Romidepsin, sold under the brand name Istodax, is a medication used in the treatment of certain types of cancer. It is classified as a histone deacetylase (HDAC) inhibitor. HDACs are enzymes that play a role in regulating gene expression by modifying the structure of chromatin, a complex of DNA and proteins. By inhibiting HDACs, romidepsin can lead to changes in gene expression that may help slow or stop the growth of cancer cells.

Romidepsin (Istodax) is an anticancer drug that induces apoptosis of tumor cells by inactivating the enzyme histone deacetylase. It is used in the treatment of patients with cutaneous and peripheral T-cell lymphomas.

Romidepsin Uses:

• Cutaneous T-cell lymphoma:
  • Used for treating cutaneous T-cell lymphoma (CTCL) in adult patients who have been given at least one prior systemic therapy
• Peripheral T-cell lymphoma:
  • Used for treating peripheral T-cell lymphoma (PTCL) in adult patients who have been given at least one prior therapy

Romidepsin (Istodax) Dose in Adults

Note: Romidepsin can make you feel nauseous and cause vomiting. To prevent this, your doctor may suggest taking anti-nausea medications along with romidepsin. These medications can help reduce the chance of feeling sick to your stomach or throwing up when you're receiving romidepsin treatment.

Romidepsin (Istodax) Dose in the treatment of Cutaneous T-cell lymphoma:

• It's given through an intravenous (IV) line.
• The dose is 14 milligrams per square meter of your body's size.
• You'll receive it on days 1, 8, and 15 of a 28-day treatment cycle.
• If it's helping and you can tolerate it, you'll repeat this cycle as long as needed to get benefits from the treatment.

Romidepsin (Istodax) Dose in the treatment of Peripheral T-cell lymphoma:

• It's given as an intravenous (IV) infusion.
• The dose is 14 milligrams per square meter of your body size.
• You'll receive it on days 1, 8, and 15 of a 28-day treatment cycle.
• If the treatment is helping you and you can handle it without too many side effects, you'll continue to repeat this 28-day cycle for as long as it keeps providing benefits.

Dose in Children:

Not indicated.

Pregnancy Risk Category: D

• Romidepsin can be harmful to a developing fetus if given to a pregnant woman.
• If you are a woman capable of becoming pregnant, your doctor will check if you are pregnant within 7 days before starting romidepsin treatment.
• During romidepsin treatment and for at least one month after your last dose, if you can get pregnant, you should use a reliable form of contraception (birth control) that doesn't involve hormones.
• If you are a man and your female partner can become pregnant, both of you should use effective contraception during your treatment with romidepsin and for at least one month after your last romidepsin dose to avoid the risk of pregnancy.

Use while breastfeeding

• It's uncertain whether romidepsin can be found in breast milk.
• Because there is a possibility of significant harmful effects on a nursing infant, the manufacturer advises that breastfeeding should be stopped while you are undergoing romidepsin treatment and for at least one week after your final romidepsin dose.
• This precaution is taken to ensure the safety of the baby.

Romidepsin Dose in Kidney Disease:

• The manufacturer's instructions do not include specific dosage adjustments for romidepsin.
• This is because there hasn't been sufficient research to determine if dose adjustments are needed in individuals with kidney problems.
• However, it's important to note that romidepsin appears to be processed by the body in a way that is not influenced by kidney function.
• If you have severe kidney disease (end-stage renal disease), there isn't enough data available to guide its use, so caution should be exercised when considering romidepsin treatment in such cases.

Romidepsin Dose in Liver disease:

• If you have mild liver impairment, meaning your bilirubin levels are within normal limits or slightly elevated, or your bilirubin is higher than normal (between 1 and 1.5 times the upper limit of normal) along with any elevation in AST (a liver enzyme), you typically won't need to adjust the starting dose of romidepsin.
• In cases of moderate liver impairment, where your bilirubin is higher (between 1.5 to 3 times the upper limit of normal), your doctor may decide to reduce the initial dose to 7 milligrams per square meter of your body size. They will also closely monitor you for any signs of side effects or toxicity.
• For severe liver impairment, when your bilirubin is greater than 3 times the upper limit of normal, the initial dose will be reduced to 5 milligrams per square meter. Frequent monitoring for potential side effects or toxicity is especially crucial in this situation.

These adjustments take into account your liver function to ensure that romidepsin is administered safely and effectively.

