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Most Serious and/or Most Frequently Observed Adverse Reactions

This list presents the most seriousa and/or most frequently observedb adverse reactions during treatment with somatropin (including events observed in patients who received brands of somatropin other than Humatrope (somatropin rdna origin) ):

  • aSudden death in pediatric patients with Prader-Willi syndrome who had risk factors including severe obesity, history of upper airway obstruction or sleep apnea and unidentified respiratory infection [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
  • aIntracranial tumors, in particular meningiomas, in teenagers/young adults treated with radiation to the head for a first neoplasm who subsequently receive somatropin [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
  • aPancreatitis [see WARNINGS AND PRECAUTIONS]
  • a,bGlucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes mellitus [see WARNINGS AND PRECAUTIONS]
  • aIntracranial hypertension [see WARNINGS AND PRECAUTIONS]
  • aSignificant diabetic retinopathy [see CONTRAINDICATIONS]
  • aSlipped capital femoral epiphysis in pediatric patients [see WARNINGS AND PRECAUTIONS]
  • aProgression of preexisting scoliosis in pediatric patients [see WARNINGS AND PRECAUTIONS]
  • bFluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias [see WARNINGS AND PRECAUTIONS]
  • aUnmasking of latent central hypothyroidism [see WARNINGS AND PRECAUTIONS]
  • aInjection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical trials performed with a second somatropin formulation, and may not reflect the adverse reaction rates observed in practice.

Pediatric Patients

GH Deficiency

As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to the protein. During the first 6 months of Humatrope (somatropin rdna origin) therapy in 314 naive patients, only 1.6% developed specific antibodies to Humatrope (somatropin rdna origin) (binding capacity ≥ 0.02 mg/L). None had antibody concentrations which exceeded 2 mg/L. Throughout 8 years of this same study, two patients (0.6%) had binding capacity > 2 mg/L. Neither patient demonstrated a decrease in growth velocity at or near the time of increased antibody production. It has been reported that growth attenuation from pituitary-derived GH may occur when antibody concentrations are > 1.5 mg/L.

In addition to an evaluation of compliance with the treatment program and of thyroid status, testing for antibodies to somatropin should be carried out in any patient who fails to respond to therapy.

In studies with GH deficient pediatric patients, injection site pain was reported infrequently. A mild and transient edema, which appeared in 2.5% of patients, was observed early during the course of treatment.

Turner Syndrome

In a randomized, concurrent-controlled, open-label trial, there was a statistically significant increase in the occurrence of otitis media (43% vs. 26%), ear disorders (18% vs. 5%) and surgical procedures (45% vs. 27%) in patients receiving Humatrope (somatropin rdna origin) compared with untreated control patients (Table 1). A similar increase in otitis media was observed in an 18-month placebo-controlled trial.

Table 1: Treatment-Emergent Adverse Reactions of Special Interest by Treatment Group in Turner Syndrome

Adverse Reaction Treatment Groupa  
Untreated Humatropeb Significance
Total Number of Patients 62 74  
Surgical procedure 17 (27.4%) 33 (44.6%) p ≤ 0.05
Otitis media 16 (25.8%) 32 (43.2%) p ≤ 0.05
Ear disorders 3 (4.8%) 13 (17.6%) p ≤ 0.05
a Open-label study.
b Dose=0.3 mg/kg/wk.

Idiopathic Short Stature

In a randomized, placebo-controlled study of Humatrope (somatropin rdna origin) treatment (0.22 mg/kg/week) to adult height in patients with idiopathic short stature, the adverse events reported in Humatrope (somatropin rdna origin) -treated patients (Table 2) were similar to those observed in other pediatric populations treated with Humatrope (somatropin rdna origin) . Mean serum glucose concentration did not change during Humatrope (somatropin rdna origin) treatment. Mean fasting serum insulin concentration increased 10% in the Humatrope (somatropin rdna origin) treatment group at the end of treatment relative to baseline, but remained within the normal reference range. For the same duration of treatment, the mean fasting serum insulin concentration decreased by 2% in the placebo group. The occurrence rates of above-range values for glucose, insulin, and HbA1c were similar in the Humatrope (somatropin rdna origin) (somatropin)- and placebo-treated groups. No patient developed diabetes mellitus. Consistent with the known mechanism of growth hormone action, Humatrope (somatropin rdna origin) -treated patients had greater mean increases, relative to baseline, in serum insulin-like growth factor-I (IGF-I) than placebo-treated patients at each study observation. However, there was no significant difference between the Humatrope (somatropin rdna origin) and placebo treatment groups in the proportion of patients who had at least one serum IGF-I concentration more than 2.0 SD above the age- and gender-appropriate mean (Humatrope (somatropin rdna origin) : 9 of 35 patients [26%]; placebo: 7 of 28 patients [25%]).

