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GENOTROPIN (somatropin [rDNA origin] for injection) Adverse Reactions

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Adverse Reactions

Adverse Drug Reaction Overview

Patients with growth hormone deficiency are characterized by extracellular volume deficit. When treatment with somatropin is started this deficit is rapidly corrected. In adult patients adverse effects related to fluid retention, such as peripheral edema, face edema, stiffness in the extremities, arthralgia, myalgia and paraesthesia are common. In general these adverse effects are mild to moderate, arise within the first months of treatment and subside spontaneously or with dose-reduction. Severe hypersensitivity has been reported in post-marketing use of somatropin products.

The incidence of these adverse effects is related to the administered dose, the age of patients, and possibly inversely related to the age of patients at the onset of growth hormone deficiency. In children such adverse effects are uncommon.

Somatropin has been reported to reduce serum cortisol levels, possibly by affecting carrier proteins or by increased hepatic clearance. The clinical relevance of these findings may be limited. Nevertheless, corticosteroid replacement therapy should be optimised before initiation of GENOTROPIN (somatropin for injection) therapy (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Children

Anti-hGH Antibodies

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 GENOTROPIN 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 419 pediatric patients evaluated in clinical studies with GENOTROPIN lyophilized powder, 244 had been treated previously with GENOTROPIN or other growth hormone preparations and 175 had received no previous growth hormone therapy. Antibodies to growth hormone (anti-hGH antibodies) were present in six previously treated patients at baseline. Three of the six became negative for anti-hGH antibodies during 6 to 12 months of treatment with GENOTROPIN. Of the remaining 413 patients, eight (1.9%) developed detectable anti-hGH antibodies during treatment with GENOTROPIN; none had an antibody binding capacity > 2 mg/L. There was no evidence that the growth response to GENOTROPIN was affected in these antibody-positive patients.

Clinical Trials in children with GHD
In clinical studies with GENOTROPIN in children, the following events were reported infrequently: injection site reactions, e.g. pain or burning associated with the injection, fibrosis, nodules, rash, inflammation, pigmentation; bleeding; lipoatrophy; headache; hematuria; hypothyroidism; mild hyperglycemia.

Clinical Trials in children with SGA
In clinical studies of 273 pediatric patients born small for gestational age treated with GENOTROPIN, the following clinically significant events were reported: mild transient hyperglycemia, one patient with benign intracranial hypertension, two patients with central precocious puberty, two patients with jaw prominence, and several patients with aggravation of preexisting scoliosis, injection site reactions, and self-limited progression of pigmented nevi. IGF-I levels ranged from <20ng/ml to 593 ng/ml.

Anti-GH antibodies were assessed at baseline, 12 and 24 months in Genotropin-treated SGA children enrolled in study 89-041. At 12 months, the study included 27 untreated SGA children, 59 SGA children treated with Genotropin at a dose of 33 µg/kg body weight/day and 51 short SGA children treated with Genotropin at a dose of 67µg/kg body weight/day. At 24 months, the study included 10 untreated SGA children, 62 short SGA children treated with Genotropin at a dose of 33 µg/kg body weight/day (including 9 children who received no treatment during the first 12 months of the study) and 56 SGA children treated with Genotropin at a dose of 67 µg/kg body weight/day (including 8 children who received no treatment during the first 12 months of the study). None of these patients were determined to be positive for anti-GH antibodies at baseline or at any time during the course of the 24 months of the study.

TABLE 1: ADVERSE EVENTS REPORTED IN ≥ 1% OF CHILDREN (BASELINE TO MONTH 12) ALL CAUSALITY

Body system / Preferred Term

Untreated
N=76

0.033 mg/kg/day N=105

0.067 mg/kg/day N=117

0.1 mg/kg/day N=19

n(%)

n(%)

n(%)

n(%)

Skin & Appendage

Naevus

0

0

1(0.9)

2(10.5)

Nail disorder

0

1(1.0)

0

0

Rash erythematous

0

1(1.0)

0

0

Skin disorder

0

1(1.0)

0

0

Urticaria acute

0

1(1.0)

0

0

Musculoskeletal

Fracture

0

1(1.0)

1(0.9)

0

Skeletal malformation

0

0

0

1(5.3)

Tooth malformation

0

1(1.0)

0

0

Central & Peripheral Nervous System

Convulsions

0

1(1.0)

0

0

Dysphonia

0

1(1.0)

0

0

Headache

0

1(1.0)

0

0

Vision

Strabismus

1(1.3)

0

1(0.9)

0

Hearing & Vestibular system

Ear disorder nos

0

1(1.0)

1(0.9)

0

Psychiatric

Nervousness

0

1(1.0)

0

0

Personality disorder

1(1.3)

0

0

1(5.3)

Gastrointestinal

Abdominal pain

0

0

1(0.9)

0

Anorexia

1(1.3)

2(1.9)

0

0

Anus disorder

1(1.3)

0

0

0

Enteritis

1(1.3)

0

0

0

Gastroenteritis

0

2(1.9)

2(1.7)

0

Hernia nos

1(1.3)

0

1(0.9)

0

Surgical intervention

0

1(1.0)

2(1.7)

0

Vomiting

2(2.6)

0

1(0.9)

0

Metabolism and Nutritional

Hyperglycaemia

0

1(1.0)

0

0

Extra Cardiac

Vein distended

0

1(1.0)

0

0

Respiratory Total

Surgical intervention

1(1.3)

2(1.9)

4(3.4)

1(5.3)

Apnea

0

1(1.0)

0

0

Asthma

2(2.6)

0

3(2.6)

0

Bronchitis

0

5(4.8)

4(3.4)

0

Coughing

2(2.6)

0

4(3.4)

1(5.3)

Epistaxis

1(1.3)

0

0

0

Laryngitis

0

0

1(0.9)

1(5.3)

Pneumonia

0

2(1.9)

2(1.7)

1(5.3)

Rhinitis

1(1.3)

2(1.9)

6(5.1)

1(5.3)

Upper respiratory tract infection

1(1.3)

7(6.7)

7(6.0)

2(10.5)

Red Blood Cell

Anemia

1(1.3)

0

0

0

White Cell

Lymphadenopathy

1(1.3)

0

0

0

Platelet/Bleed

Purpura thrombocytopenic

0

1(1.0)

0

0

Thrombocytopenia

0

1(1.0)

0

0

Reproductive-Male

Testis disorder

1(1.3)

1(1.0)

0

0

General Total

Surgical intervention

0

1(1.0)

2(1.7)

0

Accident

0

0

0

1(5.3)

Allergic reaction

0

1(1.0)

0

0

Allergy

2(2.6)

0

1(0.9)

0

Fever

2(2.6)

0

1(0.9)

1(5.3)

Influenza-like symptoms

0

0

2(1.7)

0

Application Site

Injection site reaction

0

1(1.0)

0

0

Tympanic membrane perforation

0

1(1.0)

0

0

Resistance Mechanism

Herpes zoster

0

1(1.0)

1(0.9)

0

Infection

0

3(2.9)

