LEUKERAN

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEUKERAN™ (LEUKERAN™)

Composition:

Active substance: chlorambucil;

1 tablet contains 2 mg of chlorambucil;

Excipients: anhydrous lactose, microcrystalline cellulose, anhydrous colloidal silicon dioxide, stearic acid;

Coating: Opadry® Brown 05B26836: hypromellose, titanium dioxide (E 171), polyethylene glycol 400, iron oxide yellow (E 172), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: brown, round, biconvex film-coated tablets, marked with “L” on one side and “GX EG3” on the other.

Pharmacotherapeutic group. Antineoplastic agents. Alkylating agents.

ATC code L01A A02.

Pharmacological Properties

Pharmacodynamics

Chlorambucil is an aromatic derivative of nitrogen mustard that acts as a bifunctional alkylating agent. In addition to interfering with DNA replication, chlorambucil induces cell apoptosis through accumulation of cytosolic p53 and subsequent activation of the apoptosis promoter (Bax).

The cytotoxic effect of chlorambucil is attributed to the compound itself and its primary metabolite, phenylacetic acid mustard (see section "Pharmacokinetics").

Mechanism of resistance. Chlorambucil is an aromatic derivative of nitrogen mustard. Resistance to nitrogen mustards has been reported to result from alterations in the transport of these compounds and their metabolites by multidrug resistance proteins, in the kinetics of DNA cross-link formation by these agents, and in apoptosis and DNA repair processes. Chlorambucil is not a substrate for multidrug resistance protein 1 (MRP1 or ABCC1), but its glutathione conjugates are substrates for MRP1 (ABCC1) and MRP2 (ABCC2).

Pharmacokinetics

Absorption

Chlorambucil is well absorbed via passive diffusion in the gastrointestinal tract and can be detected in the blood within 15–30 minutes after administration. The bioavailability of chlorambucil following oral administration is approximately 70–100% when a single dose of 10–200 mg is administered. In a study involving 12 patients who received chlorambucil orally at a dose of approximately 0.2 mg/kg, dose-normalized maximum plasma concentration (492±160 ng/mL) was observed within 0.25–2 hours after dosing.

Inter-individual variability in chlorambucil pharmacokinetics in plasma was relatively low after oral administration of 15–70 mg, consistent with its rapid and predictable absorption (the AUC range varied 2-fold within inter-individual variability and 2–4-fold within inter-individual variability).

Absorption of chlorambucil is delayed when administered after food intake. In a study involving 10 patients, food intake resulted in an increase in the mean time to reach Cmax by more than 100%, a reduction in maximum plasma concentration by more than 50%, and a decrease in mean AUC(0-∞) by approximately 27% (see section "Administration and Dosage").

Distribution

The volume of distribution of chlorambucil is approximately 0.14–0.24 L/kg. Chlorambucil covalently binds to plasma proteins, primarily to albumin (98%), and also covalently binds to erythrocytes.

Metabolism

Chlorambucil is extensively metabolized in the liver via monochloroethylation and β-oxidation, forming the primary metabolite phenylacetic acid mustard (PAM), which exhibits alkylating activity, as demonstrated in animal studies. Chlorambucil and PAM are degraded in vivo to form mono- and dihydroxy derivatives. Additionally, chlorambucil reacts with glutathione, forming mono- and diglutathione conjugates of chlorambucil.

After oral administration of approximately 0.2 mg/kg chlorambucil, PAM was detected in plasma within 15 minutes in some patients, and dose-normalized maximum plasma concentration (Cmax) of 306±73 ng/mL was observed within 1–3 hours.

Elimination

The elimination half-life in the terminal phase is 1.3 to 1.5 hours for chlorambucil and approximately 1.8 hours for PAM. The extent of unchanged excretion of chlorambucil and PAM in urine is very low; less than 1% of the administered dose of each compound is excreted in urine within 24 hours. The remainder of the dose is typically excreted in the form of mono- and dihydroxy derivatives.

Clinical characteristics.

Indications.

Hodgkin's disease, certain forms of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Waldenström's macroglobulinemia.

Contraindications.

Use of the medicinal product in the treatment of patients with benign neoplasms.

Hypersensitivity to chlorambucil or to any of the excipients.

