Istodax

DESCRIPTION

Romidepsin, ahistonedeacetylase (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:

ISTODAX (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.

ISTODAX is supplied as a kit containing 2 vials.

ISTODAX (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 ISTODAX is a sterile clear solution and is supplied in a single-dose vial containing 2.4 mL (2.2 mL deliverable volume). Diluent for ISTODAX contains 80% (v/v) propylene glycol, USP and 20% (v/v) dehydrated alcohol, USP.

INDICATIONS

ISTODAX is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in adult patients who have received at least one prior systemic therapy.

DOSAGE AND ADMINISTRATION

Dosage Information

The recommended dosage of romidepsin is 14 mg/m²静脉注射接种在4小时内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.

Dosage Modification

Nonhematologic Toxicities Except Alopecia

• Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to Grade 0-1 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 0-1 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 0-1 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 Toxicities

• Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC greater than or equal to 1.5×10⁹/L and platelet count greater than or equal to 75×10⁹/L or baseline, then therapy may be restarted at 14 mg/m².
• Grade 4 febrile (greater than or equal to 38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to less than or equal to Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m².

Dosage In Patients With Hepatic Impairment

For patients with moderate or severe hepatic impairment, reduce the starting dose of ISTODAX as shown in Table 1 and monitor for toxicities more frequently. Dosage adjustment is not required for patients with mild hepatic impairment.

Table 1: Recommendations for Starting Dose in Patients with Moderate and Severe Hepatic Impairment

Hepatic Impairment	Bilirubin Levels	ISTODAX Dose
Moderate	greater than 1.5 x ULN to less than or equal to 3 x ULN	7 mg/m2
Severe	greater than 3 x ULN	5 mg/m2
ULN=Upper limit of normal.

Instructions For Preparation And Intravenous Administration

ISTODAX is a hazardous drug. Use appropriate handling procedures.¹

ISTODAX must be reconstituted with the supplied diluent and further diluted with 0.9% Sodium Chloride Injection, USP, before intravenous infusion.

ISTODAX 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 ISTODAX 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 ISTODAX (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 ISTODAX 5 mg/mL. The reconstituted ISTODAX vial will contain 2 mL of deliverable volume of drug product. The reconstituted ISTODAX solution is chemically stable for up to 8 hours at room temperature.
• Extract the appropriate amount of ISTODAX from the vials to deliver the desired dose, using proper aseptic technique. Before intravenous infusion, further dilute ISTODAX 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.

HOW SUPPLIED

Dosage Forms And Strengths

For Injection

10 mg of romidepsin as a lyophilized white powder in a single-dose vial for reconstitution and further dilution.

ISTODAXis supplied as a kit including a sterile, lyophilized powder in a 10 mg single-dose vial containing 11 mg of romidepsin, 22 mg of the bulking agent,povidone, USP, and hydrochloric acid, NF, as a pH adjuster. 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 59572-984-01:ISTODAX^®KIT containing 1 vial of romidepsin and 1 vial of diluent for romidepsin per carton.

Storage And Handling

ISTODAX (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.)

ISTODAX is a hazardous drug. Follow applicable special handling and disposal procedures.¹

REFERENCES

1. OSHA Hazardous Drugs.OSHA. [Accessed on 09/11/2018, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

Manufactured by: Baxter Oncology GmbH Halle/Westfalen, Germany. Revised: Jul 2021

SIDE EFFECTS

The following adverse reactions are described in more detail in other sections of the prescribing information.

• Myelosuppression [seeWARNINGS AND PRECAUTIONS]
• Infections [seeWARNINGS AND PRECAUTIONS]
• Electrocardiographic Changes [seeWARNINGS AND PRECAUTIONS]
• Tumor Lysis Syndrome [seeWARNINGS AND PRECAUTIONS]

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.

警告和预防措施中的数据反映exposure to ISTODAX in four clinical trials involving 363 patients with T-cell lymphoma, including 185 patients with CTCL. ISTODAX was administered as a single agent at a dosage of 14 mg/m²on days 1, 8, and 15 of a 28-day cycle. Among 363 patients who received ISTODAX, 21% were exposed for 6 months or longer and 13% were exposed for greater than one year.

