Hilac

Infants, children and adolescents

- Growth disturbance due to insufficient secretion of growth hormone (growth hormone deficiency, GHD).

- Growth disturbance associated with Turner syndrome.

- Growth disturbance associated with chronic renal insufficiency.

- Growth disturbance (current height standard deviation score (SDS) < -2.5 and parental adjusted height SDS < -1) in short children/adolescents born small for gestational age (SGA), with a birth weight and/or length below -2 standard deviation (SD), who failed to show catch-up growth (height velocity (HV) SDS < 0 during the last year) by 4 years of age or later.

- Prader-Willi syndrome (PWS), for improvement of growth and body composition. The diagnosis of PWS should be confirmed by appropriate genetic testing.

Adults

- Replacement therapy in adults with pronounced growth hormone deficiency.

- Adult onset: Patients who have severe growth hormone deficiency associated with multiple hormone deficiencies as a result of known hypothalamic or pituitary pathology, and who have at least one known deficiency of a pituitary hormone not being prolactin. These patients should undergo an appropriate dynamic test in order to diagnose or exclude a growth hormone deficiency.

- Childhood onset: Patients who were growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes. Patients with childhood onset GHD should be re-evaluated for growth hormone secretory capacity after completion of longitudinal growth. In patients with a high likelihood for persistent GHD, i.e. a congenital cause or GHD secondary to a hypothalamic-pituitary disease or insult, an insulin-like growth factor-I (IGF-I) SDS < -2 off growth hormone treatment for at least 4 weeks should be considered sufficient evidence of profound GHD.

All other patients will require IGF-I assay and one growth hormone stimulation test.

Hilac is indicated for:

- the long-term treatment of children who have growth failure due to inadequate secretion of growth hormone

- the long-term treatment of growth retardation due to Turner's Syndrome confirmed by chromosome analysis.

Pediatric Patients:

Hilac (somatropin injection) ® is indicated for the treatment of pediatric patients who have growth failure due to inadequate secretion of endogenous growth hormone.

Hilac (somatropin injection) ® is indicated for the treatment of growth failure associated with Turner syndrome in patients who have open epiphyses.

Adult Patients:

Hilac (somatropin injection) ® is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who meet either of the following criteria:

1. Adult Onset: Patients who have growth hormone deficiency, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or
2. Childhood Onset: Patients who were growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.

In general, confirmation of the diagnosis of adult growth hormone deficiency in both groups usually requires an appropriate growth hormone stimulation test. However, confirmatory growth hormone stimulation testing may not be required in patients with congenital/genetic growth hormone deficiency or multiple pituitary hormone deficiencies due to organic disease.

Children:

Growth failure due to growth hormone deficiency (GHD)

Growth failure in girls due to gonadal dysgenesis (Turner syndrome)

Growth retardation in prepubertal children due to chronic renal disease

Growth disturbance (current height SDS < -2.5 and parental adjusted height SDS < -1) in short children born small for gestational age (SGA), with a birth weight and/or length below -2 SD, who failed to show catch-up growth (HV SDS < 0 during the last year) by 4 years of age or later.

Adults:

Childhood onset growth hormone deficiency:

Patients with childhood onset GHD should be re-evaluated for growth hormone secretory capacity after growth completion. Testing is not required for those with more than three pituitary hormone deficits, with severe GHD due to a defined genetic cause, due to structural hypothalamic pituitary abnormalities, due to central nervous system tumours or due to high-dose cranial irradiation, or with GHD secondary to a pituitary/hypothalamic disease or insult, if measurements of serum insulin-like growth factor-I (IGF-I) is < -2 SDS after at least four weeks off growth hormone treatment.

In all other patients an IGF-I measurement and one growth hormone stimulation test is required.

Adult onset growth hormone deficiency:

Pronounced GHD in known hypothalamic-pituitary disease, cranial irradiation, and traumatic brain injury. GHD should be associated with one other deficient axis, other than prolactin. GHD should be demonstrated by one provocative test after institution of adequate replacement therapy for any other deficient axis.

In adults, the insulin tolerance test is the provocative test of choice. When the insulin tolerance test is contraindicated, alternative provocative tests must be used. The combined arginine-growth hormone releasing hormone is recommended. An arginine or glucagon test may also be considered; however these tests have less established diagnostic value than the insulin tolerance test.

Diagnosis and therapy with somatropin should be initiated and monitored by physicians who are appropriately qualified and experienced in the diagnosis and management of patients with growth disorders.

Posology

Paediatric population

The posology and administration schedule should be individualised.

Growth disturbance due to insufficient secretion of growth hormone in paediatric patients

Generally a dose of 0.025 - 0.035 mg/kg body weight per day or 0.7 - 1.0 mg/m² body surface area per day is recommended. Even higher doses have been used.

Where childhood onset GHD persists into adolescence, treatment should be continued to achieve full somatic development (e.g. body composition, bone mass). For monitoring, the attainment of a normal peak bone mass defined as a T score > -1 (i.e. standardized to average adult peak bone mass measured by dual energy X-ray absorptiometry taking into account sex and ethnicity) is one of the therapeutic objectives during the transition period. For guidance on dosing see adult section below.

Prader-Willi syndrome, for improvement of growth and body composition in paediatric patients

Generally a dose of 0.035 mg/kg body weight per day or 1.0 mg/m² body surface area per day is recommended. Daily doses of 2.7 mg should not be exceeded. Treatment should not be used in paediatric patients with a growth velocity less than 1 cm per year and near closure of epiphyses.

Growth disturbance due to Turner syndrome

A dose of 0.045 - 0.050 mg/kg body weight per day or 1.4 mg/m² body surface area per day is recommended.

Growth disturbance in chronic renal insufficiency

A dose of 0.045 - 0.050 mg/kg body weight per day (1.4 mg/m² body surface area per day) is recommended. Higher doses may be needed if growth velocity is too low. A dose correction can be needed after six months of treatment.

Growth disturbance in short children/adolescents born small for gestational age (SGA)

A dose of 0.035 mg/kg body weight per day (1 mg/m² body surface area per day) is usually recommended until final height is reached. Treatment should be discontinued after the first year of treatment if the height velocity SDS is below + 1. Treatment should be discontinued if height velocity is < 2 cm/year and, if confirmation is required, bone age is > 14 years (girls) or > 16 years (boys), corresponding to closure of the epiphyseal growth plates.

Dose recommendations in paediatric patients

Growth hormone deficient adult patients

In patients who continue growth hormone therapy after childhood GHD, the recommended dose to restart is 0.2 - 0.5 mg per day. The dose should be gradually increased or decreased according to individual patient requirements as determined by the IGF-I concentration.

In adults with adult-onset GHD, therapy should start with a low dose, 0.15 - 0.3 mg per day. The dose should be gradually increased according to individual patient requirements as determined by the IGF-I concentration.

In both cases treatment goal should be insulin-like growth factor (IGF-I) concentrations within 2 SDS from the age corrected mean. Patients with normal IGF-I concentrations at the start of the treatment should be administered growth hormone up to an IGF-I level into the upper range of normal, not exceeding the 2 SDS. Clinical response and side effects may also be used as guidance for dose titration. It is recognized that there are patients with GHD who do not normalize IGF-I levels despite a good clinical response, and thus do not require dose escalation. The maintenance dose rarely exceeds 1.0 mg per day. Women may require higher doses than men, with men showing an increasing IGF-I sensitivity over time. This means that there is a risk that women, especially those on oral oestrogen replacement are under-treated while men are over-treated. The accuracy of the growth hormone dose should therefore be controlled every 6 months. As normal physiological growth hormone production decreases with age, dose requirements may be reduced.

Special populations

Elderly

In patients above 60 years, therapy should start with a dose of 0.1 - 0.2 mg per day and should be slowly increased according to individual patient requirements. The minimum effective dose should be used. The maintenance dose in these patients seldom exceeds 0.5 mg per day.

Method of administration

The injection should be given subcutaneously and the site varied to prevent lipoatrophy.

Hilac therapy should be used only under the supervision of a qualified physician experienced in the management of patients with growth hormone deficiency.

The dosage of administration of Hilac should be individualised for each patient.

The duration of treatment, usually a period of several years will depend on maximum achievable therapeutic benefit.

The subcutaneous administration of growth hormone may lead to loss or increase of adipose tissue at the injection site. Therefore, injection sites should be alternated.

Growth Hormone Deficiency

Generally a dose of 0.17 - 0.23 mg/kg bodyweight (approximating to 4.9 mg/m² - 6.9 mg/m² body surface area) per week divided into 6 - 7 s.c. injections is recommended (corresponding to a daily injection of 0.02 - 0.03 mg/kg bodyweight or 0.7 - 1.0 mg/m² body surface area).

The total weekly dose of 0.27 mg/kg or 8 mg/m² body surface area should not be exceeded (corresponding to daily injections of up to about 0.04 mg/kg).

Turner's Syndrome

Administration

The required dose of Hilac 10 mg/ml is administered with a ZOMAJET VISION X needle-free device or with an ordinary syringe.

Specific instructions for the use of the ZOMAJET VISION X device are given in a booklet supplied with the device.

Dosage

Pediatric Patients

The Hilac (somatropin injection) ® dosage and administration schedule should be individualized for each patient. Therapy should not be continued if epiphyseal fusion has occurred. Response to somatropin therapy in pediatric patients tends to decrease with time. However, failure to increase growth rate, particularly during the first year of therapy, should prompt careful assessment of compliance, a determination as to whether anti-rhGH neutralizing antibodies have developed, and an evaluation to rule out other causes of growth failure including hypothyroidism, under-nutrition, advanced bone age.