3(2.6)

0

Infection bacterial

1(1.3)

3(2.9)

0

0

Infection fungal

0

1(1.0)

0

0

Infection viral

6(7.9)

7(6.7)

8(6.8)

0

Otitis media

1(1.3)

8(7.6)

8(6.8)

0

Pharyngitis

6(7.9)

5(4.8)

5(4.3)

0

Less Common Clinical Trial Adverse Drug Reactions (Baseline to Month 12)

Clinical trial adverse drug reactions with a frequency of less than 1% are presented in the following listing:
Skin & Appendage disorders: eczema
Musculoskeletal disorders: bone development abnormal, spine malformation
Central and Peripheral nervous system disorders: ataxia
Psychiatric disorders: aggressive reaction, concentration impaired
Gastrointestinal disorders: abdominal pain, malabsorption
Endocrine disorders: gynaecomastia, puberty precocious
Respiratory disorders: sinusitis
Urinary disorders: dysuria
General disorders: hepatomegaly

TABLE 2: ADVERSE EVENTS REPORTED IN ≥ 1% OF CHILDREN (12 TO 24 MONTH) ALL CAUSALITY

Body system / Preferred Term

Untreated
N=53

0.033 mg/kg/day

N=106

0.067 mg/kg/day

N=118

0.1 mg/kg/day

N=19

n(%)

n(%)

n(%)

n(%)

Skin & Appendage

Eczema

0

1(0.9)

2(1.7)

0

Skin discolouration

0

0

2(1.7)

0

Musculoskeletal

Osteomyelitis

0

0

0

1(5.3)

Central & Peripheral Nervous System

Convulsions

0

0

0

1(5.3)

Vision

Myopia

0

0

1(0.8)

2(10.5)

Strabismus

0

0

0

1(5.3)

Vision abnormal

1(1.9)

0

0

0

Psychiatric

Agitation

0

0

2(1.7)

0

Gastrointestinal

Gastroenteritis

2(3.8)

1(0.9)

2(1.7)

0

Surgical intervention

1(1.9)

2(1.9)

4(3.4)

0

Respiratory

Surgical intervention

0

4(3.8)

3(2.5)

1(5.3)

Asthma

0

2(1.9)

2(1.7)

0

Bronchitis

0

3(2.8)

3(2.5)

1(5.3)

Coughing

1(1.9)

4(3.8)

2(1.7)

0

Pneumonia

1(1.9)

1(0.9)

1(0.8)

1(5.3)

Rhinitis

1(1.9)

4(3.8)

4(3.4)

1(5.3)

Sinusitis

0

0

0

1(5.3)

Upper respiratory tract infection

2(3.8)

5(4.7)

2(1.7)

0

Urinary

Urinary incontinence

1(1.9)

0

0

0

General

Surgical intervention

2(3.8)

3(2.8)

5(4.2)

1(5.3)

Allergic reaction

1(1.9)

1(0.9)

0

0

Allergy

1(1.9)

1(0.9)

3(2.5)

0

Fever

0

1(0.9)

2(1.7)

0

Influenza-like symptoms

0

2(1.9)

4(3.4)

1(5.3)

Edema pharynx

1(1.9)

0

0

0

Pain

2(3.8)

0

1(0.8)

0

Resistance Mechanism

Balanoposthitis

0

0

0

1(5.3)

Herpes simplex

0

1(0.9)

0

1(5.3)

Infection

0

1(0.9)

2(1.7)

0

Infection bacterial

2(3.8)

3(2.8)

0

0

Infection viral

3(5.7)

13(12.3)

5(4.2)

0

Otitis media

1(1.9)

7(6.6)

5(4.2)

4(21.1)

Pharyngitis

2(3.8)

8(7.5)

8(6.8)

0

Less Common Clinical Trial Adverse Drug Reactions (12 to 24 Month)

Clinical trial adverse drug reactions with a frequency of less than 1% are presented in the following listing:
Skin & Appendage disorders: acne, nail disorder, pruritus, skin dry, sweating increased, urticaria
Musculoskeletal disorders: arthralgia, fracture, spine malformation
Central and Peripheral nervous system disorders: absences, headaches
Vision: conjunctivitis
Hearing and Vestibular system disorders: earache
Gastrointestinal disorders: abdominal pain, anorexia, enteritis
Metabolism and nutritional system disorders: hypoglycemia
Endocrine disorders: puberty precocious
Extra cardiac: vein distended
Respiratory disorders: thyroid adenoma
Red blood cell: anemia
White blood cell: lymphadenopathy
Platelet/bleed disorder: purpura, thrombocytopenia
Urinary disorders: cystitis, urinary tract infection, urogenital malformation
Neoplasm disorder: neoplasm nos
General disorders: accident

 

TABLE 3: MOST FREQUENT ADVERSE EVENTS (REPORTED IN ≥1% OF CHILDREN TREATED WITH SOMATROPIN CONTINUOUSLY UP TO MONTH 72) –0-72 POPULATION

Body system / Preferred Term

0.033 mg/kg/day

N=37

0.067 mg/kg/day

N=25

Total N=62

n(%)

n(%)

n(%)

Skin & Appendage

Angioedema

1(2.7)

0

1(1.6)

Eczema

1(2.7)

0

1(1.6)

Fistula incomplete

0

1(4.0)

1(1.6)

Nail disorder

1(2.7)

0

1(1.6)

Pruritus

0

1(4.0)

1(1.6)

Rash erythematous

1(2.7)

0

1(1.6)

Skin disorder

3(8.1)

0

3(4.8)

Skin exfoliation

0

1(4.0)

1(1.6)

Sweating increased

1(2.7)

0

1(1.6)

Urticaria

1(2.7)

1(4.0)

2(3.2)

Verruca

0

1(4.0)

1(1.6)

Musculo-Skeletal

Arthrosis

1(2.7)

0

1(1.6)

Fracture

3(8.1)

1(4.0)

4(6.5)

Joint malformation

1(2.7)

0

1(1.6)

Spine malformation

1(2.7)

0

1(1.6)

Tooth malformation

1(2.7)

0

1(1.6)

Central & Peripheral Nervous System

Absences

1(2.7)

0

1(1.6)

Headache

2(5.4)

0

2(3.2)

Hyperkinesia

0

2(8.0)

2(3.2)

Muscle contractions involuntary

0

1(4.0)

1(1.6)

Neuritis

1(2.7)

0

1(1.6)

Paralysis

0

1(4.0)

1(1.6)

Vision

Conjunctivitis

1(2.7)

1(4.0)

2(3.2)

Hearing & Vestibular System

Ear disorder nos

1(2.7)

1(4.0)

2(3.2)

Earache

1(2.7)

0

1(1.6)

Psychiatric

Concentration impaired

1(2.7)

0

1(1.6)

Thinking abnormal

0

1(4.0)

1(1.6)

Gastro-Intestinal

Abdominal pain

3(8.1)

1(4.0)

4(6.5)

Anorexia

1(2.7)

0

1(1.6)

Diarrhoea

1(2.7)

