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BUSILVEX Concentrate for solution (2017)

Active ingredients: Busulfan

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Pregnancy (see section 4.6).

Special warnings and precautions for use

The consequence of treatment with Busilvex 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 agent (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.

In paediatric population, absolute neutrophil counts <0.5x109/l at a median of 3 days post transplant occurred in 100% of patients and lasted 5 and 18.5 days in autologous and allogeneic transplant respectively. In children, thrombocytopenia (<25x109/l or requiring platelet transfusion) occurred in 100% of patients. Anaemia (haemoglobin <8.0 g/dl) occurred in 100% of patients.

In children <9 kg, a therapeutic drug monitoring may be justified on a case by case basis, in particular in extremely young children and neonates (see section 5.2).

The Fanconi anaemia cells have hypersensitivity to cross-linking agents. 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 Busilvex should be used with caution in this type of patients.

Hepatic impairment

Busilvex as well as busulfan has not been studied in patients with hepatic impairment. Since busulfan is mainly metabolized through the liver, caution should be observed when Busilvex is used in patients with pre-existing impairment of liver function, especially in those with severe hepatic impairment. 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 Busilvex. 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 (see section 4.8). Caution should be exercised when using paracetamol prior to (less than 72 hours) or concurrently with Busilvex due to a possible decrease in the metabolism of busulfan (See section 4.5).

As documented in clinical studies, no treated patients experienced cardiac tamponade or other specific cardiac toxicities related to Busilvex. However cardiac function should be monitored regularly in patients receiving Busilvex (see section 4.8).

Occurrence of acute respiratory distress syndrome with subsequent respiratory failure associated with interstitial pulmonary fibrosis was reported in Busilvex 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 agents. Therefore, attention should be paid to this pulmonary issue in patients with prior history of mediastinal or pulmonary radiation (see section 4.8).

Periodic monitoring of renal function should be considered during therapy with Busilvex (see section 4.8).

Seizures have been reported with high dose busulfan treatment. Special caution should be exercised when administering the recommended dose of Busilvex to patients with a history of seizures. Patients should receive adequate anticonvulsant prophylaxis. In adults and children studies, data with Busilvex were obtained when using concomitant administration of either phenytoin or benzodiazepines for seizure prophylaxis. The effect of those anticonvulsant agents on busulfan pharmacokinetics was investigated in a phase II study (see section 4.5).

The increased risk of a second malignancy should be explained to the patient. On the basis of human data, 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.

Fertility

Busulfan can impair fertility. Therefore, men treated with busulfan 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 busulfan. 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. The solvent dimethylacetamide (DMA) may also impair fertility. DMA decreases fertility in male and female rodents.

Interaction with other medicinal products and other forms of interaction

No specific clinical trial was carried out to assess drug-drug interaction between intravenous busulfan and itraconazole or metronidazole. From published studies in adults, administration of itraconazole to patients receiving high-dose busulfan may result in reduced busulfan clearance. Also, there are published case reports of increased plasma levels of busulfan after administration of metronidazole.

Patients who are concurrently treated with busulfan and itraconazole or metronidazole should be closely monitored for signs of busulfan toxicity.

No interaction was observed when busulfan was combined with fluconazole (antifungal agent).

Published studies in adults described that ketobemidone (analgesic) might be associated with high levels of plasma busulfan. Therefore special care is recommended when combining these two compounds.

In adults, 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 Hepatic Veno Occlusive Disease (HVOD) and other regimenrelated toxicity have been observed in patients when the lag time between the last dose of oral busulfan and the first dose of cyclophosphamide is >24hours. There is no common metabolism pathway between busulfan and fludarabine. In adults, for the FB regimen, published studies did not report any mutual drug-drug interaction between intravenous busulfan and fludarabine.

In paediatric population, for the BuMel regimen it has been reported that the administration of melphalan less than 24 hours after the last oral busulfan administration may influence the development of toxicities.

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).