Pediatric Growth Hormone Deficiency (GHD)

The amount administered during the pivotal study described herein was 0.23 mg/kg of body weight/week (0.033 mg/kg/day). Generally, the recommended dosage is 0.17 - 0.3 mg/kg of body weight/week. The weekly dose should be divided into equal amounts given either daily or 6 days a week by subcutaneous injection.

Children with Turner Syndrome

The amount administered during the pivotal study utilizing the 5 mg (15 IU) formulation of Hilac (somatropin injection) ® described herein was 0.37 mg/kg of body weight/week (0.053 mg/kg/day). Generally, the recommended dose is up to 0.375 mg/kg of body weight/week. The weekly dose should be divided into equal amounts given either daily or 6 days a week by subcutaneous injection.

Adult Patients

Adult Growth Hormone Deficiency (GHD)

Based on the pivotal study described herein, the recommended dosage at the start of therapy is 0.33 mg/day (or 0.1 mL of reconstituted solution) (equivalent to 0.005 mg/kg/day in a 66 kg adult) (6 days/week) given as a subcutaneous injection. The dosage may be increased according to individual patient requirements to a maximum of 0.66 mg/day (equivalent to 0.010 mg/kg/day in a 66 kg adult) (6 days/week) after 4 weeks. Clinical response, side effects, and determination of age- and gender-adjusted serum IGF-I levels may be used as guidance in dose titration.

Alternatively, taking into account recent literature, a starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) may be used. This dose can be increased gradually every 1-2 months by increments of approximately 0.1-0.2 mg/day, according to individual patient requirements based on the clinical response and serum IGF-I concentrations. During therapy, the dose should be decreased if required by the occurrence of adverse events and/or serum IGF-I levels above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person.

A lower starting dose and smaller dose increments should be considered for older patients, who are more prone to the adverse effects of somatropin than younger individuals. In addition, obese individuals are more likely to manifest adverse effects when treated with a weight-based regimen. In order to reach the defined treatment goal, estrogen-replete women may need higher doses than men. Oral estrogen administration may increase the dose requirements in women.

Administration

The thighs are recommended as the preferred sites of injection and the injection site should be rotated to avoid lipoatrophy.

After determining the appropriate patient dose, each vial of Hilac (somatropin injection) ® should be reconstituted using the accompanying diluent. For use in patients with a known sensitivity to metacresol, Hilac (somatropin injection) ® should not be reconstituted with the supplied diluent, but instead with water for injection. The diluent supplied in the prefilled syringe or water for injection should be injected entirely into the vial of Hilac (somatropin injection) ® by aiming the stream of liquid against the glass wall. Following reconstitution, the vial should be swirled with a GENTLE rotary motion until the contents are completely dissolved, providing a 3.33 mg/mL solution of somatropin. DO NOT SHAKE. If the solution is shaken, the solution may become cloudy or develop particulate matter. The Hilac (somatropin injection) ® solution should be clear immediately after reconstitution. DO NOT INJECT the Hilac (somatropin injection) ® solution if it is cloudy or contains particulate matter immediately after reconstitution or after refrigeration. These kinds of solutions should be discarded.

If reconstituted with water for injection, do not store but discard after use, since it lacks preservative. If reconstituted with the supplied diluent, which contains preservative, label the vial with the date on which you prepared the solution and store in a refrigerator.

It is recommended that the volume of reconstituted Hilac (somatropin injection) ® solution required to provide the prescribed dose of Hilac (somatropin injection) ® should be withdrawn from the reconstituted solution and administered using sterile, disposable syringes and needles (a new disposable syringe and needle should be used for every injection).

The disposable syringes should be of small enough volume that the prescribed dose can be withdrawn from the vial with reasonable accuracy, and the needle should be fine enough to ensure patient comfort.

In order to prevent contamination of the contents of the reconstituted vial of Hilac (somatropin injection) ® by repeated needle insertions, ensure that before every injection, the septum of the vial (e.g., the rubber vial stopper) is wiped with an antiseptic solution before puncturing it with the needle, and after every injection the rubber vial stopper is also wiped with an antiseptic solution. Return the multiuse vial, reconstituted with supplied diluent, to the refrigerator after each use.

Stability and Storage

Before Reconstitution

Hilac (somatropin injection) ® powder or diluent should be stored under refrigeration (2°C-8°C/36°F-46°F). Do not freeze. Expiration dates are stated on the labels.

The product should be refrigerated prior to dispensing, but may be stored at or below 25°C (77°F) for up to three months after dispensing.

After Reconstitution With The Diluent Provided

When reconstituted with the diluent provided, the reconstituted solution may be stored under refrigeration (2°C-8°C/36°F-46°F) for up to 21 days. Avoid freezing reconstituted vials of Hilac (somatropin injection) ®.

If Reconstituted With Water For Injection

When reconstituted with sterile Water for Injection, use only one dose per Hilac (somatropin injection) ® vial and discard the unused portion if not needed immediately.

The use of Sterile Water for Injection without preservative should be reserved only for patients who have an allergy or sensitivity to metacresol or when the supplied diluent is unavailable.

Norditropin should only be prescribed by doctors with special knowledge of the therapeutic indication of use.

Posology

The dosage is individual and must always be adjusted in accordance with the individual's clinical and biochemical response to therapy.

Generally recommended dosages:

Paediatric population:

Growth hormone insufficiency

0.025-0.035 mg/kg/day or 0.7-1.0 mg/m²/day

When GHD persists after growth completion, growth hormone treatment should be continued to achieve full somatic adult development including lean body mass and bone mineral accrual (for guidance on dosing, see Replacement therapy in adults).

Turner syndrome

0.045-0.067 mg/kg/day or 1.3-2.0 mg/m²/day

Chronic renal disease

0.050 mg/kg/day or 1.4 mg/m²/day

Small for Gestational Age

0.035 mg/kg/day or 1.0 mg/m²/day

A dose of 0.035 mg/kg/day is usually recommended until final height is reached. Treatment should be discontinued after the first year of treatment, if the height velocity SDS is below +1.

Treatment should be discontinued if height velocity is < 2 cm/year and, if confirmation is required, bone age is > 14 years (girls) or > 16 years (boys), corresponding to closure of the epiphyseal growth plates.

Adult population:

Replacement therapy in adults

The dosage must be adjusted to the need of the individual patient.

In patients with childhood onset GHD, the recommended dose to restart is 0.2-0.5 mg/day with subsequent dose adjustment on the basis of IGF-I concentration determination.

In patients with adult onset GHD, it is recommended to start treatment with a low dose: 0.1- 0.3 mg/day. It is recommended to increase the dosage gradually at monthly intervals based on the clinical response and the patient's experience of adverse events. Serum IGF-I can be used as guidance for the dose titration. Women may require higher doses than men, with men showing an increasing IGF-I sensitivity over time. This means that there is a risk that women, especially those on oral oestrogen replacement are under-treated while men are over-treated.

Dose requirements decline with age. Maintenance dosages vary considerably from person to person, but seldom exceed 1.0 mg/day.

Method of administration

Generally, daily subcutaneous administration in the evening is recommended. The injection site should be varied to prevent lipoatrophy.

Somatropin must not be used when there is any evidence of activity of a tumour. Intracranial tumours must be inactive and anti-tumour therapy must be completed prior to starting GH therapy. Treatment should be discontinued if there is evidence of tumour growth.

Somatropin must not be used for growth promotion in children with closed epiphyses.

Patients with acute critical illness suffering complications following open heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure or similar conditions must not be treated with somatropin.

Hypersensitivity to somatropin or to any of the excipients.

Somatropin must not be used when there is any evidence of activity of a tumour. Intracranial tumours must be inactive and antitumour therapy must be completed prior to starting GH therapy. Treatment should be discontinued if there is evidence of tumour growth.

Somatropin should not be used for growth promotion in children with closed epiphyses.

Patients with acute critical illness suffering complications following open heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure or similar conditions should not be treated with somatropin.

In children with chronic renal disease, treatment with somatropin should be discontinued at renal transplantation.

Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses.

Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.

In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity. Since growth hormone deficiency may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor.

Somatropin should not be used to treat patients with acute critical illness due to complications following open heart surgery, abdominal surgery, or multiple accidental trauma, or those with acute respiratory failure. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (41.9% versus 19.3%) among somatropin treated patients (doses 5.3-8 mg/day) compared to those receiving placebo (see WARNINGS).

Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment (see WARNINGS). Unless patients with Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, Hilac (somatropin injection) ® is not indicated for the long-term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.

Somatropin must not be used when there is any evidence of activity of a tumour. Intracranial tumours must be inactive and antitumour therapy must be completed prior to starting growth hormone (GH) therapy. Treatment should be discontinued if there is evidence of tumour growth.

Somatropin should not be used for longitudinal growth promotion in children with closed epiphyses.

Patients with acute critical illness suffering complications following open heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure, or similar conditions should not be treated with somatropin.

In children with chronic renal disease, treatment with Hilac and Norditropin NordiFlex should be discontinued at renal transplantation.

The maximum recommended daily dose should not be exceeded.

Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. In patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required. In addition, patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses, following initiation of somatropin treatment.

