Serostim Side Effects

Generic Name: somatropin

Please note - some side effects for Serostim may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Serostim - for the Consumer

Serostim

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Serostim:

Breast enlargement; headache; mild swelling (eg, of the hands or feet); muscle or joint pain; nausea; nerve tingling; numbness.

Seek medical attention right away if any of these SEVERE side effects occur when using Serostim:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); body pain or stiffness; burning, tingling, itching, or numbness in the palm of the hand, fingers, or wrist; change in appearance or size of a mole; chest pain; constant feeling of need to empty the bowel; curvature of the spine; depression; ear infection; excessive thirst or hunger; fast heartbeat; fever; frequent urination; infection; nausea; severe or persistent swelling of the ankles, legs, hands, or feet; severe, persistent, or unusual headaches; stomach pain; visual changes; vomiting.

Children: Ear discomfort or infection; fatigue or weakness; fever, persistent cough, or trouble breathing; hip or knee pain; leukemia; limp; seizures; snoring or irregular breathing during sleep; worsening of psoriasis.

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Serostim Side Effects - for the Professional

Serostim

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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Side Effects by Body System

General

Somatropin is generally well tolerated with minimal adverse effects.

Oncologic

Oncologic side effects have included rare reports of leukemia, however, the association with human growth hormone is uncertain.

Immunologic

Immunologic adverse reactions have included the rare development of persistent antibodies in patients treated with recombinant human growth hormone. The development of antibodies may be greater with the use of somatrem than with somatropin, although the overall incidence is very low.

An IgG antibody has been identified. No antibodies to the IgE class have been detected. Growth hormone antibody binding capacities less than 2 mg/L have not led to growth attenuation. Testing for antibodies should be carried out in any patient failing to respond to treatment.

Primate studies have failed to reveal evidence of histopathological changes due to immune complex formation.

Nervous system

Nervous system effects have included headaches, weakness, paresthesia and hypethesia.

Musculoskeletal

Musculoskeletal side effects have included localized muscle pain, carpal tunnel syndrome, aggravation of preexisting scoliosis, jaw prominence and slipped capital femoral epiphysis. Patients with Short Stature Homeobox-Containing Gene (SHOX) Deficiency have reported scoliosis and arthralgia..

Endocrine

Endocrine side effects have included mild hyperglycemia, gynecomastia, and, rarely pancreatitis. Elevations in IGF-1 (insulin-like growth factor 1) and insulin levels have occurred consistently in adults. Alterations in thyroid hormone metabolism may occur. Recombinant human growth hormone may reveal diabetes mellitus in a patient, but is not the cause.

Serum levels of inorganic phosphorus, alkaline phosphatase and parathyroid hormone (PTH) may increase during treatment with somatropin. The mechanism is unknown. These potential changes should be considered when evaluating patient laboratory measurements.

During postmarketing surveillance, cases of new onset glucose intolerance, diabetes mellitus and exacerbations of preexisting diabetes mellitus have been reported in patients receiving the Serostim brand of somatropin. Some patients developed ketoacidosis and diabetic coma. In some patients, these conditions improved when Serostim was discontinued but not in all patients.

Cardiovascular

Edema occurs more often in adults, appears to be dose-related, and is due to the antinatriuretic effect of growth hormone.

Cardiovascular side effects have included mild, transient, peripheral edema in up to 2.5% of patients during early treatment with somatropin. Intracranial hypertension is a rare effect that may present with papilledema, visual changes, headache, nausea and vomiting.

Other

Athletes using human growth hormone for doping purposes may experience cardiac, renal, and splenic hypertrophy, cardiac myopathy, fluid retention, glucose intolerance, abnormal bone growth, and an increased risk of cancers.

Chronic use of human growth hormone by athletes can lead to toxicity seen in acromegaly.

There is no risk of acquiring Creutzfeldt-Jakob disease from recombinant human growth hormone, as with the previously marketed pituitary-derived human growth hormone.

Dermatologic

Dermatologic side effects have included rash, pruritus, increased sweating and increased growth of preexisting nevi (hereditary malformation of the skin). Patients with Short Stature Homeobox-Containing Gene (SHOX) Deficiency have reported excessive number of cutaneous nevi.

Metabolic

Metabolic side effects have included mild transient hyperglycemia and lipolysis in adults which resulted in a statistically significant decrease in total body fat (14% to 20%) and a significant reductions in total cholesterol and/or LDL levels. No changes in HDL have been observed. Elderly patients have exhibited triglyceride elevations. The long-term effect of recombinant human growth hormone on lipid metabolism is unknown.

Local

Local side effects have included localized injection site reactions and pain.

Other

Other side effects have included an increased incidence of otitis media and other ear disorders in Turner syndrome patients. Other side effects reported in Turner syndrome patients have included influenza-like illness, upper respiratory tract infection, eczema, excessive growth of hands and feet, and exacerbation of preexisting scoliosis.

Gastrointestinal

Gastrointestinal side effects have included diarrhea, nausea and vomiting.

Hypersensitivity

Hypersensitivity side effects have included allergic reactions.

Respiratory

Respiratory side effects have included rhinitis, bronchitis and upper respiratory tract infections.

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