Saizen Solution for Injection in a Cartridge: Indications, Dosage, Precautions, Adverse Effects
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Saizen Solution for Injection in a Cartridge - Product Information

Manufacture: EMD Serono, Inc
Country: Canada
Condition: Turner's Syndrome
Class: Hormones
Form: Liquid solution, Subcutaneous (SC)
Ingredients: somatropin, sucrose, poloxamer 188, phenol, citric acid

Summary Product Information

Route of
Administration
Dosage Form/StrengthClinically Relevant Nonmedicinal
Ingredients
Subcutaneous injection, Intramuscular injectionLyophilized powder for reconstitution/1.33 mg/vial, 3.33 mg/vial, 5 mg/vial, 8.8 mg/vialFor a complete listing see DOSAGE FORMS, COMPOSITION and PACKAGING section.
Subcutaneous injectionLyophilized powder for reconstitution/8.8 mg (8.0 mg/mL) click.easy, 8.8 mg (5.83 mg/mL) click.easy, 4 mg (1.5 mg/mL) click.easy

Solution for Injection in a Cartridge/6 mg (5.83 mg/mL), 12 mg (8 mg/mL), 20 mg (8 mg/mL)

Description

SAIZEN (somatropin for injection) is a recombinant human growth hormone, available in 1.33 mg, 3.33 mg, 5 mg and 8.8 mg doses in vials.

SAIZEN 8.8 mg (8.0 mg/mL) click.easy, 8.8 mg (5.83 mg/mL) click.easy and 4 mg (1.5 mg/mL) click.easy (somatropin for injection) are presentations of SAIZEN pre-assembled with a bacteriostatic solvent cartridge [(0.3% (w/v) metacresol in water for injection)] in a reconstitution device click.easy.
SAIZEN (somatropin, solution for injection in a cartridge) 6 mg (5.83 mg/mL), 12 mg (8 mg/mL) and 20 mg (8 mg/mL) are new presentations of SAIZEN for use with the easypodTM electromechanical auto-injector.

Somatropin is a polypeptide hormone consisting of 191 amino acid residues and its structure is identical to that of growth hormone extracted from human pituitary glands. A large loop is formed by a disulfide bond between Cys53 and Cys165. A second, smaller loop is formed by a disulfide bond near the carboxyl-terminal between Cys182 and Cys189. The solution is a slightly opalescent liquid. It is produced by recombinant (rDNA) technology in a mammalian cell expression system. SAIZEN is also therapeutically equivalent to human growth hormone of pituitary origin.

Indications and Clinical Use

SAIZEN is indicated for:

Paediatric Indications

Growth Hormone Insufficiency or Deficiency

SAIZEN is indicated for the long-term treatment of children with growth failure due to inadequate secretion of normal endogenous growth hormone. Other causes for growth failure should be ruled out.

Turner’s Syndrome

SAIZEN is indicated for the treatment of short stature in girls with gonadal dysgenesis (Turner’s Syndrome) when epiphyses are not closed.

Chronic Renal Failure

SAIZEN is indicated for the treatment of growth failure in children due to Chronic Renal Failure.

Small for Gestational Age (SGA)

SAIZEN is indicated for growth disturbance (current height Standard Deviation Score (SDS) < -2) in short children born small for gestational age (SGA) with a birth weight and/or length below -2 standard deviations (SD), who failed to show catch-up growth (Height Velocity SDS < 0 during the last year) by 2 years of age or later.

Adult Indication

Adult Growth Hormone Deficiency

SAIZEN is indicated for the replacement therapy in adult patients with acquired or idiopathic growth hormone deficiency (GHD) as diagnosed by a single dynamic test for growth hormone deficiency (peak GH ≤ 5 µg/L). Patients with a growth hormone deficiency with onset in childhood should be retested before treatment starts.

Contraindications

SAIZEN is contraindicated and should not be administered in the following cases:

  • Acute critical illness with complications following cardiac surgery, abdominal surgery, multiple accidental trauma or acute respiratory failure. Clinical studies demonstrated that high doses of somatropin, were associated with a significantly increased morbidity and mortality in those patients (see WARNINGS AND PRECAUTIONS).
  • In patients with closed epiphyses, SAIZEN has no effect on cartilaginous growth areas of the long bone. Treatment of pediatric growth disorders with SAIZEN should be discontinued when the patient has reached satisfactory adult height, or the epiphyses are fused.
  • In the presence of progression of an underlying intracranial tumour. An intracranial tumour should be inactive, with evidence of remission prior to instituting therapy, and SAIZEN should be discontinued if there is evidence of recurrent activity. Patients should be examined frequently for progression or recurrence of the underlying disease process.
  • Patients known to be hypersensitive to somatropin and to any of the excipients in the two formulations: lyophilized powder for reconstitution (and solvent) and solution for injection in a cartridge.
  • Active neoplasia (either newly diagnosed or recurrent). Any pre-existing neoplasia should be inactive. Somatropin should be discontinued if there is evidence of recurrent tumor growth
  • Proliferative or preproliferative diabetic retinopathy.

Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment. There have been reports of sudden death when somatropin was used in such patients. Saizen is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome (see SERIOUS WARNINGS AND PRECAUTIONS).

SAIZEN treatment should be discontinued in critically ill patients.

SAIZEN is not recommended for use during pregnancy and lactation.

In children with chronic renal disease, treatment with somatropin must be discontinued at the time of renal transplantation.

SAIZEN reconstituted with bacteriostatic diluent should not be administered to patients sensitive to benzyl alcohol or the preservative, metacresol, found in the diluent.

Serious Warnings and Precautions

  • SAIZEN treatment should be carried out under regular guidance of a physician experienced in the diagnosis and management of growth disorders: Growth Hormone Insufficiency or Deficiency, Turner syndrome, Chronic Renal Failure, Small for Gestational Age or adult patients with either childhood-onset or adult-onset growth hormone deficiency
  • SAIZEN shall only be used if, once reconstituted, the resulting solution is water-clear and devoid of particulate matter.
  • Benzyl alcohol, used as a preservative in Bacteriostatic Water for Injection, USP has been associated with toxicity in newborns*. When administering SAIZEN to newborns, reconstitute with sterile water for injection, USP. Only use one reconstituted dose per growth hormone vial and discard the unused portion.
  • There have been reports of fatalities associated with the use of growth hormone in pediatric patients with Prader-Willi syndrome who have one or more of the following risk factors: severe obesity, history of respiratory impairment or sleep apnea or unidentified [i.e. previously undiagnosed/mildly symptomatic] respiratory infections (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS – Congenital Disorders).

