Cladribine – Uses, Dosage, Side Effects, Interaction

Cladribine is a purine analog and antineoplastic agent used primarily in the therapy of hairy cell leukemia. Cladribine is typically given intravenously daily for 7 days, usually as a single course, and has not been associated with serum enzyme elevations during therapy or with instances of clinically apparent acute liver injury with jaundice.

Cladribine is a nucleoside metabolic inhibitor that interferes with DNA repair and synthesis, proposed by the applicant for the treatment of
relapsing forms of multiple sclerosis (MS). Cladribine causes significant depletion of circulating lymphocytes after administration which lasts
for months. Cladribine is approved in an intravenous form with an indication for the treatment of hairy cell leukemia. Relapsing forms of MS, which include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease (secondary progressive MS with relapses), are a group of chronic and potentially disabling MS phenotypes of apparent autoimmune etiology characterized by episodes of worsening focal neurological deficits and disseminated lesions of demyelination. Symptoms include recurrent paroxysms of diminished sensory or motor function that can be disabling and usually resolve within one month. Over several years, many, but not all, patients with relapsing forms of MS experience some degree of persistent disability that may gradually worsen over years. In some patients, disability may accrue progressively in the absence of obvious relapse events, a process termed secondary progressive disease. A secondary progressive disease that occurs with continued relapses is described as an active secondary progressive disease, with the relapses being the clinical
manifestation, in part, of inflammatory demyelination that is presumed to be distinct from the pathogenesis of the progressive component of the disease. In the active secondary progressive phase of the disease, patients can accrue disability both from acute relapses and from the progressive component of the disease. Active secondary progressive disease and relapsing-remitting disease overlap in evolution. Categorization as a secondary progressive disease is based on clinical judgment; there are no clinical findings or biomarkers that meaningfully define or predict the phenotypes of relapsing forms of MS.

Mechanism of Action

Cladribine is structurally related to fludarabine and pentostatin but has a different mechanism of action. Although the exact mechanism of action has not been fully determined, evidence shows that cladribine is phosphorylated by deoxycytidine kinase to the nucleotidecladribine triphosphate (CdATP; 2-chloro-2′-deoxyadenosine 5′-triphosphate), which accumulates and is incorporated into DNA in cells such as lymphocytes that contain high levels of deoxycytidine kinase and low levels of deoxynucleotides, resulting in DNA strand breakage and inhibition of DNA synthesis and repair. High levels of CdATP also appear to inhibit ribonucleotide reductase, which leads to an imbalance in triphosphorylated deoxynucleotide (dNTP) pools and subsequent DNA strand breaks, inhibition of DNA synthesis and repair, nicotinamide adenine dinucleotide (NAD) and ATP depletion, and cell death. Unlike other antimetabolite drugs, cladribine has cytotoxic effects on resting as well as proliferating lymphocytes. However, it does cause cells to accumulate at the G1/S phase junction, suggesting that cytotoxicity is associated with events critical to cell entry into S phase. It also binds purine nucleoside phosphorylase (PNP), however, no relationship between this binding and a mechanism of action has been established.

or

Cladribine is an antimetabolite. The exact mechanism of action in hairy cell leukemia is unknown. Cladribine is resistant to the action of adenosine deaminase (ADA), which deaminates deoxyadenosine to deoxyinosine. The phosphorylated metabolites of cladribine accumulate in cells with a high ratio of deoxycytidine kinase activity to 5′ nucleotidase activity (lymphocytes, monocytes ) and are converted to the active triphosphate deoxynucleotide. Intracellular accumulation of toxic deoxynucleotides selectively kills these cells, which become unable to properly repair single-strand DNA breaks, leading to disruption of cell metabolism. In addition, there is some evidence that deoxynucleotides are incorporated into the DNA of dividing cells and impair DNA synthesis. Cladribine also induces apoptosis (a form of programmed cell death in sensitive cells). Cladribine’s action is cell cycle-phase nonspecific; cladribine equally affects dividing and resting lymphocytes.

Cladribine is a synthetic purine nucleoside that acts as an antineoplastic agent with immunosuppressive effects. Cladribine differs structurally from deoxyadenosine only by the presence of a chlorine atom at position 2 of the purine ring, which results in resistance to enzymatic degradation by adenosine deaminase. Due to this resistance, cladribine exhibits a more prolonged cytotoxic effect than deoxyadenosine against resting and proliferating lymphocytes. Cladribine is one of a group of chemotherapy drugs known as the anti-metabolites. Anti-metabolites stop cells from making and repairing DNA, which are processes that are necessary for cancer cells to grow and multiply.

