NUTROPIN SIDE EFFECTS

Last updated on MDtodate: 10/11/2022

SIDE EFFECTS

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

• Increased mortality in patients with acute critical illness
• Fatalities in children with Prader-Willi syndrome
• Neoplasms
• Glucose intolerance and diabetes mellitus
• Intracranial hypertension
• Severe hypersensitivity
• Fluid retention
• Hypoadrenalism
• Hypothyroidism
• Slipped capital femoral epiphysis in pediatric patients
• Progression of preexisting scoliosis in pediatric patients
• Pancreatitis
• Lipoatrophy

Clinical Studies Experience

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

Pediatric Patients

Growth Failure Due To Inadequate Secretion Of Endogenous Growth Hormone

In an uncontrolled open-label study, 314 treatment-naive children aged >2 years who had GH deficiency were treated with HUMATROPE (0.06 mg/kg 3 times per week) for up to 8 years. Adverse reactions of special interest are reported in Table 1.

Table 1: Adverse Reactions of Special Interest Occurring in Humatrope-Treated Patients with Growth Failure Due to Inadequate Secretion of Endogenous Growth Hormone in an Open-label Study for Up to 8 Years

Adverse Reaction	HUMATROPEa (n=314)
Hypothyroidism	25%
Allergic reaction	11%
Arthralgia	6%
Bone disorder	4%
Edema	4%
Injection site pain/reaction	4%
Neoplasm/tumor	2%
Cardiovascular disorders	1%
Thyroid disorders	1%
Intracranial hypertension	0%b
a Dose=0.06 mg/kg 3 times per week for up to 8 years. b n=1

 

Short Stature Associated With Turner Syndrome

In a randomized, concurrent-controlled (untreated), open-label study until attainment of adult height, the adverse reactions of special interest occurring in 74 patients treated with Humatrope at dose 0.3 mg/kg/week (mean duration 4.1 years) and in 62 untreated patients (mean duration 3.7 years) are reported in Table 2. A similar increase in otitis media was observed in an 18-month placebo-controlled study.

Table 2: Adverse Reactions of Special Interest Occurring in Patients with Turner Syndrome in an Open-labelStudy Until Attainment of Adult Height

	Untreated (n=62)	HUMATROPE (n=74)
Surgical procedure	27%	45%
Otitis media	26%	43%
Ear disorders	5%	18%

 

Idiopathic Short Stature

Adverse reactions occurring in a randomized, placebo-controlled study of HUMATROPE treatment (0.22 mg/kg/week) until attainment of adult height (mean duration of HUMATROPE treatment 3.7 years, mean duration of placebo treatment 3.3 years) are reported in Table 3. Mean fasting serum insulin concentration increased by 10% in the HUMATROPE treatment group at the end of treatment relative to baseline, but remained within the normal reference range.

Table 3: Adverse Reactions Occurring in Patients with Idiopathic Short Stature Treated with HUMATROPE in a Randomized Placebo-controlled Study

	Placebo (n=31)	HUMATROPE (n=37)
Scoliosis	13%	19%
Otitis media	7%	16%
Hyperlipidemia	3%	8%
Gynecomastia	3%	5%
Hip pain	0	3%
Arthralgia	3%	11%
Arthrosis	7%	11%
Myalgia	13%	24%
Hypertension	0	3%

 

In a dose-response study (239 patients treated for 2 years), among HUMATROPE dose groups [0.24 mg/kg/week (n=78), 0.37 mg/kg/week (n=83), 0.24 mg/kg/week for the first year and 0.37 mg/kg/week thereafter (n=78)], mean fasting blood glucose, mean glycosylated hemoglobin, and the incidence of elevated fasting blood glucose concentrations were similar. One patient developed glucose intolerance and high serum HbA1c.

Short Stature Or Growth Failure In SHOX Deficiency

Adverse reactions of special interest from a 2-year randomized, open-label study with HUMATROPE (0.35 mg/kg/wk) compared to no treatment are presented in Table 4. 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%) for the HUMATROPE-treated group vs. 0 of 24 patients (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%) for the HUMATROPE treated group vs. 7 of 24 (29%) for the untreated group.

