Zalcaren 50 mg Injection

ZALCAREN injection, at conventional intravenous dosage, may be used in the treatment of:

• Multiple myeloma: ZALCAREN Injection, either alone or in combination with other cytotoxic medicines.
• Ovarian cancer: ZALCAREN Injection, either alone or in combination with other cytotoxic medicines.

ZALCAREN Injection, at high intravenous dosage, may be used in the treatment of:

• Multiple myeloma: With or without autologous bone marrow rescue, either as first line treatment or to consolidate a response to conventional cytoreductive chemotherapy.
• Neuroblastoma in childhood: High-dose ZALCAREN Injection with autologous bone marrow rescue has been used either alone or combined with radiotherapy and/or other cytotoxic medicines, to consolidate a response to conventional treatment.

General: ZALCAREN is a cytotoxic medicine, which falls into the general class of alkylating medicines. It should be prescribed only by medical practitioners experienced in the management of malignant disease with such medicines.

Since ZALCAREN is myelosuppressive, frequent blood counts are essential during therapy and the dosage should be adjusted if necessary (see sections 4.4 and 4.8).

Posology

Thromboembolic events: ZALCAREN, in combination with lenalidomide and prednisone or in combination with thalidomide and prednisone or dexamethasone is associated with an increased risk of venous thromboembolism. Thromboprophylaxis should be administered for at least the first 5 months of treatment especially in patients with additional thrombotic risk factors. The decision to take antithrombotic prophylactic measures should be made after careful assessment of an individual patient's underlying risk factors (see section 4.4).

If the patient experiences any thromboembolic events, treatment must be discontinued, and standard anticoagulation therapy started. Once the patient has been stabilised on the anticoagulation treatment and any complications of the thromboembolic event have been managed, ZALCAREN in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone may be restarted at the original dose. The patient should continue anticoagulation therapy during the course of ZALCAREN treatment.

Multiple myeloma: ZALCAREN has been used on an intermittent basis alone, or in combination with other cytotoxic medicines, at doses varying between 8 mg/m2 body surface area and 30 mg/m2 body surface area, given at intervals of between 2 to 6 weeks. The literature should be consulted for details.

When used as a single agent medicine, a typical intravenous dosage-schedule is 0,4 mg/kg body mass (16 mg/m2 body surface area) repeated at appropriate intervals (e.g., once every 4 weeks), provided there has been recovery of the peripheral blood count during this period.

High-dose regimens generally employ single intravenous doses of between 100 and 200 mg/m2 body surface area (approximately 2,5 to 5,0 mg/kg body mass), but autologous bone marrow rescue becomes essential following doses in excess of 140 mg/m2 body surface area. In cases of renal impairment, the dose should be reduced by fifty percent. In view of the severe myelosuppression induced by high-dose ZALCAREN, treatment should be confined to specialist centres, with the appropriate facilities, and only be administered by experienced medical practitioners (see sections 4.4 and 4.8).

Advanced ovarian adenocarcinoma: When used intravenously as a single medicine, a dose of 1 mg/kg body mass (approximately 40 mg/m2 body surface area) given at intervals of 4 weeks has often been used. When combined with other cytotoxic medicines, intravenous doses of between 0,3 and 0,4 mg/kg body mass (12 to 16 mg/m2 body surface area) have been used at intervals of 4 to 6 weeks.

Advanced malignant melanoma: Hyperthermic regional perfusion with ZALCAREN has been used as palliative treatment for advanced but localised disease. The scientific literature should be consulted for details of perfusion technique and dosage used.

Advanced neuroblastoma: Dosages between 100 and 240 mg/m2 body surface area (sometimes divided equally over 3 consecutive days) together with autologous bone marrow rescue, have been used either alone or in combination with radiotherapy and/or other cytotoxic medicines.

SPECIAL POPULATIONS

Use in children: High-dose ZALCAREN, in association with bone marrow rescue, has been administered to children and dosage guidelines based on body surface area, as for adults, may be used.

Use in the elderly: Although ZALCAREN is frequently used at conventional dosage in the elderly, there is no specific information available relating to its administration to this patient sub-group. Experience in the use of high-dose ZALCAREN in elderly patients is limited. Consideration should therefore be given to ensure adequate performance status and organ function before using high-dose ZALCAREN Injection in elderly patients.

