Pralatrexate (Folotyn) is an anti-metabolite anticancer drug that has been approved for the treatment of refractory or relapsed T-cel lymphoma.

Pralatrexate Uses:

• Peripheral T-cell lymphoma:

  • Treatment of refractory or relapsed peripheral T-cell lymphoma (PTCL)

• Off Label Use of Pralatrexate in Adults:

  • Relapsed or refractory cutaneous T-cell lymphomas.

Pralatrexate dose in Adults

Note:

• Initiate vitamin supplements before initial pralatrexate dose:
• Folic acid 1 to 1.25 mg/day orally beginning 10 days before initial pralatrexate dose; continue during treatment and for 1 month after last pralatrexate dose;
• vitamin B-12 1,000 mcg IM within 10 weeks before initial pralatrexate dose and every 8 to 10 weeks thereafter (after the first dose, subsequent B doses may be administered on the same day as pralatrexate).
• Prior to administering any dose, mucositis should be ≤ grade 1 and absolute neutrophil count (ANC) should be ≥1,000/mm³; platelets should be ≥100,000/mm³ for the first dose and ≥50,000/mm³ for subsequent doses

Pralatrexate dose in the treatment of relapsed or refractory Peripheral T-cell lymphoma (PTCL):

• IV: 30 mg/m² once weekly for 6 weeks of a 7-week treatment cycle;
• Continue until disease progression or unacceptable toxicity.

Pralatrexate dose in the treatment of relapsed or refractory cutaneous T-cell lymphoma:

• IV: 15 mg/m² once weekly for 3 weeks of a 4-week treatment cycle.

Pralatrexate dose in Childrens

Not indicated for use in children

Pregnancy Risk Factor D

• Animal reproduction studies showed adverse effects. If administered to pregnant women, may cause harm to the fetus.

Use of Pralatrexate while breastfeeding

• It is unknown if pralatrexate can be found in breast milk.
• There are potential adverse events that could occur in nursing infants.
• It is important to decide whether to stop breast-feeding or to pralatrexate. This decision will be made taking into consideration the benefits to the mother.

Pralatrexate Dose in Kidney disease:

• Peripheral T-cell lymphoma (PTCL), relapsed or refractory:

  • Estimated glomerular filtration rate (eGFR) ≥30 mL/minute/1.73 m² :
    • No dosage adjustment necessary.

• eGFR 15 to <30 mL/minute/1.73 m²:

  • Initial: Reduce dose to 15 mg/m² ;
  • if dose reductions for toxicity are necessary, reduce each dose to 10 mg/m² .

• End-stage renal disease (ESRD), including dialysis:

  • Avoid use (unless the potential benefit outweighs risks).

Pralatrexate Dose in Liver disease:

• Patients with total bilirubin >1.5 mg/dL, AST or ALT >2.5 times the upper limit of normal (ULN), or ALT or AST >5 times ULN if documented hepatic lymphoma involvement were excluded from clinical trials.

• Persistent abnormalities may indicate hepatotoxicity requiring dosage modification:

  • Grade 3 (AST or ALT >5 to 20 times ULN or bilirubin >3 to 10 times ULN):
    • Omit dose;
    • decrease to 20 mg/m² when recovers to ≤grade 2
  • Grade 4 (AST or ALT >20 times ULN or bilirubin >10 times ULN):
    • Discontinue treatment immediately.

Common Side Effects of Pralatrexate:

• Cardiovascular:

  • Edema

• Central Nervous System:

  • Fatigue

• Dermatologic:

  • Skin Rash
  • Pruritus
  • Night Sweats

• Endocrine & Metabolic:

  • Hypokalemia

• Gastrointestinal:

  • Mucositis
  • Nausea
  • Constipation
  • Vomiting
  • Diarrhea
  • Anorexia
  • Abdominal Pain

• Hematologic & Oncologic:

  • Thrombocytopenia
  • Anemia
  • Neutropenia
  • Leukopenia

• Hepatic:

  • Increased Serum Transaminases

• Infection:

  • Infection

• Neuromuscular & Skeletal:

