Cladribine

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

This medicine can pass into body fluids (urine, feces, vomit). For at least 48 hours after you receive a dose, avoid allowing your body fluids to come into contact with your hands or other surfaces. Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Do not receive a "live" vaccine while using cladribine, and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you. Live vaccines include measles, mumps, rubella (MMR), rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with cladribine, especially drugs that weaken immune system such as:

• any other cancer medication;
• steroids; or
• medicines to prevent organ transplant rejection.

This list is not complete and other drugs may interact with cladribine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Cladribine is a prescription medication used to treat hairy cell leukemia, a type of white blood cell cancer.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Cladribine may be found in some form under the following brand names:

• Leustatin

Cladribine is used to treat hairy cell leukemia (a type of blood cancer).

Cladribine can lower blood cells that help your body fight infections and help your blood to clot. You may get an infection or bleed more easily. Call your doctor if you have unusual bruising or bleeding, or signs of infection (fever, chills, body aches).

Tell your caregivers at once if you have a side effect such as numbness or tingling, weakness or burning pain in your fingers or toes, or feeling like you might pass out.

Storage

Parenteral

2–8°C; protect from light.a

Following dilution, refrigerate at 2–8°C for no more than 8 hours before administration.a

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Shortness of breath.
• Very loose stools (diarrhea).
• Very upset stomach or throwing up.
• Feeling very tired or weak.
• Very bad irritation where the shot was given.
• Patients with cancer who take cladribine may be at a greater risk of getting a bad health problem called tumor lysis syndrome (TLS). Sometimes, this has been deadly. Call your doctor right away if you have a fast heartbeat or a heartbeat that does not feel normal; any passing out; trouble passing urine; muscle weakness or cramps; upset stomach, throwing up, loose stools, or not able to eat; or feel sluggish.

Clinical Trials Experience

Adverse drug reactions reported by ≥ 1% of Cladribine-treated patients with HCL noted in the HCL clinical dataset (studies K90-091 and L91-048, n=576) are shown in the table below.

                                                                  Adverse Drug Reactions in ≥ 1% of Patients Treated with Cladribine in HCL Clinical Trials

*       Dyspnea includes dyspnea, dyspnea exertional, and wheezing

**     Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain (lower and upper)

***    Rash includes erythema, rash, and rash (macular, macula-papular, papular, pruritic, pustular and erythematous)

****  Pain includes pain, back pain, chest pain, arthritis pain, bone pain, and pain in extremity

*****Administration site reaction includes administration site reaction, catheter site (cellulitis, erythema, hemorrhage, and pain), and infusion site reaction (erythema, edema, and pain)

The following safety data are based on 196 patients with Hairy Cell Leukemia: the original cohort of 124 patients plus an additional 72 patients enrolled at the same two centers after the original enrollment cutoff.  In Month 1 of the Hairy Cell Leukemia clinical trials, severe neutropenia was noted in 70% of patients, fever in 69%, and infection was documented in 28%.  Most non-hematologic adverse experiences were mild to moderate in severity.

Myelosuppression was frequently observed during the first month after starting treatment.  Neutropenia (ANC < 500 x 106/L) was noted in 70% of patients, compared with 26% in whom it was present initially.  Severe anemia (Hemoglobin < 8.5 g/dL) developed in 37% of patients, compared with 10% initially and thrombocytopenia (Platelets < 20 x 109/L) developed in 12% of patients, compared to 4% in whom it was noted initially.

During the first month, 54 of 196 patients (28%) exhibited documented evidence of infection.  Serious infections (e.g., septicemia, pneumonia) were reported in 6% of all patients; the remainder were mild or moderate.  Several deaths were attributable to infection and/or complications related to the underlying disease.  During the second month, the overall rate of documented infection was 6%; these infections were mild to moderate and no severe systemic infections were seen.  After the third month, the monthly incidence of infection was either less than or equal to that of the months immediately preceding Cladribine therapy.

During the first month, 11% of patients experienced severe fever (i.e., ≥ 104°F).  Documented infections were noted in fewer than one-third of febrile episodes.  Of the 196 patients studied, 19 were noted to have a documented infection in the month prior to treatment.  In the month following treatment, there were 54 episodes of documented infection: 23 (42%) were bacterial, 11 (20%) were viral and 11 (20%) were fungal.  Seven (7) of 8 documented episodes of herpes zoster occurred during the month following treatment.  Fourteen (14) of 16 episodes of documented fungal infections occurred in the first two months following treatment.  Virtually all of these patients were treated empirically with antibiotics (see WARNINGS and PRECAUTIONS).

Analysis of lymphocyte subsets indicates that treatment with Cladribine is associated with prolonged depression of the CD4 counts.  Prior to treatment, the mean CD4 count was 766/μL.  The mean CD4 count nadir, which occurred four to six months following treatment, was 272/μL.  Fifteen (15) months after treatment, mean CD4 counts remained below 500/μL.  CD8 counts behaved similarly, though increasing counts were observed after nine months.  The clinical significance of the prolonged CD4 lymphopenia is unclear.

Another event of unknown clinical significance includes the observation of prolonged bone marrow hypocellularity.  Bone marrow cellularity of < 35% was noted after four months in 42 of 124 patients (34%) treated in the two pivotal trials.  This hypocellularity was noted as late as Day 1,010.  It is not known whether the hypocellularity is the result of disease related marrow fibrosis or if it is the result of Cladribine toxicity.  There was no apparent clinical effect on the peripheral blood counts.