Common Side Effects of Romidepsin (Istodax):

• Cardiovascular:
  • ECG Changes
  • Hypotension
• Central Nervous System:
  • Fatigue
  • Headache
  • Chills
• Dermatologic:
  • Pruritus
  • Dermatitis
  • Exfoliative Dermatitis
• Endocrine & Metabolic:
  • Hypocalcemia
  • Hyperglycemia
  • Hypoalbuminemia
  • Hyperuricemia
  • Hypomagnesemia
  • Hypermagnesemia
  • Hypophosphatemia
  • Hyponatremia
  • Hypokalemia
  • Weight Loss
• Gastrointestinal:
  • Nausea
  • Anorexia
  • Vomiting
  • Dysgeusia
  • Constipation
  • Diarrhea
  • Abdominal Pain
• Hematologic & Oncologic:
  • Anemia
  • Thrombocytopenia
  • Neutropenia
  • Lymphocytopenia
  • Leukopenia
• Hepatic:
  • Increased Serum AST
  • Increased Serum ALT
• Infection:
  • Infection
• Neuromuscular & Skeletal:
  • Weakness
• Respiratory:
  • Cough
  • Dyspnea
• Miscellaneous:
  • Fever

Less Common Side Effects of Romidepsin (Istodax):

• Cardiovascular:
  • Tachycardia
  • Peripheral Edema
  • 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
• Hematologic & Oncologic:
  • Tumor Lysis Syndrome
  • Febrile Neutropenia
• Hepatic:
  • Hyperbilirubinemia
• Hypersensitivity:
  • Hypersensitivity Reaction
• Infection:
  • Sepsis
• Respiratory:
  • Hypoxia
  • Pneumonia
  • Pneumonitis

Contraindications to Romidepsin (Istodax):

• In the United States, the manufacturer's labeling for romidepsin does not list any specific contraindications, meaning there are no absolute reasons why someone cannot use the medication according to the U.S. labeling.
• In Canada, the labeling differs, and it states that romidepsin should not be used in individuals who have a hypersensitivity (allergic reaction) to romidepsin itself or any of the ingredients in its formulation. This is considered a contraindication in Canada.

Warnings and precautions

Suppression of bone marrow

• When using romidepsin, there is a risk of bone marrow suppression, which can affect your blood cell counts.
• This suppression can lead to conditions like anemia (low red blood cells), leukopenia (low white blood cells), neutropenia (low levels of a specific type of white blood cell called neutrophils), lymphopenia (low levels of lymphocytes), and thrombocytopenia (low platelet count).
• Depending on the severity of these blood cell count changes, your doctor may need to adjust your romidepsin dosage.
• It's crucial to have your blood counts regularly monitored while you are undergoing treatment with romidepsin.

Gastrointestinal toxicities:

• Romidepsin can cause gastrointestinal (GI) problems.
• It has a moderate potential to make you feel nauseous and induce vomiting.
• To prevent or alleviate these GI side effects, your healthcare provider may recommend using antiemetic medications.
• Antiemetics are drugs that help prevent nausea and vomiting.
• By taking antiemetics as advised, you can reduce the chances of experiencing these uncomfortable GI side effects while undergoing romidepsin treatment.

Infection

• Romidepsin treatment can increase the risk of serious infections, and in some cases, these infections can be fatal. They may include conditions like pneumonia, sepsis, and reactivation of viruses such as Epstein-Barr and hepatitis B.
• Patients who have a history of hepatitis B infections should be closely monitored for viral reactivation during romidepsin treatment, and in some cases, doctors may consider providing antiviral prophylaxis to prevent reactivation.
• There have been cases where Epstein-Barr reactivation led to liver failure, even when ganciclovir antiviral prophylaxis was used and didn't work in one instance.
• The risk of life-threatening infections may be higher in patients who have previously received treatment with antilymphocytic monoclonal antibodies or those whose disease involves the bone marrow.

ECG changes and QTc prolongation:

• Romidepsin treatment can lead to QTc prolongation, which means it can affect the electrical rhythm of the heart as seen on an ECG (electrocardiogram).
• It's important for caution to be exercised in patients who have a history of QTc prolongation, those with congenital long QT syndrome, individuals taking medications known to lengthen the QT interval, or those with pre-existing heart conditions.
• To ensure the safety of the patient, doctors will typically perform an initial ECG before starting romidepsin treatment and then periodically throughout the treatment course. This helps to monitor any changes in the heart's electrical activity.
• Before and during treatment with romidepsin, your healthcare provider may also check and correct any imbalances in electrolytes like potassium, magnesium, and calcium, as these can influence the heart's electrical function.
• Some patients may experience T-wave and ST-segment changes on their ECGs as a result of romidepsin treatment, so regular monitoring is essential to catch and address any issues promptly.