Cutaneous T-Cell Lymphoma

ISTODAX是e的安全valuated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a dosage of 14 mg/m²on days 1, 8, and 15 of a 28-day cycle. Treatment continued as long as the patient benefitted from and tolerated the drug. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

Common Adverse Reactions

Table 2 summarizes the most frequent adverse reactions (>20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1. Laboratory abnormalities commonly reported (>20%) as adverse reactions are included in Table 2.

Table 2. ADVERSE REACTIONS Occurring in >20% of Patients in Either CTCL Study (N=185)

ADVERSE REACTIONS n (%)	Study 1 (n=102)		Study 2 (n=83)
	All grades	Grade 3 or 4	All grades	Grade 3 or 4
Any adverse reactions	99 (97)	36 (35)	83 (100)	68 (82)
Nausea	57 (56)	3 (3)	71 (86)	5 (6)
Asthenia/Fatigue	54 (53)	8 (8)	64 (77)	12 (14)
Infections	47 (46)	11 (11)	45 (54)	27 (33)
Vomiting	35 (34)	1 (<1)	43 (52)	8 (10)
Anorexia	23 (23)	1 (<1)	45 (54)	3 (4)
Hypomagnesemia	22 (22)	1 (<1)	23 (28)	0
Diarrhea	20 (20)	1 (<1)	22 (27)	1 (1)
Pyrexia	20 (20)	4 (4)	19 (23)	1 (1)
Anemia	19 (19)	3 (3)	60 (72)	13 (16)
Thrombocytopenia	17 (17)	0	54 (65)	12 (14)
Dysgeusia	15 (15)	0	33 (40)	0
Constipation	12 (12)	2 (2)	32 (39)	1 (1)
Neutropenia	11 (11)	4 (4)	47 (57)	22 (27)
Hypotension	7 (7)	3 (3)	19 (23)	3 (4)
Pruritus	7 (7)	0	26 (31)	5 (6)
Hypokalemia	6 (6)	0	17 (20)	2 (2)
Dermatitis/Exfoliative dermatitis	4 (4)	1 (<1)	22 (27)	7 (8)
Hypocalcemia	4 (4)	0	43 (52)	5 (6)
Leukopenia	4 (4)	0	38 (46)	18 (22)
Lymphopenia	4 (4)	0	47 (57)	31 (37)
Alanine aminotransferase increased	3 (3)	0	18 (22)	2 (2)
Aspartate aminotransferase increased	3 (3)	0	23 (28)	3 (4)
低白蛋白血症	3 (3)	1 (<1)	40 (48)	3 (4)
Electrocardiogram ST-T wave changes	2 (2)	0	52 (63)	0
Hyperglycemia	2 (2)	2 (2)	42 (51)	1 (1)
Hyponatremia	1 (<1)	1 (<1)	17 (20)	2 (2)
Hypermagnesemia	0	0	22 (27)	7 (8)
Hypophosphatemia	0	0	22 (27)	8 (10)
Hyperuricemia	0	0	27 (33)	7 (8)

Serious Adverse Reactions

Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in >2% of patients in Study 1 weresepsisand pyrexia (3%). In Study 2, serious adverse reactions in >2% of patients were fatigue (7%), supraventriculararrhythmia,central lineinfection,neutropenia(6%),hypotension,hyperuricemia, edema (5%),ventriculararrhythmia,thrombocytopenia, nausea,leukopenia, dehydration, pyrexia,aspartate aminotransferaseincreased, sepsis,catheterrelated infection,hypophosphatemiaanddyspnea(4%).

There were eight deaths not due to disease progression. In Study 1, there were two deaths: one due tocardiopulmonaryfailure and one due toacute renal failure. There were six deaths in Study 2: four due to infection and one each due to myocardialischemiaand acuterespiratory distress syndrome.

Discontinuations

Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, andhypomagnesemia.

Other Clinical Trials Experience

The following common adverse reactions have been reported following administration of ISTODAX as a single agent in 178 patients with peripheralT-cell lymphoma, for which ISTODAX is not indicated or recommended. The most common adverse reactions (≥30%) included nausea (63%), fatigue (61%), thrombocytopenia (49%), vomiting (39%), neutropenia (39%), pyrexia (38%), diarrhea (36%) andanemia(35%). Other common (≥10%) clinically significant adverse reactions includeddysgeusia(22%), headache (20%), cough (19%), dyspnea (15%), abdominal pain (13%) and stomatitis (10%). Grade 3 and higher adverse reactions in ≥10% were hematologic toxicities (including thrombocytopenia, neutropenia, leukopenia and anemia) and fatigue.