0

1(1.6)

Enteritis

1(2.7)

0

1(1.6)

Gastroenteritis

4(10.8)

6(24.0)

10(16.1)

Hernia nos

1(2.7)

0

1(1.6)

Intestinal obstruction

1(2.7)

0

1(1.6)

Stomatitis aphthous

1(2.7)

0

1(1.6)

Surgical intervention

1(2.7)

2(8.0)

3(4.8)

Tooth disorder

1(2.7)

0

1(1.6)

Vomiting

1(2.7)

0

1(1.6)

Metabolic & Nutritional

Hypoglycaemia

0

1(4.0)

1(1.6)

Endocrine

Osteomalacia

0

1(4.0)

1(1.6)

Puberty precocious

1(2.7)

1(4.0)

2(3.2)

Respiratory

Surgical intervention

7(18.9)

4(16.0)

11(17.7)

Asthma

1(2.7)

1(4.0)

2(3.2)

Bronchitis

4(10.8)

5(20.0)

9(14.5)

Coughing

5(13.5)

2(8.0)

7(11.3)

Laryngitis

1(2.7)

1(4.0)

2(3.2)

Pneumonia

2(5.4)

1(4.0)

3(4.8)

Rhinitis

13(35.1)

6(24.0)

19(30.6)

Sinusitis

2(5.4)

0

2(3.2)

Upper respiratory tract infection

9(24.3)

9(36.0)

18(29.0)

Red blood cell

Anaemia

0

1(4.0)

1(1.6)

White cell

Lymphadenopathy

1(2.7)

1(4.0)

2(3.2)

Platelet/Bleed

Haematoma

1(2.7)

0

1(1.6)

Urinary

Cystitis

1(2.7)

0

1(1.6)

Urinary incontinence

1(2.7)

1(4.0)

2(3.2)

Urinary tract infection

0

1(4.0)

1(1.6)

Urogenital malformation

1(2.7)

0

1(1.6)

Reproductive-Male

Penis disorder

0

1(4.0)

1(1.6)

Testis disorder

1(2.7)

0

1(1.6)

Neoplasms

Neoplasm nos

1(2.7)

0

1(1.6)

General

Surgical intervention

0

3(12.0)

3(4.8)

Allergic reaction

3(8.1)

0

3(4.8)

Allergy

2(5.4)

0

2(3.2)

Deviating laboratory value

0

1(4.0)

1(1.6)

Fatigue

1(2.7)

0

1(1.6)

Fever

1(2.7)

2(8.0)

3(4.8)

Hepatomegaly

0

1(4.0)

1(1.6)

Hypothermia

1(2.7)

0

1(1.6)

Inflammatory reaction nos

0

1(4.0)

1(1.6)

Influenza-like symptoms

2(5.4)

2(8.0)

4(6.5)

Pain

1(2.7)

0

1(1.6)

Application Site

Injection site atrophy

0

1(4.0)

1(1.6)

Injection site fibrosis

0

1(4.0)

1(1.6)

Injection site reaction

0

1(4.0)

1(1.6)

Otitis externa

0

1(4.0)

1(1.6)

Resistance Mechanism

Abscess

0

1(4.0)

1(1.6)

Herpes ocular

0

1(4.0)

1(1.6)

Herpes simplex

2(5.4)

1(4.0)

3(4.8)

Infection

5(13.5)

6(24.0)

11(17.7)

Infection bacterial

6(16.2)

0

6(9.7)

Infection fungal

1(2.7)

0

1(1.6)

Infection viral

14(37.8)

3(12.0)

17(27.4)

Otitis media

9(24.3)

8(32.0)

17(27.4)

Pharyngitis

12(32.4)

7(28.0)

19(30.6)

Sepsis

0

1(4.0)

1(1.6)

Events

Bite

2(5.4)

0

2(3.2)

Molluscum contagiosa

0

1(4.0)

1(1.6)

Adverse Events Leading to Termination of Treatment

Clinical trial adverse drug reactions that lead to treatment termination are listed below by dose group:
0.033 mg/kg/day: Thrombocytopenic purpura
0.067 mg/kg/day: Aggressive reaction, Ataxia, Retinal dystrophy (2 patients)
Discontinuous therapy: Diabetes mellitus, Surgical intervention, Muscle malformation.

Respiratory Adverse Events in children with SGA
In the open- label SGA studies, the percentage of respiratory adverse events for the 3 active treatment groups (16.2% in 0.033 mg/kg/day, 20.5% in 0.067 mg/kg/day and 26.3% in 0.1 mg/kg/day) were higher than in the untreated group (10.5%) between 0 - 12 months. Between 12 - 24 months, the incidence of respiratory events was also higher in the 3 active treatment groups (18.9% in 0.033 mg/kg/day; 13.6% in 0.067 mg/kg/day; 21.1% in 0.1 mg/kg/day) compared to 7.5% in the untreated control group. Respiratory adverse events included mostly upper respiratory tract infections. Adverse events classified as 'resistance mechanism' which included viral infection, otitis media, and pharyngitis occurred at a higher rate in 2 of the active treatment groups (21.9% in 0.033 mg/kg/day; 19.7% in 0.067 mg/kg/day; 0% in 0.1 mg/kg/day) compared to the untreated control group (15.8%) between 0 - 12 months. Between 12 - 24 months, the incidence of resistance mechanism adverse events was higher in all 3 active treatment groups (25.5% in 0.033 mg/kg/day; 16.1% in 0.067 mg/kg/day; 31.6% in 0.1 mg/kg/day) compared to 13.2% in the untreated control group. However, none of the differences among the four study groups were evaluated for statistical significance.

The adverse events most frequently reported for the study periods were: viral infections, otitis media, pharyngitis, upper respiratory tract infections, and rhinitis. Overall, these events were consistent with the pattern of normal childhood illnesses in this age group. No evidence of a dose-related pattern was apparent. There were a higher number of patients in 2 of the somatropin-treated groups (0.033 mg/kg/day, n=105; 0.067 mg/kg/day, n=117) than in the untreated group (n=76); however the highest dose group (0.1 mg/kg/day) had only 19 patients. While, the investigators did not consider these events to be treatment-related, this cannot be ruled out.

IGF-I levels:

Table 4 summarizes the frequencies of subjects with IGF-I levels below/above or within normal range, organized for all treatment groups side-by-side and across all visits from CTN 89-041 (France). Subject groups Untreated/0.033 mg/kg/wk and Untreated/0.067 mg/kg/wk include subjects who served as untreated controls for 12 months or longer, and were subsequently treated with Genotropin 0.033 mg/kg/wk or 0.067 mg/kg/wk, respectively. In figure 1, the solid reference lines were created by averaging individual upper and lower limits of normal ranges across all subjects with observed IGF-I levels at a given time-point. As such, the reference lines are for overall inference, as they represent an approximation of the exact normative values. As can be seen in the various graphs, IGF-1 levels generally ranged from <20ng/ml to 593 ng/ml.

