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Norditropin Side Effects

Generic Name: somatropin

Please note - some side effects for Norditropin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Norditropin - for the Consumer

Norditropin

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 Norditropin:

Bone pain; headache; increased sweating; mild flu-like symptoms; mild swelling (eg, of the hands or feet); muscle or joint pain; prickling sensation of the skin; redness or itching at the injection site.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); burning, tingling, itching, or numbness in the palm of the hand, fingers, or wrist; change in appearance or size of a mole; chest pain; confusion; ear pain, discharge, or discomfort; fast heartbeat; fever; hearing problems; hip or knee pain; limp; nausea or vomiting; new growth on the skin; one-sided weakness; persistent or severe cough or sore throat; severe or persistent stomach or back pain; severe or persistent swelling of the hands, ankles, or feet; shortness of breath; slurred speech; snoring or irregular breathing during sleep; sudden, severe, or persistent headache or dizziness; symptoms of high blood sugar (eg, increased thirst, hunger, or urination; unusual weakness); thickened or hardened skin at the injection site; trouble breathing; unusual bruising; vision changes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Norditropin Nordiflex

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 Norditropin Nordiflex:

Bone pain; headache; increased sweating; mild flu-like symptoms; mild swelling (eg, of the hands or feet); muscle or joint pain; prickling sensation of the skin; redness or itching at the injection site.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); burning, tingling, itching, or numbness in the palm of the hand, fingers, or wrist; change in appearance or size of a mole; chest pain; confusion; ear pain, discharge, or discomfort; fast heartbeat; fever; hearing problems; hip or knee pain; limp; nausea or vomiting; new growth on the skin; one-sided weakness; persistent or severe cough or sore throat; severe or persistent stomach or back pain; severe or persistent swelling of the hands, ankles, or feet; shortness of breath; slurred speech; snoring or irregular breathing during sleep; sudden, severe, or persistent headache or dizziness; symptoms of high blood sugar (eg, increased thirst, hunger, or urination; unusual weakness); thickened or hardened skin at the injection site; trouble breathing; unusual bruising; vision changes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Norditropin FlexPro

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 Norditropin FlexPro:

Bone pain; headache; increased sweating; mild flu-like symptoms; mild swelling (eg, of the hands or feet); muscle or joint pain; prickling sensation of the skin; redness or itching at the injection site.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); burning, tingling, itching, or numbness in the palm of the hand, fingers, or wrist; change in appearance or size of a mole; chest pain; confusion; ear pain, discharge, or discomfort; fast heartbeat; fever; hearing problems; hip or knee pain; limp; nausea or vomiting; new growth on the skin; one-sided weakness; persistent or severe cough or sore throat; severe or persistent stomach or back pain; severe or persistent swelling of the hands, ankles, or feet; shortness of breath; slurred speech; snoring or irregular breathing during sleep; sudden, severe, or persistent headache or dizziness; symptoms of high blood sugar (eg, increased thirst, hunger, or urination; unusual weakness); thickened or hardened skin at the injection site; trouble breathing; unusual bruising; vision changes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Norditropin Side Effects - for the Professional

Norditropin

Most Serious and/or Most Frequently Observed Adverse Reactions

This list presents the most seriousb and/or most frequently observeda adverse reactions during treatment with somatropin:

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.

Clinical Trials in Children with Noonan Syndrome

Norditropin was studied in a two-year prospective, randomized, parallel dose group trial in 21 children, 3-14 years old, with Noonan syndrome. Doses were 0.033 and 0.066 mg/kg/day. After the initial two-year randomized trial, children continued Norditropin treatment until final height was achieved; randomized dose groups were not maintained. Final height and adverse event data were later collected retrospectively from 18 children; total follow-up was 11 years. An additional 6 children were not randomized, but followed the protocol and are included in this assessment of adverse events.

Based on the mean dose per treatment group, no significant difference in the incidence of adverse events was seen between the two groups. The most frequent adverse events were the common infections of childhood, including upper respiratory infection, gastroenteritis, ear infection, and influenza. Cardiac disorders was the system organ class with the second most adverse events reported. However, congenital heart disease is an inherent component of Noonan syndrome, and there was no evidence of somatropin-induced ventricular hypertrophy or exacerbation of preexisting ventricular hypertrophy (as judged by echocardiography) during this study. Children who had baseline cardiac disease judged to be significant enough to potentially affect growth were excluded from the study; therefore the safety of Norditropin in children with Noonan syndrome and significant cardiac disease is not known. Among children who received 0.033 mg/kg/day, there was one adverse event of scoliosis; among children who received 0.066 mg/kg/day, there were four adverse events of scoliosis [see Warnings and Precautions (5.9)]. Mean serum IGF-I standard deviation score (SDS) levels did not exceed +1 in response to somatropin treatment. The mean serum IGF-I level was low at baseline and normalized during treatment.

