لارونیداز
Laronidase (Aldurazyme)
لارونیداز

نام ژنریک

Laronidase

شکل دارویی

اشكال دارويي:


Injection, Solution: 100IU

موارد مصرف

موارد و مقدار مصرف


درمان عوارض غير نورولوژيك بيماري موكوپلي ساكاريدوسيز تيپ I
(MPSI يا كمبود آلفا ايدورونيداز).


دوز: دارو به صورت انفوزيون وريدي به ميزان u/kg 100 هفتگي تجويز مي‌شود. سرعت اوليه انفوزيون u/kg/h 2 است كه هر 15 دقيقه افزايش يافته تا به مقدار u/kg/h 43 برسد. كل انفوزيون دارو بايد در مدت 4-3 ساعت صورت گيرد. تجويز دارو در كودكان نيز به صورت فوق انجام مي‌گيرد.

موارد منع مصرف

موارد منع مصرف و احتياط


موارد منع مصرف: حساسيت مفرط به دارو يا ديگر تركيبات فرمولاسيون.


موارد احتياط: انفوزيون دارو باعث ايجاد واكنش‌هاي حساسيتي مي‌شود. بيمار بايد به دقت مانيتور شود.


در كساني كه سابقه بيماري راههاي هوايي فوقاني دارند. احتمال اين عوارض بيشتر بوده‌ و لذا احتياط كافي در تجويز دارو در اين بيماران صورت گيرد.


تقريباً در تمام بيماران مصرف كننده دارو به خصوص بعد از سه ماه اول درمان آنتي‌بادي IgG بر ضد دارو تشكيل مي‌شود. در اين بيماران نيز تجويز دارو با احتياط صورت گيرد.

موارد قابل توجه

-

تداخل دارویی

عوارض جانبي


اعصاب مرکزي: سردرد، پارستزي، سرگيجه، بي‌قراري.


قلبي ـ عروقي: تاكيكاردي، افت فشارخون.


دستگاه گوارش: تهوع، استفراغ، اسهال، دردهاي شكمي.


تنفسي: تنگي نفس، سرفه، ديسترس تنفسي.


پوست: راش، آنژيوادم،‌ تورم صورت، كهير، خارش، تعريق سرد، آلوپسي.


عضلاني ـ اسكلتي: آرترالژي، درد كمر و درد در اندامهاي انتهايي.


ساير عوارض: فلاشينگ، لرز، احساس سرما،‌ واكنش‌هاي آنافيلاكتوئيد.

مکانیزم اثر

عوارض جانبي


اعصاب مرکزي: سردرد، پارستزي، سرگيجه، بي‌قراري.


قلبي ـ عروقي: تاكيكاردي، افت فشارخون.


دستگاه گوارش: تهوع، استفراغ، اسهال، دردهاي شكمي.


تنفسي: تنگي نفس، سرفه، ديسترس تنفسي.


پوست: راش، آنژيوادم،‌ تورم صورت، كهير، خارش، تعريق سرد، آلوپسي.


عضلاني ـ اسكلتي: آرترالژي، درد كمر و درد در اندامهاي انتهايي.


ساير عوارض: فلاشينگ، لرز، احساس سرما،‌ واكنش‌هاي آنافيلاكتوئيد.

فارماكوكینتیك

فارماكوكينتيك


جذب: دارو به صورت وريدي تجويز مي‌شود.


پخش: در هفته 26 درمان حجم توزيع دارو تقريباً L/kg 22/0 است. با ادامه درمان به دليل تشكيل آنتي‌بادي حجم توزيع دارو كاهش مي‌يابد.


متابوليسم: دارو توسط پپتيدازها هيدروليز مي‌شود.


دفع: بخش كوچكي از دارو از طريق كليوي دفع مي‌شود.

سایر اطلاعات

طبقه‌بندي فارماكولوژيك: آنزيم.


طبقه‌بندي درماني: آنالوگ نوتركيب انساني آلفا ايدورونيداز.


طبقه‌بندي مصرف در بارداري: مشخص نيست.


نام‌هاي تجاري: Aldurazyme


ملاحظات اختصاصي


1- با توجه به واكنش‌هاي حساسيتي بهتر است بيماران يك ساعت قبل از شروع انفوزيون با آنتي‌هيستامين، استامينوفن يا ايبوپروفن پيش‌درماني شوند.


2- در مواردي كه بيمار دچار واكنش‌هاي شديد حساسيتي بعد از تجويز اول دارو شده است، بهتر است علاوه بر پيش‌درماني با آنتي‌هيستامين و استامينوفن سرعت انفوزيون در دفعه بعد به يك دوم تا يك چهارم كاهش يابد.


3- بعد از رقيق شدن در محلول نرمال‌سالين، دارو را مي‌توان به مدت 24 ساعت در دماي 8-2 درجه سانتي‌گراد نگهداري كرد.


مصرف در سالمندان: ايمني و اثربخشي دارو در سن بالاتر از 65 سال مشخص نشده است.


