Myozyme

MYOZYME® (alglucosidase alfa) [see DESCRIPTION] is a lysosomal glycogen-specific enzyme indicated for use in patients with Pompe disease (GAA deficiency). MYOZYME has been shown to improve ventilator-free survival in patients with infantile-onset Pompe disease as compared to an untreated historical control, whereas use of MYOZYME in patients with other forms of Pompe disease has not been adequately studied to assure safety and efficacy [see Clinical Studies].

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data described below reflect exposure of 39 Pompe disease patients to 20 or 40 mg/kg of MYOZYME administered every other week in 2 separate clinical trials for periods ranging from 1 to 106 weeks (mean 61 weeks). Patients were ages 1 month to 3.5 years at first treatment. The population was nearly evenly distributed in gender (18 females and 21 males).

The most serious adverse reactions reported with MYOZYME were anaphylactic reactions, acute cardiorespiratory failure, and cardiac arrest.

Anaphylactic reactions have been reported during and within 3 hours after MYOZYME infusion [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

Acute cardiorespiratory failure has been observed in a few infantile-onset Pompe disease patients with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of alglucosidase alfa [see BOXED WARNING and WARNINGS AND PRECAUTIONS and Instructions for Use].

The most common serious treatment-emergent adverse reactions occurring in > 10% of patients observed in clinical studies with MYOZYME were pneumonia, respiratory failure, respiratory distress, catheter-related infection, respiratory syncytial virus infection, gastroenteritis and fever.

The most common adverse reactions requiring intervention in clinical trials were infusion reactions [see WARNINGS AND PRECAUTIONS]. Twenty of 39 patients (51%) treated with MYOZYME in clinical studies developed infusion reactions. Infusion reactions, defined as an adverse reaction occurring during the infusion or within 2 hours after completion of the infusion, that occurred in more than 1 patient in clinical studies and the expanded access program include rash, flushing, urticaria, fever, cough, tachycardia, decreased oxygen saturations, vomiting, tachypnea, agitation, increased blood pressure, cyanosis, hypertension, irritability, pallor, pruritus, retching, rigors, tremor, hypotension, bronchospasm, erythema, face edema, feeling hot, headache, hyperhidrosis, increased lacrimation, livedo reticularis, nausea, periorbital edema, restlessness, and wheezing.

The most common treatment-emergent adverse reactions occurring in ≥ 20% of patients were fever, diarrhea, rash, vomiting, cough, pneumonia, otitis media, upper respiratory tract infection, gastroenteritis and decreased oxygen saturation.

Table 2 enumerates treatment-emergent adverse reactions that occurred in at least 20% of patients treated with MYOZYME in clinical trials described above. Reported frequencies of adverse events have been classified by MedDRA terms.

Table 2: Summary of Adverse Reactions by System Organ Class and Preferred Term Occurring in at Least 20% of Patients Treated with MYOZYME® in Clinical Trials

Five additional juvenile-onset Pompe disease patients were evaluated in a single-center, open-label, non-randomized, uncontrolled clinical trial. Patients were ages 5 to 15 years, ambulatory (able to walk at least 10 meters in 6 minutes), and not receiving invasive ventilatory support at study entry. All 5 patients received treatment with 20 mg/kg MYOZYME for 26 weeks. The most common treatment-emergent adverse reactions observed with MYOZYME treatment in this study were headache (4.1%), pharyngitis (9.1%), upper abdominal pain (15.2%), malaise (6.1%) and rhinitis (6.1%).

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The majority of patients (34 of 38; 89%) in the two clinical trials tested positive for IgG antibodies to alglucosidase alfa. The data reflect the percentage of patients whose test results were considered positive for antibodies to alglucosidase alfa using an enzyme-linked immunosorbent assay (ELISA) and radioimmunoprecipitation (RIP) assay for alglucosidase alfa-specific IgG antibodies. Most patients who develop antibodies do so within the first 3 months of exposure. There is evidence to suggest that patients developing sustained titers ≥ 12,800 of anti-alglucosidase alfa antibodies may have a poorer clinical response to treatment, or may lose motor function as antibody titers increase. Treated patients who experience a decrease in motor function should be tested for neutralization of enzyme uptake or activity. Five patients with antibody titers ≥ 12,800 at Week 12 had an average increase in clearance of 50% from Week 1 to Week 12 [see CLINICAL PHARMACOLOGY].

Some patients who developed IgG antibodies to alglucosidase alfa in clinical studies or in the postmarketing setting were evaluated for the presence of inhibitory antibodies and tested positive for inhibition of enzyme activity and/or uptake in in vitro assays.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to alglucosidase alfawith the incidence of antibodies to other products may be misleading.