  • Limb Pain
  • Back Pain

• Respiratory:

  • Cough
  • Epistaxis
  • Dyspnea
  • Pharyngolaryngeal Pain

• Miscellaneous:

  • Fever

Less Common Side Effects Of Pralatrexate:

• Cardiovascular:

  • Tachycardia

• Endocrine & Metabolic:

  • Severe Dehydration

• Hematologic & Oncologic:

  • Febrile Neutropenia

• Infection:

  • Sepsis

• Neuromuscular & Skeletal:

  • Weakness

• Respiratory:

  • Upper Respiratory Tract Infection

Contraindications to Pralatrexate:

• The manufacturer's labeling does not list any contraindications.

Canadian labeling

• Additional contraindications not listed in the US labeling:
  • Hypersensitivity/allergy of pralatrexate and any component of the formulation

Warnings and precautions

• Suppression of bone marrow

  • This may cause anemia, neutropenia and thrombocytopenia. Keep an eye on your blood counts.
  • To reduce hematologic toxicities, prophylactic vitamin B and folic acid are essential.

• Dermatologic reactions

  • There have been severe and possibly fatal dermatologic reactions, including skin exfoliation, ulceration and toxic epidermal necrolysis, which can lead to skin cancer.
  • The skin reaction may be progressive and can get worse with continued treatment. It can affect the skin and subcutaneous tissue that are affected lymphoma.
  • You should monitor all skin reactions closely. If severe reactions occur, stop or withhold treatment.

• Hepatotoxicity

  • Use has been associated with liver dysfunction abnormalities and hepatotoxicity.
  • Keep an eye on your liver function. Hepatotoxicity may be suspected if there are persistent abnormalities. You may need to modify or stop your medication.

• Mucositis

  • Pralatrexate can cause mucositis, e.g. stomatitis and mucosal inflammation in the gastrointestinal or genitourinary tracts.
  • Monitor once a week; dosage modifications may be necessary.
  • To reduce treatment-related mucositis, prophylactic folic Acid and vitaminB supplements are essential.

• Tumor lysis syndrome (TLS).

  • Pralatrexate could cause (TLS).
  • Pay attention.
  • If you have tumor lysis syndrome, be sure to treat it.

• Renal impairment

  • Patients with severe or moderate renal impairment are more at risk of increased exposure and toxicities.
  • Monitor your renal function and check for systemic toxicities due to the increased exposure.
  • In severe renal impairment (eGFR 15-30 mL/minute/1.73m2), dosage adjustment is recommended.
  • Avoid use of this product in patients with end stage renal disease (ESRD), as well as patients undergoing dialysis.
  • Patients with ESRD who were undergoing dialysis experienced serious adverse reactions including mucositis and toxic epidermal necrolysis.
  • Combining pralatrexate with other drugs that have a high renal clearance (eg, NSAIDs or sulfamethoxazole/trimethoprim), can lead to delayed clearance.

Pralatrexate: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• CBC with differential (baseline and weekly),
• serum chemistries, including renal and liver function tests (prior to the first and fourth doses in each cycle);
• mucositis severity (baseline and weekly);
• monitor for signs of tumor lysis syndrome and for dermatologic reactions

How to administer Pralatrexate?

• IV: Administer IV push (undiluted) over 3 to 5 minutes into the line of a free-flowing normal saline IV

Mechanism of action of Pralatrexate:

• It's an antifolate analog.
• It inhibits DNA, RNA and protein synthesis by entering cells expressing reduced folate carriers (RFC-1), and is then polyglutamylated with folylpolyglutamate synthesise (FPGS).
• Next, it competes for the DHFR–folate binding site to inhibit dihydrofolate reducetase.

Protein binding:

• ~67%

Metabolism:

• Not significantly metabolized by phase I hepatic isoenzymes or phase II glucuronidases.

Half-life elimination:

• 12 to 18 hours

Excretion:

• Urine (~34% as unchanged

International Brands of Pralatrexate:

• Folotyn
• Difolta

Pralatrexate Brand Names in Pakistan:

No Brands Available in Pakistan.