ADVERSE REACTIONS
HIV-Associated Wasting or Cachexia
In the 12-week, placebo-controlled Clinical Trial 2, 510 patients were treated with Serostim® [somatropin (rDNA origin) for injection]. The most common adverse reactions judged to be associated with Serostim® were musculoskeletal discomfort and increased tissue turgor (swelling, particularly of the hands or feet), and were more frequently observed when Serostim® 0.1 mg/kg was administered on a daily basis (Table 7 and PRECAUTIONS). These symptoms were generally rated by investigators as mild to moderate in severity and often subsided with continued treatment or dose reduction. Approximately 23% of patients receiving Serostim® 0.1 mg/kg daily and 11% of patients receiving 0.1 mg/kg every other day required dose reductions. Discontinuations as a result of adverse events occurred in 10.3% of patients receiving Serostim® 0.1 mg/kg daily and 6.6% of patients receiving 0.1 mg/kg every other day. The most common reasons for dose reduction and/or drug discontinuation were arthralgia, myalgia, edema, carpal tunnel syndrome, elevated glucose levels, and elevated triglyceride levels.
Clinical adverse events which occurred during the first 12 weeks of study in at least 5% of the patients in any one of the three treatment groups are listed below by treatment group, without regard to causality assessment.
Table 7: Controlled Clinical Trial 2 Adverse Events
|
| Placebo |
0.1 mg/kg qod Serostim®
|
0.1 mg/kg daily Serostim®
|
| |
Patients (n=247) |
Patients (n=257) |
Patients (n=253) |
|
Body System
|
|
|
|
| Preferred Term |
% |
% |
% |
|
Musculoskeletal System Disorders
|
|
|
|
| Arthralgia |
11.3 |
24.5 |
36.4 |
| Myalgia |
11.7 |
17.9 |
30.4 |
| Arthrosis |
3.6 |
7.8 |
10.7 |
|
Gastro-Intestinal System Disorders
|
|
|
|
| Diarrhea |
10.1 |
10.1 |
5.5 |
| Nausea |
4.9 |
5.4 |
9.1 |
|
Psychiatric Disorders
|
|
|
|
| Insomnia |
6.1 |
3.9 |
5.9 |
|
Body As A Whole - General Disorders
|
|
|
|
| Edema Peripheral |
2.8 |
11.3 |
26.1 |
| Headache |
9.3 |
10.1 |
12.6 |
| Fatigue |
4.5 |
3.5 |
5.1 |
|
Respiratory System Disorders
|
|
|
|
| Rhinitis |
6.5 |
5.1 |
4.0 |
| Upper Resp Tract Infection |
5.7 |
4.3 |
3.6 |
| Bronchitis |
5.3 |
2.3 |
4.7 |
|
Endocrine Disorders
|
|
|
|
| Gynecomastia |
0.4 |
3.5 |
5.5 |
|
Centr & Periph Nervous System Disorders
|
|
|
|
| Paresthesia |
4.5 |
7.4 |
7.9 |
| Hypoesthesia |
2.4 |
1.6 |
5.1 |
|
Metabolic And Nutritional Disorders
|
|
|
|
| Edema Generalized |
1.2 |
1.2 |
5.9 |
Adverse events that occurred in 1% to less than 5% of trial participants receiving Serostim® during the first 12 weeks of Clinical Trial 2 thought to be related to Serostim® included dependent edema, periorbital edema, carpal tunnel syndrome, hyperglycemia and hypertriglyceridemia.
During the 12-week, placebo-controlled portion of Clinical Trial 2, the incidence of hyperglycemia reported as an adverse event was 3.6% for the placebo group, 1.9% for the 0.1 mg/kg qod group and 3.2% for the 0.1 mg/kg daily group. One case of diabetes mellitus was noted in the 0.1 mg/kg daily group during the first 12-weeks of therapy. In addition, during the extension phase of Clinical Trial 2, two patients converted from placebo to full dose Serostim®, and 1 patient converted from placebo to half-dose Serostim®, were discontinued because of the development of diabetes mellitus.
The types and incidences of adverse events reported during the Clinical Trial 2 extension phase were not different from, or greater in frequency than those observed during the 12-week, placebo-controlled portion of Clinical Trial 2.
HIV-Associated Adipose Redistribution Syndrome (HARS)
In the initial 12-week treatment periods of the two HARS, placebo-controlled clinical trials, 406 patients were treated with Serostim®. Clinical adverse events which occurred during the first 12 weeks of both studies combined in at least 5% of the patients in either of the two active treatment groups are listed by treatment group in Table 8, without regard to causality assessment. The most common adverse reactions judged to be associated with Serostim® were edema, arthralgia, pain in extremity, hypoesthesia, myalgia, and blood glucose increased, all of which were more frequently observed when Serostim® 4 mg was administered on a daily basis compared with alternate days. These symptoms were generally rated by investigators as mild to moderate in severity and often subsided with dose reduction. In addition, during the 12-week induction phase, 1) approximately 26% of patients receiving Serostim® 4 mg daily and 19% of patients receiving Serostim® 4 mg qod required dose reductions; and 2) discontinuations as a result of adverse events occurred in 13% of patients receiving Serostim® 4 mg daily and 5% of patients receiving Serostim® 4 mg qod. Once again, the most common reasons for dose reduction and/or drug discontinuation were peripheral edema, hyperglycemia (including blood glucose increased, blood glucose abnormal, and hyperglycemia), and arthralgia.
Table 8: Controlled HARS Studies 1 and 2 Combined - Adverse Events with >5% Incidence in Either Active Treatment Arm
|
| Placebo |
Serostim®
4 mg qod1
|
Serostim®
4 mg daily |
|
System Organ Class
|
Patients
(n=159) |
Patients
(n=80) |
Patients
(n=326) |
| Preferred Term |
% |
% |
% |
|
1 Study 22388 only |
|
2 similar terms were grouped together and reported below |
|
Musculoskeletal and connective tissue disorders
|
|
|
|
| Arthralgia |
11.9 |
27.8 |
37.1 |
| Pain in extremity |
3.8 |
5.0 |
19.3 |
| Myalgia |
3.8 |
2.5 |
12.6 |
| Musculoskeletal stiffness |
1.9 |
3.8 |
8.0 |
| Joint stiffness |
1.3 |
3.8 |
7.7 |
| Joint swelling |
0.6 |
5.0 |
6.1 |
|
General disorders and administration site conditions
|
|
|
|
| Edema peripheral |
3.8 |
18.8 |
45.4 |
| Fatigue |
1.9 |
6.3 |
8.9 |
|
Nervous system disorders
|
|
|
|
| Hypoesthesia |
0.6 |
8.8 |
15.0 |
| Headache |
3.1 |
3.8 |
14.1 |
| Paraesthesia |
2.5 |
12.5 |
11.0 |
|
Investigations (Laboratory Evaluations)
|
|
|
|
| Blood glucose increased2
|
2.5 |
3.8 |
13.8 |
|
Metabolism and nutrition disorders
|
|
|
|
| Hyperglycemia2
|
0.6 |
8.8 |
7.1 |
| Fluid retention |
0.6 |
2.5 |
5.2 |
|
Gastrointestinal disorders
|
|
|
|
| Nausea |
2.5 |
1.3 |
6.1 |
|
Psychiatric disorders
|
|
|
|
| Insomnia |
1.9 |
7.5 |
8.3 |
|
Infections and infestations
|
|
|
|
| Upper respiratory tract infection |
5.0 |
10.0 |
5.2 |
Glucose-Related Terms: Similar glucose-related adverse event terms (including hyperglycemia, blood glucose increased, blood glucose abnormal) were grouped together which resulted in a greater than 5% incidence in Serostim®-treated patients. During the initial 12-week treatment periods of HARS Studies 1 and 2, the incidence of glucose-related adverse events was 4% for the placebo group, 13% for the 4 mg qod group and 22% for the 4 mg daily group. No patients required treatment for hyperglycemia. Of the 23 patients who discontinued due to hyperglycemia during any phase of these studies, 13 were being treated with induction therapy with Serostim® 4 mg daily (and 9 of these 13 during the 12 week induction phases of HARS Studies 1 and 2). One of these patients whose baseline fasting blood glucose was 95 mg/dL demonstrated substantial hyperglycemia (384 mg/dL) 12 days after treatment with Serostim® 4 mg daily was begun; however, the patient was normoglycemic 1 month after Serostim® was discontinued without treatment for hyperglycemia. A second patient in HARS Study 2 whose fasting blood glucose was 89 mg/dL at baseline manifested a fasting blood glucose of 404 mg/dL 21 days after treatment with Serostim® 4 mg daily was begun. His last known fasting blood glucose 1 week after Serostim® had been discontinued was 224 mg/dL and then he was lost to follow-up. Whether sustained overt diabetes mellitus persisted is therefore unknown.
Breast-Related Terms: Similar breast-related adverse event terms (including nipple pain, gynecomastia, breast pain/mass/tenderness/swelling/edema/hypertrophy) were grouped together which resulted in a greater than 5% incidence in Serostim®-treated patients. The incidence of breast-related adverse event reports was 1% for the placebo group, 3% for the 4 mg qod group and 6% for the 4 mg daily group.
Adverse events that occurred in 1% to less than 5% of trial participants receiving Serostim® during the first 12 weeks of HARS Studies 1 and 2 thought to be related to Serostim® include carpal tunnel syndrome, tinel's sign and facial edema.
The adverse events reported for Serostim® 4 mg qod during the maintenance phase of HARS Study 1 (Week 12 to Week 24) were similar in frequency and quality to those observed after treatment with Serostim® 4 mg qod during the 12-week induction phase.
During safety surveillance of patients with HIV-associated wasting and HARS, cases of new onset impaired glucose tolerance, new onset type 2 diabetes mellitus and exacerbation of preexisting diabetes mellitus have been reported in patients receiving Serostim®. Some patients developed diabetic ketoacidosis and diabetic coma. In some patients, these conditions improved when Serostim® was discontinued, while in others the glucose intolerance persisted. Some of these patients required initiation or adjustment of antidiabetic treatment while on Serostim®.
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