Use with oral oestrogen therapy

If a woman taking somatropin begins oral oestrogen therapy, the dose of somatropin may need to be increased to maintain the serum IGF-1 levels within the normal age-appropriate range. Conversely, if a woman on somatropin discontinues oral oestrogen therapy, the dose of somatropin may need to be reduced to avoid excess of growth hormone and/or side effects.

Insulin sensitivity

Somatropin may reduce insulin sensitivity. For patients with diabetes mellitus, the insulin dose may require adjustment after somatropin therapy is instituted. Patients with diabetes, glucose intolerance, or additional risk factors for diabetes should be monitored closely during somatropin therapy.

Thyroid function

Growth hormone increases the extrathyroidal conversion of T4 to T3 which may result in a reduction in serum T4 and an increase in serum T3 concentrations. Whereas the peripheral thyroid hormone levels have remained within the reference ranges for healthy subjects, hypothyroidism theoretically may develop in subjects with subclinical hypothyroidism. Consequently monitoring of thyroid function should therefore be conducted in all patients. In patients with hypopituitarism on standard replacement therapy, the potential effect of growth hormone treatment on thyroid function must be closely monitored

In growth hormone deficiency, secondary to treatment of malignant disease, it is recommended to pay attention to signs of relapse of the malignancy. In childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with somatropin after their first neoplasm. Intracranial tumours, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm, were the most common of these second neoplasms.

In patients with endocrine disorders, including growth hormone deficiency, slipped epiphyses of the hip may occur more frequently than in the general population. Patients limping during treatment with somatropin should be examined clinically.

Benign intracranial hypertension

In case of severe or recurrent headache, visual problems, nausea and/or vomiting, a fundoscopy for papilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranial hypertension should be considered and, if appropriate, the growth hormone treatment should be discontinued. At present there is insufficient evidence to give specific advice on the continuation of growth hormone treatment in patients with resolved intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary.

Leukaemia

Leukaemia has been reported in a small number of growth hormone deficiency patients, some of whom have been treated with somatropin. However, there is no evidence that leukaemia incidence is increased in growth hormone recipients without predisposition factors.

Antibodies

A small percentage of patients may develop antibodies to Omnitrope. Omnitrope has given rise to the formation of antibodies in approximately 1% of patients. The binding capacity of these antibodies is low and there is no effect on growth rate. Testing for antibodies to somatropin should be carried out in any patient with otherwise unexplained lack of response.

Elderly patients

Experience in patients above 80 years is limited. Elderly patients may be more sensitive to the action of Omnitrope, and therefore may be more prone to develop adverse reactions.

Acute critical illness

The effects of somatropin on recovery were studied in two placebo controlled trials involving 522 critically ill adult patients suffering complications following open heart surgery, abdominal surgery, multiple accidental trauma or acute respiratory failure. Mortality was higher in patients treated with 5.3 or 8 mg somatropin daily compared to patients receiving placebo, 42% vs. 19%. Based on this information, these types of patients should not be treated with somatropin. As there is no information available on the safety of growth hormone substitution therapy in acutely critically ill patients, the benefits of continued treatment in this situation should be weighed against the potential risks involved.

In all patients developing other or similar acute critical illness, the possible benefit of treatment with somatropin must be weighed against the potential risk involved.

Paediatric population

Pancreatitis

Although rare, pancreatitis should be considered in somatropin-treated children who develop abdominal pain.

Prader-Willi syndrome

In patients with PWS, treatment should always be in combination with a calorie-restricted diet.

There have been reports of fatalities associated with the use of growth hormone in paediatric patients with PWS who had one or more of the following risk factors: severe obesity (those patients exceeding a weight/height of 200%), history of respiratory impairment or sleep apnoea or unidentified respiratory infection. Patients with PWS and one or more of these risk factors may be at greater risk.

Before initiation of treatment with somatropin patients with PWS should be evaluated for upper airway obstruction, sleep apnoea or respiratory infections should be assessed.

If during the evaluation of upper airway obstruction, pathological findings are observed, the child should be referred to an Ear, nose and throat (ENT) specialist for treatment and resolution of the respiratory disorder prior to initiating growth hormone treatment.

Sleep apnoea should be assessed before onset of growth hormone treatment by recognised methods such as polysomnography or overnight oxymetry, and monitored if sleep apnoea is suspected.

If during treatment with somatropin patients show signs of upper airway obstruction (including onset of or increased snoring), treatment should be interrupted, and a new ENT assessment performed.

All patients with PWS should be evaluated for sleep apnoea and monitored if sleep apnoea is suspected.Patients should be monitored for signs of respiratory infections, which should be diagnosed as early as possible and treated aggressively.

All patients with PWS should have effective weight control before and during growth hormone treatment.

Scoliosis is common in patients with PWS. Scoliosis may progress in any child during rapid growth. Signs of scoliosis should be monitored during treatment.

Experience with prolonged treatment in adults and in patients with PWS is limited.

Small for gestational age

In short children/adolescents born SGA, other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment.

In SGA children/adolescents it is recommended to measure fasting insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g. familial history of diabetes, obesity, severe insulin resistance, acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs, growth hormone should not be administered.

In SGA children/adolescents it is recommended to measure the IGF-I level before start of treatment and twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared to references for age and pubertal status, the IGF-I / IGFBP-3 ratio could be taken into account to consider dose adjustment.

Experience in initiating treatment in SGA patients near onset of puberty is limited. It is therefore not recommended to initiate treatment near onset of puberty. Experience in patients with Silver-Russell syndrome is limited.

Some of the height gain obtained with treating short children/adolescents born SGA with growth hormone may be lost if treatment is stopped before final height is reached.

Chronic renal insufficiency

In chronic renal insufficiency, renal function should be below 50 percent of normal before institution of therapy. To verify growth disturbance, growth should be followed for a year preceding institution of therapy. During this period, conservative treatment for renal insufficiency (which includes control of acidosis, hyperparathyroidism and nutritional status) should have been established and should be maintained during treatment.

The treatment should be discontinued at renal transplantation.

To date, no data on final height in patients with chronic renal insufficiency treated with Omnitrope are available.

Omnitrope 5 mg/1.5 ml solution for injection:

Because of the presence of benzyl alcohol the medicinal product must not be given to premature babies or neonates. It may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

The maximum recommended daily dose should not be exceeded.

Very rare cases of myositis have been observed and may be due to the metacresol used as preservative.). At present, there is insufficient evidence to guide clinical decision making in patients with resolved intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary.

Leukaemia has been reported in a small number of growth hormone deficient patients treated with somatropin as well as in untreated patients. However, there is no evidence that leukaemia incidence is increased in growth hormone recipients without predisposition factors.

As with all somatropin containing products, a small percentage of patients may develop antibodies to somatropin. The binding capacity of these antibodies is low and there is no effect on growth rate. Testing for antibodies to somatropin should be carried out in any patient who fails to respond to therapy.

Growth hormone increases the extrathyroidal conversion of T4 to T3 and may, as such, unmask insipiens hypothyroidism. Monitoring of thyroid function should therefore be conducted in all patients. In patients with hypopituitarism, standard replacement therapy must be closely monitored when somatropin therapy is administered.

Because somatropin may reduce insulin sensitivity, patients should be monitored for evidence of glucose intolerance. For patients with diabetes mellitus, the insuline dose may require adjustment after somatropin containing product therapy is initiated. Patients with diabetes or glucose intolerance should be monitored closely during somatropin therapy. Hilac should also be used with caution in patients with a family history predisposing for the disease.

In patients with growth hormone deficiency secondary to an intra-cranial lesion, frequent monitoring for progression or recurrence of the underlying disease process is advised. In childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with somatropin after their first neoplasm. Intracranial tumours, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm, were the most common of these second neoplasms

Discontinue Hilac therapy if progression or recurrence of the lesion occurs.

In patients with previous malignant diseases special attention should be given to signs and symptoms of relapse.

Scoliosis may progress in any child during rapid growth. Signs of scoliosis should be monitored during somatropin treatment.

Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders. A patient treated with Hilac who develops a limp or complains of hip or knee pain should be evaluated by a physician.

The effects of treatment with growth hormone on recovery were studied in two placebo controlled trials involving 522 critically ill adult patients suffering complications following open heart surgery, abdominal surgery, multiple accidental trauma, or acute respiratory failure.

Mortality was higher (42 % vs. 19 %) among patients treated with growth hormones (doses 5.3 to 8 mg/day) compared to those receiving placebo. Based on this information, such patients should not be treated with growth hormones. As there is no information available on the safety of growth hormone substitution therapy in acutely critically ill patients, the benefits of continued treatment in this situation should be weighed against the potential risks involved.

Experience of local tolerability to administration of Hilac 10 mg/ml with Zomajet Vision X needle-free device has been studied before marketing authorisation in a 12 week study including only Caucasian children.

Although rare, pancreatitis should be considered in somatropin-treated patients, especially children who develop abdominal pain.

WARNINGS

In the case of patients with a known sensitivity to the supplied diluent (metacresol) or, if sensitivity to metacresol becomes apparent after treatment has been initiated, Hilac (somatropin injection) ® should be reconstituted with 1.5 mL Water for Injection and used as a single use vial (see STABILITY AND STORAGE). See CONTRAINDICATIONS for information on increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery, or multiple accidental trauma, or those with acute respiratory failure. The safety of continuing somatropin treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with somatropin in patients experiencing acute critical illnesses should be weighed against the potential risk.

