Cytarabine - Uses, Dosage, Side Effects, Precautions, and Warnings

Overview:

Cytarabine is an anti-cancer chemotherapy drug used to manage and treat leukemia (cancer of the white blood cells) and cancers of the lymph glands. It is used to treat specific types of cancers that affect the spinal cord and brain. Cytarabine is a group of medications known as antimetabolites that slow the growth of cancer cells in the body. They kill cancer cells and prevent them from multiplying. Cytarabine should be given by physicians experienced in cancer chemotherapy.

How Does Cytarabine Work?

The cancer cells cannot copy their DNA (deoxyribonucleic acid) and do not divide properly, thus dying. Cytarabine inhibits the DNA polymerase, damages the DNA proteins, and exhibits cell phase specificity by primarily killing cells undergoing DNA synthesis. Cytarabine also blocks the progression of cells from the G1 phase to the S-phase.

Cytarabine is not absorbed effectively when taken orally due to high first-pass metabolism. It has high bioavailability when administered subcutaneously, intrathecally, or intravenously. Cytarabine has a low plasma protein binding capacity and a high volume of distribution. It is primarily metabolized to the active compound ara-U by the liver. The initial distribution of Cytarabine was in a half-life of ten minutes, followed by a second elimination phase with a half-life of one to three hours.

Uses of Cytarabine:

Cytarabine may be used as monotherapy or with other chemotherapy drugs in treating various types of leukemia, including acute myeloid leukemia (cancer of the blood and bone marrow), acute lymphocytic leukemia (cancer that develops in one of the primary white cells called lymphocytes), and chronic myelogenous leukemia (when the bone marrow makes too many white blood cells) in adults and pediatric patients.

Cytarabine is Food and Drug Administration ( FDA) - approved and may also be used in the prevention and helps treat meningeal leukemia (cancer cells spread from the primary tumor to the meninges that cover and protect the brain) alone or with other chemotherapy drugs. Cytarabine is also sometimes used to treat certain types of Hodgkin's lymphoma (cancer that develops in a network of vessels and glands throughout the body called the lymphatic system)

Limitations:

• Cytarabine causes a rare illness called Cytarabine syndrome, produced shortly after taking the drug. Symptoms like fever, rash, joint pain, and muscle pain characterize it.

• Intravenous therapy of Cytarabine causes peripheral neuropathy (damage to nerves located outside the brain and spinal cord), seizures, and cerebral dysfunction.

Route of Administration:

• Intravenous.

• Subcutaneous.

Dosage Forms and Strengths

Injectable Solution

• 10 milligrams per milliliter.

• 20 milligrams per milliliter.

• 100 milligram per milliliter.

Subcutaneous or Intrathecal injection

• 50 milligrams per 5 milliliters.

Powder for Injection

• 100 milligrams per vial.

• 500 milligrams per vial.

• 1 gram per vial.

• 2 grams per vial.

Typical Dosage:

Cytarabine is available in injection solutions at 10 mg/ml. 20 mg/ml, 100mg/ml that can be given directly into the spine or the brain, or into the vein or under the skin by the healthcare provider.

Special Considerations:

• Allergic Reactions - Cytarabine should be avoided in patients allergic to Cytarabine or any ingredients. Cytarabine injections must be avoided in patients who have a meningeal infection.

• Pregnancy and Breastfeeding - Cytarabine is in category D pregnancy. Cytarabine is contraindicated during pregnancy as it can increase the incidence of fetal malformation or irreversible damage to the fetus.

• Children - Cytarabine can temporarily lower the white blood cell count and increase the risk of infection. The drug must be administered with caution in children.

• Mind Alertness - It is advised to avoid driving, using machinery, or any such activity that requires alertness while taking Cytarabine, as it makes one dizzy or drowsy.

• Anemia - Therapy with Cytarabine must be cautiously administered in patients with preexisting anemia as Cytarabine treatment may further lower the red blood cell count.

• Leukopenia - White blood cells help to fight infections in the body. Therapy with Cytarabine makes one more susceptible to infections.

Contraindications:

• Hypersensitivity - Allergic reactions have been reported with Cytarabine therapy. They should be avoided in people with a known or past history of an allergic reaction to the drug.

• Infections - Cytarabine is contraindicated in patients with known infectious diseases. Cytarabine has a cytotoxic effect on rapidly proliferating tissues and may induce myelosuppression (bone marrow activity is decreased).

• Myelosuppression - Therapy with Cytarabine should be administered cautiously in patients whose bone marrow reserve may be severely depressed by prior chemotherapy or whose marrow function is recovering from previous cytotoxic therapy.

Warnings and Precautions

• Hepatic Dysfunction - The liver extensively metabolizes Cytarabine. Patients with impaired hepatic function may be at increased risk for central nervous system toxicity when given high doses of Cytarabine. A periodic liver function check should be performed in patients receiving Cytarabine injections.

