Dzhalaran (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Jodas Expoim, LLC (Russia)

Manufactured By

Jodas Expoim, Pvt. Ltd. (India)

ATC Code

L01AA03 (Melphalan)

Active Substance

Melphalan (Rec.INN registered by WHO)

Dosage Form

Dzhalaran

Lyophilizate for preparation of solution for intravascular administration 50 mg: vial 15 ml 1 pc.

Dosage Form, Packaging, and Composition

Lyophilizate for preparation of solution for intravascular administration in the form of a white or almost white lyophilized powder.

* each ml of the reconstituted solution contains 5 mg of melphalan (as hydrochloride).

Excipients: Lyophilizate: povidone K12, hydrochloric acid.
Solvent: sodium citrate, propylene glycol, ethanol 96%, water for injections.

15 ml – vials (1) (complete with 10 ml solvent) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Alkylating compound

Pharmacotherapeutic Group

Antineoplastic agents; alkylating agents; nitrogen mustard analogues

Pharmacological Action

Antitumor agent of alkylating action, a derivative of chlorethylamine. It is a bifunctional compound. The alkylation process consists of the covalent binding of carbon intermediates formed from two bis-2-chloroethyl groups to the 7-nitrogen of guanine in DNA and the cross-linking of two DNA strands, which leads to disruption of cell replication.

It blocks normal mitosis in rapidly proliferating tissues.

The cytotoxic effect is dose-dependent.

Pharmacokinetics

When taken orally, the absorption of melphalan is incomplete and variable: the time of detection of melphalan in blood plasma ranges from 0 to 336 minutes (associated with variable absorption in the gastrointestinal tract, rapid hydrolysis, and the presence of a first-pass effect through the liver), and the peak concentration value ranges from 70 to 630 ng/ml.

When melphalan is taken immediately after a meal, the time to reach C_max increases and AUC decreases by 39-45%.

Bioavailability ranges from 25% to 89%, averaging 61%. Binding to plasma proteins is 60-90%, with about 30% bound irreversibly. Volume of distribution is 0.5 l/kg.

It is metabolized to form inactive metabolites in body fluids and tissues.

Excreted by the kidneys – 50% (10-15% unchanged), through the intestines – 20-50%. Not removed by hemodialysis. The average T_1/2 is 1.12 ± 0.15 h.

The average bioavailability of melphalan after IV administration was 56 + 27%. It penetrates the blood-brain barrier in small amounts. Binding to plasma proteins (mainly albumin) is 69-78%.

The pharmacokinetics of melphalan after IV administration in standard and high doses corresponds to a biexponential two-compartment model.

When melphalan was administered IV bolus in doses from 0.5 to 0.6 mg/kg body weight, the initial and terminal T_1/2 were 7.7 ± 3.3 and 108 ± 20.8 min, respectively. After parenteral administration of melphalan, its metabolites – monohydroxymelphalan and dihydroxymelphalan – were detected in plasma, their concentrations reaching maximum levels at 60 and 105 minutes, respectively.

The T_1/2 when melphalan was added to patient serum in vitro at 37°C (98.6°F) was similar to that in vivo and was 126 ± 6 min. This suggests that the main factor determining the duration of T_1/2 in the human body is its spontaneous degradation rather than enzymatic metabolism.

When using high-dose (140 mg/m² body surface area) IV melphalan therapy against a background of forced diuresis, the mean initial and final T_1/2 were 6.5 ± 3.6 and 41.4 ± 16.5 min, respectively. When melphalan was administered in doses from 70 to 200 mg/m² body surface area as 2 to 20-minute infusions, the mean initial and terminal T_1/2 were 8.8 ± 6.6 and 73.1 ± 45.9 min, respectively, and the mean clearance was 564.6 ± 159.1 ml/min.

During hyperthermic (39°C (102.2°F)) perfusion of the lower limb with melphalan at a dose of 1.75 mg/kg body weight, the mean initial and terminal T_1/2 were 3.6 ± 1.5 and 465 ± 17.2 min, respectively, and the mean clearance was 55.0 ± 9.4 ml/min.

Indications

For oral administration: multiple myeloma, progressive ovarian cancer, polycythemia vera.