*A newborn infant, or neonate, is a child under 28 days of age

Warnings and Precautions

General

Injection sites should be varied to prevent localized lipoatrophy, in particular in the case of long term subcutaneous administration of SAIZEN.

Fluid retention is expected during growth hormone replacement therapy in adults. Growth hormone increases sodium retention with expansion of the extracellular volume and this anti-natriuretic effect appears to be mediated through the rennin-angiotensin-aldosterone system. Adverse events such as peripheral edema, joint swelling, myalgia, arthralgia, paresthesia, carpal tunnel syndrome and benign intracranial hypertension may be clinical manifestation of fluid retention and appear to be more frequent in elderly patients with adult-onset disease (see ADVERSE REACTIONS section). However, these symptoms/signs are usually transient and dose dependent therefore reduce dose as necessary.

In clinical studies in a significant increase in morbidity and mortality has been reported among somatropin treated patients with acute critical illness in intensive care units due to complications following cardiac surgery, abdominal surgery, multiple accident trauma or acute respiratory failure (see CONTRAINDICATIONS). Mortality was higher in patients treated with 5.3 mg or 8 mg somatropin daily (41.9 %) compared to patients receiving placebo (19.3 %). Based on this information, these patients must not be treated with somatropin.

Slipped capital femoral epiphysis is often associated with endocrine disorders such as GHD and hypothyroidism, and with growth spurts. In children treated with growth hormone, slipped capital femoral epiphysis may either be due to underlying endocrine disorders or to the increased growth velocity caused by treatment. Physicians and parents should be alert to the development of a limp or complaints of hip or knee pain in children treated with SAIZEN.

Concomitant glucocorticoid therapy may inhibit the response to SAIZEN and should not exceed 10-15 mg hydrocortisone equivalent/m2 body surface area during SAIZEN treatment.
To avoid transmission of disease, cartridge and prefilled syringe shall not be used by more than one person. Instructions on appropriate use should be given.

SAIZEN has not been shown to increase the incidence of scoliosis. Progression of scoliosis can occur in pediatric patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are treated with growth hormone should be monitored for progression of scoliosis.

Carcinogenesis and Mutagenesis

Carcinogenicity studies have not been conducted. Mutagenicity studies showed no mutagenic activity with SAIZEN.

Leukemia has been reported in a small number of growth hormone deficient patients, treated with growth hormone. Based on the current evidence, experts cannot conclude that growth hormone therapy is responsible for these occurrences.

Treatment with growth hormone may have an increased risk of developing neoplasm.

Secondary Neoplasm in Survivors of Childhood Cancer

In childhood cancer survivors, an increased risk of a second neoplasm (benign and malignant) has been reported in patients treated with growth hormones. 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. However, in childhood cancer survivors, no increased risk of primary cancer recurrence has been reported in patients treated with growth hormones. Given the limited data available, patients under GH therapy should be carefully monitored.

Congenital Disorders

Prader-Willi Syndrome

SAIZEN is not indicated for the long-term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willy Syndrome, unless they also have a diagnosis of growth hormone deficiency. There have been reports of fatalities after initiating therapy with growth hormone 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 (i.e. previously undiagnosed/mildly symptomatic) 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 growth hormone. If during treatment with growth hormone, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new onset of sleep apnea, treatment should also be interrupted and the patients should be treated as indicated. All patients with Prader-Willi syndrome treated growth hormone 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. Unless patients with Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, SAIZEN is not indicated for the long-term treatment of pediatric patients who have growth failure due to genetically-confirmed Prader-Willi syndrome.

Turner Syndrome

Patients with Turner syndrome may be at increased risk for development of intracranial hypertension therefore these patients should be evaluated for signs and symptoms of intracranial hypertension and treated aggressively before initiation of treatment with somatropin.

Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders before and during treatment with growth hormones since these patients have an increased risk of ear or hearing disorders. In the presence of ear infection or hearing disorders, these patients should be treated as indicated.

Patients with Turner syndrome are at risk for cardiovascular disorders (e.g. stroke, aortic aneurysm, hypertension) and these conditions should be monitored closely before and during treatment with somatropin.

Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease. Therefore, patients should have periodic thyroid function tests and be treated as indicated.

Skeletal abnormalities including scoliosis are commonly seen in untreated Turner syndrome patients.

Dependence/Tolerance

Inappropriate use of somatropin by individuals who do not have indications for which growth hormone is approved, may result in clinically significant negative health consequences.

Endocrine and Metabolism

Because human growth hormone may induce a state of insulin-resistance, SAIZEN patients should be monitored for evidence of glucose intolerance. SAIZEN should be used with caution in patients with diabetes mellitus (adjustment of their antidiabetic therapy may be required) or a family history of diabetes mellitus (see MONITORING AND LABORATORY TESTS). SGA patients are a subgroup of patients at higher risk of developing diabetes in whom fasting insulin and blood glucose should be closely monitored before initiating and during treatment with SAIZEN. SAIZEN administration is followed by a transient phase of hypoglycemia of approximately 2 hours, then from 2-4 hours onward by an increase in blood glucose levels despite high insulin concentrations. To detect insulin resistance, patients should be monitored for evidence of glucose intolerance.

In adults with risk factors for insulin resistance or glucose intolerance, such as obesity, a family history of diabetes mellitus and those on high dose corticosteroid therapy, growth hormone therapy may induce Type II Diabetes Mellitus if the insulin secretory capacity is impaired.

Growth hormone can affect the metabolism of thyroid hormones by increasing the extrathyroidal conversion of T4 to T3 and this lowering effect on T4 may unmask incipient central hypothyroidism in hypopituitary patients. Therefore, thyroid function should be evaluated before starting SAIZEN therapy and regularly assessed during treatment, not less frequently than annually. If hypothyroidism is diagnosed in the course of SAIZEN therapy, it should be corrected because untreated hypothyroidism will jeopardize the response to growth hormone.