مصرف در شيردهي: دارو در شير ترشح مي‌شود. بهتر است شيردهي حين مصرف دارو صورت نگيرد.


مصرف در بارداري: در مطالعات حيواني، دارو اثرات سوء روي جنين نداشته است ولي در انسان مشخص نيست، لذا مصرف دارو حين حاملگي توصيه نمي‌شود.

Laronidase (Aldurazyme)

ALDURAZYME®
(laronidase) Solution for Intravenous Infusion Only

WARNING

Risk of anaphylaxis.

Life-threatening anaphylactic reactions have been observed in some patients during ALDURAZYME (laronidase) infusions. Therefore, appropriate medical support should be readily available when ALDURAZYME (laronidase) is administered. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.

DRUG DESCRIPTION

ALDURAZYME® (laronidase) is a polymorphic variant of the human enzyme, α-L-iduronidase that is produced by recombinant DNA technology in a Chinese hamster ovary cell line. α-L-iduronidase (glycosaminoglycan α-L-iduronohydrolase, EC 3.2.1.76) is a lysosomal hydrolase that catalyses the hydrolysis of terminal α-L-iduronic acid residues of dermatan sulfate and heparan sulfate.

Laronidase is a glycoprotein with a molecular weight of approximately 83 kD. The predicted amino acid sequence of the recombinant form, as well as the nucleotide sequence that encodes it, are identical to a polymorphic form of human α-L-iduronidase. The recombinant protein is comprised of 628 amino acids after cleavage of the N-terminus and contains 6 N-linked oligosaccharide modification sites. Two oligosaccharide chains terminate in mannose-6-phosphate sugars. ALDURAZYME (laronidase) has a specific activity of approximately 172 U/mg.

ALDURAZYME (laronidase) , for intravenous infusion, is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution that must be diluted prior to administration in 0.9% Sodium Chloride Injection, USP, containing 0.1% Albumin (Human). The solution in each vial contains a nominal laronidase concentration of 0.58 mg/mL and a pH of approximately 5.5. The extractable volume of 5.0 mL from each vial provides 2.9 mg laronidase, 43.9 mg sodium chloride, 63.5 mg sodium phosphate monobasic monohydrate, 10.7 mg sodium phosphate dibasic heptahydrate, and 0.05 mg polysorbate 80. ALDURAZYME (laronidase) does not contain preservatives; vials are for single use only.

What are the possible side effects of laronidase (Aldurazyme)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Some people receiving a laronidase injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you have a headache, skin rash or itching, warmth or tingly feeling, or trouble breathing when laronidase is injected.

Less serious side effects may include:

  • runny or stuffy nose, sore throat, cough;
  • mild skin rash;
  • numbness or...

Read All Potential Side Effects and See Pictures of Aldurazyme »

Last reviewed on RxList: 2/4/2009
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

ALDURAZYME (laronidase) is indicated for patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for patients with the Scheie form who have moderate to severe symptoms. The risks and benefits of treating mildly affected patients with the Scheie form have not been established.

ALDURAZYME (laronidase) has been shown to improve pulmonary function and walking capacity. ALDURAZYME (laronidase) has not been evaluated for effects on the central nervous system manifestations of the disorder.

DOSAGE AND ADMINISTRATION

The recommended dosage regimen of ALDURAZYME (laronidase) is 0.58 mg/kg of body weight administered once-weekly as an intravenous infusion.

Pretreatment with antipyretics and/or antihistamines is recommended 60 minutes prior to the start of the infusion (see WARNINGS: Anaphylaxis and Allergic Reactions).

The total volume of the infusion is determined by the patient's body weight and should be delivered over approximately 3 to 4 hours. Patients with a body weight of 20 kg or less should receive a total volume of 100 mL. Patients with a body weight of greater than 20 kg should receive a total volume of 250 mL. The initial infusion rate of 10 mcg/kg/hr may be incrementally increased every 15 minutes during the first hour, as tolerated, until a maximum infusion rate of 200 mcg/kg/hr is reached. The maximum rate is then maintained for the remainder of the infusion (2-3 hours).

For Patients Weighing 20 kg or Less

Total Volume of ALDURAZYME Infusion = 100 mL
2 mL/hr x 15 minutes
(10 mcg/kg/hr)
Obtain vital signs, if stable then increase the rate to…
4 mL/hr x 15 minutes
(20 mcg/kg/hr)
Obtain vital signs, if stable then increase the rate to…
8 mL/hr x 15 minutes
(50 mcg/kg/hr)
Obtain vital signs, if stable then increase the rate to…
16 mL/hr x 15 minutes
(100 mcg/kg/hr)
Obtain vital signs, if stable then increase the rate to…
32 mL/hr x ~3 hours
(200 mcg/kg/hr)
For the remainder of the infusion.

