Fludarabine (Fludara) is a purine analog - a chemotherapeutic drug that is used in the management of hematological malignancies.

Indications of Fludarabine (Fludara):

• Chronic lymphocytic leukemia (refractory or progressive):
  • It is indicated for the treatment of B-cell chronic lymphocytic leukemia (CLL) in adults who showed no response or progression during treatment with at least one standard regimen containing an alkylating agent.
• Off Label Use of Fludarabine in Adults:
  • Acute myeloid leukemia (newly diagnosed)
  • Acute myeloid leukemia (refractory or high/poor risk)
  • Hematopoietic stem cell transplant (allogeneic) myeloablative conditioning regimen (older adults)
  • Hematopoietic stem cell transplant (allogeneic) nonmyeloablative conditioning regimen
  • Hematopoietic stem cell transplant (allogeneic) reduced-intensity conditioning regimen
  • Non-Hodgkin lymphoma: Follicular lymphoma (relapsed/refractory)
  • Non-Hodgkin lymphoma: Mantle cell lymphoma (relapsed/refractory)
  • Waldenström macroglobulinemia

Fludarabine (Fludara) dose in adults:

Fludarabine (Fludara) Treatment dose of refractory or progressive Chronic lymphocytic leukemia (CLL): 

For Chronic Lymphocytic Leukemia (CLL), when it's hard to treat or getting worse:

• IV Treatment: The medicine is given through a vein. The dose is 25 milligrams for each square meter of the patient's body surface. This happens once a day for 5 days in a row. After 28 days, this cycle is repeated. This treatment should continue for at least 3 more cycles after the best response is seen.
• Oral Treatment (Canada only): In Canada, the medicine is taken by mouth. The dose is 40 milligrams for each square meter of the body's surface. This is done once a day for 5 days in a row. After 28 days, this cycle starts again.

Combining Treatments for CLL (Not standard but sometimes used):

• FC Regimen: The medicine is given through a vein. The dose is 30 milligrams for each square meter of the body's surface every day for 3 days. This is done every 28 days for 6 cycles. It's combined with another medicine called cyclophosphamide.
• FCR Regimen: The medicine is given through a vein. The dose is 25 milligrams for each square meter of the body's surface every day for 3 days. This is done every 28 days for 6 cycles. It's combined with cyclophosphamide and another medicine called rituximab.
• FR Regimen: The medicine is given through a vein. The dose is 25 milligrams for each square meter of the body's surface every day for 5 days. This is done every 28 days for 6 cycles. It's combined with rituximab.
• OFAR Regimen: The medicine is given through a vein. The dose is 30 milligrams for each square meter of the body's surface every day for 2 days. This is done every 28 days for 6 cycles. It's combined with three other medicines: oxaliplatin, cytarabine, and rituximab.

Fludarabine (Fludara) Treatment dose of newly diagnosed Acute myeloid leukemia (off-label): 

• IV Treatment: The medicine is given through a vein. The dose is 30 milligrams for each square meter of the body's surface every day for 5 days. This is done along with other medicines like cytarabine, and sometimes with other treatments like G-CSF and idarubicin. These combinations are called FA, FLAG, or FLAG-IDA regimens.
• After this initial treatment, there's something called "consolidation therapy." This means further treatment to make sure the leukemia is under control. The decision about this is made by the doctor based on the patient's condition.

Fludarabine (Fludara) Treatment dose of refractory or high/poor-risk patients with Acute myeloid leukemia, (off-label):

• IV Treatment: The medicine is given through a vein. The dose is 30 milligrams for each square meter of the body's surface every day for 5 days.
• FLAG Regimen: This is when fludarabine is used together with two other medicines, cytarabine and filgrastim. If there's only a partial improvement, this treatment can be given again (so, done twice in total).
• FLAG-IDA Regimen: This is another combination. Fludarabine is used with three other medicines: cytarabine, idarubicin, and filgrastim. This treatment is done for 1 or 2 cycles, each cycle lasting 5 days.