In patients with hypopituitarism (multiple hormonal deficiencies) standard hormonal replacement therapy should be monitored closely when human growth hormone therapy is administered (see MONITORING and LABORATORY TESTS).

Immune

Local allergic reactions

With growth hormone therapies patients may experience redness, swelling, pain, inflammation, or itching at the site of injection. (see ADVERSE REACTIONS) . Most of these minor reactions usually resolve in a few days to a few weeks. They may occur if the injection is not properly made (irritants in the skin cleansing agent or poor injection technique), or if the patient is allergic to the growth hormone or any excipients. (see CONTRAINDICATIONS).

SC administration of SAIZEN can result in lipoatrophy (depression in the skin). Patients should be advised to consult their doctor if they notice any of these conditions.

Injection sites should be varied to prevent localized lipoatrophy, in particular in the case of long-term, subcutaneous administrations of SAIZEN. On rare occasion, injection site reactions may require discontinuation of SAIZEN therapy.

Systemic allergic reactions

There is a potential risk with somatropin that severe cases of generalized allergy including anaphylactic reaction may be life threatening.

Antibody Production

As with all protein pharmaceuticals, a small percentage of patients may develop antibodies during treatment with growth hormones. The clinical significance of these antibodies is unknown, though to date the antibodies have been of low binding capacity and have not been associated with growth deceleration except in patients with gene deletions. If growth deceleration is observed that is not attributable to another cause, testing for antibodies to somatropin should be considered for any patient who fails to respond to therapy.

Intracranial Hypertension (IH)

Intracranial hypertension with papilloedema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with growth hormone products. Symptoms usually occurred within the first eight weeks of initiation of growth hormone therapy.

In all reported cases, IH-associated signs and symptoms resolved after discontinuation of therapy or a reduction of growth hormone dose. Physicians and parents should be attentive to relevant symptoms such as headache and visual problems in patients under SAIZEN therapy. Fundoscopic examination should be performed routinely before initiating treatment with SAIZEN to exclude pre-existent papilloedema and repeated if there is any clinical suspicion. If papilloedema is confirmed by fundoscopy, SAIZEN treatment should be stopped. It can be restarted at a lower dose after idiopathic-intracranial hypertension has resolved which occurs rapidly when treatment is withdrawn. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary, and treatment should be discontinued if intracranial hypertension reoccurs.

Musculoskeletal

Increased tissue turgor and musculoskeletal discomfort may occur during treatment with growth hormones (see ADVERSE REACTIONS). These symptoms may resolve spontaneously, with analgesic therapy, or after reducing the dosage.

Carpal tunnel syndrome may occur during treatment with growth hormone, SAIZEN (see ADVERSE REACTIONS). If the symptoms of carpal tunnel syndrome do not resolve by decreasing the dosage of growth hormone, it is recommended that treatment be discontinued.

Pancreatitis in Children

Children treated with growth hormone may have an increased risk of developing pancreatitis compared to adults. Although rare, pancreatitis should be considered in growth hormone-treated children who develop abdominal pain.

Renal / Hepatic / Biliary / Pancreatic Impairments

SAIZEN is indicated for the treatment of growth failure in children due to Chronic Renal Failure. The safety of SAIZEN has not been established in patients with hepatic, biliary or pancreatic impairments. Growth hormone requirements may need to be adjusted in patients with renal and/or hepatic and/or biliary and/or pancreatic impairments.

Reproduction Studies

No adequate and well controlled studies in pregnant women have been performed. From the reproductive studies performed in animals with Saizen, there is no evidence of an increased risk of adverse reactions for the embryo or foetus.

Hematologic

Serum levels of inorganic phosphorus, alkaline phosphatase, and IGF-1 may increase with SAIZEN therapy.

Sensitivity

Patients who are sensitive to the preservative metacresol, found in the diluent, should consider using SAIZEN supplied with bacteriostatic diluent containing benzyl alcohol as preservative.

Information For Patients

Patients and/or their parents should be informed about potential advantages and disadvantages of growth hormone therapy including the possible side effects. If home use is determined to be desirable by the physician, patients should also be offered instruction for use of injection devices, storage, travelling and other pertinent information. 

Female patients should be advised to inform their doctor if they are pregnant or are contemplating pregnancy. Careful monitoring, as well as general health is essential in pregnant patients. (see SPECIAL POPULATIONS).

Special Populations

Pregnant Women

There are no adequate and well controlled studies in pregnant women. Therefore SAIZEN should be used during pregnancy only if it clearly indicated and under medical supervision. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo-fetal development, parturition or postnatal development (reproductive toxicology studies do not indicate any adverse effect on fertility and reproduction, despite administration of doses sufficiently high to produce some pharmacological effects on growth).

Patients shall inform their doctor if they are pregnant or are contemplating pregnancy. Caution should be exercised when prescribing to pregnant women.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Due to the large molecular weight, it is unlikely that it would be passed intact into the maternal milk and absorption of intact protein from the gastrointestinal tract of the infant is also unlikely. However, secretion of breakdown products of the drug in breast milk has not been studied. Because many drugs are excreted in human milk, caution should be exercised when somatropin is administered to a nursing mother.

Pediatrics

SAIZEN is indicated for use in children (see INDICATIONS AND CLINICAL USE). Patients with endocrine disorders, including growth hormone deficiency, may develop slipped capital epiphyses more frequently. Any pediatric patient with onset of a limp during SAIZEN therapy should be evaluated.

Adult Patients

Patients with ephiphyseal closure who were treated with growth hormone replacement therapy in childhood should be re-evaluated according to the criteria in INDICATIONS AND CLINICAL USE before continuation of SAIZEN at the reduced dose level required for growth hormone-deficient adults.

Experience with prolonged treatment in adults is limited.

Geriatrics (> 65 years of age)

Not indicated for treatment in the geriatric population.

Monitoring and Laboratory Tests

With SAIZEN the need for regular IGF-1 monitoring shall be considered to maintain IGF-1 within the normal range for age and sex. Because human growth hormone may induce a state of insulin resistance, patients should be observed for evidence of glucose intolerance. Patients with diabetes or glucose intolerance should be monitored closely during therapy with human growth hormone.

Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear or hearing disorders.

Patients with Turner syndrome are at risk for cardiovascular disorders (e.g. stroke, aortic aneurysm, and hypertension) and these conditions should be monitored closely.

Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease. Therefore, patients should have periodic thyroid function tests and be treated as indicated (see ENDOCRINE AND METABOLISM).

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

Hypothyroidism may develop during treatment with human growth hormone. Inadequate treatment of hypothyroidism may prevent optimal response to human growth hormone. Thyroid function should be evaluated before starting growth hormone therapy and regularly assessed during treatment and should be treated with thyroid hormone when indicated.

Serum levels of inorganic phosphorus, alkaline phophatase, and parathyroid hormone (PTH) may increase with growth hormone therapy.

Patients on growth hormone therapy should be monitored for the emergence of any new malignancy and the treatment discontinued if a new tumor or signs of relapse are detected.

Patients with growth failure due to chronic renal failure should be regularly examined and monitored for progression of renal osteodystrophy. Slipped capital femoral epiphysis or avascular necrosis of the femoral head may occur in children with advanced renal osteodystrophy and it is uncertain whether these complications are affected by growth hormone therapy. In these patients, radiograms of the hips and laboratory exams (serum calcium, phosphorus, alkaline phosphatase and PTH) should be made prior to initiating growth hormone therapy and regularly followed subsequently. Physicians and parents should be alert to the development of a limp or complaints of hip or knee pain (as knee pain may be referred hip pain) in patients treated with growth hormone therapy.

Bone age should be monitored periodically during SAIZEN administration especially in patients who are pubertal and/or receiving concomitant thyroid replacement therapy. Under these circumstances, epiphyseal maturation may progress rapidly.

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

Patients with an intra or extracranial neoplasia in remission who are receiving treatment with growth hormone should be examined carefully and at regular intervals by the physician. Patients developing neoplasia should be reported to Health Canada by the treating physician.

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

For SGA patients, it is recommended to measure IGF-I level before start of treatment and twice a year thereafter. If on repeated measurements IFG-I levels exceed +2 SD compared to references for age and pubertal status, the IGF-I/GFBP-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 with SGA patients with Silver-Russel syndrome is limited.

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.

In case of persistent oedema or severe paraesthesia the dosage should be decreased in order to avoid the development of carpal tunnel syndrome. Growth hormone deficiency in the Adult is a lifelong condition and should be treated accordingly, however experience with patients over sixty years and experience with prolonged treatment is limited.

Growth hormone administration is followed by a transient phase of hypoglycemia of approximately 2 hours, then from 2-4 hours onward by an increase in blood glucose levels despite high insulin concentrations. To detect insulin resistance, patients should be monitored for evidence of glucose intolerance.

Occupational Hazards

SAIZEN does not interfere with the patient’s ability to drive or use machinery.

Adverse Reactions

Adverse Drug Reactions Overview

General Disorders and Administration Site Conditions

Common

Injection site reactions: Some patients may experience redness and itching at the site of injection, particularly when the subcutaneous route is used.

Localized lipoatrophy, which can be avoided by varying the site of injection

Common (in adults), Uncommon (in children)

Fluid retention: peripheral oedema, stiffness, arthralgia, myalgia, paresthesia

Nervous System Disorders

Uncommon

Benign intracranial hypertension, which can be resolved after discontinuation of therapy or a reduction of growth hormone dose

Endocrine Disorders

Very Rare

Hypothyroidism

Musculo-skeletal disorders

Very Rare

Slipped capital femoral epiphysis (epiphysiolysis)

Metabolism disorders

Common

Hyperglycemia

Intermittent dosage has been associated with the appearance of hypoglycaemia.

Slipped capital femoral epiphysis at the site of the hip joint may occur. A child with an unexplained limp should be examined.

Some cases of acute leukemia have been reported in growth hormone deficient children, untreated as well as treated with growth hormone, and might possibly represent a slightly increased incidence compared with non-growth hormone deficient children. A causal relationship to growth hormone therapy has not yet been established.

Toxicity in newborns has been associated with benzyl alcohol as a preservative (see WARNINGS and PRECAUTIONS).

