Saizen

Somatropin.

Each vial of Saizen contains somatropin (recombinant human growth hormone) 3.33 mg, 8 mg accompanied by a vial of diluent containing 5 mL saline diluent with benzyl alcohol (0.9% sodium chloride and 0.9% benzyl alcohol).

Pharmacology: Pharmacodynamics: The most important pharmacological effect resulting from the parenteral administration of somatropin is stimulation of the growth levels through the medium of the somatomedins or IGF. However, somatropin is active neither in the presence of stunted growth resulting from a deficiency of somatomedins or of their receptors, nor in patients of short stature due to pituitary deficiency, whose epiphyses are already closed.
Somatropin also exerts effects on protein metabolism (anabolic effect), glucose metabolism (alteration of the glucose tolerance) and lipid metabolism (lipolytic effect). In addition, somatropin modulates the activity of the hepatic cytochrome P-450 3A4.
Clinical Efficacy in the Case of Pronounced Growth Hormone Deficiency which Started in Infancy or in Adulthood: The effects of growth hormone deficiency in adults are influenced by Saizen as follows: In a pivotal, double-blind, placebo-controlled study in 115 patients, carried out over a period of 6 months the following parameters were observed: At the start of treatment, a dosage of 0.005 mg/kg daily was administered by SC injection. After 4 weeks of treatment, if the tolerability was good, the dosage was increased by 0.01 mg/kg daily.
Primary Endpoint: Change in the fat-free mass (measured by means of DEXA, dual energy X-ray absorptiometry): Statistically significant increase by an average of 2.23 kg. Men show a more pronounced increase than women.
Secondary Endpoint: Change in the total fatty mass (measured by means of DEXA): Average reduction by 2.3 kg in the recombinant human growth hormone (r-hGH) group, compared with 0.47 kg in the placebo group (statistically significant).
Cardiac Function: 2-dimensional echocardiography shows an average increase of the percentage ejection fraction by 5.05% in the r-hGH group, compared with 3.01% in the placebo group, and an average decrease of the left ventricular end-systolic volume by 4.29 mL in the r-hGH group, compared with 1.14 mL in the placebo group.
Quality of Life: Apart from a statistically significant improvement (by 11% in the r-hGH group) in the "emotional reactions" area (p=0.017), the results of the nottingham health profile questionnaire (mobility, sleep, energy, pain, social isolation) showed no improvement.
Physical Performance: Physical performance (measured on the basis of oxygen consumption on the treadmill) remained unchanged.
Bone Density: Bone density remained unchanged.
Clinical Efficacy in Case of Growth Hormone Deficiency in Children Born Small for their Gestational Age: In the course of clinical trials in prepubertal children of short stature who were born small for their gestational age, 3 years of treatment with the dosage of 0.067 mg/kg daily resulted in an average gain in height of +1.8 SDS.
Patients who did not receive any additional treatment maintained a gain in height of +0.7 SDS at their final height.
Patients who received a 2nd cycle of treatment after a period of observation showed a total gain in height of +1.3 SDS at their final height, after an average cumulative duration of treatment of 6.1 years.
A clinical trial evaluating 2 discontinuous treatment regimes, corresponding to a cumulative dosage of 0.033 mg/kg daily for 4 years, showed an acceleration of growth and a gain in height of +1.55 and +1.43 SDS, respectively, at the end of the trial.
The data on long-term safety are still limited.
Pharmacokinetics: After administration of a single dose of r-hGH in healthy volunteers, the maximum plasma concentration (t_max) is reached 3 hrs after IM injection, while it appears between 4 and 6 hrs after SC injection. The areas under the curves (AUC) are comparable for the 2 routes of administration. The t_max values correlate well with those for natural growth hormone, as published in the literature.
The pharmacokinetics of Saizen are linear up to a dose of 8 IU (2.67 mg). With higher doses (60 IU/20 mg), a certain degree of nonlinearity, although not clinically relevant, cannot be discounted.
After administration by IV injection in healthy volunteers, the distribution volume in the steady state is about 7 L, the total clearance is about 15 L/hr, while the renal clearance is negligible. The elimination half-life of Saizen is from 20-35 min.
After SC or IM injection of Saizen, the final half-life is distinctly longer, namely about 2-4 hrs; this is due to limitation of the rate of absorption.
The maximum serum concentrations of growth hormone are reached after approximately 4 hrs and the serum levels return to normal in 24 hrs; this indicates that there will be no accumulation of growth hormone in the course of repeated administration.
The absolute bioavailability, by the 2 routes of administration, is from 70-90%.
Exogenous human growth hormone follows the same route of metabolisation as the endogenous hormone: It is inactivated by proteases and is metabolized in the liver and the kidneys, following the routes of metabolization of the proteins. It is not recovered in the urine.
In patients suffering from chronic hepatic and/or renal insufficiency, the clearance of somatropin is reduced.
Toxicology: Preclinical Safety Data: Preclinical data based on conventional studies of the safety pharmacology, chronic toxicity and genotoxicity of Saizen reveal no special risk for humans.

