Vexfan 6mg Solution for infusion

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

VEXFAN should not be given by rapid IV injection or bolus.
VEXFAN should be administered under the supervision of a qualified medical practitioner who is experienced in conditioning treatment prior to haematopoeietic progenitor cell transplantation, in the use of cancer chemotherapeutic medicines and in the management of patients with severe pancytopenia. It is recommended to use actual body weight for dosing. 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.
The recommended dosage and regimen is 0,8 mg/kg body weight of VEXFAN as a two hour infusion every 6 hours over 4 consecutive days, for a total of 16 doses prior to haematopoietic progenitor cell transplantation.
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).
Administration: VEXFAN must be diluted before administration. A final concentration of approximately 0,5mg/ml busulfan should be achieved (see section 6.6 for the detailed preparation of dilution). VEXFAN should be administered by IV infusion via central venous catheter.

• Hypersensitivity to busulfan or to any of the excipients of VEXFAN.
• Pregnancy and lactation.
• The safety and efficacy in children have not been established.
• Hepatic insufficiency.

VEXFAN should not be given by rapid IV injection or bolus. The consequence of treatment with VEXFAN 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 quantitative platelet counts should be monitored during the treatment and until recovery is achieved. Prophylactic or empiric use of anti-infective medicines (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 use of growth factors such as granulocyte colony stimulating medicine (G-CSF), should be employed as medically indicated. Absolute neutrophil counts < 0,5x109/l at a median of 4 days post-transplant may present in patients and recover at median day 10 and 13 days following autologous and allogeneic transplant respectively (median neutropenic period of 6 and 9 days respectively). Prophylactic use of anti-infective medicines should be considered for the prevention and management of infections during the neutropenic period. Thrombocytopenia (< 25x109/l or requiring platelet transfusion) can occur in patients. Anaemia (haemoglobin < 8,0 g/dl) may also develop. VEXFAN has not been studied in patients with hepatic impairment. Since busulfan is mainly metabolised through the liver exposure to VEXFAN is expected to increase if liver function is impaired and the use of VEXFAN in hepatic impaired population is contraindicated.
Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or a prior progenitor cell transplant may be at an increased risk of developing hepatic veno-occlusive disease with the recommended dose and regimen. Caution should be exercised when using paracetamol prior to (less than 72 hours) or concurrently with VEXFAN due to a possible decrease in the metabolism of busulfan (See section 4.5). Cardiac function should be monitored regularly in patients receiving VEXFAN (see section 4.8). Acute respiratory distress syndrome with subsequent respiratory failure associated with interstitial pulmonary fibrosis has been reported. 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 (see section 4.8). Dose modification is not recommended for patients with renal impairment; however, caution is advised. Periodic monitoring of renal function should be considered during therapy with VEXFAN (see section 4.8). Seizures have been reported with high dose busulfan treatment. Special caution should be exercised when administering the recommended dose of VEXFAN to patients with a history of seizures, head trauma, or receiving other potentially epileptogenic medicines. Patients should receive adequate anticonvulsant prophylaxis. The increased risk of a second malignancy should be explained to the patient. Busulfan has been classified by the International Agency for Research on Cancer (IARC) as a human carcinogen. The World Health Organisation has concluded that there is a causal relationship between busulfan exposure and cancer. Leukaemia patients treated with busulfan developed many different cytological abnormalities, and some developed carcinomas. Busulfan is thought to be leukemogenic. Busulfan can impair fertility. Therefore, men treated with VEXFAN 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 VEXFAN. Ovarian suppression and amenorrhoea with menopausal symptoms commonly occur in pre-menopausal patients. Impotence, sterility, azoospermia, and testicular atrophy have been reported in male patients. The solvent dimethylacetamide (DMA) may also impair fertility. Cases of thrombotic microangiopathy after hematopoietic cell transplantation (HCT), including fatal cases, have been reported in high-dose conditioning regimens in which busulfan was administered in combination with another conditioning treatment.

Administration of itraconazole to patients receiving high-dose VEXFAN may result in reduced busulfan clearance. Plasma levels of busulfan may increase after administration of metronidazole. Patients should be monitored for signs of busulfan toxicity when itraconazole or metronidazole is used as an antifungal prophylaxis with VEXFAN. No interaction is observed when busulfan is combined with fluconazole (antifungal medicine). 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 (see section 4.4). 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 5-HT3 antiemetics such as ondansetron or granisetron.

Women of child-bearing potential must use effective contraception during and up to 6 months after treatment.
Pregnancy: VEXFAN is contra-indicated in pregnancy.
Breastfeeding: It is not known whether VEXFAN is excreted in breast milk. Because of the tumorigenicity shown for busulfan in human and animal studies, breastfeeding should be discontinued at the start of therapy.
Fertility: Busulfan and DMA can impair fertility in man or woman. Therefore, it is advised not to father a child during the treatment 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 (see section 4.4).

