Summary Basis of Decision for Folotyn

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Folotyn is located below.

Recent Activity for Folotyn

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Folotyn

Updated:

2020-10-07

The following table describes post-authorization activity for Folotyn, a product which contains the medicinal ingredient pralatrexate. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

Drug Identification Number (DIN):

  • DIN 02481820 - 20 mg/mL pralatrexate, solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control numberDate submittedDecision and dateSummary of activities
Drug product (DIN 02481820) market notificationNot applicableDate of first sale:
2019-01-15
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 2075452017-07-18Issued NOC under NOC/c Guidance
2018-10-26
Notice of Compliance issued under the NOC/c Guidance for New Drug Submission.
Summary Basis of Decision (SBD) for Folotyn

Date SBD issued: 2019-04-29

The following information relates to the new drug submission for Folotyn.

Pralatrexate

Drug Identification Number (DIN):

  • DIN 02481820 - 20 mg/mL, solution, intravenous administration
  • DIN 02481855 - 40 mg/2 mL, solution, intravenous administration

Servier Canada Inc.

New Drug Submission Control Number: 207545

On October 26, 2018, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Servier Canada Inc. for the drug product Folotyn. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-harm-uncertainty profile of Folotyn is favourable for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma.

The approval is based on response rates demonstrated in a single-arm trial. Prolongation of progression-free survival, overall survival, and improvement in quality-of-life have not been demonstrated.

1 What was approved?

Folotyn, an antineoplastic agent and folic acid analogue, was authorized for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma.

The approval is based on response rates demonstrated in a single-arm trial. Prolongation of progression-free survival, overall survival, and improvement in quality-of-life have not been demonstrated.

Folotyn should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. The safety and efficacy of Folotyn have not been established in the pediatric population. Use of Folotyn in geriatric patients has not been associated with differences in safety or effectiveness, although greater sensitivity of some older individuals cannot be ruled out. Due to the contribution of renal excretion to overall clearance of Folotyn, age-related decline in renal function may lead to a reduction in clearance and a commensurate increase in plasma exposure.

Folotyn is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Folotyn was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Folotyn (20 mg/mL and 40 mg/2 mL pralatrexate) is presented as solution for intravenous use. In addition to the medicinal ingredient pralatrexate, the solution also contains sodium chloride, sodium hydroxide, and hydrochloric acid if needed to adjust the pH.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Folotyn Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Folotyn approved?

Health Canada considers that the benefit-harm-uncertainty profile of Folotyn is favourable for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Its approval is based on response rates demonstrated in a single-arm trial. Prolongation of progression-free survival, overall survival, and improvement in quality-of-life have not been demonstrated. Folotyn was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.

Peripheral T-cell lymphomas are a heterogeneous and rare group of non-Hodgkin lymphomas. The prevalence estimates for 2016 suggested that approximately 8,000 new cases of non-Hodgkin lymphomas would be diagnosed in Canada. Peripheral T-cell lymphoma accounts for approximately 7% of all non-Hodgkin lymphomas cases, representing a very rare disease in Canada. It tends to be aggressive and chemo-refractory, with about 70% of patients developing relapsed or refractory disease. Relapsed or refractory peripheral T-cell lymphoma patients show extremely poor outcome with short remissions, and with a median survival after relapse of approximately 5.5 months.

There is currently no widely accepted standard of care for the treatment of patients with peripheral T-cell lymphoma. The combination of cyclophosphamide, doxorubicin, vincristine, and prednisone is the primary first-line treatment for most subtypes of peripheral T-cell lymphoma, which is adopted from the management of B-cell non-Hodgkin lymphomas. Unfortunately, most patients with peripheral T-cell lymphoma do not respond to the first-line treatment and experience disease progression after initial treatment. Subsequently, they experience treatment failure following available salvage therapies as the disease develops drug resistance, leading to death.

