Alkeran (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Aspen Pharma Trading, Limited (Ireland)

Manufactured By

Excella, GmbH & Co. KG (Germany)

Or

Cenexi-Laboratoires Thissen, S.A. (Belgium)

ATC Code

L01AA03 (Melphalan)

Active Substance

Melphalan (Rec.INN registered by WHO)

Dosage Forms

	Alkeran	Lyophilisate for preparation of solution for intravascular administration 50 mg: vial 1 pc. in a set with solvent
		Film-coated tablets 2 mg: 25 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex, with the inscription “GX EH3” embossed on one side and “A” on the other; the tablet core is white or almost white.

Excipients: microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate.

Coating composition Opadry white YS-1-18097-A (hypromellose, titanium dioxide, macrogol).

25 pcs. – dark glass bottles (1) – cardboard packs.

Lyophilisate for preparation of solution for intravascular administration white or almost white color; supplied solvent – transparent, colorless solution with an alcoholic odor, practically free of visible particles; when dissolved in 10 ml of solvent, it is practically free of visible particles.

Excipients: povidone K12, hydrochloric acid.

Solvent sodium citrate, propylene glycol, ethanol (96%), water for injections.

Glass vials (1) in a set with solvent (vial 10 ml) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Alkylating compound

Pharmacotherapeutic Group

Antineoplastic agent, alkylating compound

Pharmacological Action

Antitumor drug, bifunctional alkylating 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 cross-linking of two DNA strands, which leads to disruption of cell replication.

Intravenous administration of Alkeran as monotherapy or in combination with other cytotoxic drugs is as effective in multiple myeloma as oral administration of Alkeran. High-dose intravenous administration of Alkeran (with or without hematopoietic stem cell transplantation) as first-line therapy or for consolidation of remission after standard cytostatic chemotherapy results in complete remission in 50% of patients with multiple myeloma.

High-dose Alkeran (with or without stem cell transplantation) has been used both as monotherapy and in combination with radiation therapy and/or other cytotoxic drugs for consolidation of remission after standard treatment for advanced neuroblastoma in children.

Intravenous administration of Alkeran as monotherapy and in combination with other cytotoxic drugs achieves an objective effect in approximately 50% of patients with advanced ovarian adenocarcinoma.

Administration of the drug as monotherapy or in combination with other drugs has a significant therapeutic effect in a number of patients with advanced breast carcinoma; in addition, Melphalan has been used as part of adjuvant therapy after surgery for breast carcinoma.

Effective in the treatment of patients with polycythemia vera.

Pharmacokinetics

Absorption

In 13 patients receiving oral Melphalan at a dose of 0.6 mg/kg body weight, absorption was characterized by high variability – both in terms of time to first appearance of the drug in plasma (range from 0 to 336 min) and in terms of C_max in plasma (range from 70 to 63 ng/ml). In 5 patients who received an equivalent dose of melphalan intravenously, the mean absolute bioavailability was 56±27%.

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

In 18 patients receiving oral Melphalan at doses of 0.2 to 0.25 mg/kg body weight, C_max in plasma (range from 87 to 350 ng/ml) was reached within 0.5-2.0 hours. When taking melphalan tablets immediately after a meal, the time to reach C_max in plasma increased and AUC decreased by 39 – 45%.

Distribution

After administration of the drug as a two-minute infusion at doses from 5 to 23 mg/m² body surface area (approximately 0.1- 0.6 mg/kg body weight) to 10 patients with ovarian cancer or myeloma, the mean V_d at steady state and the central compartment were 29.1±13.6 L and 12.2±6.5 L, respectively. In 28 patients with various malignant neoplasms receiving the drug at doses from 70 to 200 mg/m² body surface area as 2-20-minute infusions, the mean Vd at steady state and the central compartment were 40.2±18.3 L and 18.2±11.7 L, respectively.