Dosage in renal impairment: ZALCAREN clearance, though variable, is decreased in renal impairment. When ZALCAREN Injection is used at conventional intravenous dosage (8 - 40 mg/m2 body surface area), it is recommended that the initial dose should be reduced by 50 % in patients with moderate to severe renal impairment, and subsequent dosage determined according to the degree of haematological suppression. For high intravenous doses of ZALCAREN Injection (100 - 240 mg/m2), the need for dose reduction depends upon the degree of renal impairment, whether autologous bone marrow stem cells are reinfused, and therapeutic need. As a guide, for moderate to severe impairment [Ethylenediaminetetraacetic acid (EDTA) clearance 30 - 50 mL/min], a dose reduction of 50 % is usual. Adequate hydration and forced diuresis are also necessary. High-dose ZALCAREN is not recommended in patients with more severe renal impairment (EDTA clearance less than 30 mL/min).

Method of Administration: Parenteral administration: Except in cases where regional arterial perfusion is indicated, ZALCAREN Injection is for intravenous use only. It is recommended that ZALCAREN Injection solution is injected slowly into a fast-running infusion solution via a swabbed injection port. If direct injection into a fast-running infusion is not appropriate, ZALCAREN Injection solution may be administered diluted in an infusion bag.

• ZALCAREN should not be given to patients who have suffered a previous allergic reaction to melphalan or to any of the excipients of ZALCAREN listed in section 6.1.
• Lactation: Mothers receiving ZALCAREN should not breastfeed.
• Pregnancy: The use of melphalan is contra-indicated during pregnancy, as mutagenicity has been documented in animals.
• Immunisation with live attenuated organism vaccines.

ZALCAREN IS AN ACTIVE CYTOTOXIC MEDICINE FOR USE ONLY UNDER THE DIRECTION OF MEDICAL PRACTITIONERS EXPERIENCED IN THE ADMINISTRATION OF SUCH MEDICINES.

Warnings

• Safe handling of ZALCAREN formulations should follow guidelines for the handling of cytotoxic medicines according to prevailing local recommendations and/or regulations.
• Immunisation with live organism vaccines: Immunization using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunizations with live organism vaccines are contraindicated.
• Renal Impairment: Patients with renal impairment should be closely observed, as they may have uraemic marrow suppression. Dosage reduction may be necessary.
• A fifty percent dosage reduction is essential in patients with impaired renal function, who are given high-dose ZALCAREN Injection.

Monitoring: Since ZALCAREN is a potent myelosuppressive medicine, it is essential that careful attention should be paid to the monitoring of blood counts to avoid the possibility of excessive myelosuppression and the risk of irreversible bone marrow aplasia. Blood counts may continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in leukocyte or platelet counts, treatment should be temporarily interrupted.

Thromboembolic events: Patients treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone, have an increased risk of thromboembolic events (see section 4.8). Especially in patients with additional thrombotic risk factors antithrombotic prophylactic measures should be considered (see sections 4.2 and 4.8).

Neutropenia and thrombocytopenia: Increased rate of haematological toxicities, particularly, neutropenia and thrombocytopenia, was observed in newly diagnosed elderly multiple myeloma in patients treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone. Patients and medical practitioners are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxis, especially in patients receiving combination drug regimens described.

Mutagenicity: ZALCAREN is mutagenic in animals, and chromosome aberrations have been observed in patients being treated with the medicine.

Carcinogenicity: Melphalan may be leukaemogenic in man. There have been reports of acute leukaemia occurring after prolonged melphalan treatment for diseases such as amyloid, malignant melanoma, multiple myeloma, macroglobulinaemia, cold agglutinin syndrome and ovarian cancer. A comparison of patients with ovarian cancer who received alkylating medicines with those who did not, showed that the use of alkylating medicines, including melphalan, significantly increased the incidence of acute leukaemia. The leukaemogenic risk must be balanced against the potential therapeutic benefit when considering the use of melphalan.

Ethanol: ZALCAREN contains small amounts of ethanol (alcohol), 0,52 mL per 10 mL.

• Nalidixic acid together with high-dose intravenous melphalan has caused deaths in children due to haemorrhagic enterocolitis.
• Impaired renal function has been described in bone marrow transplant patients who were preconditioned with high-dose intravenous melphalan.
• Ciclosporin: those who subsequently received ciclosporin to prevent graft-versus-host disease.
• Vaccinations with live organism vaccines are not recommended in immunocompromised individuals.

Women of childbearing potential / Contraception in males and females: Adequate contraceptive precautions should be advised when either partner is receiving ZALCAREN and for at least a year after cessation of treatment.

