Imiglucerase - Uses and Precautions

Overview

Imiglucerase is an analog of beta-glucocerebrosidase produced by recombinant DNA technology. It was approved by the United States Food and Drug Administration (USFDA) in 1994 and by European Medicines Agency (EMA) in 1997. It is a lysosomal glucocerebrosidase-specific enzyme indicated for adult and pediatric patients(above two years) with Gaucher disease.

How Does Imiglucerase Work?

Patients with Gaucher disease have decreased levels of a beta-glucocerebrosidase enzyme, which controls glucocerebroside (a natural substance made of sugar and fat), resulting in the accumulation of glucocerebroside in the liver, bone marrow, and spleen. Imiglucerase is an artificial enzyme that breaks down glucocerebroside into glucose and ceramide and prevents its accumulation in the body tissues.

Indications of Imiglucerase

Imiglucerase is indicated in patients with type I (non-neuronopathic) or type III (chronic non -neuronopathic) Gaucher disease as a long-term enzyme replacement therapy.

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

• Anemia (exclusion of other causes such as iron deficiency).

• Thrombocytopenia.

• Bone disease (exclusion of other causes such as vitamin D deficiency).

• Hepatomegaly or splenomegaly.

Dosage

Imiglucerase is available as 400 units of lyophilized powder in a single dose vial for reconstitution.The dosage levels of Imiglucerase are recommended based on the severity and the clinical manifestations of Gaucher disease. It ranges from 2.5 units/kg to be taken thrice a week to 60 units/kg once every two weeks.

Administration

• Once the dose is determined and well-established based on the patient’s dosage regimen, the vials are removed from the refrigerator. Each 400-unit vial of Imiglucerase is reconstituted by slowly injecting 10.2 mL of sterile water down the inside wall of each vial.

• The vial is rolled and tilted to dissolve the powder completely so that each vial yields a concentration of Imiglucerase at 40 units/mL after reconstitution.

• The solution is inspected after reconstitution, and the solution must be discarded if the particles are opaque or discolored.

• Up to 10 mL per vial is withdrawn, and the unused portion is discarded.

• Imiglucerase solution is diluted with 0.9 % Sodium chloride injection to a final volume of 100 - 200 ml and only up to a final volume of 100 ml for patients less than 18 kg.

• The infusion bag is gently inverted to avoid shaking and agitation, and the solution is inspected again before administration.

• Diluted Imiglucerase solution is infused over one to two hours for patients above 18kg, and patients below 18 kg, it is infused for more than two hours. Patients must be monitored for any hypersensitivity reactions.

Warnings and Precautions

• Severe hypersensitivity reactions to Imiglucerase and other reactions during or after the drug infusion have been reported. Patients must be monitored during the first year of treatment with Imiglucerase for IgG antibody formation, as patients with antibodies to this drug are at a high risk of developing hypersensitivity reactions. In case of severe hypersensitivity reactions, the treatment with Imiglucerase is discontinued, and appropriate medical treatment is advised.

• Pretreatment with antihistamines or corticosteroids, along with the reduction in the infusion rate of the Imiglucerase, is considered in case of re-administration, and the patients must be monitored for the development of any new signs and symptoms.

Adverse Reactions

The following adverse reactions in different system organ classes were observed during the clinical trials and post-marketing phase:

• Gastrointestinal disorders include nausea, vomiting, abdominal pain, and diarrhea.

• Nervous system disorders include headache and dizziness.

• Vascular disorders include cyanosis, flushing, and hypotension.

• Respiratory disorders include pneumonia, pulmonary hypertension, cough, and dyspnoea.

• Cardiac disorders include tachycardia.

• Skin disorders include rash, urticaria, pruritis and angioedema.

• Musculoskeletal disorders include back pain.

• Immune system disorders include hypersensitivity reactions and anaphylaxis.

• General disorders include fever, chills, fatigue, and chest discomfort.

• Adverse reactions at the site of infusion include swelling, burning sensation, and discomfort. Infusion must be discontinued in such cases, and antihistamines or corticosteroids can treat symptoms.

• No overdose cases have been reported on patients with Imiglucerase treatment, even in doses up to 240 U/kg (units per kilogram) body weight used once every two weeks.

