4.1. Therapeutic indications

Cerezyme (imiglucerase) is indicated for use as long-term enzyme replacement therapy in patients with a confirmed diagnosis of non-neuronopathic (Type 1) or chronic neuronopathic (Type 3) Gaucher disease who exhibit clinically significant non-neurological manifestations of the disease.

The non-neurological manifestations of Gaucher disease include one or more of the following conditions:

• anaemia after exclusion of other causes, such as iron deficiency

• thrombocytopenia

• bone disease after exclusion of other causes such as Vitamin D deficiency

• hepatomegaly or splenomegaly

4.2. Posology and method of administration

Disease management should be directed by physicians knowledgeable in the treatment of Gaucher disease.

Posology

Due to the heterogeneity and the multi-systemic nature of Gaucher disease, dosage should be individualised for each patient based on a comprehensive evaluation of all clinical manifestations of the disease. Once individual patient response for all relevant clinical manifestations is well-established, dosages and frequency of administration may be adjusted with the goal to either maintain already reached optimal parameters for all clinical manifestations or further improve those clinical parameters which have not yet been normalised.

A range of dosage regimens has proven effective towards some or all of the non-neurological manifestations of the disease. Initial doses of 60 U/kg of body weight once every 2 weeks have shown improvement in haematological and visceral parameters within 6 months of therapy and continued use has either stopped progression of or improved bone disease. Administration of doses as low as 15 U/kg of body weight once every 2 weeks has been shown to improve haematological parameters and organomegaly, but not bone parameters. The usual frequency of infusion is once every 2 weeks; this is the frequency of infusion for which the most data are available.

Paediatric population

No dose adjustment is necessary for the paediatric population.

The efficacy of Cerezyme on neurological symptoms of chronic neuronopathic Gaucher patients has not been established and no special dosage regimen can be recommended for these manifestations (see section 5.1).

Method of administration

After reconstitution and dilution, the preparation is administered by intravenous infusion. At initial infusions, Cerezyme should be administered at a rate not exceeding 0.5 unit per kg body weight per minute. At subsequent administrations, infusion rate may be increased but should not exceed 1 unit per kg body weight per minute. Infusion rate increases should occur under supervision of a health care professional.

Infusion of Cerezyme at home may be considered for patients who are tolerating their infusions well for several months. Decision to have patient move to home infusion should be made after evaluation and recommendation by the treating physician. Infusion of Cerezyme by the patient or caregiver at home requires training by a health care professional in a clinical setting. The patient or caregiver will be instructed in infusion technique and the keeping of a treatment diary. Patients experiencing adverse events during the infusion need to immediately stop the infusion process and seek the attention of a healthcare professional. Subsequent infusions may need to occur in a clinical setting. Dose and infusion rate should remain constant while at home, and not be changed without supervision of a health care professional.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

Medical or healthcare professionals are encouraged to register Gaucher patients, including those with chronic neuronopathic manifestations of the disease, in the “ICGG Gaucher Registry” (see section 5.1).

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Hypersensitivity

Current data using a screening ELISA followed by a confirmatory radioimmunoprecipitation assay, suggest that, during the first year of therapy, IgG antibodies to imiglucerase are formed in approximately 15% of the treated patients. It appears that patients who will develop IgG antibody are most likely to do so within 6 months of treatment and will rarely develop antibodies to Cerezyme after 12 months of therapy. It is suggested that patients suspected of a decreased response to the treatment be monitored periodically for IgG antibody formation to imiglucerase.

Patients with antibody to imiglucerase have a higher risk of hypersensitivity reactions (see section 4.8). If a patient experiences a reaction suggestive of hypersensitivity, subsequent testing for imiglucerase antibodies is advised. As with any intravenous protein product, severe allergic-type hypersensitivity reactions are possible, but occur uncommonly. If these reactions occur, immediate discontinuation of the Cerezyme infusion is recommended and appropriate medical treatment should be initiated. The current medical standards for emergency treatment are to be observed.

Patients who have developed antibodies or symptoms of hypersensitivity to Ceredase (alglucerase) should be treated with caution when administering Cerezyme (imiglucerase).

Infusion-Associated Reactions (IAR)

Infusion-associated reactions (IAR) such as angioedema, pruritus, rash, urticaria, chest discomfort, chills, fatigue, infusion-site burning, infusion-site discomfort, infusion-site swelling, pyrexia and transient hypertension have been observed in patients treated with imiglucerase (see section 4.8).

