Laronidase

Laronidase is used to treat some of the symptoms of a genetic condition called Hurler syndrome, also called mucopolysaccharidosis (MYOO-koe-pol-ee-SAK-a-rye-DOE-sis), or MPS I. Forms of MPS I include Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome."

MPS I 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 MPS I.

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

You should not use laronidase if you are allergic to it.

Before you receive laronidase, tell your doctor if you have heart disease, kidney disease, lung disease, seizures, migraine headaches, or sleep apnea.

Tell your doctor if you have been sick with a fever, head cold, or chest cold. You may need to wait until you get better before receiving your dose of laronidase.

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

You should not use laronidase if you are allergic to it.

To make sure laronidase is safe for you, tell your doctor if you have any of these other conditions:

• fever or cold symptoms (cough, sore throat, chest congestion, sinus pain, runny or stuffy nose, sneezing);
• heart disease;
• kidney disease;
• asthma or other lung disease;
• epilepsy or other seizure disorder;
• migraine headaches; or
• if you have sleep apnea and you use a continuous positive airway pressure (CPAP) machine.

You may be encouraged to join 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 MPS I.

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

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of laronidase on the baby.

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.

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 catalyzes the hydrolysis of terminal α-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 therapy in MPS I is to provide exogenous enzyme for uptake into lysosomes and increase the catabolism of GAG. ALDURAZYME 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 (CNS) by the blood brain barrier, effects of intravenously administered ALDURAZYME on cells within the CNS cannot be inferred from activity in sites outside the CNS. The ability of ALDURAZYME to cross the blood brain barrier has not been evaluated in animal models or in clinical studies.

Pharmacodynamics

The pharmacodynamic effect of ALDURAZYME was assessed by reductions in urinary GAG levels. The responsiveness of urinary GAG to dosage alterations of ALDURAZYME is unknown, and the relationship of urinary GAG to other measures of clinical response has also not been established [see Clinical Studies].

Pharmacokinetics

The pharmacokinetics of laronidase were evaluated in 6 year old or older patients (N=10 to 12) with MPS I who received 0.58 mg/kg of body weight once weekly of ALDURAZYME as a 4-hour infusion in the placebocontrolled clinical study (Study 1). After the 1st, 12th, and 26th weekly infusions, the mean maximum plasma concentrations (Cmax) ranged from 1.2 to 1.7 μg/mL for the 3 time points. The mean area under the plasma concentration-time curve (AUC∞) ranged from 4.5 to 6.9 μg • hour/mL. The mean volume of distribution (Vz) ranged from 0.24 to 0.60 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.

Most patients who received once weekly infusions of ALDURAZYME in Study 1 developed antibodies to laronidase by Week 12. Between Weeks 1 and 12, increases in the plasma clearance of laronidase were observed in some patients and 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.

The pharmacokinetics of laronidase were evaluated in 6 year old or younger patients (N=7 to 9) with MPS I disease who received 0.58 mg/kg of body weight once weekly of ALDURAZYME as a 4-hour infusion in the open label clinical study (Study 3). After the 26th infusion, the 95% confidence interval of the geometric mean values of PK parameters ranged from 0.6 to 1.6 μg/mL for the maximum plasma concentrations (Cmax), from 1.3 to 4.4 μg • hour/mL for area under the plasma concentration-time curve (AUC∞), from 0.12 to 0.56 L/kg for volume of distribution (Vz), from 2.2 to 7.7 mL/min/kg for plasma clearance (CL), and from 0.3 to 1.9 hours for elimination half-life (t½).

Clinical Studies

The safety and efficacy of ALDURAZYME were assessed in three clinical studies.

Clinical Studies in Patients 6 Years and Older

Study 1 was a randomized, double-blind, placebo-controlled study in 45 patients with MPS I, ages 6 to 43 years old, including 1 patient with the Hurler form, 37 patients with Hurler-Scheie form, and 7 patients with Scheie form of MPS I. All patients had a baseline percent predicted forced vital capacity (FVC) less than or equal to 77%. Patients received ALDURAZYME at 0.58 mg/kg of body weight once weekly 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 percent predicted FVC and distance walked in 6 minutes (6- minute walk test). After 26 weeks, patients treated with ALDURAZYME showed improvement in percent predicted FVC and in 6-minute walk test compared to placebo-treated patients (see Table 4).

Table 4: Primary Efficacy Outcomes in the Placebo-controlled Study (Study 1)

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

Study 2 was a 182-week, open-label, uncontrolled extension study of all 45 patients who completed Study 1. Patients received ALDURAZYME at 0.58 mg/kg body weight once weekly. For patients treated with ALDURAZYME, the mean increase in 6-minute walk test distance was maintained for an additional 182 weeks through completion of Study 2.