Table 2: Non-serious Clinically Significant Treatment-Emergent Adverse Reactions by Treatment Group in Idiopathic Short Stature

Adverse Reaction Treatment Group
Placebo Humatrope
Total Number of Patients 31 37
Scoliosis 4 (12.9%) 7 (18.9%)
Otitis media 2 (6.5%) 6 (16.2%)
Hyperlipidemia 1 (3.2%) 3 (8.1%)
Gynecomastia 1 (3.2%) 2 (5.4%)
Hip pain 0 1 (2.7%)
Arthralgia 1 (3.2%) 4 (10.8%)
Arthrosis 2 (6.5%) 4 (10.8%)
Myalgia 4 (12.9%) 9 (24.3%)
Hypertension 0 1 (2.7%)

The adverse events observed in the dose-response study (239 patients treated for 2 years) did not indicate a pattern suggestive of a somatropin dose effect. Among Humatrope (somatropin rdna origin) dose groups, mean fasting blood glucose, mean glycosylated hemoglobin, and the incidence of elevated fasting blood glucose concentrations were similar. One patient developed abnormalities of carbohydrate metabolism (glucose intolerance and high serum HbA1c) on treatment.

SHOX Deficiency

Clinically significant adverse events (adverse events previously observed in association with growth hormone treatment in general) were assessed prospectively during the 2-year randomized, open-label study; those observed are presented in Table 3. In both treatment groups, the mean fasting plasma glucose concentration at the end of the first year was similar to the baseline value and remained in the normal range. No patient developed diabetes mellitus or had an above normal value for fasting plasma glucose at the end of one-year of treatment. During the 2 year study period, the proportion of patients who had at least one IGF-I concentration greater than 2.0 SD above the age- and gender-appropriate mean was 10 of 27 [37.0%] for the Humatrope (somatropin rdna origin) -treated group vs. 0 of 24 patients [0.0%] for the untreated group. The proportion of patients who had at least one IGFBP-3 concentration greater than 2.0 SD above the age and gender appropriate mean was 16 of 27 [59.3%] for the Humatrope (somatropin rdna origin) treated group vs. 7 of 24 [29.2%] for the untreated group.

Table 3: Clinically Significant Treatment-Emergent Adverse Reactionsa,b by Treatment Group in Patients with SHOX Deficiency

Adverse Reaction Treatment Group
Untreated Humatrope
Total Number of Patients 25 27
Patients with at least one event 2 5
Arthralgia 2 (8.0%) 3 (11.1%)
Gynecomastiac 0 (0.0%) 1 (8.3%)
Excessive number of cutaneous nevi 0 (0.0%) 2 (7.4%)
Scoliosis 0 (0.0%) 1 (3.7%)
a All events were non-serious.
b Events are included only if reported for a greater number of Humatrope (somatropin rdna origin) -treated than Untreated patients.
c Percentage calculated for males only (1/12).

Small for Gestational Age

Study 1 — In a 2-year, multicenter, randomized study, 193 non-GH deficient children with short stature born SGA who failed to demonstrate catch-up growth were treated with 2 different Humatrope (somatropin rdna origin) treatment regimens: a fixed dose of 0.067 mg/kg/day (FHD group) or an individually adjusted dose regimen (IAD group; starting dose 0.035 mg/kg/day which could be increased as early as Month 3 to 0.067 mg/kg/day based on a validated growth prediction model). The most frequently reported adverse events were common childhood infectious diseases. Adverse events possibly/probably related to Humatrope (somatropin rdna origin) were otitis media and headaches (where there was a suggestion of a modest dose response), and slipped capital femoral epiphysis (1 child) [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. There were no clear cut cases of new-onset diabetes mellitus, no children treated for hyperglycemia, and no children whose fasting blood glucose exceeded 126 mg/dL at any time during the study. However, 6 children (4 in the FHD group and 2 in the IAD group whose dose was increased from 0.035 mg/kg/day to 0.067 mg/kg/day [one at Month 3 and one at Year 1]) manifested impaired fasting glucose at Year 2. Two of these six children displayed impaired fasting glucose during the study as well, and one of them was required to discontinue Humatrope (somatropin rdna origin) at Month 15 as a consequence [see WARNINGS AND PRECAUTIONS)]. A modestly dose-dependent increase in mean serum IGF-I SDS concentrations within the reference range was observed; of note, at study completion, 20-25% of these children had serum IGF-I SDS values > +2.

Study 2 — A 2-year, open-label, single-arm study of Humatrope (somatropin rdna origin) at a dosage of 0.067 mg/kg/day in 35 non-GH deficient children with short stature born SGA who failed to demonstrate catch-up growth did not reveal further safety data of note.