Fludarabine (Fludara) Treatment dose of Hematopoietic stem cell transplant (allogeneic) myeloablative conditioning regimen (off label):

• IV Treatment: The medicine is given through a vein. The dose is 40 milligrams for each square meter of the body's surface. This is done daily for 4 days.
• It's used together with another medicine called busulfan.
• This combined treatment starts 6 days before the actual transplantation process.

Fludarabine (Fludara) Treatment dose of allogeneic hematopoietic stem cell transplant (reduced-intensity conditioning regimen) (off-label):

• IV Treatment: The medicine, fludarabine, is given through a vein. The dose is 30 milligrams for each square meter of the body's surface.
• In Combination with Melphalan and Alemtuzumab: Fludarabine is given daily for 5 days before the transplant.
• Starting 10 Days Before Transplant: Another way to use fludarabine is to give it daily for 6 days, starting 10 days before the transplant.
• Starting 6 Days Before Transplant: Yet another method is to give fludarabine daily for 5 days, beginning 6 days before the transplant. In this method, it's combined with another medicine called busulfan. Sometimes another medicine, antithymocyte globulin, might also be added.

Fludarabine (Fludara) Treatment dose of allogeneic Hematopoietic stem cell transplant (nonmyeloablative conditioning regimen) (off-label): 

• IV Treatment: The drug, fludarabine, is given through a vein. The dose is 30 milligrams for each square meter of the body's surface.
• Combined with Cyclophosphamide and Rituximab: Fludarabine is given for 3 days, starting 5 days before the transplant.
• Combined with Total Body Irradiation: Alternatively, fludarabine can be given for 3 days, but starting 4 days before the transplant. In this method, there's also a treatment where the whole body is exposed to radiation (total body irradiation).

Fludarabine (Fludara) Treatment dose of Non-Hodgkin lymphomas (off-label): 

FCR Regimen:

• Dose: Fludarabine is given at 25 milligrams for each square meter of the body's surface.
• Schedule: Given for 3 days in a row, then there's a break until 21 days from the start. This cycle is repeated for 4 rounds.
• Combo: Fludarabine is combined with two other medicines, cyclophosphamide and rituximab.

FCMR Regimen:

• Dose: Same as above, 25 milligrams for each square meter.
• Schedule: Given for 3 days in a row, then a break until 28 days from the start. This cycle is done for 4 rounds.
• Combo: Fludarabine is combined with three other medicines: cyclophosphamide, mitoxantrone, and rituximab.

FNDR Regimen:

• Dose: Again, 25 milligrams for each square meter.
• Schedule: Given for 3 days, then a break until 28 days from the start. This cycle can be done up to 8 times.
• Combo: Fludarabine is combined with three other meds: mitoxantrone, dexamethasone, and rituximab.

FR Regimen:

• Dose: The same 25 milligrams for each square meter.
• Schedule: This time, it's given for 5 days in a row, followed by a break until 28 days from the start. This is done for 6 rounds.
• Combo: Fludarabine is combined with just one other medicine, rituximab.

Fludarabine (Fludara) Treatment dose of Mantle cell lymphoma, relapsed, or refractory:

FC Regimen:

• Dose Option 1: Fludarabine is given at 20 milligrams for each square meter of the body's surface. This is done for 4 to 5 days in a row.
• Dose Option 2: Alternatively, it can be given at 25 milligrams for each square meter of the body's surface, also for 3 to 5 days in a row.
• Combo: In both cases, fludarabine is used alongside another medicine called cyclophosphamide.

Fludarabine (Fludara) Treatment dose of Waldenstrom macroglobulinemia (off-label):

Solo Treatment:

• Dose: Fludarabine is given at 25 milligrams for each square meter of the body's surface.
• Schedule: This is done daily for 5 days in a row, then there's a break until 28 days from the start. This cycle is then repeated.

