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FOLOTYN(pralatrexate injection)

2012-12-15 11:02:08  作者:新特药房  来源:互联网  浏览次数:220  文字大小:【】【】【
简介: 部分中文Folotyn处方资料(仅供参考) 中文名:普拉曲沙注射液 英文化学名:N-(4-(1-((2,4-Diamino-6-pteridinyl)methyl)-3-butynyl)benzoyl)-L-glutamic acid;10-Propargyl-10-deazaaminopterin中文 ...

FOLOTYN -pralatrexate injection 
Allos Therapeutics, Inc.
适应症:
复发性外周T细胞淋巴瘤
生产商:Allos Therapeutics
批准日期:2009年9月24日
Folotyn(pralatrexate)为首个获批上市的治疗外周T细胞淋巴瘤(PTCL)药物。PTCL为浸润性非霍奇金淋巴瘤,在美国每年有约9500名患者发病,被确定为罕见性疾病,Folotyn被指定为孤儿药。FDA通过快速审批程序批准该药。用于治疗复发性或其它化学疗法疗效不佳的PTCL患者。
基于Folotyn能够有效缩小肿瘤体积,FDA批准其上市,通常肿瘤缩小被作为延长癌症患者生存期的替代指标。对109名PTCL患者试验研究,成像扫描结果27%患者被确定肿瘤体积缩小。
Folotyn的最常见不良反应为激越或粘膜溃疡,如嘴唇、口腔、消化道溃疡,和血小板计减少、白细胞减少、发热、恶心和疲惫。Folotyn对胎儿有危害。
Folotyn由美国柯罗拉多州威斯敏斯特的Allos Therapeutics Inc公司制造。由于Folotyn为有条件批准,Allos公司将继续进行研究,以证明肿瘤缩小与延长患者生存期的正效应。
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use FOLOTYN® safely and effectively. See full prescribing information for FOLOTYN.
FOLOTYN (pralatrexate injection)
Solution for intravenous injection
Initial U.S. Approval: 2009
INDICATIONS AND USAGE
FOLOTYN is a folate analog metabolic inhibitor indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is based on overall response rate. Clinical benefit such as improvement in progression-free survival or overall survival has not been demonstrated. (1)
DOSAGE AND ADMINISTRATION
The recommended dose of FOLOTYN is 30 mg/m2 administered as an intravenous push over 3 to 5 minutes once weekly for 6 weeks in 7-week cycles. (2.1)
Supplement patients with vitamin B12 1 mg intramuscularly every 8-10 weeks and folic acid 1.0-1.25 mg orally on a daily basis. (2.2)
Treatment interruption or dose reduction to 20 mg/m2 may be needed to manage adverse drug reactions. (2.5)
DOSAGE FORMS AND STRENGTHS
Sterile, single-use 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) (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
Thrombocytopenia, neutropenia, and anemia may occur. Monitor blood counts and omit or modify dose for hematologic toxicities. (2.5, 5.1)
Mucositis may occur. If ≥ Grade 2 mucositis is observed, omit or modify dose. (2.5, 5.2)
FOLOTYN can cause fetal harm. Women should avoid becoming pregnant while being treated with FOLOTYN, and pregnant women should be informed of the potential harm to the fetus. (5.4, 8.1)
Use caution in patients with moderate to severe renal function impairment. (5.5)
Elevated liver function test abnormalities may occur. If liver function test abnormalities are ≥ Grade 3, omit or modify dose. (2.5, 5.6)
ADVERSE REACTIONS
Most common adverse reactions are mucositis, thrombocytopenia, nausea, and fatigue. Most common serious adverse reactions are pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Allos Therapeutics, Inc at 1-888-ALLOS88 (1-888-255-6788) or www.FOLOTYN.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DRUG INTERACTIONS
Co-administration with probenecid, NSAIDs, and trimethoprim/sulfamethaxazole may result in delayed renal clearance. (7)
USE IN SPECIFIC POPULATIONS
Women should be advised against breastfeeding while being treated with FOLOTYN. (8.3)
See 17 for PATIENT COUNSELING INFORMATION 
Revised: 04/2010

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

FOLOTYN is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is based on overall response rate. Clinical benefit such as improvement in progression-free survival or overall survival has not been demonstrated.

2 DOSAGE AND ADMINISTRATION

FOLOTYN should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

2.1 Peripheral T-cell Lymphoma

The recommended dose of FOLOTYN is 30 mg/m2 administered as an intravenous (IV) push over 3-5 minutes via the side port of a free-flowing 0.9% Sodium Chloride Injection, USP IV line once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity.