TABLE 4: FREQUENCY OF SUBJECTS WITH IGF-I LEVELS BELOW/ABOVE OR WITHIN NORMAL RANGE FOR ALL TREATMENT GROUPS AND ACROSS ALL VISITS (STUDY 89-041)

Month

Treatment group

0.033 mg/kg/wk

0.067 mg/kg/wk

Untreated/0.033 mg/kg/wk

Untreated/0.067 mg/kg/wk

IGF-I status

IGF-I status

IGF-I status

IGF-I status

Below

Normal

Above

Below

Normal

Above

Below

Normal

Above

Below

Normal

Above

N

%

N

%

N

%

N

%

N

%

N

%

N

%

N

%

N

%

N

%

N

%

N

%

0

1

2.5

38

95.0

1

2.5

1

3.2

30

96.8

-

-

-

-

7

87.5

1

12.5

-

-

4

100.0

-

-

6

-

-

24

85.7

4

14.3

3

11.1

20

74.1

4

14.8

-

-

2

100.0

-

-

-

-

2

100.0

-

-

12

2

5.4

31

83.8

4

10.8

2

5.7

22

62.9

11

31.4

2

33.3

4

66.7

-

-

2

40.0

3

60.0

-

-

18

1

3.4

23

79.3

5

17.2

3

10.7

17

60.7

8

28.6

-

-

4

80.0

1

20.0

-

-

5

83.3

1

16.7

24

4

10.8

27

73.0

6

16.2

3

11.1

14

51.9

10

37.0

1

14.3

6

85.7

-

-

-

-

6

85.7

1

14.3

30

1

4.3

18

78.3

4

17.4

-

-

12

70.6

5

29.4

-

-

6

100.0

-

-

-

-

5

83.3

1

16.7

36

3

11.5

17

65.4

6

23.1

-

-

10

66.7

5

33.3

1

12.5

6

75.0

1

12.5

-

-

6

100.0

-

-

42

-

-

8

53.3

7

46.7

-

-

3

37.5

5

62.5

-

-

4

100.0

-

-

-

-

3

60.0

2

40.0

48

1

7.1

11

78.6

2

14.3

-

-

4

66.7

2

33.3

-

-

3

60.0

2

40.0

-

-

4

80.0

1

20.0

54

1

8.3

8

66.7

3

25.0

-

-

5

62.5

3

37.5

-

-

2

40.0

3

60.0

-

-

4

80.0

1

20.0

60

-

-

6

60.0

4

40.0

1

14.3

5

71.4

1

14.3

-

-

2

66.7

1

33.3

-

-

2

50.0

2

50.0

66

-

-

6

75.0

2

25.0

-

-

5

83.3

1

16.7

-

-

2

66.7

1

33.3

-

-

3

60.0

2

40.0

72

-

-

6

66.7

3

33.3

-

-

5

62.5

3

37.5

-

-

2

100.0

-

-

-

-

2

66.7

1

33.3

Clinical Trials in children with Turner Syndrome
In two clinical studies with GENOTROPIN in pediatric patients with Turner syndrome, the most frequently reported adverse events were respiratory illnesses (influenza, tonsillitis, otitis, sinusitis), joint pain, and urinary tract infection. The only treatment-related adverse event that occurred in more than 1 patient was joint pain. In one study in children with TS, none of the 42 patients discontinued from the study early while in the second study, none of the patients discontinued before 18 months.

TABLE 5: SUMMARY OF ADVERSE EVENTS (AE) THAT OCCURRED IN AT LEAST 1 PATIENT IN STUDY 87-055 - ALL CAUSALITY

WHO Dictionary Term

Genotropin

N= 22

Genotropin plus ethinyloestradiol

N=20

Joint Pain

4 (18.2%)

3 (15.0%)

Epilepsy

1 (4.5%)

1 (5.0%)

Sinusitis

1 (4.5%)

1(5.0%)

Cellulitis

1 (4.5%)

0

Urinary Tract Infection

0

1 (5.0%)

Dysfunctional voiding

0

1 (5.0%)

Menarche

1 (4.5%)

0

Varicella

1 (4.5%)

0

Measles

1 (4.5%)

0

Herpes Zoster

1 (4.5%)

0

Total AEs

9(41.0%)

6 (30.0%)

TABLE 6: SUMMARY OF ADVERSE EVENTS THAT OCCURRED IN AT LEAST 1 PATIENT IN STUDY 86-092 – ALL CAUSALITY

WHO dictionary term

Genotropin

N=17

Genotropin + oxandrolone

N=17

Skin and appendage disorders

Furonculosis

1 (5.9%)

0

Loss of hair

1 (5.9%)

0

Eczema

0

1 (5.9%)

Musculo-skeletal system disorders

Joint Pain

1 (5.9%)

1 (5.9%)

Radius fracture

0

1 (5.9%)

Hearing and vestibular disorders

Tympanic membrane

1 (5.9%)

0

Psychiatric disorders

   

Nervousness

1 (5.9%)

0

Increased Appetite

0

2 (11.8 %)

Liver and biliary system

   

Hepatitis A

1 (5.9%)

0

Hepatic injury

0

1 (5.9%)

Metabolic and nutritional disorders

Insulin value increased

0

1 (5.9%)

Endocrine disorders

   

Hypothyroidism

1 (5.9%)

0

Thyroiditis

1 (5.9%)

0

Vascular (extra cardiac) disorders

Flushing

1 (5.9%)

0

Respiratory Infections

Otitis

3 (17.6%)

1 (5.9%)

Tonsillitis

2 (11.8%)

3 (17.6%)

Rhinitis

1

0

Sinusitis

2 (11.8%)

1 (5.9%)

Influenza

1 (5.9%)

4 (23.5%)

Pneumonia

0

1 (5.9%)

Bronchitis

0

2 (11.8 %)

White cell and res disorders

Neutropenia, chronic

1 (5.9%)

0

Platelet, bleeding and clotting disorders

Epistaxis

2 (11.8%)

0

Hematoma

0

1 (5.9%)

Urinary system disorders

Urinary Tract Infection

3 (17.6%)

0

Hematuria

1 (5.9%)

0

Enuresis

0

1 (5.9%)

Reproductive disorders

Metrorrhagia

0

1 (5.9%)

Leukorrhea

0

1 (5.9%)

Spotting

0

1 (5.9%)

Hemorrhage

0

1 (5.9%)

Vaginitis

0

1 (5.9%)

Body as a whole – General disorders

Car accident

0

1 (5.9%)

Fatigue

0

1 (5.9%)

Voice alteration

0

1 (5.9%)

Clinical Trials in children with Turner’s syndrome
In one study with patients with TS, respiratory infections (otitis, tonsillitis, sinusitis, influenza, bronchitis) represented the majority of adverse events in children with TS with eight patients in the Genotropin group and 11 patients in the Genotropin and oxandrolone groups. The instances of the respiratory infections were assessed as unrelated to study drug. No patient discontinued treatment due to a treatment related adverse event. Younger patients, including patients with TS, treated or untreated, are known to have generally greater incidence of otitis media and ear problems.