There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females.

Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin. If, during treatment with somatropin, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi syndrome treated with somatropin should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively (see CONTRAINDICATIONS). Unless patients with Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, Hilac (somatropin injection) ® is not indicated for the long-term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.

PRECAUTIONS

General

Therapy with Hilac (somatropin injection) ® should be directed by physicians who are experienced in the diagnosis and management of pediatric patients with growth hormone deficiency and Turner syndrome, or adult patients with either childhood-onset or adult-onset growth hormone deficiency.

Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked during somatropin treatment. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus, such as obesity (including obese patients with Prader-Willi syndrome), Turner syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during somatropin therapy. The doses of antihyperglycemic drugs (i.e., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients.

Patients with preexisting tumors or growth hormone deficiency secondary to an intracranial lesion should be examined routinely for progression or recurrence of the underlying disease process. In pediatric patients, clinical literature has revealed no relationship between somatropin replacement therapy and central nervous system (CNS) tumor recurrence or new extracranial tumors. However, in childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with somatropin after their first neoplasm. Intracranial tumors, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm, were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence.

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with somatropin products. Symptoms usually occur within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with Turner syndrome, chronic renal insufficiency, and Prader-Willi syndrome may be at increased risk for the development of IH.

In patients with hypopituitarism (multiple hormone deficiencies), standard hormonal replacement therapy should be monitored closely when somatropin therapy is administered.

Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in children. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with growth hormone deficiency, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.

Patients should be monitored carefully for any malignant transformation of skin lesions.

When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This can be avoided by rotating the injection site (see DOSAGE AND ADMINISTRATION).

As with any protein, local or systemic allergic reactions may occur. Parents/Patient should be informed that such reactions are possible and that prompt medical attention should be sought if allergic reactions occur.

Pediatric Patients (See PRECAUTIONS, General)

Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including pediatric growth hormone deficiency and Turner syndrome) or in patients undergoing rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated.

Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis. However, somatropin has not been shown to increase the occurrence of scoliosis. Skeletal abnormalities including scoliosis are commonly seen in untreated Turner syndrome patients. Scoliosis is also commonly seen in untreated patients with Prader-Willi syndrome. Physicians should be alert to these abnormalities, which may manifest during somatropin therapy.

Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing disorders (see ADVERSE REACTIONS). Somatropin treatment may increase the occurrence of otitis media in patients with Turner syndrome. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions.

Adult Patients (See PRECAUTIONS, General)

Patients with epiphyseal closure who were treated with somatropin replacement therapy in childhood should be reevaluated according to the criteria in INDICATIONS AND USAGE before continuation of somatropin therapy at the reduced dose level recommended for growth hormone deficient adults. Fluid retention during somatropin replacement therapy in adults may occur. Clinical manifestations of fluid retention are usually transient and dose dependent (see ADVERSE REACTIONS).

Experience with prolonged treatment in adults is limited.

Laboratory Tests

Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-I may increase during somatropin therapy.

Carcinogenicity studies have not been conducted with somatropin.

Somatropin was not genotoxic with and without metabolic activation in the Ames bacterial mutagenicity assay, the in vitro Chinese Hamster Ovary and Chinese Hamster Lung cell chromosomal aberration assay, and the in vivo mouse micronucleus assay.

Male and female rats given SC doses of 1, 3, 10 IU/kg/day of somatropin from premating day 60 and premating day 14 to gestation day 7, respectively, did not show any adverse effect on fertility, mating or early development. This represents systemic exposures 1 to 15 times the human therapeutic levels based on body surface area comparisons.

Pregnancy

Pregnancy Category B. There are no adequate and well controlled studies of Hilac (somatropin injection) ® in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Subcutaneous reproduction studies have been performed with somatropin in rats and rabbits at doses up to 15 and 30 times, respectively, human therapeutic levels based on body surface area comparisons.

In pregnant rats given SC doses of 1, 3, 10 IU/kg/day of somatropin from gestation day 7 and 17 through organogenesis, an increase in embryolethality was observed in all somatropin-treated groups (3.88, 4.85, 4.72 %) compared to control (0.54%), representing systemic exposures 1 to 14 times human therapeutic levels based on body surface area comparisons.

In pregnant rabbits given SC doses of 1, 3, 10 IU/kg/day of somatropin from gestation days 6 and 18 through organogenesis at doses up to 30 times the human dose, no developmental adverse effects were observed.

In perinatal and post-natal studies in rats, somatropin at doses of 1, 3, 10 IU/kg/day given from gestation day 7 to lactation day 21, did not result in adverse effects on gestation, morphogenesis, parturition, lactation or post-natal weight of offspring (the only parameter evaluated), representing systemic exposures 1 to 14 times human therapeutic levels based on body surface area comparisons.

Nursing Mothers

There have been no studies conducted with Hilac (somatropin injection) ® in nursing mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Hilac (somatropin injection) ® is administered to a nursing woman.

Geriatric Use

The safety and effectiveness of Hilac (somatropin injection) ® in patients aged 65 and over has not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of somatropin, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients (see DOSAGE AND ADMINISTRATION).

Children treated with somatropin should be regularly assessed by a specialist in child growth. Somatropin treatment should always be instigated by a physician with special knowledge of growth hormone insufficiency and its treatment. This is true also for the management of Turner syndrome, chronic renal disease, and SGA. Data of final adult height following the use of Norditropin for children with chronic renal disease are not available.

The maximum recommended daily dose should not be exceeded.

The stimulation of longitudinal growth in children can only be expected until epiphyseal closure.

Children

Treatment of growth hormone deficiency in patients with Prader-Willi syndrome

There have been reports of sudden death after initiating somatropin therapy in patients with Prader- Willi syndrome, who had one or more of the following risk factors: Severe obesity, history of upper airway obstruction or sleep apnoea, or unidentified respiratory infection.

Small for Gestational Age

In short children born SGA other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment.

Experience in initiating treatment in SGA patients near onset of puberty is limited. It is therefore not recommended to initiate treatment near onset of puberty.

Experience with patients with Silver-Russell syndrome is limited.

Turner syndrome

Monitoring of growth of hands and feet in Turner syndrome patients treated with somatropin is recommended and a dose reduction to the lower part of the dose range should be considered if increased growth is observed.

Girls with Turner syndrome generally have an increased risk of otitis media, which is why otological evaluation is recommended on at least an annual basis.

Chronic renal disease

The dosage in children with chronic renal disease is individual and must be adjusted according to the individual response to therapy. The growth disturbance should be clearly established before somatropin treatment by following growth on optimal treatment for renal disease over one year. Conservative management of uraemia with customary medicinal product, and if needed, dialysis should be maintained during somatropin therapy.

Patients with chronic renal disease normally experience a decline in renal function as part of the natural course of their illness. However, as a precautionary measure during somatropin treatment, renal function should be monitored for an excessive decline, or increase in the glomerular filtration rate (which could imply hyperfiltration).

Scoliosis

Scoliosis may progress in any child during rapid growth. Signs of scoliosis should be monitored during treatment. However, somatropin treatment has not been shown to increase the incidence or severity of scoliosis.

Blood glucose and insulin

In Turner syndrome and SGA children it is recommended to measure fasting insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk of diabetes mellitus (e.g. familial history of diabetes, obesity, severe insulin resistance, acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs, somatropin should not be administered.

Somatropin has been found to influence carbohydrate metabolism, therefore, patients should be observed for evidence of glucose intolerance.

IGF-I

In Turner syndrome and SGA children it is recommended to measure the IGF-I level before start of treatment and twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared to references for age and pubertal status, the dose should be reduced to achieve an IGF-I level within the normal range.

Some of the height gain obtained with treating short children born SGA with somatropin may be lost if treatment is stopped before final height is reached.

Adults

Growth hormone deficiency in adults

Growth hormone deficiency in adults is a lifelong disease and needs to be treated accordingly, however, experience in patients older than 60 years and in patients with more than five years of treatment in adult growth hormone deficiency is still limited.

General

Neoplasms

There is no evidence for increased risk of new primary cancers in children or in adults treated with somatropin.

In patients in complete remission from tumours or malignant disease, somatropin therapy has not been associated with an increased relapse rate.

An overall slight increase in second neoplasms has been observed in childhood cancer survivors treated with growth hormone, with the most frequent being intracranial tumours. The dominant risk factor for second neoplasms seems to be prior exposure to radiation.

Patients who have achieved complete remission of malignant disease should be followed closely for relapse after commencement of somatropin therapy.

Leukaemia

Leukaemia has been reported in a small number of growth hormone deficient patients, some of whom have been treated with somatropin. However, there is no evidence that leukaemia incidence is increased in somatropin recipients without predisposition factors.

Benign intracranial hypertension

In the event of severe or recurrent headache, visual problems, nausea, and/or vomiting, a funduscopy for papilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranial hypertension should be considered, and if appropriate, the somatropin treatment should be discontinued.

At present there is insufficient evidence to guide clinical decision making in patients with resolved intracranial hypertension. If somatropin treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary.

Patients with growth hormone deficiency secondary to an intracranial lesion should be examined frequently for progression or recurrence of the underlying disease process.

Thyroid function

Somatropin increases the extrathyroidal conversion of T4 to T3 and may, as such, unmask incipient hypothyroidism. Monitoring of thyroid function should therefore be conducted in all patients. In patients with hypopituitarism, standard replacement therapy must be closely monitored when somatropin therapy is administered.