For parenteral use: regional arterial perfusion – localized malignant melanoma of the extremities; localized soft tissue sarcoma of the extremities. Standard dose therapy: multiple myeloma; advanced ovarian cancer. High-dose therapy: multiple myeloma; advanced neuroblastoma in children.

ICD codes

Dosage Regimen

The dosage regimen is set individually based on the indication, therapeutic protocol, and patient’s clinical status.

For standard dose therapy in multiple myeloma or advanced ovarian cancer, administer a dose of 16 mg/m² intravenously. Administer as a slow intravenous infusion over 15-20 minutes. Repeat doses at 2-week intervals for 4 doses. Subsequently, after adequate hematological recovery, continue with doses at 4-week intervals.

For high-dose therapy prior to hematopoietic stem cell transplantation, administer 100-200 mg/m² as an intravenous infusion. The specific dose depends on the transplant protocol and patient tolerance. Pre-medicate with antiemetics. Ensure adequate hydration and diuresis before and after administration to reduce the risk of renal toxicity and hemorrhagic cystitis.

For regional arterial perfusion in localized melanoma or sarcoma of the extremities, use a dose of 0.5-1.75 mg/kg body weight. The exact dose and duration of perfusion are determined by the surgical and oncological team based on the perfusion circuit and tumor volume.

Reconstitute the 50 mg vial with the provided 10 ml solvent. Gently shake to dissolve the lyophilized powder. The resulting solution contains 5 mg/ml of melphalan. Dilute the required dose immediately in 0.9% sodium chloride solution to a final concentration not exceeding 0.45 mg/ml. Administer the diluted solution within 60 minutes of preparation due to instability.

Monitor complete blood count weekly. Withhold therapy if the leukocyte count falls below 3000/µl or the platelet count falls below 100,000/µl. Do not administer subsequent doses until adequate hematological recovery is confirmed. Adjust the dose based on the nadir blood counts from the previous cycle.

In patients with renal impairment, consider a dose reduction due to increased risk of myelosuppression. For patients with severe renal impairment, the initial dose should be reduced by 50%.

Adverse Reactions

From the hematopoietic system: rarely – anemia, very rarely – hemolytic anemia; frequency unknown – leukopenia, neutropenia (secondary infections may develop against the background of leukopenia/neutropenia), thrombocytopenia, acute leukemia (with long-term use of melphalan).

Allergic reactions frequency unknown – urticaria, edema, skin rash; anaphylactic shock. Rare cases of cardiac arrest associated with the development of allergic reactions have been reported.

From the respiratory system: rarely – interstitial pneumonia, pulmonary fibrosis, including fatal cases.

From the digestive system: very often – vomiting; frequency unknown – nausea, diarrhea, stomatitis, gastric and duodenal ulcers (the risk of developing these adverse reactions is significantly increased during combined cytostatic therapy).

From the liver and biliary tract: rarely – changes in the activity of functional liver tests, hepatitis, jaundice.

From the cardiovascular system: rarely – veno-occlusive disease after high-dose therapy.

From the urinary system: often – transient increase in plasma urea levels in patients with initial signs of impaired renal function.

From the skin and subcutaneous tissues often – alopecia; rarely – maculopapular rash, skin itching..

From the reproductive system: frequency unknown – amenorrhea, azoospermia.

From laboratory parameters: frequency unknown – hyperuricemia, transient increase in plasma urea levels (in patients with initial signs of renal failure).

Other: with parenteral use very often – sensation of heat and/or tingling. With regional arterial perfusions very often – muscle atrophy, muscle fibrosis, myalgia, increased serum creatine phosphokinase levels; often – compartment syndrome. Muscle necrosis and rhabdomyolysis may also develop. With long-term use, acute leukemia may develop.

Local reactions with parenteral use in case of extravasation – skin ulceration at the injection site, skin necrosis.

Contraindications

Hypersensitivity to melphalan; pregnancy, breastfeeding period.

With caution: condition after radiation therapy preceding cytostatic therapy; with anemia, leukopenia (leukocyte count below 2000/µl), thrombocytopenia (platelet count below 50000/µl); bone marrow infiltration by tumor cells; acute infectious diseases of viral (including chickenpox, herpes zoster), fungal or bacterial nature (risk of severe complications and generalization of the process), in the terminal stage of the disease; with impaired renal function; with severe concomitant diseases: parenchymal hepatitis, gouty arthritis, urate nephropathy, nephritis and diseases of the cardiovascular system in the stage of decompensation.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Should be used with caution in parenchymal hepatitis.