Clinical Trials in Children with Turner Syndrome

In two clinical studies wherein children with Turner syndrome were treated until final height with various doses of Norditropin as described in Clinical Studies (14.2), the most frequently reported adverse events were common childhood diseases including influenza-like illness, otitis media, upper respiratory tract infection, otitis externa, gastroenteritis and eczema. Otitis media adverse events in Study 1 were most frequent in the highest dose groups (86.4% in the 0.045-0.067-0.089 mg/kg/day group vs. 78.3% in the 0.045-0.067 mg/kg/day group vs. 69.6% in the 0.045 mg/kg/day group) suggesting a possible dose-response relationship. Of note, approximately 40-50% of these otitis media adverse events were designated as “serious” [see Warnings and Precautions (5.10)]. No patients in either study developed clearcut overt diabetes mellitus; however, in Study 1, impaired fasting glucose at Month 48 was more frequent in patients in the 0.045-0.067 mg/kg/day group (n=4/18) compared with the 0.045 mg/kg/day group (n=1/20). Transient episodes of fasting blood sugars between 100 and 126 mg/dL, and, on occasion, exceeding 126 mg/dL also occurred more often with larger doses of Norditropin in both studies [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. Three patients withdrew from the 2 high dose groups in Study 1 because of concern about excessive growth of hands or feet. In addition, in Study 1, exacerbation of preexisting scoliosis was designated a serious adverse reaction in two patients in the 0.045 mg/kg/day group [see Warnings and Precautions (5.9)].

Clinical Trials in Children Born Small for Gestational Age (SGA) with No Catch-up Growth by Age 2-4 Years

Study 1 (Long-Term)

In a multi-center, randomized, double-blind study, 53 non-GHD children with short stature born SGA with failure to catch-up were treated with 2 doses of Norditropin (0.033 or 0.067 mg/kg/day) to final height for up to 13 years (mean duration of treatment 7.9 and 9.5 years for girls and boys, respectively). The most frequently reported adverse events were common childhood diseases including influenza-like illness, upper respiratory tract infection, bronchitis, gastroenteritis, abdominal pain, otitis media, pharyngitis, arthralgia, and headache. Adverse events possibly/probably related to Norditropin were otitis media, arthralgia, headaches (no confirmed diagnoses of benign intracranial hypertension), gynecomastia, and increased sweating. One child treated with 0.067 mg/kg/day for 4 years was reported with disproportionate growth of the lower jaw, and another child treated with 0.067 mg/kg/day developed a melanocytic nevus [see Warnings and Precautions (5.3)]. There were no clear cut reports of exacerbation of preexisting scoliosis or slipped capital femoral epiphysis. No apparent differences between the treatment groups were observed. In addition, the timing of puberty was age-appropriate in boys and girls in both treatment groups. Therefore, it can be concluded that no novel adverse events potentially related to treatment with Norditropin were reported in long-term Study 1.

Study 2 (Short-Term)

In a multi-center, randomized, double-blind, parallel-group study, 98 Japanese non-GHD children with short stature born SGA with failure to catch-up were treated with 2 doses of Norditropin (0.033 or 0.067 mg/kg/day) for 2 years or were untreated for 1 year. The most frequently reported adverse events were common childhood diseases almost identical to those reported above for Study 1. Adverse events possibly/probably related to Norditropin were otitis media, arthralgia and impaired glucose tolerance. No apparent differences between the treatment groups were observed. However, arthralgia and transiently impaired glucose tolerance were only reported in the 0.067 mg/kg/day treatment group. Therefore, it can also be concluded that no novel adverse events potentially related to treatment with rhGH were reported in short-term Study 2.

As with all protein drugs, some patients may develop antibodies to the protein. Eighteen of the 76 children (~24%) treated with Norditropin developed anti-rhGH antibodies. However, these antibodies did not appear to be neutralizing in that the change from baseline in height SDS at Year 2 was similar in antibody positive and antibody negative children by treatment group.

