ISTODAX
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ISTODAX (ISTODAX).
Histone deacetylase (HDAC) inhibitor; induces cell cycle arrest and apoptosis in malignant cells.
| Metabolism | Primarily metabolized by CYP3A4; minor metabolism by CYP3A5, CYP2B6, CYP2C19, and CYP2D6. |
| Excretion | Renal: <20% unchanged drug; fecal: ~70% (as metabolites); hepatic metabolism primarily via CYP3A4, with minor contributions from CYP2A6, CYP2C19, and CYP2E1. |
| Half-life | Terminal elimination half-life is approximately 3.0 hours (range 1.3–5.0 h) in patients with advanced malignancies; no clinically relevant accumulation with weekly dosing. |
| Protein binding | Approximately 92–96% bound to human plasma proteins, primarily albumin and α-1-acid glycoprotein, with concentration-dependent binding at high drug levels. |
| Volume of Distribution | Volume of distribution at steady state (Vdss) is approximately 2–4 L/kg (range 1.8–4.5 L/kg), indicating extensive tissue distribution and penetration into peripheral tissues. |
| Bioavailability | Only intravenous administration is approved; bioavailability is 100% by IV route. Oral bioavailability is not clinically relevant (no oral formulation). |
| Onset of Action | Intravenous: Clinical responses (e.g., reduction in cutaneous T-cell lymphoma lesions) are typically observed after 2–4 cycles of therapy (each cycle = 4 weeks). No oral formulation available. |
| Duration of Action | Duration of clinical effect is variable; for cutaneous T-cell lymphoma, median duration of response is approximately 5 months (range 1–16+ months) in responding patients. |
14 mg/m2 intravenously over 4 hours on days 1, 8, and 15 of a 28-day cycle.
| Dosage form | POWDER |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl >=30 mL/min). Not recommended in severe renal impairment (CrCl <30 mL/min) or end-stage renal disease. |
| Liver impairment | For Child-Pugh A: 14 mg/m2; Child-Pugh B: reduce to 14 mg/m2 with close monitoring or consider 10 mg/m2; Child-Pugh C: not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. No recommended dose. |
| Geriatric use | No specific dose adjustment recommended; monitor for increased toxicity due to age-related renal or hepatic function decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ISTODAX (ISTODAX).
| Breastfeeding | It is unknown whether romidepsin is excreted in human milk. Due to the potential for serious adverse reactions in the breastfed infant, women should not breastfeed during treatment and for at least 1 week after the last dose. The milk-to-plasma ratio (M/P) has not been determined in humans; however, based on molecular weight (about 540 Da) and high protein binding (>90%), excretion is likely minimal but cannot be ruled out. |
| Teratogenic Risk | Istodax (romidepsin) is classified as Pregnancy Category D. In animal studies, romidepsin caused embryofetal toxicity and teratogenicity at doses below the recommended human dose. Based on its mechanism of action (histone deacetylase inhibitor), it is expected to cause fetal harm if administered during pregnancy. First trimester exposure carries the highest risk of major malformations. Second and third trimester exposure may cause fetal growth restriction and neurodevelopmental effects. Use during pregnancy is contraindicated unless no safer alternative exists and the potential benefit justifies the risk. |
■ FDA Black Box Warning
ISTODAX can cause serious and potentially fatal thrombocytopenia, neutropenia, and anemia. Dose modification or discontinuation may be required.
| Serious Effects |
["Hypersensitivity to romidepsin or any component of the formulation","Concurrent use with drugs that prolong QT interval"]
| Precautions | ["Hematologic toxicity (thrombocytopenia, neutropenia, anemia)","Serious infections including opportunistic infections","Hepatotoxicity","Electrocardiogram changes including QT prolongation","Fetal harm if used during pregnancy"] |
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| Fetal Monitoring | Monitor complete blood counts (CBC) with differential and platelets at baseline and before each dose due to myelosuppression. Serum electrolytes, including potassium, magnesium, and calcium, should be monitored due to risk of electrolyte imbalances and QT prolongation. Liver function tests (AST, ALT, bilirubin) and renal function (creatinine) should be assessed periodically. ECG should be performed to monitor for QT interval prolongation. In pregnant patients, fetal ultrasonography is recommended to assess growth and anatomy. |
| Fertility Effects | Romidepsin may impair fertility in both males and females based on animal studies. In female rats, ovarian changes including decreased corpora lutea and follicular degeneration were observed. In male dogs, testicular degeneration and decreased sperm count occurred. Amenorrhea and oligomenorrhea have been reported in clinical trials. The effects on human fertility are not fully characterized, but reversible or permanent impairment may occur. |