The general approach in managing relapsed or refractory peripheral T-cell lymphoma has been to administer further treatment with the hope of attaining a remission and proceeding to curative stem cell transplant. Observational, population-based trials confirmed that the outcome was superior in patients able to receive a stem cell transplant. However, many patients never receive a stem cell transplant, or relapse following the procedure. With no guide for salvage therapy sequence in the palliative setting, often the decision of treatment selection is guided by co-morbidities and treatment tolerance.

Agents currently available to treat peripheral T-cell lymphoma patients in the relapsed or refractory setting include romidepsin (Istodax) and brentuximab vedotin (Adcetris), both conditionally approved based on single-arm Phase II clinical trials. Istodax is a histone deacetylase inhibitor, approved on the basis of an overall response rate of 25% in the pivotal trial, with serious adverse events of pancytopenia, QT interval prolongation, fatal infections, and tumor lysis syndrome associated with treatment. Adcetris, an antibody-drug conjugate, is only indicated for a small subset of patients with relapsed or refractory peripheral T-cell lymphoma.

Pralatrexate (the medicinal ingredient of Folotyn) is a folate analogue metabolic inhibitor that selectively enters cells expressing reduced folate carrier type 1 (RFC-1), a protein that is overexpressed on certain cancer cells compared to normal cells. In addition, pralatrexate inhibits the enzyme dihydrofolate reductase, and polyglutamylation by the enzyme folylpolyglutamyl synthetase. This inhibition leads to the depletion of thymidine and other biological molecules, which results in inhibiting ribonucleic acid synthesis and deoxyribonucleic acid replication. The disruption of deoxyribonucleic acid replication in dividing cells leads to subsequent death of rapidly dividing cells like tumour cells.

Folotyn has been shown to be efficacious in the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. The market authorization with conditions was based on a Phase II, single-arm, multicentre clinical trial, PDX-008. Overall response rate, determined by an Independent Review Committee was the primary efficacy endpoint of this trial. Results from the PDX-008 trial showed that the overall response rate was 27% (95% confidence interval: 19, 36) with a corresponding median duration of response of 287 days (range: 1 to 503). The complete response rate was 8%. Five of the patients who responded to Folotyn did not have evidence of response to any prior therapy. Fourteen patients who responded to Folotyn did not have evidence of response to their most recent prior therapy. Four patients who had a response underwent stem cell transplantation as their initial subsequent therapy after discontinuing treatment with Folotyn.

The most common toxicities associated with Folotyn in the PDX-008 trial were mucosal inflammation and bone marrow suppression (mostly thrombocytopenia and neutropenia). Serious adverse events were reported in 44% of patients, most commonly (>3%) pyrexia, mucosal inflammation, sepsis, herpes zoster, pneumonia, neutropenia, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. Treatment discontinuation occurred in 23% of patients, most frequently due to mucosal inflammation and thrombocytopenia adverse events. The majority of all dose omissions and reductions were due to mucosal inflammation. Other significant toxicities associated with Folotyn, many of which led to fatalities, include toxic epidermal necrolysis, pulmonary toxicity, renal toxicity, hepatic toxicity, and infection. Folotyn was not studied in pregnant women; however, non-clinical reproductive studies indicated a risk of fetal harm and loss. These safety findings, as well as monitoring and management recommendations are adequately described in the Folotyn Product Monograph.

A Serious Warnings and Precautions box has been included in the Product Monograph for Folotyn. It specifically addresses: dermatologic reactions, bone marrow suppression, infection, mucosal inflammation, tumour lysis syndrome, potential fetal harm, and pulmonary toxicity.

While there are significant toxicities associated with Folotyn, they are generally tolerated and consistent with other agents of the anti-folate class. Health Canada therefore considers the demonstrated anti-tumor activity of Folotyn to be meaningfully promising evidence of clinical benefit. However, the submitted data package does lack robust evidence of survival or quality-of-life benefits, which remain uncertain. Therefore, Health Canada recommended that Folotyn be granted market authorization under the Notice of Compliance with Conditions (NOC/c) Guidance. Under the NOC/c Guidance, Health Canada has requested that the sponsor confirm the clinical benefit of the product by submitting the final results of the confirmatory Phase III study SPI-BEL-101. (see What follow-up measures will the company take?)

