NDC 0069-0983 Romidepsin

Romidepsin

NDC Product Code 0069-0983

NDC 0069-0983-01

Package Description: 1 KIT in 1 CARTON * 2 mL in 1 VIAL, GLASS (0069-0972-01) * 2 mL in 1 VIAL, GLASS (0069-0961-01)

NDC Product Information

Romidepsin with NDC 0069-0983 is a a human prescription drug product labeled by Pfizer Laboratories Div Pfizer Inc. The generic name of Romidepsin is romidepsin. The product's dosage form is kit and is administered via form.

Labeler Name: Pfizer Laboratories Div Pfizer Inc

Dosage Form: Kit - A packaged collection of related material.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • POVIDONES (UNII: FZ989GH94E)
  • ALCOHOL (UNII: 3K9958V90M)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Pfizer Laboratories Div Pfizer Inc
Labeler Code: 0069
FDA Application Number: NDA022393 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA AUTHORIZED GENERIC - A product marketed as a “generic” drug under an approved New Drug Application (NDA), rather than an Abbreviated New Drug Application (ANDA),. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 01-04-2010 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

End Marketing Date: 03-31-2021 What is the End Marketing Date?
This is the date the product will no longer be available on the market. If a product is no longer being manufactured, in most cases, the FDA recommends firms use the expiration date of the last lot produced as the EndMarketingDate, to reflect the potential for drug product to remain available after manufacturing has ceased. Products that are the subject of ongoing manufacturing will not ordinarily have any EndMarketingDate. Products with a value in the EndMarketingDate will be removed from the NDC Directory when the EndMarketingDate is reached.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

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Information for Patients

Romidepsin Injection

Romidepsin Injection is pronounced as (roe'' mi dep' sin)

Why is romidepsin injection medication prescribed?
Romidepsin injection is used to treat cutaneous T-cell lymphoma (CTCL; a group of cancers of the immune system that first appear as skin rashes) in people who have alread...
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Romidepsin Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

  • Romidepsin is indicated for:Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

2.1 Dosing Information

The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug.

2.2 Dose Modification

  • Nonhematologic toxicities except alopeciaGrade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2.Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2.Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction.Hematologic toxicitiesGrade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2.Grade 4 febrile (≥ 38.5ºC) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤ Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2.

2.3 Instructions For Preparation And Intravenous Administration

  • Romidepsin is a cytotoxic drug. Use appropriate handling procedures. Romidepsin must be reconstituted with the supplied diluent and further diluted with 0.9% Sodium Chloride Injection, USP before intravenous infusion. Romidepsin and diluent vials contain an overfill to ensure the recommended volume can be withdrawn at a concentration of 5 mg/mL.Each 10 mg single-dose vial of romidepsin must be reconstituted with 2.2 mL of the supplied diluent.With a suitable syringe, aseptically withdraw 2.2 mL from the supplied diluent vial, and slowly inject it into the romidepsin for injection vial. Swirl
  • The contents of the vial until there are no visible particles in the resulting solution. The reconstituted solution will contain romidepsin 5 mg/mL. The reconstituted
  • Romidepsin vial will contain 2 mL of deliverable volume of drug product. The reconstituted romidepsin solution is chemically stable for up to 8 hours at room
  • Temperature.Extract the appropriate amount of romidepsin from the vials to deliver the desired dose, using proper aseptic technique. Before intravenous infusion, further dilute romidepsin in 500 mL 0.9% Sodium Chloride Injection, USP.Infuse over 4 hours.The diluted solution is compatible with polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyethylene (PE) infusion bags as well as glass bottles, and is chemically stable for up to 24 hours when stored at room temperature. However, it should be administered as soon after dilution as possible.Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

3 Dosage Forms And Strengths

Romidepsin is supplied as a kit which includes a sterile, lyophilized powder in a 10 mg single-dose vial containing 11 mg of romidepsin and 22 mg of the bulking agent,
povidone, USP. In addition, each kit includes a single-dose sterile vial containing 2.4 mL (2.2 mL deliverable volume) of the diluent composed of 80% propylene glycol, USP, and
20% dehydrated alcohol, USP.

