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Drug Details

FABRAZYME 5 mg Solution for Infusion

• Drug Class Description
  Alimentary tract and metabolism products – enzymes
• Generic Name
  Agalsidase Beta
• Presentation
  Powder for concentrate for solution for infusion White to off-white lyophilized cake or powder
• Description
  Each vial of Fabrazyme contains a nominal value of 5 mg of agalsidase beta. After reconstitution with 1.1 ml water for injections, each vial of Fabrazyme contains 5 mg/ml of agalsidase beta. The reconstituted solution must be diluted further. Agalsidase beta is a recombinant form of human ?-galactosidase A and is produced by recombinant DNA technology using a mammalian Chinese Hamster Ovary (CHO) cell culture. The amino acid sequence of the recombinant form, as well as the nucleotide sequence which encoded it, are identical to the natural form of ?-galactosidase.
• Indications
  

  Fabrazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease.

• Adult Dosage
  

  Fabrazyme treatment should be supervised by a physician experienced in the management of patients with Fabry Disease or other inherited metabolic diseases.

  The recommended dose of Fabrazyme is 1mg/kg body weight administered once every 2 weeks as an intravenous infusion.

  Alternative dosing regimens have been used in clinical studies. In one of these studies, after an initial dose of 1.0 mg/kg every 2 weeks for 6 months, 0.3 mg/kg every 2 weeks may maintain clearance of GL-3 in certain cell types in some patients; however, the long term clinical relevance of these findings has not been established.

  The initial infusion rate should be no more than 0.25 mg/min (15 mg/hour) to minimise the potential occurrence of infusion-associated reactions. After patient tolerance is established, the infusion rate may be increased gradually with subsequent infusions.

  No dose adjustment is necessary for patients with renal insufficiency.

  Studies in patients with hepatic insufficiency have not been performed.

  The safety and efficacy of Fabrazyme in patients older than 65 years have not been established and no dosage regimen can presently be recommended in these patients.

  Paediatric patients

  Studies in children 0-7 years have not been performed and no dosage regimen can presently be recommended in patients in this paediatric age group as safety and efficacy have not yet been established. No dose adjustment is necessary for children 8-16 years.

• Child Dosage
  There is no experience in children. The safety and efficacy of Fabrazyme in children below the age of 16 years have not been established and no dosage regimen can presently be recommended in these patients.
• Elderly Dosage
  There is no experience in children. The safety and efficacy of Fabrazyme in patients older than 65 years have not been established and no dosage regimen can presently be recommended in these patients.
• Contra Indications
  

  Life threatening hypersensitivity (anaphylactic reaction) to the active substance or any of the excipients.

• Special Precautions
  

  Since agalsidase beta (r-hαGAL) is a recombinant protein, the development of IgG antibodies is expected in patients with little or no residual enzyme activity. The majority of patients developed IgG antibodies to r-hαGAL, typically within 3 months of the first infusion with Fabrazyme. Over time, the majority of seropositive patients in clinical trials demonstrated either a downward trend in titers (based on a 4-fold reduction in titer from the peak measurement to the last measurement) (40% of the patients), tolerised (no detectable antibodies confirmed by 2 consecutive radioimmunoprecipitation (RIP) assays) (14% of the patients) or demonstrated a plateau (35% of the patients).

  Patients with antibodies to r-hαGAL have a greater potential to experience infusion-associated reactions (IARs), which are defined as any related adverse event occurring on the infusion day. These patients should be treated with caution when re-administering agalsidase beta. Antibody status should be regularly monitored.

  In clinical trials, sixty seven percent (67 %) of the patients experienced at least one infusion-associated reaction. The frequency of IARs decreased over time. Patients experiencing mild or moderate infusion-associated reactions when treated with agalsidase beta during clinical trials have continued therapy after a reduction in the infusion rate (~0.15 mg/min; 10 mg/hr) and/or pre-treatment with antihistamines, paracetamol, ibuprofen and/or corticosteroids.

  As with any intravenous protein product, allergic-type hypersensitivity reactions are possible.

  A small number of patients have experienced reactions suggestive of immediate (Type I) hypersensitivity. If severe allergic or anaphylactic-type reactions occur, immediate discontinuation of the administration of Fabrazyme should be considered and appropriate treatment initiated. The current medical standards for emergency treatment are to be observed. With careful rechallenge Fabrazyme has been re-administered to all 6 patients who tested positive for IgE antibodies or had a positive skin test to Fabrazyme in a clinical trial. In this trial, the initial rechallenge administration was at a low dose and a lower infusion rate (¹/₂ the therapeutic dose at ¹/₂₅ the initial standard recommended rate). Once a patient tolerates the infusion, the dose may be increased to reach the therapeutic dose of 1 mg/kg and the infusion rate may be increased by slowly titrating upwards, as tolerated.