Tumor lysis syndrome

• Tumor lysis syndrome (TLS) is a condition that can occur when cancer cells break down quickly, releasing their contents into the bloodstream. This can lead to various metabolic imbalances and potential complications.
• Patients with advanced disease or a high tumor burden are at a greater risk of developing TLS when undergoing romidepsin treatment.
• To minimize the risk of TLS, healthcare providers should closely monitor patients with these risk factors. Regular assessments can help detect any early signs of TLS.
• If TLS does occur, appropriate treatment should be initiated promptly. This typically involves managing the metabolic imbalances and complications associated with the syndrome.
• Monitoring and addressing TLS risk is an essential aspect of managing patients receiving romidepsin, particularly in those with advanced disease or a heavy tumor burden.

Hepatic impairment

• Romidepsin does not appear to be significantly affected by mild hepatic (liver) impairment based on pharmacokinetic analysis.
• However, for patients with moderate or severe hepatic impairment, the initial dose of romidepsin should be reduced.
• This is done to account for potential differences in how the medication is processed by the liver in these individuals.
• Close and frequent monitoring for toxicities, particularly during the first treatment cycle, is essential for patients with moderate or severe hepatic impairment.
• This monitoring helps ensure the safety and effectiveness of romidepsin in these individuals.

Renal impairment

• Romidepsin does not appear to be significantly influenced by mild, moderate, or severe renal (kidney) impairment based on pharmacokinetic analysis. This means that its processing in the body does not seem to be significantly affected by kidney function.
• However, when it comes to patients with end-stage renal disease (severe kidney impairment), there is limited information available, and romidepsin hasn't been specifically studied in this population.
• Therefore, for individuals with end-stage renal disease, it is recommended to use romidepsin with caution due to the lack of comprehensive data regarding its safety and effectiveness in this specific group of patients.

Romidepsin: Drug Interaction

Monitoring parameters:

Check Your Electrolytes (Serum Electrolytes):

• They will test your levels of potassium and magnesium.
• This helps ensure that your body's electrolytes are in balance, which is important for your overall health.

Monitor Your Blood Counts (CBC with Differential and Platelets):

• Regular blood tests will be done to check your blood counts.
• This helps identify any changes in your red blood cells, white blood cells, and platelets.

Pregnancy Test for Females of Reproductive Potential:

• If you are a woman capable of getting pregnant, they will do a pregnancy test within 7 days before starting romidepsin treatment.

Heart Monitoring (ECG):

• Before you begin treatment and periodically during treatment, they will perform an electrocardiogram (ECG).
• This is especially important if you have heart issues, a history of long QT syndrome, or if you are taking medications that can affect your heart's rhythm (QT-prolonging medications).

Watch for Signs of Infection:

• Your healthcare team will keep an eye out for any signs or symptoms of infection.
• Prompt detection and treatment of infections are crucial for your safety.

Monitor for Tumor Lysis Syndrome:

• If you have advanced disease or a high tumor burden, they will closely watch for any signs of tumor lysis syndrome.
• Detecting and managing this condition early is essential for your well-being.

These monitoring steps help ensure that you receive romidepsin treatment safely and effectively while minimizing potential side effects and complications.

How to administer Romidepsin (Istodax)?

• Romidepsin is typically given through an intravenous (IV) infusion.
• To minimize the risk of nausea and vomiting, which can be moderate with romidepsin, antiemetic medications are recommended.
• The infusion should be administered slowly over a period of 4 hours.

This careful administration process, along with antiemetics, helps ensure that patients receiving romidepsin treatment have a more comfortable experience and can better manage potential side effects like nausea and vomiting.

Mechanism of action of Romidepsin (Istodax):

• Romidepsin is classified as a histone deacetylase (HDAC) inhibitor.
• HDACs are enzymes that play a role in removing acetyl groups from certain proteins, including histones and transcription factors.
• When you inhibit HDAC with romidepsin, it prevents the removal of acetyl groups from these proteins.
• This accumulation of acetyl groups leads to changes in the structure of chromatin (a complex of DNA and proteins) and activates transcription factors.
• These changes in chromatin and transcription factor activity result in several effects:
  • It stops the growth of cells (cell cycle arrest) at the G1 and G2/M phases.
  • Ultimately, this can lead to the death of the affected cells.

Protein binding:

• Romidepsin is highly bound to proteins in the bloodstream, with a binding rate of approximately 92% to 94%. It primarily attaches to a protein called α-acid glycoprotein.

Metabolism:

• Romidepsin is metabolized primarily in the liver.
• The main enzyme responsible for its metabolism is CYP3A4.
• There is also some minor metabolism of romidepsin by enzymes CYP3A5, 1A1, 2B6, and 2C19.

Half-life elimination:

• The half-life of elimination for romidepsin is approximately 3 hours.
• This means that within 3 hours after taking a dose, half of the romidepsin in the bloodstream is expected to be cleared from the body.

International Brand Names of Romidepsin:

• Istodax (Overfill)
• Istodax

Romidepsin Brand Names in Pakistan:

Not available.