Possible cross-sensitivity reactions between chlorambucil and other alkylating agents. Do not use in patients who have shown resistance to the drug during prior treatment.

Special precautions.

Leukeran™ film-coated tablets should be handled in accordance with guidelines for handling cytotoxic agents according to current local recommendations and/or regulatory requirements.

Pregnant healthcare workers should not handle cytotoxic agents.

Risk when handling Leukeran™ film-coated tablets is absent provided the tablet coating remains intact. Leukeran™ film-coated tablets should not be divided.

Interaction with other medicinal products and other forms of interactions.

Vaccination with live vaccines is not recommended in immunocompromised patients (see section "Special instructions for use").

Purine nucleoside analogs (such as fludarabine, pentostatin, and cladribine) have been shown to enhance chlorambucil cytotoxicity ex vivo.

Clinically, combination therapy using purine nucleoside analogs together with alkylating agents has demonstrated greater clinical response, but also a higher incidence of hematotoxic effects. Animal studies have shown that patients receiving phenylbutazone should have standard doses of Leukeran™ reduced due to the potential for increased toxicity.

Special precautions for use.

Since immunization with live vaccines may potentially lead to infectious complications in immunocompromised patients, it is not recommended.

Chlorambucil should not be administered for prolonged periods to patients who may potentially undergo autologous stem cell transplantation.

Monitoring

Since LEUKERAN™ may cause irreversible bone marrow suppression, careful monitoring of blood counts is required throughout the entire treatment period. Administration of a cumulative dose of approximately 6.5 mg/kg body weight is associated with a risk of irreversible bone marrow damage.

At therapeutic doses, LEUKERAN™ causes suppression of lymphocytosis and a more moderate, although progressive, effect on neutrophils, platelets, and hemoglobin levels. Discontinuation of LEUKERAN™ is not necessary at the first signs of neutrophil reduction; however, it should be noted that this reduction may continue for 10 days or more after the last dose.

LEUKERAN™ should not be administered to patients who have undergone radiation therapy or received other cytotoxic agents within the previous 4 weeks.

LEUKERAN™ should be used with particular caution in patients with impaired bone marrow function or lymphocytic infiltration of the bone marrow. In the presence of lymphocytic bone marrow infiltration or in cases of bone marrow hypoplasia, the daily dose should not exceed 0.1 mg/kg body weight.

Rare cases of skin rashes have been reported, with possible progression to erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson syndrome. LEUKERAN™ should be discontinued immediately in patients who develop skin-related adverse reactions.

Pediatric patients with nephrotic syndrome, those receiving high-dose pulse therapy, and those with a history of epileptic seizures require particularly close monitoring during LEUKERAN™ treatment, as they are at increased risk of developing seizures.

Patients should be informed that the main toxicities of chlorambucil may manifest as hypersensitivity, drug fever, myelosuppression, hepatotoxicity, infertility, seizures, gastrointestinal toxicity, and secondary malignancies. Patients should not use the drug without medical supervision. Patients should also consult a physician if they experience skin rashes, bleeding, fever, jaundice, persistent cough, seizures, nausea, vomiting, amenorrhea, or unusual lumps.

Renal impairment

Patients with signs of renal dysfunction should be closely monitored, as additional myelosuppression associated with azotemia may occur.

Hepatic impairment

The metabolism of LEUKERAN™ is still insufficiently studied; therefore, reduced doses should be administered to patients with severe hepatic impairment.

Mutagenicity and carcinogenicity

Chlorambucil has been shown to cause chromatid and chromosomal damage in humans and has demonstrated carcinogenic properties in animal studies. The potential for such effects should be considered when selecting a long-term treatment regimen.

Cases of secondary acute hematological malignancies (particularly leukemia and myelodysplastic syndrome) have been reported, primarily after prolonged treatment (see section "Adverse reactions").

Comparative data on the course of disease in women with ovarian cancer who received alkylating agents versus those who did not show that the use of alkylating agents, including chlorambucil, significantly increases the incidence of acute leukemias. Cases of acute myeloid leukemia have been reported in a small number of patients treated with LEUKERAN™ as long-term adjuvant therapy for breast cancer.

When prescribing LEUKERAN™, the risk of leukemia development should be weighed against the potential beneficial effects of the drug.