In patients with a pituitary disease in progression, hypothyroidism may develop.

Patients with Turner syndrome have an increased risk of developing primary hypothyroidism associated with anti-thyroid antibodies. As hypothyroidism interferes with the response to somatropin therapy, patients should have their thyroid function tested regularly and should receive replacement therapy with thyroid hormone when indicated.

Insulin sensitivity

Because somatropin may reduce insulin sensitivity, patients should be monitored for evidence of glucose intolerance. For patients with diabetes mellitus, the insulin dose may require adjustment after somatropin containing product therapy is instituted. Patients with diabetes or glucose intolerance should be monitored closely during somatropin therapy.

Antibodies

As with all somatropin containing products, a small percentage of patients may develop antibodies to somatropin. The binding capacity of these antibodies is low and there is no effect on growth rate.

Testing for antibodies to somatropin should be carried out in any patient who fails to respond to therapy.

Acute adrenal insufficiency

Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. In patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required. In addition, patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses, following initiation of somatropin treatment.

Use with oral oestrogen therapy

If a woman taking somatropin begins oral oestrogen therapy, the dose of somatropin may need to be increased to maintain the serum IGF-1 levels within the normal age-appropriate range. Conversely, if a woman on somatropin discontinues oral oestrogen therapy, the dose of somatropin may need to be reduced to avoid excess of growth hormone and/or side effects.

Clinical trial experience

Two placebo-controlled clinical trials of patients in intensive care units have demonstrated an increased mortality among patients suffering from acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or acute respiratory failure, who were treated with somatropin in high doses (5.3-8 mg/day). The safety of continuing somatropin treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with somatropin in patients having acute critical illnesses should be weighed against the potential risk.

One open-label, randomised clinical trial (dose range 0.045-0.090 mg/kg/day) with patients with Turner syndrome indicated a tendency for a dose-dependent risk of otitis externa and otitis media. The increase in ear infections did not result in more ear operations/tube insertions compared to the lower dose group in the trial.

Omnitrope has no or negligible influence on the ability to drive and use machines.

Somatropin containing products have no influence on the ability to drive and use machines.

Hilac and Norditropin NordiFlex has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

Patients with growth hormone deficiency are characterised by extracellular volume deficit. When treatment with somatropin is started this deficit is rapidly corrected. In adult patients adverse reactions related to fluid retention, such as peripheral oedema, musculoskeletal stiffness, arthralgia, myalgia and paraesthesia are common. In general these adverse reactions are mild to moderate, arise within the first months of treatment and subside spontaneously or with dose-reduction.

The incidence of these adverse reactions 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 reactions are uncommon.

Omnitrope has given rise to the formation of antibodies in approximately 1% of the patients.

Tabulated list of adverse reactions

Tables 1-6 show the adverse reactions ranked under headings of System Organ Class and frequency using the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data) for each of the indicated conditions.

Clinical trials in children with GHD

*In general, these adverse effects are mild to moderate, arise within the first months of treatment, and subside spontaneously or with dose-reduction. The incidence of these adverse effects is related to the administered dose, the age of the patients, and possibly inversely related to the age of the patients at the onset of growth hormone deficiency.

$ Transient injection site reactions in children have been reported.

‡ Clinical significance is unknown

†Reported in growth hormone deficient children treated with somatropin, but the incidence appears to be similar to that in children without growth hormone deficiency.

Clinical trials in children with Turner syndrome

*In general, these adverse effects are mild to moderate, arise within the first months of treatment, and subside spontaneously or with dose-reduction. The incidence of these adverse effects is related to the administered dose, the age of the patients, and possibly inversely related to the age of the patients at the onset of growth hormone deficiency.

$ Transient injection site reactions in children have been reported.

‡ Clinical significance is unknown

†Reported in growth hormone deficient children treated with somatropin, but the incidence appears to be similar to that in children without growth hormone deficiency.

Clinical trials in children with chronic renal insufficiency

*In general, these adverse effects are mild to moderate, arise within the first months of treatment, and subside spontaneously or with dose-reduction. The incidence of these adverse effects is related to the administered dose, the age of the patients, and possibly inversely related to the age of the patients at the onset of growth hormone deficiency.

$ Transient injection site reactions in children have been reported.

‡ Clinical significance is unknown

†Reported in growth hormone deficient children treated with somatropin, but the incidence appears to be similar to that in children without growth hormone deficiency.

Clinical trials in children with SGA

*In general, these adverse effects are mild to moderate, arise within the first months of treatment, and subside spontaneously or with dose-reduction. The incidence of these adverse effects is related to the administered dose, the age of the patients, and possibly inversely related to the age of the patients at the onset of growth hormone deficiency.

$ Transient injection site reactions in children have been reported.

‡ Clinical significance is unknown

†Reported in growth hormone deficient children treated with somatropin, but the incidence appears to be similar to that in children without growth hormone deficiency.

Clinical trials in PWS

*In general, these adverse effects are mild to moderate, arise within the first months of treatment, and subside spontaneously or with dose-reduction. The incidence of these adverse effects is related to the administered dose, the age of the patients, and possibly inversely related to the age of the patients at the onset of growth hormone deficiency.

$ Transient injection site reactions in children have been reported.

‡ Clinical significance is unknown

†Reported in growth hormone deficient children treated with somatropin, but the incidence appears to be similar to that in children without growth hormone deficiency.

Clinical trials in adults with GHD

*In general, these adverse effects are mild to moderate, arise within the first months of treatment, and subside spontaneously or with dose-reduction. The incidence of these adverse effects is related to the administered dose, the age of the patients, and possibly inversely related to the age of the patients at the onset of growth hormone deficiency.

$ Transient injection site reactions in children have been reported.

‡ Clinical significance is unknown

Description of selected adverse reactions

Reduced serum cortisol levels

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 therapy.

Prader-Willi syndrome

In the post-marketing experience rare cases of sudden death have been reported in patients affected by Prader-Willi syndrome treated with somatropin, although no causal relationship has been demonstrated.

Leukaemia

Cases of leukaemia (rare or very rare) have been reported in growth hormone deficient children treated with somatropin and included in the post-marketing experience. However, there is no evidence of an increased risk of leukaemia without predisposition factors, such as radiation to the brain or head.

Slipped capital femoral epiphysis and Legg-Calvé-Perthes disease

Slipped capital femoral epiphysis and Legg-Calvé-Perthes disease have been reported in children treated with GH. Slipped capital femoral epiphysis occurs more frequently in case of endocrine disorders and Legg-Calvé-Perthes is more frequent in case of short stature. But it is unknown if these 2 pathologies are more frequent or not while treated with somatropin. Their diagnosis should be considered in a child with a discomfort or pain in the hip or knee.

Other adverse drug reactions

Other adverse drug reactions may be considered somatropin class effects, such as possible hyperglycaemia caused by decreased insulin sensitivity, decreased free thyroxin level and benign intra-cranial hypertension.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.

The subcutaneous administration of growth hormone may lead to loss or increase of adipose tissue as well as punctual haemorrhage and bruising at the injection site.

Pancreatitis has been reported post-marketing during GH therapy (frequency unknown).

Antibodies anti-somatropin: the protein somatropin may give rise to the formation of antibodies. Depending on the concerned product, these antibodies have been identified in a definite percentage of the treated population. Their binding capacity and their titres are generally low with no clinical consequence. However, testing for antibodies to somatropin should be performed in case of absence of response to somatropin therapy.

Leukaemia: cases of leukaemia (very rare) have been reported in children with a GH deficiency, some of them being treated with somatropin and included in the post-marketing experience. However, there is no evidence of an increased risk of leukaemia without predisposition factors.

Slipped capital femoral epiphysis and Legg-Calve-Perthes disease have been reported in children treated with GH. Slipped capital femoral epiphysis occurs more frequently in case of endocrine disorders and Legg-Calve-Perthes is more frequent in case of short stature. But, it is unknown if these 2 pathologies are more frequent or not while treated with somatropin. A discomfort, a pain in the hip and/or the knee must evocate their diagnosis.

Other adverse drug reactions may be considered as class effect, as the hyperglycaemia due to the decrease in insulin-sensitivity, the decreased of free thyroxin level and the possible development of a benign intra-cranial hypertension.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.

Pediatric Patients With GHD

In a clinical study in which Hilac (somatropin injection) ® 0.053mg/kg/day (vs. the same dose of an active somatropin control) was administered to 98 children with GHD for 12 months, the following adverse events were seen most frequently (≥5.0% in either treatment group): headache, pyrexia, cough, respiratory tract infection, diarrhea, vomiting and pharyngitis (see Table 7). The incidence of all of these adverse events were similar in the 2 treatment groups, and these adverse events reflect very common pediatric illnesses.

Table 7
Adverse Events Observed In Children With GHD Treated with Hilac (somatropin injection) ® vs. Comparator for 12 Months

During this study, a very modest degree of glucose intolerance was observed in the 98 patients treated with Hilac (somatropin injection) ® for 12 months (which was comparable to that observed in the comparator group). No de novo cases of overt diabetes mellitus were diagnosed. See PRECAUTIONS, General regarding somatropin-induced glucose intolerance.