A Risk Management Plan (RMP) for Folotyn was submitted by Servier Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. As part of the NOC/c Qualifying Notice, the sponsor has been requested to provide any updates to the Canadian RMP when available.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Folotyn Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Folotyn was accepted.

Overall, the therapeutic benefits of Folotyn therapy as seen in the Phase II PDX-008 pivotal study are promising and are considered to outweigh the potential risks. Considering the proposed indication and currently available therapies, Folotyn has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and pharmacovigilance. Appropriate warnings and precautions are described in the Folotyn Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Folotyn will be ongoing. Further evaluation will take place upon the submission of the confirmatory trial results after they become available.

This New Drug Submission (NDS) qualifies for authorization under the NOC/c Guidance. This NDS complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Folotyn?

Submission Milestones: Folotyn

Submission MilestoneDate
Pre-submission meeting:2017-01-31
Submission filed:2017-07-18
Screening
Screening Deficiency Notice issued:2017-08-31
Response filed:2017-10-05
Screening Acceptance Letter issued:2017-11-15
Review
Quality Evaluation complete:2018-09-07
Review of Risk Management Plan complete:2018-06-07
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2018-09-10
Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued:2018-09-10
Review of Response to NOC/c-QN:
Response filed (Letter of Undertaking):2018-09-28
Clinical Evaluation complete:2018-10-18
Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance:2018-10-26

The Canadian regulatory decision on the non-clinical and clinical review of Folotyn was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was used as an added reference.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

In addition to requirements outlined in the Food and Drugs Act and Regulations, and in keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Guidance, the sponsor has agreed to provide the final report of the confirmatory Phase III study SPI-BEL-301 which compares beleodaq + cyclophosphamide + doxorubicin + vincristine + prednisone (CHOP) or Folotyn + CHOP to the CHOP regimen alone (1:1:1 randomization). A complete clinical study report based on a pre-specified data cut-off date should be submitted with all supporting datasets. The clinical study report should permit the confirmation of objective response rate and contain reliable estimate of time-to-event endpoints, for example, duration of response, progression-free survival, and overall survival.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

Clinical Pharmacology

Pralatrexate (the medicinal ingredient in Folotyn) is a folate analog metabolic inhibitor that selectively enters cells expressing reduced folate carrier type 1 (RFC-1), a protein that is overexpressed on certain cancer cells compared to normal cells. Pralatrexate competitively inhibits dihydrofolate reductase as well as polyglutamylation by the enzyme folylpolyglutamyl synthetase. This inhibition results in the depletion of thymidine and other biological molecules, which leads to the inhibition of ribonucleic acid synthesis and deoxyribonucleic acid replication in dividing cells and to cancer growth inhibition and apoptosis.

The recommended dose of Folotyn is 30 mg/m2 administered as an intravenous push over 3 to 5 minutes. A pharmacokinetic study demonstrated that the pralatrexate exposure in patients with severe renal impairment administered a dose of 15 mg/m2 was comparable to the exposure in those with normal renal clearance, as well as mild and moderate renal impairment administered a dose of 30 mg/m2. Consequently, the recommended use in patients with severe renal impairment is 15 mg/m2. The pharmacokinetics of Folotyn was not investigated in pediatric patients. No dose adjustment is recommended based on age or race according to a population pharmacokinetic analysis. Folotyn has not been studied in patients with hepatic impairment.

Pralatrexate has a terminal elimination half-life of 12 to 18 hours, with total systemic exposure and maximum plasma concentration increasing proportionally with dose. The pharmacokinetics of pralatrexate does not change significantly over multiple treatment cycles, and no accumulation of pralatrexate is observed.