In a second study, one patient experienced sinusitis, orbital cellulitis and grand mal seizure. These events were considered to be unlikely related to the study drug as per the investigator and they were also low in frequency.

Clinical Trials in children with Idiopathic Short Stature
In two open-label clinical studies with GENOTROPIN in pediatric patients with ISS, the most commonly encountered adverse events include upper respiratory tract infections, influenza, tonsillitis, nasopharyngitis, gastroenteritis, headaches, increased appetite, pyrexia, fracture, altered mood, and arthralgia. In one of the two studies, during GENOTROPIN treatment, the mean IGF-1 standard deviation (SD) scores were maintained in the normal range. IGF-1 SD scores above +2 SD were observed as follows: 1 subject (3%), 10 subjects (30%) and 16 subjects (38%) in the untreated control, 0. 23 and the 0.47 mg/kg/week groups, respectively, had at least one measurement; while 0 subjects (0%), 2 subjects (7%) and 6 subjects (14%) had two or more consecutive IGF-1 measurements above +2 SD.

TABLE 7: INCIDENCE OF TREATMENT-EMERGENT ADVERSE EVENTS THAT OCCURRED IN AT LEAST 1 PATIENT

Body system / Preferred Term

Prepubertal

Pubertal

Genotropina

0.033 and 0.067 mg/kg/day

N = 112

Untreated Controlsb

N = 61

0.033 mg/kg/day

N = 47

0.067 mg/kg/day

N = 49

Untreated Controls

N = 46

0.067 mg/kg/day

N = 16

Untreated Controls

N = 15

n(%)

n(%)

n(%)

n(%)

n(%)

n(%)

n(%)

Blood and lymphatic system disorders

Anaemia

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Eosinophilia

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Iron deficiency anaemia

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.7)

0 (0.0)

1 (1.6)

Lymphadenopathy

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Mononucleosis syndrome

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Congenital, familial and genetic disorders

Epidermal naevus

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Pigmented naevus

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Skeleton dysplasia

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Ear and labyrinth disorders

Motion sickness

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Vertigo

0 (0.0)

0 (0.0)

1 (2.2)

1 (6.3)

0 (0.0)

1 (0.9)

1 (1.6)

Endocrine disorders

Delayed puberty

0 (0.0)

0 (0.0)

4 (8.7)

0 (0.0)

0 (0.0)

0 (0.0)

4 (6.6)

Goitre

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Pituitary cyst

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Precocious puberty

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Thyroid disorder

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Eye disorders

Astigmatism

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Conjunctivitis

1 (2.1)

1 (2.0)

1 (2.2)

1 (6.3)

0 (0.0)

3 (2.7)

1 (1.6)

Conjunctivitis allergic

1 (2.1)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

2 (1.8)

0 (0.0)

Eye inflammation

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.3)

0 (0.0)

1 (0.9)

0 (0.0)

Eye redness

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.3)

0 (0.0)

1 (0.9)

0 (0.0)

Visual disturbance

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Gastrointestinal disorders

Abdominal pain

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.7)

0 (0.0)

1 (1.6)

Abdominal pain upper

1 (2.1)

4 (8.2)

0 (0.0)

0 (0.0)

0 (0.0)

5 (4.5)

0 (0.0)

Constipation

2 (4.3)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

2 (1.8)

0 (0.0)

Nausea

0 (0.0)

2 (4.1)

1 (2.2)

0 (0.0)

0 (0.0)

2 (1.8)

1 (1.6)

Tooth disorder

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Vomiting

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

General disorders and administration site conditions

Chest discomfort

1 (2.1)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

2 (1.8)

0 (0.0)

Chest pain

1 (2.1)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

2 (1.8)

0 (0.0)

Disease recurrence

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Fatigue

1 (2.1)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

2 (1.8)

0 (0.0)

Hunger

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.3)

0 (0.0)

1 (0.9)

0 (0.0)

Edema peripheral

1 (2.1)

0 (0.0)

0 (0.0)

1 (6.3)

0 (0.0)

2 (1.8)

0 (0.0)

Pain

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Pyrexia

8 (17.0)

4 (8.2)

2 (4.3)

1 (6.3)

0 (0.0)

13 (11.6)

2 (3.3)

Thirst

0 (0.0)

2 (4.1)

0 (0.0)

1 (6.3)

0 (0.0)

3 (2.7)

0 (0.0)

Immune system disorders

Hypersensitivity

1 (2.1)

3 (6.1)

2 (4.3)

0 (0.0)

0 (0.0)

4 (3.6)

2 (3.3)

Seasonal allergy

1 (2.1)

3 (6.1)

1 (2.2)

1 (6.3)

1 (6.7)

5 (4.5)

2 (3.3)

Infections and infestations

Appendicitis

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.7)

0 (0.0)

1 (1.6)

Borrelia infection

0 (0.0)

1 (2.0)

1 (2.2)

0 (0.0)

0 (0.0)

1 (0.9)

1 (1.6)

Ear infection

1 (2.1)

3 (6.1)

0 (0.0)

0 (0.0)

0 (0.0)

4 (3.6)

0 (0.0)

Eye infection

1 (2.1)

0 (0.0)

0 (0.0)

1 (6.3)

0 (0.0)

2 (1.8)

0 (0.0)

Gastroenteritis

7 (14.9)

4 (8.2)

0 (0.0)

1 (6.3)

1 (6.7)

12 (10.7)

1 (1.6)

Impetigo

1 (2.1)

2 (4.1)

0 (0.0)

0 (0.0)

0 (0.0)

3 (2.7)

0 (0.0)

Infectious mononucleosis

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.7)

0 (0.0)

1 (1.6)

Influenza

8 (17.0)

7 (14.3)

2 (4.3)

3 (18.8)

1 (6.7)

18 (16.1)

3 (4.9)

Mycoplasma infection

2 (4.3)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

3 (2.7)

0 (0.0)

Nasopharyngitis

7 (14.9)

5 (10.2)

1 (2.2)

0 (0.0)

0 (0.0)

12 (10.7)

1 (1.6)

Orchitis

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Otitis media acute

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Parotitis

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Pertussis

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Pharyngitis

3 (6.4)

0 (0.0)

1 (2.2)

1 (6.3)

0 (0.0)

4 (3.6)

1 (1.6)

Pneumonia

1 (2.1)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

2 (1.8)

0 (0.0)

Pyelonephritis

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.7)

0 (0.0)

1 (1.6)

Respiratory tract infection

0 (0.0)

2 (4.1)

0 (0.0)

0 (0.0)

0 (0.0)

2 (1.8)

0 (0.0)

Rhinitis

1 (2.1)

2 (4.1)

0 (0.0)

0 (0.0)

0 (0.0)

3 (2.7)

0 (0.0)

Scarlet fever

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Sinusitis

0 (0.0)

1 (2.0)

1 (2.2)

0 (0.0)

0 (0.0)

1 (0.9)

1 (1.6)

Streptococcal infection

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Tonsillitis

7 (14.9)

5 (10.2)

2 (4.3)

1 (6.3)