Pregnancy: ZALCAREN should not be used during pregnancy. There are no data from the use of melphalan in pregnant women. Studies in animals have shown reproductive toxicity. In view of its mutagenic properties and structural similarity to known teratogenic compounds, it is possible that ZALCAREN could cause congenital defects in the offspring of patients treated with the medicine.

Breast-feeding: Mothers receiving ZALCAREN should not breast-feed.

Effects on fertility: ZALCAREN causes suppression of ovarian function in premenopausal women, resulting in amenorrhoea in a significant number of patients.

Sterility in males: It is possible that ZALCAREN may cause temporary or permanent sterility in male patients. It is recommended that men who are receiving treatment with melphalan not father a child during treatment and up to 6 months afterwards and that they have a consultation on sperm reservation before treatment due to the possibility of irreversible infertility as a result of melphalan treatment.

Effects on the ability to drive and operate machinery in patients taking this medicine have not been studied.

Undesirable effects may vary in their incidence depending on the indication and dose received and also when given in combination with other therapeutic medicines.

a. Tabulated list of adverse reactions

System organ class

Frequent

Less frequent

Frequency unknown

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Secondary acute myeloid leukaemia, myelodysplastic syndrome

Blood and the lymphatic system disorders

Bone marrow depression leading to leucopaenia and thrombocytopaenia, anaemia

Haemolytic anaemia

Immune system disorders

Allergic reactions

Vascular disorders

Deep vein thrombosis, pulmonary embolism

Respiratory, thoracic and mediastinal disorders

Interstitial lung disease, pulmonary fibrosis (including fatal reports)

Gastrointestinal disorders

Nausea, vomiting, diarrhoea, stomatitis (at high dose)

Stomatitis (at conventional dose)

Hepato-biliary disorders

Hepatic disorders, ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice, veno-occlusive disease has been reported following high dose treatment

Skin and subcutaneous tissue disorders

Alopecia (at high and conventional dose)

Maculopapular rashes, pruritus

Musculoskeletal and connective tissue disorders

Muscle atrophy, muscle fibrosis, myalgia, increased blood creatine phosphokinase, compartment syndrome (injection, following isolated limb perfusion)

Muscle necrosis, rhabdomyolysis (injection, following isolated limb perfusion)

Reproductive system and breast disorders

Azoospermia, amenorrhoea

General disorders and administrative site conditions

A subjective and transient sensation of warmth and/or tingling

Investigations

Temporary significant elevation of the blood urea has been seen in the early stages of ZALCAREN therapy in myeloma patients with renal damage

b. Description of selected adverse reactions

Allergic reactions: Allergic reactions of ZALCAREN such as urticaria, oedema, skin rashes and anaphylaxis have been reported following initial or subsequent dosing, particularly after intravenous administration in patients who were treated over several months. Cardiac arrest has occurred in association with such events.

Gastrointestinal disorders: The incidence of diarrhoea, vomiting and stomatitis becomes the dose-limiting toxicity in patients given high IV doses of ZALCAREN in association with haemopoietic stem cell rescue. Cyclophosphamide pre-treatment has been shown to reduce the severity of the gastrointestinal damage induced by high-dose ZALCAREN; the literature should be consulted for details.

c. Other special population: Chemotherapy: ZALCAREN should be used with caution in patients who have undergone recent radiotherapy or chemotherapy in view of increased bone marrow toxicity. Renal Impairment: Such patients should be closely observed for uraemic marrow suppression. Temporary significant elevation of blood urea has been seen in the early stages of treatment in myeloma patients with renal damage. Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS): Before the start of the treatment, the leukaemogenic risk (AML and MDS) must be balanced against the potential therapeutic benefit, especially if the use of melphalan in combination with thalidomide or lenalidomide and prednisone is considered, as it has been shown that these combinations may increase the leukaemogenic risk.

d. Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via The u20186.04 Adverse Drug Reactions Reporting Formu2019. Found under SAHPRAu2019s publications: https://www/sahpra.org.za/Publications/Index/8.

Symptoms and signs: The immediate effects of acute intravenous over dosage are nausea and vomiting. Damage to the gastrointestinal mucosa may also ensue, and diarrhoea, sometimes haemorrhagic, has been reported after overdosage. The principal toxic effect is bone marrow suppression, leading to leucopaenia, thrombocytopaenia and anaemia.

Treatment: General supportive measures, together with appropriate blood transfusion, should be instituted if necessary. There is no specific antidote. The blood picture should be closely monitored for at least four weeks following overdosage until there is evidence of recovery and consideration given to hospitalisation, antibiotic cover, and the use of haemotological growth factors.