Pralatrexate is not significantly metabolized by hepatic cytochrome (CYP) 450 isozymes or glucuronidases, and has low potential to induce or inhibit hepatic CYP450 enzymes. In vitro studies suggested limited metabolism of pralatrexate; a mass balance study showed that an average of 39% of administered pralatrexate dose was excreted unchanged in urine, and 34% in feces. Pralatrexate is approximately 67% to 84% bound to plasma proteins.

Pralatrexate has low potential to induce or inhibit hepatic phase I enzymes or transporter systems. Pralatrexate is a substrate for breast cancer resistance protein (BCRP), multidrug resistance-associated protein (MRP) 2, MRP3, and organic anion transport protein 1B3 (OATP1B3) transporter systems. Co-administration of probenecid (an inhibitor of multiple transporter systems) resulted in delayed clearance of pralatrexate. The potential for this interaction is appropriately outlined in the Folotyn Product Monograph.

Based on the review of the clinical pharmacology studies provided in the submission, there are no issues to preclude approval of Folotyn for the recommended indication.

For further details, please refer to the Folotyn Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Folotyn was evaluated primarily in an open-label Phase II, single-arm, multicentre, international study (PDX-008) conducted in 115 patients with relapsed or refractory peripheral T-cell lymphoma. One hundred and eleven patients were treated with Folotyn at 30 mg/m2 once weekly by intravenous push over 3 to 5 minutes for 6 weeks in 7-week cycles until disease progression or unacceptable toxicity. Vitamin B12 and folic acid supplementation was administered concurrently to mitigate drug-related toxicities. Of the 111 patients treated, 109 patients were evaluable for efficacy. Evaluable patients had histologically confirmed peripheral T-cell lymphoma 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 endpoint in the PDX-008 study was overall response rate (the proportion of patients who achieved either a partial response, complete response, or complete response uncertified as best response) as assessed by the 1999 International Workshop Criteria by an independent review committee assessment. 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.

The median age of treated patients was 59.0 years (range 21 to 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 to 322.3).

As determined by histopathology central review, 53% of patients had an unspecified peripheral T-cell lymphoma, 15% anaplastic large cell lymphoma, 12% angioimmunoblastic T-cell lymphoma, 11% transformed mycosis fungoides, and 10% other T-cell lymphoma subtypes (i.e., blastic natural killer cell lymphoma, nasal natural killer T-cell lymphoma, unspecified extranodal peripheral natural killer T-cell lymphoma or adult T-cell leukemia/lymphoma) at study entry.

The median number of prior systemic therapies was 3 (range 1 to 12). Approximately one-fourth of patients (24%, number of patients [n] = 26) did not have evidence of response to any previous therapy. Approximately two-thirds of patients (63%, number of patients [n] = 69) did not have evidence of response to their most recent prior therapy before entering the study and 16% (n = 18) had a relapse after autologous stem cell transplantation. Median time from diagnosis to study entry was 15.6 months.

Results from the PDX-008 study demonstrated that the response rate according to the 1999 International Workshop Criteria by independent central review was 27% (n = 29). Nine patients (8%) achieved a complete response and 20 patients (18%) achieved a partial response. Twenty-four patients (22%) had stable disease. The median duration of treatment was 70 days (range: 1 to 540). The median number of cycles administered to patients (based on cycles initiated) was 2.0 (range: 1 to 12).

Nineteen patients (66% of responders) responded within cycle 1. The median time to first response was 45 days (range 37 to 349 days).

Response rate by histopathology was similar among the subtypes, with the possible exception of angioblastic T-cell lymphoma. A responder rate of 8% was reported for this histological subtype (i.e., there was only 1 responder out of 13 patients). The study was not designed to assess tumour responsiveness by histological subtype.

Indication

The New Drug Submission for Folotyn was filed by the sponsor with the following indication:

  • Folotyn (pralatrexate injection) is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma.