• Renal Dysfunction - The kidneys remove Cytarabine from the body. Patients with renal dysfunction can be at increased risk for central nervous system toxicity during high-dose Cytarabine therapy.

• Immunization - It is advised to avoid immunization with the live vaccine (rubella, mumps, or measles) while taking Cytarabine treatment and for up to 12 months afterward. The length of time depends on the treatment one is having.

For Patients

What Is Leukemia?

Leukemia is a cancer of blood-forming tissues, including bone marrow and the lymphatic system. It occurs due to the uncontrolled growth of specific cells that undergo changes and survive better than normal cells. These cells, over some time, suppress the development of normal cells and replace them. The cause of leukemia is unknown, but people are exposed to intense radiation, and certain chemicals, such as benzene and viruses, are at higher risk. Leukemia usually starts in the bone marrow, moves quickly into the bloodstream, and later spreads to other parts, such as lymph nodes, spleen, liver, and central nervous system.

Symptoms of Leukemia:

The symptoms of leukemia are mild at first and worsen gradually. The major symptoms include

• Increased bruising and bleeding.

• Repeated infections.

• Mouth sores.

• Fever.

• Sweats.

• Cough.

• Irritation while passing urine.

• Bone pain.

• Headaches.

• Vomiting.

• Enlargement of lymph glands.

• Chest pain.

Why Is Cytarabine Prescribed For Leukemia?

Cytarabine is approved to prevent and treat leukemia that has spread to the meninges (membrane that protects the brain and spinal cord). The drug is FDA-approved for use with other drugs to treat leukemia.

Facts One Should Know About Cytarabine:

• Cytarabine injection must be given under the supervision of an experienced chemotherapy doctor.

• The drug may cause a severe fall in the number of blood cells in the bone marrow. Resulting in an increased risk of developing infection or bleeding.

• Only receive immunization or vaccination while taking Cytarabine after informing the doctor.

• Use barrier methods of contraceptives, such as condoms, and do not conceive while taking Cytarabine.

How Should One Take Cytarabine?

• Cytarabine injection is not active orally, and the schedule and method of administration vary with the program therapy used.

• Cytarabine injection may be given as an intravenous infusion, subcutaneously, or intrathecally (injection into the spinal cord).

• Induction therapy should be administered in a facility with a laboratory and supportive sources to monitor drug tolerance and manage cases of drug toxicity.

• The dosage is based on the medical condition, body size, and response to the therapy. Cytarabine is usually given as a course of several treatment cycles and varies on the type of cancer.

• Drinking plenty of water while taking this medicine is advised as it helps the kidneys remove the drug from the body and causes minimal side effects.

• In case of a missed dose, take it soon after one remembers. However, do not take two tablets together as it may cause adverse reactions.

Information to Be Given to the Doctor Before Taking Cytarabine:

• Medical History - It is advised to inform the doctor of one's prescription and nonprescription medications, vitamins, supplements, and herbal products that one may be taking.

• Allergy - Inform the doctor if one has had an allergic reaction to Cytarabine or its ingredients. Check the drug composition for the components.

• Pregnancy and Breastfeeding - Inform the doctor if one is planning a pregnancy, pregnant, or breastfeeding. It is advised to avoid getting pregnant while taking Cytarabine injections as it can harm the fetus.

Safety of Cytarabine:

High doses of Cytarabine can cause adverse effects, including central nervous system, cardiovascular, gastrointestinal, or pulmonary toxicity. It may cause ocular toxicity and conjunctivitis.

Effectiveness of Cytarabine:

Standard intensive treatment improves early death rates and long-term survival compared with palliation (relief of symptoms caused by cancer). High dose regimen of Cytarabine has an overall survival data of approximately 40 percent with remission rates of 70 to 80 percent and relapse-free five years survival of 40 to 70 percent. Cytarabine therapy kills cancer cells by stopping them from making or repairing DNA (deoxyribonucleic acid) and (RNA) ribonucleic acid that is required for them to grow and multiply. The growth of cancer cells in an unbalanced way leads to the death of these cells.

Side Effects Expected With Cytarabine:

The main toxic effects of Cytarabine injection are bone marrow suppression (decreased production of cells responsible for providing immunity) with leukopenia (low level of white blood cells), thrombocytopenia (low blood platelet count), and anemia.

Some severe side effects may include

• Pain, redness, swelling, or burning at the injection site.

• Fainting.

• Dizziness.

• Fast or irregular heartbeat.

• Hives.

• Chest pain.

• Difficulty in breathing.

• Yellowing of the skin and eyes.

• Numbness in the hands, feet, or legs.

• Decreased urination.

• Shortness of breath.

• Seizures.