Indications

  • For the treatment of active hairy cell leukemia (leukemic reticuloendotheliosis) as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms. Also used as an alternative agent for the treatment of chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin’s lymphoma, and cutaneous T-cell lymphoma.
  • Treatment of adult patients with highly active relapsing multiple sclerosis (MS) as defined by clinical or imaging features.
  • Litak is indicated for the treatment of hairy-cell leukemia.
  • Multiple Sclerosis
  • Chronic Lymphocytic Leukemia (CLL)
  • Cutaneous T Cell Lymphomas (CTCL)
  • Hairy Cell Leukemia (HCL)
  • Non-Hodgkin’s Lymphoma (NHL)
  • Active confirmed by clinical features, confirmed by imaging features relapsing multiple sclerosis (MS)

Use in Cancer

Cladribine is approved to treat:

Cladribine is also being studied in the treatment of other types of cancer.

Contraindications

  • hepatic cirrhosis,
  • chronic kidney disease,
  • active malignancy,
  • HIV, or tuberculosis.
  • Other contraindications to cladribine include a history of use of other immunosuppressants, including cyclophosphamide, azathioprine, methotrexate, or mitoxantrone.
  • Sexually active men and women should receive counseling about cladribine’s teratogenicity and its effects on sperm quality and viability.
  • a bad infection
  • decreased function of bone marrow
  • anemia
  • a reduction in the body’s resistance to infection
  • decreased function of bone marrow
  • anemia
  • a decreased number of lymphocytes in the blood
  • inflammation of the liver called hepatitis
  • severe liver disease
  • decreased kidney function
  • abnormal liver function tests
  • decreased blood platelets
  • low levels of a type of white blood cell called neutrophils
  • a painful condition that affects the nerves in the legs and arms called peripheral neuropathy
  • severe liver disease
  • the high amount of uric acid in the blood
  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • progressive multifocal leukoencephalopathy, a type of brain infection
  • chronic kidney disease stage 3A (moderate)
  • chronic kidney disease stage 3B (moderate)
  • chronic kidney disease stage 4 (severe)
  • chronic kidney disease stage 5 (failure)
  • Child-Pugh class B liver impairment
  • Child-Pugh class C liver impairment

Dosage

Strengths: 1 mg/mL; 10 mg

Hairy Cell Leukemia

  • 0.09 mg/kg/day by continuous IV infusion for 7 days

Alternate dosing recommendation:

  • Subcutaneous bolus injection: 0.14 mg/kg/day subcutaneously for 5 consecutive days
  • IV infusion: 0.1 mg/kg/day IV for 7 consecutive days
  • Under certain hematological conditions (e.g., recovery of severe myelosuppression) a small number of patients may require a second cycle and occasionally a third cycle to achieve a stable and prolonged response.

Cladribine for multiple sclerosis is an orally administered drug. The FDA-approved dose is 3.5 mg/kg given over two years, administered as 1.75 mg/kg per year. Two treatment courses are separated by twelve months. The first course is given over four to five consecutive days in the first month, followed by an equivalent dose over four to five consecutive days in the second month.

The second course of cladribine follows twelve months later with the same frequency and dosing. For an adult of average body weight, dosing is estimated at approximately 10 to 20 mg daily for 4 to 5 days. Prescribers need to follow the manufacturer’s specific guidelines for weight-based dosing according to approved federal guidelines of the Risk Evaluation and Mitigation Strategies (REMS) program. Monitoring occurs as described below to assure safe remission of the disease without severe lymphopenia or other adverse events.

Side Effects

The Most Common

  • nausea
  • vomiting
  • diarrhea
  • stomach pain
  • constipation
  • loss of appetite
  • skin rash
  • headache
  • excessive sweating
  • pain, redness, swelling, or sores in the place where the medication was injected
  • pale skin
  • excessive tiredness
  • shortness of breath
  • dizziness
  • fast heartbeat

More Common

  • constipation
  • diarrhea
  • dizziness
  • headache
  • joint pain
  • loss of appetite
  • muscle pain
  • nausea
  • the overall feeling of discomfort or illness
  • sleeping problems
  • unusual tiredness
  • heart problems–swelling, rapid weight gain, feeling short of breath;
  • low blood cell counts–fever, swollen glands, stomach pain, cough, runny nose, joint pain, mouth sores, skin sores or rash, easy bruising, unusual bleeding;
  • liver problems–nausea, vomiting, stomach pain, tiredness, loss of appetite, yellowing of your skin or eyes, dark urine;
  • signs of shingles–flu-like symptoms, tingly or painful blistering rash on one side of your body; or
  • signs of tuberculosis: fever, cough, night sweats, loss of appetite, weight loss, and feeling very tired.
  • low white blood cell counts; or
  • cold symptoms such as stuffy nose, sneezing, and sore throat.