2.2 Vitamin Supplementation

Patients should take low-dose (1.0-1.25 mg) oral folic acid on a daily basis. Folic acid should be initiated during the 10-day period preceding the first dose of FOLOTYN, and dosing should continue during the full course of therapy and for 30 days after the last dose of FOLOTYN. Patients should also receive a vitamin B12 (1 mg) intramuscular injection no more than 10 weeks prior to the first dose of FOLOTYN and every 8-10 weeks thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with FOLOTYN [see Warnings and Precautions (5.3)].

2.3 Preparation and Administration 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 [see References (15)].

2.4 Preparation for Intravenous Push Administration

  1. FOLOTYN vials should be refrigerated at 2-8°C (36-46°F) until use.
  2. FOLOTYN vials should be stored in original carton to protect from light until use.
  3. FOLOTYN 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.
  4. The calculated dose of FOLOTYN should be aseptically withdrawn into a syringe for immediate use.
  5. Do not dilute FOLOTYN.
  6. FOLOTYN vials contain no preservatives and are intended for single use only. After withdrawal of dose, discard vial including any unused portion.
  7. 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.

2.5 Monitoring and Dose Modifications

Management of severe or intolerable adverse reactions may require dose omission, reduction, or interruption of FOLOTYN therapy.

Monitoring

Complete blood cell counts and severity of mucositis should be monitored weekly. Serum chemistry tests, including renal and hepatic function, should be performed prior to the start of the first and fourth dose of a given cycle.

Dose Modification Recommendations

Prior to administering any dose of FOLOTYN:

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

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.

Table 1 FOLOTYN Dose Modifications for Mucositis
Mucositis Gradea on Day of Treatment Action Dose upon Recovery to ≤ Grade 1

a Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 3.0)

Grade 2 Omit dose Continue prior dose
Grade 2 recurrence Omit dose 20 mg/m2
Grade 3 Omit dose 20 mg/m2
Grade 4 Stop therapy

Table 2 FOLOTYN Dose Modifications for Hematologic Toxicities
Blood Count on Day of Treatment Duration of Toxicity Action Dose upon Restart
Platelet < 50,000/μL 1 week Omit dose Continue prior dose
2 weeks Omit dose 20 mg/m2
3 weeks Stop therapy
ANC 500-1,000/μL and no fever 1 week Omit dose Continue prior dose
ANC 500-1,000/μL with fever
or
ANC < 500/μL
1 week Omit dose, give G‑CSF or GM‑CSF support Continue prior dose with G‑CSF or GM‑CSF support
2 weeks or recurrence Omit dose, give G‑CSF or GM‑CSF support 20 mg/m2 with G‑CSF or GM‑CSF support
3 weeks or 2nd recurrence Stop therapy

Table 3 FOLOTYN Dose Modifications for All Other Treatment-related Toxicities
Toxicity Grade a on Day of Treatment Action Dose upon Recovery to ≤ Grade 2

a Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 3.0)

Grade 3 Omit dose 20 mg/m2
Grade 4 Stop therapy

3 DOSAGE FORMS AND STRENGTHS

FOLOTYN is available in sterile, single-use 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 suppress bone marrow function, manifested by thrombocytopenia, neutropenia, and anemia. Dose modifications are based on ANC and platelet count prior to each dose [see Dosage and Administration (2.5) and Adverse Reactions (6)].

5.2 Mucositis

Treatment with FOLOTYN may cause mucositis. If ≥ Grade 2 mucositis is observed, omit dose and follow guidelines in Section 2.5, Table 1 [see Dosage and Administration (2.5)].

5.3 Folic Acid and Vitamin B12 Supplementation

Patients should be instructed to take folic acid and receive vitamin B12 to potentially reduce treatment-related hematological toxicity and mucositis [see Dosage and Administration (2.2)].

5.4 Pregnancy Category D

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)].

5.5 Decreased Renal Function

Although FOLOTYN has not been formally tested in patients with renal impairment, caution is advised when administering FOLOTYN to patients with moderate to severe impairment. Monitor patients for renal function and systemic toxicity due to increased drug exposure [see Clinical Pharmacology (12.3)].

5.6 Elevated Liver Enzymes

Liver function test abnormalities have been observed after FOLOTYN administration. Persistent liver function test abnormalities may be indicators of liver toxicity and require dose modification. Monitor patients for liver function [see Dosage and Administration (2.5)].

5.7 Dermatologic Reactions

Dermatologic reactions have been reported in clinical studies and post-marketing safety reports in patients treated with FOLOTYN. Dermatologic reactions have included skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN). These reactions, as well as tumor lysis syndrome, may involve skin and subcutaneous sites of known lymphoma. Skin reactions may be progressive and increase in severity with further treatment. Severe skin reactions have been associated with fatal outcomes. Patients with skin reactions should be monitored closely, and if skin reactions are severe, FOLOTYN should be withheld or discontinued.

