"The U.S. Food and Drug Administration announced today that injectable drugs used in total parenteral nutrition (TPN) in critical shortage will be imported into the United States and available to patients this week.
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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.
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 1824 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 patient 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.
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 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.
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.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 6/23/2014
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