Fertility

LEUKERAN™ may cause ovarian function suppression; cases of amenorrhea following treatment have been reported. High rates of sterility in males have been documented following treatment with the drug during prepubertal and pubertal periods. Azoospermia has been observed in adult males treated with LEUKERAN™; however, it has been established that a total cumulative dose of at least 400 mg is required for its development. Various degrees of recovery of spermatogenesis have been observed in lymphoma patients after treatment with LEUKERAN™ at total doses of 410–2600 mg.

Teratogenicity

Like other cytostatic agents, LEUKERAN™ is a potentially teratogenic drug.

Laboratory tests

Patients should be carefully monitored to prevent life-threatening bone marrow damage during treatment. Weekly complete blood counts should be performed to determine hemoglobin levels, leukocyte counts (total and differential), and platelet counts. Additionally, during the first 3–6 weeks of therapy, leukocyte counts should be determined every 3 or 4 days following each weekly complete blood count. It is considered advisable for such patients to record blood test results together with body weight, temperature, spleen size, etc. It is considered dangerous to leave a patient without hematological and clinical evaluation for more than 2 weeks during treatment.

Sugar intolerance

The drug contains lactose (each 2 mg tablet contains 68 mg of lactose); therefore, patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not use the drug.

Use during pregnancy or breastfeeding.

Pregnancy

LEUKERAN™ should not be administered during pregnancy, especially during the first trimester, if possible. In each individual case, the expected benefit for the mother should be weighed against the potential risk to the fetus. As with treatment with other cytostatic agents, adequate contraceptive measures are recommended during treatment of either partner with LEUKERAN™. Partners should be informed about the effects of drugs on germ cells.

Breastfeeding

Women undergoing treatment with LEUKERAN™ should not breastfeed.

Fertility

LEUKERAN™ may cause suppression of ovarian function; cases of amenorrhea after treatment have been reported. Azoospermia has been observed in adult males treated with LEUKERAN™; however, it has been established that a total cumulative dose of at least 400 mg is required for its development. Various degrees of recovery of spermatogenesis have been observed in lymphoma patients after treatment with LEUKERAN™ at total doses of 410–2600 mg.

Teratogenicity

Like other cytostatic agents, LEUKERAN™ is a potentially teratogenic drug.

Ability to influence reaction rate when driving or operating machinery.

There is no information available regarding the effect of chlorambucil on the ability to drive a vehicle or operate machinery.

Method of Administration and Dosage

Leukeran™ is an active cytotoxic agent and should therefore be administered only under the supervision of an oncologist experienced in the use of such agents, and with conditions available for continuous monitoring of clinical, biochemical, and hematological parameters during and after treatment.

Dosage

Hodgkin’s Disease

For palliative monotherapy with Leukeran™ in advanced-stage disease, the standard dose for adults and children is 0.2 mg/kg/day for 4–8 weeks. Usually, Leukeran™ is used as part of combination therapy with various treatment regimens.

Leukeran™ may also be used as a substitute for nitrogen mustard, offering lower toxicity with comparable therapeutic efficacy.

Non-Hodgkin’s Lymphoma

For monotherapy with Leukeran™, the standard initial dose for adults and children is 0.1–0.2 mg/kg/day for 4–8 weeks. Subsequently, maintenance therapy is continued with a reduced daily dose or intermittent treatment courses.

Leukeran™ is indicated for the treatment of patients with advanced-stage diffuse lymphocytic lymphoma and those with recurrences after radiation therapy.

In treating patients with advanced-stage non-Hodgkin’s lymphocytic lymphoma, there is no significant difference in overall outcomes between combination chemotherapy and monotherapy with Leukeran™.

Chronic Lymphocytic Leukemia

Treatment with Leukeran™ in adults is usually initiated only after the patient develops clinical symptoms or signs of impaired bone marrow function (but not bone marrow failure) as indicated by peripheral blood analysis. Initially, Leukeran™ is administered to adults at a dose of 0.15 mg/kg/day until the total leukocyte count decreases to 10,000 per 1 µL. Treatment may be resumed 4 weeks after completion of the first course and continued at a dose of 0.1 mg/kg/day.