Rare

  • numbness or tingling of the hands or feet
  • pain, swelling, or redness at the site of injection
  • shortness of breath
  • signs of bleeding (e.g., bloody nose, blood in urine, coughing blood, cuts that don’t stop bleeding)
  • skin rash
  • stomach pain
  • sweating, pale skin
  • swelling of feet or lower legs
  • unusually fast heartbeat
  • fever or chills
  • flu-like symptoms (e.g., cough, hoarseness, sore throat, fever or chills)
  • difficulty moving arms or legs
  • shortness of breath
  • signs of bleeding in the stomach (e.g., bloody, black, or tarry stools, spitting up of blood, vomiting blood or material that looks like coffee grounds)
  • signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
  • signs of a severe skin reaction (such as blistering, peeling, a rash covering a large area of the body, a rash that spreads quickly, or a rash combined with fever or discomfort)
  • signs of a skin reaction at the injection site (e.g., red streaks along vein where medication was injected, pain at injection site, redness, or warmth at site of injection)

Drug Interaction

Pregnancy and Lactation

AU TGA pregnancy category: D
US FDA pregnancy category: D

Pregnancy

This drug can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should use effective contraception during therapy and for 6 months after the last dose. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Men being treated with this drug should be advised not to father a child up to 6 months after the last dose.

Lactation

Data in one patient indicates that the drug is rapidly eliminated over 24 hours and undetectable at 48 hours after a dose. It is suggested that breastfeeding be withheld for at least 48 hours after a dose of cladribine and perhaps up to a week,[1,2] although the manufacturers recommend a 7-day (Europe) or 10-day (US) abstinence period. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breast milk.[3] Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.

How should this medicine be used?

Cladribine injection comes as a solution (liquid) to be injected intravenously (into a vein) by a doctor or nurse in a medical facility. It is usually given slowly over 7 days as a continuous intravenous injection.

What special precautions should I follow?

Before receiving cladribine,

  • tell your doctor and pharmacist if you are allergic to cladribine, any other medications, or any of the ingredients in cladribine injection. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: immunosuppressants such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), methotrexate (Rheumatrex), sirolimus (Rapamune), and tacrolimus (Prograf). Your doctor will need to monitor you carefully for side effects. Many other medications may also interact with cladribine, 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 if you have or have ever had liver disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. You should not become pregnant while you are receiving cladribine. If you become pregnant while receiving cladribine, call your doctor. Cladribine may harm the fetus.

References

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf
  2. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/022561Orig1s000SumR.pdf
  3. https://pubchem.ncbi.nlm.nih.gov/compound/Cladribine
  4. https://pubchem.ncbi.nlm.nih.gov/compound/Cladribine-5_-monophosphate-diammonium
  5. https://www.cancer.gov/about-cancer/treatment/drugs/cladribine
  6. https://www.medbroadcast.com/drug/getdrug/cladribine-for-injection
  7. https://go.drugbank.com/drugs/DB00242
  8. https://en.wikipedia.org/wiki/Cladribine
  9. https://medlineplus.gov/druginfo/meds/a693015.htm
  10. https://www.ncbi.nlm.nih.gov/books/NBK545307/
  11. https://www.drugs.com/mtm/cladribine.html
  12. ChemIDplus Chemical Information Classification
  13. CompTox Chemicals Dashboard Chemical Lists
  14. (2R,3S,5R)-5-(6-Amino-2-chloropurin-9-yl)-2-(hydroxymethyl)oxalan-3-ol
    (2R,3S,5R)-5-(6-Amino-2-chloropurin-9-yl)-2-(hydroxymethyl)oxalan-3-ol
  15. NCI Thesaurus Tree
  16. NORMAN Suspect List Exchange Classification
  17. LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
  18. PubChem
  19. 2-CHLORO-2′-DEOXYADENOSINE
    2-CHLORO-2′-DEOXYADENOSINE
    2-CHLORO-9-(2-DEOXY-BETA-L-ERYTHRO-PENTOFURANOSYL)-ADENINE
  20. Therapeutic category of drugs in Japan
    Anatomical Therapeutic Chemical (ATC) classification
    Target-based classification of drugs
  21. NCBI