RomiDEPsin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution Reconstituted, Intravenous:

Istodax: 10 mg (1 ea [DSC]) [contains alcohol, usp, propylene glycol]

Istodax (Overfill): 10 mg (1 ea) [contains alcohol, usp, propylene glycol]

Generic: 10 mg (1 ea)

Pharmacology

Mechanism of Action

Romidepsin is a histone deacetylase (HDAC) inhibitor; HDACs catalyze acetyl group removal from protein lysine residues (including histone and transcription factors). Inhibition of HDAC results in accumulation of acetyl groups, leading to alterations in chromatin structure and transcription factor activation causing termination of cell growth (induces arrest in cell cycle at G1 and G2/M phases) leading to cell death.

Pharmacokinetics/Pharmacodynamics

Metabolism

Hepatic, primarily via CYP3A4, minor metabolism from CYP3A5, 1A1, 2B6 and 2C19

Half-Life Elimination

~3 hours

Protein Binding

92% to 94%; primarily to α₁-acid glycoprotein

Use in Specific Populations

Special Populations: Hepatic Function Impairment

Romidepsin clearance decreased with increased severity of hepatic impairment. In patients with cancer, the geometric mean C_max values after administration of 14, 7, and 5 mg/m² romidepsin in patients with mild (bilirubin ≤ULN and AST >ULN or bilirubin 1 to 1.5 times ULN and any AST), moderate (bilirubin >1.5 to 3 times ULN and any AST), and severe (bilirubin >3 times ULN and any AST) impairment were approximately 111%, 96%, and 86%, respectively, compared to a 14 mg/m² dose in patients with normal hepatic function. The geometric mean AUC_inf values in patients with mild, moderate, and severe impairment were approximately 144%, 114%, and 116%, respectively, compared to patients with normal hepatic function.

Use: Labeled Indications

Cutaneous T-cell lymphoma: Treatment of cutaneous T-cell lymphoma (CTCL) in adult patients who have received at least one prior systemic therapy

Peripheral T-cell lymphoma: Treatment of peripheral T-cell lymphoma (PTCL) in adult patients who have received at least one prior therapy

Contraindications

There are no contraindications listed in the manufacturer’s US labeling.

Canadian labeling: Hypersensitivity to romidepsin or any component of the formulation.

Dosage and Administration

Dosing: Adult

Note: Romidepsin is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016).

Cutaneous T-cell lymphoma: IV: 14 mg/m² days 1, 8, and 15 of a 28-day treatment cycle; repeat cycle as long as benefit continues and treatment is tolerated.

Peripheral T-cell lymphoma: IV: 14 mg/m² days 1, 8, and 15 of a 28-day treatment cycle; repeat cycle as long as benefit continues and treatment is tolerated.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Nonhematologic toxicity (excluding alopecia):

Grade 2 or 3: Delay treatment until toxicity returns to ≤grade 1 or baseline, may restart at 14 mg/m²

Grade 4 or recurrent grade 3 toxicity: Delay treatment until toxicity returns to ≤grade 1 or baseline, permanently reduce dose to 10 mg/m²

Recurrent grade 3 or 4 toxicity despite dosage reduction: Discontinue treatment

Hematologic toxicity:

Grade 3 or 4 neutropenia or thrombocytopenia: Delay treatment until ANC ≥1,500/mm³ and/or platelets ≥75,000/mm³ or baseline, may restart at 14 mg/m²

Grade 4 febrile neutropenia or thrombocytopenia requiring platelet transfusion: Delay treatment until toxicity returns to ≤grade 1 or baseline, permanently reduce dose to 10 mg/m²

Dosing: Obesity

American Society of Clinical Oncology (ASCO) Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

Reconstitute each vial of romidepsin with 2.2 mL of supplied diluent to a reconstituted concentration of 5 mg/mL (both the drug and diluent vials contain overfill to ensure the appropriate volume can be withdrawn); swirl until dissolved. The reconstituted vial will contain a deliverable volume of 2 mL of product. Further dilute in 500 mL normal saline; compatible with polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyethylene (PE) and glass infusion containers.

Administration

IV: Romidepsin is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016).

Infuse over 4 hours.

Storage

Store intact vials at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). The reconstituted solution is stable for 8 hours at room temperature. Solutions diluted for infusion in NS are stable for 24 hours at room temperature; however, the manufacturer recommends use as soon as possible after dilution.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of RomiDEPsin. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of RomiDEPsin. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Rifabutin: May decrease the serum concentration of RomiDEPsin. Monitor therapy

RifAMPin: May increase the serum concentration of RomiDEPsin. Avoid combination

Rifapentine: May decrease the serum concentration of RomiDEPsin. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

St John's Wort: May decrease the serum concentration of RomiDEPsin. Avoid combination

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Warfarin: RomiDEPsin may enhance the anticoagulant effect of Warfarin. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: ECG changes (ST-T wave changes: 2% to 63%), hypotension (7% to 23%)

Central nervous system: Fatigue (53% to 77%), headache (15% to 34%), chills (11% to 17%)

Dermatologic: Pruritus (7% to 31%), dermatitis (≤27%), exfoliative dermatitis (≤27%)

Endocrine & metabolic: Hypocalcemia (4% to 52%), hyperglycemia (2% to 51%), hypoalbuminemia (3% to 48%), hyperuricemia (≤33%), hypomagnesemia (22% to 28%), hypermagnesemia (≤27%), hypophosphatemia (≤27%), hyponatremia (≤20%), hypokalemia (6% to 20%), weight loss (10% to 15%)