Either phenytoin or benzodiazepines were administered for seizure prophylaxis in patients participating to the clinical trials conducted with intravenous busulfan (see section 4.2 and 4.4). The concomitant systemic administration of phenytoin to patients receiving high-dose of oral busulfan has been reported to increase busulfan clearance, due to induction of glutathion-S-transferase whereas no interaction has been reported when benzodiazepines such as diazepam, clonazepam or lorazepam have been used to prevent seizures with high-dose busulfan. No evidence of an induction effect of phenytoin has been seen on Busilvex data. A phase II clinical trial was performed to evaluate the influence of seizure prophylaxis treatment on intravenous busulfan pharmacokinetics. In this study, 24 adult patients received clonazepam (0.025-0.03 mg/kg/day as IV continuous infusions) as anticonvulsant therapy and the PK data of these patients were compared to historical data collected in patients treated with phenytoin. The analysis of data through a population pharmacokinetic method indicated no difference on intravenous busulfan clearance between phenytoin and clonazepam based therapy and therefore similar busulfan plasma exposures were achieved whatever the type of seizure prophylaxis.

No interaction was observed when busulfan was combined with 5 HT3 antiemetics such as ondansetron or granisetron.

Fertility, pregnancy and lactation

Pregnancy

HPCT is contraindicated in pregnant women; therefore, Busilvex is contraindicated during pregnancy.

Studies in animals have shown reproductive toxicity (embryo-fetal lethality and malformations) (see section 5.3).

There are no or limited amount of data from the use of busulfan or 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.

Women of childbearing potential

Women of childbearing potential have to use effective contraception during and up to 6 months after treatment.

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 and DMA can impair fertility in man or woman. Therefore it is advised not to father 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).

Effects on ability to drive and use machines

Not relevant.

Undesirable effects

Summary of the safety profile

Busilvex in combination with cyclophosphamide or melphalan

In adults

Adverse events information is derived from two clinical trials (n=103) of Busilvex. Serious toxicities involving the haematologic, hepatic and respiratory systems were 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, were the major causes of morbidity and mortality, especially in allogeneic HPCT.

Blood and lymphatic system disorders: Myelo-suppression and immuno-suppression were the desired therapeutic effects of the conditioning regimen. Therefore all patients experienced profound cytopenia: leucopenia 96%, thrombocytopenia 94%, and anemia 88%. The median time to neutropenia was 4 days for both autologous and allogeneic patients. The median duration of neutropenia was 6 days and 9 days for autologous and allogeneic patients.

Immune system disorders: The incidence of acute graft versus host disease (a-GVHD) data was collected in OMC-BUS-4 study (allogeneic)(n=61). A total of 11 patients (18%) experienced a-GVHD. The incidence of a-GVHD grades I-II was 13% (8/61), while the incidence of grade III-IV was 5% (3/61). Acute GVHD was rated as serious in 3 patients. Chronic GVHD (c-GVHD) was reported if serious or the cause of death, and was reported as the cause of death in 3 patients.

Infections and infestations: 39% of patients (40/103) experienced one or more episodes of infection, of which 83% (33/40) were rated as mild or moderate. Pneumonia was fatal in 1% (1/103) and life-threatening in 3% of patients. Other infections were considered severe in 3% of patients. Fever was reported in 87% of patients and graded as mild/moderate in 84% and severe in 3%. 47% of patients experienced chills which were mild/moderate in 46% and severe in 1%.

Hepato-biliary disorders: 15% of SAEs involved liver toxicity. HVOD is a recognized potential complication of conditioning therapy post-transplant. Six of 103 patients (6%) experienced HVOD. HVOD occurred in: 8.2% (5/61) allogeneic patients (fatal in 2 patients) and 2.5% (1/42) of autologous patients. Elevated bilirubin (n=3) and elevated AST (n=1) were also observed. Two of the above four patients with serious serum hepatotoxicity were among patients with diagnosed HVOD.

Respiratory, thoracic and mediastinal disorders: One patient experienced a fatal case of acute respiratory distress syndrome with subsequent respiratory failure associated with interstitial pulmonary fibrosis in the Busilvex studies. Paediatric population Adverse events information are derived from the clinical study in paediatrics (n=55). Serious toxicities involving the hepatic and respiratory systems were considered as expected consequences of the conditioning regimen and transplant process.