DRUG INTERACTIONS

Warfarin Or Coumarin Derivatives

Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Monitor PT and INR more frequently in patients concurrently receiving ISTODAX and warfarin [seeCLINICAL PHARMACOLOGY].

Drugs That Inhibit CYP3A4 Enzymes

Strong CYP3A4 inhibitors increase concentrations of romidepsin [seeCLINICAL PHARMACOLOGY]. Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity [seeDOSAGE AND ADMINISTRATION] when ISTODAX is initially co-administered with strong CYP3A4 inhibitors.

Drugs That Induce CYP3A4 Enzymes

Rifampin (a potent CYP3A4 inducer) increased the concentrations of romidepsin [seeCLINICAL PHARMACOLOGY]. Avoid co-administration of ISTODAX with rifampin. The use of other potent CYP3A4 inducers should be avoided when possible.

WARNINGS

Included as part of the"PRECAUTIONS"Section

PRECAUTIONS

Myelosuppression

Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia. Monitor blood counts regularly during treatment with ISTODAX and modify the dose as necessary [seeDOSAGE AND ADMINISTRATIONandADVERSE REACTIONS].

Infections

Fatal and serious infections have been reported in clinical trials of ISTODAX, includingpneumonia, sepsis, and viral reactivation, including reactivation of Epstein Barr andhepatitis Bviruses. These infections can occur during and following treatment. The risk of life-threatening infections may be greater in patients with a history of prior treatment withmonoclonalantibodies directed againstlymphocyteantigens and in patients with disease involvement of thebone marrow[seeADVERSE REACTIONS].

Reactivation ofhepatitisB virusinfection was reported in 1% of patients in clinical trials. In patients with evidence of prior hepatitis B infection, consider monitoring for reactivation, and consider抗病毒prophylaxis.

Reactivation of Epstein Barrviral infectionleading toliver failurehas occurred in recipients of ISTODAX including after ganciclovir prophylaxis.

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 [seeADVERSE REACTIONS].

In patients withcongenitallong QT syndrome, patients with a history of significantcardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, considercardiovascularmonitoring of ECGs at baseline and periodically during treatment.

Confirm thatpotassiumand magnesium levels are withinnormal rangebefore administration of ISTODAX [seeADVERSE REACTIONS].

Tumor Lysis Syndrome

Tumorlysissyndrome (TLS) has been reported to occur in recipients of ISTODAX, including in 1% of patients with tumor stage CTCL. Patients with advanced stage disease and/or high tumor burden are at greater risk, should be closely monitored, and managed as appropriate.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, ISTODAX can cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and caused adverse developmental outcomes at exposures below those in patients at the recommended dose of 14 mg/m². Advise females of reproductive potential to use effective contraception during treatment and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 1 month after the last dose [seeUse In Specific PopulationsandCLINICAL PHARMACOLOGY].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Low Blood Counts

建议病人that treatment with ISTODAX 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 [seeWARNINGS AND PRECAUTIONS]

Infections

建议病人that infections may occur during treatment with ISTODAX. 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 [seeWARNINGS AND PRECAUTIONS].

Tumor Lysis Syndrome

建议病人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 [seeWARNINGS AND PRECAUTIONS].

Nausea And Vomiting

建议病人that nausea and vomiting are common following treatment with ISTODAX.Prophylacticantiemetics推荐给所有的病人。建议病人to report these symptoms so that appropriate treatment can be instituted [seeADVERSE REACTIONS].

Embryo-Fetal Toxicity

建议病人that ISTODAX can cause fetal harm when administered during pregnancy [seeWARNINGS AND PRECAUTIONSandUse In Specific Populations].

Contraception

建议使用ef的雌性生殖潜力fective contraception during treatment with ISTODAX and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ISTODAX and for 1 month after the last dose [Use In Specific Populations].

Lactation

Advise lactating women not to breastfeed during treatment with ISTODAX and for 1 week after the last dose [seeUse In Specific Populations].

