Clofarabin-Teva (Concentrate) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

S.C. Sindan-Pharma S.R.L. (Romania)

ATC Code

L01BB06 (Clofarabine)

Active Substance

Clofarabine (Rec.INN registered by WHO)

Dosage Form

Clofarabine-Teva

Concentrate for solution for infusion 1 mg/ml: 20 ml vial 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion in the form of a clear, colorless liquid.

Excipients: sodium chloride – 9 mg, water for injections – up to 1 ml, hydrochloric acid 0.1M – to pH 4.8±0.3.

20 ml – vial (1) – cardboard package.

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Antitumor agent, antimetabolite from the group of purine antagonists.

The action of clofarabine is due to 3 mechanisms

• Inhibition of DNA polymerase α, leading to cessation of DNA chain elongation and/or DNA synthesis/repair;
• Inhibition of ribonucleotide reductase with depletion of the cellular pool of deoxynucleotidetriphosphate (dNTP);
• Disruption of mitochondrial membrane integrity with release of cytochrome C and other apoptosis factors, leading to programmed cell death even in non-dividing lymphocytes.

Clofarabine first diffuses or is transported into target cells, where it is sequentially phosphorylated by intracellular kinases to mono- and diphosphate, after which the active conjugate, Clofarabine 5′-triphosphate, is formed. Clofarabine has a high affinity for one of the enzymes activating phosphorylation – deoxycytidine kinase, which exceeds the affinity of the natural substrate of deoxycytidine kinase – deoxycytidine.

Furthermore, Clofarabine has higher resistance to degradation in cells under the influence of adenosine deaminase and reduced sensitivity to phosphorolytic cleavage, compared to other active substances of the same class, while the degree of affinity of clofarabine triphosphate for DNA polymerase α and ribonucleotide reductase is equal to or exceeds that of deoxyadenosine triphosphate.

In vitro studies have shown that Clofarabine slows cell growth and exerts a cytotoxic effect on many rapidly proliferating cell lines in hematopoietic tumors and solid tumors. Clofarabine also exhibited activity against resting lymphocytes and macrophages. Furthermore, Clofarabine slowed tumor growth and, in some cases, caused regression of a number of human and murine tumor xenografts implanted in mice.

Pharmacokinetics

V_d (at steady state) is 172 L/m². Plasma protein binding is 47.1%, serum albumin binding is 27.0%. T_1/2 of clofarabine is 5.2 h, T_1/2 of clofarabine triphosphate (a metabolite of clofarabine) is more than 24 h. Total clearance – 28.8 L/h/m² renal clearance – 10.8 L/h/m.

Clofarabine is eliminated by both renal and non-renal routes. Approximately 60% of the administered dose of clofarabine is excreted unchanged by the kidneys within 24 hours. The clearance of clofarabine significantly exceeds the glomerular filtration rate, indicating that the main mechanisms of renal elimination are not only glomerular filtration but also tubular secretion. However, since Clofarabine is practically not metabolized by CYP450 isoenzymes, the non-renal excretion pathways currently remain unknown.

Indications

Treatment of acute lymphoblastic leukemia in children over 1 year of age with relapse or refractoriness to therapy after at least two prior chemotherapy regimens and in the absence of other means to achieve sustained remission.

ICD codes

Dosage Regimen

Administer this medication under the supervision of a physician experienced in the treatment of acute leukemias.

Prepare the solution for intravenous infusion using aseptic technique. Dilute the calculated dose in 0.9% sodium chloride injection solution prior to administration.

Infuse the total daily dose intravenously over two hours. Do not administer as a bolus or rapid intravenous injection.

The recommended dosage is 52 mg/m² of body surface area once daily for five consecutive days.

Repeat treatment cycles following a recovery period of two to six weeks, contingent upon the return of adequate non-hematologic organ function and hematologic recovery.

Initiate subsequent cycles only when the ANC is ≥ 0.75 x 10⁹/L and the platelet count is ≥ 50 x 10⁹/L.

Adjust the dosage based on the severity of non-hematologic toxicity. For Grade 3 or higher non-hematologic toxicity, except for nausea and vomiting, withhold the drug.

Resume treatment, typically at a 25% dose reduction, upon resolution of the adverse reaction to Grade 1 or lower.

Discontinue treatment permanently in patients experiencing life-threatening or disabling non-infectious non-hematologic toxicity.

For patients with prolonged Grade 4 neutropenia lasting more than four weeks, reduce the dose by 25% for the next cycle.

Provide adequate intravenous hydration throughout the five-day treatment period to reduce the risk of tumor lysis syndrome and other renal complications.

Consider prophylactic antiemetics and corticosteroids to mitigate potential adverse effects.

