Omnitrope · 4.8 Undesirable effects · 2

HOS-094056 · has-adverse-reaction-information · PDF-Seite 9

a. 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. Adverse reactions related to fluid retention, such as peripheral oedema and arthralgia are very common; musculoskeletal stiffness, 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. Omnitrope has given rise to the formation of antibodies in approximately 1% of the patients. The binding capacity of these antibodies has been low and no clinical changes have been associated with their formation, see section 4.4. b. Tabulated list of adverse reactions Table 1 shows 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. Table 1 System Very Common Uncommon Rare Very Not known organ Class commo (≥1/100 to (≥1/1,000 to (≥1/10, rare (cannot be n <1/10) <1/100) 0 (<1/10,00 estimated (≥1/10) 00 to 0) from <1/100 available 0) data) Neoplasms (Children) benign, Leukaemia† malignant, and unspecified (including cysts and polyps) 9  System Very Common Uncommon Rare Very Not known organ Class commo (≥1/100 to (≥1/1,000 to (≥1/10, rare (cannot be n <1/10) <1/100) 0 (<1/10,00 estimated (≥1/10)

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HOS-094062 · has-adverse-reaction-information · PDF-Seite 24

a. 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. Adverse reactions related to fluid retention, such as peripheral oedema and arthralgia are very common; musculoskeletal stiffness, 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. Omnitrope has given rise to the formation of antibodies in approximately 1% of the patients. The binding capacity of these antibodies has been low and no clinical changes have been associated with their formation, see section 4.4. b. Tabulated list of adverse reactions Table 1 shows 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. Table 1 System Very Common Uncommon Rare Very Not known organ Class commo (≥1/100 to (≥1/1,000 to (≥1/10, rare (cannot be n <1/10) <1/100) 0 (<1/10,00 estimated (≥1/10) 00 to 0) from <1/100 available 0) data) Neoplasms (Children) benign, Leukaemia† 24  System Very Common Uncommon Rare Very Not known organ Class commo (≥1/100 to (≥1/1,000 to (≥1/10, rare (cannot be n <1/10) <1/100) 0 (<1/10,00 estimated (≥1/10) 00 to 0) from

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HOS-094058 · has-contraindication-information · PDF-Seite 19

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 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. 19 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 (regarding patients undergoing substitution therapy, see section 4.4).

HOS-094052 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 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. 4 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 (regarding patients undergoing substitution therapy, see section 4.4).

HOS-094051 · has-indication-information · PDF-Seite 2

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. 2  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.

HOS-094057 · has-indication-information · PDF-Seite 17

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 17  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.

HOS-094054 · has-interaction-information · PDF-Seite 8

Concomitant treatment with glucocorticoids inhibits the growth-promoting effects of Omnitrope. Patients with ACTH deficiency should have their glucocorticoid replacement therapy carefully adjusted to avoid any inhibitory effect on growth. Growth hormone decreases the conversion of cortisone to cortisol and may unmask previously undiscovered central hypoadrenalism or render low glucocorticoid replacement doses ineffective (see section 4.4). In women on oral oestrogen replacement, a higher dose of growth hormone may be required to achieve the treatment goal (see section 4.4). Data from an interaction study performed in growth hormone deficient adults suggests that somatropin administration may increase the clearance of compounds known to be metabolised by cytochrome P450 isoenzymes. The clearance of compounds metabolised by cytochrome P450 3A4 (e.g. sex steroids, corticosteroids, anticonvulsants and ciclosporin) may be especially increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown. Also see section 4.4 for statements regarding diabetes mellitus and thyroid disorder and section 4.2 for statement on oral oestrogen replacement therapy.

HOS-094060 · has-interaction-information · PDF-Seite 23

Concomitant treatment with glucocorticoids inhibits the growth-promoting effects of Omnitrope. Patients with ACTH deficiency should have their glucocorticoid replacement therapy carefully adjusted to avoid any inhibitory effect on growth. Growth hormone decreases the conversion of cortisone to cortisol and may unmask previously undiscovered central hypoadrenalism or render low glucocorticoid replacement doses ineffective (see section 4.4). In women on oral oestrogen replacement, a higher dose of growth hormone may be required to achieve the treatment goal (see section 4.4). Data from an interaction study performed in growth hormone deficient adults suggests that somatropin administration may increase the clearance of compounds known to be metabolised by cytochrome P450 isoenzymes. The clearance of compounds metabolised by cytochrome P450 3A4 (e.g. sex steroids, corticosteroids, anticonvulsants and ciclosporin) may be especially increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown. Also see section 4.4 for statements regarding diabetes mellitus and thyroid disorder and section 4.2 for statement on oral oestrogen replacement therapy. 23

HOS-094055 · has-pregnancy-information · PDF-Seite 8

Pregnancy There are no or limited amount of data from the use of somatropin in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Somatropin is not recommended during pregnancy and in women of childbearing potential not using contraception. 8 Breast-feeding There have been no clinical studies conducted with somatropin containing products in breast-feeding women. It is not known if somatropin is excreted into breast milk, but absorption of intact protein from the gastrointestinal tract of the infant is extremely unlikely. Therefore caution should be exercised when Omnitrope is administered to breast-feeding women. Fertility Fertility studies with Omnitrope have not been performed.

HOS-094061 · has-pregnancy-information · PDF-Seite 24

Pregnancy There are no or limited amount of data from the use of somatropin in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Somatropin is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding There have been no clinical studies conducted with somatropin containing products in breast-feeding women. It is not known if somatropin is excreted into breast milk, but absorption of intact protein from the gastrointestinal tract of the infant is extremely unlikely. Therefore caution should be exercised when Omnitrope is administered to breast-feeding women. Fertility Fertility studies with Omnitrope have not been performed.

HOS-094059 · has-warning-information · PDF-Seite 20

The maximum recommended daily dose should not be exceeded (see section 4.2). Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Hypoadrenalism 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 (see section 4.5). 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 (see section 4.5). 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 Neoplasms 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 pat

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HOS-094053 · has-warning-information · PDF-Seite 5

The maximum recommended daily dose should not be exceeded (see section 4.2). Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Hypoadrenalism 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 (see section 4.5). 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 (see section 4.5). 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 Neoplasms 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 pat

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