Combined with Rituximab:

• Dose: Fludarabine is given at 25 milligrams for each square meter of the body's surface, once daily for 5 days.
• Schedule: This is done during specific weeks: weeks 5, 9, 13, 19, 23, and 27.
• Combo: During this treatment, fludarabine is used alongside another medicine called rituximab.

Fludarabine (Fludara) dose in children:

Fludarabine (Fludara) Treatment dose of Relapsed Acute lymphocytic leukemia (ALL) or AML:

For Children and Adolescents:

• Continuous IV Infusion Method:
  • Dose: Start with a one-time dose (bolus) of 10.5 milligrams for each square meter of the body's surface. Then, give 30.5 milligrams for each square meter every day, but it’s infused continuously for 48 hours.
  • Combo: This is done with another medicine called cytarabine.
• Intermittent IV Dosing Method (specifically for ALL):
  • Dose: Fludarabine is given at 25 milligrams for each square meter of the body's surface.
  • Schedule: This is done once daily for 5 days in a row.
  • Combo: The treatment is combined with two other medicines: cytarabine and daunorubicin.

Fludarabine (Fludara) Treatment dose of allogeneic stem cell transplant (conditioning regimen), reduced-intensity (hematologic malignancy):

For Children and Adolescents:

• Dose: Fludarabine is given at 30 milligrams for each square meter of the body's surface.
• Schedule: It's given once daily, and the patient gets 6 doses in total. This treatment starts 7 to 10 days before the actual transplant.
• Combo: Fludarabine is used with two other medicines: busulfan and thymoglobulin.

Fludarabine (Fludara) Treatment dose of allogeneic Stem cell transplant (conditioning regimen), reduced-toxicity (myeloid malignancies and non-malignant diseases [eg, sickle cell cisease]): 

For Children and Adolescents:

• Dose: Fludarabine is given at 30 milligrams for each square meter of the body's surface.
• Schedule: It's given once daily. The treatment is scheduled on specific days: from day -8 to day -3, where the day of transplant is considered day 0. This means they get the treatment for 6 days in total, starting 8 days before the actual transplant and stopping 3 days before the transplant.
• Combo: Fludarabine is used alongside two other medicines: busulfan and alemtuzumab.

Fludarabine Dosing adjustment for toxicity:

(Note: The information given is mostly from adult cases. For children, specific guidelines might be different, so it's important to look at specialized instructions for kids if available.)

For Adults:

• Blood-Related or Other Harm (excluding nerve-related harm):
  • Doctors might think about waiting a bit before giving the next dose or reducing the amount of the medicine given.
• Hemolysis (when red blood cells are destroyed):
  • Doctors will stop the treatment.
• Neurotoxicity (harm to the nervous system):
  • Doctors might consider waiting before giving the next dose or might even decide to stop the treatment altogether.

Pregnancy Risk Factor D

• Studies done in animals have shown negative effects on pregnancy outcomes.
• Due to how the drug works, it's possible that fludarabine might harm a developing fetus if taken during pregnancy.
• To avoid pregnancy risks, both women and men with female partners who could become pregnant should use effective contraception during the treatment period and even after the treatment is finished.

Use Fludarabine while breastfeeding

• We're not sure if fludarabine can get into breast milk.
• Because there's a risk of harmful effects on a baby being breastfed, mothers have to make a choice: either stop breastfeeding or stop taking fludarabine. The decision should consider how important the treatment is for the mother's health.

Fludarabine Dose adjustment in kidney disease:

When given through a vein (IV):

• CrCl (Creatinine Clearance) ≥80 mL/minute: Normal dose (25 mg/m^2) is fine.
• CrCl 50 to 79 mL/minute: Decrease dose to 20 mg/m^2.
• CrCl 30 to 49 mL/minute: Decrease dose to 15 mg/m^2.
• CrCl <30 mL/minute: It's not advised to use fludarabine.

For the oral pill (which is available in Canada but not in the U.S.):

• CrCl 30 to 70 mL/minute: Cut the dose by up to half.
• CrCl <30 mL/minute: Using fludarabine is not allowed.