During hyperthermic (39°C (102.2°F)) perfusion of the lower limb with melphalan at a dose of 1.75 mg/kg body weight in 11 patients with advanced melanoma, the mean Vd at steady state and the central compartment were 2.87±0.8 L and 1.01±0.28 L, respectively.

Metabolism

Data obtained in vivo and in vitro suggest that the main factor determining the T_1/2 of the drug in humans is spontaneous degradation rather than enzymatic degradation.

Elimination

In 13 patients after oral administration of melphalan at a dose of 0.6 mg/kg body weight, the mean T_1/2 of the terminal phase was 90±57 min, with 11% of the drug detected in the urine within 24 hours.

In 8 patients after a single bolus injection of Alkeran at a dose of 0.5-0.6 mg/kg, the T_1/2 in the initial and terminal phases 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 min, 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.

After administration of the drug as a two-minute infusion at doses from 5 to 23 mg/m² body surface area (approximately 0.1-0.6 mg/kg body weight) to 10 patients with ovarian cancer or myeloma, the T_1/2 in the initial and terminal phases were 8.1±6.6 and 76.9±40.7 minutes, respectively, and the mean clearance was 342.7±96.8 ml/min.

In 15 children and 11 adults receiving high-dose (140 mg/m² body surface area) intravenous melphalan therapy against a background of forced diuresis, the mean T_1/2 in the initial and terminal phases were 6.5±3.6 and 41.4±16.5 min, respectively. In 28 patients with various malignant neoplasms receiving the drug at doses from 70 to 200 mg/m² body surface area as 2-20-minute infusions, the mean T_1/2 in the initial and terminal phases were 8.8±.6 and 73.1±45.9 min, respectively, and the mean clearance was 564.6±159.1 ml/min.

During hyperthermic (39^oC) perfusion of the lower limb with melphalan at a dose of 1.75 mg/kg body weight in 11 patients with advanced melanoma, the mean T_1/2 in the initial and terminal phases were 3.6±1.5 and 465±17.2 min, respectively, and the mean clearance was 55.0±9.4 ml/min.

In 18 patients receiving oral Melphalan at a dose of 0.2-0.25 mg/kg body weight, the mean T_1/2 was 1.12±0.15 hours.

Indications

For parenteral use

Regional arterial perfusion is indicated for

• Localized melanoma of the extremities;
• Localized soft tissue sarcoma of the extremities.

Intravenous administration in standard doses is used for

• Multiple myeloma;
• Advanced ovarian cancer.

Intravenous administration in high doses is used for the treatment of

• Multiple myeloma;
• Advanced neuroblastoma in children.

For oral administration

Indicated for

• Multiple myeloma;
• Advanced ovarian adenocarcinoma.

May be used for

• Breast carcinoma;
• Polycythemia vera.

ICD codes

Dosage Regimen

Alkeran should be prescribed only by physicians experienced in cytostatic therapy of malignant neoplasms.

Adults with multiple myeloma for parenteral administration Alkeran injection solution is prescribed in an intermittent regimen, both as monotherapy and in combination with other cytotoxic agents, in a dose range from 8 to 30 mg/m² body surface area, at intervals from 2 to 6 weeks. Some treatment regimens additionally include prednisolone. More detailed treatment regimens are provided in the specialized literature. For intravenous monotherapy, the usual dosing regimen for Alkeran is 0.4 mg/kg body weight (16 mg/m²) with repeated administration at appropriate intervals (for example, once every 4 weeks) provided that peripheral blood counts recover during this period. When used in a high-dose therapy regimen, Alkeran is administered as a single intravenous dose of 100 to 200 mg/m² (approximately 2.5 to 5.0 mg/kg body weight). When using the drug in doses greater than 140 mg/m² body surface area, it is very important to perform hematopoietic stem cell transplantation. In case of impaired renal function, the drug dose should be reduced by 50. Given the pronounced myelosuppressive effect during high-dose intravenous therapy, this therapy should be carried out only in specialized centers under the supervision of experienced specialists.