For Patients Weighing Greater than 20 kg

Total Volume of ALDURAZYME Infusion = 250 mL
5 mL/hr x 15 minutes
(10 mcg/kg/hr)
Obtain vital signs, if stable then increase the rate to…
10 mL/hr x 15 minutes
(20 mcg/kg/hr)
Obtain vital signs, if stable then increase the rate to…
20 mL/hr x 15 minutes
(50 mcg/kg/hr)
Obtain vital signs, if stable then increase the rate to…
40 mL/hr x 15 minutes
(100 mcg/kg/hr)
Obtain vital signs, if stable then increase the rate to…
80 mL/hr x ~3 hours(200 mcg/kg/hr) For the remainder of the infusion.

Each vial of ALDURAZYME provides 2.9 mg of laronidase in 5.0 mL of solution and is intended for single use only. Do not use the vial more than one time. The concentrated solution for infusion must be diluted with 0.1% Albumin (Human) in 0.9% Sodium Chloride Injection, USP using aseptic techniques. ALDURAZYME (laronidase) should be prepared using PVC containers and administered with a PVC infusion set equipped with an in-line, low protein binding 0.2 micrometer (μm) filter. There is no information on the compatibility of diluted ALDURAZYME (laronidase) with glass containers.

Instructions for Use (Aseptic Techniques)

1. Determine the number of vials to be diluted based on the individual patient's weight and the recommended dose of 0.58 mg/kg [Patient's weight (kg) x 1 mL/kg of ALDURAZYME (laronidase) = Total # mL of ALDURAZYME (laronidase) , then Total # of mL of ALDURAZYME (laronidase) ÷ 5 mL per Vial = Total # of Vials]. Round up to the nearest whole vial. Remove the required number of vials from the refrigerator to allow them to reach room temperature. Do not heat or microwave vials.

2. Before withdrawing the ALDURAZYME (laronidase) from the vial, visually inspect each vial for particulate matter and discoloration. The ALDURAZYME (laronidase) solution should be clear to slightly opalescent and colorless to pale yellow. A few translucent particles may be present. Do not use if the solution is discolored or if there is particulate matter in the solution.

3. Determine the total volume of the infusion to be used based on the patient's body weight. The total final volume should be either 100 mL (if weight is less than or equal to 20 kg) or 250 mL (if weight is greater than 20 kg).

4. Using the chart below, prepare an infusion bag of 0.1% Albumin (Human) in 0.9% Sodium Chloride Injection, USP. Remove and discard a volume of 0.9% Sodium Chloride Injection, USP equal to the volume of Albumin (Human) to be added to the infusion bag. Add the appropriate volume of Albumin (Human) to the infusion bag and gently rotate the infusion bag to ensure proper distribution of the Albumin.

Total Volume
of ALDURAZYME (laronidase)
Infusion
Volume of
Albumin (Human) 5%
to be Added
Volume of
Albumin (Human) 25%
to be Added
100 mL 2 mL 0.4 mL
250 mL 5 mL 1 mL

5. Withdraw and discard a volume of the 0.1% Albumin (Human) in 0.9% Sodium Chloride Injection, USP from the infusion bag, equal to the volume of ALDURAZYME (laronidase) concentrate to be added.

6. Slowly withdraw the calculated volume of ALDURAZYME (laronidase) from the appropriate number of vials using caution to avoid excessive agitation. Do not use a filter needle, as this may cause agitation. Agitation may denature ALDURAZYME (laronidase) , rendering it biologically inactive.

7. Slowly add the ALDURAZYME (laronidase) solution to the 0.1% Albumin (Human) in 0.9% Sodium Chloride Injection, USP using care to avoid agitation of the solutions. Do not use a filter needle.

8. Gently rotate the infusion bag to ensure proper distribution of ALDURAZYME (laronidase) . Do not shake the solution.

ALDURAZYME (laronidase) does not contain any preservatives; therefore, after dilution with saline in the infusion bags, any unused product or waste material should be discarded and disposed of in accordance with local requirements.

ALDURAZYME (laronidase) must not be mixed with other medicinal products in the same infusion.

The compatibility of ALDURAZYME (laronidase) in solution with other products has not been evaluated.

Storage

Store ALDURAZYME (laronidase) under refrigeration at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE OR SHAKE. DO NOT USE ALDURAZYME (laronidase) after the expiration date on the vial. This product contains no preservatives.

The diluted solution should be used immediately. If immediate use is not possible, the diluted solution should be stored refrigerated at 2°C to 8°C (36°F to 46°F). The in-use storage should not be longer than 36 hours from the time of preparation to completion of administration. Room temperature storage of diluted solution is not recommended.

HOW SUPPLIED

ALDURAZYME (laronidase) is supplied as a sterile solution in clear Type I glass 5 mL vials (2.9 mg laronidase per 5 mL). The closure consists of a siliconized butyl stopper and an aluminum seal with a plastic flip-off cap.