Infertility

Advise females and males of reproductive potential that ISTODAX may causeinfertility[seeNonclinical Toxicology].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenicin vitroin the bacterial reverse mutation assay (Ames test) or the mouselymphomaassay. Romidepsin was not clastogenic in anin vivo鼠骨髓微核分析测试的时候出现the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m²in 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 ISTODAX. In a 26-weektoxicologystudy, 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 vesicleandprostateorgan 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 highaffinityfor binding toestrogenreceptors inpharmacologystudies. In a 26-week toxicology study in rats,atrophywas seen in the ovary,uterus,vaginaandmammary glandof 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 ofovarianfollicles 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.

Use In Specific Populations

Pregnancy

Risk Summary

Based on its mechanism of action and findings from animal studies, ISTODAX can cause embryo-fetal harm when administered to a pregnant woman [seeCLINICAL PHARMACOLOGY].

没有可用数据ISTODAX怀孕的使用nant women to inform a drug associated risk of major birth defects andmiscarriage. In an animal reproductive study, romidepsin was embryocidal and caused adverse developmental outcomes including embryo-fetal toxicity and malformations at exposures below those in patients at the recommended dose (seeData). Advise pregnant women of the potential risk to a fetus and to avoid becoming pregnant while receiving ISTODAX and for at least 1 month after the last dose.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk ofbirth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 24% and 15-20%, respectively.

Data

Animal Data

Romidepsin was administered intravenously to pregnant rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantialresorptionor postimplantation 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 reduced fetal body weights, foldedretina, rotated limbs, and incomplete sternalossification.

Lactation

Risk Summary

There are no data on the presence of ISTODAX or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the breastfed child, advise lactating women not to breastfeed during treatment with ISTODAX and for 1 week after the last dose.

Females And Males Of Reproductive Potential

ISTODAX can cause fetal harm when administered to a pregnant woman [seePregnancy].

Pregnancy Testing

Perform pregnancy testing in females of reproductive potential within 7 days prior to initiating therapy with ISTODAX.

Contraception

Females

建议使用ef的雌性生殖潜力fective contraception during treatment with ISTODAX and for 1 month after the last dose. ISTODAX may reduce the effectiveness of estrogen-containing contraceptives. Therefore, alternative methods of non-estrogen containing contraception (e.g., condoms,intrauterinedevices) should be used in patients receiving ISTODAX.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with ISTODAX and for 1 month after the last dose.

Infertility

Based on findings in animals, romidepsin has the potential to affect male and female fertility [seeNonclinical Toxicology].

Pediatric Use

一个安全d effectiveness of ISTODAX in pediatric patients have not been established.

Geriatric Use

Of the 186 patients with CTCL who received ISTODAX in clinical studies, 51 (28%) were 65 years of age and older, while 16 (9%) were 75 years of age. No overall differences in safety or effectiveness were observed between patients 65 years or age and over and younger patients; however, greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment

在肝损伤的一项研究中,ISTODAX evaluated in 19 patients with advanced cancer and mild (8), moderate (5), or severe (6) hepatic impairment. There were 4 deaths during the first cycle of treatment: 1 patient with mild hepatic impairment, 1 patient with moderate hepatic impairment, and 2 patients with severe hepatic impairment. No dose adjustments are recommended for patients with mild hepatic impairment. Reduce the ISTODAX starting dose for patients with moderate and severe hepatic impairment [seeDOSAGE AND ADMINISTRATIONandCLINICAL PHARMACOLOGY]. Monitor patients with hepatic impairment more frequently for toxicity, especially during the first cycle of therapy.

OVERDOSE

No specific information is available on the treatment of overdosage of ISTODAX.

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 irregularrespiration, irregular heartbeat, staggeringgait,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 knownantidotefor ISTODAX and it is not known if ISTODAX is dialyzable.

CONTRAINDICATIONS

None.

CLINICAL PHARMACOLOGY

Mechanism Of Action

Romidepsin is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from acetylatedlysineresidues in histones, resulting in the modulation ofgene expression. HDACs also deacetylate non-histone proteins, such astranscriptionfactors.In vitro, romidepsin causes the accumulation of acetylated histones, and inducescell cyclearrest andapoptosisof some cancer cell lines with IC₅₀values in the nanomolar range. The mechanism of theantineoplasticeffect of romidepsin observed in nonclinical and clinical studies has not been fully characterized.