Adults with multiple myeloma for oral administration are usually prescribed 0.15 mg/kg body weight in several doses over 4 days, repeating the cycles at 6-week intervals. However, many other regimens have been used, which can be found in detail in the specialized literature. Oral melphalan with simultaneous prednisolone may be more effective than melphalan monotherapy. Combination therapy is usually prescribed on an intermittent schedule.

Therapy lasting more than 1 year in patients responding to therapy does not appear to be associated with higher efficacy.

For advanced ovarian adenocarcinoma with intravenous administration in monotherapy mode, Alkeran is usually used at a dose of 1 mg/kg body weight (approximately 40 mg/m²) at 4-week intervals. When used in combination with other cytotoxic agents, the recommended doses of Alkeran are from 0.3 to 0.4 mg/kg body weight (from 12 to 16 mg/m²) at 4-6 week intervals. For oral administration, 0.2 mg/kg body weight per day is usually prescribed for 5 days, repeating the cycles every 4 – 8 weeks or after recovery of the peripheral blood picture.

For melanoma, hyperthermic regional perfusion with Alkeran solution is used as adjuvant therapy after removal of melanoma at an early stage of the disease, as well as for palliative treatment of locally advanced stage. Detailed information on perfusion technique and recommended doses is provided in the specialized literature.

For soft tissue sarcoma, hyperthermic regional perfusion of Alkeran solution is used at all stages of localized soft tissue sarcoma, usually in combination with surgical treatment. Alkeran is also prescribed in combination with actinomycin D. Detailed information on recommended doses is provided in the specialized literature.

For breast carcinoma, Alkeran is prescribed orally at a dose of 0.15 mg/kg body weight or 6 mg/m² body surface area per day for 5 days, repeating the cycles every 6 weeks. In case of toxic effects on bone marrow hematopoiesis, the dose is reduced.

For polycythemia vera, for induction of remission, the drug is prescribed orally at doses from 6 to 10 mg per day for 5-7 days, after which they switch to taking it at a dose of 2 to 4 mg per day until sufficient disease control is achieved. For maintenance therapy, the drug is prescribed at a dose of 2 to 6 mg once a week.

Given the possibility of severe myelosuppression with continuous melphalan use, it is very important to regularly examine the blood picture throughout the entire therapy, adjusting the dose or taking breaks in treatment if necessary to maintain good blood picture control.

For advanced neuroblastoma in children, Alkeran injection solution is prescribed at doses from 100 to 240 mg/m² (sometimes this dose is divided into several equal parts and administered over three consecutive days) both as monotherapy and in combination with radiation therapy and/or with other cytotoxic agents, in combination with hematopoietic stem cell transplantation.

Melphalan in the traditional dose range is prescribed to children only in rare cases, so it is not possible to provide clearly defined dosing recommendations.

Alkeran is often used in elderly and senile patients at standard doses; there is no information on the features of its use in this age subgroup.

Experience with high-dose Alkeran in elderly and senile patients is limited. Before starting high-dose intravenous melphalan therapy in patients of this category, adequate general condition should be achieved.

In case of impaired renal function, the clearance of melphalan may decrease, although it varies greatly. When administering the drug intravenously in standard doses (8-40 mg/m²) to patients with moderate or severe renal failure, it is recommended to reduce the initial dose by 50%, and then adjust the dose depending on the degree of bone marrow suppression.

When administering the drug intravenously in high doses (100-240 mg/m²), the need for dose reduction depends on the degree of renal impairment, whether hematopoietic stem cell transplantation is performed, and therapeutic necessity. As a rule, when performing high-dose melphalan therapy without hematopoietic stem cell transplantation in patients with moderate renal failure (CC 30-50 ml/min), the dose is reduced by 50%. In severe renal failure, high-dose melphalan therapy without hematopoietic stem cell transplantation is not recommended.

High-dose melphalan therapy in combination with hematopoietic stem cell transplantation has been successfully performed even in patients with end-stage renal failure on hemodialysis.