At the end of Study 2, the decrease in mean urinary GAG was similar to the decrease in urinary GAG reported in ALDURAZYME-treated patients at the end of Study 1. The relationship of urinary GAG to other measures of clinical response has not been established.

Clinical Studies in Patients 6 Years and Younger

Study 3 was a 52-week, open-label, uncontrolled clinical study in 20 patients with MPS I, ages 6 months to 5 years old (at enrollment), including 16 patients (80%) with the Hurler form and 4 patients (20%) with the Hurler-Scheie form. All 20 patients received ALDURAZYME at 0.58 mg/kg of body weight once weekly for 26 weeks. After 26 weeks of treatment, 16 patients continued to receive 0.58 mg/kg of body weight once weekly through Week 52, and 4 patients received 1.16 mg/kg of body weight once weekly from Week 26 through Week 52.

Reduction in mean urinary GAG was demonstrated at Week 13 and was maintained through Week 52. No patient receiving ALDURAZYME reached the normal range for urinary GAG levels during this 52-week study. Changes in urinary GAG levels in children 6 years and younger were similar to changes reported in older patients in Studies 1 and 2 (6 through 43 years old). The relationship of urinary GAG to other measures of clinical response has not been established.

Mechanism of Action

Recombinant alpha-L-iduronidase, an enzyme (deficient in mucopolysaccharidosis I) involved in the breakdown of glycosaminoglycans within lysosomes; walking capacity and pulmonary function improves in patients treated with this recombinant product

Absorption

Peak plasma concentration: 1.2-1.7 mcg/mL

AUC: 4.5-6.9 mcg•hr/mL

Onset: 3-6 wk (initial effect); 26 wk (max effect)

Distribution

Vd: 0.24-0.6 L/kg

Elimination

Half-life: 1.5-3.6 hr

Plasma clearance: 1.7-2.7 mL/min/kg

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Laronidase falls into category B:

There are no well-done studies that have been done in humans with Laronidase. But in animal studies, pregnant animals were given this medication, and the babies did not show any medical issues related to this medication.

OR

In animal studies, pregnant animals were given Laronidase, and some babies had problems. But in human studies, pregnant women were given this medication and their babies did not have any problems related to this medication.

• Importance of notifying clinician immediately if manifestations of infusion reaction (fever, flushing, headache, rash, cough, difficulty breathing) occur.b

• Importance of informing patients that a registry has been established to monitor the variability and progression of MPS I and to evaluate treatments for the disease; importance of encouraging patient participation and of advising patients that participation may involve long-term follow-up.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, dietary supplements, and herbal products.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing patients of other important precautionary information. (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Note: Premedicate with antipyretic and/or antihistamines 1 hour prior to start of infusion.

MPS I (Hurler syndrome, Hurler-Scheie, and Scheie forms): Children ≥6 months: IV: 0.58 mg/kg once weekly; dose should be rounded up to the nearest whole vial

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

Applies to laronidase: intravenous solution

Along with its needed effects, laronidase may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking laronidase:

• Abdominal or stomach pain
• accumulation of pus
• back pain
• black, tarry stools
• bleeding gums
• blood in urine or stools
• blurred vision
• chest pain
• chest tightness
• chills
• clay-colored stools
• confusion
• dark urine
• dizziness
• drowsiness
• facial swelling
• faintness
• fast, pounding, or irregular heartbeat or pulse
• fever
• flushing
• headache
• hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at injection site
• itching
• lightheadedness when getting up from a lying or sitting position suddenly
• loss of appetite
• nausea or vomiting
• pale skin
• pinpoint red spots on skin
• shortness of breath
• skin rash
• sweating
• swollen, red, or tender area of infection
• trouble breathing
• unpleasant breath odor
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting of blood
• yellow eyes or skin

• Cough
• difficulty breathing
• itching skin
• large, hive-like swelling on face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• noisy breathing
• redness of skin
• tightness in chest
• wheezing

Some side effects of laronidase may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bleeding, blistering, burning, coldness, or discoloration of skin
• blindness
• body aches or pain
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• decreased vision
• diarrhea
• difficulty in moving
• ear congestion
• feeling of pressure
• loss of voice
• muscle pain or stiffness
• nasal congestion
• overactive reflexes
• pain in joints
• runny nose
• sneezing
• sore throat
• swelling of legs and feet
• swelling or puffiness of face
• varicose or spider veins