Adagen

ADAGEN® (pegademase bovine) Injection is a modified enzyme used for enzyme replacement therapy for the treatment of severe combined immunodeficiency disease (SCID) associated with a deficiency of adenosine deaminase.

ADAGEN® (pegademase bovine) Injection is supplied in an isotonic, pyrogen free, sterile solution, pH 7.2-7.4, for intramuscular injection only. The solution is clear and colorless. It is supplied in 1.5 mL single-dose vials. The chemical name for ADAGEN® (pegademase bovine) Injection is (monomethoxypolyethylene glycol succinimidyl) 11-17­adenosine deaminase. It is a conjugate of numerous strands of monomethoxypolyethylene glycol (PEG), molecular weight 5,000, covalently attached to the enzyme adenosine deaminase (ADA). ADA (adenosine deaminase EC 3.5.4.4) used in the manufacture of ADAGEN® (pegademase bovine) Injection is derived from bovine intestine.

The structural formula of ADAGEN® (pegademase bovine) Injection is:

 x ≈ 114 oxyethylene groups per PEG strand.
y ≈ 11-17 primary amino groups of lysine onto which succinyl PEG is attached.

Each milliliter of ADAGEN® (pegademase bovine) Injection contains:

Pegademase bovine ................................................................ 250 units*
Monobasic sodium phosphate, USP ........................................... 1.20 mg
Dibasic sodium phosphate, USP ................................................ 5.58 mg
Sodium Chloride, USP ................................................................ 8.50 mg
Water for injection, USP..................................................... q.s. to 1.0 mL

*One unit of activity is defined as the amount of ADA that converts 1μM of adenosine to inosine per minute at 25°C and pH 7.3.

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

Call your doctor at once if you have:

• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

• pale or yellowed skin, dark colored urine, fever, confusion or weakness; or

• signs of infection--fever, chills, sore throat, mouth sores, flu symptoms, skin sores or swelling.

Common side effects may include:

• headache; or

• redness or itching where the medicine was injected.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In the U.S.

• Adagen

Available Dosage Forms:

• Solution

Therapeutic Class: Immune Stimulant

Pharmacologic Class: Enzyme

A nurse or other trained health professional will give you or your child this medicine. This medicine is given as a shot into one of your or your child's muscles.

You may be taught how to give this medicine at home. Make sure you understand all instructions before giving yourself or your child an injection. Do not use more medicine or use it more often than your doctor tells you to.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For injection dosage form:
  • For treatment of lack of ADA:
    • Children—Dose is based on body weight and must be determined by your doctor. The usual dose is 10 to 20 Units per kilogram (kg) (4.55 to 9.09 Units per pound) of body weight, injected into a muscle once a week. If you are receiving pegademase at home, follow your doctor's orders or the directions on the label. If you have any questions about the proper dose of pegademase, ask your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store in the refrigerator. Do not freeze.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Throw away used needles in a hard, closed container that the needles cannot poke through. Keep this container away from children and pets.

For all patients taking Adagen:

• Tell all of your child's health care providers that your child is taking this medicine. This includes your child's doctors, nurses, pharmacists, and dentists.
• Have your child's blood work checked often. Talk with your child's doctor.
• Your child may bleed more easily. Make sure your child is careful and avoids injury. Be sure your child has a soft toothbrush.

If your child is pregnant or breast-feeding a baby:

• Talk with the doctor if your child is pregnant, becomes pregnant, or is breast-feeding a baby. You will need to talk about the benefits and risks of using Adagen.

• If you need to store Adagen at home, talk with your child's doctor, nurse, or pharmacist about how to store it.

Severe Combined Immunodeficiency Disease Associated with ADA Deficiency

Severe combined immunodeficiency disease (SCID) associated with a deficiency of ADA is a rare, inherited, and often fatal disease. In the absence of the ADA enzyme, the purine substrates adenosine and 2′-deoxyadenosine accumulate, causing metabolic abnormalities that are directly toxic to lymphocytes.

