Leustatin

See also Warning section.Nausea, vomiting, dizziness, headache, cough, weakness, diarrhea, joint/muscle pain, trouble sleeping, stomach/abdominal pain, constipation, or pain/swelling/redness at injection site may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.People using this medication may have serious side effects. However, your doctor has prescribed this drug because he or she has judged that the benefit to you is greater than the risk of side effects. Careful monitoring by your doctor may decrease your risk.Tell your doctor right away if you have any serious side effects, including: pain/swelling/redness of arms or legs, mental/mood changes, seizures, shortness of breath.A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.Cladribine can commonly cause a mild rash that is usually not serious. However, you may not be able to tell it apart from a rare rash that could be a sign of a severe allergic reaction. Therefore, get medical help right away if you develop any rash.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Cladribine is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting.

Cladribine must be given slowly through an IV infusion, and you will receive it around the clock for 7 days in a row. Your doctor will determine how many 7- day treatments you will receive and how often.

You may receive other medications to help prevent certain side effects of cladribine.

Cladribine can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests. Visit your doctor regularly.

Contact your doctor at once if you develop signs of infection such as fever, chills, sore throat, flu symptoms, cough with yellow or green mucus, loss of appetite, mouth sores, unusual weakness.

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Since this medication is given in a healthcare setting around the clock, you will not miss a dose.

Dosage Forms & Strengths

injectable solution

• 1mg/mL

Hairy Cell Leukemia

0.09 mg/kg/day IV for 7 days continuous infusion; may repeat q28-35Days 

Monitor: CBC, chemistries

Orphan Indications

Multiple Sclerosis

Non-Hodgkin Lymphoma

Acute Myeloid Leukemia

Chronic Lymphocytic Leukemia

Orphan indications sponsor

• Orphan indication sponsor: Ortho Biotech Oncology Research & Development, Unit of J & J Pharmaceutical Research & Dev., LLC; 920 Route 202 South, P.O. Box 300; Raritan, NJ 08869-0602

Other Indications & Uses

Off-label: Cutaneous T-cell lymphoma, AML, CLL, NHL, autoimmune hemolytic anemia, mycosis fungoides, Sezary syndrome

Safety and efficacy not established

Mechanism of Action

Purine analog, impairs DNA repair

Pharmacokinetics

Half-Life: 5.4 hr

Protein bound: 20%

Vd: 4.5 L/kg

Clearance: 978 mL/hr/kg

Excretion: urine

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Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Leustatin, there are no specific foods that you must exclude from your diet when receiving this medication.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child. Avoid pregnancy while prescribed Leustatin.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Tell your caregivers at once if you have a serious side effect such as:

• numbness, tingling, weakness, or burning pain in your fingers or toes;

• numbness or tingly feeling around your mouth;

• a light-headed feeling, like you might pass out;

• redness, swelling, or itching under your skin;

• lower back pain, blood in your urine, urinating less than usual or not at all;

• muscle weakness, tightness, or contraction, overactive reflexes;

• fast or slow heart rate, weak pulse, feeling short of breath;

• pale or yellowed skin, dark colored urine, fever, confusion;

• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin; or

• signs of infection such as fever, chills, sore throat, flu symptoms, cough with yellow or green mucus, loss of appetite, mouth sores, unusual weakness.

Common side effects may include:

• headache, tired feeling;

• nausea, diarrhea, constipation;

• mild itching or skin rash;

• cough; or

• pain, swelling, or irritation around the IV needle.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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.

Cellular Resistance and Sensitivity

The selective toxicity of 2-chloro-2΄-deoxy-β-D-adenosine towards certain normal and malignant lymphocyte and monocyte populations is based on the relative activities of deoxycytidine kinase and deoxynucleotidase. Cladribine passively crosses the cell membrane. In cells with a high ratio of deoxycytidine kinase to deoxynucleotidase, it is phosphorylated by deoxycytidine kinase to 2-chloro-2΄-deoxy- β -D-adenosine monophosphate (2-CdAMP). Since 2-chloro-2΄-deoxy- β -D-adenosine is resistant to deamination by adenosine deaminase and there is little deoxynucleotide deaminase in lymphocytes and monocytes, 2-CdAMP accumulates intracellularly and is subsequently converted into the active triphosphate deoxynucleotide, 2-chloro-2΄-deoxy- β -D-adenosine triphosphate (2-CdATP). It is postulated that cells with high deoxycytidine kinase and low deoxynucleotidase activities will be selectively killed by 2-chloro-2΄-deoxy- β -D-adenosine as toxic deoxynucleotides accumulate intracellularly.

Cells containing high concentrations of deoxynucleotides are unable to properly repair single-strand DNA breaks. The broken ends of DNA activate the enzyme poly (ADP-ribose) polymerase resulting in NAD and ATP depletion and disruption of cellular metabolism. There is evidence, also, that 2-CdATP is incorporated into the DNA of dividing cells, resulting in impairment of DNA synthesis. Thus, 2-chloro-2΄-deoxy- β -D-adenosine can be distinguished from other chemotherapeutic agents affecting purine metabolism in that it is cytotoxic to both actively dividing and quiescent lymphocytes and monocytes, inhibiting both DNA synthesis and repair.

Pharmacokinetics

In a clinical investigation, 17 patients with Hairy Cell Leukemia and normal renal function were treated for 7 days with the recommended treatment regimen of Leustatin Injection (0.09 mg/kg/day) by continuous intravenous infusion. The mean steady-state serum concentration was estimated to be 5.7 ng/mL with an estimated systemic clearance of 663.5 mL/h/kg when Leustatin was given by continuous infusion over 7 days. In Hairy Cell Leukemia patients, there does not appear to be a relationship between serum concentrations and ultimate clinical outcome.

In another study, 8 patients with hematologic malignancies received a two (2) hour infusion of Leustatin Injection (0.12 mg/kg). The mean end-of-infusion plasma Leustatin concentration was 48±19 ng/mL. For 5 of these patients, the disappearance of Leustatin could be described by either a biphasic or triphasic decline. For these patients with normal renal function, the mean terminal half-life was 5.4 hours. Mean values for clearance and steady-state volume of distribution were 978±422 mL/h/kg and 4.5±2.8 L/kg, respectively.

Cladribine plasma concentration after intravenous administration declines multi-exponentially with an average half-life of 6.7 +/- 2.5 hours. In general, the apparent volume of distribution of cladribine is approximately 9 L/kg, indicating an extensive distribution in body tissues.

Cladribine penetrates into cerebrospinal fluid. One report indicates that concentrations are approximately 25% of those in plasma.

Leustatin is bound approximately 20% to plasma proteins.

Except for some understanding of the mechanism of cellular toxicity, no other information is available on the metabolism of Leustatin in humans. An average of 18% of the administered dose has been reported to be excreted in urine of patients with solid tumors during a 5-day continuous intravenous infusion of 3.5–8.1 mg/m2/day of Leustatin. The effect of renal and hepatic impairment on the elimination of cladribine has not been investigated in humans.

Leustatin Injection is indicated for the treatment of active Hairy Cell Leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia or disease-related symptoms.