1 (6.7)

13 (11.6)

3 (4.9)

Upper respiratory tract infection

14 (29.8)

20 (40.8)

5 (10.9)

2 (12.5)

2 (13.3)

36 (32.1)

7 (11.5)

Urinary tract infection

0 (0.0)

0 (0.0)

1 (2.2)

1 (6.3)

0 (0.0)

1 (0.9)

1 (1.6)

Varicella

1 (2.1)

0 (0.0)

2 (4.3)

1 (6.3)

0 (0.0)

2 (1.8)

2 (3.3)

Viral infection

0 (0.0)

0 (0.0)

0 (0.0)

2 (12.5)

0 (0.0)

2 (1.8)

0 (0.0)

Injury, poisoning and procedural complications

Ankle fracture

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Clavicle fracture

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Concussion

2 (4.3)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

2 (1.8)

0 (0.0)

Contusion

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Eye injury

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Fall

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Femur fracture

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Hand fracture

1 (2.1)

0 (0.0)

0 (0.0)

1 (6.3)

0 (0.0)

2 (1.8)

0 (0.0)

Head injury

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Joint dislocation

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.7)

1 (0.9)

1 (1.6)

Joint injury

2 (4.3)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

3 (2.7)

0 (0.0)

Limb injury

1 (2.1)

1 (2.0)

1 (2.2)

0 (0.0)

1 (6.7)

2 (1.8)

2 (3.3)

Lower limb fracture

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Mouth injury

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Overdose

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Radius fracture

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Road traffic accident

1 (2.1)

1 (2.0)

1 (2.2)

0 (0.0)

1 (6.7)

2 (1.8)

2 (3.3)

Skull fracture

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.7)

0 (0.0)

1 (1.6)

Tibia fracture

1 (2.1)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

2 (1.8)

0 (0.0)

Wound

2 (4.3)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

2 (1.8)

0 (0.0)

Investigations

Blood immunoglobulin G decreased

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Blood testosterone decreased

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Blood thyroid stimulating hormone decreased

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

1 (6.7)

1 (0.9)

1 (1.6)

Cardiac murmur

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Haemoglobin decreased

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.7)

0 (0.0)

1 (1.6)

Heart rate irregular

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.7)

0 (0.0)

1 (1.6)

Heart sounds abnormal

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Thyroxine decreased

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.7)

0 (0.0)

1 (1.6)

Thyroxine free decreased

0 (0.0)

2 (4.1)

0 (0.0)

0 (0.0)

0 (0.0)

2 (1.8)

0 (0.0)

Metabolism and nutrition disorders

Appetite disorder

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Decreased appetite

2 (4.3)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

2 (1.8)

0 (0.0)

Increased appetite

6 (12.8)

5 (10.2)

0 (0.0)

3 (18.8)

0 (0.0)

14 (12.5)

0 (0.0)

Lactose intolerance

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.3)

0 (0.0)

1 (0.9)

0 (0.0)

Markedly reduced dietary intake

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Musculoskeletal and connective tissue disorders

Arthralgia

2 (4.3)

5 (10.2)

1 (2.2)

0 (0.0)

1 (6.7)

7 (6.3)

2 (3.3)

Back disorder

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Back pain

0 (0.0)

5 (10.2)

1 (2.2)

0 (0.0)

2 (13.3)

5 (4.5)

3 (4.9)

Jaw disorder

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Limb discomfort

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Lower limb deformity

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Muscle cramp

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Neck pain

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Osteochondrosis

0 (0.0)

0 (0.0)

1 (2.2)

1 (6.3)

0 (0.0)

1 (0.9)

1 (1.6)

Pain in extremity

1 (2.1)

3 (6.1)

0 (0.0)

0 (0.0)

0 (0.0)

4 (3.6)

0 (0.0)

Patellofemoral pain syndrome

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Periostitis

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Scoliosis

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.3)

0 (0.0)

1 (0.9)

0 (0.0)

Tendonitis

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Torticollis

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.3)

0 (0.0)

1 (0.9)

0 (0.0)

Nervous system disorders

Disturbance in attention

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Epilepsy

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Facial paresis

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Headache

5 (10.6)

9 (18.4)

5 (10.9)

2 (12.5)

0 (0.0)

16 (14.3)

5 (8.2)

Migraine

1 (2.1)

1 (2.0)

1 (2.2)

1 (6.3)

1 (6.7)

3 (2.7)

2 (3.3)

Movement disorder

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Nervous system disorder

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Paraesthesia

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.3)

0 (0.0)

1 (0.9)

0 (0.0)

Petit mal epilepsy

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Psychomotor hyperactivity

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Syncope

2 (4.3)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

3 (2.7)

0 (0.0)

Psychiatric disorders

Aggression

3 (6.4)

3 (6.1)

0 (0.0)

0 (0.0)

0 (0.0)

6 (5.4)

0 (0.0)

Apathy

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Attention deficit/hyperactivity disorder

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Depressed mood

1 (2.1)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

2 (1.8)

0 (0.0)

Depression

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Dissociative identity disorder

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Eating disorder

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Elevated mood

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Euphoric mood

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Impulse-control disorder

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Irritability

2 (4.3)

2 (4.1)

0 (0.0)

0 (0.0)

0 (0.0)

4 (3.6)

0 (0.0)

Mental disorder

1 (2.1)

0 (0.0)

2 (4.3)

0 (0.0)

0 (0.0)

1 (0.9)

2 (3.3)

Mood altered

3 (6.4)

7 (14.3)

0 (0.0)

2 (12.5)

0 (0.0)

12 (10.7)

0 (0.0)

Mood swings

3 (6.4)

3 (6.1)

1 (2.2)

0 (0.0)

0 (0.0)

6 (5.4)

1 (1.6)

Personality change

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

School refusal

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Sleep disorder

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Social phobia

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Stress symptoms

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Renal and urinary disorders

Calculus bladder

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Reproductive system and breast disorders

Dysmenorrhoea

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.7)

0 (0.0)

1 (1.6)

Gynaecomastia

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Hydrocele

0 (0.0)

1 (2.0)

1 (2.2)

0 (0.0)

0 (0.0)

1 (0.9)

1 (1.6)

Menorrhagia

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Phimosis

1 (2.1)

0 (0.0)

0 (0.0)

1 (6.3)

0 (0.0)

2 (1.8)

0 (0.0)

Testicular torsion

0 (0.0)

1 (2.0)

0 (0.0)

1 (6.3)

0 (0.0)

2 (1.8)

0 (0.0)

Respiratory, thoracic and mediastinal disorders

Asthma

1 (2.1)

3 (6.1)

2 (4.3)

1 (6.3)

0 (0.0)

5 (4.5)

2 (3.3)

Cough

2 (4.3)

2 (4.1)

1 (2.2)

1 (6.3)

0 (0.0)

5 (4.5)

1 (1.6)

Dyspnoea

1 (2.1)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

1 (0.9)

1 (1.6)

Nasal congestion

1 (2.1)

2 (4.1)

0 (0.0)

0 (0.0)