4 Contraindications

None.

5.1 Myelosuppression

Treatment with romidepsin can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia. Monitor blood counts regularly during treatment with romidepsin, and modify the dose as necessary [see Dosage and Administration (2.2) and Adverse Reactions (6)].

5.2 Infections

Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, including Epstein Barr and hepatitis B viruses, have been reported in clinical trials with romidepsin. These can occur during treatment and within 30 days after treatment. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow [see Adverse Reactions (6)].Reactivation of hepatitis B virus infection has occurred in 1% of PTCL patients in clinical trials in Western populations [see Adverse Reactions (6)]. In patients with evidence of prior hepatitis B infection, consider monitoring for reactivation, and consider antiviral prophylaxis.Reactivation of Epstein Barr viral infection leading to liver failure has occurred in a trial of patients with relapsed or refractory extranodal NK/T-cell lymphoma. In one case, ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation.

5.3 Electrocardiographic Changes

Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [see Adverse Reactions (6)].In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment.Confirm that potassium and magnesium levels are within normal range before administration of romidepsin [see Adverse Reactions (6)].

5.4 Tumor Lysis Syndrome

Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden are at greater risk, should be closely monitored, and managed as appropriate.

5.5 Use In Pregnancy

There are no adequate and well-controlled studies of romidepsin in pregnant women. However, based on its mechanism of action and findings in animals, romidepsin may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking romidepsin, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

6 Adverse Reactions

  • The following adverse reactions are described in more detail in other sections of the prescribing information.Myelosuppression [see Warnings and Precautions (5.1)]Infections [see Warnings and Precautions (5.2)]Electrocardiographic Changes [see Warnings and Precautions (5.3)]Tumor Lysis Syndrome [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Cutaneous T-Cell LymphomaThe safety of romidepsin was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

6.2 Postmarketing Experience

No additional safety signals have been observed from postmarketing experience.

7.1 Warfarin Or Coumarin Derivatives

Prolongation of PT and elevation of INR were observed in a patient receiving romidepsin concomitantly with warfarin. Although the interaction potential between romidepsin and warfarin has not been formally studied, monitor PT and INR more frequently in patients concurrently receiving romidepsin and warfarin [see Clinical Pharmacology (12.3)].

7.2 Drugs That Inhibit Cytochrome P450 3A4 Enzymes

Romidepsin is metabolized by CYP3A4. Strong CYP3A4 inhibitors increase concentrations of romidepsin. In a pharmacokinetic drug interaction trial the strong CYP3A4 inhibitor ketoconazole increased romidepsin (AUC0-∞) by approximately 25% [see Clinical Pharmacology (12.3)].Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity [see Dosage and Administration (2.2)] when romidepsin is initially co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole).

7.3 Drugs That Induce Cytochrome P450 3A4 Enzymes

Avoid co-administration of romidepsin with rifampin.In a pharmacokinetic drug interaction trial with co-administered rifampin (a strong CYP3A4 inducer), romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively [see Clinical Pharmacology (12.3)]. Typically, co-administration of CYP3A4 inducers decrease concentrations of drugs metabolized by CYP3A4. The increase in exposure seen after co-administration with rifampin is likely due to rifampin’s inhibition of an undetermined hepatic uptake process that is predominantly responsible for the disposition of romidepsin. It is unknown if other potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) would alter the exposure of romidepsin. Therefore, the use of other potent CYP3A4 inducers should be avoided when possible.

7.4 Drugs That Inhibit Drug Transport Systems

Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If romidepsin is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.

8.1 Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.5)].There are no adequate and well-controlled studies of romidepsin in pregnant women. However, based on its mechanism of action and findings in animals, romidepsin may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking romidepsin, the patient should be apprised of the potential hazard to the fetus.Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures (AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification.

8.3 Nursing Mothers

It is not known whether romidepsin 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 romidepsin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of romidepsin in pediatric patients has not been established.

8.5 Geriatric Use

Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were >65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment

No dedicated hepatic impairment study for romidepsin has been conducted. Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dedicated renal impairment study for romidepsin has been conducted. Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [see Clinical Pharmacology (12.3)].

10 Overdosage

No specific information is available on the treatment of overdosage of romidepsin.Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heartbeat, staggering gait, tremor, and tonic convulsions.In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for romidepsin and it is not known if romidepsin is dialyzable.

11 Description

Romidepsin, a histone deacetylase (HDAC) inhibitor, is a bicyclic depsipeptide. At room temperature, romidepsin is a white powder and is described chemically as (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone. The empirical formula is C24H36N4O6S2.The molecular weight is 540.71 and the structural formula is:Romidepsin for injection is intended for intravenous infusion only after reconstitution with the supplied diluent and after further dilution with 0.9% Sodium Chloride, USP.Romidepsin is supplied as a kit containing 2 vials.Romidepsin for injection is a sterile lyophilized white powder and is supplied in a 10 mg single-dose vial containing 11 mg romidepsin and 22 mg povidone, USP.Diluent for romidepsin is a sterile clear solution and is supplied in a single-dose vial containing 2.4 mL (2.2 mL deliverable volume). Diluent for romidepsin contains
80% (v/v) propylene glycol, USP and 20% (v/v) dehydrated alcohol, USP.

12.1 Mechanism Of Action

Romidepsin is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate non-histone proteins, such as transcription factors. In vitro, romidepsin causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of some cancer cell lines with IC50 values in the nanomolar range. The mechanism of the antineoplastic effect of romidepsin observed in nonclinical and clinical studies has not been fully characterized.

12.2 Pharmacodynamics

Cardiac ElectrophysiologyThe effect of romidepsin on the heart-rate corrected QTc/QTcF was evaluated in 26 subjects with advanced malignancies given romidepsin at doses of 14 mg/m2 as a 4-hour intravenous infusion, and at doses of 8, 10 or 12 mg/m2 as a 1–hour infusion. Patients received premedications with antiemetics. No large changes in the mean QTc interval (> 20 milliseconds) from baseline based on Fridericia correction method were detected in the trial. Small increase in mean QT interval (< 10 milliseconds) and mean QT interval increase between 10 to 20 milliseconds cannot be excluded because of the limitations in the trial design. Romidepsin was associated with a delayed concentration-dependent increase in heart rate in patients with advanced cancer with a maximum mean increase in heart rate of 20 beats per minute occurring at the 6 hour time point after start of romidepsin infusion for patients receiving 14 mg/m2 as a 4-hour infusion.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.Based on nonclinical findings, male and female fertility may be compromised by treatment with romidepsin. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-∞ values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-∞ values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area.