NDC 58468-0070-1

ALDURAZYME (laronidase) is manufactured by: BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949. ALDURAZYME (laronidase) is distributed by: Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142. 1-800-745-4447 (phone). 04/08. FDA revision date: 4/14/2008

Last reviewed on RxList: 2/4/2009
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

The most serious adverse reactions reported with ALDURAZYME (laronidase) during clinical trials and the postmarketing period were anaphylactic and allergic reactions (see BOXED WARNING and WARNINGS: Anaphylaxis and Allergic Reactions).

The most common adverse reactions associated with ALDURAZYME (laronidase) treatment in the clinical studies were upper respiratory tract infection, rash, and injection site reaction.

In clinical studies, the most common adverse reactions requiring intervention were infusion-related reactions reported in 32% (7 of 22) of patients treated with ALDURAZYME (laronidase) . The most common infusion-related reactions were flushing, fever, headache, and rash. Flushing occurred in 5 patients (23%) receiving ALDURAZYME (laronidase) ; the other reactions were less frequent. Infusion-related reactions were not significantly different between the ALDURAZYME (laronidase) treatment group and the placebo treatment group who received infusions of diluent and all components of ALDURAZYME except the laronidase enzyme. All reactions were classified as being mild to moderate in severity. The frequency of infusion-related reactions decreased with continued use during the open-label extended use period. Less common infusion-related reactions include: cough, bronchospasm, dyspnea, urticaria, angioedema, and pruritus. Most infusion-related reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, and/or administering additional antipyretics and/or antihistamines.

The data described below reflect exposure to 0.58 mg/kg of ALDURAZYME (laronidase) for 26 weeks in a placebo-controlled double-blind study in 45 patients with MPS I (N=22 ALDURAZYME (laronidase) , and N=23 placebo). All 45 patients continued into an open-label study of ALDURAZYME (laronidase) treatment for an additional 36 weeks. An additional 10 patients participated in a Phase 1 open-label study with continued infusions for up to 3 years. The population in the placebo-controlled study was evenly distributed for gender (N=23 females and 22 males) and ranged in ages from 6 to 43 years. Of the 45 patients in the placebo-controlled study, 1 was clinically assessed as having Hurler form, 37 Hurler-Scheie, and 7 Scheie. All patients were treated with antipyretics and antihistamines prior to the infusions.

Because clinical trials are conducted under widely varying and controlled conditions, the observed adverse reaction rates may not predict the rates observed in patients in clinical practice.

Table 2 enumerates adverse events and selected laboratory abnormalities that occurred during the placebo-controlled trial in at least 2 patients more in the ALDURAZYME (laronidase) group than was observed in the placebo group. Reported adverse events have been classified using standard WHOART terms. Observed adverse events in the Phase 1 study and the open-label treatment period following the controlled study were not different in nature or severity.

Table 2: Number and (%) of Patients with Adverse Events and Selected Laboratory Abnormalities in the Placebo-Controlled Study

Adverse Event Placebo
(N = 23)
ALDURAZYME
(N = 22)
Respiratory System
  Upper respiratory tract infection 4 (17) 7 (32)
Body as a Whole
  Chest pain 0 2 (9)
Nervous System
  Hyperreflexia 0 3 (14)
  Paresthesia 1 (4) 3 (14)
Skin and Appendages
  Rash 5 (22) 8 (36)
Resistance Mechanism
  Abscess 0 2 (9)
Liver and Biliary System
  Bilirubinemia 0 2 (9)
Vascular
  Vein disorder 1 (4) 3 (14)
Urinary System
  Facial edema 0 2 (9)
Cardiovascular, General
  Hypotension 0 2 (9)
  Dependent edema 0 2 (9)
Vision
  Corneal opacity 0 2 (9)
Application Site
  Injection site pain 0 2 (9)
  Injection site reaction 0 4 (18)
Platelet, Bleeding and Clotting
  Thrombocytopenia 0 2 (9)

In postmarketing experience with ALDURAZYME (laronidase) , severe and serious infusionrelated reactions have been reported, some of which were life-threatening (see BOXED WARNING and WARNINGS: Anaphylaxis and Allergic Reactions). The most frequently reported adverse reactions (using MedDRA terminology) included: chills, vomiting, nausea, arthralgia, diarrhea, tachycardia, abdominal pain, blood pressure increased, and oxygen saturation decreased.

Immunogenicity

In clinical studies, 50 of 55 patients (91%) treated with ALDURAZYME were positive for antibodies to laronidase. The clinical significance of antibodies to ALDURAZYME (laronidase) is not known, including the potential for product neutralization.

The data reflect the percentage of patients whose test results were considered positive for antibodies to ALDURAZYME (laronidase) using an enzyme-linked immunosorbent assay (ELISA) for laronidase-specific IgG binding antibodies, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibodies in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ALDURAZYME (laronidase) with the incidence of antibodies to other products may be misleading.