Study 3 — Additional safety information was obtained from 340 short children born SGA followed in an observational study who received an average Humatrope (somatropin rdna origin) dosage of 0.041 mg/kg/day (maximum dose: 0.084 mg/kg/day) for an average of 3.0 years. Type 2 diabetes mellitus apparently precipitated by Humatrope (somatropin rdna origin) therapy was reported in a single patient, but appeared to resolve after discontinuation of Humatrope (somatropin rdna origin) treatment, as the child had a normal oral glucose tolerance test and was receiving no antihyperglycemic medications 9 months after the drug was discontinued. One patient manifested carpal tunnel syndrome and another developed an exacerbation of preexisting scoliosis [see WARNINGS AND PRECAUTIONS] which may have been related to Humatrope (somatropin rdna origin) treatment.

In both Study 1 and Study 2, after treatment with Humatrope (somatropin rdna origin) , bone maturation did not accelerate excessively, and the timing of puberty was age-appropriate in boys and girls.

Therefore, it can be concluded that no novel adverse events potentially related to treatment with Humatrope (somatropin rdna origin) were reported in either short-term study or were apparent after a review of the post-marketing, observational, safety database.

Adult Patients

In clinical studies in which high doses of Humatrope (somatropin rdna origin) were administered to healthy adult volunteers, the following events occurred infrequently: headache, localized muscle pain, weakness, mild hyperglycemia, and glucosuria.

Adult-Onset GH Deficiency

In the first 6 months of controlled blinded trials during which patients received either Humatrope (somatropin rdna origin) or placebo, adult-onset GH deficient adults who received Humatrope (somatropin rdna origin) experienced a statistically significant increase in edema (Humatrope (somatropin rdna origin) 17.3% vs. placebo 4.4%, p=0.043) and peripheral edema (11.5% vs. 0%, respectively, p=0.017). In patients with adult-onset GH deficiency, edema, muscle pain, joint pain, and joint disorder were reported early in therapy and tended to be transient or responsive to dosage titration.

Two of 113 adult-onset patients developed carpal tunnel syndrome after beginning maintenance therapy without a low dose (0.00625 mg/kg/day) lead-in phase. Symptoms abated in these patients after dosage reduction.

All treatment-emergent adverse events with ≥ 5% overall occurrence rate during 12 or 18 months of replacement therapy with Humatrope (somatropin rdna origin) are shown in Table 4 (adult-onset patients) and in Table 5 (childhood-onset patients).

Adult patients treated with Humatrope (somatropin rdna origin) who had been diagnosed with GH deficiency in childhood reported side effects less frequently than those with adult-onset GH deficiency.

Table 4: Treatment-Emergent Adverse Reactions with ≥ 5% Overall Occurrence in Adult-Onset Growth Hormone-Deficient Patients Treated with Humatrope (somatropin rdna origin) for 18 Months as Compared with 6-Month Placebo and 12-Month Humatrope (somatropin rdna origin) Exposurea

Adverse Reaction 18 Months Exposure [Placebo (6 Months)/GH (12 Months)] (N=46) 18 Months GH Exposure (N=52)
n % n %
Edemab 7 15.2 11 21.2
Arthralgia 7 15.2 9 17.3
Paresthesia 6 13.0 9 17.3
Myalgia 6 13.0 7 13.5
Pain 6 13.0 7 13.5
Rhinitis 5 10.9 7 13.5
Peripheral edemac 8 17.4 6 11.5
Back pain 5 10.9 5 9.6
Headache 5 10.9 4 7.7
Hypertension 2 4.3 4 7.7
Acne 0 0 3 5.8
Joint disorder 1 2.2 3 5.8
Surgical procedure 1 2.2 3 5.8
Flu syndrome 3 6.5 2 3.9
a Abbreviations: GH=Humatrope (somatropin rdna origin) ; N=number of patients receiving treatment in the period stated; n=number of patients reporting each treatment-emergent adverse event.
b p=0.04 as compared to placebo (6 months).
c p=0.02 as compared to placebo (6 months).