Adverse Reactions

Infections and parasitic diseases: septic shock, sepsis, bacteremia, herpes zoster, herpes simplex, oral candidiasis, Clostridium difficile colitis.

Benign, malignant and unspecified neoplasms (including cysts and polyps): tumor lysis syndrome.

From the hematopoietic system: febrile neutropenia, neutropenia.

Allergic reactions: hypersensitivity.

From metabolism dehydration, hyponatremia.

Mental disorders: anxiety, agitation, restlessness, changes in mental status.

From the nervous system headache, drowsiness, peripheral neuropathy, paresthesia, dizziness, tremor.

From the hearing organ: hypoacusis.

From the cardiovascular system: pericardial effusion, tachycardia, flushing, arterial hypotension; capillary leak syndrome.

From the respiratory system: respiratory distress syndrome, epistaxis, dyspnea, tachypnea, cough, pneumonia.

From the digestive system anorexia, decreased appetite, nausea, vomiting, stomatitis, oral mucosal ulcers, mouth bleeding, gum bleeding, hematemesis, abdominal pain, epigastric pain, diarrhea, proctalgia, increased serum amylase and lipase activity against the background of pancreatitis, enterocolitis (including neutropenic colitis, typhlitis and Clostridium difficile colitis), hyperbilirubinemia, jaundice, increased ALT and AST activity.

From the urinary system hematuria.

From the skin and subcutaneous tissues: palmar-plantar erythrodysesthesia syndrome, pruritus, maculopapular rash, petechiae, erythema, pruritic rash, desquamation, generalized rash, alopecia, generalized erythema, skin hyperpigmentation, erythematous rash, dry skin, hyperhidrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the musculoskeletal system: limb pain, myalgia, bone pain, chest pain, arthralgia, neck and back pain.

Other increased fatigue, irritability, pyrexia, chills, mucosal inflammation, multi-organ failure, systemic inflammatory response syndrome, pain, edema, peripheral edema, feeling hot, malaise, veno-occlusive disease, hematomas, weight loss, contusions.

Contraindications

Severe renal failure; severe hepatic failure; pregnancy; lactation (breastfeeding); children under 1 year of age (lack of data on safety and efficacy of clofarabine use in this age group); hypersensitivity to clofarabine.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Since the effect of clofarabine on human reproductive function is unknown, planning for conception should be discussed with patients on a case-by-case basis.

Women of reproductive age and men who are sexually active should use reliable methods of contraception during treatment. Since it is unknown whether clofarabine therapy affects human fertility, patients should be advised, if necessary, to consider sperm or egg cryopreservation before starting a course of clofarabine treatment.

Use in Hepatic Impairment

The drug should be used with caution in patients with mild or moderate hepatic impairment.

Contraindicated for use in patients with severe hepatic impairment.

Use in Renal Impairment

The drug should be used with caution in patients with mild or moderate renal impairment.

Contraindicated for use in patients with severe renal impairment.

Pediatric Use

Contraindicated for use in children under 1 year of age (lack of data on safety and efficacy of clofarabine use in this age group).

Geriatric Use

Currently, there are insufficient data on the efficacy and safety of clofarabine in adult patients over 21 years of age (including elderly patients).

Special Precautions

With caution: mild or moderate renal failure; mild or moderate hepatic failure; history of hematopoietic stem cell transplantation.

During treatment, the following should be carefully monitored

• Complete blood count with platelet count on a regular basis; in patients who develop cytopenias, these tests should be repeated more frequently;
• Renal and liver function before treatment, during active treatment, and after treatment; with a significant increase in creatinine or bilirubin concentration, clofarabine treatment should be immediately discontinued;
• Respiratory function, blood pressure, fluid and electrolyte balance, and body weight during and immediately after completion of the 5-day clofarabine therapy.

Suppression of bone marrow function should be expected, which is generally reversible and dose-dependent. Severe bone marrow suppression, including neutropenia, anemia, and thrombocytopenia, has been observed in patients treated with clofarabine. Furthermore, in clinical studies, most patients had hematological abnormalities at the start of treatment, which are manifestations of leukemia. Due to pre-existing immunodeficiency and prolonged neutropenia that may develop during clofarabine treatment, patients are at risk of developing severe concomitant infections, including sepsis with a potentially fatal outcome. Patients should be constantly monitored for signs and symptoms of infection and appropriate therapy should be administered.

Cases of enterocolitis, including neutropenic colitis, typhlitis, and Clostridium difficile colitis, have been reported during clofarabine treatment, most often developing within 30 days of starting treatment and with the use of combination chemotherapy. These conditions can lead to complications such as necrosis, intestinal perforation, or sepsis, which can be fatal. Therefore, patients should be monitored for timely detection of symptoms and signs of enterocolitis.

