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Romidepsin – Uses, Dosage, Side Effects, Interaction – Rxharun

Romidepsin – Uses, Dosage, Side Effects, Interaction

Romidepsin is an intravenously administered histone deacetylase inhibitor and antineoplastic agent that is approved for use in refractory or relapsed cutaneous and peripheral T-cell lymphomas. Romidepsin is associated with a modest rate of minor serum enzyme elevations during therapy but has not been linked to cases of clinically apparent liver injury, although it has been reported to cause reactivation of hepatitis B.

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]

Indications

  • Chemical substances, produced by microorganisms, inhibiting or preventing the proliferation of neoplasms.
  • Romidepsin is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in adult patients who have received at least one prior systemic therapy.[rx]
  • Romidepsin is an intravenously administered histone deacetylase inhibitor and antineoplastic agent that is approved for use in refractory or relapsed cutaneous and peripheral T cell lymphomas.
  • Romidepsin is a histone deacetylase (HDAC) inhibitor used to treat cutaneous T-cell lymphoma.
  • Treatment of peripheral T-cell lymphoma (PTCL),
  • Treatment of peripheral T-cell lymphoma (nodal, other extranodal, and leukemic/disseminated).

Romidepsin is used to treat T-cell lymphoma affecting the skin (cutaneous T-cell lymphoma). Romidepsin is given after at least one other cancer treatment did not work or has stopped working. Romidepsin may also be used for purposes not listed in this medication guide.

Use in Cancer

Romidepsin is approved to treat:

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

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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.

Why is this medication prescribed?

Romidepsin injection is used to treat cutaneous T-cell lymphoma (CTCL; a group of cancers of the immune system that first appear as skin rashes) in people who have already been treated with at least one other medication. Romidepsin injection is also used to treat peripheral T-cell lymphoma (PTCL; a type of non-Hodgkin’s lymphoma) in people who have already been treated with at least one other medication. Romidepsin injection is in a class of medications called histone deacetylase (HDAC) inhibitors. It works by slowing the growth of cancer cells.

How should this medicine be used?

Romidepsin injection comes as a powder to be mixed with liquid to be injected intravenously (into a vein) over a 4-hour period by a doctor or nurse. It is usually given on days 1, 8, and 15 of a 28-day cycle. This cycle may be repeated as long as the medication continues to work and does not cause severe side effects.

Talk to your doctor about any side effects you experience during your treatment with romidepsin injection. If you experience certain severe side effects, your doctor may stop your treatment permanently or temporarily and/or may decrease your dose. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient. This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before receiving romidepsin injection,

  • tell your doctor and pharmacist if you are allergic to romidepsin injection, any other medications, or any of the ingredients in romidepsin injection. Ask your pharmacist or check the patient information for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: certain antibiotics such as clarithromycin (Biaxin), erythromycin (E.E.S., E-Mycin, Erythrocin), moxifloxacin (Avelox), and telithromycin (Ketek); anticoagulants (blood thinners) such as warfarin (Coumadin, Jantoven); antifungals such as itraconazole (Sporanox), ketoconazole (Nizoral), and voriconazole (Vfend); cisapride (Propulsid) (not available in the U.S.); dexamethasone; medications for human immunodeficiency virus (HIV) such as atazanavir (Reyataz), indinavir (Crixivan), nelfinavir (Viracept), ritonavir (in Kaletra, Norvir), and saquinavir (Invirase); medications for irregular heartbeat such as amiodarone (Cordarone), disopyramide (Norpace), dofetilide (Tikosyn), procainamide (Procanbid, Pronestyl), quinidine (Quinidex), and sotalol (Betapace, Betapace AF); certain medications for seizures such as carbamazepine (Epitol, Equetro, Tegretol), phenobarbital, and phenytoin (Dilantin); nefazodone; pimozide (Orap); rifabutin (Mycobutin); rifampin (Rifadin, in Rifamate, in Rifater, Rimactane); rifapentine (Priftin); sparfloxacin (Zagam); or thioridazine (Mellaril). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with romidepsin injection, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
  • tell your doctor what herbal products you are taking, especially St. John’s wort.
  • tell your doctor if you have nausea, vomiting, or diarrhea before you begin your treatment with romidepsin injection. Also tell your doctor if you have or have ever had a prolonged QT interval (a rare heart problem that may cause irregular heartbeat, fainting, or sudden death), an irregular or fast heartbeat, too much or too little potassium or magnesium in your blood, hepatitis B (HBV; a virus that infects the liver and may cause severe liver damage or liver cancer), Epstein Barr virus (EBV; a herpes virus that causes infectious mononucleosis and is associated with certain cancers), or liver, kidney, or heart disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. Your doctor may check to see if you are pregnant before you begin your treatment. You should use birth control to prevent pregnancy during your treatment with romidepsin injection and for at least one month after your final dose. However, you should not use hormonal (estrogen) contraceptives (birth control pills, patches, rings, implants, or injections) because romidepsin injection may stop these medications from working as they should. If you are a male with a female partner who could become pregnant, be sure to use birth control during your treatment with romidepsin injection and for at least one month after your final dose. Talk to your doctor about birth control methods that you can use. If you become pregnant while receiving romidepsin injection, call your doctor. Romidepsin injection may harm the fetus. You should not breastfeed during your treatment with romidepsin injection and for at least 1 week after your final dose.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are receiving romidepsin injection.

References

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