Immune system disorders: The incidence of acute graft versus host disease (a-GVHD) data was collected in allogeneic patients (n=28). A total of 14 patients (50%) experienced a-GVHD. The incidence of a-GVHD grades I-II was 46.4% (13/28), while the incidence of grade III-IV was 3.6% (1/28). Chronic GVHD was reported only if it is the cause of death: one patient died 13 months post-transplant. Infections and infestations: Infections (documented and non documented febrile neutropenia) were experienced in 89% of patients (49/55). Mild/moderate fever was reported in 76% of patients.

Hepato-biliary disorders: Grade 3 elevated transaminases were reported in 24% of patients. Veno occlusive disease (VOD) was reported in 15% (4/27) and 7% (2/28) of the autologous and allogenic transplant respectively. VOD observed were neither fatal nor severe and resolved in all cases.

Busilvex in combination with fludarabine (FB)

In adults

The safety profile of Busilvex combined with fludarabine (FB) has been examined through a review of adverse events reported in published data from clinical trials in RIC regimen. In these studies, a total of 1574 patients received FB as a reduced intensity conditioning (RIC) regimen prior to haematopoietic progenitor cell transplantation.

Myelo-suppression and immuno-suppression were the desired therapeutic effects of the conditioning regimen and consequently were not considered undesirable effects.

Infections and infestations: The occurrence of infectious episodes or reactivation of opportunistic infectious agents mainly reflects the immune status of the patient receiving a conditioning regimen. The most frequent infectious adverse reactions were Cytomegalovirus (CMV) reactivation [range: 30.7%-80.0%], Epstein-Barr Virus (EBV) reactivation [range: 2.3%-61%], bacterial infections [range: 32.0%-38.9%] and viral infections [range: 1.3%-17.2%].

Gastrointestinal disorders: The highest frequency of nausea and vomiting was 59.1% and the highest frequency of stomatitis was 11%.

Renal and urinary disorders: It has been suggested that conditioning regimens containing fludarabine were associated with higher incidence of opportunistic infections after transplantation because of the immunosuppressive effect of fludarabine. Late haemorrhagic cystitis occurring 2 weeks post-transplant are likely related to viral infection/reactivation. Haemorrhagic cystitis including haemorrhagic cystitis induced by viral infection was reported in a range between 16% and 18.1%.

Hepato-biliary disorders: VOD was reported with a range between 3.9% and 15.4%.

The treatment-related mortality/non-relapse mortality (TRM/NRM) reported until day+100 posttransplant has also been examined through a review of published data from clinical trials. It was considered as deaths that could be attributable to secondary side effects after HPCT and not related to the relapse/progression of the underlying haematological malignancies. The most frequent causes of reported TRM/NRMs were infection/sepsis, GVHD, pulmonary disorders and organ failure.

Tabulated summaries of adverse reactions

Frequencies are defined as: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100) or not known (cannot be estimated from the available data). Undesirable effects coming from post-marketing survey have been implemented in the tables with the incidence “not known”.

Busilvex in combination with cyclophosphamide or melphalan

Adverse reactions reported both in adults and paediatric patients as more than an isolated case are listed below, by system organ class and by frequency. Within each frequency grouping, adverse events are presented in order of decreasing seriousness.

Infections and infestations

Very common: Rhinitis, Pharyngitis

Blood and lymphatic system disorders

Very common: Neutropenia, Thrombocytopenia, Febrile neutropenia, Anaemia, Pancytopenia

Immune system disorders

Very common: Allergic reaction

Endocrine disorders

Not known: Hypogonadism**

Metabolism and nutrition disorders

Very common: Anorexia, Hyperglycaemia, Hypocalcaemia, Hypokalaemia, Hypomagnesaemia, Hypophosphatemia

Common: Hyponatraemia

Psychiatric disorders

Very common: Anxiety, Depression, Insomnia

Common: Confusion

Uncommon: Delirium, Nervousness, Hallucination, Agitation

Nervous system disorders

Very common: Headache, Dizziness

Uncommon: Seizure, Encephalopathy, Cerebral haemorrhage

Eye disorders

Not known: Cataract, Corneal thinning, Lens disorders***

Cardiac disorders

Very common: Tachycardia

Common: Arrhythmia, Atrial fibrillation, Cardiomegaly, Pericardial effusion, Pericarditis