14.1 Cutaneous T-Cell Lymphoma

Romidepsin was evaluated in 2 multicenter, single-arm clinical studies in patients with CTCL. Overall, 167 patients with CTCL were treated in the US, Europe, and Australia. Study 1 included 96 patients with confirmed CTCL after failure of at least 1 prior systemic therapy. Study 2 included 71 patients with a primary diagnosis of CTCL who received at least 2 prior skin directed therapies or one or more systemic therapies. Patients were treated with romidepsin at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days.In both studies, patients could be treated until disease progression at the discretion of the investigator and local regulators. Objective disease response was evaluated according to a composite endpoint that included assessments of skin involvement, lymph node and visceral involvement, and abnormal circulating T-cells ("Sézary cells").The primary efficacy endpoint for both studies was overall objective disease response rate (ORR) based on the investigator assessments, and defined as the proportion of patients with confirmed complete response (CR) or partial response (PR). CR was defined as no evidence of disease and PR as ≥ 50% improvement in disease. Secondary endpoints in both studies included duration of response and time to response.Baseline Patient CharacteristicsDemographic and disease characteristics of the patients in Study 1 and Study 2 are provided in Table 3.Table 3. Baseline Patient Characteristics(CTCL Population)CharacteristicStudy 1(N=96)Study 2(N=71)Age   N9671  Mean (SD)57 (12)56 (13)  Median (Range)57 (21, 89)57 (28, 84)Sex, n (%)  Men59 (61)48 (68)  Women37 (39)23 (32)Race, n (%)  White90 (94)55 (77)  Black5 ( 5)15 (21)  Other/Not Reported1 ( 1)1 ( 1)Stage of Disease at Study Entry, n (%)  IA0 ( 0)1 ( 1)  IB15 (16)6 ( 9)  IIA13 (14)2 ( 3)  IIB21 (22)14 (20)  III23 (24)9 (13)  IVA24 (25)27 (38)  IVB0 ( 0)12 (17)Number of Prior Skin-Directed Therapies  Median (Range)2 (0,6)1 (0,3)Number of Prior Systemic Therapies  Median (Range)2 (1, 8)2 (0, 7)Clinical ResultsEfficacy outcomes for CTCL patients are provided in Table 4. Median time to first response was 2 months (range 1 to 6) in both studies. Median time to CR was 4 months in Study 1 and 6 months in Study 2 (range 2 to 9). Table 4. Clinical Results for CTCL PatientsResponse RateStudy 1(N=96)Study 2(N=71)ORR (CR + PR), n (%) [95% Confidence Interval]33 (34) [25, 45]25 (35) [25, 49]            CR, n (%)            [95% Confidence Interval]6 (6) [2, 13]4 (6) [2, 14]            PR, n (%)            [95% Confidence Interval]27 (28) [19, 38]21 (30) [20, 43]Duration of Response (months)            N3325            Median (range)15 (1, 20*)11 (1, 66*)    *denotes censored value

14.2 Peripheral T-Cell Lymphoma

Romidepsin was evaluated in a multicenter, single-arm, international clinical study in patients with PTCL who had failed at least 1 prior systemic therapy (Study 3). Patients in US, Europe, and Australia were treated with romidepsin at a dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days. Of the 131 patients treated, 130 patients had histological confirmation by independent central review and were evaluable for efficacy (HC Population). Six cycles of treatment were planned; patients who developed progressive disease (PD), significant toxicity, or who met another criterion for study termination were to discontinue treatment. Responding patients had the option of continuing treatment beyond 6 cycles at the discretion of the patient and Investigator until study withdrawal criteria were met.Primary assessment of efficacy was based on rate of complete response (CR + CRu) as determined by an Independent Review Committee (IRC) using the International Workshop Response Criteria (IWC). Secondary measures of efficacy included IRC assessment of duration of response and objective disease response (ORR, CR + CRu + PR).Baseline Patient CharacteristicsDemographic and disease characteristics of the PTCL patients are provided in Table 5.*Stage of disease was reported at time of diagnosis for Study 3 and at time of study entry for Study 4.Table 5. Baseline Patient Characteristics(PTCL Population)CharacteristicStudy 3 (N=130)Study 4(N=47)Age (years), n13047  Mean (SD)59 (13)59 (13)  Median6159Sex, n (%)  Male88 (68)25 (53)  Female42 (32)22 (47)Race, n (%)  White116 (89)40 (85)  Black7 (5)4 (9)  Asian3 (2)3 (6)  Other4 (3)0PTCL Subtype Based on Central Diagnosis, n (%)  PTCL Unspecified (NOS)69 (53)28 (60)  Angioimmunoblastic T-cell lymphoma (AITL)27 (21)7 (15)  ALK-1 negative anaplastic large cell lymphoma (ALCL)21 (16)5 (11)  Other13 (10)7 (16)Stage of Disease, n (%)*  I/II39 (30)2 (4)  III/IV91 (70)45 (96)ECOG Performance Status, n (%)  046 (35)20 (43)  167 (51)22 (47)  217 (13)4 (9)Number of Prior Systemic Therapies  Median (Range)2 (1, 8)3 (1, 6)All patients in both studies had received prior systemic therapy for PTCL. In Study 4, a greater percentage of patients had extensive prior radiation and chemotherapy. Twenty-one patients (16%) in Study 3 and 18 patients (38%) in Study 4 had received prior autologous stem cell transplant and 31 (24%) and 19 (40%) patients, respectively, had received prior radiation therapy.Clinical ResultsEfficacy outcomes for PTCL patients as determined by the IRC are provided in Table 6 for Study 3. The complete response rate was 15% and overall response rate was 26%. Similar complete response rates were observed by the IRC across the 3 major PTCL subtypes (NOS, AITL, and ALK-1 negative ALCL). Median time to objective response was 1.8 months (~2 cycles) for the 34 patients who achieved CR, CRu, or PR and median time to CR was 3.5 months (~4 cycles) for the 20 patients with complete response. The responses in 12 of the 20 patients achieving CR and CRu were known to exceed 11.6 months; the follow-up on the remaining 8 patients was discontinued prior to 8.5 months. Table 6. Clinical Results for PTCL PatientsResponse RateStudy 3 (N=130)1 Primary Endpoint.2 Secondary Endpoint.3 Two-sided 95% Confidence Interval.CR+CRu, n (%)120 (15.4) [9.7, 22.8]3PR, n (%)214 (10.8) [6.0, 17.4]3ORR (CR+CRu+PR), n (%)234 (26.2) [18.8, 34.6]3In a second single-arm clinical study in patients with PTCL who had failed prior therapy (Study 4), patients were treated with romidepsin at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days. Patients could be treated until disease progression at the discretion of the patient and the Investigator. The percentage of patients achieving CR + CRu in Study 4 was similar to that in Study 3.

