"The U.S. Food and Drug Administration today approved Tivicay (dolutegravir), a new drug to treat HIV-1 infection.
Tivicay is an integrase strand transfer inhibitor that interferes with one of the enzymes necessary for HIV to multiply. "...
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 Warning and Precautions (5.4]). 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
|Placebo||0.1 mg/kg every other day Serostim®||0.1 mg/kg daily Serostim®|
|Body System Preferred Term||Patients
|Musculoskeletal System Disorders|
|Gastrointestinal System Disorders|
|Body As A Whole - General Disorders|
|Central & Peripheral Nervous System Disorders|
|Metabolic And Nutritional Disorders|
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
|System Organ Class Preferred Term||Placebo||Serostim® 4 mg every other day1||Serostim ≥ 4 mg daily|
|Musculoskeletal and connective tissue disorders|
|Pain in extremity||3.8||5||19.3|
|General disorders and administration site conditions|
|Nervous system disorders|
|Investigations (Laboratory Evaluations)|
|Blood glucose increased2||2.5||3.8||13.8|
|Metabolism and nutrition disorders|
|1Study 22388 only
2similar terms were grouped together and reported below
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 6). 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 Weeks 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 1and 2 Combined)
|Serostim® 4 mg every other day
|Serostim® 4 mg daily
|Baseline||Mean (SD)||0.4 (1.4)||1.3 (2.1)||0.0 (1.6)|
|Range||(-2.5, 4.8)||(-2.0, 13.7)||(-3.0, 11.9)|
|Week 12||Mean (SD)||0.8 (1.6)||5.1 (3.4)||6.1 (5.0)|
|Range||(-2.6, 6.7)||(-0.7, 17.2)||(-1.8, 29.2)|
|Change from||Mean (SD)||0.4 (1.3)||3.9 (3.1)||6.1 (4.6)|
|Baseline to||Range||(-2.9, 7.7)||(-9.4, 11.8)||(-2.4, 24.3)|
|Meana diff (SEM)||3.5 (0.5)||5.7 (0.4)|
|a Proportionally weighted least squares means
from a two-way ANOVA model on raw data including effects for treatment, sex,
and the treatment by sex interaction.
b P-value from a Wilcoxon Signed Rank test on the change from baseline to Week 12.
c P-value from a two-way ANOVA model on ranked data including effects for treatment, sex, and the treatment by sex interaction.
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.
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.
- 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®.
Read the Serostim (somatropin (rdna origin)) Side Effects Center for a complete guide to possible side effects
Formal drug interaction studies have not been conducted. No data are available on drug interactions between Serostim® and HIV protease inhibitors or the non-nucleoside reverse transcriptase inhibitors.
11β-Hydroxysteroid Dehydrogenase Type 1
The microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Somatropin inhibit 11βHSD-1. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1.
Cytochrome P450-metabolized drugs
Limited published data indicate that somatropin treatment increases cytochrome P450 (CP450)-mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds metabolized by CP450 liver enzymes (e.g., corticosteroids, six steroids, anticonvulsants, cyclosporine). Therefore, careful monitoring is advised when somatropin is administered in combination with drugs metabolized by CP450 liver enzymes. However, formal drug interaction studies have not been conducted.
Because oral estrogens may reduce the serum IGF-1 response to somatropin treatment, girls and women receiving oral estrogen replacement may require greater somatropin dosages [see DOSAGE AND ADMINISTRATION].
Insulin and/or Other Oral/Injectable Hypoglycemic Agents
Read the Serostim Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 4/16/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Serostim Information
Report Problems to the Food and Drug Administration
Get breaking medical news.