Adagen

Name: Adagen

What is the most important information I should know about Adagen (pegademase bovine)?

You should not use pegademase bovine if have severe thrombocytopenia (low levels of platelets in blood).

What should I avoid while using Adagen (pegademase bovine)?

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

What other drugs will affect Adagen (pegademase bovine)?

Other drugs may interact with pegademase bovine, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Before Using Adagen

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of pegademase in children.

Geriatric

No information is available on the relationship of age to the effects of pegademase in geriatric patients.

Pregnancy

Pregnancy Category Explanation
All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Pentostatin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Bleeding problems (e.g., thrombocytopenia) or
  • Infections—Use with caution. May make these conditions worse.
  • Thrombocytopenia, severe—Should not be used in patients with this condition.

Uses of Adagen

  • It is used to treat adenosine deaminase deficiency in children who have a weak immune system.

Precautions

General

Any laboratory or clinical indication of a decrease in potency of Adagen® (pegademase bovine) Injection should be reported immediately by telephone to Sigma-Tau Pharmaceuticals, Inc. Telephone 1-866-792-5172.

There have been no reports of hypersensitivity reactions in patients who have been treated with Adagen® (pegademase bovine) Injection.

One of 12 patients showed an enhanced rate of clearance of plasma ADA activity after 5 months of therapy at 15 U/kg/week. Enhanced clearance was correlated with the appearance of an antibody that directly inhibited both unmodified ADA and Adagen® (pegademase bovine) Injection. Subsequently, the patient was treated with twice weekly intramuscular injections at an increased dose of 20 U/kg, or a total weekly dose of 40 U/kg. No adverse effects were observed at the higher dose and effective levels of plasma ADA were restored. After 4 months, the patient returned to a weekly dosage schedule of 20 U/kg and effective plasma levels have been maintained.

Appropriate care to protect immune deficient patients should be maintained until improvement in immune function has been documented. The degree of immune function improvement may vary from patient to patient and, therefore, each patient will require appropriate care consistent with immunologic status.

Laboratory Tests

The treatment of SCID associated with ADA deficiency with Adagen® (pegademase bovine) Injection should be monitored by measuring plasma ADA activity and red blood cell dATP levels.

Plasma ADA activity and red cell dATP should be determined prior to treatment. Once treatment with Adagen® (pegademase bovine) Injection has been initiated, a desirable range of plasma ADA activity (trough level before maintenance injection) should be 15–35 μmol/hr/mL. This minimum trough level will ensure that plasma ADA activity from injection to injection is maintained above the level of total erythrocyte ADA activity in the blood of normal individuals.

Plasma ADA activity (pre-injection) should be determined every 1-2 weeks during the first 8-12 weeks of treatment in order to establish an effective dose of Adagen® (pegademase bovine) Injection. After 2 months of maintenance treatment with Adagen® (pegademase bovine) Injection, red cell dATP levels should decrease to a range of ≤ 0.005 to 0.015 μmol/mL. The normal value of dATP is below 0.001 μmol/mL. Once the level of dATP has fallen adequately, it should be measured 2-4 times a year during the remainder of the first year and 2-3 times a year thereafter, assuming no interruption in therapy.

Between 3 and 9 months, plasma ADA should be determined twice a month, then monthly until after 18-24 months of treatment with Adagen® (pegademase bovine) Injection.

Patients who have successfully been maintained on therapy for two years should continue to have plasma ADA measured every 2-4 months and red cell dATP measured twice yearly. More frequent monitoring would be necessary if therapy were interrupted or if an enhanced rate of clearance of plasma ADA activity develops.

Once effective ADA plasma levels have been established, should a patient’s plasma ADA activity level fall below 10 μmol/hr/mL (which cannot be attributed to improper dosing, sample handling or antibody development) then the patients receiving this lot of Adagen® (pegademase bovine) Injection should be requested to have a blood sample for plasma ADA determination taken prior to their next injection of Adagen® (pegademase bovine) Injection.

Immune function, including the ability to produce antibodies, generally improves after 2-6 months of therapy, and matures over a longer period. Compared with 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. However, the lag between the correction of the metabolic abnormalities and improved immune function with a trend toward diminished frequency of infections and complications of infection is variable, and has ranged from a few weeks to approximately 6 months. Improvement in the general clinical status of the patient may be gradual (as evidenced by improvement in various clinical parameters) but should be apparent by the end of the first year of therapy. Antibody to Adagen® (pegademase bovine) Injection may develop in patients and may result in more rapid clearance of Adagen® (pegademase bovine) Injection. Antibody to Adagen® (pegademase bovine) Injection should be suspected if a persistent fall in pre-injection levels of plasma ADA to < 10 μmol/hr/mL occurs. If other causes for a decline in plasma ADA levels can be ruled out [such as improper storage of Adagen® (pegademase bovine) Injection vials (freezing or prolonged storage at temperatures above 8°C), or improper handling of plasma samples (e.g., repeated freezing and thawing during transport to laboratory)], then a specific assay for antibody to ADA and Adagen® (pegademase bovine) Injection (ELISA, enzyme inhibition) should be performed.

