Romidepsin

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Serious and sometimes fatal infections may occur during treatment and within 30 days after treatment with romidepsin. Call your doctor right away if you have signs of infection such as:

• fever, chills, cold or flu symptoms,
• rapid heart rate, rapid and shallow breathing, feeling like you might pass out;
• stabbing chest pain, wheezing, cough with yellow or green mucus;
• swollen gums, painful mouth sores, muscle pain, feeling very tired; or
• upper stomach pain, loss of appetite, dark urine, jaundice (yellowing of the skin or eyes).

Also call your doctor at once if you have:

• worsening of CTCL skin symptoms;
• pain or burning when you urinate;
• chest pain, feeling short of breath;
• low platelets--easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;
• low red blood cells--pale skin, feeling light-headed or short of breath, trouble concentrating;
• signs of tumor cell breakdown--lower back pain, blood in your urine, little or no urinating; numbness or tingly feeling around your mouth; muscle weakness or tightness; fast or slow heart rate, weak pulse; confusion, fainting; or
• symptoms of a serious heart rhythm problem--headache with chest pain and severe dizziness, fainting, fast or pounding heartbeats.

Common side effects may include:

• nausea, vomiting, loss of appetite; or
• mild tired feeling.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Romidepsin is a prescription medication used to treat T-cell lymphoma affecting the skin when other treatments have not be successful. Romidepsin belongs to a group of drugs called histone deacetylase inhibitors. This medication works by interfering with the growth of tumor cells.

This medication comes in an injectable form. It is given directly into a vein (IV) by a healthcare provider every 7 days for 3 weeks.

Common side effects of romidepsin include nausea, vomiting, diarrhea, loss of appetite, and tiredness. Do not drive or operate heavy machinery until you know how romidepsin affects you.

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to romidepsin injection.

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with romidepsin, especially:

• dexamethasone;

• a blood thinner (warfarin, Coumadin, Jantoven);

• St. John's wort;

• an antibiotic--clarithromycin, telithromycin; antifungal medicine--itraconazole, ketoconazole, voriconazole;

• an antidepressant--citalopram, nefazodone; seizure medicine--carbamazepine, phenobarbital, phenytoin;

• heart rhythm medicine--amiodarone, disopyramide, dofetilide, flecainide, ibutilide, procainamide, quinidine, sotalol; or

• HIV/AIDS medicine--atazanavir, delavirdine, indinavir, nelfinavir, ritonavir, saquinavir; medicine to treat tuberculosis--isoniazid, rifampin.

This list is not complete. Other drugs may interact with romidepsin, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Contraindications

• No known contraindications.1

Warnings/Precautions

Electrolyte Monitoring

Patients with CTCL are at risk of hypomagnesemia.3 9 Because of the risk of QT prolongation and other ECG abnormalities associated with hypomagnesemia and hypokalemia as well as with HDAC inhibitor therapy (including romidepsin), serum concentrations of potassium and magnesium should be within the normal range prior to romidepsin administration.1 3 Also consider electrolyte and ECG monitoring at baseline and periodically during romidepsin therapy in patients at high risk for QT-interval prolongation (see ECG Changes under Cautions).1

Hematologic Effects

Risk of thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia.1 Monitor these hematologic parameters during therapy and adjust dosage if necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

ECG Changes

Treatment-related ECG changes, including T-wave and ST-segment changes, reported.1 6 7 May also prolong QT interval; further studies needed.1 3 6 7 15 Clinical importance of these ECG changes unknown.1

Consider appropriate cardiovascular monitoring precautions (e.g., monitor electrolytes and ECG at baseline and periodically during therapy) in patients with congenital long QT syndrome, those with a history of substantial cardiovascular disease, and those taking antiarrhythmic drugs or other agents that can cause clinically important QT-interval prolongation. 1 (See Electrolyte Monitoring under Cautions and see also Drugs that Prolong QT Interval under Interactions.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;1 a study in rats did not expose pregnant animals to enough romidepsin to fully evaluate possible adverse outcomes.1 (See Advice to Patients.)

Interactions with Estrogen-containing Contraceptives

An in vitro binding assay demonstrated that romidepsin competes with β-estradiol for binding to estrogen receptors.1 15 May reduce effectiveness of estrogen-containing contraceptives (e.g., oral contraceptives, patches, implants, IUDs), possibly resulting in pregnancy.1 15 (See Advice to Patients.)

Specific Populations

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Not known whether distributed into human milk; discontinue nursing or the drug.1

Safety and efficacy not established in children <18 years of age.1 (See Special Populations under Pharmacokinetics.)