Current pharmacokinetic data do not allow confident recommendation of a dose reduction for oral melphalan in patients with impaired renal function, but it may be advisable to reduce the dose at the beginning of therapy until the drug’s tolerability is determined.

When prescribing the drug orally, it should be taken into account that since the absorption of the drug after oral administration varies, careful dose escalation may be required to guarantee the achievement of therapeutic concentrations until myelosuppression develops.

Rules for preparing the injection solution

The solution is prepared at room temperature by mixing the lyophilized powder with the solvent supplied with the Alkeran vial.

10 ml of solvent should be added to the vial with Alkeran lyophilized powder (at once) and shaken vigorously until completely dissolved. The resulting solution contains 5 mg of anhydrous melphalan in 1 ml and has a pH of about 6.5.

The prepared Alkeran injection solution is not sufficiently stable and must be prepared immediately before use. Unused solution should be destroyed. The prepared Alkeran solution should not be stored in the refrigerator, as this causes precipitation.

Alkeran injection solution is administered only intravenously, except in cases where regional arterial perfusion is indicated.

For intravenous use, it is recommended to administer the Alkeran solution slowly through a special closed access in the infusion system against the background of a rapid infusion of another solution. If direct administration into a rapidly administered other solution is not possible, then the Alkeran solution can be diluted in an infusion container.

It is recommended to dilute the Alkeran solution only with 0.9% sodium chloride injection solution and not to mix it with infusion solutions containing dextrose (glucose).

When further diluting the Alkeran injection solution in an infusion solution, its stability decreases, and the rate of its degradation rapidly increases with increasing ambient temperature. At room temperature (approximately 25°C (77°F)), the total time from the moment of preparation of the Alkeran injection solution to the completion of its infusion should not exceed 1.5 hours.

If cloudiness or crystallization appears in the prepared or diluted Alkeran solution, it should be destroyed.

Care must be taken to avoid the possible administration of Alkeran not into the vein, but into the surrounding tissues. In case of difficult access to peripheral veins, the drug is administered into central veins. High doses of Alkeran (with or without hematopoietic stem cell transplantation) are recommended to be administered into central veins.

When using the drug for regional arterial perfusion, it is recommended to familiarize yourself with the details of the technique in the specialized literature.

Adverse Reactions

Modern clinical data on the frequency of adverse reactions when using this drug are not available. The frequency of adverse reactions varies depending on the indication and the doses administered, as well as on the use of the drug in combination with other agents.

The following principles were used to classify the frequency of adverse reactions: very common – ≥0.1, common – ≥0.01 but <0.1, uncommon – ≥0.001 but <0.01, rare – ≥0.0001 but <0.001, very rare – <0.00001

Blood and lymphatic system disorders: very common – bone marrow suppression with the development of leukopenia and thrombocytopenia; rare – hemolytic anemia.

Immune system disorders : rare – allergic reactions (urticaria, edema, skin rash, itching and anaphylactic shock upon first and subsequent administrations were infrequent, mainly during IV therapy with Alkeran). There are reports of rare cases of cardiac arrest due to allergic reactions to Alkeran.

Respiratory system disorders: rare – interstitial pneumonia and pulmonary fibrosis (including fatal outcomes).

Gastrointestinal system disorders: very common – nausea, vomiting and diarrhea; with high-dose regimen – stomatitis; rare – liver lesions, ranging from changes in liver function tests to clinically manifest hepatitis and jaundice, veno-occlusive disease after high-dose therapy, stomatitis with standard doses. With parenteral administration: diarrhea, nausea, vomiting are dose-limiting factors of toxicity in patients receiving IV high-dose therapy with Alkeran along with hematopoietic stem cell transplantation. Prior therapy with cyclophosphamide appears to reduce the severity of gastrointestinal symptoms caused by a high dose of Alkeran. With oral administration: according to available data, up to 30% of patients receiving oral Melphalan in standard doses report side effects from the digestive system, such as nausea and vomiting.