Gastrointestinal: Nausea (56% to 86%), anorexia (23% to 54%), vomiting (34% to 52%), dysgeusia (15% to 40%), constipation (12% to 40%), diarrhea (20% to 36%), abdominal pain (13% to 14%)

Hematologic & oncologic: Anemia (19% to 72%; grades 3/4: 3% to 28%), thrombocytopenia (17% to 72%; grades 3/4: ≤36%), neutropenia (11% to 66%; grades 3/4: 4% to 47%), lymphocytopenia (4% to 57%; grades 3/4: ≤37%), leukopenia (4% to 55%; grades 3/4: ≤45%)

Hepatic: Increased serum AST (3% to 28%), increased serum ALT (3% to 22%)

Infection: Infection (46% to 54%; including infection of central line)

Neuromuscular & skeletal: Weakness (53% to 77%)

Respiratory: Cough (18% to 21%), dyspnea (13% to 21%)

Miscellaneous: Fever (20% to 47%)

1% to 10%:

Cardiovascular: Tachycardia (≤10%), peripheral edema (6% to 10%), chest pain, deep vein thrombosis, edema, prolonged Q-T interval on ECG, pulmonary embolism, supraventricular cardiac arrhythmia, syncope, ventricular arrhythmia

Dermatologic: Cellulitis

Endocrine & metabolic: Dehydration

Gastrointestinal: Stomatitis (6% to 10%)

Hematologic & oncologic: Tumor lysis syndrome (1% to 2%), febrile neutropenia

Hepatic: Hyperbilirubinemia

Hypersensitivity: Hypersensitivity reaction

Infection: Sepsis

Respiratory: Hypoxia, pneumonia, pneumonitis

<1%, postmarketing, and/or case reports: Acute renal failure, acute respiratory distress, atrial fibrillation, bacteremia, candidiasis, cardiac failure, cardiogenic shock, ischemic heart disease, multi-organ failure, reactivation of latent Epstein-Barr virus, respiratory failure, septic shock

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Anemia, leukopenia, neutropenia, lymphopenia and thrombocytopenia may occur. May require dosage modification. Monitor blood counts during treatment.
• Gastrointestinal toxicity: Romidepsin is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016).
• Infection: Serious infections (occasionally fatal), including pneumonia, sepsis, and viral reactivation (eg, Epstein Barr and hepatitis B) have occurred during or within 30 days of treatment. Monitor patients with a history of hepatitis B infections closely for viral reactivation; consider antiviral prophylaxis. Epstein Barr reactivation leading to liver failure has also been reported, with ganciclovir antiviral prophylaxis failure in one case. The risk of life-threatening infection may be increased in patients who have received prior treatment with antilymphocytic monoclonal antibodies or who have disease involvement in the bone marrow.
• QTc prolongation/ECG changes: QTc prolongation has been observed; use caution in patients with a history of QTc prolongation, congenital long QT syndrome, with medications known to prolong the QT interval, or with pre-existing cardiac disease. Obtain baseline and periodic ECG (12-lead); monitor and correct electrolyte (potassium, magnesium, and calcium) abnormalities prior to and during treatment. T-wave and ST-segment changes have also been reported.
• Tumor lysis syndrome: Tumor lysis syndrome (TLS) has been observed; closely monitor patients with advanced disease and/or with a high tumor burden (risk of TLS is higher). If TLS occurs, initiate appropriate treatment.

Disease-related concerns:

• Hepatic impairment: Mild hepatic impairment does not significantly influence the pharmacokinetics of romidepsin (based on pharmacokinetic analysis). Initial dose should be reduced in patients with moderate or severe hepatic impairment; monitor closely/frequently for toxicities, especially during the first treatment cycle.
• Renal impairment: The pharmacokinetics of romidepsin are unaffected by mild, moderate or severe renal impairment (based on pharmacokinetic analysis). Use with caution in patients with end-stage renal disease (has not been studied).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Serum electrolytes (baseline and periodic; especially potassium and magnesium); CBC with differential and platelets, pregnancy test (within 7 days prior to treatment initiation in females of reproductive potential); ECG (baseline and periodic; in patients with significant cardiovascular disease, congenital long QT syndrome, and in patients taking QT-prolonging medications); signs/symptoms of infection or tumor lysis syndrome

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and findings from animal reproduction studies, romidepsin may cause fetal harm if administered to a pregnant female.

Evaluate pregnancy status in females of reproductive potential within 7 days prior to initiating treatment with romidepsin. Females of reproductive potential should use an effective non-hormonal method of contraception during treatment and for at least 1 month after the final romidepsin dose. Males with female partners of reproductive potential should use effective contraception during treatment and for at least 1 month after the last romidepsin dose.

Patient Education

What is this drug used for?

• It is used to treat a type of lymphoma.

Frequently reported side effects of this drug

• Headache
• Constipation
• Diarrhea
• Lack of appetite
• Abdominal pain
• Weight loss
• Nausea
• Vomiting
• Change in taste
• Mouth irritation
• Mouth sores

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting
• Infection
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Swelling of arms or legs
• Shortness of breath
• Flu-like symptoms
• Muscle pain
• Chest pain
• Fast heartbeat
• Abnormal heartbeat
• Dizziness
• Passing out
• Severe loss of strength and energy
• Unable to pass urine
• Change in amount of urine passed
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.