Folotyn (Page 2 of 5)

2.3 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 available^1-4.

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FOLOTYN vials should be refrigerated at 2-8°C (36-46°F) until use.

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FOLOTYN vials should be stored in original carton to protect from light until use.

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FOLOTYN vials contain no preservatives and are intended for single use only. After withdrawal of dose, discard vial including any unused portion.

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Unopened vial(s) of FOLOTYN 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.

3 DOSAGE FORMS AND STRENGTHS

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)

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Bone Marrow Suppression

FOLOTYN 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 2.2Table 2. Administer vitamin B₁₂ and instruct patients to take folic acid to reduce the risk of treatment-related hematological toxicity [see Dosage and Administration (2.1, 2.2) and Adverse Reactions (6.1)].

5.2 Mucositis

FOLOTYN can cause mucositis. Monitor for mucositis weekly and if ≥ Grade 2 mucositis is observed, omit and/or reduce the dose as outlined in Section 2.2Table 1. Administer vitamin B₁₂ and instruct patients to take folic acid to reduce the risk of mucositis [see Dosage and Administration (2.1, 2.2) and Adverse Reactions (6.1) ].

5.3 Dermatologic Reactions

FOLOTYN 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 FOLOTYN [see Adverse Reactions (6.2) and Use in Specific Populations (8.7)].

5.4 Tumor Lysis Syndrome

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

5.5 Hepatic Toxicity

FOLOTYN 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 [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

5.6 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 FOLOTYN therapy. Avoid FOLOTYN use in patients with end stage renal disease including those undergoing dialysis unless the potential benefit justifies the potential risk [see Dosage and Administration (2.2), Adverse Reactions (6.2), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

5.7 Embryo-Fetal Toxicity

FOLOTYN can cause fetal harm when administered to a pregnant woman. FOLOTYN 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 [see Use in Specific Populations (8.1) ].

6 ADVERSE REACTIONS

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

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Bone Marrow Suppression [see Warnings and Precautions (5.1)]

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Mucositis [see Warnings and Precautions (5.2)]

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Dermatologic Reactions [see Warnings and Precautions (5.3)]

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Tumor Lysis Syndrome [see Warnings and Precautions (5.4)]

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Hepatic Toxicity [see Warnings and Precautions (5.5)]

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

6.1 Clinical Trials Experience

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 FOLOTYN 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 cycles. The median duration of treatment was 70 days (range 1-540 days).

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).

Table 4 Adverse Reactions Occurring in PTCL Patients (Incidence ≥ 10% of patients)

	N=111
	Total		Grade 3		Grade 4
Preferred Term	N	%	N	%	N	%
Any Adverse Event	111	100	48	43	34	31
Mucositisa	78	70	19	17	4	4
Thrombocytopeniab	45	41	15	14	21	19b
Nausea	44	40	4	4	0	0
Fatigue	40	36	5	5	2	2
Anemia	38	34	17	15	2	2
Constipation	37	33	0	0	0	0
Pyrexia	36	32	1	1	1	1
Edema	33	30	1	1	0	0
Cough	31	28	1	1	0	0
Epistaxis	29	26	0	0	0	0
Vomiting	28	25	2	2	0	0
Neutropenia	27	24	14	13	8	7
Diarrhea	23	21	2	2	0	0
Dyspnea	21	19	8	7	0	0
Anorexia	17	15	3	3	0	0
Hypokalemia	17	15	4	4	1	1
Rash	17	15	0	0	0	0
Pruritus	16	14	2	2	0	0
Pharyngolaryngeal pain	15	14	1	1	0	0
Liver function test abnormalc	14	13	6	5	0	0
Abdominal pain	13	12	4	4	0	0
Pain in extremity	13	12	0	0	0	0
Back pain	12	11	3	3	0	0
Leukopenia	12	11	3	3	4	4
Night sweats	12	11	0	0	0	0
Asthenia	11	10	1	1	0	0
Tachycardia	11	10	0	0	0	0
Upper respiratory tract infection	11	10	1	1	0	0

^c Alanine aminotransferase, aspartate aminotransferase, and transaminases increased

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

Discontinuations

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

Dose Modifications

The target dose of FOLOTYN 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.