Romidepsin – Uses, Dosage, Side Effects, Interaction

Romidepsin is a drug that has been approved by the U.S. Food and Drug Administration (FDA) under the brand name Istodax for the treatment of certain types of cancer. Romidepsin is also being studied as an investigational drug as part of a strategy to cure HIV infection. As an HIV investigational drug, romidepsin belongs to a group of drugs called latency-reversing agents.

Romidepsin is a selective inhibitor of histone deacetylase, approved in the US in 2009 for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

Mechanism of action

Romidepsin is a prodrug, where it becomes active once taken up into the cell. The active metabolite has a free thiol group, which interacts with zinc ions in the active site of class 1 and 2 HDAC enzymes, resulting in inhibition of its enzymatic activity. Certain tumors have over expressed HDACs and downregulated/mutated histone acetyltransferases. This imbalance of HDAC relative to histone acetyltransferase can lead to a decrease in regulatory genes, ensuing tumorigenesis. Inhibition of HDAC may restore normal gene expression in cancer cells and result in cell cycle arrest and apoptosis.

Romidepsin acts as a prodrug with the disulfide bond undergoing reduction within the cell to release a zinc-binding thiol. The thiol binds to a zinc atom in the binding pocket of Zn-dependent histone deacetylase to block its activity. Thus it is an HDAC inhibitor. Many HDAC inhibitors are potential treatments for cancer through the ability to epigenetically restore normal expression of tumor suppressor genes, which may result in cell cycle arrest, differentiation, and apoptosis.^[rx]

Use in Cancer

Romidepsin is approved to treat:

• Cutaneous T-cell lymphoma in adults who have already been treated with at least one other type of systemic therapy.

Romidepsin is also being studied in the treatment of other types of cancer

Contraindications

• a bad infection
• low amount of magnesium in the blood
• low amount of potassium in the blood
• anemia
• decreased blood platelets
• low levels of white blood cells
• low levels of a type of white blood cell called neutrophils
• a decreased number of lymphocytes in the blood
• prolonged QT interval on EKG
• abnormal heart rhythm
• abnormal EKG with QT changes from birth
• severe liver disease
• pregnancy
• a patient who is producing milk and breastfeeding
• chronic kidney disease stage 5 (failure)

Dosage

Strengths: 10 mg; 5 mg/mL

Cutaneous T-cell Lymphoma

• 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.
• For the treatment of cutaneous T-cell Lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL) in patients who have received at least 1 prior systemic therapy.

Peripheral T-cell Lymphoma

• 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
• For the treatment of cutaneous T-cell Lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL) in patients who have received at least 1 prior systemic therapy.

Dose Adjustments

NONHEMATOLOGIC TOXICITIES (EXCEPT ALOPECIA):

• Grade 2 or 3: Delay therapy until toxicity returns to Grade 1 or less or baseline; resume at 14 mg/m2.
• Grade 3 recurrence: Delay therapy until toxicity returns to Grade 1 or less or baseline; permanently reduce dose to 10 mg/m2.
• Grade 4: Delay therapy until toxicity returns to Grade 1 or less or baseline; permanently reduce dose to 10 mg/m2.
• Grade 3 or 4 recurrence after dose reduction: Discontinue therapy.

HEMATOLOGIC TOXICITIES:

• Grade 3 or 4 neutropenia or thrombocytopenia: Delay therapy until specific cytopenia returns to absolute neutrophil count (ANC) of 1.5 x 10(9)/L or greater and/or platelet count is 75 x 10(9)/L or baseline; restart at 14 mg/m2.
• Grade 4 febrile (38.5C or greater) neutropenia or thrombocytopenia requiring platelet transfusion: Delay therapy until specific cytopenia returns to Grade 1 or less or baseline; permanently reduce dose to 10 mg/m2.

Administration advice:

• Administer IV over a 4-hour period.
• Nausea and vomiting are commonly reported; consider antiemetic support
• Preparation, handling, and disposal should be handled in a manner consistent with safe procedures and handling for cytotoxic drugs.
• 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.
• Prolongation of PT and elevation of INR were observed in a patient receiving this drug concomitantly with warfarin. Monitor PT and INR more frequently in these patients.
• Strong CYP450 3A4 inhibitors increase concentrations of this drug. Monitor for toxicity related to increased exposure to this drug and follow the dose modifications for toxicity.
• Rifampin (a potent CYP450 3A4 inducer) increases the concentrations of this drug. Avoid coadministration of this drug with rifampin. The use of other potent CYP450 3A4 inducers should be avoided when possible.

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.
• Monitor patients with advanced stage disease and/or high tumor burden; institute precautions and treat as needed.

Patient advice:

• Report nausea and vomiting to your healthcare provider.
• This drug can lower blood counts and lower resistance to infection; contact your healthcare provider immediately if you experience with signs of infection, significant fatigue, or bleeding.

Side Effects

The Most Common

• nausea
• vomiting
• diarrhea
• constipation
• stomach pain
• mouth sores
• headache
• changed sense of taste
• loss of appetite
• itching
• tiredness or weakness
• pale skin
• shortness of breath
• chest pain
• irregular heartbeat
• feeling dizzy or faint
• easy bruising or bleeding
• fever, cough, flu-like symptoms, muscle aches, burning on urination, worsening skin problems, and other signs of infection (may occur up to 30 days after your treatment)
• rash
• blistering or peeling skin
• swelling of the hands, feet, ankles, or lower legs

More common

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• blurred vision
• bone pain
• chest pain
• chills
• confusion
• cough
• decreased urine output
• difficulty with breathing
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• drowsiness
• dry mouth
• fast or irregular heartbeat
• fever
• flushed, dry skin
• fruit-like breath odor
• headache
• hoarseness
• increased hunger
• increased thirst
• increased urination
• joint pain, stiffness, or swelling
• loss of appetite
• lower back or side pain
• muscle cramps in the hands, arms, feet, legs, or face
• muscle spasms or twitching
• nausea
• numbness or tingling in the hands, fingertips, feet, or lips
• painful or difficult urination
• pale skin
• pinpoint red spots on the skin
• seizures
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• stomach cramps or pain
• sweating
• swelling of the face, ankles, feet, lower legs, or hands
• swollen glands
• tremor
• trouble breathing
• unexplained weight loss
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting

Rare

• Change in taste
• constipation
• cracks in the skin
• diarrhea
• itching
• lack or loss of strength
• loss of heat from the body
• loss of taste
• red, swollen skin
• scaly skin
• weight loss

Drug Interactions

Pregnancy and Lactation

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned.

Pregnancy

Based on its mechanism of action and findings from animal studies, Romidepsin Injection can cause embryofetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on romidepsin 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 romidepsin 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% to 4% and 15% to 20%, respectively.

Lactation

There are no data on the presence of romidepsin 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 Romidepsin Injection and for at least 1 week after the last dose.