Out of 98 patients with pediatric GHD randomized to treatment with Hilac (somatropin injection) ® in the pivotal study described above, 26 (26.5%) had preexisting central hypothyroidism. Exacerbation of this preexisting central hypothyroidism appeared to be common. During 12 months of Hilac (somatropin injection) ® treatment, 18 out of these 26 patients (~69%) with preexisting central hypothyroidism (who were being treated with a thyroxine preparation prior to study entry) required up-titration of their thyroxine replacement dose (primarily based on declining levels of free T4). On the other hand, none of the 72 patients without preexisting central hypothyroidism manifested de novo central hypothyroidism while on-study. See PRECAUTIONS, DRUG INTERACTIONS.

The 1 patient with preexisting central hypoadrenalism enrolled in this study required a slight increase in her maintenance hydrocortisone replacement dose after treatment with Hilac (somatropin injection) ®, possibly compatible with somatropin-induced exacerbation of preexisting central hypoadrenalism. None of the remaining 97 patients without preexisting central hypoadrenalism manifested de novo central hypoadrenalism while on-study. See PRECAUTIONS, DRUG INTERACTIONS.

In addition, during the clinical trial described above, low titer anti-rhGH antibodies* were reported in 3 patients treated with Hilac (somatropin injection) ® (vs. 1 patient treated with the comparator), and low titer anti-host cell protein antibodies were observed in 2 patients treated with Hilac (somatropin injection) ®. These antibodies appeared after 6 months of treatment, disappeared after 12 months of treatment, and did not attenuate the growth response of these children.

*As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to the protein. Anti-growth hormone antibodies with binding capacity lower than 2 mg/L have not been associated growth attenuation. In some patients, when binding capacity was greater than 2 mg/L, interference with growth response was observed in published data. Any patient with well documented pediatric GHD who fails to respond to Hilac (somatropin injection) ® therapy should be tested for neutralizing antibodies to rhGH and undergo a careful evaluation to rule out other causes of growth failure (see DOSAGE AND ADMINISTRATION).

In published literature, leukemia has been reported in a small number of pediatric GHD patients treated with somatropin. It is uncertain whether this increased risk is related to the pathology of GHD itself, somatropin therapy, or other associated treatments such as radiation therapy for intracranial tumors. So far, epidemiological data have failed to confirm the hypothesis of a relationship between somatropin therapy and leukemia.

Pediatric Patients With Turner Syndrome

TS children with short stature were treated with 0.37 mg/kg/week of Hilac (somatropin injection) ® (5 mg = 15 IU formulation) (n=30) and 0.33 mg/kg/week of Eutropin™ INJ (1.33 mg = 4 IU formulation qualitatively identical to Hilac (somatropin injection) ®) (n=60) during Study 1 and Study 2, respectively. Adverse events were reported by 10 (33.3%) children during Study 1. Most of these adverse events reflect very common pediatric illnesses. The most frequently (≥1.0%) reported adverse events were respiratory tract infections and ear infections (see Table 8). Turner syndrome patients are more prone to ear disorders and treatment with somatropin may increase the occurrence of these problems. One patient developed low titer antibodies to rhGH, and one other patient developed low titer anti-yeast antibodies which proved to be transient. During Study 2, a similar pattern of adverse events was observed (data not shown). Two patients developed low titer anti-rhGH antibodies at Month 12. Of interest, there were no reports in either study of benign intracranial hypertension, aggravation of preexisting scoliosis, slipped capital femoral epiphysis and hypertension. Somatropin-induced glucose intolerance will be discussed separately in the next paragraph. All patients with reported adverse events recovered during continued treatment.

Table 8
Adverse Events Observed In Children
With Turner Syndrome Treated with Hilac (somatropin injection) ® for 12 Months

During Study 1, a modest degree of glucose intolerance was observed in the 30 patients treated with Eutropin™ INJ for 12 months. No de novo cases of overt diabetes mellitus were diagnosed.

On the other hand, during Study 2, a much greater amount of glucose intolerance was observed: a) 3 patients (with normal fasting blood glucose [FBG] values at baseline [<100 mg/dL]) had FBG values between 130 and 145 mg/dL at Month 12 as well as at other study time points and (given the absence of follow-up data after study termination) may have developed somatropin-induced de novo diabetes mellitus; and b) 16 out of 41 patients (with normal FBG values at baseline) had FBG values between 100-126 mg/dL at Month 12 (and 3 of these 16 patients had FBG values >126 mg/dL transiently during the study). Since the amount of somatropin administered in Study 2 (0.33 mg/kg/week) was slightly less than the amount administered in Study 1 (0.37 mg/kg/week), these findings are difficult to interpret. It is possible that some of these patients were not actually fasting when blood samples were taken. See PRECAUTIONS (General) regarding the well known potential of somatropin drug products to cause or unmask glucose intolerance, especially in patients at greater inherent risk for diabetes mellitus, i.e. patients with Turner syndrome.

Adult Patients With GHD

Adult GHD patients were treated with Eutropin™ INJ (1.33 mg = 4 IU formulation; qualitatively identical to Hilac (somatropin injection) ®, a 5 mg = 15 IU formulation) vs. placebo during the pivotal clinical study. Ninety two patients received at least 3 months of treatment with Eutropin™ INJ (31 of these patients were treated with Eutropin™ INJ for an additional 3 months), and 61 patients received 3 months of treatment with placebo. Adverse events with an incidence of ≥5.0% are presented in Table 9.

The most frequent adverse event during treatment with Eutropin™ INJ was edema, which was reported more frequently than during placebo treatment. In some of these patients, edema resulted in down-titration of the dose of Eutropin™ INJ as per protocol. Myalgia was reported by 2 patients receiving Eutropin™ INJ and 2 patients treated with placebo. Arthralgia was reported by 2 patients receiving Eutropin™ INJ. There were no reports of carpal tunnel syndrome. These types of adverse events are thought to be related to the fluid accumulating effects of somatropin. Most adverse events reported during the study were mild in severity.

Table 9
Adverse Events Observed In Adults With GHD Treated
With Eutropin™ INJ vs. Placebo

During the pivotal study in adult GHD patients, a modest degree of glucose intolerance was observed in the 92 patients treated with Eutropin™ INJ for at least 3 months (31 of whom were treated for an additional 3 months). Of note, however, is the fact that 2 of the 26 patients in Group C with normal FBG values at baseline (who were treated with Eutropin™ INJ for 3 months from Month 4 through the end of Month 6 after being crossed over from placebo) had FBG values at Month 6 of 251 and 132 mg/dL. Absent follow-up data after study termination, these patients may have developed somatropin-induced de novo diabetes mellitus. In addition, 4 of these 26 patients had FBG values between 100-126 at Month 6. See PRECAUTIONS (General) regarding the well known potential of somatropin drug products to cause or unmask glucose intolerance.

Eight of the 92 patients in this study were enrolled (as per protocol) with a preexisting diagnosis of diabetes mellitus (3 of these 8 patients in fact were being treated with oral agent combination therapy and the remaining 5 patients were without drug therapy). In general, these diabetic patients tolerated treatment with Eutropin™ INJ reasonably well, i.e. no post-treatment FBG values exceeded 164 mg/dL on-study.

Seventy five out of the 92 adult GHD patients in the pivotal study (~81%) had preexisting central hypothyroidism and most of them were being treated with thyroxine replacement therapy - usually in conjunction with panhypopituitarism. None of these patients manifested clinical signs/symptoms of an exacerbation of preexisting central hypothyroidism (serial thyroid function tests were not obtained per protocol) during treatment with Eutropin™ INJ, i.e. there were no changes in maintenance thyroxine dose nor adverse events related to the thyroid during Eutropin™ INJ therapy. Furthermore, none of the remaining 17 patients enrolled in this study manifested clinical evidence of de novo central hypothyroidism. See PRECAUTIONS, DRUG INTERACTIONS.

Seventy five out of the 92 adult GHD patients in the pivotal study (~81%) also had preexisting central hypoadrenalism and most of them were being treated with glucocorticoid replacement therapy. None of these patients demonstrated convincing clinical evidence of an exacerbation of preexisting central hypoadrenalism; 2 patients required an increase in hydrocortisone replacement dosages while they were taking placebo approximately 2 months removed from treatment with Eutropin™ INJ. Furthermore, none of the remaining 17 patients enrolled in this study manifested clinical evidence of de novo central hypoadrenalism. See PRECAUTIONS, DRUG INTERACTIONS.

Growth hormone deficient patients are characterised by extracellular volume deficit. When treatment with somatropin is initiated, this deficit is corrected. Fluid retention with peripheral oedema may occur especially in adults. Carpal tunnel syndrome is uncommon, but may be seen in adults. The symptoms are usually transient, dose dependent and may require transient dose reduction.

Mild arthralgia, muscle pain and paresthesia may also occur, but are usually self-limiting.

Adverse reactions in children are uncommon or rare.

Clinical trial experience:

In children with Turner syndrome increased growth of hands and feet has been reported during somatropin therapy.

A tendency for increased incidence of otitis media in Turner syndrome patients treated with high doses of Norditropin has been observed in one open-label randomised clinical trial. However, the increase in ear infections did not result in more ear operations/tube insertions compared to the lower dose group in the trial.