Four patients in the controlled study who experienced severe infusion-related reactions were tested for ALDURAZYME (laronidase) -specific IgE antibodies and complement activation. IgE testing was performed by ELISA and complement activation was measured by the Quidel Enzyme Immunoassay. One of the four patients had an anaphylactic reaction consisting of urticaria and airway obstruction and tested positive for both ALDURAZYME (laronidase) -specific IgE binding antibodies and complement activation (see BOXED WARNING and WARNINGS: Anaphylaxis and Allergic Reactions).

Other allergic reactions were also seen in patients receiving ALDURAZYME (laronidase) (see ADVERSE REACTIONS).

Read the Aldurazyme (laronidase) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

No formal drug interaction studies have been conducted.

Last reviewed on RxList: 2/4/2009
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Anaphylaxis and Allergic Reactions (see BOXED WARNING)

Life-threatening anaphylactic reactions have been observed in some patients during or up to three hours after ALDURAZYME (laronidase) infusions. Reactions have included respiratory failure, respiratory distress, stridor, tachypnea, bronchospasm, airway obstruction, hypoxia, hypotension, bradycardia, and urticaria. Interventions have included resuscitation, mechanical ventilatory support, emergency tracheotomy, hospitalization, and treatment with inhaled beta-adrenergic agonists, epinephrine, and intravenous corticosteroids.

In clinical trials and post-marketing safety experience with ALDURAZYME (laronidase) , approximately 1% of patients experienced severe or serious allergic reactions. In patients with MPS I, pre-existing upper airway obstruction may have contributed to the severity of some reactions. Due to the potential for severe allergic reactions, appropriate medical support should be readily available when ALDURAZYME (laronidase) is administered. Because of the potential for recurrent reactions, some patients who experience initial severe reactions may require prolonged observation.

Patients with an acute illness at the time of ALDURAZYME (laronidase) infusion appear to be at greater risk for infusion-related reactions. Careful consideration should be given to the patient's clinical status prior to administration of ALDURAZYME (laronidase) . One patient with acute bronchitis and hypoxia experienced increased tachypnea during the first ALDURAZYME (laronidase) infusion that resolved without intervention. The patient's respiratory symptoms returned within 30 minutes of completing the infusion and responded to bronchodilator therapy. Approximately six hours after the infusion, the patient experienced coughing, then respiratory arrest, and died.

Patients should receive antipyretics and/or antihistamines prior to infusion (see ADVERSE REACTIONS). If an infusion reaction occurs, regardless of pre-treatment, decreasing the infusion rate, temporarily stopping the infusion, and/or administration of additional antipyretics and/or antihistamines may ameliorate the symptoms (see ADVERSE REACTIONS).

If anaphylactic or other severe allergic reactions occur, immediately discontinue the infusion of ALDURAZYME (laronidase) and initiate appropriate treatment. Caution should be exercised if epinephrine is being considered for use in patients with MPS I due to the increased prevalence of coronary artery disease in these patients.

The risks and benefits of re-administering ALDURAZYME (laronidase) following an anaphylactic or severe allergic reaction should be considered. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to re-administer the product.

PRECAUTIONS

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies to assess the mutagenic and carcinogenic potential of ALDURAZYME (laronidase) have not been conducted.

Reproductive studies in rats have not demonstrated impairment of fertility (see PRECAUTIONS:Pregnancy).

Pregnancy: Category B

Reproduction studies have been performed in male and female rats at doses up to 6.2 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to ALDURAZYME (laronidase) . However, there are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ALDURAZYME (laronidase) should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ALDURAZYME (laronidase) is administered to a nursing woman (see PRECAUTIONS: Information for Patients regarding a registry program. Nursing women are encouraged to participate in this program.).

Pediatric Use

Patients younger than 5 were not included in the clinical studies because of inability to comply with efficacy outcome assessments. It is not known if children younger than 5 respond differently from older children.

Geriatric Use

Clinical studies of ALDURAZYME (laronidase) did not include patients aged 65 and over. It is not known whether they respond differently from younger patients.

Last reviewed on RxList: 2/4/2009
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

There is no experience with overdoses of ALDURAZYME (laronidase) .

CONTRAINDICATIONS

There are no known contraindications to the use of ALDURAZYME (laronidase) .

Last reviewed on RxList: 2/4/2009
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). Mucopolysaccharidosis I (MPS I) is characterized by the deficiency of α-L-iduronidase, a lysosomal hydrolase which catalyses the hydrolysis of terminal oc-L-iduronic acid residues of dermatan sulfate and heparan sulfate. Reduced or absent α-L-iduronidase activity results in the accumulation of the GAG substrates, dermatan sulfate and heparan sulfate, throughout the body and leads to widespread cellular, tissue, and organ dysfunction.

The rationale of ALDURAZYME (laronidase) therapy in MPS I is to provide exogenous enzyme for uptake into lysosomes and increase the catabolism of GAG. ALDURAZYME (laronidase) uptake by cells into lysosomes is most likely mediated by the mannose-6-phosphate-terminated oligosaccharide chains of laronidase binding to specific mannose-6-phosphate receptors.