0 (0.0)

3 (2.7)

0 (0.0)

Pharyngolaryngeal pain

1 (2.1)

5 (10.2)

2 (4.3)

0 (0.0)

0 (0.0)

6 (5.4)

2 (3.3)

Rhinitis allergic

1 (2.1)

3 (6.1)

0 (0.0)

0 (0.0)

0 (0.0)

4 (3.6)

0 (0.0)

Skin and subcutaneous tissue disorders

Cafe au lait spots

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Dermal cyst

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Dermatitis allergic

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.3)

0 (0.0)

1 (0.9)

0 (0.0)

Eczema

2 (4.3)

1 (2.0)

1 (2.2)

0 (0.0)

0 (0.0)

3 (2.7)

1 (1.6)

Hyperhidrosis

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Ingrowing nail

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Pigmentation disorder

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.3)

0 (0.0)

1 (0.9)

0 (0.0)

Prurigo

1 (2.1)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

1 (0.9)

1 (1.6)

Psoriasis

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Skin disorder

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Urticaria

1 (2.1)

0 (0.0)

2 (4.3)

0 (0.0)

0 (0.0)

1 (0.9)

2 (3.3)

Social circumstances

Corrective lens user

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Death of parent

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Death of relative

1 (2.1)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

2 (1.8)

0 (0.0)

Death of sibling

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Divorced parents

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (6.7)

0 (0.0)

1 (1.6)

Physical assault

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Smoker

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Social problem

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Surgical and medical procedures

Appendicectomy

1 (2.1)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

2 (1.8)

0 (0.0)

Brain tumour operation

0 (0.0)

0 (0.0)

1 (2.2)

0 (0.0)

0 (0.0)

0 (0.0)

1 (1.6)

Ear tube insertion

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Hernia repair

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Meniscus operation

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Skin neoplasm excision

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Surgery

1 (2.1)

0 (0.0)

1 (2.2)

1 (6.3)

0 (0.0)

2 (1.8)

1 (1.6)

Tonsillectomy

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Tooth extraction

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Vascular disorders

Hypertension

0 (0.0)

1 (2.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Hypotension

1 (2.1)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

1 (0.9)

0 (0.0)

Table 8: Study TRN 88-080: Treatment-Related Adverse Events Based on Probable, Possible, Not Assessable, and Unknown Definition and Reported in ≥2% of Genotropin Treated Subjects
a
Includes all Genotropin Treated Subjects in the Safety Analysis Population.
b

Includes all Untreated Controls in the Safety Analysis Population.

c
Consists of: ankle fracture (n = 1 Genotropin), clavicle fracture (n = 1 Genotropin), radius fracture (n = 1 Genotropin), tibia fracture
(n = 2 Genotropin).

Adverse Event

Genotropina

0.033 and 0.067 mg/kg/day

N = 112

Untreated Controlsb

N = 61

Prepubertal

Pubertal

0.033 mg/kg/day

N = 47

0.067 mg/kg/day

N = 49

Untreated Controls

N = 46

0.067 mg/kg/day

N = 16

Untreated Controls

N = 15

n

%

N

%

N

%

n

%

N

%

N

%

n

%

Upper respiratory infection

15

13.4

2

3.3

8

17.0

6

12.2

2

4.3

1

6.3

0

0.0

Increased appetite

14

12.5

0

0.0

6

12.8

5

10.2

0

0.0

3

18.8

0

0.0

Mood altered

11

9.8

0

0.0

3

6.4

6

12.2

0

0.0

2

12.5

0

0.0

Headache

10

8.9

1

1.6

5

10.6

4

8.2

1

2.2

1

6.3

0

0.0

Influenza

9

8.0

0

0.0

5

10.6

3

6.1

0

0.0

1

6.3

0

0.0

Gastroenteritis

6

5.4

0

0.0

3

6.4

3

6.1

0

0.0

0

0.0

0

0.0

Nasopharyngitis

6

5.4

1

1.6

4

8.5

2

4.1

1

2.2

0

0.0

0

0.0

Aggression

5

4.5

0

0.0

3

6.4

2

4.1

0

0.0

0

0.0

0

0.0

Fracturec

4

3.6

0

0.0

2

4.2

2

4.1

0

0.0

0

0.0

0

0.0

Pharyngolaryngeal pain

4

3.6

1

1.6

1

2.1

3

6.1

1

2.2

0

0.0

0

0.0

Rhinitis allergic

4

3.6

0

0.0

1

2.1

3

6.1

0

0.0

0

0.0

0

0.0

Mood swings

4

3.6

1

1.6

3

6.4

1

2.0

1

2.2

0

0.0

0

0.0

Ear infection

3

2.7

0

0.0

1

2.1

2

4.1

0

0.0

0

0.0

0

0.0

Tonsillitis

3

2.7

2

3.3

0

0.0

2

4.1

2

4.3

1

6.3

0

0.0

Cough

3

2.7

1

1.6

1

2.1

2

4.1

1

2.2

0

0.0

0

0.0

Study 88-080: Adverse Events Leading to Termination of Treatment

Clinical trial adverse drug reactions that lead to treatment termination are listed below:
Dissociative identity disorder, pituitary cyst, mood swings and irritability.

Table 9: Study CTN 89-050: Incidence (%) of Treatment-Emergent Adverse Events Reported in ≥ 1% of Patients