6 ADVERSE REACTIONS

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 %

aStomatitis or mucosal inflammation of the gastrointestinal and genitourinary tracts.

bFive patients with platelets < 10,000/μL

cAlanine aminotransferase, aspartate aminotransferase, and transaminases increased

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

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.

7 DRUG INTERACTIONS

In vitro studies indicate that pralatrexate is not a substrate, inhibitor, or inducer of CYP450 isoenzymes and has low potential for drug-drug interactions at CYP450 isoenzymes [see Clinical Pharmacology (12.3)]. No formal clinical assessments of pharmacokinetic drug-drug interactions between FOLOTYN and other drugs have been conducted. The effect of co-administration of the uricosuric drug probenecid 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.

Due to the contribution of renal excretion (approximately 34%) to the overall clearance of pralatrexate, concomitant administration of drugs that are subject to substantial renal clearance (eg, NSAIDs, trimethoprim/sulfamethoxazole) may result in delayed clearance of pralatrexate.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.4)].

FOLOTYN 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.

8.3 Nursing Mothers

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 FOLOTYN, taking into account the importance of FOLOTYN to the mother.

8.4 Pediatric Use

Pediatric patients were not included in clinical studies with FOLOTYN. The safety and effectiveness of FOLOTYN in pediatric patients have not been established.

8.5 Geriatric Use

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).

No dosage adjustment is required in elderly patients with normal renal function [see Clinical Pharmacology (12.3)]

8.6 Hepatic Impairment

Formal studies have not been performed with FOLOTYN 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.

8.7 Renal Impairment

[see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

No specific information is available on the treatment of overdosage of FOLOTYN. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. Based on FOLOTYN'S mechanism of action the prompt administration of leucovorin should be considered.

11 DESCRIPTION

FOLOTYN (pralatrexate injection) contains pralatrexate, which is an antineoplastic folate analog. Pralatrexate has the chemical name (2S)-2-[[4-[(1RS)-1-[(2, 4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid. The structural formula is as follows:

Pralatrexate is a 1:1 racemic mixture of S- and R- diastereomers at the C10 position (indicated with *).

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

Pralatrexate is an off-white to yellow solid. It is soluble in aqueous solutions at pH 6.5 or higher. Pralatrexate is practically insoluble in chloroform and ethanol. The pKa values are 3.25, 4.76, and 6.17.

FOLOTYN is supplied as a preservative-free, sterile, isotonic, non-pyrogenic clear yellow aqueous parenteral solution contained in a single-use clear glass vial (Type I) for intravenous administration. Each 1 mL of solution contains 20 mg of pralatrexate, sufficient sodium chloride to achieve an isotonic (280-300 mOsm) solution, and sufficient sodium hydroxide, and hydrochloric acid if needed, to adjust and maintain the pH at 7.5-8.5. FOLOTYN is supplied as either 20 mg (1 mL) or 40 mg (2 mL) single-use vials at a concentration of 20 mg/mL.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.3 Pharmacokinetics

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. In in vitro studies using MDR1-MDCK and Caco-2 cell systems, pralatrexate was not a substrate for P-glycoprotein (Pgp)-mediated transport nor did it inhibit Pgp-mediated transport.

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. In vitro studies indicated that pralatrexate has low potential to induce or inhibit the activity of CYP450 isozymes.

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.

Patients with Renal Impairment

Approximately 34% of pralatrexate was excreted unchanged into urine following a single dose of 30 mg/m2 administered as an intravenous push over 3-5 minutes. In a population pharmacokinetic analysis drug clearance decreased with decreasing creatinine clearance [see Warnings and Precautions (5.5)].

Patients with Hepatic Impairment

Pralatrexate has not been studied in patients with hepatic impairment.

Effects of Age and Gender

Due to the contribution of renal excretion to overall clearance of pralatrexate, age-related decline in renal function may lead to a reduction in clearance and a commensurate increase in plasma exposure. There was no significant effect of gender on pharmacokinetics.

13 NONCLINICAL TOXICOLOGY

13.1 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.

14 CLINICAL STUDIES

Peripheral T-cell Lymphoma (PTCL)

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

Table 5 Response Analysis per Independent Central Review (IWC)
Evaluable Patients
(N=109)

Fourteen patients went off treatment in cycle 1; 2 patients were unevaluable for response by IWC due to insufficient materials provided to central review.

CR = Complete Response, CRu = Complete Response unconfirmed, PR = Partial Response

N (%) 95% CI Median Duration of Response Range of Duration of Response
Overall Response
CR+CRu+PR 29 (27) 19, 36 287 days
(9.4 months)
1-503 days
CR/CRu 9 (8)
PR 20 (18)
Responses ≥ 14 weeks
CR+CRu+PR 13 (12) 7, 20 Not Reached 98-503 days
CR/CRu 7 (6)
PR 6 (6)

The initial response assessment was scheduled at the end of cycle 1. Of the responders, 66% responded within cycle 1. The median time to first response was 45 days (range 37-349 days).

