ISTODAX (Page 3 of 7)

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 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in >2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%).

There were eight deaths not due to disease progression. In Study 1, there were two deaths: one due to cardiopulmonary failure and one due to acute renal failure. There were six deaths in Study 2: four due to infection and one each due to myocardial ischemia and acute respiratory 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, and hypomagnesemia.

Other Clinical Trials Experience

The following common adverse reactions have been reported following administration of ISTODAX as a single agent in 178 patients with peripheral T-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%) and anemia (35%). Other common (≥10%) clinically significant adverse reactions included dysgeusia (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.

7 DRUG INTERACTIONS

7.1 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 [see Clinical Pharmacology (12.3)].

7.2 Drugs That Inhibit CYP3A4 Enzymes

Strong CYP3A4 inhibitors increase concentrations of romidepsin [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 ISTODAX is initially co-administered with strong CYP3A4 inhibitors.

7.3 Drugs That Induce CYP3A4 Enzymes

Rifampin (a potent CYP3A4 inducer) increased the concentrations of romidepsin [see Clinical Pharmacology (12.3)]. Avoid co-administration of ISTODAX with rifampin. The use of other potent CYP3A4 inducers should be avoided when possible.

8 USE IN SPECIFIC POPULATIONS

8.1 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 [see Clinical Pharmacology (12.1)].

There are no available data on ISTODAX use in pregnant women to inform a drug associated risk of major birth defects and miscarriage. 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 (see Data). 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 of birth 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 2-4% 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. Substantial resorption or 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, folded retina, rotated limbs, and incomplete sternal ossification.

8.2 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.

8.3 Females and Males of Reproductive Potential

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

Pregnancy Testing

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

Contraception

Females

Advise females of reproductive potential to use effective 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, intrauterine devices) 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 [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of ISTODAX in pediatric patients have not been established.

8.5 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.

8.6 Hepatic Impairment

In a hepatic impairment study, ISTODAX was 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 [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Monitor patients with hepatic impairment more frequently for toxicity, especially during the first cycle of therapy.

10 OVERDOSAGE

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 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 ISTODAX and it is not known if ISTODAX is dialyzable.

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