Because many proteins in the blood are restricted from entry into the central nervous system by the blood brain barrier, effects of intravenously administered ALDURAZYME (laronidase) on cells within the central nervous system (CNS) cannot be inferred from activity in sites outside the CNS. The ability of ALDURAZYME (laronidase) to cross the blood brain barrier has not been evaluated in animal models or in clinical trials.

Pharmacokinetics

The pharmacokinetics of laronidase were evaluated in 12 patients with MPS I who received 0.58 mg/kg of ALDURAZYME (laronidase) as a 4 hour infusion. After the 1st, 12th and 26th weekly infusions, the mean maximum plasma concentrations (Cmax) ranged from 1.2 to 1.7 mcg/mL for the 3 time points. The mean area under the plasma concentration-time curve (AUC) ranged from 4.5 to 6.9 mcg • hour/mL. The mean volume of distribution (Vz) ranged from 0.24 to 0.6 L/kg. Mean plasma clearance (CL) ranged from 1.7 to 2.7 mL/min/kg, and the mean elimination half-life (t½) ranged from 1.5 to 3.6 hours.

Effects of Antibodies

Most patients who received once-weekly infusions of ALDURAZYME developed antibodies to laronidase by week 12. Between weeks 1 and 12, increases in plasma clearance of laronidase were observed in some patients which appeared to be proportional to the antibody titer. At week 26, plasma clearance of laronidase was comparable to that at week 1, in spite of the continued and, in some cases, increased titers of antibodies.

Clinical Studies

ALDURAZYME (laronidase) was studied in a randomized, placebo-controlled clinical trial of 45 MPS I patients of whom 1 patient was clinically assessed as having the Hurler form, 37 Hurler-Scheie, and 7 Scheie. All patients had a baseline forced vital capacity (FVC) less than or equal to 77% of predicted. Patients received ALDURAZYME (laronidase) at 0.58 mg/kg or placebo once-weekly for 26 weeks. All patients were treated with antipyretics and antihistamines prior to each infusion.

The primary efficacy outcome assessments were FVC and distance walked in 6 minutes (6-minute walk test, 6MWT). After 26 weeks, patients treated with ALDURAZYME (laronidase) showed improvement in FVC and in 6MWT compared to placebo-treated patients (see Table 1).

Table 1: Primary Efficacy Outcomes

  ALDURAZYME
N = 22
Placebo
N = 23
Forced Vital Capacity (percent of predicted normal)
Baseline Mean ± s.d. 48 ± 15 54 ± 16
Week 26 Mean ± s.d. 50 ± 17 51 ±13
Change from baseline to week 26 Mean ± s.d. 1 ±7 -3 ±7
Median 1 -1
Difference between groups Mean 4
Median (95% CI) 2 (0.4, 7) p=0.02*
6-Minute Walk Distance (meters)
Baseline Mean ± s.d. 319 ± 131 367 ±114
Week 26 Mean + s.d. 339 ± 127 348 ± 129
Change from baseline to week 26 Mean ± s.d. 20 ± 69 -18 ± 67
Median 28 -11
Difference between groups Mean 38
Median (95% CI) 39 (-2, 79) p=0.07*
* By Wilcoxon Rank Sum Test

Evaluations of bioactivity were changes in liver size and urinary GAG levels. Liver size and urinary GAG levels decreased in patients treated with ALDURAZYME (laronidase) compared to patients treated with placebo. No subject in the group receiving ALDURAZYME (laronidase) reached the normal range for urinary GAG levels during this 6-month study.

All 45 patients received open-label ALDURAZYME (laronidase) for 36 weeks following the double-blind period. Maintenance of mean FVC and an additional increase in mean 6MWT distance were observed compared to the start of the open-label period among patients who were initially randomized to and then continued to receive ALDURAZYME (laronidase) . Among patients who had been initially randomized to placebo, improvements from baseline in mean FVC and 6MWT distance were observed compared to the start of the open-label period.

Last reviewed on RxList: 8/27/2008
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Patients should be informed that a registry for MPS I patients has been established in order to better understand the variability and progression of MPS I disease, and to continue to monitor and evaluate treatments. Patients should be encouraged to participate and advised that their participation may involve long-term follow-up.

Information regarding the registry program may be found at www.MPSIregistry.com or by calling (800) 745-4447.

Last reviewed on RxList: 2/4/2009
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

Patients should be informed that a registry for MPS I patients has been established in order to better understand the variability and progression of MPS I disease, and to continue to monitor and evaluate treatments. Patients should be encouraged to participate and advised that their participation may involve long-term follow-up.

Information regarding the registry program may be found at www.MPSIregistry.com or by calling (800) 745-4447.

Last reviewed on RxList: 2/4/2009
This monograph has been modified to include the generic and brand name in many instances.

ALDURAZYME®
(laronidase) Solution for Intravenous Infusion Only

WARNING

Risk of anaphylaxis.

