Usage
Cladribine is prescribed for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting disease and active secondary progressive disease, in adults who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS. It is also used to treat hairy cell leukemia.
It’s classified as an antineoplastic antimetabolite, specifically a purine nucleoside analogue.
Cladribine’s mechanism of action involves becoming phosphorylated intracellularly to its active triphosphate metabolite. This metabolite incorporates into DNA, leading to DNA strand breaks and inhibition of DNA synthesis, ultimately causing cell death, primarily targeting lymphocytes.
Alternate Names
Cladribine is also known as 2-chlorodeoxyadenosine (2-CdA). Brand names include Mavenclad (for MS) and Leustatin (for hairy cell leukemia).
How It Works
Pharmacodynamics: Cladribine’s primary effect is inducing cell death in rapidly dividing cells, particularly lymphocytes, thereby suppressing the immune system. This is believed to reduce the immune-mediated attacks that characterize MS relapses.
Pharmacokinetics:
- Absorption: Orally administered cladribine has a bioavailability of approximately 37-55%.
- Metabolism: It is a prodrug activated intracellularly by phosphorylation to its active metabolites, cladribine monophosphate (Cd-AMP), diphosphate (Cd-ADP), and triphosphate (Cd-ATP).
- Elimination: Cladribine and its metabolites are primarily eliminated renally (kidneys), with some non-renal clearance. The terminal half-life is estimated to be around 1 day.
Mode of Action: Cladribine selectively targets lymphocytes due to their high levels of deoxycytidine kinase, the enzyme responsible for phosphorylating cladribine to its active form. Cd-ATP incorporates into DNA, disrupting DNA synthesis and repair mechanisms. This leads to DNA strand breaks and apoptosis (programmed cell death).
Receptor Binding/Enzyme Inhibition: The mechanism of action primarily involves deoxycytidine kinase activation and subsequent DNA incorporation rather than direct receptor binding or specific enzyme inhibition.
Elimination Pathways: Cladribine is eliminated via both renal and non-renal pathways, primarily by active renal tubular secretion. Approximately 50% of clearance is non-renal, involving minimal hepatic metabolism and extensive intracellular distribution within lymphocytes.
Dosage
Standard Dosage
Adults (MS):
The recommended cumulative dose for MS is 3.5 mg/kg body weight over two years, given as 1.75 mg/kg per year. Each yearly course consists of two treatment weeks, one at the beginning of the first and second months of the respective treatment year. Each treatment week involves 4 or 5 days of oral administration, with one or two 10 mg tablets as a single daily dose, depending on body weight (maximum 2 tablets/day).
Adults (Hairy Cell Leukemia):
The usual dose is 0.09 mg/kg/day given by continuous IV infusion for 7 days. Alternative dosing regimens exist.
Children:
Use is not recommended for children with MS. For hairy cell leukemia, safety and efficacy in children haven’t been established.
Special Cases:
- Elderly Patients: Use with caution due to potential age-related decline in organ function.
- Patients with Renal Impairment: Moderate to severe renal impairment (creatinine clearance <60 mL/min): Not recommended for MS. Use with caution for hairy cell leukemia.
- Patients with Hepatic Dysfunction: Moderate to severe hepatic impairment (Child-Pugh >6): Not recommended for MS. Use with caution for hairy cell leukemia.
- Patients with Comorbid Conditions: Evaluate for active chronic infections, prior malignancy, or HIV before initiating treatment.
Clinical Use Cases (Not Applicable for Oral Cladribine in MS):
The clinical use cases listed (intubation, surgical procedures, etc.) are not relevant to oral cladribine used for MS. These scenarios might apply to other medications, particularly those used in critical care settings. Intravenous cladribine formulations used in hairy cell leukemia would also not typically be relevant to these clinical situations.
Dosage Adjustments:
See “Special Cases” above for dosage adjustments based on renal and hepatic function.
Side Effects
Common Side Effects:
Upper respiratory tract infections, headache, nausea, vomiting, diarrhea, skin rash, hair loss, decreased lymphocyte count, fatigue.
Rare but Serious Side Effects:
Progressive multifocal leukoencephalopathy (PML), herpes zoster infections, malignancies (e.g., skin cancer), severe lymphopenia.
Long-Term Effects:
The potential long-term effects of cladribine therapy for MS are still being investigated. Ongoing monitoring for malignancies is crucial.
Adverse Drug Reactions (ADR):
Severe lymphopenia requiring dose modification or interruption, PML, severe infections.
Contraindications
- Pregnancy
- Breastfeeding
- Active malignancy
- Active chronic infection (e.g., tuberculosis, hepatitis)
- HIV infection
- Hypersensitivity to cladribine
Drug Interactions
- Other immunosuppressants (increased risk of infection)
- Live attenuated vaccines (contraindicated)
Pregnancy and Breastfeeding
Cladribine is contraindicated during pregnancy and breastfeeding. Effective contraception must be used during treatment and for 6 months after the last dose. Breastfeeding is contraindicated during treatment and for 10 days (FDA) or 1 week (EMA) after the last dose.
Drug Profile Summary
- Mechanism of Action: Purine nucleoside analogue; incorporates into DNA, leading to DNA strand breaks and cell death, targeting lymphocytes.
- Side Effects: Lymphopenia, infections, rash, nausea, headache. Rarely: PML, malignancies.
- Contraindications: Pregnancy, breastfeeding, active malignancy, active infection, HIV.
- Drug Interactions: Other immunosuppressants, live vaccines.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage (MS): 3.5 mg/kg over 2 years, divided into two treatment courses.
- Monitoring Parameters: Lymphocyte counts, signs of infection, malignancy screening.
Popular Combinations (Limited Data Available for MS):
Cladribine is generally used as monotherapy in MS.
Precautions
- General Precautions: Monitor for infections and malignancies. Complete blood counts and lymphocyte counts should be obtained before, during, and after treatment.
- Specific Populations: See “Dosage - Special Cases” and “Pregnancy and Breastfeeding”.
- Lifestyle Considerations: Patients should be advised about the increased risk of infections and the need to avoid exposure to sick individuals.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Cladribine in MS?
A: 3.5 mg/kg body weight over 2 years, administered as two treatment courses of 1.75 mg/kg each.
Q2: How is Cladribine administered for MS?
A: Orally, as tablets, usually in two treatment weeks per year for two years.
Q3: What are the most common side effects of Cladribine?
A: Upper respiratory infections, lymphopenia, headache, rash, nausea, hair loss.
Q4: What are the serious side effects of Cladribine?
A: Progressive multifocal leukoencephalopathy (PML), malignancies, severe infections.
Q5: Can Cladribine be used during pregnancy or breastfeeding?
A: No, cladribine is contraindicated during pregnancy and breastfeeding.
Q6: How does Cladribine work in multiple sclerosis?
A: It reduces the number of circulating lymphocytes, believed to lessen immune attacks on the nervous system.
Q7: What are the contraindications to using Cladribine?
A: Active malignancy, active serious infection, HIV infection, pregnancy, breastfeeding.
Q8: Does Cladribine interact with other medications?
A: Yes, it can interact with other immunosuppressants, increasing the risk of infection. Live vaccines are contraindicated.
Q9: How long after the last dose of Cladribine can a woman try to conceive?
A: At least 6 months after the last dose.
Q10: What monitoring is needed for patients taking Cladribine?
A: Regular blood counts to monitor lymphocyte levels and check for infections. Regular skin checks and cancer screening guidelines should also be followed.