For Patients

What Is Gaucher Disease?

Gaucher disease is a rare inherited metabolic disorder resulting from a deficiency of the lysosomal enzyme called beta-glucosidase, responsible for controlling the levels of glucocerebroside. As the enzyme levels are reduced, it leads to the accumulation of large quantities of glucocerebroside (fatty substances) in bone marrow, liver, and spleen cells. It can adversely affect the quality of life and, in children, it can lead to retarded growth and delayed puberty.

What Are the Signs and Symptoms of Gaucher’s Disease?

Type I Gaucher disease is the most common among the different types; some of the signs and symptoms include:

• Abdominal discomfort (due to enlarged liver and spleen).

• Weakened bones (increased risk for fractures).

• Anemia (decreased red blood cells) results in easy bruising, nose bleeding, and severe fatigue.

• In some rare cases, it might affect the brain resulting in abnormal eye movements, seizures, difficulty swallowing, and muscle rigidity.

How Is Imiglucerase Stored?

Imiglucerase must be used immediately after it is diluted with sterile water and should not be stored. It can be held for up to 24 hours only if it is kept under refrigeration and in the dark between 2 to 8 degrees Celsius. Reconstituted vials can be stored for up to 12 hours. Unopened vials of Imiglucerase must always be stored in the refrigerator (2 to 8 degree Celsius) and kept out of children's reach.

What Are Some of the Instructions for the Patients?

• Imiglucerase must be used only under the doctor's supervision, and the doctor determines the dose based on the severity of the disease. Depending on the symptoms, the dose may be altered, and the patient is regularly monitored.

• Patients must inform the doctor immediately in case of allergic reactions during or after the treatment with Imiglucerase.

• Patients with Gaucher disease may have pulmonary hypertension (high blood pressure in the lungs). The doctor must be informed immediately if the patients experience shortness of breath or severe cough during or after the treatment.

• Patients must inform the doctor if they take other medications, herbal or vitamin supplements, or over-the-counter (OTC) medicines.

• Female patients must inform the doctor if they are pregnant, breastfeeding, or planning to become pregnant before the initiation of treatment.

• Imiglucerase contains 41 mg of sodium per vial, which should be taken into consideration by patients on a low-sodium diet.

• If the patient misses an infusion appointment, the doctor must be contacted.

What Are Some of the Side Effects of Imiglucerase?

Some of the side effects of Imiglucerase include:

• Dyspnoea (difficulty in breathing).

• Coughing, chest discomfort.

• Hypersensitivity reactions (allergies)such as itching and rash.

• Urticaria.

• Pruritis.

• Nausea and vomiting.

• Abdominal cramps and diarrhea.

• Dizziness.

• Headache.

• Paraesthesia.

• Tachycardia (increased heart rate).

• Cyanosis (bluish skin)

• Arthralgia (joint pain).

• Backache.

• Fever and fatigue.

• Tingling, burning sensation, or numbness of the skin.

Some side effects may be seen immediately or shortly after the administration of Imiglucerase, such as itching, breathlessness, bluish skin, backache, tingling, burning or numbness, and localized skin swelling. The doctor must be immediately informed if the patient experiences any of these symptoms.

For Doctors

Description:

Imiglucerase is an analog of the beta-glucocerebrosidase enzyme produced by a recombinant DNA technology (mammalian cell culture), containing a glycoprotein of 497 amino acids. It differs from placental glucocerebrosidase by one amino acid, where histidine is substituted for arginine. Imiglucerase is intended for intravenous use and is supplied as a sterile, non-pyrogenic lyophilized powder for reconstitution with sterile water for injection.

Each vial contains the following components:

• Imiglucerase (424 units).

• Mannitol (340mg).

• Polysorbate 80, NF (1.06mg).

• Sodium citrates such as disodium hydrogen citrate and trisodium citrate.