Treatment of growth failure in children caused by decreased or absent secretion of endogenous growth hormone; growth failure in girls with gonadal dysgenesis (Turner Syndrome), confirmed by chromosomal analysis; retarded growth in children born small for their gestational age defined as follows: Present height <-2.5 SDS and the SDS of the adjusted height of the parents is <-1; weight and/or height at birth <-2 SDS, in children who have not reached their normal growth rate by the age of ≥4 years (ie, with a growth rate <0 SDS in the course of the last year).
Adults with pronounced growth hormone deficiency with onset in childhood or adulthood. The deficiency must be confirmed by 2 dynamic tests, 1 of which must preferably be the GHRH + arginine test. If deficit of a further pituitary axis is detected, 1 single test is sufficient. The tests must be carried out under adequate substitution of the other hormone deficiencies.
Childhood Onset: Patients who were diagnosed as growth hormone deficient during childhood must be retested and their growth hormone deficiency confirmed before replacement therapy with Saizen is started.
Adult Onset: Patients must have growth hormone deficiency as a result of hypothalamic or pituitary disease and at least 1 other hormone deficiency diagnosed (except for prolactin) and adequate replacement therapy instituted, before replacement therapy using growth hormone may begin.

Saizen is intended for single-use. Saizen dosage should be individualised for each patient based on body surface area (BSA) or on body weight (BW). It is recommended that Saizen be administered at bedtime according to the following dosage: Growth Failure Due to Inadequate Endogenous Growth Hormone Secretion: 0.7-1 mg/m² body surface area (BSA) daily or 0.025-0.035 mg/kg body weight (BW) daily by SC or IM administration.
Growth Failure in Girls Due to Gonadal Dysgenesis (Turner Syndrome): 1.4 mg/m² BSA daily or 0.045-0.050 mg/kg BW daily by SC administration. Concomitant therapy with non-androgenic anabolic steroids in patients with Turner Syndrome can enhance the growth response.
Growth Failure in Children Born Small for their Gestational Age: The daily dose is 0.035-0.067 mg/kg BW (or 1-2 mg/m² daily) administered by SC injection.
Duration of Treatment in Children: The treatment is generally continued for several years. The duration of the treatment depends on the development of the patient's height and on the therapeutic target that is set. The treatment must be terminated when the patient has reached a satisfactory adult height or when the epiphyses are closed.
In the case of retarded growth in children born small for their gestational age, the treatment is generally continued until the child reaches final height. It must be stopped after the 1st year if the growth rate is <+1 SDS. It must also be stopped if final height is reached (growth rate <2 cm/year) and when confirmation proves necessary, if the bone age, based on the epiphyseal closures, is >14 years (girls) or >16 years (boys).
Growth Hormone Deficiency: Adults: At the start of the treatment with somatropin, it is recommended to start with low doses, 0.15-0.3 mg daily administered by SC injection. The dose should then be increased gradually. The dosage must be checked, taking into account the clinical reaction, the side effects that appear and the concentration of the IGF-1 in the serum. If necessary, the dosage may be increased once a month. The final dosage of growth hormone required is rarely >1 mg daily. Women may need higher dosages than men. Generally, the lowest effective dosage should be administered; the requirement may fall with increasing age or in patients who are overweight.
Duration of the Treatment in Adults: The duration of the treatment in adults is generally several years. The optimal duration of the treatment is not defined. It is recommended to check, in the course of annual specialist medical examinations, whether the treatment should be continued.

No case of overdosage has been reported up until now. In the case of acute overdosage, hypoglycaemia is observed, followed by hyperglycaemia. Long-term overdosage is characterized by the appearance of signs and symptoms of gigantism and/or acromegaly, consistent with the known effects of an excess of growth hormone.