Life-threatening anaphylactic reactions have been observed in some patients during ALDURAZYME (laronidase) infusions. Therefore, appropriate medical support should be readily available when ALDURAZYME (laronidase) is administered. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.

DRUG DESCRIPTION

ALDURAZYME® (laronidase) is a polymorphic variant of the human enzyme, α-L-iduronidase that is produced by recombinant DNA technology in a Chinese hamster ovary cell line. α-L-iduronidase (glycosaminoglycan α-L-iduronohydrolase, EC 3.2.1.76) is a lysosomal hydrolase that catalyses the hydrolysis of terminal α-L-iduronic acid residues of dermatan sulfate and heparan sulfate.

Laronidase is a glycoprotein with a molecular weight of approximately 83 kD. The predicted amino acid sequence of the recombinant form, as well as the nucleotide sequence that encodes it, are identical to a polymorphic form of human α-L-iduronidase. The recombinant protein is comprised of 628 amino acids after cleavage of the N-terminus and contains 6 N-linked oligosaccharide modification sites. Two oligosaccharide chains terminate in mannose-6-phosphate sugars. ALDURAZYME (laronidase) has a specific activity of approximately 172 U/mg.

ALDURAZYME (laronidase) , for intravenous infusion, is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution that must be diluted prior to administration in 0.9% Sodium Chloride Injection, USP, containing 0.1% Albumin (Human). The solution in each vial contains a nominal laronidase concentration of 0.58 mg/mL and a pH of approximately 5.5. The extractable volume of 5.0 mL from each vial provides 2.9 mg laronidase, 43.9 mg sodium chloride, 63.5 mg sodium phosphate monobasic monohydrate, 10.7 mg sodium phosphate dibasic heptahydrate, and 0.05 mg polysorbate 80. ALDURAZYME (laronidase) does not contain preservatives; vials are for single use only.

Last reviewed on RxList: 2/4/2009
This monograph has been modified to include the generic and brand name in many instances.

ALDURAZYME®
(laronidase) Solution for Intravenous Infusion Only

WARNING

Risk of anaphylaxis.

Life-threatening anaphylactic reactions have been observed in some patients during ALDURAZYME (laronidase) infusions. Therefore, appropriate medical support should be readily available when ALDURAZYME (laronidase) is administered. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.

DRUG DESCRIPTION

ALDURAZYME® (laronidase) is a polymorphic variant of the human enzyme, α-L-iduronidase that is produced by recombinant DNA technology in a Chinese hamster ovary cell line. α-L-iduronidase (glycosaminoglycan α-L-iduronohydrolase, EC 3.2.1.76) is a lysosomal hydrolase that catalyses the hydrolysis of terminal α-L-iduronic acid residues of dermatan sulfate and heparan sulfate.

Laronidase is a glycoprotein with a molecular weight of approximately 83 kD. The predicted amino acid sequence of the recombinant form, as well as the nucleotide sequence that encodes it, are identical to a polymorphic form of human α-L-iduronidase. The recombinant protein is comprised of 628 amino acids after cleavage of the N-terminus and contains 6 N-linked oligosaccharide modification sites. Two oligosaccharide chains terminate in mannose-6-phosphate sugars. ALDURAZYME (laronidase) has a specific activity of approximately 172 U/mg.

ALDURAZYME (laronidase) , for intravenous infusion, is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution that must be diluted prior to administration in 0.9% Sodium Chloride Injection, USP, containing 0.1% Albumin (Human). The solution in each vial contains a nominal laronidase concentration of 0.58 mg/mL and a pH of approximately 5.5. The extractable volume of 5.0 mL from each vial provides 2.9 mg laronidase, 43.9 mg sodium chloride, 63.5 mg sodium phosphate monobasic monohydrate, 10.7 mg sodium phosphate dibasic heptahydrate, and 0.05 mg polysorbate 80. ALDURAZYME (laronidase) does not contain preservatives; vials are for single use only.

Last reviewed on RxList: 2/4/2009
This monograph has been modified to include the generic and brand name in many instances.

ALDURAZYME®
(laronidase) Solution for Intravenous Infusion Only

WARNING

Risk of anaphylaxis.

Life-threatening anaphylactic reactions have been observed in some patients during ALDURAZYME (laronidase) infusions. Therefore, appropriate medical support should be readily available when ALDURAZYME (laronidase) is administered. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.

DRUG DESCRIPTION

ALDURAZYME® (laronidase) is a polymorphic variant of the human enzyme, α-L-iduronidase that is produced by recombinant DNA technology in a Chinese hamster ovary cell line. α-L-iduronidase (glycosaminoglycan α-L-iduronohydrolase, EC 3.2.1.76) is a lysosomal hydrolase that catalyses the hydrolysis of terminal α-L-iduronic acid residues of dermatan sulfate and heparan sulfate.