Other dosage adjustments based on different sources (Aronoff 2007):

• CrCl 10 to 50 mL/minute: Decrease dose to 75% of the usual dose.
• CrCl <10 mL/minute: Cut the dose in half.
• Hemodialysis (cleaning the blood when kidneys aren't working well): Halve the dose and give it after the dialysis session.
• CAPD (a type of dialysis): Halve the dose.
• CRRT (a continuous form of dialysis): Use 75% of the usual dose.

Fludarabine (Fludara) Dose adjustment in liver disease:

There are no dosage adjustments provided in the manufacturer's labeling.

Common Side Effects of Fludarabine (Fludara):

• Cardiovascular:
  • Edema
• Central Nervous System:
  • Fatigue
  • Neurological Signs And Symptoms
  • Pain
  • Chills
  • Paresthesia
• Dermatologic:
  • Skin Rash
  • Diaphoresis
• Gastrointestinal:
  • Nausea And Vomiting
  • Anorexia
  • Diarrhea
  • Gastrointestinal Hemorrhage
• Genitourinary:
  • Urinary Tract Infection
• Hematologic & Oncologic:
  • Anemia
  • Neutropenia
  • Thrombocytopenia
  • Bone Marrow Depression
• Infection:
  • Infection
• Neuromuscular & Skeletal:
  • Weakness
  • Myalgia
• Ophthalmic:
  • Visual Disturbance
• Respiratory:
  • Cough
  • Pneumonia
  • Dyspnea
  • Upper Respiratory Tract Infection
• Miscellaneous:
  • Fever

Rare Side Effects Of Fludarabine (Fludara):

• Cardiovascular:
  • Angina Pectoris
  • Cardiac Arrhythmia
  • Cardiac Failure
  • Cerebrovascular Accident
  • Myocardial Infarction
  • Supraventricular Tachycardia
  • Deep Vein Thrombosis
  • Phlebitis
  • Aneurysm
  • Transient Ischemic Attacks
• Central Nervous System:
  • Malaise
  • Headache
  • Sleep Disorder
  • Cerebellar Syndrome
  • Depression
  • Difficulty Thinking
• Dermatologic:
  • Alopecia
  • Pruritus
  • Seborrhea
• Endocrine & Metabolic:
  • Hyperglycemia
  • Dehydration
• Gastrointestinal:
  • Stomatitis
  • Cholelithiasis
  • Esophagitis
  • Constipation
  • Mucositis
  • Dysphagia
• Genitourinary:
  • Dysuria
  • Urinary Hesitancy
  • Hematuria
  • Proteinuria
• Hematologic & Oncologic:
  • Hemorrhage
  • Tumor Lysis Syndrome
• Hepatic:
  • Abnormal Hepatic Function Tests
  • Hepatic Failure
• Hypersensitivity:
  • Anaphylaxis
• Neuromuscular & Skeletal:
  • Osteoporosis
  • Arthralgia
• Otic:
  • Hearing Loss
• Renal:
  • Renal Failure
  • Renal Function Test Abnormality
• Respiratory:
  • Pharyngitis
  • Hypersensitivity Pneumonitis
  • Hemoptysis
  • Sinusitis
  • Bronchitis
  • Epistaxis
  • Hypoxia

Contraindications to Fludarabine (Fludara):

• In the U.S.: The manufacturer's guidelines don't list any specific situations where the drug shouldn't be used.
• In Canada: The guidelines say not to use fludarabine if:
  • The person is allergic to fludarabine or anything else in the drug.
  • Their kidneys are working very poorly (specifically, if the CrCl, a measure of kidney function, is less than 30 mL/minute).
  • They have a severe form of a condition called hemolytic anemia that's getting worse.
  • They are also taking a drug called pentostatin.