The effect of antibody development on the long-term efficacy of MYOZYME is not fully understood. However, CRIM-negative infants have shown poorer clinical response in the presence of high sustained IgG antibody titers and positive inhibitory antibodies.

Infusion reactions were reported in 20 of 39 patients (51%) treated with MYOZYME in clinical studies and appear to be more common in antibody-positive patients: 8 of 15 patients with high antibody titers experienced infusion reactions, whereas none of 3 antibody-negative patients experienced infusion reactions [see WARNINGS AND PRECAUTIONS].

Patients who develop IgE antibodies to alglucosidase alfa appear to be at a higher risk for the occurrence of anaphylaxis and severe allergic reactions [see WARNINGS AND PRECAUTIONS]. Therefore, these patients should be monitored more closely during administration of MYOZYME.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of MYOZYME. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In postmarketing experience with MYOZYME, severe and serious infusion reactions have been reported, some of which were life-threatening, including anaphylactic shock [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. Acute cardiorespiratory failure, possibly associated with fluid overload, has been reported in infantile-onset Pompe disease patients with pre-existing hypertrophic cardiomyopathy [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. In addition to the infusion reactions reported in clinical trials and expanded access programs, the following infusion reactions have been reported in patients during postmarketing use of MYOZYME: cardiac arrest, respiratory arrest, apnea, stridor, pharyngeal edema, peripheral edema, chest pain, chest discomfort, muscle spasm, fatigue and conjunctivitis [see WARNINGS AND PRECAUTIONS].

Additional adverse drug reactions included proteinuria and nephrotic syndrome [see WARNINGS AND PRECAUTIONS].

Recurrent reactions consisting of flu-like illness or a combination of events such as fever, chills, myalgia, arthralgia, pain, or fatigue occurring after completion of infusions and lasting for 1-3 days have been observed in some patients treated with alglucosidase alfa. The majority of patients were successfully rechallenged with alglucosidase alfa using lower doses and/or pretreatment with anti-inflammatory drugs and/or corticosteroids and were able to continue treatment under close clinical supervision.

Systemic and cutaneous immune mediated reactions, including ulcerative and necrotizing skin lesions, and nephrotic syndrome secondary to membranous glomerulonephritis have been reported in postmarketing safety experience with alglucosidase alfa [see WARNINGS AND PRECAUTIONS].

Myozyme is a prescription medication used to treat patients with Pompe disease, a rare, inherited disorder caused by the buildup of a complex sugar called glycogen in the body's cells. The accumulation of glycogen in certain organs and tissues, especially muscles, impairs their ability to function normally.

Myozyme belongs to a group of drugs called a lysosomal glycogen-specific enzyme. These work by replacing the deficient GAA, which is seen in Pompe disease, thereby reducing the accumulated glycogen in heart and skeletal muscle cells.

This medication is available in an injectable form to be given directly into a vein (IV) by a healthcare professional.

Common side effects of Myozyme include infusion-related reactions and severe allergic reactions.

Serious side effects have been reported with Myozyme including the following:

Anaphylaxis and allergic reactions. Severe allergic reactions have been reported in some patients during a Myozyme infusion and for up to 3 hours after it is complete. Tell your healthcare provider about any signs or symptoms of an allergic reaction, which include the following:

• chest pain
• swelling of the eyes, face, lips, tongue, arms, or legs
• difficulty breathing or swallowing
• rash

Severe skin reactions. Your immune system may develop certain proteins called antibodies that can cause severe reactions to Myozyme. These reactions have occurred several weeks to 3 years after receiving Myozyme. Your doctor should monitor you for development of any skin or other reactions to Myozyme. Tell your doctor or get medical help right away if you get any of these symptoms at anytime during your treatment:

• painful sores or ulcers on your skin, lips, or in your mouth
• blisters
• peeling skin
• rash

Risk of acute cardiorespiratory failure. People with heart or lung problems may be at risk for a serious acute worsening of their condition when receiving Myozyme and for up to 72 hours after the infusion is complete. Tell your doctor if you have any conditions that affect your heart or lungs.

Infusion reactions. Infusion reactions can occur with this medication. Tell your doctor or get medical help right away if you get any of these symptoms during or after an infusion this medication:

• hives (red itchy welts) or rash
• itching
• swelling of your lips, tongue, throat or face
• sudden cough
• shortness of breath, difficulty breathing, or wheezing
• weakness
• dizziness or feel faint
• palpitations (feel like your heart is racing or fluttering)
• chest pain

Antibody formation. You can develop IgG antibodies (proteins that your immune system produces in response to something it does not recognize as a normal part of your body) in response to Myozyme that increase your risk for allergic and infusion reactions to Myozyme. Your doctor will perform blood tests to monitor for development of these antibodies once every 3 months for 2 years and then once a year thereafter.