Laronidase is a glycoprotein with a molecular weight of approximately 83 kD. The predicted amino acid sequence of the recombinant form, as well as the nucleotide sequence that encodes it, are identical to a polymorphic form of human α-L-iduronidase. The recombinant protein is comprised of 628 amino acids after cleavage of the N-terminus and contains 6 N-linked oligosaccharide modification sites. Two oligosaccharide chains terminate in mannose-6-phosphate sugars. ALDURAZYME (laronidase) has a specific activity of approximately 172 U/mg.

ALDURAZYME (laronidase) , for intravenous infusion, is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution that must be diluted prior to administration in 0.9% Sodium Chloride Injection, USP, containing 0.1% Albumin (Human). The solution in each vial contains a nominal laronidase concentration of 0.58 mg/mL and a pH of approximately 5.5. The extractable volume of 5.0 mL from each vial provides 2.9 mg laronidase, 43.9 mg sodium chloride, 63.5 mg sodium phosphate monobasic monohydrate, 10.7 mg sodium phosphate dibasic heptahydrate, and 0.05 mg polysorbate 80. ALDURAZYME (laronidase) does not contain preservatives; vials are for single use only.

Last reviewed on RxList: 2/4/2009
This monograph has been modified to include the generic and brand name in many instances.

Aldurazyme Patient Information Including Side Effects

Brand Names: Aldurazyme

Generic Name: laronidase (Pronunciation: lah RAH nih daze)

What is laronidase (Aldurazyme)?

Laronidase is used to treat some of the symptoms of a genetic condition called Hurler syndrome. Hurler syndrome is also called mucopolysaccharidosis (MYOO-koe-pol-ee-SAK-a-rye-DOE-sis).

Hurler syndrome is a metabolic disorder in which the body lacks the enzyme needed to break down certain sugars and proteins. These substances can build up in the body, causing enlarged organs, abnormal bone structure, changes in facial features, breathing problems, heart problems, vision or hearing loss, and changes in mental or physical abilities.

Laronidase may improve breathing and walking ability in people with this condition. However, this medication is not a cure for Hurler syndrome.

Laronidase may also be used for other purposes not listed in this medication guide.

What are the possible side effects of laronidase (Aldurazyme)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Some people receiving a laronidase injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you have a headache, skin rash or itching, warmth or tingly feeling, or trouble breathing when laronidase is injected.

Less serious side effects may include:

  • runny or stuffy nose, sore throat, cough;
  • mild skin rash;
  • numbness or tingling; or
  • pain, redness, swelling, or other irritation where the medicine was injected.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Read the Aldurazyme (laronidase) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about laronidase (Aldurazyme)?

Laronidase may improve breathing and walking ability in people with Hurler syndrome. However, laronidase is not a cure for this condition.

Some people receiving a laronidase injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you have a headache, skin rash or itching, warmth or tingly feeling, or trouble breathing when laronidase is injected.

Your name may need to be listed on a patient registry while you are using this medication. The purpose of this registry is to track the progression of this disorder and the effects that laronidase has on long-term treatment of Hurler syndrome.

Side Effects Centers

Aldurazyme Patient Information including How Should I Take

What should I discuss with my healthcare provider before receiving laronidase (Aldurazyme)?

You should not use this medication if you are allergic to laronidase.

Before using laronidase, tell your doctor if you are allergic to any drugs.

Your name may need to be listed on a patient registry while you are using this medication. The purpose of this registry is to track the progression of this disorder and the effects that laronidase has on long-term treatment of Hurler syndrome.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether laronidase passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I use laronidase (Aldurazyme)?

Laronidase is given as an injection through a needle placed into a vein. You will most likely receive this injection in a clinic or hospital setting. Laronidase is usually given once per week.

The medicine must be given slowly through an IV infusion, and can take up to 4 hours to complete.

Your doctor may also prescribe other medications to help prevent an allergic reaction to laronidase. Take all of your medications as directed.

To be sure this medication is helping your condition and not causing harmful effects, your doctor will need to check your progress on a regular basis. Do not miss any scheduled appointments.

Side Effects Centers

Aldurazyme Patient Information including If I Miss a Dose

What happens if I miss a dose (Aldurazyme)?

Contact your doctor if you miss an appointment for your laronidase injection.

What happens if I overdose (Aldurazyme)?

Seek emergency medical attention if you think you have received too much of this medicine.

Symptoms of a laronidase overdose are not known.

What should I avoid while receiving laronidase (Aldurazyme)?

Follow your doctor's instructions about any restrictions on food, beverages, or activity while you are receiving laronidase.

What other drugs will affect laronidase (Aldurazyme)?

There may be other drugs that can interact with laronidase. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

Where can I get more information?

Your doctor or pharmacist can provide more information about laronidase.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 2.03. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

Healthwise

Side Effects Centers

توزیع کنندگان این دارو
شرکت های تولید کننده یا وارد کننده دارو

دارونـــما
نوآوری برای سلامت

طراحی و اجرا M.Ramezani
ارتباط با ما Info@darunama.com