• Confusion.

• Sudden vision change.

Cytarabine may cause side effects that may include,

• Nausea.

• Vomiting.

• Diarrhea.

• Stomach pain.

• Loss of appetite.

• Sores in the mouth and throat.

• Hair loss.

• Joint pain.

• Sore throat.

• Tiredness.

• Sore eyes.

Cytarabine Syndrome - It happens about 6 to 12 hours after taking Cytarabine. It is a combination of symptoms, like

• High temperature.

• Aching muscles.

• Bone pain.

• Chest pain.

• A rash.

• Extreme weakness.

The symptoms usually resolve within 24 hours when Cytarabine has been discontinued.

Can One Stop Taking Cytarabine Suddenly Without the Doctor's Approval?

• Cytarabine must be administered under the supervision of an experienced chemotherapy doctor.

• Never stop taking medicines without talking to the doctor. The doctor will decrease the dose gradually.

• Do not take the drug more than advised by the doctor.

Dietary Restrictions to Consider When Taking Cytarabine:

• Alcohol - It is advised to limit alcohol consumption. Drinking alcohol during Cytarabine therapy can make one more dizzy or drowsy and should be avoided.

• Acidic Foods - Avoid acidic foods like oranges, lemons, and grapefruit during Cytarabine therapy.

Drinking plenty of water and chewing sugar-free gums can help to keep the mouth and teeth clean and moist.

Storage of Cytarabine:

• Keep the medicine in their original packaging.

• Once a vial is opened, use it immediately. Do not store unused portions of medicines.

• Store at room temperature between 15 to 30 degrees. The injections before reconstitution may be stored at 20 to 25 degrees centigrade.

• Direct contact with heat, air, and light may damage the medicines. Therefore, keep the medicines away from direct light and heat.

• Keep all medicines out of reach of children and pets. Always lock the safety caps of the medication to protect small children from poisoning themselves.

Disposal of Cytarabine:

• Do not keep outdated medicines or medicines that are no longer needed. Discard any unused portion of the reconstituted vial.

• If a spill occurs, restrict access to the affected area, and adequate protection, including gloves and safety spectacles, should be worn. After cleaning with absorbent paper, the spill may be treated with five percent sodium hypochlorite.

• The contaminated material may be placed in a leakproof disposal bag for cytotoxics and incinerated at 1100 degrees.

• In case the medicine passes its expiry date or the treatment is stopped by the doctor, return the syringes to the pharmacist. Do not flush them down the toilet or throw them away in the trash.

Overdose:

• In case of an overdose, call the poison control helpline.

• Call the emergency services if the person has collapsed or has trouble breathing.

• High doses of Cytarabine can worsen side effects, like moth sores, or decrease the number of white blood cells and platelets, and symptoms, like difficulty in speaking, abnormal eye movements, confusion, sleepiness, problems of coordination, dizziness, coma, or convulsion.

• There is no specific antidote for Cytarabine overdose. Cessation of therapy followed by the management of bone marrow depression may require whole blood or platelet transfusion and antibiotics.

For Doctors

Indications:

Cytarabine may be given alone or in combination with other antineoplastic agents. The drug is indicated for induction of remission and maintenance in patients with acute myeloid leukemia, acute non-lymphoblastic leukemias, acute lymphoblastic leukemias, acute lymphocytic leukemia, erythroleukemia, blast crisis of chronic myeloid leukemia, diffuse histiocytic lymphomas (non-hodgkin's lymphomas of high malignancy), meningeal leukemia, and meningeal neoplasms.

Pharmacology of Cytarabine:

Description

Cytarabine injection is a sterile solution for intravenous, intrathecal, or subcutaneous administration. It is an odorless, white to off-white crystalline powder which is freely soluble in water and slightly soluble in alcohol.

Components

Active Ingredients - Cytarabine.

Inactive Ingredients

• Macrogol 400.

• Trometamol.

• Water for injection.

• Sodium hydroxide.

• Hydrochloric acid.

Clinical Pharmacology:

Mechanism of Action - Cytarabine is a cell cycle phase-specific antineoplastic agent that affects cells only during the S-phase of cell division. Intracellularly, Cytarabine is converted into Cytarabine-5-triphosphate, which is the active metabolite. The incorporation of Cytarabine into DNA and RNA contributes to its cytotoxic effects. The drug acts through the inhibition of DNA polymerase. The drug also has antiviral and immunosuppressive properties.

Pharmacodynamics

Cytarabine is a pyrimidine analog that is cell cycle phase-specific. It primarily kills cells undergoing DNA synthesis (S-phase) and blocks the progression of cells from the G1 phase to the S-phase.

Pharmacokinetics

Cytarabine is widely and rapidly distributed into tissues and fluids and crosses the placenta.

• The Mean Cmax- 30 to 50 micrograms per milliliter.

