Detener 60,0 mg Concentrate for solution for infusion

Conditioning treatment prior to haematopoeietic progenitor cell transplantation (HPCT) in adults when the combination of busulfan and cyclophosphamide (Bu/Cy2) is considered the best available option.

DETENER should be administered under the supervision of a qualified medical practitioner who is experienced in conditioning treatment prior to HPCT in the use of cancer chemotherapeutic medicines and in the management of patients with severe pancytopenia.

Posology It is recommended to use actual body weight for dosing. The recommended dosage and regimen is 0,8 mg/kg body weight of DETENER as a two hour infusion every 6 hours over 4 consecutive days, for a total of 16 doses prior to haematopoietic progenitor cell transplantation.

Special populations Obese patients: For obese or severely obese patients, dosing based on adjusted ideal body weight could be considered. Ideal body weight (IBW) should be calculated as follows (height in cm and weight in kg): IBW (kg; men) = 50 + 0,91 X (height - 152); IBW (kg; women) = 45 + 0,91 X (height-152). Adjusted ideal body weight (AIBW) should be calculated as follows: AIBW = IBW + 0,25 X (actual body weight - IBW)

Method of administration: DETENER should be administered by IV infusion via central venous catheter. DETENER should not be given by rapid IV injection or bolus. All patients should be premedicated with anticonvulsant medicines to prevent seizures reported with the use of high dose busulfan. Antiemetics should be administered prior to the first dose and continued on a fixed schedule through its administration.

Precautions to be taken before handling or administering the medicinal product. DETENER must be diluted before administration. A final concentration of approximately 0,5mg/ml busulfan should be achieved. For instructions on dilution of the medicinal product before administration, see section 6.6. DETENER should be administered by IV infusion via central venous catheter.

Hypersensitivity to busulfan or to any of the excipients listed in section 6.1. Pregnancy and lactation (see section 4.6). The safety and efficacy in children have not been established. Hepatic insufficiency.

The consequence of treatment with DETENER at the recommended dose and schedule is profound myelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anaemia, or any combination thereof may develop. Frequent complete blood counts, including differential white blood cell counts, and platelet counts should be monitored during the treatment and until recovery is achieved.

Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the prevention and management of infections during the neutropenic period. Platelet and red blood cell support, as well as the use of growth factors such as granulocyte colony stimulating factor (G-CSF), should be employed as medically indicated.

In adults, absolute neutrophil counts < 0,5x109/L at a median of 4 days post transplant occurred in 100% of patients and recovered at median day 10 and 13 days following autologous and allogeneic transplant respectively (median neutropenic period of 6 and 9 days respectively). Thrombocytopenia (< 25x109/L or requiring platelet transfusion) occurred at a median of 5-6 days in 98% of patients. Anaemia (haemoglobin< 8.0 g/dL) occurred in 69% of patients.

There is limited clinical experience of the use of busulfan as a component of a conditioning regimen prior to HSCT in children with Fanconi's anaemia. Therefore DETENER should be used with caution in this type of patients.

Hepatic impairment DETENER as well as busulfan has not been studied in patients with hepatic impairment. Since busulfan is mainly metabolised through the liver, exposure to busulfan is expected to increase if liver function is impaired and the use of DETENER in hepatic impaired populations is contra- indicated. It is recommended when treating these patients that serum transaminase, alkaline phosphatase, and bilirubin should be monitored regularly 28 days following transplant for early detection of hepatotoxicity.

Hepatic veno-occlusive disease is a major complication that can occur during treatment with DETENER. Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk.

Caution should be exercised when using paracetamol prior to (less than 72 hours) or concurrently with DETENER due to a possible decrease in the metabolism of busulfan (see section 4.5).

Cardiac function should be monitored regularly in patients receiving DETENER. Occurrence of acute respiratory distress syndrome with subsequent respiratory failure associated with interstitial pulmonary fibrosis was reported in busulfan studies in one patient who died, although, no clear aetiology was identified. In addition, busulfan might induce pulmonary toxicity that may be additive to the effects produced by other cytotoxic medicines. Therefore, attention should be paid to this pulmonary issue in patients with prior history of mediastinal or pulmonary radiation.

Periodic monitoring of renal function should be considered during therapy with DETENER. Seizures have been reported with high dose busulfan treatment. Special caution should be exercised when administering the recommended dose of DETENER to patients with a history of seizures, head trauma or receiving other potentially epileptogenic medicines. Patients should receive adequate anticonvulsant prophylaxis.

Administration of itraconazole to patients receiving high-dose busulfan may result in reduced busulfan clearance. Patients should be monitored for signs of busulfan toxicity when itraconazole is used as an antifungal prophylaxis with busulfan.

Ketobemidone may be associated with high levels of busulfan. Special care is recommended when combining these two medicines. For the BuCy2 regimen it has been reported that the time interval between the last oral busulfan administration and the first cyclophosphamide administration may influence the development of toxicities. A reduced incidence of HVOD and other regimen-related toxicity have been observed in patients when the lag time between the last dose of oral busulfan and the first dose of cyclophosphamide is > 24 hours.

Paracetamol is described to decrease glutathione levels in blood and tissues and may therefore decrease busulfan clearance when used in combination.

