laronidase    

Action and Spectrum

Actions and Spectrum: 

The mechanism of action of laronidase involves the administration of a recombinant form of the human alpha-L-iduronidase enzyme, which is genetically engineered using recombinant DNA technology. Alpha-L-iduronidase breaks down certain complex carbohydrates called glycosaminoglycans (GAGs), essential for normal cell function. In patients with Hurler syndrome, a genetic mutation leads to a deficiency in this enzyme, accumulating GAGs within cells and various organs.  

By supplying exogenous alpha-L-iduronidase through laronidase treatment, the drug helps to restore enzymatic activity and facilitate the breakdown of accumulated GAGs. laronidase is administered intravenously, allowing it to reach different tissues and organs affected by the accumulation of GAGs.  

Regarding the spectrum of activity, laronidase is primarily effective against the accumulation of GAGs associated with Hurler syndrome, a subtype of MPS I. It specifically targets the accumulation of dermatan sulfate and heparan sulfate, two types of GAGs commonly found in affected tissues and organs in Hurler syndrome patients. By reducing the levels of accumulated GAGs, laronidase can slow down disease progression, improve physical symptoms, and help maintain organ function. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Injection site reaction (18%) 

Hyperreflexia (14%) 

Chills (20%; children six months to 5 years) 

Upper respiratory tract infection (32%) 

Rash (36%) 

Poor venous access (14%) 

Paresthesia (14%) 

Otitis media 

Infusion reactions 

Flushing (11%) 

Headache (9%) 

Nausea (7%) 

Feeling hot or cold (7%) 

Pruritus (4%) 

Urticaria (4%) 

Rash (13%) 

Pyrexia (11%) 

Abdominal pain or discomfort (9%) 

Diarrhea (7%) 

Vomiting (4%) 

Arthralgia (4%) 

1-10% 

Corneal opacity (9%) 

Face edema (9%) 

Injection site pain (9%) 

Hypotension (9%) 

Thrombocytopenia (9%) 

Chest pain (9%) 

Gravitational edema (9%) 

Hyperbilirubinemia (9%)  

<1% 

Laryngeal edema 

Peripheral edema 

Cyanosis 

Anaphylactic shock 

Fatigue 

Erythema 

Angioedema 

Black Box Warning

Black box warning: 

ANAPHYLAXIS AND INFUSION-ASSOCIATED REACTIONS 

Life-threatening anaphylactic and severe allergic reactions have been observed in some patients during and after laronidase infusions. These reactions may include respiratory distress, respiratory failure, laryngeal edema, bronchospasm, dyspnea, cyanosis, hypertension, and urticaria.

Other infusion-associated reactions have also been reported, including localized or generalized urticaria and rash, fever, headache, nausea, vomiting, abdominal pain, diarrhea, and asthenia.  

Patients with compromised respiratory function or acute respiratory disease may be at risk of severe acute exacerbation of their respiratory compromise due to infusion reactions and require additional monitoring.” 

Contraindication / Caution

Contraindications/caution: 

Contraindications: 

• Hypersensitivity: laronidase is contraindicated in individuals with known hypersensitivity or severe allergic reactions to laronidase or its components. Allergic reactions can be severe and life-threatening, so caution should be exercised in patients with a history of hypersensitivity to laronidase or similar medications. 
• Acute Respiratory Compromise: laronidase is contraindicated in patients with compromised respiratory function or acute respiratory distress. Infusion reactions associated with laronidase administration may exacerbate respiratory compromise in these individuals. Close monitoring and appropriate management should be implemented in patients with compromised respiratory function. 

Caution: 

• Hypersensitivity Reactions: Although hypersensitivity reactions are listed as a contraindication, it’s worth noting that allergic reactions can still occur even in patients without known hypersensitivity to laronidase. Therefore, caution should be exercised during laronidase administration. Patients should be closely monitored for any signs of allergic or hypersensitivity reactions.  
• Infusion-Associated Reactions: laronidase infusions may be associated with infusion-related reactions, including localized or generalized urticaria (hives), rash, fever, headache, nausea, vomiting, abdominal pain, diarrhea, and asthenia (weakness). These reactions are generally mild to moderate in severity, but they should still be monitored and managed appropriately. If such reactions occur, the infusion rate may be slowed or temporarily interrupted, and symptomatic treatment may be administered as necessary. 

• Respiratory Compromise: Patients with compromised respiratory function or acute respiratory disease may be at increased risk of respiratory exacerbation due to infusion reactions. Therefore, caution is advised when administering laronidase to these individuals, and additional respiratory monitoring should be considered. Prompt management of any respiratory distress or failure is essential in such cases. 

• Use in Pregnancy and Breastfeeding: The safety of laronidase use during pregnancy and breastfeeding has not been adequately studied. Therefore, caution should be exercised when considering the use of laronidase in pregnant or breastfeeding women, and the potential benefits and risks should be carefully evaluated. 

• Use in Pediatric Patients: laronidase has been studied and approved for use in pediatric patients. However, caution should still be exercised in this population, particularly in patients with compromised respiratory function or acute respiratory disease, as they may be at an increased risk of infusion-related respiratory exacerbations. 