Body system / Preferred Term

Genotropin

0.047 mg/kg/day

N = 18

Control group

N = 19

n

%

N

%

ENDOCRINE DISORDERS

Hypothyroidism

2

11.1

0

0.0

Infection

3

16.7

1

5.3

EYE DISORDERS

Hypermetropia

1

5.6

0

0.0

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

Influenza like illness

2

11.1

0

0.0

Injection site rash

1

5.6

0

0.0

Pyrexia

1

5.6

0

0.0

INVESTIGATIONS

Increased alanine aminotransferase

1

5.6

0

0.0

Increased aspartate aminotransferase

1

5.6

0

0.0

Increased blood insulin

1

5.6

0

0.0

Decreased blood thyroid stimulating hormone

1

5.6

0

0.0

Increased blood thyroid stimulating hormone

1

5.6

0

0.0

Increased tri-iodothyronine

1

5.6

0

0.0

Increased blood triglycerides

1

5.6

0

0.0

Eosinophil percentage increased

2

11.1

0

0.0

Decreased oestradiol

1

5.6

0

0.0

METABOLISM AND NUTRITION DISORDERS

Impaired glucose tolerance

1

5.6

0

0.0

Trace element deficiency

1

5.6

0

0.0

EAR AND LABYRINTH DISORDERS

Middle ear effusion

1

5.6

0

0.0

GASTROINTESTINAL DISORDERS

Diarrhoea

1

5.6

1

5.3

Nausea

1

5.6

0

0.0

Umbilical hernia

1

5.6

0

0.0

Vomiting

2

11.1

1

5.3

INFECTIONS AND INFESTATIONS

Acute tonsillitis

4

22.2

0

0.0

Bronchitis

3

16.7

3

15.8

Ear infection

1

5.6

0

0.0

Febrile infection

2

11.1

1

5.3

Gastroenteritis

2

11.1

1

5.3

Measles

0

0.0

1

5.3

Nasopharyngitis

2

11.1

0

0.0

Otitis media

1

5.6

1

5.3

Otitis media acute

0

0.0

1

5.3

Rhinitis

2

11.1

0

0.0

Rubella

1

5.6

0

0.0

Scarlet fever

1

5.6

1

5.3

Sinusitis

1

5.6

0

0.0

Skin infection

1

5.6

0

0.0

Tonsillitis

3

16.7

0

0.0

INFECTIONS AND INFESTATIONS

Upper respiratory tract infection

2

11.1

1

5.3

Varicella

0

0.0

1

5.3

Viral infection

2

11.1

0

0.0

Viral upper respiratory tract infection

0

0.0

1

5.3

INJURY, POISONING AND PROCEDURAL COMPLICATIONS

Arthropod bite

1

5.6

0

0.0

Concussion

1

5.6

0

0.0

Fall

1

5.6

0

0.0

Foot fracture

1

5.6

0

0.0

Skin injury

1

5.6

0

0.0

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

Arthralgia

1

5.6

0

0.0

NERVOUS SYSTEM DISORDERS

Disturbance in attention

1

5.6

0

0.0

Dizziness

1

5.6

0

0.0

Headache

4

22.2

0

0.0

Mental impairment

1

5.6

0

0.0

Petit mal epilepsy

1

5.6

0

0.0

RENAL AND URINARY DISORDERS

Leukocyturia

1

5.6

0

0.0

REPRODUCTIVE SYSTEM AND BREAST DISORDERS

Balanitis

0

0.0

1

5.3

Breast induration

1

5.6

0

0.0

Breast swelling

1

5.6

0

0.0

Gynaecomastia

1

5.6

0

0.0

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

Asthma

0

0.0

1

5.3

Cough

1

5.6

0

0.0

Pharyngolaryngeal pain

1

5.6

0

0.0

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

Dermatitis allergic

1

5.6

0

0.0

Dermatitis atopic

1

5.6

0

0.0

Eczema

1

5.6

0

0.0

Hyperhidrosis

1

5.6

0

0.0

Neurodermatitis

1

5.6

1

5.3

Pruritus

1

5.6

0

0.0

Psoriasis

1

5.6

0

0.0

SURGICAL AND MEDICAL PROCEDURES

Adenoidectomy

0

0.0

1

5.3

Adenotonsillectomy

0

0.0

1

5.3

Myringotomy

0

0.0

1

5.3

Nasal polypectomy

0

0.0

1

5.3

Umbilical hernia repair

1

5.6

0

0.0

Clinical Trials in children with Idiopathic Short Stature
In ISS studies, the most frequently encountered respiratory adverse events, seen in ≥5% of subjects, included infections and infestations (upper respiratory tract infections, influenza, tonsillitis, nasopharyngitis).

In the pivotal study, eight of the 15 subjects with upper respiratory infection were in the lower dose Genotropin treatment group (0.033 mg/kg/day; prepubertal) and seven received 0.067 mg/kg/day (six prepubertal and one pubertal).

Influenza occurred in four subjects that received 0.067 mg/kg/day (three prepubertal and one pubertal) and in five subjects that received 0.033 mg/kg/day. Nasopharyngitis was also reported only in prepubertal Genotropin treated subjects (four at 0.033 mg/kg/day and two at 0.067 mg/kg/day).

Adults

Clinical Trials in adults with GHD
Recurrence of pituitary adenoma and of craniopharyngioma were reported in one case each. In these patient categories tumour recurrence is not uncommon, but it is as yet not possible to compare rates between patients on GH treatment and those without such substitution.

In clinical trials with GENOTROPIN in 1,145 GHD adults, the majority of the adverse events consisted of mild to moderate symptoms of fluid retention, including peripheral swelling, arthralgia, pain and stiffness of the extremities, peripheral edema, myalgia, paresthesia, and hypoesthesia. These events were reported early during therapy, and tended to be transient and/or responsive to dosage reduction.

Table 10 displays the adverse events reported by 5% or more of adult GHD patients in clinical trials after various durations of treatment with GENOTROPIN. Also presented are the corresponding incidence rates of these adverse events in placebo patients during the 6-month double-blind portion of the clinical trials.

TABLE 10: ADVERSE EVENTS REPORTED BY ≥ 5% OF 1,145 ADULT GHD PATIENTS DURING CLINICAL TRIALS OF GENOTROPIN AND PLACEBO, GROUPED BY DURATION OF TREATMENT
 

* Increased significantly when compared to placebo, P≤.025: Fisher´s Exact Test (one-sided)

 

n = number of patients receiving treatment during the indicated period.

 
% = percentage of patients who reported the event during the indicated period.
 

Double Blind Phase

Open Label Phase

GENOTROPIN

Adverse Event

Placebo

0–6 mo.

n = 572

% Patients

GENOTROPIN

0–6 mo.

n = 573

% Patients

6–12 mo.

n = 504

% Patients

12–18 mo.

n = 63

% Patients

18–24 mo.

n = 60

% Patients

Swelling, peripheral

5.1

17.5*

5.6

0

1.7

Arthralgia

4.2

17.3*

6.9

6.3

3.3

Upper respiratory infection

14.5

15.5

13.1

15.9

13.3

Pain, extremities

5.9

14.7*

6.7

1.6

3.3

Edema, peripheral

2.6

10.8*

3.0

0

0

Paresthesia

1.9

9.6*

2.2

3.2

0

Headache

7.7

9.9

6.2

0

0

Stiffness of extremities

1.6

7.9*

2.4

1.6

0

Fatigue

3.8

5.8

4.6

6.3

1.7

Myalgia

1.6

4.9*

2.0

4.8

6.7

Back pain

4.4

2.8

3.4

4.8

5.0

Post-Trial Extension Studies in Adults
In expanded post-trial extension studies, diabetes mellitus developed in 12 of 3,031 patients (0.4%) during treatment with GENOTROPIN. All 12 patients had predisposing factors, e.g., elevated glycosylated hemoglobin levels and/or marked obesity, prior to receiving GENOTROPIN. Of the 3,031 patients receiving GENOTROPIN, 61 (2%) developed symptoms of carpal tunnel syndrome, which lessened after dosage reduction or treatment interruption (52) or surgery (9). Other adverse events that have been reported include generalized edema and hypoesthesia.

Post-Market Adverse Drug Reactions

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 (see Clinical Trials Adverse Reactions) in children and adults.

Leukemia has been reported in a small number of GHD 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 and Warnings and Precautions)].

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

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with post­ marketing use of somatropin products (see CONTRAINDICATIONS and WARNINGS and PRECAUTIONS – Immune).

New-onset type 2 diabetes mellitus has been reported.

Slipped capital femoral epiphysis and Legg-Calve-Perthes disease have been reported in children treated with growth hormone. No causal relationship has been demonstrated with somatropin.

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