The concomitant systemic administration of phenytoin to patients receiving high-dose busulfan has been reported to increase busulfan clearance, due to induction of glutathion-S-transferase. However, no evidence of this effect has been seen in the IV data.

No interaction has been reported when benzodiazepines such as diazepam, clonazepam or lorazepam have been used to prevent seizures with high-dose busulfan. No interaction was observed when busulfan was combined with fluconazole or 5-HT3 antiemetics such as ondansetron or granisetron.

Women of childbearing potential/contraception in males and females Women of childbearing potential must use effective contraception during and up to 6 months after treatment.

Pregnancy HPCT is contraindicated in pregnant women; therefore, DETENER is contraindicated during pregnancy. There are no or limited amount of data from the use of busulfan or dimethylacetamide (DMA) in pregnant women. A few cases of congenital abnormalities have been reported with low-dose oral busulfan, not necessarily attributable to the active substance, and third trimester exposure may be associated with impaired intrauterine growth.

Breast-feeding It is unknown whether busulfan and DMA are excreted in human milk. Because of the potential for tumorigenicity shown for busulfan in human and animal studies, breast-feeding should be discontinued during treatment with busulfan.

Fertility Busulfan can impair fertility. Therefore, men treated with DETENER are advised not to father a child during and up to 6 months after treatment and to seek advice on cryo-conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with DETENER. Ovarian suppression and amenorrhoea with menopausal symptoms commonly occur in pre-menopausal patients. Busulfan treatment in a pre-adolescent girl prevented the onset of puberty due to ovarian failure. Impotence, sterility, azoospermia, and testicular atrophy have been reported in male patients.

Not relevant

a. Summary of the safety profile Most patients were considered high-risk for transplant, having at least one of the following risk factors such as previous transplant, active disease, refractory and/or relapsed disease and co-morbid factors such as age over 45 year.

- The most frequent, serious, toxic effect of busulfan is myelosuppression resulting in leukopenia, thrombocytopenia and anaemia in all patients.

- Serious adverse events involved liver toxicity.

b. Tabulated summary of adverse reactions System organ class Frequency Side - effect Blood and lymphatic system disorders Frequent Neutropenia Thrombocytopenia Anaemia Pancytopenia Febrile neutropenia Immune system disorders Frequent Allergic reaction Nervous system disorders Frequent Dizziness Less frequent Encephalopathy Cerebral haemorrhage Seizure Psychiatric disorders Frequent Insomnia Anxiety Depression Confusion Less frequent Delirium Nervousness Hallucination Agitation Metabolism and nutrition disorders Frequent Hyperglycaemia Hypomagnesaemia Hypokalaemia Hypocalcaemia Hypophosphataemia Hyponatraemia Cardiac disorders Frequent Tachycardia Arrhythmia Atrial fibrillation Cardiomegaly Pericardial effusion Pericarditis Less frequent Ventricular extrasystoles Bradycardia Vascular disorders Frequent Hypertension Hypotension Vasodilation Thrombosis Less frequent Femoral artery thrombosis Capillary leak syndrome Respiratory thoracic and mediastinal disorders Frequent Dyspnoea Cough Hiccup Epistaxis Hyperventilation Respiratory failure Alveolar haemorrhages Asthma Atelectasis Pleural effusion Less frequent Hypoxia Acute respiratory distress syndrome Infections and infestations Frequent Rhinitis Pharyngitis Less frequent Pneumonia Graft versus host disease One or more episodes of infection (mostly mild to moderate) Gastrointestinal disorders Frequent Nausea Stomatitis Vomiting Anorexia Diarrhoea Constipation Dyspepsia Anus discomfort Oesophagitis Ileus Haematemesis Less frequent Gastrointestinal haemorrhage Hepato-biliary disorders Frequent Hyperbilirubinaemia Jaundice Increased hepatic enzymes Blood alkaline phosphatase increased Hepatomegaly Less frequent Hepatic veno - occlusive disease (HVOD) Severe AST elevations Skin and subcutaneous tissue disorders Frequent Rash Pruritis Alopecia Musculoskeletal and connective tissue disorders Frequent Back pain Myalgia Arthralgia Renal and urinary disorders Frequent Dysuria Oligurea Haematuria Moderate renal insufficiency General disorders and administration site conditions Frequent Fever Headache Abdominal pain Asthenia Chills Pain Oedema Oedema general Pain or inflammation at the injection site Chest pain Investigations Frequent Decreased ejection fraction Creatinine elevated BUN increase Weight increase Abnormal breath sounds

c. Description of selected adverse reactions 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 medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

The principal toxic effect is profound myeloablation and pancytopenia but the central nervous system, liver, lungs, and gastrointestinal tract may also be affected.

There is no known antidote to DETENER other than haematopoietic progenitor cell transplantation. In the absence of haematopoietic progenitor cell transplantation, the recommended dose of DETENER would constitute an overdose of busulfan. The haematologic status should be closely monitored and vigorous supportive measures instituted as medically indicated. Dialysis should be considered in the case of an overdose. Since, busulfan is metabolised through conjugation with glutathione, administration of glutathione might be considered. It must be considered that overdose of DETENER will also increase exposure to DMA. No specific antidote for DMA overdose is known. In case of overdose, management would include general supportive care.