Adverse reactions : תופעות לוואי

4.8 Undesirable effects

For this product there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the dose received and also when given in combination with other therapeutic agents.

The following convention has been utilised for the classification of frequency: Very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000) and not known (frequency cannot be estimated from the available data).

The following table of adverse reactions originated from the use of busulfan, or busulfan in combination with other therapeutic agents.

System organ class                 Frequency         Side effects

Neoplasms benign, malignant        Common            Leukaemia secondary to oncology and unspecified (including cysts                     chemotherapy (see section 4.4) and polyps)

Blood and lymphatic system         Very              Dose-related bone marrow failure, manifesting disorders *                        common            as leukopenia and particularly thrombocytopenia

Rare              Aplastic anaemia

Nervous system disorders           Rare              At high-dose: seizure (see section 4.4 and 4.5) 

Very rare         Myasthenia gravis
Eye disorders                      Rare              Lens disorder and cataract (which may be bilateral) corneal thinning (reported after bone marrow transplantation preceded by high-dose
Myleran treatment)

Cardiac disorders                  Common            At high-dose: cardiac tamponade in patients with thalassaemia

Respiratory, thoracic and          Very              At high-dose: idiopathic pneumonia syndrome mediastinal disorders *            common

System organ class                 Frequency         Side effects

Common            Interstitial lung disease following long term conventional dose use
Gastrointestinal disorders         Very              At high-dose: nausea, vomiting, diarrhoea, common            mouth ulceration

Rare              At conventional dose: nausea, vomiting,
diarrhoea, mouth ulceration, which may possibly be ameliorated by using divided doses.
Dry mouth

Not known         Tooth hypoplasia
Hepatobiliary disorders *          Very              At-high-dose: hyperbilirubinaemia, jaundice, common            venoocclusive liver disease (see section 4.4 and 4.5) and biliary fibrosis with hepatic atrophy and hepatic necrosis
Rare              Jaundice and abnormal hepatic function abnormal at conventional dose. Biliary fibrosis

Skin and subcutaneous tissue       Common            Alopecia at high-dose. Skin hyperpigmentation disorders *                                          (see also General disorders and administration site conditions)

Rare              Alopecia at conventional dose, skin reactions including urticaria, erythema multiforme,
erythema nodosum, porphyrianon-acute, rash,
dry skin and fragility of the skin with complete anhydrosis cheilosis, Sjögren’s syndrome. An increased radiation skin injury in patients receiving radiotherapy soon after high-dose
Myleran
Musculoskeletal and connective     Rare              Sjögren’s syndrome tissue disorders

Injury, poisoning and procedural   Rare              Radiation skin injury is increased in patients complications                                        receiving radiotherapy soon after high-dose busulfan

Renal and urinary disorders        Common            At high-dose: in combination with cyclophosphamide cystitis haemorrhagic

Reproductive system and breast     Very              Ovarian disorder and amenorrhoea with disorders *                        common            menopausal symptoms in pre-menopausal patients at high-dose; severe and persistent ovarian failure, including pubertal failure after administration to young girls and pre- adolescents at high-dose. Male infertility,
azoospermia and testicular atrophy in male patients receiving Myleran


System organ class                 Frequency         Side effects

Uncommon          Ovarian disorder and amenorrhoea with menopausal symptoms in pre-menopausal patients at conventional dose.

Very rare         Gynaecomastia
General disorders and              Rare              Dysplasia administration site conditions *


Description of selected adverse events

Blood and lymphatic system disorders

Aplastic anaemia (sometimes irreversible) has been reported rarely, typically following long- term conventional doses and also high doses of Myleran.

Respiratory, thoracic and mediastinal disorders

Pulmonary toxicity after either high or conventional dose treatment typically presents with non-specific non-productive cough, dyspnoea and hypoxia with evidence of abnormal pulmonary physiology. Other cytotoxic agents may cause additive lung toxicity (see section 4.5). It is possible that subsequent radiotherapy can augment subclinical lung injury caused by busulfan. Once pulmonary toxicity is established the prognosis is poor despite busulfan withdrawal and there is little evidence that corticosteroids are helpful.

Idiopathic pneumonia syndrome is a non-infectious diffuse pneumonia which usually occurs within three months of high-dose Myleran conditioning prior to allogeneic or autologous haemopoietic     transplant. Diffuse alveolar haemorrhage may also be detected in some cases after broncholavage. Chest X-rays or CT scans show diffuse or non-specific focal infiltrates and biopsy shows interstitial pneumonitis and diffuse alveolar damage and sometimes fibrosis.

Interstitial pneumonitis may occur following conventional dose use and lead to pulmonary fibrosis. This usually occurs after prolonged treatment over a number of years. The onset is usually insidious but may also be acute. Histological features include atypical changes of the alveolar and bronchiolar epithelium and the presence of giant cells with large hyperchromatic nuclei. The lung pathology may be complicated by superimposed infections.
Pulmonary ossification and dystrophic calcification have also been reported.

Hepatobiliary disorders

Busulfan is not generally considered to be significantly hepatotoxic at normal therapeutic doses. However, retrospective review of postmortem reports of patients who had been treated with low-dose busulfan for at least two years for chronic myeloid leukaemia showed evidence of centrilobular sinusoidal fibrosis.

Skin and subcutaneous tissue disorders

Hyperpigmentation occurs, particularly in those with a dark complexion. It is often most marked on the neck, upper trunk, nipples, abdomen and palmar creases. This may also occur as part of a clinical syndrome (see General disorders and administration site conditions).

Reproductive system and breast disorders

Studies of busulfan treatment in animals have shown reproductive toxicity (see section 5.3).

In very rare cases, recovery of ovarian function has been reported with continuing treatment.

General disorders and administration site conditions
Clinical syndrome (weakness, severe fatigue, anorexia, weight loss, nausea and vomiting and hyperpigmentation of the skin) resembling adrenal insufficiency (Addison's disease) but without biochemical evidence of adrenal suppression, mucous membrane hyperpigmentation or hair loss (see Skin and subcutaneous tissue disorders) has been seen in a few cases following prolonged Myleran therapy. The syndrome has sometimes resolved when busulfan has been withdrawn.

Many histological and cytological changes have been observed in patients treated with busulfan, including widespread dysplasia affecting uterine cervical, bronchial and other epithelia. Most reports relate to long-term treatment but transient epithelial abnormalities have been observed following short-term, high-dose treatment.

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il/ Additionally, you can report to the company via the following address: Padagis.co.il