• Median Tmax- 20 to 60 minutes.

[Cmax- Maximum concentration achieved by a drug in the blood, cerebrospinal fluid, or target organ after administration of a dose]

[Tmax- Time taken for a drug to reach maximum concentration after administration of a dose]

Pharmacokinetic Changes:

A. Distribution

• Steady-state Plasma Levels - 50 percent.

• Mean Half-Life - 10 minutes.

• Protein Bound - 13 percent.

• Mean Volume of Distribution - 2.6 liters per kilogram.

B. Metabolism

• Metabolic Processes - Cytarabine is rapidly and extensively metabolized, primarily hepatic. Cytidine deaminase also metabolizes in the kidneys, gastrointestinal mucosa, granulocytes, and other tissues. The drug is minimally metabolized in the CSF.

C. Elimination

Cytarabine is excreted mainly in the urine. Eighty percent of the dose is eliminated either as an inactive metabolite (uracil arabinoside) or as unchanged Cytarabine.

• Half-Life - One to three hours.

• Cerebrospinal Fluid Clearance Rate - 0.24 milliliter per minute.

Drug Interactions:

• Adalimumab - Taking Adalimumab (a monoclonal antibody used to treat rheumatoid arthritis) with Cytarabine can increase the risk of severe and potentially life-threatening infections.

• Digoxin - Cytarabine induces changes in the intestinal mucosa by decreasing absorption of Digoxin (used to treat abnormal arrhythmias). It is essential to adjust the Digoxin dose and monitor its levels.

• Ciprofloxacin - Therapy with Cytarabine causes intestinal changes leading to decreased absorption of Ciprofloxacin (an antibiotic used to treat bacterial infections).

• Fludarabine - Anti-cancer drugs, like Fludarabine, first cause a five-fold increase in intracellular Cytarabine concentration in leukemic cells. This is due to competition for deoxycytidine kinase, which is needed to convert both drugs to their active triphosphate.

What Have Clinical Trials Shown About Cytarabine?

Trial 1:

Objective - A phase III trial to compare Idarubicin (IDR) and Daunorubicin (DNR) in combination with Cytarabine in acute myelogenous leukemia.

• A randomized clinical trial on newly diagnosed patients of acute myelogenous leukemia.

• Four courses were planned at 13-week intervals.

• The patients were given a daily infusion of Cytarabine 100 milligrams for seven days and randomly received DNR (45 milligrams) or IDR (12 milligrams) daily for the first three days.

Primary Outcome Endpoint - Patients achieving complete remission were given three consolidation courses consisting of Cytarabine and Thioguanine every 12 hours for five days or either DNR or IDR on the first day of each cycle.

Secondary Outcome End Point - After consolidation, patients received late intensification (consisting of the same drugs used in induction), except Cytarabine was given for five days and Anthracycline for two days.

Results - The complete remission rates were 75 of 105 on the IDR arm and 65 of 113 on the DNR arm. The median survival was significantly longer for patients who received late intensification. The trial demonstrated that IDR was more effective than DNR remission induction in acute myelogenous leukemia.

Trial 2:

Objective: A study of Venetoclax in combination with low-dose Cytarabine versus low-dose Cytarabine alone in treatment-naive patients with acute myeloid leukemia who are ineligible for intensive chemotherapy.

• A phase III, randomized, double-blind, placebo-controlled, multicenter study in 112 patients with acute myeloid leukemia of 18 years and older who have not been treated before.

• Patients participating in this study should not be suitable for intensive induction chemotherapy.

Primary Outcome Measures - Overall survival time frame includes the time from randomization to the date of death. It was analyzed using the Kaplan-Meier methodology.

Secondary Outcome Measures - Percentage of participants with complete remission or complete remission with incomplete blood count recovery and partial hematologic recovery.

Result - Venetoclax with Cytarabine works well for people with acute myeloid leukemia and produces rapid and durable remission.

Complications or Side Effects Management:

• Low Blood Count - Treatment with Cytarabine temporarily decreases the white and red blood cells and increases the risk of infection, anemia, or bleeding. Avoid crowds or people with colds.

• Mouth Sores - Use a soft toothbrush and rinse at least three times a day with lukewarm water to help treat or prevent mouth sores. Drink plenty of water, avoid acidic foods, and chew gum to keep the mouth moist.

• Bleeding - Minimize bleeding by avoiding activities or sports that can cause injury.

• Nausea and Vomiting - Eat smart and frequent meals to reduce nausea. Anti-nausea medication, such as Ondansetron, Aprepitant, or Prochlorperazine, may be helpful.

• Skin Rash - Skin changes, such as dryness, itching, and rashes, may occur. Moisturizing skin with creams recommended by the doctor can be helpful. Use a high factor sunblock when going out.