Clinical Trial Adverse Drug Reactions

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

Paediatric Indications

Growth Hormone Deficiency

Percentage of Patients with Adverse Events by System Organ Class, Preferred Term
(whether on or off treatment with SAIZEN)
System Organ ClassPreferred TermOn
treatment
(N=224)
Off
treatment
(N=15)
Infections and infestationsNasopharyngitis21.4%
Upper respiratory tract infection17.9%
Influenza17.0%
Bronchitis12.5%
Otitis media9.4%
Ear infection8.9%
Varicella7.6%6.7%
Pharyngitis streptococcal7.1%
Pharyngitis6.7%
Tonsillitis6.7%
Viral infection6.7%
Rhinitis6.3%
Sinusitis5.8%6.7%
Gastroenteritis viral6.3%
Urinary tract infection5.4%
Gastroenteritis5.4%
Acute tonsillitis4.0%6.7%
Scarlet fever4.5%
Pneumonia4.0%
Herpes simplex1.8%
Rubella1.8%
Mumps1.3%
Impetigo1.3%
Respiratory tract infection1.3%
Viral pharyngitis1.3%
General disorders and administration site conditionsPyrexia38.4%6.7%
Injection site pain6.7%
Fatigue6.3%
Asthenia1.8%
Chest pain1.3%
Injection site bruising1.3%
Injection site reaction1.3%
Respiratory, thoracic and mediastinal disordersPharyngolaryngeal pain32.6%
Cough30.4%
Nasal congestion7.6%
Epistaxis6.7%
Rhinorrhoea4.9%
Asthma3.1%
Rhinitis allergic3.1%
Paranasal sinus hypersecretion1.3%
Wheezing1.3%
Dysphonia1.3%
Sinus congestion1.3%
Nervous system disordersHeadache37.5%
Convulsion3.6%
Dizziness2.7%
Epilepsy2.2%
Disturbance in attention1.8%
Lethargy1.3%
Gastrointestinal disordersVomiting17.4%
Diarrhoea11.6%
Abdominal pain upper9.8%
Gastrointestinal disorder7.6%
Abdominal pain5.4%
Nausea4.5%
Stomach discomfort4.0%
Constipation2.7%
Toothache1.3%
Dental discomfort1.3%
InvestigationsThyroxine decreased19.2%
Hormone level abnormal2.2%
Blood triglycerides increased1.8%6.7%
Body temperature increased1.8%
Weight increased1.3%
Cardiac murmur1.3%
Drug specific antibody present1.3%
Surgical and medical proceduresSubstitution therapy12.9%
Tooth extraction2.7%
Appendicectomy1.8%
Myringotomy1.8%
Tonsillectomy1.3%
Musculoskeletal and connective tissue disordersArthralgia12.9%
Pain in extremity9.4%
Muscle spasms2.7%
Back pain1.8%
Bone pain1.3%
Myalgia1.3%
Skin and subcutaneous tissue disordersRash7.1%
Eczema2.7%
Pruritus2.7%
Psoriasis1.8%13.3%
Erythema2.2%
Urticaria1.8%
Acne1.3%
Injury, poisoning and procedural complicationsTreatment noncompliance3.6%
Joint injury2.2%
Hand fracture2.2%
Road traffic accident1.8%6.7%
Fall1.8%
Skin laceration1.8%
Arthropod bite1.3%
Joint sprain1.3%
Foot fracture1.3%
Endocrine disordersDelayed puberty6.3%
Hypothyroidism5.8%6.7%
Hypogonadism2.2%
Hypopituitarism1.8%
Diabetes insipidus1.3%
Secondary hypogonadism1.3%
Ear and labyrinth disordersEar pain11.6%
Hypoacusis1.3%
Middle ear effusion1.3%
Otorrhoea1.3%
Metabolism and nutrition disordersHypoglycaemia3.1%
Iron deficiency2.2%
Obesity2.2%
Insulin resistance1.3%
Reproductive system and breast disordersVaricocele2.2%
Gynaecomastia1.8%
Immune system disordersHypersensitivity4.5%
Seasonal allergy4.5%
Psychiatric disordersMental disorder1.8%
Nervousness1.8%
Depression1.3%
Blood and lymphatic system disordersLymphadenopathy2.7%
Anaemia2.2%
Renal and urinary disordersEnuresis2.7%
Eye disordersConjunctivitis2.2%
Congenital, familial and genetic disordersCryptorchism2.7%13.3%
Neoplasms benign, malignant and unspecified (incl cysts and polyps)Craniopharyngioma1.8%

The most frequently reported AEs were those commonly reported in any paediatric patient population, with pharyngolaryngeal pain (32.6%), pyrexia (38.4%), cough (30.4%), headache (37.5%), nasopharyngititis (21.4%), upper respiratory tract infection (17.9%) and influenza (17.0%) being the most frequently reported. These events were well tolerated without the need for hospitalisation. In addition to the treatment related adverse events reported above, two patients developed anti-hGH antibodies. In both cases, the antibodies did not have any growth inhibiting effect. None of the patients developed antibodies to host cell protein. Three transfer patients who had anti-hGH antibodies prior to treatment became negative within 6 months of treatment with SAIZEN. Hypothyroidism (5.8%) and decreased thyroxine (19.2%) were seen in several patients. One patient died of recurrent craniopharyngioma and one patient experienced lipoatrophy.

Turner’s Syndrome

Percentage of Patients with Adverse Events by System Organ Class, Preferred Term
(whether on or off treatment with SAIZEN)
System Organ ClassPreferred TermOn
treatment
(N=81)
Off
treatment
(N=0)
Respiratory, thoracic and mediastinal disordersCough51.9%
Pharyngolaryngeal pain45.7%
Epistaxis14.8%
Dysphonia11.1%
Rhinorrhoea8.6%
Vocal cord thickening1.2%
General disorders and administration site conditionsPyrexia46.9%
Injection site reaction16.0%
Injection site pain12.3%
Oedema2.5%
Localised oedema1.2%
Infections and infestationsRhinitis17.3%
Influenza9.9%
Ear infection6.2%
Otitis media6.2%
Bronchitis4.9%
Sinusitis4.9%
Fungal infection3.7%
Nasopharyngitis3.7%
Urinary tract infection3.7%
Varicella3.7%
Fungal skin infection2.5%
Scarlet fever2.5%
Tonsillitis2.5%
Pneumonia1.2%
Candidiasis1.2%
Acute tonsillitis1.2%
Gastroenteritis1.2%
Helminthic infection1.2%
Herpes zoster1.2%
Measles1.2%
Meningitis viral1.2%
Mumps1.2%
Otitis media chronic1.2%
Paronychia1.2%
Pertussis1.2%
Pharyngitis1.2%
Respiratory tract infection1.2%
Viral infection1.2%
Vulvitis1.2%
Rhinitis17.3%
Influenza9.9%
Ear infection6.2%
Otitis media6.2%
Nervous system disordersHeadache44.4%
Petit mal epilepsy1.2%
Convulsion1.2%
Dizziness1.2%
Epilepsy1.2%
Febrile convulsion1.2%
Hypertonia1.2%
Ear and labyrinth disordersEar pain28.4%
Hearing impaired2.5%

A clinical study was conducted in 91 girls with Turner’s syndrome to receive either SAIZEN alone or in conjunction with oxandrolone (see Dosage Regimen Table under CLINICAL TRIALS).

In girls treated with SAIZEN alone the percentage of patients who experienced specific adverse events were: skin reaction at injection site (13%), pain at injection site (7%), deepening/hoarseness of voice (7%), pain in limbs (7%), pigmented naevi (4%), clitorimegaly (3%), hypercholesterolaemia (3%), and 1% each for edema, hair loss, increased ephelides and seborrhea.

For the group treated with SAIZEN and oxandrolone the percentage of patients who experienced adverse events were: clitoromegaly (30%), pain in limbs (11%), deepening/hoarseness of voice (9%), pain at injection site (9%), skin reaction at injection site (8%), elevated creatinine kinase (4%), hypercholesterolaemia (4%), and 2% each for virilization, exanthem, hyperlipidemia, pigmented naevi, edema, lipodystrophy, haematoma, muscle cramps, increased freckles and hair loss. Thus, the addition of oxandrolone was associated with some virilizing effects, especially at doses of more than 0.05 mg/kg daily.