The vast majority of rashes were mild.  Most episodes of nausea were mild, not accompanied by vomiting, and did not require treatment with antiemetics.  In patients requiring antiemetics, nausea was easily controlled, most frequently with chlorpromazine.

When used in other clinical settings the following ADRs were reported: bacteremia, cellulitis, localized infection, pneumonia, anemia, thrombocytopenia (with bleeding or petechiae), phlebitis, purpura, crepitations, localized edema and edema. 

For a description of adverse reactions associated with use of high doses in non-Hairy Cell Leukemia patients, see WARNINGS.

Postmarketing Experience

The following additional adverse reactions have been reported since the drug became commercially available.  These adverse reactions have been reported primarily in patients who received multiple courses of Cladribine injection:

Infections and infestations: Septic shock.  Opportunistic infections have occurred in the acute phase of treatment.

Blood and lymphatic system disorders: Bone marrow suppression with prolonged pancytopenia, including some reports of aplastic anemia; hemolytic anemia (including autoimmune hemolytic anemia), which was reported in patients with lymphoid malignancies, occurring within the first few weeks following treatment.  Rare cases of myelodysplastic syndrome have been reported.

Immune system disorders: Hypersensitivity.

Metabolism and nutrition disorders: Tumor lysis syndrome.

Psychiatric disorders: Confusion (including disorientation).

Hepatobiliary disorders: Reversible, generally mild increases in bilirubin (uncommon) and transaminases.

Nervous System disorders: Depressed level of consciousness, neurological toxicity (including peripheral sensory neuropathy, motor neuropathy (paralysis), polyneuropathy, paraparesis); however, severe neurotoxicity has been reported rarely following treatment with standard Cladribine dosing regimens.

Eye disorders: Conjunctivitis.

Respiratory, thoracic and mediastinal disorders: Pulmonary interstitial infiltrates (including lung infiltration, interstitial lung disease, pneumonitis and pulmonary fibrosis); in most cases, an infectious etiology was identified.

Skin and tissue disorders: Urticaria, hypereosinophilia; Stevens-Johnson.  In isolated cases toxic epidermal necrolysis has been reported in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause these syndromes.

Renal and urinary disorders: Renal failure (including renal failure acute, renal impairment).

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Generic: 10 mg/10 mL (10 mL)

Hypersensitivity to cladribine or any component of the formulation

Refer to adult dosing.

Acute myeloid leukemia (off-label use): IV: 8.9 mg/m2/day continuous infusion for 5 days for 1 or 2 courses (Krance, 2001) or 9 mg/m2/day over 30 minutes for 5 days for 1 course (in combination with cytarabine) (Crews, 2002; Rubnitz, 2009)

Langerhans cell histiocytosis, refractory (off-label use): IV: 5 mg/m2/day over 2 hours for 5 days every 21 days for up to 6 cycles (Weitzman, 2009)

No dosage adjustment provided in the manufacturer’s labeling (due to inadequate data); use with caution. The following adjustments have been used (Aronoff, 2007):

Adults:

CrCl 10-50 mL/minute: Administer 75% of dose

CrCl <10 mL/minute: Administer 50% of dose

Continuous ambulatory peritoneal dialysis (CAPD): Administer 50% of dose

Children:

CrCl 10-50 mL/minute: Administer 50% of dose

CrCl <10 mL/minute: Administer 30% of dose

Hemodialysis: Administer 30% of dose

Continuous renal replacement therapy (CRRT): Administer 50% of dose

A precipitate may develop at low temperatures and may be resolubilized at room temperature or by shaking the solution vigorously. Inadvertent freezing does not affect the solution; if freezing occurs prior to dilution, allow to thaw naturally; do not heat or microwave; do not refreeze.

To prepare a 24-hour continuous infusion: Dilute in 500 mL NS. The manufacturer recommends filtering with a 0.22 micron hydrophilic syringe filter prior to adding to infusion bag.

To prepare a 7-day continuous infusion: Dilute to a total volume of 100 mL in a CADD medication cassette reservoir using bacteriostatic NS. Filter diluent and cladribine with a 0.22 micron hydrophilic filter prior to adding to cassette/reservoir.

Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light. A precipitate may develop at low temperatures and may be resolubilized at room temperature or by shaking the solution vigorously. Inadvertent freezing does not affect the solution; if freezing occurs prior to dilution, allow to thaw naturally prior to reconstitution; do not heat or microwave; do not refreeze.

24-hour continuous infusion: Dilutions in NS for infusion should be used promptly; if not used promptly, the 24-hour infusion may be stored refrigerated for up to 8 hours prior to administration.

7-day continuous infusion: Dilutions in NS for infusion should be used promptly; if not used promptly, the 7-day infusion may be stored refrigerated for up to 8 hours prior to administration. Reconstituted solution is stable for 7 days (when diluted in bacteriostatic NS) in a CADD® medication cassette reservoir. For patients weighing >85 kg, the effectiveness of the preservative in the bacteriostatic diluent may be reduced (due to dilution).

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

AU: Use is contraindicated. UK, US: A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Data not available Comment: -Because this drug may be excreted into human milk in human milk and because there is potential for serious adverse reactions in nursing infants, breastfeeding should not be undertaken during treatment and for 6 months after the last dose.