Known hypersensitivity to somatropin or to 1 of the inactive ingredients of Saizen, or to the components of the solvent. Presence of an active tumour and/or active intracranial lesions or evidence of progression or recurrence of an underlying intracranial lesion, critically ill patients with complications following open-heart or abdominal operations, presence of multiple trauma or acute respiratory insufficiency; proliferative or pre-proliferative diabetic retinopathy.
As a growth hormone deficiency can, in rare cases, be an early sign of the presence of a cerebral tumour, tumours of this type must be excluded before the start of the treatment. Any already existing tumour should be inactive and its treatment should be stopped before starting the treatment with Saizen. Saizen is ineffective in children whose epiphyses are closed.
For Saizen 8 mg: 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. Regarding patients undergoing Somatropin therapy and becoming critically ill (see Precautions).
Use in pregnancy & lactation: There are no controlled studies available on the use of Saizen in animals or in pregnant women. Saizen must not be administered during pregnancy (see Precautions), as it is not yet known what the effect of an increase in the concentration of growth hormone on specific stages of embryogenesis or fetal growth may be.
Consequently, pregnancy must be excluded throughout the whole period of the treatment with Saizen and the patients must be informed of the possible non-hormonal methods of contraception. In the event of a pregnancy occurring, the treatment must be stopped. If the treatment with Saizen is continued in girls after the 1st menstruation, a non-hormonal method of contraception must be envisaged.
There is no indication that hGH passes into the mother's milk. It is not known if exogenous peptide hormones are excreted into breast milk but absorption of intact protein from the gastrointestinal tract of the infant is unlikely. However, as a precaution, weaning is indicated before Saizen is administered.
For Saizen 8 mg: It is not known if exogenous peptide hormones are excreted into breast milk but absorption of intact protein from the gastrointestinal tract of the infant is unlikely.

Relative Contraindications: Patients with Down's syndrome, bloom's syndrome, fanconi anemia should not be treated with Saizen.
The bone age must be measured periodically during treatment with Saizen, especially in pubertal patients and/or in patients receiving thyroid substitution therapy, because in these patients, maturation of the epiphyses can proceed rapidly.
In the case of somatropin deficiency secondary to antitumour therapy, it is recommended to look out for possible signs of renewal of the malignant process, even though according to the present state of knowledge, the tumour relapse rate under therapy with somatropin is not increased. If there is evidence of renewal of the malignant process, treatment with Saizen must be stopped.
Patients with growth hormone deficiency due to an intracranial lesion will be examined regularly in order to detect any progression or relapse of a disease.
During substitution therapy in adults, fluid retention is to be expected.
Hypothyroidism: During treatment with Saizen, thyroid levels in the serum may fall as a result of increased peripheral deiodisation from T4 to T3. Hypothyroidism can develop, which if not treated can impair the action of Saizen. Regular testing of the thyroid function is recommended during treatment with Saizen. Hypothyroidism appearing during the treatment with growth hormone must be substituted with the administration of thyroid hormone, in order to obtain an adequate therapeutic effect.
Benign Intracranial Hypertension: In cases of severe or recurrent headaches, visual disorders, nausea and/or vomiting, a fundoscopy is recommended in order to detect a possible papilloedema. If papilloedema is confirmed, a diagnosis of benign intracranial hypertension (or pseudotumor cerebri) has to be considered and if necessary the treatment with Saizen must be stopped. At present, there is insufficient evidence to guide clinical decision making in patients with normalized intracranial hypertension. If the treatment with growth hormone is restarted, the patient must be kept under observation for possible signs of intracranial hypertension.