A total of 18 (20%) patients exhibited a treatment emergent abnormality in the response to glucose loading at some time during the study, of whom only 7 patients (7.7%) had detectable glucose intolerance on two or more occasions. Four patients discontinued treatment in association with these abnormalities. It should be noted that impaired glucose tolerance is commonly found in Turner’s syndrome patients.

Chronic Renal Failure

Percentage of Patients with Adverse Events by System Organ Class, Preferred Term 
(whether on or off treatment with SAIZEN)
System Organ ClassPreferred TermOn
treatment
(N=65)
Off
treatment
(N=11)
Infections and infestationsUpper respiratory tract infection26.2%
Otitis media20.0%
Viral infection20.0%
Catheter related infection18.5%9.1%
Rhinitis16.9%
Urinary tract infection13.8%
Influenza13.8%
Gastroenteritis10.8%
Nasopharyngitis9.2%
Herpes simplex7.7%
Bronchitis7.7%
Pharyngitis7.7%
Tonsillitis7.7%
Varicella7.7%
Staphylococcal infection6.2%
Pyelonephritis4.6%
Sinusitis4.6%
Tonsillitis streptococcal4.6%
Sepsis3.1%
Cytomegalovirus infection3.1%
Infection parasitic3.1%
Hepatitis C3.1%
Localised infection3.1%
Pharyngitis streptococcal3.1%
Respiratory tract infection viral3.1%
Streptococcal infection3.1%
Ear infection1.5%
Fungal infection1.5%
Abscess1.5%
Appendicitis1.5%
Cystitis1.5%
Dental caries1.5%
Endotoxic shock1.5%
Gastroenteritis viral1.5%
Hepatitis B1.5%
Herpes zoster1.5%
Infection1.5%
Injection site abscess1.5%
Laryngitis1.5%
Onychomycosis1.5%
Paronychia1.5%
Pseudomonas infection1.5%
Scarlet fever1.5%
Skin infection1.5%
Staphylococcal sepsis1.5%
Vaginal candidiasis1.5%
Vaginal infection1.5%
Viral rash1.5%
Gastrointestinal disordersPeritonitis20.0%
Vomiting20.0%
Diarrhoea15.4%
Abdominal pain7.7%
Inguinal hernia7.7%
Gingival hyperplasia7.7%
Constipation6.2%
Nausea6.2%
Abdominal pain upper4.6%
Tooth disorder3.1%
Dysphagia3.1%
Abdominal hernia1.5%
Breath odour1.5%
Colonic polyp1.5%
Dyspepsia1.5%
Enteritis1.5%
Faecal incontinence1.5%
Food poisoning1.5%
Frequent bowel movements1.5%
Gastritis1.5%
Gingival hypertrophy1.5%
Intestinal obstruction1.5%
Salivary gland enlargement1.5%
Stomach discomfort1.5%
Umbilical hernia1.5%
General disorders and administration site conditionsPyrexia23.1%9.1%
Fatigue4.6%
Face oedema4.6%
Oedema peripheral3.1%
Chest pain3.1%
Gait disturbance3.1%
Injection site haemorrhage3.1%
Injection site pain3.1%
Local swelling1.5%
Asthenia1.5%
Catheter site inflammation1.5%
Chills1.5%
Difficulty in walking1.5%
Generalised oedema1.5%
Inflammation1.5%
Influenza like illness1.5%
Injection site reaction1.5%
Oedema1.5%
Nervous system disordersHeadache23.1%
Dizziness4.6%
Convulsion3.1%
Psychomotor hyperactivity1.5%
Benign intracranial hypertension1.5%
Paraesthesia1.5%
Petit mal epilepsy1.5%
Balance disorder1.5%
Brain oedema1.5%
Cerebral infarction1.5%
Coordination abnormal1.5%
Hypertonia1.5%
Mental retardation severity unspecified1.5%
Nervous system disorder1.5%
Optic neuritis1.5%
Surgical and medical proceduresRenal transplant27.7%45.5%
Renal and urinary disordersRenal failure12.3%9.1%
Dysuria4.6%
Renal impairment4.6%
Proteinuria3.1%
Enuresis3.1%
Hydronephrosis1.5%
Renal disorder1.5%
Bladder disorder1.5%
Haematuria1.5%
Micturition disorder1.5%
Neurogenic bladder1.5%
Pyuria1.5%
Urethral disorder1.5%
Urinary retention1.5%
Respiratory, thoracic and mediastinal disordersPharyngolaryngeal pain15.4%
Cough13.8%
Rhinitis allergic6.2%9.1%
Rhinorrhoea4.6%
Epistaxis3.1%
Adenoidal hypertrophy3.1%
Pulmonary oedema3.1%
Wheezing3.1%
Asthma1.5%
Pharyngeal erythema1.5%
Respiratory tract congestion1.5%
Atelectasis1.5%
Dyspnoea1.5%
Mediastinal disorder1.5%
Nasal congestion1.5%
Nasal discomfort1.5%
Rales1.5%
Sneezing1.5%
Throat irritation1.5%
Musculoskeletal and connective tissue disordersPain in extremity13.8%
Arthralgia10.8%
Neck pain4.6%
Back pain4.6%
Renal osteodystrophy3.1%
Bone pain3.1%
Groin pain1.5%
Aseptic necrosis bone1.5%
Muscle spasms1.5%
Musculoskeletal discomfort1.5%
Osteochondrosis1.5%
Arthropathy1.5%
Epiphysiolysis1.5%
Knee deformity1.5%
Lower limb deformity1.5%
Myalgia1.5%
Rickets1.5%
Shoulder pain1.5%
Metabolism and nutrition disordersHypercalcaemia7.7%
Hyperkalaemia6.2%
Glucose tolerance impaired3.1%
Fluid overload3.1%
Hyperphosphataemia3.1%
Decreased appetite3.1%
Hyperuricaemia3.1%
Anorexia1.5%9.1%
Diabetes mellitus1.5%
Fluid retention1.5%
Hyperglycaemia1.5%
Hyperlipidaemia1.5%
Hypermagnesaemia1.5%
Hypervolaemia1.5%
Hypokalaemia1.5%
Malnutrition1.5%
Metabolic acidosis1.5%
Injury, poisoning and procedural complicationsInjury13.8%
Accidental overdose3.1%
Fall3.1%
Arthropod bite1.5%
Excoriation1.5%
Post procedural vomiting1.5%
InvestigationsBlood creatinine increased7.7%
Weight decreased3.1%
Aspartate aminotransferase increased1.5%
Blood parathyroid hormone increased1.5%
Blood pressure decreased1.5%
Blood urea increased1.5%
Blood urine present1.5%
Body temperature increased1.5%
Liver function test abnormal1.5%
Metabolic function test1.5%
Urine output decreased1.5%
Skin and subcutaneous tissue disordersAcne4.6%
Rash1.5%
Onychorrhexis1.5%
Rash pruritic1.5%
Skin depigmentation1.5%
Skin hypertrophy1.5%
Skin nodule1.5%
Urticaria1.5%
Alopecia1.5%
Angioneurotic oedema1.5%
Dermatitis contact1.5%
Ecchymosis1.5%
Eczema1.5%
Nail dystrophy1.5%
Psoriasis1.5%
Rash papular1.5%
Skin discolouration1.5%
Skin inflammation1.5%
Skin reaction1.5%
Immune system disordersTransplant rejection6.2%9.1%
Hypersensitivity4.6%
Kidney transplant rejection4.6%
Drug hypersensitivity1.5%
Blood and lymphatic system disordersAnaemia9.2%
Lymphadenopathy7.7%
Nephrogenic anaemia4.6%
Neutropenia1.5%
Coagulopathy1.5%
Leukocytosis1.5%
Vascular disordersHypertension9.2%
Hypotension6.2%
Haemorrhage3.1%
Hypertensive crisis1.5%
Haematoma1.5%
Hot flush1.5%
Peripheral coldness1.5%
Vasculitis1.5%
Vasospasm1.5%
Reproductive system and breast disordersGynaecomastia3.1%
Testicular torsion3.1%
Balanitis1.5%
Breast disorder1.5%
Epididymitis1.5%
Testicular disorder1.5%
Eye disordersEyelid oedema3.1%
Eye pain1.5%
Optic atrophy1.5%
Optic discs blurred1.5%
Papilloedema1.5%
Vision blurred1.5%
Ear and labyrinth disordersEar pain4.6%
Ear disorder1.5%
Hypoacusis1.5%
Ear discomfort1.5%
Endocrine disordersHyperparathyroidism4.6%
Hypoparathyroidism1.5%
Hypothyroidism1.5%
Cardiac disordersCyanosis1.5%
Cardiac disorder1.5%
Cardiac failure1.5%
Pericarditis1.5%
Congenital, familial and genetic disordersHydrocele3.1%
Congenital foot malformation1.5%
Neoplasms benign, malignant and unspecified (incl cysts and polyps)Skin papilloma3.1%
Parathyroid tumour benign1.5%
Psychiatric disordersAttention deficit/hyperactivity disorder1.5%
Insomnia1.5%