Dermatological reactions : very common – alopecia during high-dose therapy, common – alopecia with standard doses; rare – maculopapular rash and skin itching.

Urinary system disorders: common – transient significant increase in blood urea levels in patients with multiple myeloma and impaired renal function.

Other: with parenteral administration very common – subjective transient sensation of heat and/or tingling.

Contraindications

• Hypersensitivity to melphalan.

Use in Pregnancy and Lactation

The use of melphalan during pregnancy should be avoided, especially in the first trimester. In each individual case, the potential risk to the fetus must be weighed against the expected benefit to the mother.

Women receiving Alkeran should discontinue breastfeeding.

If either partner is receiving Alkeran, reliable methods of contraception should be used.

The teratogenic potential of Alkeran has not been studied. Given its mutagenic properties and structural similarity to known teratogenic compounds, it is possible that Alkeran may cause congenital malformations in children born to patients receiving this drug.

In a significant number of premenopausal women, Alkeran suppresses ovarian function, causing amenorrhea. Some data indicate the possibility of an adverse effect of Alkeran on spermatogenesis; therefore, its use may lead to the development of transient or permanent sterility in men.

Use in Renal Impairment

In case of renal impairment, the clearance of melphalan may decrease, although it varies greatly. When administering the drug IV in standard doses (8-40 mg/m²) to patients with moderate or severe renal failure, it is recommended to reduce the initial dose by 50%, and subsequently adjust the dose depending on the degree of bone marrow suppression.

When administering the drug IV in high doses (100-240 mg/m²), the need for dose reduction depends on the degree of renal impairment, whether hematopoietic stem cell transplantation is performed, and the therapeutic necessity. As a rule, when conducting high-dose therapy with melphalan without hematopoietic stem cell transplantation in patients with moderate renal failure (CrCl 30-50 ml/min), the dose is reduced by 50%. In severe renal failure, high-dose therapy with melphalan without hematopoietic stem cell transplantation is not recommended.

Special Precautions

Immunization with a live vaccine can sometimes cause the development of infection in an immunocompromised patient. For this reason, the use of live vaccines during therapy with melphalan is not recommended.

In case of extravasation, the Alkeran injection solution can cause local damage to the tissues surrounding the vessel, so it should not be administered directly into a peripheral vein. It is recommended to administer the Alkeran solution slowly against a background of rapid infusion through a special closed access in the infusion system or into a central vein.

Given the high risk and the need for complex supportive therapy during treatment with the drug, IV high-dose therapy with Alkeran should be carried out only in specialized centers with appropriate facilities, under the supervision of experienced specialists. In patients receiving high-dose IV therapy with Alkeran, the issue of prophylactic administration of antibacterial drugs and, if necessary, blood components should be addressed. Before conducting high-dose therapy with melphalan, adequate general condition of the body and organ function must be ensured.

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

When using Alkeran, the recommendations for the use of cytotoxic drugs should be followed.

The elimination of melphalan in patients with renal failure may be reduced. In addition, renal failure may cause bone marrow suppression of uremic origin. In such cases, a dose reduction of the drug may be required, and patients should be under close medical supervision.

Chromosomal aberrations have been detected in patients treated with Alkeran.

Melphalan, like other alkylating agents, can cause the development of leukemia in humans. There are reports of acute leukemia after long-term therapy with melphalan for amyloidosis, melanoma, multiple myeloma, macroglobulinemia, cold agglutinin syndrome and ovarian cancer. A comparative analysis of patients with ovarian cancer who received and did not receive alkylating agents, including Melphalan, revealed a significant increase in the incidence of acute leukemia in the first group. Before prescribing Alkeran, the risk of developing leukemia should be weighed against the potential therapeutic effect of the drug.

Laboratory monitoring

Since Alkeran is a myelosuppressive agent, it is very important to regularly determine the blood cell count during therapy, adjusting the dose or temporarily postponing the administration of the drug if necessary to avoid the possible development of excessive myelosuppression and the risk of irreversible bone marrow aplasia. Blood cell counts may continue to decrease even after discontinuation of the drug, so at the first signs of too sharp a decrease in the number of leukocytes or platelets, treatment should be temporarily stopped.