Insulin Resistance: The administration of growth hormone results in a transient hypoglycemic phase of about 2 hrs. After 2-4 hrs, the blood-sugar level rises in spite of high insulin concentrations.
Somatropin can induce insulin resistance, which can lead to hyperinsulinism and in rare cases to hyperglycemia. In order to diagnose insulin resistance, regular checking of the blood-sugar level is recommended. Factors that increase the risk of developing diabetes during the treatment with somatropin are: Obesity, familial predisposition, treatment with steroids or existing reduced glucose tolerance. Patients who show 1 of these factors must be kept under close observation during the treatment with Saizen. Saizen should be used with caution in patients with diabetes mellitus or with a family history of this disease. In diabetic patients, it may be necessary to adjust the antidiabetic therapy accordingly.
Dislocation of the Femoral Epiphysis: Patients with endocrine disorders, including growth hormone deficiency or hypothyroidism and in periods of growth, run the risk of increased dislocation of the femoral epiphysis. In children who are being treated with growth hormone, an epiphysiolysis of this type can be caused by the underlying endocrine disease or by the increased rate of growth due to the treatment. Doctors and parents should ensure that any child who develops a limp or complains of pain in the hips or the knees during the treatment with growth hormone is given an appropriate clinical examination.
In children born small for their gestational age, other medical or therapeutic causes that could explain this growth retardation must be excluded before the treatment is started.
In children born small for their gestational age, it is recommended to measure the insulin and glycemic levels in the fasting state before the start of treatment and then once a year. In patients presenting an increased risk of developing diabetes [eg, with a family history of diabetes, obesity, raised body mass index (BMI), severe insulin resistance, acanthosis nigricans] a provoked hyperglycemia test by the oral route must be carried out. In case of clinical diabetes, the growth hormone must not be administered.
In children born small for their gestational age, it is recommended to measure the IGF-1 level before the start of the treatment and then twice a year. If, with repeated measurements, the IGF-1 levels are found to be higher than +2 SDS compared with the standard values for the child's age and pubertal stage, the IGF-1/IGFBP-3 ratio must be taken into account for the adjustment of the dose.
Experience in children born small for their gestational age, with treatment that is started when they are on the point of starting puberty is limited. Consequently, it is not recommended to start the treatment in these patients. Experience in patients with Silver-Russell syndrome is also limited. Part of the increase in height obtained in children of short stature who were born small for their gestational age and who are being treated with somatropin may be lost if the treatment is stopped before they have reached final height.
Patients with Turner's syndrome should be examined by a doctor at regular intervals for possible signs of Scheuermann's disease, especially with the appearance of bone pain.
In the presence of partial or total antepituitary deficiency, substitution therapy with additional hormones (eg, glucocorticoids) may prove to be necessary. In this case, the dosage of this concomitant treatment must be accurately adjusted in order to prevent any growth-inhibiting effects.
Effects on the Ability to Drive or Operate Machinery: Saizen does not interfere with the patient's ability to drive or use machinery.
Use in the elderly: There is only limited experience in patients >60 years. Growth hormone deficiency in adults is a life-long disease and requires appropriate treatment.