Warnings and precautions

Autoimmune effects: [US-Boxed Warning]

• Fludarabine can cause serious and sometimes deadly autoimmune reactions. This means the body starts attacking its own cells. Some of these reactions include:
  • Hemolytic anemia: Where the body destroys its own red blood cells.
  • ITP: A condition where the body attacks its own platelets, which help with blood clotting.
  • Evans syndrome: A rare condition where the body destroys both its red cells and platelets.
  • Acquired hemophilia: A condition where the blood doesn't clot as it should.
• These problems can happen to anyone taking fludarabine, even if they don't have a history of these conditions or show any warning signs like a positive Coombs test. It can happen whether the patient's main disease is active or in remission.
• Steroid medications might help with these reactions, but not always.
• If someone taking fludarabine starts having these problems (like hemolysis or red cell destruction), the drug should be stopped.
• Most importantly, if a patient who had this problem with fludarabine takes it again in the future, it's very likely the problem will come back.

Suppression of bone marrow: [US Boxed Warning]

• Fludarabine can cause serious problems in the bone marrow, leading to a drop in different types of blood cells. This can result in anemia (low red blood cells), thrombocytopenia (low platelets), and neutropenia (low white blood cells).
• This decrease in blood cells can happen repeatedly with each dose.
• When looking at how long it takes for the blood cell counts to reach their lowest after taking the drug:
  • Granulocytes (a type of white blood cell) usually reach their lowest count around 13 days.
  • Platelets (cells that help with clotting) reach their lowest count around 16 days.
• There are rare cases where the bone marrow almost stops producing blood cells or stops entirely. This can last from 2 months to even a year.
• When fludarabine is used as a first-line treatment with other drugs, the low blood cell counts can last even longer. Older patients are more at risk for these extended periods of low blood cell counts.
• Patients with existing bone marrow problems should be watched closely when taking fludarabine, as they're at higher risk of experiencing these side effects. Adjustments to the dosage might be needed.

Infection

• Fludarabine can increase the risk of serious and even life-threatening infections. These infections can be ones that take advantage of weakened immune systems, called "opportunistic infections."
• Some viruses that may have been dormant in the body, like the Varicella-Zoster Virus (which causes chickenpox and shingles) and the Epstein-Barr Virus, can become active again after taking fludarabine.
• To help prevent these infections, doctors might give patients other medications that fight or prevent infections, especially if the patient is at a high risk of getting these opportunistic infections.
• Fludarabine should be used carefully in patients:
  • Who currently have infections.
  • With a fever.
  • Who have weakened immune systems.
  • With a history of getting opportunistic infections.

Neurotoxicity: [US Boxed Warn]

• Taking more fludarabine than recommended (up to 96 mg/m^2 daily for 5 to 7 days) can cause very serious problems with the nervous system, such as delayed blindness, falling into a coma, and even death.
• However, even when taking the usual dose for CLL (25 mg/m^2 daily for 5 days), there have been rare reports of people experiencing serious nervous system side effects, like agitation, falling into a coma, confusion, and seizures.
• The signs of these nervous system problems due to overdose usually appear between 21 to 60 days after the last dose of fludarabine. But, they can show up as early as 7 days or as late as 225 days after stopping the medicine.
• It's not clear what the long-term nervous system effects might be for people who take fludarabine for many courses of treatment.
• Symptoms like tiredness, weakness, blurry vision, confusion, and seizures can happen. So, patients should be careful about doing things that need them to be alert, like driving or using machinery.

Progressive multifocal Leukoencephalopathy

• PML is a severe and typically fatal brain disease caused by the JC virus.
• There have been reports of PML in people taking fludarabine. Most of these patients had also been treated with other cancer drugs before or were taking them at the same time as fludarabine.
• The onset of PML can be quick, starting just a few weeks after taking the drug. However, in some cases, it might take up to a year for symptoms to appear.
• If anyone taking fludarabine starts showing neurological or brain-related symptoms, they should seek medical evaluation immediately.

Reproductive effects

• Fludarabine can harm the testicles and the sperm cells.

Transfusion-associated Graft-versus-Hom Disease:

• GVHD is a condition where donated cells attack the recipient's body. This has happened in people treated with fludarabine who received blood transfusions of non-irradiated blood, and it can be deadly.
• To prevent this, anyone on fludarabine should only get blood products that have been treated with radiation, as this helps prevent GVHD.