In clinical studies with SAIZEN in Chronic Renal Failure, the following adverse events were considered possibly related to treatment by the investigator: pseudotumor cerebri, deterioration of renal function, hyperthyroidism, injection site infection, renal transplant rejection, papilloedema, hypothyroidism, impaired OGTT and abnormal SGOT.

Small for Gestational Age

Common and very common adverse reactions (frequency ≥ 1%) are tabulated below.

Percentage of Patients with Adverse Events by System Organ Class, Preferred Term
(whether on or off treatment with SAIZEN - pooling of GF 4001 and GF 6283)
System Organ ClassPreferred TermOn
treatment
(N=100)
Off
treatment
(N=34)
Infections and infestationsEar infection19.0%14.7%
Bronchitis19.0%8.8%
Nasopharyngitis14.0%20.6%
Gastroenteritis14.0%5.9%
Varicella13.0%11.8%
Otitis media7.0%11.8%
Otitis media acute4.0%2.9%
Tonsillitis4.0%
Laryngitis4.0%
Lung infection3.0%2.9%
Pharyngitis2.0%5.9%
Influenza2.0%2.9%
Urinary tract infection2.0%2.9%
Upper respiratory tract infection2.0%
Viral infection2.0%
Acute tonsillitis2.9%
Tooth abscess1.0%2.9%
Cystitis1.0%
Furuncle1.0%
Helicobacter gastritis2.9%
Infectious mononucleosis1.0%
Paronychia1.0%
Pneumonia viral1.0%
Respiratory tract infection1.0%
Rubella1.0%
Sepsis1.0%
Sinusitis1.0%
Tracheobronchitis1.0%
Viral rash1.0%
Respiratory, thoracic and mediastinal disordersPharyngolaryngeal pain17.0%8.8%
Rhinitis5.0%5.9%
Asthma5.0%
Maxillary sinusitis3.0%
Epistaxis2.0%
Lung disorder1.0%
Nasal congestion1.0%
Rales1.0%
Gastrointestinal disordersDiarrhoea2.0%5.9%
Constipation2.0%2.9%
Abdominal pain1.0%2.9%
Vomiting1.0%2.9%
Food poisoning1.0%
Gastrooesophageal reflux disease1.0%
Inguinal hernia1.0%
Irritable bowel syndrome1.0%
Peritonitis1.0%
Toothache2.9%
Injury, poisoning and procedural complicationsHead injury2.0%
Upper limb fracture1.0%2.9%
Arthropod sting1.0%
Burns second degree2.9%
Cervical vertebral fracture1.0%
Contusion1.0%
Fall1.0%
Foreign body trauma1.0%
Joint sprain1.0%
Thermal burn1.0%
Traumatic haematoma1.0%
Wrist fracture1.0%
Surgical and medical proceduresTonsillectomy4.0%
Appendicectomy3.0%
Ear tube insertion3.0%
Myringoplasty1.0%
Gastric operation1.0%
Otorhinolaryngological surgery1.0%
Skin neoplasm excision1.0%
Nervous system disordersHeadache5.0%5.9%
Coma1.0%
Dizziness1.0%
Febrile convulsion1.0%
Tremor1.0%
Blood and lymphatic system disordersAnaemia3.0%
Hypochromic anaemia2.0%2.9%
Eosinophilia2.0%2.9%
Thrombocytopenia2.0%2.9%
Pancytopenia1.0%
Granulocytopenia1.0%
Iron deficiency anaemia1.0%
Musculoskeletal and connective tissue disordersArthralgia3.0%2.9%
Muscle hypertrophy1.0%
Myalgia1.0%
Osteoarthritis1.0%
Osteochondrosis1.0%
General disorders and administration site conditionsPyrexia4.0%
Injection site inflammation1.0%
Difficulty in walking1.0%
Skin and subcutaneous tissue disordersUrticaria1.0%2.9%
Acne1.0%
Henoch-Schonlein purpura1.0%
Pruritus generalised1.0%
Rash1.0%
InvestigationsAspartate aminotransferase increased1.0%
Blood glucose increased1.0%
Body temperature increased1.0%
Glycosylated haemoglobin increased1.0%
Haemoglobin decreased1.0%
Renal and urinary disordersHaematuria1.0%
Polyuria2.9%
Renal insufficiency1.0%
Ureteric stenosis1.0%
Psychiatric disordersSleep disorder2.0%
Aggression1.0%
Polydipsia psychogenic1.0%
Congenital, familial and genetic disordersCryptorchism2.9%
Eyelid ptosis congenital1.0%
Pigmented naevus2.9%
Cardiac disordersCardiac disorder1.0%
Cardiac failure1.0%
Endocrine disordersAutoimmune thyroiditis1.0%
Hypothyroidism2.9%
Immune system disordersAllergy to animal1.0%
Drug hypersensitivity1.0%
Eye disordersConjunctivitis2.9%
Metabolism and nutrition disordersGlucose tolerance impaired1.0%
Neoplasms benign, malignant and unspecified (incl cysts and polyps)Cyst1.0%
Reproductive system and breast disordersHypertrophy breast2.9%