There are no controlled studies available on the use of Saizen in animals or in pregnant women. Saizen must not be administered during pregnancy (see Precautions), as it is not yet known what the effect of an increase in the concentration of growth hormone on specific stages of embryogenesis or fetal growth may be.
Consequently, pregnancy must be excluded throughout the whole period of the treatment with Saizen and the patients must be informed of the possible non-hormonal methods of contraception. In the event of a pregnancy occurring, the treatment must be stopped. If the treatment with Saizen is continued in girls after the 1st menstruation, a non-hormonal method of contraception must be envisaged.
There is no indication that hGH passes into the mother's milk. It is not known if exogenous peptide hormones are excreted into breast milk but absorption of intact protein from the gastrointestinal tract of the infant is unlikely. However, as a precaution, weaning is indicated before Saizen is administered.
For Saizen 8 mg: It is not known if exogenous peptide hormones are excreted into breast milk but absorption of intact protein from the gastrointestinal tract of the infant is unlikely.

Formation of Antibodies: The development of antibodies against somatropin has been observed in some patients. The clinical significance of these antibodies is not known although until now they have proved to be antibodies with limited binding capacity and they have not been connected with growth impairment, except in patients with genetic deletions.
In very rare cases of short stature associated with deletion of the growth hormone gene, the treatment with growth hormone can lead to the formation of antibodies that impair the growth.
Any patient suffering from confirmed growth hormone deficiency who does not respond to the treatment with Saizen should be examined for the presence of antibodies against human growth hormone and the thyroid status should be determined.
Treatment with human proteins can cause hypersensitive reactions (eg, redness and itching at the site of the injection).
A deficit of the extracellular volume is characteristic in patients with growth hormone deficiency. This deficit is rapidly corrected after the start of the treatment with somatropin.
Manifestations of hypersensitivity, intolerance, hypothyroidism or hyperglycaemia, appearance of unexplained claudication or concomitant treatment with glucocorticoids (see Precautions).
Certain cases of leukemia have been reported in a small number of children suffering from growth hormone deficiency, both in children who were receiving treatment with growth hormone and those who were not treated. The incidence could be slightly higher in the children with growth hormone deficiency. A causal relationship with the growth hormone therapy has not been established.
During substitution therapy with growth hormone in adults, fluid retention is to be expected.
Oedemas, swelling of the joints, arthralgia, myalgia and paraesthesia can be clinical manifestations of fluid retention. These symptoms or clinical signs are, however, normally transient and dose-dependent. The side effects are listed according to the incidence, as follows: Very frequent: >1/10; frequent: >1/100 to <1/10; occasional: >1/1000 to <1/100; rare: >1/10,000 to <1/1000; very rare: <1/10,000.
Application Site Reactions: Frequent injection site reactions eg, pain, paraesthesia, redness or oedema. Local lipoatrophy, which can be prevented by changing the injection site.
Nervous System Disorders: Frequent in Adults/Occasional in Children: Paraesthesia, hypoaesthesia (only in adults). Occasional: Benign idiopathic intracranial hypertension.
Endocrinal Disorders: Very Rare: Hypothyroidism.
Musculoskeletal, Connective Tissue and Bone Disorders: Very Frequent in Adults (23.3%)/Occasional in Children: Arthralgia. Frequent in Adults/Occasional in Children: Myalgia, carpal tunnel syndrome (only in adults), bone pain (only in adults), rigidity. Very Rare: Dislocation of the femoral epiphysis (epiphyseolysis capitis femoris).
Blood and Lymphatic System Disorders: Very Frequent in Adults (up to 15%)/Occasional in Children: Oedema.
Metabolic and Nutritional Disorders: Insulin resistance can lead to hyperinsulinism and in rare cases to hyperglycaemia.
Side effects appear mainly in the initial phase of the treatment and subside either spontaneously or after the dosage is reduced.
Adult patients with growth hormone deficiency that was already diagnosed in childhood report side effects less frequently than patients whose growth hormone deficiency was not diagnosed until adulthood.
The irregular IM administration of Saizen has been associated with the appearance of hypoglycaemia.
Side Effects Observed in the Same Therapeutic Class: In rare cases, convulsions, exacerbation of existing psoriasis and disorders of the fluid balance can appear. Cases of gynaecomastia and premature larche have been reported with other growth hormone preparations.
There are reports of isolated cases of sleep apnoea and sudden death in patients with Prader-Willi syndrome under treatment with growth hormone. Saizen is not indicated for the treatment of patients with Prader-Willi syndrome.

Concomitant treatment with corticosteroids can inhibit the therapeutic effect of Saizen (see Precautions). Moreover, the following substances can influence the efficacy of somatropin: Gonadotropins, estrogens, androgens and anabolic agents.
There are published in vitro data available indicating that somatropin can increase the clearance of substances that are metabolized by the cytochrome P-450 3A4 eg, sexual steroids, corticosteroids, anticonvulsants and cyclosporin. If somatropin is used together with drugs that are metabolized through CYP-450 3A4-dependent liver enzymes, the clinical efficacy of these drugs should be monitored.
Influence on Diagnostic Methods: Treatment with Saizen can lead to increases in the plasma levels of inorganic phosphorus, alkaline phosphatase and IGF-1.
Incompatibilities: No incompatibilities of Saizen with other pharmaceutical preparations are known at present.

For Saizen 3.33 mg: Instructions for Use/Handling: Reconstitution: Saizen powder for solution for injection should be used with the enclosed solvent for parenteral use. The reconstituted solution for injection should be clear with no particles. If the solution contains particles, it must not be injected.
Use with a Syringe: To reconstitute Saizen, inject 5 mL of the bacteriostatic solvent into the vial of Saizen, aiming the liquid against the glass wall. Swirl the vial in a gentle rotatory motion until the content is dissolved completely. Avoid vigorous shaking.

Store at 2°-8°C in the original package.
Store the reconstituted product at 2°-8°C in the original package. Do not freeze.
Shelf-Life: 3.33 mg: 2 years; 8 mg: 3 years.

Trophic Hormones & Related Synthetic Drugs

H01AC01 - somatropin ; Belongs to the class of somatropin and somatropin agonists. Used in anterior pituitary lobe hormone and analogue preparations.

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