Pregnancy / Lactation

Pregnancy consideration: Caution should be exercised when considering the use of laronidase in pregnant women 

Lactation: Excretion of the drug in human breast milk is unknown 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester.   

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data available with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

laronidase works by replacing the deficient alpha-L-iduronidase enzyme in patients with MPS I. This enzyme breaks down glycosaminoglycans (GAGs), long chains of complex sugars in many body tissues. In individuals with MPS I, alpha-L-iduronidase activity is deficient, accumulating GAGs in various organs, which results in progressive cellular damage and organ dysfunction. laronidase acts as a replacement for the missing enzyme and helps to break down the accumulated GAGs, thereby preventing further cellular damage. 

Pharmacodynamics: 

laronidase therapy reduces the level of GAGs in the urine and serum of patients with MPS I. The reduction in GAG levels is typically seen within the first few weeks of treatment and is maintained with continued therapy. The clinical benefit of laronidase therapy in MPS I patients includes improvement in respiratory function, cardiac function, growth, and skeletal manifestations.  

In summary, laronidase is a recombinant human alpha-L-iduronidase enzyme that replaces the deficient enzyme in patients with MPS I and helps to break down accumulated GAGs. 

Pharmacokinetics: 

Absorption 

laronidase is administered intravenously, which ensures complete and rapid systemic absorption. Due to its intravenous route of administration, the drug bypasses the need for absorption from the gastrointestinal tract.  

Distribution 

laronidase distributes throughout the body to various tissues and organs affected by mucopolysaccharidosis I (MPS I). It is expected to distribute within the interstitial and intracellular spaces where it can act on target tissues. The specific distribution characteristics, such as volume of distribution, are not readily available in the public domain.  

Metabolism 

laronidase is not metabolized by the liver or other significant metabolic pathways. It is administered as a recombinant enzyme replacement therapy. It acts directly on the target substrate without undergoing substantial metabolic transformations.  

Elimination and Excretion 

The primary route of elimination for laronidase is renal excretion. It is cleared from the body through the kidneys, with limited information regarding the extent of renal clearance. The elimination half-life of laronidase is relatively short, approximately 3-6 minutes. 

Adminstartion

Administration: 

laronidase (Aldurazyme) is administered intravenously under the supervision of a healthcare professional experienced in treating patients with mucopolysaccharidosis I (MPS I).   

Preparation: 

• laronidase is supplied as a sterile, preservative-free lyophilized powder in single-use vials. 
• The vial should be visually inspected for particulate matter and discoloration before preparation. If any abnormalities are observed, the vial should not be used. 
• The appropriate dosage of laronidase should be calculated based on the patient’s body weight and prescribed by the healthcare professional. 

Reconstitution: 

• An aseptic technique should be followed during reconstitution. 
• The laronidase vial should be reconstituted with the recommended volume of sterile, preservative-free 0.9% sodium chloride injection or other compatible diluents as directed by the healthcare professional. 
• Gently swirl the vial to aid in dissolution. Avoid vigorous shaking as it may cause foaming. 
• Inspect the reconstituted solution visually for particulate matter and discoloration. If any abnormalities are observed, the solution should not be used. 

Administration: 

• laronidase should be administered intravenously over a specified duration, as directed by the healthcare professional. 
• The infusion rate may be adjusted based on the individual patient’s tolerance and the occurrence of infusion-related reactions. 
• Patients should be monitored closely during the infusion for signs of hypersensitivity or infusion-related reactions. 
• Appropriate medical treatment and interventions should be readily available to manage potential adverse reactions. 
• Upon completion of the infusion, any unused solution should be discarded appropriately according to local regulations. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: laronidase 

Why do we use laronidase? 

laronidase (Aldurazyme) is primarily used to treat mucopolysaccharidosis type I (MPS I), a rare genetic disorder. MPS I is caused by a deficiency of alpha-L-iduronidase, which breaks down certain complex carbohydrates called glycosaminoglycans (GAGs). laronidase is an enzyme replacement therapy (ERT) that provides the deficient enzyme to individuals with MPS I, helping to break down the accumulated GAGs and mitigate the associated symptoms and complications. 

• Treatment of Hurler Syndrome: Hurler syndrome is the most severe form of MPS I. laronidase is used as a long-term treatment to improve the clinical manifestations of Hurler syndrome, including growth retardation, skeletal abnormalities, heart and lung problems, cognitive impairment, and organ damage. 
• Treatment of Hurler-Scheie Syndrome: Hurler-Scheie syndrome is an intermediate form of MPS I with milder symptoms than Hurler syndrome. laronidase is also used in individuals with Hurler-Scheie syndrome to improve symptoms and slow disease progression. 
• Maintenance Therapy: laronidase is typically administered as a lifelong maintenance therapy for individuals with MPS I. Regular infusions of laronidase help maintain enzyme levels, prevent GAG accumulation of GAGs, and manage the symptoms and complications associated with the disease.