Laronidase

Registered South African indications:

• Mucopolysaccharidosis I (MPS I; α-L-iduronidase deficiency)
  - For long-term enzyme replacement therapy in patients with a confirmed diagnosis to treat the non-neurological manifestations of the disease

Contraindications

• Severe hypersensitivity (e.g. anaphylactic reaction) to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Pre-existent severe underlying upper airway involvement
• Acute underlying illness at the time of infusion
• Patients who have developed antibodies or symptoms of infusion-associated reactions
• Resumption of treatment following prolonged interruption
• Sodium-controlled diet
• Severe allergic-type hypersensitivity reactions to IV protein products
• May impair ability to drive and operate machinery
  - No studies on the effects on the ability to drive and use machines have been performed

Forms avail. in SA and covered in this monograph: inf

Mucopolysaccharidosis I (MPS I; α-L-iduronidase deficiency)
- For long-term enzyme replacement therapy in patients with a confirmed diagnosis to treat the non-neurological manifestations of the disease

• IV: 100units/kg, as an infusion over 3-4hrs, administered every week

Laronidase is to be administered as an IV infusion at an initial infusion rate of 2units/kg/hr and may be incrementally increased every 15mins, if tolerated, to a maximum of 43units/kg/hr. The total volume of the administration should be delivered in approximately 3-4hrs

See additional prescribing points for reconstitution instructions

Treatment should be supervised by a physician experienced in the management of patients with MPS I or other inherited metabolic diseases

Administration should be carried out in an appropriate clinical setting where resuscitation equipment to manage medical emergencies would be readily available

Forms avail. in SA and covered in this monograph: inf

Mucopolysaccharidosis I (MPS I; α-L-iduronidase deficiency)
- For long-term enzyme replacement therapy in patients with a confirmed diagnosis to treat the non-neurological manifestations of the disease

• See adult dosage

Pregnancy

• Caution
• There are inadequate data on the use of laronidase in pregnant women. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonal/ foetal development, parturition and postnatal development. The potential risk for humans is unknown. Therefore laronidase should not be used during pregnancy unless clearly necessary

Breastfeeding

• Caution; not recommended
• Laronidase may be excreted in milk. Because there are no data available in neonates exposed to laronidase via breast milk, it is recommended to stop breastfeeding during laronidase treatment

Fertility

• There are no clinical data on the effects of laronidase on fertility. Preclinical data did not reveal any significant adverse finding

Renal Impairment

• Caution; no information available
  The safety and efficacy of laronidase in patients with renal insufficiency have not been evaluated and no dosage regimen can be recommended in these patients
  The renal elimination of laronidase is considered to be a minor pathway for clearance

Hepatic Impairment

• Caution; no information available 
  The safety and efficacy of laronidase in patients with hepatic insufficiency have not been evaluated and no dosage regimen can be recommended in these patients
  Laronidase is a protein and is expected to be metabolically degraded through peptide hydrolysis. Consequently, impaired hepatic function is not expected to affect the pharmacokinetics of laronidase in a clinically significant way

Elderly

• Caution; no information available
  The safety and efficacy of laronidase in patients >65 years have not been established and no dosage regimen can be recommended in these patients

Porphyria

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Restlessness
• Headache
• Paraesthesia
• Dizziness
• Fatigue

Cardiovascular Disorders

• Tachycardia
• Hypotension
• Pallor
• Peripheral coldness
• Flushing

Respiratory Disorders

• Respiratory distress
• Dyspnoea
• Cough
• Cyanosis
• Hypoxia
• Decreased oxygen saturation
• Tachypnoea
• Bronchospasm
• Respiratory arrest

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal pain
• Diarrhoea

Endocrine and Metabolic Disorders

• Increased body temperature

Musculoskeletal Disorders

• Arthropathy
• Arthralgia
• Back pain
• Pain in extremity
• Musculoskeletal pain

Skin and Subcutaneous Tissue Disorders

• Rash
• Angioneurotic oedema
• Swelling face
• Urticaria
• Pruritus
• Cold sweat
• Alopecia
• Hyperhidrosis
• Erythema
• Facial oedema
• Laryngeal oedema
• Infusion site reaction
• Extravasation

Immune, Blood and Lymphatic System Disorders

• Anaphylactic reaction
• Formation of IgG antibodies
• Peripheral oedema
• Influenza-like illness
• Fever

Others

• Chills
• Feeling hot
• Feeling cold
• Infusion-associated reactions
  - Cyanosis
  - Hypoxia
  - Tachypnoea
  - Fever
  - Vomiting
  - Chills
  - Erythema