Pharmacodynamics

Cardiac Electrophysiology

At doses of 14 mg/m²as a 4-hour intravenous infusion, and at doses of 8 (0.57 times the recommended dose), 10 (0.71 times the recommended dose) or 12 (0.86 times the recommended dose) mg/m²as a 1-hour infusion, no large changes in the mean QTc interval (>20 milliseconds) from baseline based on Fridericia correction method were detected. Small increase in mean QT interval (< 10 milliseconds) and mean QT interval increase between 10 to 20 milliseconds cannot be excluded.

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/m²as a 4-hour infusion.

Pharmacokinetics

In patients with T-cell lymphomas who received 14 mg/m²of romidepsin intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle, geometric mean values of the maximum plasma concentration (Cmax) and the area under the plasma concentration versus time curve (AUC0-∞) were 377 ng/mL and 1549 ng*hr/mL, respectively. Romidepsin exhibited linear pharmacokinetics across doses ranging from 1.0 (0.07 times the recommended dose) to 24.9 (1.76 times the recommended dose) mg/m²when administered intravenously over 4 hours in patients with advanced cancers.

Distribution

Romidepsin is highly protein bound in plasma (92% to 94%) over the concentration range of 50 ng/mL to 1000 ng/mL with α1-acid-glycoprotein(AAG) being the principal binding protein. Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1).

In vitro第六,romidepsin积累成人类肝细胞a an unknown active uptake process. Romidepsin is not a substrate of the following uptake transporters: BCRP, BSEP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. In addition, romidepsin is not an inhibitor of BCRP, MRP2, MDR1 or OAT3. Although romidepsin did not inhibit OAT1, OCT2, and OATP1B3 at concentrations seen clinically (1 μmol/L), modest inhibition was observed at 10 μmol/L. Romidepsin was found to be an inhibitor of BSEP and OATP1B1.

Metabolism

Romidepsin undergoes extensivemetabolismin vitroprimarily by CYP3A4 with minor contribution from CYP3A5, CYP1A1, CYP2B6, and CYP2C19. At therapeutic concentrations, romidepsin did not competitively inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4in vitro.

At therapeutic concentrations, romidepsin did not cause notable induction of CYP1A2, CYP2B6 and CYP3A4in vitro. Therefore, pharmacokinetic drug-drug interactions are unlikely to occur due to CYP450 induction or inhibition by romidepsin when co-administered with CYP450 substrates.

Excretion

Following 4-hour intravenous administration of romidepsin at 14 mg/m²on days 1, 8, and 15 of a 28-day cycle in patients with T-cell lymphomas, the terminal half-life (t_1/2) was approximately 3 hours. No accumulation of plasma concentration of romidepsin was observed after repeated dosing.

Drug Interactions

Ketoconazole

Following co-administration of 8 mg/m²ISTODAX (4-hour infusion) with ketoconazole, the overall romidepsin exposure was increased by approximately 25% and 10% for AUC0-∞ and Cmax, respectively, compared to romidepsin alone, and the difference in AUC0-∞ between the 2 treatments was statistically significant.

Rifampin

Following co-administration of 14 mg/m²ISTODAX (4-hour infusion) with rifampin, the overall romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively, compared to romidepsin alone, and the difference between the 2 treatments was statistically significant. Co-administration of rifampin decreased the romidepsin clearance and volume of distribution by 44% and 52%, respectively. 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 predominant for the disposition of ISTODAX.

Drugs That Inhibit P-Glycoprotein

Drugs that inhibit p-glycoprotein may increase the concentration of romidepsin.

Specific Populations

Effect Of Age, Gender, Race Or Renal Impairment

The pharmacokinetics of romidepsin was not influenced by age (27 to 83 yrs), gender, race (white vs. black) or mild (estimated creatinine clearance 50 -80 mL/min), moderate (estimated creatinine clearance 30-50 mL/min), or severe (estimated creatinine clearance <30 mL/min) renal impairment. The effect ofend-stage renal disease(estimatedcreatineclearance less than 15 mL/min) on romidepsin pharmacokinetics has not been studied.