Use in Renal Impairment

Should be used with caution in patients with impaired renal function. In patients with renal failure, suppression of hematopoietic function may occur against the background of uremia. In patients with myeloma and impaired renal function, a temporary marked increase in blood urea levels was observed in the early stages of treatment with melphalan.

Pediatric Use

Can be used in children according to indications, in doses and dosage forms recommended for the respective age.

Geriatric Use

Should be prescribed with caution to elderly patients to avoid worsening of concomitant diseases.

Special Precautions

Melphalan should be used only under the supervision of a physician experienced in the use of anticancer drugs.

Given the side effects of melphalan and the need for supportive therapy, parenteral use should be carried out in a specialized hospital and only by experienced specialists.

During treatment, regular monitoring of hematological parameters should be carried out to avoid the possible development of severe myelosuppression and the risk of irreversible bone marrow aplasia. After discontinuation of melphalan, a decrease in blood cell count is possible, so at the first signs of excessive leukopenia or thrombocytopenia, treatment should be temporarily stopped.

Melphalan, like other alkylating agents, can have a leukemogenic effect in humans. There are reports of the development of acute leukemia after long-term treatment with melphalan for diseases such as amyloidosis, malignant melanoma, multiple myeloma, macroglobulinemia, cold agglutinin syndrome, and ovarian cancer. It has been shown that in patients with ovarian cancer, the use of alkylating agents, including Melphalan, significantly increased the incidence of acute leukemia compared to patients who were not treated with alkylating drugs. When deciding on the use of melphalan, the risk of leukemogenic effects and the potential therapeutic effect of melphalan should be weighed.

Melphalan should be used with caution in patients who have recently undergone a course of radiation therapy or chemotherapy, due to the possibility of increased toxic effects on the bone marrow.

In patients with renal failure, suppression of hematopoietic function may occur against the background of uremia.

In patients with myeloma and impaired renal function, a temporary marked increase in blood urea levels was observed in the early stages of treatment with melphalan.

Melphalan suppresses ovarian function in premenopausal women, leading to amenorrhea in a significant number of patients.

To prevent hyperuricemia, plenty of fluids, urine-alkalinizing drugs, and allopurinol are recommended.

It is necessary to avoid immunization (unless approved by a doctor) in the interval from 3 months to 1 year after taking melphalan; other family members living with the patient should avoid immunization with oral polio vaccine (avoid contact with people who have received the polio vaccine, or wear a protective mask covering the nose and mouth).

Women and men with preserved reproductive potential during treatment with melphalan and for at least 3 months after its completion should use reliable methods of contraception.

Before administering high doses of melphalan, the adequacy of the patient’s general condition and the function of internal organs should be ensured; it is also recommended to prescribe antibacterial agents for prophylactic purposes and maintain abundant diuresis immediately after melphalan administration (by using hydration and forced diuresis).

Effect on ability to drive vehicles and mechanisms

During the use of melphalan, patients should exercise caution when driving vehicles and mechanisms, as well as when engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

Simultaneous administration of melphalan with nalidixic acid in children can lead to death due to the development of hemorrhagic enterocolitis.

Prescription of chlorpromazine, chloramphenicol and metamizole sodium to patients taking Melphalan leads to an increase in the severity of the myelodepressive effect.

Cisplatin induces impaired renal function and reduces the clearance of melphalan. Cyclosporine and high doses of melphalan are a potentially dangerous combination due to the possible development of impaired renal function (Melphalan itself does not have nephrotoxicity).

With simultaneous use of melphalan with live viral vaccines, intensification of the replication process of the vaccine virus, an increase in its adverse reactions and/or a decrease in the production of antibodies in the patient’s body in response to the vaccine administration are possible.

In patients who received high doses of melphalan IV before hematopoietic stem cell transplantation and were subsequently prescribed cyclosporine to prevent graft-versus-host disease, cases of impaired renal function have been described.

Pharmaceutical incompatibility. The solution of melphalan is incompatible with infusion solutions containing dextrose (glucose).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.