Uncommon: Ventricular extrasystoles, Bradycardia

Vascular disorders

Very common: Hypertension, Hypotension, Thrombosis, Vasodilatation

Uncommon: Femoral artery thrombosis, Capillary leak syndrome

Respiratory thoracic and mediastinal disorders

Very common: Dyspnoea, Epistaxis, Cough, Hiccup

Common: Hyperventilation, Respiratory failure, Alveolar haemorrhages, Asthma, Atelectasis, Pleural effusion

Uncommon: Hypoxia

Not known: Interstitial lung disease**

Gastrointestinal disorders

Very common: Stomatitis, Diarrhoea, Abdominal pain, Nausea, Vomiting, Dyspepsia, Ascites, Constipation, Anus discomfort

Common: Haematemesis, Ileus, Oesophagitis

Uncommon: Gastrointestinal haemorrhage

Not known: Tooth hypoplasia**

Hepato-biliary disorders

Very common: Hepatomegaly, Jaundice

Common: Veno occlusive liver disease *

Skin and subcutaneous tissue disorders

Very common: Rash, Pruritis, Alopecia

Common: Skin desquamation, Erythema, Pigmentation disorder

Musculoskeletal and connective tissue disorders

Very common: Myalgia, Back pain, Arthralgia

Renal and urinary disorders

Very common: Dysuria, Oligurea

Common: Haematuria, Moderate renal Insufficiency

Reproductive system and breast disorders

Not known: Premature menopause, Ovarian failure**

General disorders and administration site conditions

Very common: Asthenia, Chills, Fever, Chest pain, Oedema, Oedema general, Pain, Pain or inflammation at injection site, Mucositis

Investigations

Very common: Transaminases increased, Bilirubin increased, GGT increased, Alkaline phosphatases increased, Weight increased, Abnormal breath sounds, Creatinine elevated

Common: Bun increase, Decrease ejection fraction

* veno occlusive liver disease is more frequent in paediatric population.
** reported in post marketing with IV busulfan
*** reported in post marketing with oral busulfan

Busilvex in combination with fludarabine (FB)

The incidence of each adverse reactions presented in the following table has been defined according to the highest incidence observed in published clinical trials in RIC regimen for which the population treated with FB was clearly identified, whatever the schedules of busulfan administrations and endpoints. Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency.

Infections and infestations

Very common: Viral infection, CMV reactivation, EBV reactivation, Bacterial infection

Common: Invasive fungal infection, Pulmonary infection

Not known*: Brain abscess, Cellulitis, Sepsis

Blood and lymphatic system disorders

Not known*: Febrile neutropenia

Metabolism and nutrition disorders

Very common: Hypoalbuminaemia, Electrolyte disturbance, Hyperglycaemia

Not known*: Anorexia

Psychiatric disorders

Not known*: Agitation, Confusional state, Hallucination

Nervous system disorders

Common: Headache, Nervous system disorders [Not Elsewhere Classified]

Not known*: Cerebral haemorrhage, Encephalo-pathy

Cardiac disorders

Not known*: Atrial fibrillation

Vascular disorders

Common: Hyper-tension

Respiratory thoracic and mediastinal disorders

Common: Pulmonary haemorrhage

Not known*: Respiratory failure

Gastro-intestinal disorders

Very common: Nausea, Vomiting, Diarrhoea, Stomatitis

Not known*: Gastro-intestinal haemorrhage, Tooth hypoplasia*

Hepato-biliary disorders

Very common: Veno occlusive liver disease

Not known*: Jaundice, Liver disorders

Skin and subcutaneous tissue disorders

Common: Rash

Renal and urinary disorders

Very common: Haemorrhagic cystitis**

Common: Renal disorder

Not known*: Oliguria

General disorders and administration site conditions

Very common: Mucositis

Not known*: Asthenia, Oedema, Pain

Investigations

Very common: Transaminases increased, Bilirubine increased, Alkaline phosphatases increased

Common: Creatinine elevated

Not known*: Blood lactate dehydrogenase increased, Blood uric acid increased, Blood urea increased, GGT increased, Weight increased

* reported in post marketing experience
** include haemorrhagic cystitis induced by viral infection

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product 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 via the national reporting system listed in Appendix V.

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Do not use polycarbonate syringes with Busilvex.