Post-marketing experience:

In addition to the above mentioned adverse drug reactions, those presented below have been spontaneously reported and are by an overall judgement considered possibly related to Norditropin treatment. Frequences of these adverse events cannot be estimated from the available data:

- Neoplasms benign and malignant (including cysts and polyps): Leukaemia has been reported in a small number of growth hormone deficiency patients

- Immune system disorders: Hypersensitivity. Formation of antibodies directed against somatropin. The titres and binding capacities of these antibodies have been very low and have not interfered with the growth response to Norditropin administration

- Endocrine disorders: Hypothyroidism. Decrease in serum thyroxin levels

- Metabolism and nutrition disorders: Hyperglycemia

- Nervous system disorders: Benign intracranial hypertension

- Musculoskeletal and connective tissue disorders: Slipped capital femoral epiphysis. Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders. Legg- Calvé-Perthes disease. Legg-Calvé-Perthes disease may occur more frequently in patients with short stature

- Investigations: Increase in blood alkaline phosphatase level.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms:

Acute overdose could lead initially to hypoglycaemia and subsequently to hyperglycaemia.

Long-term overdose could result in signs and symptoms consistent with the known effects of human growth hormone excess.

The recommended dose of Hilac should not be exceeded.

Although there have been no reports of overdose with Hilac, acute overdose may result in an initial hypoglycaemia followed by a subsequent hyperglycaemia.

The effects of long-term, repeated use of Hilac in doses exceeding those recommended, are unknown. However, it is possible that such use might produce signs and symptoms consistent with the known effects of excess human growth hormone (e.g. acromegaly).

Short-term overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Moreover, overdose with somatropin is likely to cause fluid retention.

Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess hGH.

Acute overdosage can lead to low blood glucose levels initially, followed by high blood glucose levels. These decreased glucose levels have been detected biochemically, but without clinical signs of hypoglycemia. Long-term overdosage could result in signs and symptoms consistent with the known effects of human growth hormone excess.

Pharmacotherapeutic group: Anterior pituitary lobe hormones and analogues, ATC code: H01AC01.

Omnitrope is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu

Mechanism of action

Somatropin is a potent metabolic hormone of importance for the metabolism of lipids, carbohydrates and proteins. In children with inadequate endogenous growth hormone, somatropin stimulates linear growth and increases growth rate. In adults as well as in children, somatropin maintains a normal body composition by increasing nitrogen retention and stimulation of skeletal muscle growth, and by mobilisation of body fat. Visceral adipose tissue is particularly responsive to somatropin. In addition to enhanced lipolysis, somatropin decreases the uptake of triglycerides into body fat stores. Serum concentrations of IGF-I (Insulin-like Growth Factor-I) and IGFBP3 (Insulin-like Growth Factor Binding Protein 3) are increased by somatropin. In addition, the following actions have been demonstrated.

Pharmacodynamic effects

Lipid metabolism

Somatropin induces hepatic LDL cholesterol receptors, and affects the profile of serum lipids and lipoproteins. In general, administration of somatropin to growth hormone deficient patients results in reduction in serum LDL and apolipoprotein B. A reduction in serum total cholesterol may also be observed.

Carbohydrate metabolism

Somatropin increases insulin but fasting blood glucose is commonly unchanged. Children with hypopituitarism may experience fasting hypoglycaemia. This condition is reversed by somatropin.

Water and mineral metabolism

Growth hormone deficiency is associated with decreased plasma and extracellular volumes. Both are rapidly increased after treatment with somatropin. Somatropin induces the retention of sodium, potassium and phosphorus.

Bone metabolism

Somatropin stimulates the turnover of skeletal bone. Long-term administration of somatropin to growth hormone deficient patients with osteopenia results in an increase in bone mineral content and density at weight-bearing sites.

Physical capacity

Muscle strength and physical exercise capacity are improved after long-term treatment with somatropin. Somatropin also increases cardiac output, but the mechanism has yet to be clarified. A decrease in peripheral vascular resistance may contribute to this effect.

Clinical efficacy and safety

In clinical trials in short children/adolescents born SGA doses of 0.033 and 0.067 mg/kg body weight per day have been used for treatment until final height is reached. In 56 patients who were continuously treated and have reached (near) final height, the mean change from height at start of treatment was +1.90 SDS (0.033 mg/kg body weight per day) and +2.19 SDS (0.067 mg/kg body weight per day). Literature data from untreated SGA children/adolescents without early spontaneous catch-up suggest a late growth of 0.5 SDS. Long-term safety data are still limited.

Pharmacotherapeutic group: Somatropin and somatropin agonists

ATC code: H 01 AC 01

Pharmacodynamic properties:

Identical to pituitary-derived human growth hormone (pit-hGH) in amino acid sequence, chain length (191 amino acids) and pharmacokinetic profile. Hilac can be expected to produce the same pharmacological effects as the endogenous hormone.

Skeletal system:

Growth hormone produces a generally proportional growth of the skeletal bone in man. Increased linear growth in children with confirmed deficiency of pit-hGH has been demonstrated after exogenous administration of Hilac. The measurable increase in height after administration of Hilac results from an effect on the epiphyseal plates of long bones. In children who lack adequate amounts of pit-hGH, Hilac produces increased growth rates and increased IGF-1 (Insulin-like Growth Factor/Somatomedin-C) concentrations that are similar to those seen after therapy with pit- hGH. Elevations in mean serum alkaline phosphatase concentrations are also involved.

Other organs and tissues:

An increase in size, proportional to total increase in body weight, occurs in other tissues in response to growth hormone, as well. Changes include: increased growth of connective tissues, skin and appendages; enlargement of skeletal muscle with increase in number and size of cells; growth of the thymus; liver enlargement with increased cellular proliferation; and a slight enlargement of the gonads, adrenals, and thyroid.

Disproportionate growth of the skin and flat bones, and accelerated sexual maturation have not been reported in association with the growth hormone replacement therapy.

Protein, carbohydrate and lipid metabolism:

Growth hormone exerts a nitrogen-retaining effect and increases the transport of amino acids into tissue. Both processes augment the synthesis of protein. Carbohydrate use and lipogenesis are depressed by growth hormone. With large doses or in the absence of insulin, growth hormone acts as a diabetogenic agent, producing effects seen typically during fasting (i.e. intolerance to carbohydrate, inhibition of lipogenesis, mobilisation of fat and ketosis).

Mineral metabolism:

Conservation of sodium, potassium, and phosphorous occurs after treatment with growth hormone. Increased calcium loss by the kidney is offset by increased absorption in the gut. Serum calcium concentrations are not significantly altered in patients treated with Hilac or with pit-hGH. Increased serum concentrations of inorganic phosphates have been shown to occur both after Hilac and pit-hGH. Accumulation of these minerals signals an increased demand during tissue synthesis.

Pharmacotherapeutic group: Somatropin and somatropin agonists. ATC: H01AC01.

Mechanism of action

Hilac and Norditropin NordiFlex contains somatropin, which is human growth hormone produced by recombinant DNA-technology. It is an anabolic peptide of 191 amino acids stabilized by two disulphide bridges with a molecular weight of approximately 22,000 Daltons.

The major effects of somatropin are stimulation of skeletal and somatic growth and pronounced influence on the body's metabolic processes.

Pharmacodynamic effect

When growth hormone deficiency is treated a normalisation of body composition takes place resulting in an increase in lean body mass and a decrease in fat mass.

Somatropin exerts most of its actions through insulin-like growth factor I (IGF-I), which are produced in tissues throughout the body, but predominantly by the liver.

More than 90% of IGF-I is bound to binding proteins (IGFBPs) of which IGFBP-3 is the most important.

A lipolytic and protein sparing effect of the hormone becomes of particular importance during stress.

Somatropin also increases bone turnover indicated by an increase in plasma levels of biochemical bone markers. In adults bone mass is slightly decreased during the initial months of treatment due to more pronounced bone resorption, however, bone mass increases with prolonged treatment.

Clinical efficacy and safety

In clinical trials in short children born SGA doses of 0.033 and 0.067 mg/kg/day have been used for treatment until final height. In 56 patients who were continuously treated and have reached (near) final height, the mean change from height at start of treatment was +1.90 SDS (0.033 mg/kg/day) and +2.19 SDS (0.067 mg/kg/day). Literature data from untreated SGA children without early spontaneous catch-up suggest a late growth of 0.5 SDS. Long-term safety data are still limited.

Absorption

The bioavailability of subcutaneously administered somatropin is approximately 80% in both healthy subjects and growth hormone deficient patients.

A subcutaneous dose of 5 mg of Omnitrope 5 mg/1.5 ml solution for injection in healthy adults results in plasma C_max and t_max values of 72 ± 28 µg/l and 4.0 ± 2.0 hours, respectively.

A subcutaneous dose of 5 mg of Omnitrope 10 mg/1.5 ml solution for injection in healthy adults results in plasma C_max and t_max values of 74 ± 22 µg/l and 3.9 ± 1.2 hours, respectively.

Elimination

The mean terminal half-life of somatropin after intravenous administration in growth hormone deficient adults is about 0.4 hours. However, after subcutaneous administration of Omnitrope 5 mg/1.5 ml, Omnitrope 10 mg/1.5 ml solution for injection, a half-life of 3 hours is achieved. The observed difference is likely due to slow absorption from the injection site following subcutaneous administration.

Special populations

The absolute bioavailability of somatropin seems to be similar in males and females following subcutaneous administration.

Information about the pharmacokinetics of somatropin in geriatric and paediatric populations, in different races and in patients with renal, hepatic or cardiac insufficiency is either lacking or incomplete.