In patients undergoing treatment with Adagen® (pegademase bovine) Injection, a decline in immune function, with increased risk of opportunistic infections and complications of infection, will result from failure to maintain adequate levels of plasma ADA activity [whether due to the development of antibody to Adagen® (pegademase bovine) Injection, to improper calculation of Adagen® (pegademase bovine) Injection dosage, to interruption of treatment or to improper storage of Adagen® (pegademase bovine) Injection with subsequent loss of activity]. If a persistent decline in plasma ADA activity occurs, immune function and clinical status should be monitored closely and precautions should be taken to minimize the risk of infection. If antibody to ADA or Adagen® (pegademase bovine) Injection is found to be the cause of a persistent fall in plasma ADA activity, then adjustment in the dosage of Adagen® (pegademase bovine) Injection and other measures may be taken to induce tolerance and restore adequate ADA activity.

Drug Interactions

There are no known drug interactions with Adagen® (pegademase bovine) Injection. However, Vidarabine is a substrate for ADA and 2′-deoxycoformycin is a potent inhibitor of ADA. Thus, the activities of these drugs and Adagen® (pegademase bovine) Injection could be substantially altered if they are used in combination with one another.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenic studies in animals have not been performed with Adagen® (pegademase bovine) Injection nor have studies been performed on impairment of fertility.

Adagen® (pegademase bovine) Injection did not exhibit a mutagenic effect when tested against Salmonella typhimurium strains in the Ames assay.

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Adagen® (pegademase bovine) Injection. It is also not known whether Adagen® (pegademase bovine) Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Adagen® (pegademase bovine) Injection should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether Adagen® (pegademase bovine) Injection is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Adagen® (pegademase bovine) Injection is administered to a nursing woman.

Adverse Reactions

Clinical experience with Adagen® (pegademase bovine) Injection has been limited. The following adverse reactions were reported: headache in one patient and pain at the injection site in two patients. The following adverse reactions have been identified during post-approval use of Adagen® (pegademase bovine) Injection. Because these reactions are reported voluntarily from a very small population, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hematologic events: hemolytic anemia, auto-immune hemolytic anemia, thrombocythemia, thrombocytopenia and autoimmune thrombocytopenia.

Dermatological events: injection site erythema, urticaria.
Lymphomas

To report SUSPECTED ADVERSE REACTIONS, contact Sigma-Tau Pharmaceuticals, Inc. at 1-888-393-4584 or by email at drugsafety@sigmatau.com or contact the FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch.

References

• Hershfield MS, Buckley RH, Greenberg ML, et al. Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase. N Engl J Med 1987; 316:589-96. • Levy Y, Hershfield MS, Fernandez-Mejia C, Polmar ST, Scudiery D, Berger M, Sorensen RU. Adenosine deaminase deficiency with late onset of recurrent infections: response to treatment with polyethylene glycolmodified adenosine deaminase. J Pediatr 1988; 113:312-17. • Kredich NM, Hershfield MS. Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. 6th ed. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. New York: McGraw Hill, 1989; 1045-75. • Hirschhorn R. Inherited enzyme deficiencies and immunodeficiency: adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiencies. Clin Immunol Immunopathol 1986; 40:157-65. • Hirschhorn R, Roegner-Maniscalco V, Kuritsky L, Rosen FS. Bone marrow transplantation only partially restores purine metabolites to normal adenosine deaminase-deficient patients. J Clin Invest 1981; 68:1387-93. • Polmar AH, Stern RC, Schwartz AL, Wetzler EM, Chase PA, Hirschhorn R. Enzyme replacement therapy for adenosine deaminase deficiency and severe combined immunodeficiency. N Engl J Med 1976; 295:1337-43. • Rubinstein A, Hirschhorn R, Sicklick M, Murphy RA. In vivo and in vitro effects of thymosin and adenosine deaminase on adenosine-deaminase-deficient lymphocytes. N Engl J Med 1979; 300:387-92. • Hirschhorn R, Papageorgiou PS, Kesarwala HH, Taft LT. Amelioration of neurologic abnormalities after “enzyme replacement” in adenosine deaminase deficiency. N Engl J Med 1980; 303:377-80. • Hirschhorn R, Ratech H, Rubinstein A, et al. Increased excretion of modified adenine nucleosides by children with adenosine deaminase deficiency. Pediatr Res 1982; 16:362-9. • Polmar SH. Enzyme replacement and other biochemical approaches to the therapy of adenosine deaminase deficiency. In: Elliott K, Whelan J, eds. Enzyme defects and immune dysfunction. Amsterdam: Excerpta Medica, 1979; 213-30.

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Revised 6/2014

I-001-17-US-F

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