Confusion and dizziness have been reported with the use of VEXFAN. Therefore, caution is recommended when driving or operating machines.

a) Summary of the safety profile
Serious toxicities involving the haematologic, hepatic and respiratory systems are considered as expected consequences of the conditioning regimen and transplant process. These include infection and Graft-versus host disease (GVHD) which although not directly related, are the major causes of morbidity and mortality, especially in allogeneic HPCT.
Blood and lymphatic system disorders: Myelo-suppression and immuno-suppression are the desired therapeutic effects of the conditioning regimen. Therefore, all patients can experience profound cytopenia.
Immune system disorders: Patients may experience a graft versus host disease (a-GVHD). Chronic GVHD (c-GVHD) may cause death.
Infections and infestations: Patients may experience episodes of mild or moderate infection. Pneumonia can be fatal or life-threatening, including mild/ moderate fever and chills.
Hepato-biliary disorders: Hepatic Veno Occlusive Disease (HVOD) is a recognized potential complication of conditioning therapy post-transplant. Mild to moderate jaundice may develop in patients, associated with GVHD or HVOD. Severe AST elevations can occur, that are mild to moderate.
Respiratory, thoracic and mediastinal disorders: Acute respiratory distress syndrome with subsequent respiratory failure associated with interstitial pulmonary fibrosis may occur.
b) Tabulated summary of adverse reactions
The following side effects to be considered in patients treated with VEXFAN:
System organ class Frequent Less frequent Frequency unknown Infections and infestations Rhinitis Pharyngitis Blood and lymphatic disorders Neutropenia Thrombocytopenia Febrile neutropenia Anaemia Pancytopenia Immune system disorders Allergic reaction Endocrine disorders Hypogonadism Metabolism and nutrition disorders Anorexia Hyperglycaemia Hypocalcaemia Hypokalaemia Hypomagnesaemia Hypophosphatemia Hyponatremia Psychiatric disorders Anxiety Depression Insomnia Confusion Delirium Nervousness Hallucination Agitation Nervous system disorders Headache Dizziness Seizure Encephalopathy Cerebral haemorrhage Eye disorders Cataract Corneal thinning Cardiac disorders Tachycardia Dysrhythmia Atrial fibrillation Cardiomegaly Pericardial effusion Pericarditis Ventricular extrasystoles Bradycardia Vascular disorders Hypertension, Hypotension Thrombosis Femoral artery thrombosis Capillary leak syndrome Respiratory system, thoracic and mediastinal disorders Dyspnoea, Epistaxis Cough Hiccup Hyperventilation Respiratory failure Alveolar haemorrhages Asthma Atelectasis Pleural effusion Hypoxia Interstitial lung disease Gastrointestinal disorders Stomatitis Diarrhoea Abdominal pain Nausea Vomiting Dyspepsia Ascites Constipation Anus discomfort Haematemesis Ileus Oesophagitis Gastrointestinal haemorrhage Tooth hypoplasia Hepatobiliary disorders Hepatomegaly Jaundice Veno-occlusive liver disease Increased hepatic enzymes Skin and subcutaneous tissue disorders Rash Pruritis Alopecia Skin desquamation Erythema Pigmentation disorder Musculoskeletal and connective tissue disorders Myalgia Back pain Arthralgia Renal and urinary disorders Dysuria Oligurea Haematuria Moderate renal insufficiency Reproductive system and breast disorders Premature menopause Ovarian failure General disorders and administration site Asthenia conditions Chills Fever Chest pain Oedema Oedema general Pain Pain or inflammation at injection site Mucositis Investigations Transaminases increased Bilirubin increased GGT increased Alkaline phosphatases increased Weight increased Abnormal breath sounds Creatinine elevated Blood urea nitrogen increase Decrease ejection fraction 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. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

The main toxic effect is profound myeloablation and pancytopenia, but the central nervous system, liver, lungs and gastrointestinal tract may be affected. There is no known antidote to VEXFAN other than haematopoietic progenitor cell transplantation. In the absence of haematopoietic progenitor cell transplantation, the recommended dose of VEXFAN 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 metabolized through conjugation with glutathione, administration of glutathione might be considered. It must be considered that overdose of VEXFAN will also increase exposure to DMA. The principal toxic effects are hepatotoxicity and central nervous system (CNS) effects. CNS changes precede any of the more severe side effects. No specific antidote for DMA overdose is known. In case of overdose, management would include general supportive care.