The immune deficiency can be cured by bone marrow transplantation. When a suitable bone marrow donor is unavailable or when bone marrow transplantation fails, non-selective replacement of the ADA enzyme has been provided by periodic irradiated red blood cell transfusions. However, transmission of viral infections and iron overload are serious risks associated with irradiated red blood cell transfusions, and relatively few ADA deficient patients have benefitted from chronic transfusion therapy.

Adagen® (pegademase bovine) Injection provides specific and direct replacement of the deficient enzyme, but will not benefit patients with immunodeficiency due to other causes.

In patients with ADA deficiency, rigorous adherence to a schedule of Adagen® (pegademase bovine) Injection administration can eliminate the toxic metabolites of ADA deficiency and result in improved immune function. It is imperative that treatment with Adagen® (pegademase bovine) Injection be carefully monitored by measurement of the level of ADA activity in plasma. Monitoring of the level of deoxyadenosine triphosphate (dATP) in erythrocytes is also helpful in determining that the dose of Adagen® (pegademase bovine) Injection is adequate.

Actions

Adagen® (pegademase bovine) Injection provides specific replacement of the deficient enzyme.

In the absence of the enzyme ADA, the purine substrates adenosine, 2′-deoxyadenosine and their metabolites are toxic to lymphocytes. The direct action of Adagen® (pegademase bovine) Injection is the correction of these metabolic abnormalities. Improvement in immune function and diminished frequency of opportunistic infections compared with the natural history of combined immunodeficiency due to ADA deficiency only occurs after metabolic abnormalities are corrected. There is a lag between the correction of the metabolic abnormalities and improved immune function. This period of time is variable, and has been reported to be from a few weeks to as long as 6 months. In contrast to the natural history of combined immunodeficiency disease due to ADA deficiency, a trend toward diminished frequency of opportunistic infections and fewer complications of infections has occurred in patients receiving Adagen® (pegademase bovine) Injection.

Pharmacokinetics

The pharmacokinetics and biochemical effects of Adagen® (pegademase bovine) Injection have been studied in six children ranging in age from 6 weeks to 12 years with SCID associated with ADA deficiency.

After the intramuscular injection of Adagen® (pegademase bovine) Injection, peak plasma levels of ADA activity were reached 2 to 3 days following administration. The plasma elimination half-life of ADA following the administration of Adagen® (pegademase bovine) Injection was variable, even for the same child. The range was 3 to > 6 days. Following weekly injections of Adagen® (pegademase bovine) Injection at 15 U/kg, the average trough level of ADA activity in plasma was between 20 and 25 μmol/hr/mL.

Biochemical Effects

The changes in red blood cell deoxyadenosine nucleotide (dATP) and S-adenosylhomocysteine hydrolase (SAHase) have been evaluated. In patients with ADA deficiency, inadequate elimination of 2′-deoxyadenosine caused a marked elevation in dATP and a decrease in SAHase level in red blood cells. Prior to treatment with Adagen® (pegademase bovine) Injection, the levels of dATP in the red blood cells ranged from 0.056 to 0.899 μmol/mL of erythrocytes. After 2 months of maintenance treatment with Adagen® (pegademase bovine) Injection, the levels decreased to 0.007 to 0.015 μmol/mL. The normal value of dATP is below 0.001 μmol/mL. In the same period of time, the levels of SAHase increased from the pretreatment range of 0.09 to 0.22 nmol/hr/mg protein to a range of 2.37 to 5.16 nmol/hr/mg protein. The normal value for SAHase is 4.18 ± 1.9 nmol/hr/mg protein.

The optimal dosage and schedule of administration of Adagen® (pegademase bovine) Injection should be established for each patient, based on monitoring of plasma ADA activity levels (trough levels before maintenance injection), biochemical markers of ADA deficiency (primarily red cell dATP content), and parameters of immune function. Since improvement in immune function follows correction of metabolic abnormalities, maintenance dosage in individual patients should be aimed at achieving the following biochemical goals: 1) maintain plasma ADA activity (trough levels) in the range of 15-35 μmol/hr/mL (assayed at 37°C); and 2) decline in erythrocyte dATP to ≤ 0.005-0.015 µmol/mL packed erythrocytes, or ≤ 1% of the total erythrocyte adenine nucleotide (ATP + dATP) content, with a normal ATP level, as measured in a pre-injection sample.