Safe handling rules for the drug

When handling melphalan, the instructions for handling cytostatics in accordance with local recommendations and/or regulations should be followed.

The Alkeran solution should be prepared under the supervision of an experienced pharmacist who is proficient in the safe handling of the drug and familiar with its properties. The melphalan solution should be prepared under aseptic conditions on special equipment (in a laminar flow cabinet), or, if not available, in a specially designated isolated room in a pharmacy or clinic. Personnel preparing solutions or giving injections should wear special protective clothing: high-quality disposable surgical latex or polyvinyl chloride gloves (rubber ones are not suitable), a surgical mask of appropriate quality, protective goggles, which should be thoroughly washed with water after use, and a disposable apron.

When working under aseptic conditions, other clothing will be required.

In case of splashing or spilling of the solution, personnel dressed in appropriate protective clothing should immediately wipe the surface with wet disposable paper towels, which are then immediately placed in a hazardous waste container and then destroyed according to established procedure. The surface on which the drug has been spilled should be washed with plenty of water.

If the melphalan solution gets on the skin, it should be immediately and thoroughly washed with plenty of cold water and soap; in such cases, it is advisable to consult a doctor.

If it comes into contact with the eye mucosa, immediately rinse with sodium chloride eye solution and consult a doctor without delay. If sodium chloride solution is not available, plenty of water can be used.

Safe handling rules for melphalan tablets

When handling melphalan dosage forms, the instructions for handling cytostatics available in local recommendations and/or relevant regulations must be observed.

If the outer coating of the tablet is intact, handling melphalan tablets is not associated with risk. Melphalan tablets should not be broken.

Drug disposal rules

The Alkeran solution must be destroyed in accordance with established requirements. In the absence of such, it is subject to the same disposal procedure as other toxic chemicals, for example, high-temperature incineration and deep burial.

Disposal of sharp objects (e.g., needles, syringes, infusion systems and ampoules) must be carried out in rigid containers with a warning label about the hazard. Personnel carrying out disposal must be informed about observing all precautions. Disposal procedures must comply with local regulatory requirements.

Melphalan tablets are destroyed in accordance with local regulatory requirements for the disposal of cytostatics.

Overdose

Symptoms: the first manifestations of acute overdose of Alkeran with IV administration are nausea and vomiting, damage to the gastrointestinal mucosa with diarrhea, sometimes hemorrhagic, may develop. With oral administration, the most likely first symptoms of acute overdose are gastrointestinal adverse reactions, including nausea, vomiting and diarrhea. The main toxic effect of melphalan (both oral and parenteral administration) is the suppression of bone marrow hematopoiesis with the development of leukopenia, thrombocytopenia and anemia.

Treatment: if necessary, general supportive measures should be carried out, along with transfusions of blood and platelet mass, and the issue of hospitalization of patients for anti-infective therapy and the administration of hematopoietic stimulants should be addressed. There is no specific antidote. Peripheral blood parameters must be carefully monitored for at least four weeks after the overdose, until signs of their normalization appear.

Drug Interactions

IV administration of high doses of melphalan simultaneously with nalidixic acid led to fatal outcomes in children due to the development of hemorrhagic enterocolitis.

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

Pharmaceutical incompatibility

The drug solution is incompatible with infusion solutions containing dextrose (glucose). It is recommended to administer it only in 0.9% sodium chloride solution for IV infusion.

Storage Conditions

The packaging of the drug in the form for parenteral administration should be stored in a light-protected place, out of the reach of children, at a temperature not exceeding 30°C (86°F); the shelf life of the lyophilized powder for solution preparation is 3 years.

The drug in tablet form should be stored out of the reach of children at a temperature of 2 to 8°C (46.4°F); the shelf life of the tablets is 2 years.

The drug should not be used after the expiration date indicated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

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.