Childhood-Onset GH Deficiency

Two double-blind, placebo-controlled trials were conducted in 67 adult patients with childhood-onset GH deficiency who had received previous somatropin treatment during childhood. Patients were randomized to receive either placebo injections or Humatrope (somatropin rdna origin) (0.00625 mg/kg/day [6.25 μg/kg/day] for the first 4 weeks, then 0.0125 mg/kg/day [12.5 μg/kg/day] thereafter) for the first 6 months, followed by open-label Humatrope (somatropin rdna origin) for the next 12 months for all patients. The patients in these studies reported side effects less frequently than those with adult-onset GH deficiency. During the placebo-controlled phase (first 6 months) of the study, elevations of serum glutamic oxaloacetic transferase were reported significantly more often for Humatrope (somatropin rdna origin) -treated (12.5%) than placebo-treated patients (0.0%, p=0.031). No other events were reported significantly more often for Humatrope (somatropin rdna origin) -treated patients during the placebo-controlled phase. The following events were reported for at least 5% of patients in either of the 2 treatment groups over the 18-month duration of the study, listed in descending order of maximum frequency for either group: aspartate aminotransferase increased 13%, headache 11%, edema 9%, pain 9%, alanine aminotransferase increased 6%, asthenia 6%, myalgia 6%, respiratory disorder 6%.

Table 5: Treatment-Emergent Adverse Reactions with ≥ 5% Overall Occurrence in Childhood-Onset Growth Hormone-Deficient Patients Treated with Humatrope (somatropin rdna origin) for 18 Months as Compared with 6-Month Placebo and 12-Month Humatrope (somatropin rdna origin) Exposurea

Adverse Reaction 18 Months Exposure [Placebo (6 Months)/GH (12 Months)] (N=35) 18 Months GH Exposure (N=32)
n % n %
Flu syndrome 8 22.9 5 15.6
AST increasedb 2 5.7 4 12.5
Headache 4 11.4 3 9.4
Asthenia 1 2.9 2 6.3
Cough increased 0 0 2 6.3
Edema 3 8.6 2 6.3
Hypesthesia 0 0 2 6.3
Myalgia 2 5.7 2 6.3
Pain 3 8.6 2 6.3
Rhinitis 2 5.7 2 6.3
ALT increased 2 5.7 2 6.3
Respiratory disorder 2 5.7 1 3.1
Gastritis 2 5.7 0 0
Pharyngitis 5 14.3 1 3.1
a Abbreviations: GH=Humatrope (somatropin rdna origin) ; N=number of patients receiving treatment in the period stated; n=number of patients reporting each treatment-emergent adverse event; ALT=alanine aminotransferase, formerly SGPT; AST=aspartate aminotransferase, formerly SGOT.
b p=0.03 as compared to placebo (6 months).

Post-Marketing Experience

Because these adverse events 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. The adverse events reported during post-marketing surveillance do not differ from those listed/discussed above in Sections 6.1 and 6.2 in children and adults.

Other adverse events that have been reported in somatropin-treated patients include the following:

Neurologic — Headaches (common in children and occasional in adults).

Skin — Increase in size or number of cutaneous nevi, especially in patients with Turner syndrome and those with SHOX deficiency [see WARNINGS AND PRECAUTIONS].

Endocrine — Gynecomastia.

Gastrointestinal — Pancreatitis. Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting a greater risk in children compared with adults. Published literature indicates that girls who have Turner syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin-treated patient, especially a child, who develops abdominal pain [see WARNINGS AND PRECAUTIONS].

Neoplasia — Leukemia has been reported in a small number of GH deficient children treated with somatropin, somatrem (methionylated rhGH), and GH of pituitary origin. It is uncertain whether these cases of leukemia are related to GH therapy, the pathology of GH deficiency itself, or other associated treatments such as radiation therapy. On the basis of current evidence, experts have not been able to conclude that GH therapy per se was responsible for these cases of leukemia. The risk for children with GH deficiency, if any, remains to be established [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

In an ongoing post-marketing observational study of somatropin treatment in 3,102 GH-deficient adults, hypertension, dyspnea, and sleep apnea were reported by 1% to less than 10% of patients after various durations of treatment.

Read the Humatrope (somatropin rdna origin) Side Effects Center for a complete guide to possible side effects


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. GH and somatropin inhibit 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. As a consequence, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin. In addition, 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.

Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment

Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth promoting effects of somatropin in children. Therefore, glucocorticoid replacement dosing should be carefully adjusted in children receiving concomitant somatropin and glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth.

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, sex 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.

Oral Estrogen

Because oral estrogens may reduce the serum IGF-I response to somatropin treatment, girls and women receiving oral estrogen replacement may require greater somatropin dosages [see DOSAGE AND ADMINISTRATION].

Insulin and/or Other Hypoglycemic Agents

Patients with diabetes mellitus who receive concomitant treatment with somatropin may require adjustment of their doses of insulin and/or other hypoglycemic agents [see WARNINGS AND PRECAUTIONS].

Drug Abuse And Dependence

Inappropriate use of somatropin by individuals who do not have indications for which somatropin is approved, may result in significant negative health consequences. Somatropin is not a drug of dependence.

Read the Humatrope Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 8/11/2010
This monograph has been modified to include the generic and brand name in many instances.


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