Hepatic Impairment

Romidepsin clearance decreased with increased severity of hepatic impairment. In patients with cancer, the geometric mean Cmax values after administration of 14, 7, and 5 mg/m²romidepsin in patients with mild (B1: bilirubin ≤ULN and AST >ULN; B2: bilirubin >ULN but ≤1.5 x ULN and any AST), moderate (bilirubin >1.5 x ULN to ≤3 x ULN and any AST), and severe (bilirubin >3 x ULN and any AST) hepatic impairment were approximately 111%, 96%, and 86% of the corresponding value after administration of 14 mg/m²romidepsin in patients with normal (bilirubin ≤upper limit of normal (ULN) and aspartateaminotransferase(AST) ≤ULN) hepatic function, respectively. The geometric mean AUCinf values in patients with mild, moderate, and severe hepatic impairment were approximately 144%, 114%, and 116% of the corresponding value in patients with normal hepatic function, respectively. Among these 4 cohorts, moderate interpatient variability was noted for the exposure parameters Cmax and AUCinf, as the coefficient of variation (CV) ranged from 30% to 54%.

Clinical Studies

ISTODAX was evaluated in 2 multicenter, single-arm clinical studies in patients with CTCL (Study 1 [NCT00106431] and Study 2 [NCT00007345]). 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 priorsystemic 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 ISTODAX at a starting dose of 14 mg/m²infused 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.Objectivedisease response was evaluated according to a composite endpoint that included assessments of skin involvement,lymph nodeandvisceralinvolvement, 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 was 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 Characteristics

Demographic and disease characteristics of the patients in Study 1 and Study 2 are provided in Table 3.

Table 3. Baseline Patient Characteristics (CTCL Population)

Characteristic	Study 1 (N=96)	Study 2 (N=71)
Age
N	96	71
Mean (SD)	57 (12)	56 (13)
Median (Range)	57 (21, 89)	57 (28, 84)
Sex, n (%)
Men	59 (61)	48 (68)
Women	37 (39)	23 (32)
Race, n (%)
White	90 (94)	55 (77)
Black	5 (5)	15 (21)
Other/Not Reported	1 (1)	1 (1)
Stage of Disease at Study Entry, n (%)
IA	0 (0)	1 (1)
IB	15 (16)	6 (9)
IIA	13 (14)	2 (3)
IIB	21 (22)	14 (20)
III	23 (24)	9 (13)
IVA	24 (25)	27 (38)
IVB	0 (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 Results

Efficacy 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 Patients

Response Rate	Study 1 (N=96)	Study 2 (N=71)
ORR(CR + PR), n (%) [95% Confidence Interval]	33 (34) [25, 45]	25(35)(25岁,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)
N	33	25
Median (range)	15 (1, 20*)	11 (1, 66*)
*Denotes censored value.

PATIENT INFORMATION

ISTODAX
(ISS toe dax)
(romidepsin) for injection

What is ISTODAX?

ISTODAX is a prescription medicine used to treat people with a type of cancer calledcutaneousT-cell lymphoma (CTCL) after at least one other type of medicine by mouth or injection has been tried.

It is not known if ISTODAX is safe and effective in children under 18 years of age.

Before receiving ISTODAX, tell your healthcare provider about all of your medical conditions, including if you:

• have any heart problems, including an irregular or fast heartbeat, or a condition called QT prolongation.
• have kidney problems
• have liver problems, including a history of hepatitis B
• have problems with the amount of potassium or magnesium in your blood
• have nausea, vomiting, or diarrhea
• are pregnant or plan to become pregnant. ISTODAX may harm your unborn baby.
  • Females who are able to become pregnant:
    • Your healthcare provider will perform a pregnancy test within 7 days before you start treatment with ISTODAX.
    • You should avoid becoming pregnant during treatment with ISTODAX and for 1 month after the last dose.
    • You should use effective birth control (contraception) during treatment with ISTODAX and for 1 month after your last dose.
    • ISTODAX may affect the way estrogen-containing birth control works. Talk to your healthcare provider for more information about other types of birth control to use during treatment with ISTODAX.
    • Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ISTODAX.
  • Males with a female sexual partner who can become pregnant:
    • ISTODAX can harm the unborn baby of your partner.
    • You should use a condom and avoid fathering a child during treatment with ISTODAX and for 1 month after treatment with ISTODAX. Talk to your healthcare provider if this is a concern for you.
  • ISTODAX may cause fertility problems in males and females. Talk to your healthcare provider if this is a concern for you.
• are breastfeeding or plan to breastfeed. It is not known if ISTODAX passes into your breast milk. You should not breastfeed during treatment with ISTODAX and for 1 week after the last dose. Talk to your healthcare provider about the best way to feed your baby while you are being treated with ISTODAX.