15 REFERENCES

  1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165.
  2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/o tm/otm_vi/otm_vi_2.html
  3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
  4. Polovich, M., White, J. M., & Kelleher, L. O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

16 HOW SUPPLIED/STORAGE AND HANDLING

FOLOTYN 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)

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

Handle and dispose of FOLOTYN according to guidelines issued for cytotoxic drugs, including the use of gloves and other protective clothing to prevent skin contact [see References (15)].

Each vial of FOLOTYN is intended for single use only. Any unused drug remaining after injection must be discarded.

Rx only

17 PATIENT COUNSELING INFORMATION

17.1 Need for Folic Acid and Vitamin B12

Patients treated with FOLOTYN must be instructed to take folic acid and vitamin B12 as a prophylactic measure to potentially reduce possible side effects [see Dosage and Administration (2.2)].

17.2 Mucositis

Physicians should discuss with patients the signs and symptoms of mucositis. Patients should be instructed on ways to reduce the risk of its development, and/or ways to maintain nutrition and control discomfort from mucositis if it occurs.

17.3 Low Blood Cell Counts

Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any signs of infection develop, including fever. Patients should also be instructed to contact their physician if bleeding or symptoms of anemia occur.

17.4 Concomitant Medications

Patients should be instructed to inform their physician if they are taking any concomitant medications including prescription drugs (such as trimethoprim/sulfamethoxazole) and nonprescription drugs (such as nonsteroidal anti-inflammatory drugs) [see Drug Interactions (7)].

17.5 Pregnancy/Nursing

Patients should be instructed to tell their physician if they are pregnant or plan to become pregnant due to the risk of fetal harm. Patients should be instructed to tell their physician if they are nursing.

17.6 Dermatologic Reactions

Physicians should discuss with patients the signs and symptoms of dermatologic reactions. Patients should be made aware to immediately notify their physician if any untoward skin reactions occur [see Warnings and Precautions (5.7)].
用于复发性或难治性外周T细胞淋巴瘤的新制剂获批
Folotyn被批准应用于PTCL是基于一项临床试验获得的患者总体反应率。其时,此药的临床获益,如疾病无进展生存率或总体生存率的改善,仍未确定。鉴于Folotyn获得FDA的加速批准,Allos公司同意开展更多的临床研究以进一步确定和描述此药对于T细胞淋巴瘤患者的临床益处。
FDA批准Folotyn的应用是基于一项关键的开放标签非对照多中心Ⅱ期国际临床试验的结果。这项研究纳入了115例复发性或难治性PTCL患者。根据此研究方案的要求,来自其中109例患者的数据被认为可用于疗效评价。
在入组前,患者接受系统治疗的中位次数为3次(1~12次)。约1/4的患者对之前进行的PTCL治疗均无反应。
研究给予受试者30 mg/m2剂量的Folotyn,静脉推注,每次3~5min,每周1次连续6周,每7周1个疗程,直至疾病进展或发生无法接受的毒性反应。另外,患者每8~10周肌内注射1 mg维生素B12,每日口服1.0~1.25 mg叶酸。
患者对pralatrexate的总体反应率为28%(30/109),中位反应时间为9.4个月,这是通过应用国际研讨会准则进行中央独立肿瘤评价获得的数据。在对pralatraxate治疗有反应的患者中,21例(70%)在1个疗程后即对治疗产生了反应。患者的中位总体生存时间为14.7个月,57%的有反应者至少存活12个月。
此临床试验中最常见的不良反应为黏膜炎(70%)、血小板减少症(41%)、恶心(40%)和疲劳(36%)。在不考虑诱因的情况下,最常见的严重不良反应(>3%)为发热、黏膜炎、脓毒症、发热性中性粒细胞减少症、脱水、呼吸困难和血小板减少症。有44%的患者在研究期间或者在最后一次接受Folotyn治疗后30天内发生了严重不良反应事件。23%的患者因不良反应中止治疗。
------------------------------------------------------------
产地国家: 美国
原产地英文商品名:
FOLOTYN 40mg/2ml/vial
原产地英文药品名:
PRALATREXATE
中文参考商品译名:
FOLOTYN 40毫克/2毫升/瓶
中文参考药品译名:
普拉曲沙
生产厂家中文参考译名:
Allos
生产厂家英文名:
Allos
------------------------------------------------------------
产地国家: 美国
原产地英文商品名:
FOLOTYN 20mg/vial
原产地英文药品名:
PRALATREXATE
中文参考商品译名:
FOLOTYN 20毫克/瓶
中文参考药品译名:
普拉曲沙
生产厂家中文参考译名:
Allos
生产厂家英文名:
Allos

责任编辑:admin


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