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Mild hepatic impairment does not substantially affect pharmacokinetics of romidepsin.1 Effects of moderate and severe hepatic impairment on pharmacokinetics of romidepsin not known; use with caution in patients with moderate or severe hepatic impairment.1

Pharmacokinetics have not been formally studied in patients with renal impairment and end-stage renal disease (see Special Populations under Pharmacokinetics).1 Use with caution in patients with end-stage renal disease.1

Common Adverse Effects

Nausea,1 3 4 asthenia/fatigue,1 3 4 infections,1 3 vomiting,1 3 4 anorexia,1 3 4 hypomagnesemia,1 3 4 diarrhea,1 pyrexia,1 4 anemia,1 3 thrombocytopenia,1 3 dysgeusia,1 3 constipation,1 neutropenia,1 3 hypotension,1 pruritus,1 4 hypokalemia,1 dermatitis/exfoliative dermatitis,1 hypocalcemia,1 3 leukopenia, 1 3 lymphopenia,1 3 elevated transaminase concentrations,1 3 hypoalbuminemia,1 3 ECG changes (ST-T wave changes), 1 hyperglycemia,1 3 hyponatremia,1 hypermagnesemia,1 hypophosphatemia,1 and hyperuricemia.1 3

Absorption

Exhibits linear pharmacokinetics across dosages ranging from 1–24.9 mg/m2 when given as an IV infusion over 4 hours in patients with advanced cancers.1 22 No accumulation of plasma romidepsin concentrations observed after repeated dosing.1

Distribution

Extent

Not known whether distributed into human milk.1

Plasma Protein Binding

92–94% (mainly to α1-acid glycoprotein).1

Elimination

Metabolism

Extensively metabolized, principally by CYP3A4 and, to a lesser extent, by CYP3A5, CYP1A1, CYP2B6, and CYP2C19.1 15 22

Half-life

Terminal half-life is approximately 3 hours.1 22

Special Populations

In a population pharmacokinetic analysis, pharmacokinetics of romidepsin not substantially affected by mild hepatic impairment.1

In a population pharmacokinetic analysis, pharmacokinetics not substantially affected by mild (Clcr of 50–80 mL/minute), moderate (Clcr of 30–50 mL/minute), or severe (Clcr <30 mL/minute) renal impairment.1 Effect of end-stage renal disease on romidepsin pharmacokinetics not studied.1

Age, gender, or race did not appear to affect the pharmacokinetics of romidepsin in a population pharmacokinetic analysis.1 In a limited number of pediatric patients (aged from 2–21 years), pharmacokinetics of romidepsin were similar to those reported in adults in a phase I trial.14

• If you have an allergy to romidepsin or any other part of romidepsin.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Low potassium or magnesium levels.
• If you are taking any of these drugs: Carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, or St. John's wort.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take romidepsin with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about romidepsin, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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 romidepsin. 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 romidepsin.

Review Date: October 4, 2017

• Antineoplastic Agent, Histone Deacetylase (HDAC) Inhibitor

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

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

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). However, dosage adjustment is not likely necessary since pharmacokinetics are unaffected by renal impairment. Use with caution in patients with end-stage renal disease (has not been studied).

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).

14 mg/m2 IV over 4 hours on days 1, 8, and 15 of a 28-day cycle

Repeat cycle every 28 days provided patient continues to benefit and is tolerating therapy.

Comments:
-Dose reduction, discontinuation or interruption of therapy may be necessary to manage adverse reactions.
-Avoid use with rifampin and strong CYP450 3A4 inducers.

Uses:
Treatment of cutaneous T-cell Lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL) in patients who have received at least 1 prior systemic therapy.

Administration advice:
-Prior to each administration, serum potassium and magnesium must be within normal range.
-Preparation, handling, and disposal should be handled in a manner consistent with safe procedures and handling for cytotoxic drugs.
-Administer IV over a 4-hour period.
-Nausea and vomiting are commonly reported; consider anti-emetic support.

Storage requirements:
-Store in carton until use.

Reconstitution/preparation techniques:
-Reconstitution/preparation techniques: The manufacturer product information should be consulted.

General:
-Reconstituted solution (5 mg/mL) is chemically stable for up to 8 hours at room temperature.
-Diluted solution is chemically stable for up to 24 hours at room temperature; however administration as soon as possible following dilution is advised.

Monitoring:
-Perform ECG at baseline and periodically, especially in patients with a history of significant cardiovascular disease, those on concomitant QT interval prolonging drugs, or those receiving antiarrhythmic drugs.
-Verify normal serum potassium and magnesium levels prior to initiating treatment, and periodically during therapy, especially in higher risk patients.
-Monitor for thrombocytopenia, anemia, neutropenia and lymphopenia during therapy; modify treatment as necessary.
-Closely monitor patients with advanced stage disease and/or high tumor burden; institute appropriate precautions and treat as appropriate.

Patient advice:
-Advise patients to report nausea and vomiting so that appropriate therapy can be instituted.
-Treatment can lower blood counts and lower resistance to infection. Contact physician immediately with signs or symptoms of infection, significant fatigue, or bleeding.
-If pregnancy occurs during treatment, patients should be advised to seek immediate medical advice and counseling.