To ensure safe and effective use of the product, Health Canada approved the following indication:

  • Folotyn (pralatrexate injection) is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma.
  • Approval is based on response rates demonstrated in a single-arm trial. Prolongation of progression-free survival, overall survival, and improvement in quality-of-life has not been demonstrated.

The additional statements were added to provide additional details regarding the limitations of the supportive data.

For more information, refer to the Folotyn Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Folotyn was primarily based on the evaluation of the open-label Phase II, single-arm, multicentre international study previously described in the Clinical Efficacy section. The median duration of Folotyn exposure was 70 days, with range of 1 to 540 days. Treatment emergent adverse events occurred in all of 111 patients in the study.

The safety profile of Folotyn was generally similar to other drugs of the anti-folate class. The most common adverse events (≥20%) observed in patients treated with Folotyn were mucosal inflammation and thrombocytopenia, reported in 70% and 41% of patients, respectively. Other frequently reported adverse events (>25% of patients) were nausea (41%), fatigue (36%), anemia (34%), constipation (33%), pyrexia (32%), edema (30%), cough (28%), epistaxis (26%), vomiting (25%), and diarrhea (21%).

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 mucosal inflammation (6%, n = 7) and thrombocytopenia (5%, n = 5).

Forty-four percent of patients (n = 49) experienced a serious adverse event during treatment or within 30 days after their last dose of Folotyn. The most common serious adverse events (≥3%), were pyrexia (7%), febrile neutropenia (5%), sepsis (5%), dehydration (4%), dyspnea (4%), mucosal inflammation (4%), herpes zoster (3%), neutropenia (3%), pneumonia (3%), and thrombocytopenia (3%).

Eight patients (7%) died while still on treatment with Folotyn or within 30 days of their last dose of pralatrexate, mostly due to disease progression.

The following warnings have been included in a Serious Warnings and Precautions box in the Product Monograph for Folotyn: dermatologic reactions, bone marrow suppression, infection, mucosal inflammation, tumour lysis syndrome, potential fetal harm, and pulmonary toxicity.

The post-marketing safety profile of Folotyn was consistent with that identified in clinical studies. Toxic epidermal necrolysis, pulmonary and dermatologic toxicities were identified as new significant adverse reactions, and fatal events were reported for mucosal inflammation, thrombocytopenia, neutropenia, dermatological reactions, with a notably high frequency of fatal infection and dyspnea (20% and 17%, respectively).

For more information, refer to the Folotyn Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

Single and repeat-dose toxicity studies were conducted in rats (up to 28 weeks) and dogs (up to 9 months). Most toxicities were associated with gastrointestinal effects like emesis, abnormal feces, and diarrhea resulting in weight loss. Repeat doses also resulted in anemia and leukopenia. Pralatrexate (the medicinal ingredient in Folotyn) was not genotoxic in the standard battery of tests. Pralatrexate was fetotoxic, causing resorption and post-implantation loss in rats and rabbits, but did not cause fetal malformation. The Folotyn Product Monograph includes adequate labelling warning patients about the potential risk to embryo-fetal development.

Safety pharmacology studies were conducted to address cardiovascular, respiratory, and central nervous system safety. No significant toxicities were observed. Pralatrexate did not induce any adverse signs of neurological toxicity. Tissue distribution in rats showed the highest measurable content in liver and kidney. The primary route of excretion of radio-labelled pralatrexate was fecal, followed by urine and exhaled carbon dioxide. Pralatrexate possesses moderate ability to bind human plasma protein and did not significantly inhibit or induce cytochrome (CYP) 450 enzymes or P-glycoproteins.

Based on the review of the non-clinical studies provided in the Folotyn submission, there are no issues to preclude approval of Folotyn for the recommended indication.

For more information, refer to the Folotyn Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Folotyn has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 60 months is acceptable when packaged in the commercial packaging and stored refrigerated (2ºC to 8ºC) with protection from light.

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

None of the excipients used in the formulation of Folotyn is of human or animal origin.