Tumor lysis syndrome

• Tumor lysis syndrome (TLS) is a condition where cancer cells break down rapidly, releasing their contents into the bloodstream. Fludarabine can cause this.
• People with a lot of cancer cells (a large tumor burden) before treatment are at a higher risk.
• To help prevent TLS, patients at risk might need to:
  • Drink more fluids (hydration).
  • Take medicines to lower uric acid levels in the blood (prophylactic antihyperuricemic therapy).

Renal impairment

• Fludarabine should be used carefully in people with kidney issues. This is because the body's ability to clear out a major breakdown product of the drug (called 2-fluoro-ara-A) is reduced when the kidneys aren't working well.
• For those with mild to moderate kidney problems (with a creatinine clearance between 30 and 79 mL/minute), a lower dose of fludarabine is recommended. Close monitoring is crucial to check for any severe side effects.
• If the kidneys are working very poorly (creatinine clearance below 30 mL/minute), using fludarabine is not advised.

Fludarabine: Drug Interaction

Monitoring parameters:

Blood Tests:

• CBC (Complete Blood Count) with differential: To check overall health and detect disorders like anemia or infection.
• Platelet Count: To measure the number of platelets, which help with clotting.
• AST & ALT: Liver tests to check liver function.
• Serum Creatinine: To check kidney function.
• Serum Albumin: To assess the liver's function and nutritional status.
• Uric Acid: To measure the amount of uric acid in the blood, which can be related to tumor lysis syndrome.

What to Watch For:

• Infection Signs: Symptoms like fever, chills, or swelling.
• Neurotoxicity: Brain or nerve issues, such as confusion or seizures.
• Tumor Lysis Syndrome: A rapid release of cells into the blood, can cause symptoms like nausea, irregular heartbeat, and cloudy urine.

How to administer Fludarabine (Fludara)?

Given through a vein (IV):

• Standard Use (for CLL treatment): The official recommendation is to give it over about 30 minutes.
• Off-label Use: Some special treatment plans might give it continuously or as a quick 15-minute injection. Specific instructions are in individual studies.

Taken by mouth (Oral - available in Canada):

• How to Take: The tablet can be taken with or without food.
• Instructions: Drink it down with water. Don't chew, break, or crush the tablet.

Mechanism of action of Fludarabine (Fludara):

• Fludarabine stops DNA from being made in cells.
• It does this by blocking several key tools the cell uses to make DNA:
  • DNA polymerase: Helps build the DNA chain.
  • Ribonucleotide reductase: Helps prepare the building blocks for DNA.
  • DNA primase: Gets the DNA building process started.
  • DNA ligase I: Connects pieces of DNA together.

Distribution:

• After entering the bloodstream, it spreads out. The volume of distribution is between 11 to 96 L/m.

Binding in Blood:

• The active part of fludarabine, 2-fluoro-ara-A, binds to proteins in the blood about 19% to 29% of the time.

How It's Processed (Metabolism):

• When given through a vein, fludarabine quickly changes in the blood to its active form, 2-fluoro-araA. Inside cancer cells, it transforms into an even more active form, 2-fluoro-ara-ATP.

How Much is Absorbed (Bioavailability):

• If taken as a pill, about 50% to 65% of the active part, 2-fluoro-ara-A, gets into the bloodstream.

How Long it Lasts (Half-life):

• The active part, 2-fluoro-ara-A, stays in the body for around 20 hours before it's reduced by half.

Time to Reach Maximum Level:

• After taking a pill, the highest level in the blood is reached in 1 to 2 hours.

How It Leaves the Body (Excretion):

• It's mostly removed from the body through urine.

International Brands of Fludarabine:

• Fludara
• Beneflur
• Eupifluda
• Flucozol
• Fludabine
• Fludacel
• Fludamin

Fludarabine Brand Names in Pakistan: