SEROSTIM SIDE EFFECTS

SIDE EFFECTS

The following important adverse reactions are also described elsewhere in the labeling:

Acute Critical Illness

Neoplasms

Impaired glucose tolerance and diabetes mellitus

Intracranial hypertension

Severe hypersensitivity

Fluid retention/Carpal tunnel syndrome

Lipoatrophy

Pancreatitis

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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.

Clinical Trials in HIV-Associated Wasting Or Cachexia

In the 12-week, placebo-controlled Clinical Trial 2, 510 patients were treated with SEROSTIM. 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 1 and Warnings and Precautions (5)]. These symptoms 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 reactions 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 reactions which occurred during the first 12 weeks of study in at least 5% of the patients in either active treatment group and at an incidence greater than placebo are listed below, without regard to causality assessment.

Table 1: Controlled Clinical Trial 2 Adverse Reactions Occurring in at least 5% of Patients in one of the Treatment Groups, and at an Incidence Greater than Placebo

Adverse reactions 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 dose 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 reaction was 3.6% for the placebo group, 1.9% for the 0.1 mg/kg every other day 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 reactions 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.

Adverse Reactions From Treatment With SEROSTIM in Clinical Trials in HIV Lipodystrophy

SEROSTIM was evaluated for the treatment of patients with HIV lipodystrophy in two double-blind, placebo-controlled trials that excluded patients with a history of diabetes, impaired fasting glucose or impaired glucose (approximately 20% of the patients screened were excluded from study enrollment as a result of a diagnosis of diabetes or glucose intolerance). The studies included a 12-week double-blind, placebo-controlled, parallel group “induction” phase followed by maintenance phases of different durations (12 and 24 weeks, respectively). In the initial 12-week treatment periods of the two, placebo-controlled clinical trials, 406 patients were treated with SEROSTIM. Clinical adverse reactions 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 2, 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 often subsided with dose reduction. During the 12-week induction phase, 1) approximately 26% of patients receiving SEROSTIM 4 mg daily and 19% of patients receiving SEROSTIM 4 mg every other day required dose reductions; and 2) discontinuations as a result of adverse reactions occurred in 13% of patients receiving SEROSTIM 4 mg daily and 5% of patients receiving SEROSTIM 4 mg every other day. 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 2: Controlled HIV Lipodystrophy Studies 1 and 2 Combined – Adverse Reactions with > 5% Incidence in Either Active Treatment Arm

Glucose metabolism related adverse reactions: During the initial 12-week treatment periods of Studies 1 and 2, the incidence of glucose-related adverse reactions was 4% for the placebo group, 13% for the 4 mg every other day group and 22% for the 4 mg daily group.

Twenty-three patients discontinued due to hyperglycemia while receiving SEROSTIM during any phase of these studies (3.2% in the 12-week induction phases and 2.1% in the extension phases).

Breast-Related Terms: When grouped together, breast-related adverse reactions (e.g. nipple pain, gynecomastia, breast pain/mass/tenderness/swelling/edema/hypertrophy) had an incidence of 1% for the placebo group, 3% for the SEROSTIM 4 mg every other day group and 6% for the SEROSTIM 4 mg daily group.

Adverse reactions that occurred in 1% to less than 5% of trial participants receiving SEROSTIM during the first 12 weeks of HIV Lipodystrophy Studies 1 and 2 thought to be related to SEROSTIM include carpal tunnel syndrome, Tinel’s sign and facial edema.

The adverse reactions reported for SEROSTIM 4 mg every other day during the maintenance phase of HIV Lipodystrophy Study 1 (Week 12 to Week 24) were similar in frequency and quality to those observed after treatment with SEROSTIM 4 mg every other day during the 12-week induction phase.

IGF-1 serum concentrations increased statistically in SEROSTIM-treated patients when compared to placebo (Table 3). In the SEROSTIM treated patients at baseline, the proportion of subjects with serum IGF-1 SDS levels ≥ +2 was approximately 10 to 20%, while with treatment with either dose regimen of SEROSTIM the percentage increased to 80 to 90% by Week 12.

Table 3: Change from Baseline to Week 12 in Serum IGF-1 SDS After Treatment with SEROSTIM 4 mg daily vs. Placebo (Modified ITT Population; Studies 1 and 2 Combined)

As with all therapeutic proteins, there is potential for immunogenicity. 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 influences 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 SEROSTIM with the incidence of antibodies to other products may be misleading.

After 12 weeks of treatment, none of the 651 study participants with HIV-associated wasting treated with SEROSTIM for the first time developed detectable antibodies to growth hormone ( > 4 pg binding). Patients were not rechallenged. Data beyond 3 months is not available.

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of SEROSTIM. 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.

Hypersensitivity: Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products.

Endocrine:

• new onset impaired glucose tolerance
• new onset type 2 diabetes mellitus
• exacerbation of preexisting diabetes mellitus
• diabetic ketoacidosis
• 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.

Gastrointestinal: Pancreatitis.

SRC: NLM .