15 References

“OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16.1 How Supplied

Romidepsin is supplied as a kit including a sterile, lyophilized powder in a 10 mg single-dose vial containing 11 mg of romidepsin and 22 mg of the bulking agent,
povidone, USP. In addition, each kit includes a single-dose sterile diluent vial containing 2.4 mL (2.2 mL deliverable volume) of 80% propylene glycol, USP, and 20%
dehydrated alcohol, USP.NDC 0069-0983-01: Romidepsin Kit containing 1 vial of romidepsin and 1 vial of diluent for romidepsin per carton.

16.2 Storage

Romidepsin for Injection is supplied as a kit containing 2 vials in a single carton. The carton must be stored at 20° to 25°C, excursions permitted between 15° to 30°C. (See USP Controlled Room Temperature.)Procedures for proper handling and disposal of anticancer drugs should be considered. A guideline on this subject has been published [see References (15)].

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

17.1 Instructions

  • Nausea and Vomiting
  • Advise patients that nausea and vomiting are common following treatment with romidepsin. Prophylactic antiemetics are recommended for all patients. Advise patients to report these symptoms so that appropriate treatment can be instituted [see Adverse Reactions (6)].Low Blood Counts
  • Advise patients that treatment with romidepsin can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [see Warnings and Precautions (5.1)].Infections
  • Advise patients that infections may occur during treatment with romidepsin. Advise patients to report fever, cough, shortness of breath with or without chest pain, burning on urination, flu-like symptoms, muscle aches, or worsening skin problems. Advise patients to report any previous history of hepatitis B before starting romidepsin [see Warnings and Precautions (5.2)].Tumor Lysis Syndrome
  • Advise patients of the risk of tumor lysis syndrome (especially those with advanced stage disease and/or high tumor burden) to maintain high fluid intake for at least 72 hours after each dose [see Warnings and Precautions (5.4)].Use in Pregnancy
  • If pregnancy occurs during treatment with romidepsin, female patients should be advised to seek immediate medical advice and counseling [see Warnings and Precautions (5.5)].Patients should be instructed to read the patient insert carefully.

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