Do not take Myozyme if you are allergic to Myozyme or to any of its ingredients.

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.

Myozyme falls into category B. There are no well-done studies that have been done in humans with Myozyme. In animal studies, pregnant animals were given this medication, and the babies did not show any medical issues related to this medication. Myozyme should only be used in pregnant women if clearly needed.

A registry has been created to better understand Pompe disease and evaluate the long-term effects of Myozyme. The registry also monitors the effects of Myozyme on pregnant women and their offspring. For more information on joining this registry, talk to your doctor or visit www.pomperegistry.com.

If Myozyme is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Storage

Parenteral

2–8°C.1 Vials are for single use only; discard any unused product.1 Administer reconstituted and diluted solution without delay; if not used immediately, solution is stable for up to 24 hours at 2–8°C.1

Protect reconstituted and diluted solutions from light; do not freeze, shake, or store at room temperature.1

• Importance of encouraging caregivers and patients, including nursing women and women of childbearing potential, to participate in the Pompe disease registry (http://www.pomperegistry.com or 800-745-4447).1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.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.)

In the U.S.

• Lumizyme
• Myozyme

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Enzyme Replacement

Pharmacologic Class: Enzyme

This section provides information on the proper use of a number of products that contain alglucosidase alfa. It may not be specific to Myozyme. Please read with care.

A nurse or other trained health professional will give you or your child this medicine in a hospital. This medicine is given through a needle placed in one of your veins.

This medicine must be given slowly, so the needle will remain in place for a few hours. You or your child may also receive medicines to help prevent possible allergic reactions to the injection.

Along with its needed effects, a medicine 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:

• Blue lips, fingernails, or skin
• body aches or pain
• chest discomfort or pain
• chills
• cough
• difficult or labored breathing
• difficulty with swallowing
• dizziness
• dry, red, hot, or irritated skin
• ear congestion
• fast, pounding, or irregular heartbeat or pulse
• feeling of warmth
• fever
• headache
• hives, itching, or skin rash
• increased sweating
• irregular, fast, slow, or shallow breathing
• lightheadedness, dizziness, or fainting
• loss of voice
• nasal congestion
• pain
• pale skin
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• rapid shallow breathing
• redness of the face, neck, arms, and occasionally, upper chest
• redness or pain at the catheter site
• runny nose
• shakiness in the legs, arms, hands, or feet
• slow or irregular heartbeat
• sneezing
• sore throat
• swollen, painful, or tender lymph glands in the neck, armpit, or groin
• tightness in the chest
• trembling or shaking of the hands or feet
• troubled breathing
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness

• Blood in the urine
• convulsions
• decreased urine
• dry mouth
• increased thirst
• loss of appetite
• mood changes
• muscle pain or cramps
• nausea or vomiting
• numbness or tingling in the hands, feet, or lips
• pain in the groin or genitals
• sharp back pain just below the ribs

• Blue-green to black skin discoloration
• blurred vision
• confusion
• dilated neck veins
• extreme fatigue
• heart stops
• inability to speak
• no breathing
• no pulse or blood pressure
• pain, redness, swelling, or sloughing of the skin at the place of injection
• seizures
• severe or sudden headache
• severe pain in the chest
• slurred speech
• sudden and severe weakness in the arm or leg on one side of the body
• sudden onset of severe breathing difficulty
• swelling of the face, fingers, feet, or lower legs
• temporary blindness
• unconscious
• weight gain

Some side effects 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:

• Abdominal or stomach pain
• acid or sour stomach
• belching
• body aches or pain
• change in hearing
• congestion
• constipation
• dryness or soreness of the throat
• ear discomfort or pain
• ear drainage
• earache
• feeling of constant movement of self or surroundings
• general feeling of discomfort or illness
• heartburn
• hoarseness
• indigestion
• muscle or bone pain, stiffness, or tightness
• muscle twitching
• redness of the skin
• redness or swelling in the ear
• sensation of spinning
• sore mouth or tongue
• stomach discomfort, upset, or pain
• tender, swollen glands in the neck
• upper abdominal or stomach pain
• voice changes
• welts
• white patches in the mouth or on the tongue

• Bloody nose
• sleepiness or unusual drowsiness

• Burning, dry, or itching eyes
• discharge, excessive tearing
• muscle spasm
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• If you have an allergy to alglucosidase alfa or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are breast-feeding. Do not breast-feed for 24 hours after getting Myozyme.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take Myozyme. This includes your doctors, nurses, pharmacists, and dentists.
• If you will be getting anesthesia, talk with your doctor. The chance of a heartbeat that is not normal and sudden death caused by heart problems may be raised in some people.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Have your urine checked as you have been told by your doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.