  The effect of Fabrazyme treatment on the kidneys may be limited in patients with advanced renal disease.

  Studies have not been conducted to assess the potential effects of Fabrazyme on impairment of fertility.

• Interactions
  

  No interaction studies and no in vitro metabolism studies have been performed. Based on its metabolism, agalsidase beta is an unlikely candidate for cytochrome P450 mediated drug-drug interactions.

  Fabrazyme should not be administered with chloroquine, amiodarone, benoquin or gentamycin due to a theoretical risk of inhibition of intra-cellular α-galactosidase activity.

• Adverse Drug Reactions
  

  Adverse drug reactions (ADRs) reported from clinical trials to be related to Fabrazyme administered at a dose of 1mg/kg in a total of 168 patients (154 males and 14 females) treated with Fabrazyme for a minimum of one infusion up to a maximum of 5 years are listed by System Organ Class and frequency (very common 1/10; common 1/100 to < 1/10 and uncommon 1/1000 to < 1/100) in the table below. The occurrence of an ADR in a single patient is defined as uncommon in light of the relatively small number of patients treated. ADRs only reported during the Post Marketing period are also included in the table below at a frequency category of “unknown”. ADRs were mostly mild to moderate in severity:

  Incidence of Related Adverse Events with Fabrazyme Treatment

  System Organ Class	Very common	Common	Uncommon	Frequency unknown
  Infections and infestations		nasopharyngitis	rhinitis
  Immune system disorders				anaphylactoid reaction
  Nervous system disorders	Headache, paraesthesia	dizziness, somnolence, hypoaesthesia, burning sensation, lethargy, syncope	hyperaesthesia, tremor
  Eye disorders	---	lacrimation increased	eye pruritus, ocular hyperaemia
  Ear and labyrinth disorders	---	tinnitus, vertigo	auricular swelling, ear pain
  Cardiac Disorders	---	tachycardia, palpitations, bradycardia	sinus bradycardia

  Incidence of Related Adverse Events with Fabrazyme Treatment (continued)

  System Organ Class	Very common	Common	Uncommon	Frequency unknown
  Vascular disorders	---	flushing, hypertension, pallor, hypotension, hot flush	peripheral coldness	---
  Respiratory, thoracic and mediastinal disorders	---	dyspnoea, nasal congestion, throat tightness, wheezing, cough, dyspnoea exacerbated	bronchospasm, pharyngolaryngeal pain, rhinnorhoea, tachypnoea, upper respiratory tract congestion	---
  Gastrointestinal Disorders	nausea, vomiting	abdominal pain, abdominal pain upper, abdominal discomfort, stomach discomfort, hypoaesthesia oral, diarrhoea	dyspepsia, dysphagia	---
  Skin and subcutaneous tissue disorders	---	pruritus, urticaria, rash, erythema, pruritus generalized, angioneurotic oedema, swelling face, rash maculo-papular	livedo reticularis, rash erythematous, rash pruritic, skin discolouration, skin discomfort	leukocytoclastic vasculitis
  Musculoskeletal and connective tissue disorders	---	pain in extremity, myalgia, back pain, muscle spasms, arthralgia, muscle tightness, musculoskeletal stiffness	musculoskeletal pain	---
  General disorders and administration site conditions	chills, pyrexia, feeling cold	fatigue, chest discomfort, feeling hot, oedema peripheral, pain, asthenia, chest pain, face oedema, hyperthermia	feeling hot and cold, influenza-like illness, infusion site pain, infusion site reaction, injection site thrombosis, malaise, oedema/td>	---
  For the purpose of this table, 1% is defined as events occurring in 2 or more patients.AE terminology is based upon the Medical Dictionary for Regulatory Activities (MedDRA)

  Infusion associated reactions consisted most often of fever and chills. Additional symptoms included mild or moderate dyspnoea, throat tightness, chest discomfort, flushing, pruritus, urticaria, face oedema, angioneurotic oedema, rhinitis, bronchospasm, tachypnea, wheezing, hypertension, hypotension, tachycardia, palpitations, abdominal pain, nausea, vomiting, infusion-related pain including pain at the extremities, myalgia, and headache.

  The infusion-associated reactions were managed by a reduction in the infusion rate together with the administration of non-steroidal anti-inflammatory medicinal products, antihistamines and/or corticosteroids. Sixty seven percent (67%) of the patients experienced at least one infusion-associated reaction. The frequency of these reactions decreased over time. The majority of these reactions can be attributed to the formation of IgG antibodies and/or complement activation. In a limited number of patients IgE antibodies were demonstrated.

  Paediatric patients

  Limited information suggests that the safety profile of Fabrazyme treatment in paediatric patients (above the age of 7) is not different with that seen in adults.