Clinical Pharmacology

Mechanism of Action of Imiglucerase:

• The deficiency of beta- glucocerebrosidase leads to the accumulation of glucocerebroside in macrophages of tissues leading to Gaucher disease. These accumulations are typically noted in the liver, spleen, and bone marrow; they may be occasionally seen in the lungs, intestine, and kidneys. This presents as a gradual and progressive enlargement of the liver and spleen. Other complications include severe anemia and thrombocytopenia, osteonecrosis, and osteopenia, which can lead to pathological fractures.

• The genetically engineered variant of human glucocerebrosidase or Imiglucerase acts by catalyzing the glucocerebroside accumulated into glucose and ceramide, reducing the enlarged liver and spleen, decrease in cachexia and correcting anemia and thrombocytopenia.

Pharmacodynamics:

Imiglucerase replaces enzyme deficiency activity by hydrolyzing glucocerebroside into glucose and ceramide, improves liver and spleen conditions, normalizes blood cell abnormalities, and eliminates bone crises, thus improving the quality of life. Imiglucerase reduces chitotriosidase (a biomarker for glucocerebroside), accumulating in the macrophages and providing a response to treatment. It also normalizes puberty development in children leading to normal height and bone density.

Pharmacokinetics:

Following an infusion of four doses at 7.5,15, 30, and 60 units per kg of Imiglucerase over an hour, the attainment of steady-state was noted by 30 minutes. After intravenous infusions, the enzymatic activity in plasma declines rapidly, with a half-life range from 3.6 to 10.4 minutes. The clearance from plasma ranged from 9.8 to 20.3ml per minute per kg with a mean value of approximately 14.5 ml/min/kg. The volume of distribution ranged between 0.09 to 0.15 liter per kg. These variables of pharmacokinetics are not influenced by either the dose or duration of infusing Imiglucerase.

Immunogenicity:

Development of IgG antibodies to Imiglucerase was observed in 15% of patients treated and tested during the first year of therapy, and about 46 % of patients with detectable IgG antibodies experienced hypersensitivity symptoms. Patients who developed IgG antibodies to Imiglucerase had increased elimination of half-life compared to patients without the development of antibodies.

Toxicology:

• Carcinogenesis: Long-term studies to evaluate the carcinogenic potential have not been performed with Imiglucerase.

• Mutagenesis: Ames test demonstrated a negative response with respect to imiglucerase.

• Impairment of Fertility: During the 13-week toxicity studies conducted on the reproductive organs of monkeys and rats, no histopathological findings were observed. Animal studies in relation to fertility have not been performed.

Clinical Studies:

The International Collaborative Gaucher Group (ICGG) registry comprises almost 528 patients with Gaucher disease. It was noticed that the concentration of hemoglobin, platelet count, and the size of the liver and spleen improved with the increased dose of Imiglucerase administered once every two weeks. It was noticed that those patients receiving 60 units per kg demonstrated a maximum effect and faster response compared to other doses. An increase in bone mineral density as measured in dual-energy X-ray absorptiometry (DXA) was demonstrated after a duration of eight years. The bone pain was relieved as early as three months in those receiving a high dose of 60 units per kg of Imiglucerase every two weeks. However, the effect of Imiglucerase on the neurological effects of the disease could not be established as no controlled clinical studies were conducted in humans.

Use of Imiglucerase in Specific Populations:

• Pregnancy: According to the available data, no risks are reported with the association of Imiglucerase in pregnant females or the development of the fetus. However, it is estimated that pregnancy may exacerbate the symptoms of existing Gaucher disease and be associated with risks of birth defects, miscarriage, or other adverse outcomes. Close monitoring is required throughout the pregnancy for any clinical manifestations of Gaucher's disease. To achieve optimal health and safe pregnancy, treatment with Imiglucerase must be considered before conception.

• Lactation: Small amounts of Imiglucerase are present in breast milk immediately following the drug infusion; however, no data is available on its effects on milk production. Development of the infant and the health benefits of breastfeeding must be considered, along with the mother’s requirement for Imiglucerase and any potential adverse effects on the infant from Imiglucerase.

• Pediatric Use: Imiglucerase is safe and effective for treating Gaucher disease in pediatric patients above two years of age. This is supported by evidence from well-controlled studies and adequate data from medical literature and post-marketing experience reports. However, the safety and effectiveness of Imiglucerase are not determined in pediatric patients below two years of age.