In both Study 1 and Study 2, there were no clear cut cases of new onset diabetes mellitus, no children treated for hyperglycemia, and no adverse event withdrawals due to abnormalities in glucose tolerance. In Study 2, after treatment with either dose of Norditropin for 2 years, there were no children with consecutive fasting blood glucose levels between 100 and 126 mg/dL, or with fasting blood glucose levels > 126 mg/dL. Furthermore, mean hemoglobin A1c levels tended to decrease during long-term treatment in Study 1, and remained normal in Study 2. However, in Study 1, 4 children treated with 0.067 mg/kg/day of Norditropin and 2 children treated with 0.033 mg/kg/day of Norditropin shifted from normal fasting blood glucose levels at baseline to increased levels after 1 year of treatment (100 to 126 mg/dL or > 126 mg/dL). In addition, small increases in mean fasting blood glucose and insulin levels (within the normal reference range) after 1 and 2 years of Norditropin treatment appeared to be dose-dependent  [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

In both Study 1 and Study 2, there was no acceleration of bone maturation. A dose-dependent increase in mean serum IGF-I SDS levels within the reference range (but including a substantial number of children with serum IGF-1 SDS > +2) was observed after both long-term (Study 1) and short-term (Study 2) Norditropin treatment.

Clinical Trials in Adult GHD Patients

Adverse events with an incidence of ≥5% occurring in patients with AO GHD during the 6 month placebo-controlled portion of the largest of the six adult GHD Norditropin trials are presented in Table 1. Peripheral edema, other types of edema, arthralgia, myalgia, and paraesthesia were common in the Norditropin-treated patients, and reported much more frequently than in the placebo group. These types of adverse events are thought to be related to the fluid accumulating effects of somatropin. In general, these adverse events were mild and transient in nature. During the placebo-controlled portion of this study, approximately 5% of patients without preexisting diabetes mellitus treated with Norditropin were diagnosed with overt type 2 diabetes mellitus compared with none in the placebo group [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. Anti-GH antibodies were not detected.

Of note, the doses of Norditropin employed during this study (completed in the mid 1990s) were substantially larger than those currently recommended by the Growth Hormone Research Society, and, more than likely, resulted in a greater than expected incidence of fluid retention- and glucose intolerance-related adverse events. A similar incidence and pattern of adverse events were observed during the other three placebo-controlled AO GHD trials and during the two placebo-controlled CO GHD trials.

Table 1 - Adverse Reactions with ≥5% Overall Incidence in Adult Onset Growth Hormone Deficient Patients Treated with Norditropin During a Six Month Placebo-Controlled Clinical Trial

Norditropin

(N=53)

Placebo

(N=52)
Adverse Reactions n

%

 n %
Peripheral Edema 22 42 4 8
Edema 13 25 0 0
Arthralgia 10 19 8 15
Leg Edema 8 15 2 4
Myalgia 8 15 4 8
Infection (non-viral) 7 13 4 8
Paraesthesia 6 11 3 6
Skeletal Pain 6 11 1 2
Headache 5 9 3 6
Bronchitis 5 9 0 0
Flu-like symptoms 4 8 2 4
Hypertension 4 8 1 2
Gastroenteritis 4 8 4 8
Other Non-Classifiable Disorders
(excludes accidental injury)		 4 8 3 6
Increased sweating 4 8 1 2
Glucose tolerance abnormal 3 6 1 2
Laryngitis 3 6 3 6

The adverse event pattern observed during the open label phase of the study was similar to the one presented above.

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 Norditropin with the incidence of antibodies to other products may be misleading. In the case of growth hormone, antibodies with binding capacities lower than 2 mg/mL have not been associated with growth attenuation. In a very small number of patients treated with somatropin, when binding capacity was greater than 2 mg/mL, interference with the growth response was observed.

In clinical trials, GHD pediatric patients receiving Norditropin for up to 12 months were tested for induction of antibodies, and 0/358 patients developed antibodies with binding capacities above 2 mg/L. Amongst these patients, 165 had previously been treated with other somatropin formulations, and 193 were previously untreated naive patients.

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.

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 GHD 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 GHD, if any, remains to be established [see Contraindications (4.3) and Warnings and Precautions (5.3)].

The following additional adverse reactions have been observed during the appropriate use of somatropin: headaches (children and adults), gynecomastia (children), and pancreatitis (children and adults [see Warnings and Precautions (5.14)])..

New-onset type 2 diabetes mellitus has been reported.

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Side Effects by Body System - for Healthcare Professionals

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. New-onset type 2 diabetes mellitus in children and adults has been reported in postmarketing experience. Elevations in IGF-1 (insulin like growth factor 1) and insulin levels have occurred consistently in adults. Alterations in thyroid hormone metabolism may occur.

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. Postmarketing reports have included hypertension.

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. Postmarketing reports have included dyspnea and sleep apnea.

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