dose) |
| Mild to moderate (CrCl ≥ 30 mL/min) | No dosage adjustment necessary |
| Severe (CrCl 15-29 mL/min) | 50% |
| End-stage renal disease (ESRD), including dialysis | Avoid (unless the potential benefit outweighs risks*) |
*Serious reactions, including fatal cases of TEN and severe mucositis have been reported in patients with end-stage renal disease undergoing dialysis
No overall differences in efficacy and safety were observed in patients ≥65 years compared with patients <65 years. No dose adjustment required; however, close monitoring for toxicity is recommended.
There was no significant effect of gender on pharmacokinetics.
No significant effect of ethnic origin on pharmacokinetics observed.
The safety and effectiveness of pralatrexate have not been established.
-
Pralatrexate is for intravenous use only.
-
Administered undiluted as an intravenous push over 3-5 minutes into the line of a free-flowing 0.9% sodium chloride Injection.
- Refrigerate at 2-8°C; protect from light.
- Patients with known hypersensitive to pralatrexate, any ingredient in the formulation or component of the container.
-
Patients should be cautioned not to drive cars, use machines or perform hazardous tasks if they experience fatigue.
Other Drug Properties:
-
Carcinogenicity:
No data
-
Mutagenicity:
No data
-
Embryotoxicity:
Documented in animals
Pralatrexate is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 8 weeks after the last dose.
-
Fetotoxicity:
Documented in animals
-
Breastfeeding:
Unknown
Breastfeeding is not recommended.
-
Fertility effects:
Unknown
Semen preservation prior to initiation of pralatrexate therapy could be considered.
No formal clinical drug interaction assessments have been conducted.
In vitro studies indicate that pralatrexate is not a substrate, inhibitor, or inducer of cytochrome P-450 (CYP) isoenzymes. Pralatrexate is a substrate for BCRP, MRP2, MRP3 and OATP1B3. It is not a substrate of P-gp, OATP1B1, OCT2, OAT1, and OAT3 transport systems. Pralatrexate is an inhibitor of MRP2 and MRP3 but is not an inhibitor of P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B1, and OATP1B3.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Probenecid | ↑ pralatrexate concentration and/or toxicity | delayed clearance | Caution; monitor closely |
| NSAIDs | ↑ pralatrexate concentration and/or toxicity | ↓ renal excretion | Caution; monitor closely |
| Drugs eliminated by renal excretion (i.e. trimethoprim/sulfamethoxazole) | ↑ pralatrexate concentration and/or toxicity | delayed clearance | Caution; monitor for systemic toxicity due to ↑ drug exposure with drugs that undergo substantial renal excretion |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the PRAL regimen monograph for alternate schedule monitoring info.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline and weekly |
Liver function tests |
Prior to the first and fourth doses in each cycle and as clinically indicated |
Renal function tests |
Prior to the first and fourth doses in each cycle and as clinically indicated |
Mucosal inflammation |
Baseline and weekly |
Clinical toxicity assessment for signs of infection, electrolyte imbalances, TLS, cardiac, dermatologic, GI, pulmonary, and musculoskeletal effects. |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
New Drug Funding Program (NDFP Website )
- Pralatrexate - Relapsed or Refractory Peripheral T-cell Lymphoma (PTCL)
FOLOTYN ® (pralatrexate) Product Monograph. Servier Canada Inc, October 19, 2018.
Horwitz SM, Kim YH, Foss F, et al. Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood. 2012 May 3;119(18):4115-22. doi: 10.1182/blood-2011-11-390211
O'Connor OA, Amengual J, Colbourn D, et al. Pralatrexate: a comprehensive update on pharmacology, clinical activity and strategies to optimize use. Leuk Lymphoma. 2017 Nov;58(11):2548-2557. doi: 10.1080/10428194.2017.1306642
O'Connor OA, Pro B, Pinter-Brown L et al. Pralatrexate in patients with relapsed or refractory peripheral t-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol 2011;29(9):1182-9.
December 2021 Added reference to alternate schedule in Dosing and Monitoring sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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