Careful consideration should be given to the patient's clinical status prior to administration of Cerezyme.

Antihistamines, antipyretics, and/or corticosteroids can be given to prevent or reduce IARs. However, IARs may still occur in patients after receiving pre-treatment. If mild or moderate IARs occur regardless of pre-treatment, decreasing the infusion rate or temporarily stopping the infusion may ameliorate the symptoms. If severe IARs occur, immediate discontinuation of the administration of Cerezyme should be considered and appropriate medical treatment should be initiated. The benefits and risks of re-administering Cerezyme following severe IARs should be considered (see section 4.8).

Sodium

This medicinal product contains 41 mg sodium per vial, equivalent to 2% of the WHO recommended maximum daily intake of 2 g sodium for an adult. It is administered in 0.9% sodium chloride intravenous solution (see section 6.6). To be taken into consideration by patients on a controlled sodium diet.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6. Fertility, pregnancy and lactation

Pregnancy

Limited experience from 150 pregnancy outcomes (primarily based on spontaneous reporting and literature review) is available suggesting that use of Cerezyme is beneficial to control the underlying Gaucher disease in pregnancy. Furthermore, these data indicate no malformative toxicity for the foetus by Cerezyme, although the statistical evidence is low. Foetal demise has been reported rarely, although it is not clear whether this related to the use of Cerezyme or to the underlying Gaucher disease.

No animal studies have been carried out with respect to assessing the effects of Cerezyme on pregnancy, embryonal/foetal development, parturition and postnatal development. It is not known whether Cerezyme passes via the placenta to the developing foetus.

In pregnant Gaucher patients and those intending to become pregnant, a risk-benefit treatment assessment is required for each pregnancy. Patients who have Gaucher disease and become pregnant may experience a period of increased disease activity during pregnancy and the puerperium. This includes an increased risk of skeletal manifestations, exacerbation of cytopenia, haemorrhage, and an increased need for transfusion. Both pregnancy and lactation are known to stress maternal calcium homeostasis and to accelerate bone turnover. This may contribute to skeletal disease burden in Gaucher disease.

Treatment naïve women should be advised to consider commencing therapy prior to conception in order to attain optimal health. In women receiving Cerezyme treatment continuation throughout pregnancy should be considered. Close monitoring of the pregnancy and clinical manifestations of Gaucher disease is necessary for the individualization of dose according to the patient's needs and therapeutic response.

Breast-feeding

It is not known whether this active substance is excreted in human milk, however, the enzyme is likely to be digested in the child's gastrointestinal tract

4.7. Effects on ability to drive and use machines

Cerezyme has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Tabulated list of adverse reactions

Adverse reactions are listed by system organ class and frequency (common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000 to <1/1,000)) in the table below. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

MedDRA System Organ Class

Common

Uncommon

Rare

Not known

Nervous system disorders

Dizziness, headache, paraesthesia

Cardiac disorders

Tachycardia, cyanosis

Vascular disorders

Flushing, hypotension

Transient hypertension

Respiratory, thoracic and mediastinal disorders

Dyspnoea, coughing

Gastrointestinal disorders

Vomiting, nausea, abdominal cramping, diarrhoea

Immune system disorders

Hypersensitivity reactions

Anaphylactoid reactions

Skin and subcutaneous tissue disorders

Urticaria/angioedema, pruritus, rash

Musculoskeletal and connective tissue disorders

Arthralgia, backache

General disorders and administration site conditions

Infusion site discomfort, infusion site burning, infusion site swelling, injection site sterile abscess, chest discomfort, fever, rigors, fatigue

Description of selected adverse reactions

Hypersensitivity (including anaphylaxis)

Symptoms suggestive of hypersensitivity have been noted, overall in approximately 3% of the patients. Onset of such symptoms like paraesthesia, tachycardia, cyanosis, flushing, hypotension, dyspnoea, coughing, urticaria/angioedema, pruritus, rash, backache and chest discomfort has occurred during or shortly after infusions(see section 4.4).

Infusion-Associated Reactions

Infusion-associated reactions (IAR) such as angioedema, pruritus, rash, urticaria, chest discomfort, chills, fatigue, infusion-site burning, infusion-site discomfort, infusion-site swelling, pyrexia and transient hypertension have been observed in patients treated with imiglucerase (see section 4.4)

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 Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No case of overdose has been reported. In patients dosages up to 240 U/kg body weight once every two weeks have been used.