Twenty-four (24) healthy adult subjects received 1.67 mg somatropin either by conventional s.c. injection or by ZomaJet Vision needle free device. Peak plasma levels of around 20 ng/ml were observed 3.5 to 4 hours after administration of the medicinal product.

A terminal half-life 2.6 hours was observed when the compound was administered with Zomajet vision needle-free device which is likely to be due to a rate limiting absorption process.

Data from other somatropin containing products suggest that the bioavailability subcutaneously administered somatropin is approximately 80% in healthy adults and that both liver and kidney have been shown to be important protein catabolism organs eliminating the compound.

In a single dose study in 24 healthy volunteers, subcutaneous administration of 0.073 mg/kg of body weight of Hilac (somatropin injection) ® resulted in a mean maximum serum concentration (Cmax) of 43.97 ng/mL and an area under the curve (AUC_0-24h) of 369.90 ng·hr/mL. Cmax was reached at 4.00 hr and terminal elimination half-life was 3.03 hr.

The metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products is returned to the systemic circulation.

I.v. infusion of Norditropin (33 ng/kg/min for 3 hours) to nine growth hormone deficient patients, gave the following results: serum half-time of 21.1 ± 1.7 min., metabolic clearance rate of 2.33 ± 0.58 ml/kg/min. and a distribution space of 67.6 ± 14.6 ml/kg.

S.c. injection of Hilac (Hilac is the cartridge containing the solution for injection in Norditropin NordiFlex) 2.5 mg/m² in 31 healthy subjects (with endogenous somatropin suppressed by continuous infusion of somatostatin) gave the following results:

Maximal concentration of human growth hormone (42-46 ng/ml) after approximately 4 hours. Thereafter human growth hormone declined with a half-life of approximately 2.6 hours.

In addition the different strengths of Hilac were demonstrated to be bioequivalent to each other and to conventional Norditropin after subcutaneous injection to healthy subjects.

In studies with Omnitrope regarding subacute toxicity and local tolerance, no clinically relevant effects have been observed.

In other studies with somatropin regarding general toxicity, local tolerance and reproduction toxicity no clinically relevant effects have been observed.

With somatropins, in vitro and in vivo genotoxicity studies on gene mutations and induction of chromosome aberrations have been negative.

An increased chromosome fragility has been observed in one in vitro study on lymphocytes taken from patients after long term treatment with somatropin and following the addition of the radiomimetic drug bleomycin. The clinical significance of this finding is unclear.

In another study with somatropin, no increase in chromosomal abnormalities was found in the lymphocytes of patients who had received long-term somatropin therapy.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated-dose toxicity and genotoxicity.

Genetically engineered somatropin is identical to endogenous human pituitary growth hormone. It has the same biological properties and it is usually administered in physiological doses. Therefore, studies on safety pharmacology, toxicity to reproduction and carcinogenicity have not been conducted as no such effects are anticipated.

The general pharmacological effects on the CNS, cardiovascular, and respiratory systems following administration of Hilac with and without forced degradation were investigated in mice and rats; renal function was also evaluated. The degraded product showed no difference in effect when compared with Hilac and Norditropin. All three preparations showed the expected dose dependent decrease in urine volume and retention of sodium and chloride ions.

In rats, similar pharmacokinetics has been demonstrated between Hilac and Norditropin. Degraded Hilac has also been demonstrated to be bioequivalent with Hilac.

Single and repeated dose toxicity and local tolerance studies of Hilac or the degraded product did not reveal any toxic effect or damage to the muscle tissue.

The toxicity of poloxamer 188 has been tested in mice, rats, rabbits, and dogs and no findings of toxicological relevance were revealed.

Poloxamer 188 was rapidly absorbed from the injection site with no significant retention of the dose at the site of injection. Poloxamer 188 was excreted primarily via the urine.

Hilac is the cartridge containing the solution for injection in Norditropin NordiFlex.

Omnitrope 5 mg/1.5 ml solution for injection is a sterile, ready-to-use solution for subcutaneous injection filled in a glass cartridge.

This presentation is intended for multiple use. It should only be administered with the Omnitrope Pen 5, an injection device specifically developed for use with Omnitrope 5 mg/1.5 ml solution for injection. It has to be administered using sterile, disposable pen needles. Patients and caregivers have to receive appropriate training and instruction on the proper use of the Omnitrope cartridges and the pen from the physician or other suitable qualified health professionals.

Omnitrope 10 mg/1.5 ml solution for injection is a sterile, ready-to-use solution for subcutaneous injection filled in a glass cartridge.

This presentation is intended for multiple use. It should only be administered with the Omnitrope Pen 10, an injection device specifically developed for use with Omnitrope 10 mg/1.5 ml solution for injection. It has to be administered using sterile, disposable pen needles. Patients and caregivers have to receive appropriate training and instruction on the proper use of the Omnitrope cartridges and the pen from the physician or other suitable qualified health professionals.

The following is a general description of the administration process. The manufacturer's instructions with each pen must be followed for loading the cartridge, attaching the injection needle and for the administration.

1. Hands should be washed.

2. If the solution is cloudy or contains particulate matter, it should not be used. The content must be clear and colourless.

3. Disinfect the rubber membrane of the cartridge with a cleansing swab

4. Insert the cartridge into the Omnitrope Pen following the instructions for use provided with the pen.

5. Clean the site of injection with an alcohol swab.

6. Administer the appropriate dose by subcutaneous injection using a sterile pen needle. Remove the pen needle and dispose of it in accordance with local requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

Reconstitution

The powder should be reconstituted only by introducing the provided solvent contained in the syringe into the vial.

See the package leaflet for detailed instructions for reconstitution.

The following is a general description of the reconstitution and administration process. Reconstitution should be performed in accordance with good practice rules, particularly in the respect of asepsis.

1. Hands should be washed.

2. Flip off the yellow plastic protective caps from the vial.

3. The top of the vial should be wiped with an antiseptic solution to prevent contamination of the content.

4. Place the vial adaptor or the solvent transfer connector over the centre of the vial with the spike facing downwards then push down firmly until it clicks into place. Remove the adaptor cap.

5. Take the syringe. Remove the grey cap. Place the syringe into the adaptor / connector of the vial and inject the solvent slowly into the vial aiming the stream of liquid against the glass wall in order to avoid foam.

6. Place the adaptor cap / connector cap back on the adaptor / connector.

7. Gently swirl the vial a few times until the content is completely dissolved. Do not shake; this may cause denaturation of the active substance.

8. If the solution is cloudy or contains particulate matter, it should not be used. In the case of cloudiness after refrigeration, the product should be allowed to warm to room temperature. If cloudiness persists, discard the vial and its contents. The content must be clear and colourless after reconstitution.

Any unused product or waste material should be disposed of in accordance with local requirements.

Reconstitution with vial adaptor for use with ZomaJet Vision X device

Step 9

The vial must then be swirled gently until the powder has dissolved completely to form a clear, colourless solution.

Place the reconstituted vial of Hilac in an upright position in the refrigerator at 2°C to 8°C.

Avoid shaking or vigorous mixing. If the solution remains cloudy or contains particles, the vial and its contents should be discarded. In case of cloudiness after refrigeration, the solution should be allowed to warm up to room temperature. If cloudiness still persists, discard the vial and its contents.

Reconstitution with solvent transfer connector for injection with an ordinary syringe

Avoid shaking or vigorous mixing. If the solution remains cloudy or contains particles, the vial and its contents should be discarded. In case of cloudiness after refrigeration, the solution should be allowed to warm up to room temperature. If cloudiness still persists, discard the vial and its contents.

Hilac 5 mg/1.5 ml (orange), 10 mg/1.5 ml (blue) and 15 mg/1.5 ml (green) should only be prescribed for use with the matching colour-coded NordiPen (NordiPen 5 (orange), 10 (blue) and 15 (green), respectively). If the matching colour-coded NordiPen® is not used it will result in incorrect dosing. Instructions for use of Norditropin® SimpleXx® in NordiPen® are provided within the respective packs. Patients should be advised to read these instructions very carefully.

Patients should be reminded to wash their hands thoroughly with soap and water and/or disinfectant prior to any contact with Norditropin. Norditropin should not be shaken vigorously at any time

Do not use Hilac if the growth hormone solution for injection is cloudy or discoloured.

Norditropin NordiFlex is a pre-filled pen designed to be used with NovoFine or NovoTwist disposable needles. up to a length of 8 mm.

Norditropin NordiFlex 5 mg/1.5 ml delivers a maximum of 1.5 mg somatropin per dose in increments of 0.025 mg somatropin.

Norditropin NordiFlex 10 mg/1.5 ml delivers a maximum of 3.0 mg somatropin per dose in increments of 0.050 mg somatropin.

Norditropin NordiFlex 15 mg/1.5 ml delivers a maximum of 4.5 mg somatropin per dose in increments of 0.075 mg somatropin.

To ensure proper dosing and avoid injection of air, check the growth hormone flow before the first injection. Do not use Norditropin NordiFlex if a drop of growth hormone does not appear at the needle tip. A dose is selected by turning the dosage selector, until the desired dose appears at the window of the housing. If the wrong dose is selected, the dose can be corrected by turning the dosage selector the opposite way. The push-button is pressed to inject the dose.

Norditropin NordiFlex should not be shaken vigorously at any time.

Do not use Norditropin NordiFlex if the growth hormone solution for injection is cloudy or discoloured. Check this by turning the pen upside down once or twice.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.