Tell your healthcare provider about all of the medicines you take,including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Some medicines may affect how ISTODAX works, or ISTODAX may affect how other medicines work. Especially tell your healthcare provider if you take or use:

• warfarin sodium (Coumadin, Jantoven) or any other blood thinner medicine. Ask your healthcare provider if you are not sure if you are taking a blood thinner. Your healthcare provider may want to test your blood more often.
• a medicine to treat abnormal heartbeats
• St. John’s wort (Hypericum perforatum)
• Dexamethasone (asteroid)
• Medicine for:
  • tuberculosis(TB)
  • seizures (epilepsy)
  • bacterial infections (antibiotics)
  • fungal infections (antifungals)
  • HIV(AIDS)
  • depression

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How will I receive ISTODAX?

• ISTODAX will be given to you by your healthcare provider or nurse as an intravenous injection into your vein usually over 4 hours.
• ISTODAX is usually given on Day 1, Day 8, and Day 15 of a 28-day cycle of treatment.
• Your healthcare provider will decide how long you will receive treatment with ISTODAX.
• Your healthcare provider will check your blood cell counts and other blood tests regularly during your treatment with ISTODAX to check for side effects of ISTODAX. Your healthcare provider may decide to do other tests to check your health as needed.
• Your healthcare provider may stop your treatment, change when you get your treatment, or change the dose of your treatment if you have certain side effects while receiving ISTODAX.

What are the possible side effects of ISTODAX?

ISTODAX may cause serious side effects, including:

• Low blood cell counts:Your healthcare provider will regularly do blood tests to check your blood counts.
  • Low platelets:can cause unusual bleeding or bruising under the skin. Talk to your healthcare provider right away if this happens.
  • Low red blood cells:may make you feel tired and you may get tired easily. You may look pale and feel short of breath. Tell your healthcare provider if you have these symptoms.
  • Low white blood cells:can cause you to get infections, which may be serious.
• Serious infections.People receiving ISTODAX can develop serious infections that can sometimes lead to death. These infections can happen during and after treatment with ISTODAX. Your risk of infection may be higher if you have hadchemotherapyin the past. Tell your healthcare provider right away if you have any of these symptoms of infection:
  • Fever
  • cough
  • shortness of breath with or without chest pain
  • burning with urination
  • flu-like symptoms
  • muscle aches
  • worsening skin problems
• Changes in your heartbeat.Your healthcare provider may check your heart by doing anECG(electrocardiogram) and blood tests to check your potassium and magnesium levels, before you start ISTODAX treatment. Tell your healthcare provider if you feel an abnormal heartbeat, feel dizzy or faint, have chest pain or shortness of breath.
• Tumor Lysis Syndrome (TLS).TLS is a problem of the rapid breakdown of cancer cells that can happen during your treatment with ISTODAX. You should drink plenty of fluids in the 3 days after you receive treatment with ISTODAX. Your healthcare provider may do blood tests to check for TLS and may give you medicine to prevent or treat TLS.

The most common side effects of ISTODAX include:

• nausea, tiredness, vomiting, loss of appetite, changes insenseof taste, constipation, and itching.

These are not all the possible side effects of ISTODAX. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of ISTODAX

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. This Patient Information leaflet summarizes the most important information about ISTODAX. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ISTODAX that is written for health professionals.

What are the ingredients in ISTODAX?

Active ingredient:romidepsin

Inactive ingredients:povidone, hydrochloric acid as a pH adjuster. The diluent contains 80% propylene glycol and 20% dehydrated alcohol.

This Patient Information has been approved by the U.S. Food and Drug Administration.