The development of Stevens-Johnson syndrome and toxic epidermal necrolysis, including fatal cases, has been reported with the use of clofarabine. If exfoliative or bullous rash develops or if Stevens-Johnson syndrome and toxic epidermal necrolysis are suspected, clofarabine therapy should be discontinued. The use of clofarabine leads to a rapid decrease in the number of peripheral leukemic cells. Patients receiving clofarabine therapy should be constantly monitored for the occurrence of manifestations and symptoms of tumor lysis syndrome and cytokine release (such as tachypnea, tachycardia, arterial hypotension, pulmonary edema), which can lead to the development of systemic inflammatory response syndrome (SIRS), capillary leak syndrome and/or organ dysfunction.

In anticipation of the development of hyperuricemia (occurring in tumor lysis syndrome), the prophylactic use of allopurinol should be considered.

Patients require intravenous fluid administration throughout the entire 5-day period of clofarabine treatment to reduce the effects of tumor lysis and other complications.

Prophylactic use of corticosteroids (e.g., 100 mg/m² hydrocortisone from day 1 to day 3 of the clofarabine therapy cycle) may be useful to prevent the development of SIRS or capillary leak syndrome.

If early signs of SIRS, capillary leak syndrome, or severe organ dysfunction appear, clofarabine administration should be immediately discontinued and treatment for these severe complications should be initiated. Furthermore, clofarabine treatment should be discontinued in case of decreased blood pressure for any reason during the 5-day drug administration period. After the patient’s condition stabilizes and organ function returns to baseline, resumption of clofarabine therapy can be considered, usually at a lower dose.

Patients with heart disease or those taking medications that affect blood pressure or heart function should be under constant medical supervision during clofarabine therapy.

Patients receiving Clofarabine may experience vomiting and diarrhea, so patients should be warned about appropriate measures to prevent dehydration. Patients should be instructed to seek medical attention if they experience dizziness, lightheadedness, fainting, or decreased urine output. The prophylactic use of antiemetic drugs should be considered.

There is no experience with the use of clofarabine in patients with impaired liver function (with serum bilirubin concentration >1.5×ULN in combination with increased AST and ALT activity >5×ULN), however, the liver is a target organ for clofarabine toxicity. In this regard, Clofarabine should be used with caution in mild and moderate hepatic impairment. Concomitant use of hepatotoxic drugs should be avoided if possible. If a patient develops hematological toxicity in the form of grade 4 neutropenia (ANC < 0.5×10⁹/L) lasting > 4 weeks, the dose of clofarabine should be reduced by 25% in the next cycle.

All patients who developed severe non-hematological toxicity (grade 3 according to US NCI CTC) in the third cycle, severe toxicity that lasted more than 14 days (except for nausea and vomiting), or life-threatening or disabling non-infectious non-hematological toxicity (grade 4 according to US NCI CTC) should discontinue clofarabine treatment.

Patients with a prior history of hematopoietic stem cell transplantation may be at higher risk of hepatotoxicity in the form of veno-occlusive disease after treatment with clofarabine (40 mg/m²) in combination with etoposide (100 mg/m²) and cyclophosphamide (440 mg/m²). Adverse reactions of serious hepatotoxicity in the form of veno-occlusive disease, which could be fatal, have been observed in children and adult patients (see section “Adverse Reactions”). In a phase I/II study of combination therapy with clofarabine in pediatric patients with relapsed or refractory acute leukemia, severe hepatotoxic complications were observed.

Effect on ability to drive vehicles and operate machinery

Adverse effects (dizziness, lightheadedness, fainting) may develop during treatment; if the described adverse reactions occur, one should not drive vehicles or operate machinery.

Drug Interactions

Inhibitors or inducers of CYP isoenzymes – interaction is unlikely, since Clofarabine is practically not metabolized by the cytochrome P450 enzyme system. Furthermore, it is unlikely that Clofarabine can inhibit any of the 5 major CYP isoenzymes (1A2, 2C9, 2C19, 2D6 and 3A4) or induce two of these isoenzymes (1A2 and 3A4) at plasma concentrations achieved after intravenous infusion at a dose of 52 mg/m²/day. Thus, Clofarabine is not expected to affect the metabolism of active substances that are substrates of these isoenzymes.

Drugs with nephrotoxic effects and eliminated by tubular secretion, such as NSAIDs, amphotericin B, methotrexate, aminoglycosides, platinum drugs, sodium foscarnet, pentamidine, cyclosporine, tacrolimus, acyclovir and valganciclovir – concomitant use should be avoided, especially during the 5-day period of clofarabine administration, since Clofarabine is eliminated mainly by the kidneys.

Drugs with hepatotoxic effects – concomitant use should be avoided, since the liver is a potential target organ for the manifestation of cytotoxic action.

Medications affecting blood pressure or heart function – patients should be carefully monitored.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.