In some patients, after approximately 2 years of treatment, white blood cell counts return to normal, palpable spleen and lymph nodes disappear, and the proportion of lymphocytes in the bone marrow decreases to less than 20% of the initial level (determined before initiation of chemotherapy) in an individual patient.

Patients showing signs of bone marrow failure should initially be treated with prednisolone, and evidence of bone marrow regeneration should be obtained before starting Leukeran™ therapy.

Comparative studies of intermittent high-dose courses versus daily administration of Leukeran™ have shown no significant differences in treatment outcomes or frequency of adverse effects.

Waldenström’s Macroglobulinemia

Leukeran™ is one of the drugs of choice for this condition. It is recommended to start with a dose of 6–12 mg/day in adults until leukopenia develops, followed by long-term maintenance therapy at a dose of 2–8 mg/day.

Special Patient Populations

Renal Impairment

Urinary excretion of chlorambucil is minimal; therefore, renal elimination is not considered a major route of elimination for this drug. Dose adjustment is not considered necessary in patients with renal impairment. However, specific studies on the impact of renal impairment on the pharmacokinetics of chlorambucil have not been conducted.

Hepatic Impairment

Careful monitoring for signs and symptoms of toxicity is required in patients with hepatic impairment. Since chlorambucil is primarily metabolized in the liver, dose reduction should be considered in patients with severe hepatic impairment. However, data on the use of the drug in patients with hepatic impairment are insufficient to provide specific dosage recommendations.

Pediatric Patients

Leukeran™ is used for the treatment of Hodgkin’s disease and non-Hodgkin’s lymphomas in pediatric patients. Dosage regimens are similar to those used in adults.

Use in Elderly Patients

No specific studies involving elderly patients have been conducted. However, monitoring of renal and hepatic function is recommended, and particular caution should be exercised if impairments are detected.

Although clinical experience has not revealed age-related differences in response to the drug, dosage should be carefully titrated in elderly patients, typically starting at the lowest end of the recommended dosage range.

Method of Administration

Leukeran™ is intended for oral administration. High gastric pH values are known to significantly reduce the bioavailability of Leukeran™; therefore, the drug should be taken on an empty stomach (1 hour before or 3 hours after meals).

Children

Leukeran™ is used for the treatment of Hodgkin’s disease and non-Hodgkin’s lymphomas in pediatric patients. Dosage regimens are similar to those used in adults.

Overdose

Symptoms

Accidental overdose of chlorambucil primarily results in reversible pancytopenia. Various degrees of neurotoxicity may also occur, ranging from excessive excitability and ataxia to multiple tonic-clonic epileptic seizures.

Treatment

As there is no specific antidote, careful monitoring of blood counts is required, along with general supportive therapy and appropriate blood transfusions as needed.

Adverse reactions.

There is no current clinical documentation available for this medicinal product to determine the frequency of adverse reactions.

The frequency of occurrence of adverse reactions depends on the dose of the drug and the combination of Leukeran™ with other medicinal products, and is classified as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from the available data).

1Despite the high frequency of occurrence, bone marrow suppression is usually reversible if Leukeran™ is discontinued promptly.

2Patients with a history of epileptic seizures may be particularly sensitive to the drug.

3In patients with chronic lymphocytic leukemia receiving prolonged treatment with the drug, severe interstitial pulmonary fibrosis may occasionally develop. However, it may be reversible after discontinuation of Leukeran™.

4Skin rashes have been reported, which may have serious complications, including Stevens–Johnson syndrome and toxic epidermal necrolysis.

5A high level of sterility in males has been documented following drug administration during prepubertal and pubertal periods.

Post-marketing observations

In post-marketing surveillance, amenorrhea, confusion, anxiety with agitation, ataxia, flaccid paresis (as a consequence of peripheral neuropathy), hallucinations, and erythema multiforme have been reported.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit/risk balance of this medicinal product. Healthcare professionals should report all suspected adverse reactions through the national reporting system.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature of 2 °C to 8 °C, in a place inaccessible to children.

Packaging.

25 tablets in a dark glass bottle with a child-resistant cap. 1 bottle per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Excella GmbH & Co. KG.

Manufacturer's address and location of operations.

Nürnberger Str. 12, 90537 Feucht, Germany.