In vitro immunologic data (lymphocyte response to mitogens and lymphocyte surface antigens) were obtained, but their clinical significance is unknown. Prior to treatment with Adagen® (pegademase bovine) Injection, immune status was significantly below normal, as indicated by < 10% of normal mitogen responses and circulating mononuclear cells bearing T-cell surface antigens. These parameters improved, though not always to normal, within 2 to 6 months of therapy.

Before prescribing Adagen® (pegademase bovine) Injection the physician should be thoroughly familiar with the details of this prescribing information. For further information concerning the essential monitoring of Adagen® (pegademase bovine) Injection therapy, the prescribing physician should contact Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, MD 20878. Telephone 1-866-792-5172.

Adagen® (pegademase bovine) Injection is recommended for use in infants from birth or in children of any age at the time of diagnosis.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permits.

Adagen® (pegademase bovine) Injection should not be diluted nor mixed with any other drug prior to administration.

Adagen® (pegademase bovine) Injection should be administered every 7 days as an intramuscular injection. The dosage of Adagen® (pegademase bovine) Injection should be individualized. The recommended dosing schedule is 10 U/kg for the first dose, 15 U/kg for the second dose, and 20 U/kg for the third dose. The usual maintenance dose is 20 U/kg per week. Further increases of 5 U/kg/week may be necessary, but a maximum single dose of 30 U/kg should not be exceeded. Plasma levels of ADA more than twice the upper limit of 35 μmol/hr/mL have occurred on occasion in several patients, and have been maintained for several weeks in one patient who received twice weekly injections (20 U/kg per dose) of Adagen® (pegademase bovine) Injection. No adverse effects have been observed at these higher levels; there is no evidence that maintaining pre-injection plasma ADA above 35 μmol/hr/mL produces any additional clinical benefits.

Dose proportionality has not been established and patients should be closely monitored when the dosage is increased. Adagen® (pegademase bovine) Injection is not recommended for intravenous administration.

The optimal dosage and schedule of administration should be established for each patient based on monitoring of plasma ADA activity levels (trough levels before maintenance injection) and biochemical markers of ADA deficiency (primarily red cell dATP content). Since improvement in immune function follows correction of metabolic abnormalities, maintenance dosage in individual patients should be aimed at achieving the following biochemical goals: 1) maintain plasma ADA activity (trough levels before maintenance injection) in the range of 15-35 μmol/hr/mL (assayed at 37°C); and 2) decline in erythrocyte dATP to ≤ 0.005-0.015 μmol/mL packed erythrocytes, or ≤ 1% of the total erythrocyte adenine nucleotide (ATP + dATP) content, with a normal ATP level, as measured in a pre-injection sample. In addition, continued monitoring of immune function and clinical status is essential in any patient with a primary immunodeficiency disease and should be continued in patients undergoing treatment with Adagen® (pegademase bovine) Injection.

NDC 57665-001-01

Adagen®
(pegademase bovine)
Injection

Four 1.5 mL single-dose vials.
250 units per mL

Sterile-For intramuscular use only.
See package insert for dosage information.
Discard if cloudy or frozen.

Store at + 2° C to + 8° C (36° F to 46° F)
REFRIGERATE-DO NOT FREEZE

Inactive Ingredients: 1.2 mg Monobasic Sodium Phosphate, 5.58 mg Dibasic Sodium Phosphate, 8.5 mg Sodium Chloride, and Water for Injection qs to 1.0 mL. Contains no preservative.
Rx Only

Manufactured by Sigma-Tau Pharmasource, Inc.
Indianapolis, IN 46268

Distributed by Sigma-Tau Pharmaceuticals, Inc.
Gaithersburg, MD 20878

Carton Label

Pregnancy Category: C

Lactation: Not known if distributed into breast milk, use caution

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.