• Chloroquine
• Procaine

• Vital signs
• Serum antibodies to alpha-L-iduronidase
• Forced vital capacity (FVC)
• Height
• Weight
• Range of motion
• Urine levels of glycosaminoglycans (GAG)

Additional observations

• Change in liver size
• Infusion-associated reactions

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

Reconstitution instructions

• Each vial is intended for single use only. The concentrate for solution for infusion has to be diluted with sodium chloride 9mg/ml (0.9%) solution for infusion using aseptic technique. It is recommended that the diluted solution be administered to patients using an infusion set equipped with a 0.2µm in-line filter
• Preparation of the laronidase Infusion (Use aseptic technique):
  - Determine the number of vials to be diluted based on the individual patient's weight. Remove the required vials from the refrigerator approximately 20 minutes in advance in order to allow them to reach room temperature (below 30˚C)
  - Before dilution, visually inspect each vial for particulate matter and discolouration. The clear to slightly opalescent and colourless to pale yellow solution should be free of visible particles. Do not use vials exhibiting particles or discolouration
  - Determine the total volume of infusion based on the individual patient's weight, either 100ml (if body weight is less or equal than 20kg) or 250ml (if body weight is more than 20kg) of sodium chloride 9mg/ml (0.9%) solution for infusion
  - Withdraw and discard a volume of the sodium chloride 9mg/ml (0.9%) solution for infusion from the infusion bag equal to the total volume of laronidase to be added
  - Withdraw the required volume from the laronidase vials and combine the withdrawn volumes
  - Add the combined volumes of laronidase to the sodium chloride 9mg/ml (0.9%) solution for infusion
  - Mix the solution for infusion gently
  - Prior to use visually inspect the solution for particulate matter. Only clear and colourless solutions without visible particles should be used

Infusion-associated reactions 

• Patients treated with laronidase may develop infusion-associated reactions (IARs), defined as any related adverse event occurring during the infusion or until the end of the infusion day. Some of these IARs may be severe
• Patients treated should be closely monitored and all cases of infusion-associated reactions, delayed reactions and possible immunological reactions reported. Antibody status should be regularly monitored and reported
• Severe IARs have been reported in patients with pre-existent severe underlying upper airway involvement and therefore specifically these patients should continue to be closely monitored and only be infused with laronidase in an appropriate clinical setting where resuscitation equipment to manage medical emergencies would be readily available
• Patients with an acute underlying illness at the time of infusion appear to be at greater risk for IARs. Careful consideration should be given to the patient's clinical status prior to administration
• Based on the Phase 3 clinical trial, almost all patients are expected to develop IgG antibodies to laronidase, mostly within 3 months of initiation of treatment. Patients who have developed antibodies or symptoms of IARs should be treated with caution

Management of infusion-associated reactions

• In clinical studies, IARs were usually manageable by slowing the rate of infusion and by (pre-) treating the patient with antihistamines and/or antipyretics (paracetamol or ibuprofen), thus enabling the patient to continue treatment
• As there is little experience on resumption of treatment following prolonged interruption, use caution due to the theoretical increased risk of hypersensitivity reaction after treatment interruption
• With initial administration or upon re-administration following interruption of treatment, it is recommended that patients be administered pre-treatment medicines (antihistamines and/or antipyretics) approximately 60 minutes prior to the start of the infusion, to minimise the potential occurrence of IARs. If clinically indicated, administration of pre-treatment medications with subsequent infusions should be considered
• In case of a mild or moderate IAR, treatment with antihistamines and paracetamol/ ibuprofen should be considered and/or a reduction in the infusion rate to half the infusion rate at which the reaction occurred

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs). MPS I is a heterogeneous and multisystemic disorder characterised by the deficiency of α-L-iduronidase, a lysosomal hydrolase which catalyses the hydrolysis of terminal α-L-iduronic residues of dermatan sulfate and heparan sulfate. Reduced or absent α-L-iduronidase activity results in the accumulation of the GAGs, dermatan sulfate and heparan sulfate in many cell types and tissues. Thus, the rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to hydrolyse the accumulated substrate and to prevent further accumulation. After intravenous infusion, laronidase is rapidly removed from the circulation and taken up by cells into lysosomes, most likely via mannose-6 phosphate receptors. Purified laronidase is a glycoprotein with a molecular weight of approximately 83kDa. Laronidase is comprised of 628 amino acids after cleavage of the N-terminus. The molecule contains 6 N-linked oligosaccharide modifications sites.

Injection (per 5ml) 500U

• Aldurazyme (Sanofi) originator