Table 4: Adverse Reactions of Special Interest Occurring in Patients with SHOX Deficiency By Treatment Groupin an Open-label Study

	Untreated (n=25)	HUMATROPE (n=27)
Arthralgia	8%	11%
Gynecomastiaa	0%	8%
Excessive number of cutaneous nevi	0%	7%
Scoliosis	0%	47%
a Percentage calculated for males only: Untreated (0/1), HUMATROPE (1/12)

 

Small For Gestational Age (SGA) With No Catch-up Growth By Age 2-4 Years

In a 2-year, multicenter, randomized study, 193 pediatric patients were treated with 2 different HUMATROPE 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). Reported adverse reactions included: common childhood infectious diseases, otitis media, headaches, and slipped capital femoral epiphysis (n=1. Six patients (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]) had impaired fasting glucose at Year 2. Two of 6 had impaired fasting glucose during the study, and one discontinued HUMATROPE at month 15 as a consequence. At study completion, 20-25% of patients had serum IGF-I SDS values > +2.

The following adverse reactions were reported from an observational study of 340 pediatric patients who received HUMATROPE with an average 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 (n=1), carpal tunnel syndrome (n=1) and an exacerbation of preexisting scoliosis (n=1).

Adult Patients

Adult-Onset GH Deficiency

In the first 6 months of controlled blinded studies during which patients received either HUMATROPE or placebo, patients who received HUMATROPE experienced an increase in edema (17% vs. 4%) and peripheral edema (12% vs. 0%). 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 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.

Adverse reactions with ≥5% overall occurrence rate during 12 or 18 months of replacement therapy with HUMATROPE are shown in Table 5 (adult-onset patients) and in Table 6 (childhood-onset patients).

Table 5: Adverse Reactions with ≥5% Overall Occurrence in Adult-Onset Growth Hormone-Deficient Patients Treated with HUMATROPE for 18 Months as Compared with 6-Month Placebo and 12-Month HUMATROPE Exposure

Adverse Reaction	18 Months Exposure [Placebo (6 Months)/Humatrope (12 Months)] (n=44)	18 Months Humatrope Exposure (n=52)
Edema	11%	21%
Arthralgia	14%	17%
Paresthesia	14%	17%
Myalgia	9%	14%
Pain	14%	14%
Peripheral edema	18%	12%
Headache	7%	8%
Hypertension	5%	8%
Joint disorder	2%	6%
Rhinitis	11%	13%
Back pain	9%	10%
Acne	0%	6%
Surgical procedure	2%	6%
Flu syndrome	7%	4%

 

Childhood-Onset GH Deficiency

Two double-blind, placebo-controlled studies were conducted in 67 adult patients who had received previous somatropin treatment during childhood. Patients were randomized to receive either placebo injections or HUMATROPE (0.00625 mg/kg/day for the first 4 weeks, then 0.0125 mg/kg/day thereafter) for the first 6 months, followed by open-label use of HUMATROPE for the next 12 months for all patients. During the placebo-controlled phase (first 6 months) of the study, elevations of serum glutamic oxaloacetic transferase were reported more for HUMATROPE-treated (13% vs. 0%) than placebo-treated patients.

Table 6: Adverse Reactions with ≥5% Overall Occurrence in Childhood-Onset Growth Hormone-Deficient Patients Treated with HUMATROPE for 18 Months as Compared with 6-Month Placebo and 12-Month HUMATROPE Exposure

Adverse Reaction	18 Months Exposure [Placebo (6 Months)/Humatrope (12 Months)] (n=30)	18 Months Humatrope Exposure (n=32)
ASTa increased	7%	13%
Headache	7%	9%
Asthenia	3%	6%
Edema	10%	6%
Myalgia	7%	6%
Pain	10%	6%
ALT a increased	7%	6%
Flu syndrome	10%	16%
Cough increased	0%	6%
Hypesthesia	0%	6%
Rhinitis	7%	6%
Respiratory disorder	7%	3%
Gastritis	7%	0%
Pharyngitis	7%	3%
a Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase

 

Immunogenicity

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 influenced 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 HUMATROPE with the incidence of antibodies to other products may be misleading.

In a clinical study with HUMATROPE during the first 6 months of HUMATROPE therapy in 314 naive patients, 1.6% developed specific antibodies to HUMATROPE (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.

Postmarketing Experience

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

Severe Hypersensitivity Reactions – Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products

Neurologic – Headaches (common in pediatric patients and occasional in adults)

Skin – Increase in size or number of cutaneous nevi

Endocrine – Gynecomastia

Gastrointestinal – Pancreatitis

Metabolic – New-onset type 2 diabetes mellitus

Neoplasia – Leukemia has been reported in a small number of GH deficient pediatric patients treated with somatropin