The most common (incidence > 5%) adverse events observed in clinical trials with SGA patients were mild to moderate in severity. The most frequently reported AEs were those commonly reported in any paediatric patient population, with ear infection, bronchitis, nasopharyngitits, gastroenteritis, varicella and pharyngolaryngeal pain being the most frequently reported. These events were well tolerated without the need for drug discontinuation. The number, type and severity of events did not differ between periods with r-hGH treatment and periods with observation without treatment, or between the first and second and third year of r-hGH treatment.

Oral glucose tolerance tests (OGTT) were used during the treatment and observation periods in studies GF 4001 and GF 6283. Increased insulin levels were observed after 18 months of r-hGH treatment in study GF 4001 and this increase was sustained during the 3-year treatment period but were normalised during the follow-up period. Similar results were observed for the children who received continuous treatment (Group TTOO), but were less apparent for children who received intermittent treatment (Group TOTO) in study GF 6283. Abnormal glucose levels during the OGTT indicative of impaired glucose tolerance were observed in a few patients in both studies, and more often during continuous treatment (study GF 4001 and Group TTOO in study GF 6283) than during intermittent treatment (Group TOTO in study GF 6283). There was no report on diabetes mellitus in any of the studies but in one child (patient no. 6283102003) in study GF 6283, who had received r-hGH treatment continuously for 2 years, a fasting glucose value of 11.2 mmol/L was observed after 2 years of observation without treatment. There was no withdrawal in any of the studies due to change in glucose tolerance. These results are similar to those reported in the literature.

Adult Indications

Adult Growth Hormone Deficiency

Percentage of Patients with Adverse Events by System Organ Class, Preferred Term
(whether on or off treatment with SAIZEN)
System Organ ClassPreferred TermOn
treatment
(N=107)
Off
treatment
(N=44)
Musculoskeletal and connective tissue disordersArthralgia35.5%18.2%
Back pain13.1%6.8%
Myalgia9.3%2.3%
Pain in extremity9.3%2.3%
Joint swelling6.5%6.8%
Joint stiffness6.5%
Musculoskeletal stiffness4.7%2.3%
Tendonitis4.7%
Groin pain1.9%4.5%
Shoulder pain3.7%
Muscle spasms1.9%2.3%
Pain in jaw1.9%2.3%
Chest wall pain1.9%
Dupuytren's contracture1.9%
Musculoskeletal discomfort1.9%
Nervous system disordersHeadache20.6%18.2%
Paraesthesia9.3%2.3%
Dizziness7.5%6.8%
Carpal tunnel syndrome7.5%4.5%
Hypoaesthesia6.5%
Sinus headache3.7%2.3%
Sciatica1.9%4.5%
Memory impairment2.8%
Loss of consciousness1.9%
Infections and infestationsInfluenza17.8%4.5%
Nasopharyngitis14.0%2.3%
Lower respiratory tract infection9.3%6.8%
Urinary tract infection4.7%2.3%
Bronchitis3.7%4.5%
Upper respiratory tract infection4.7%
Tooth abscess4.7%
Ear infection1.9%2.3%
Gastroenteritis2.8%
Otitis externa1.9%
Tonsillitis1.9%
General disorders and administration site conditionsOedema peripheral16.8%9.1%
Fatigue10.3%4.5%
Influenza like illness6.5%2.3%
Injection site bruising1.9%6.8%
Asthenia2.8%4.5%
Chest pain2.8%
Oedema1.9%2.3%
Pyrexia2.8%
Chills1.9%
Pain1.9%
InvestigationsFree fatty acids increased10.3%4.5%
Insulin-like growth factor increased7.5%
Blood cholesterol increased2.8%2.3%
Thyroxine free decreased3.7%
Alanine aminotransferase increased2.8%
Glycosylated haemoglobin increased2.8%
Weight decreased2.8%
Neutrophil count increased1.9%
White blood cell count increased1.9%
Blood urine present1.9%
Lymphocyte count decreased1.9%
Gastrointestinal disordersNausea6.5%6.8%
Diarrhoea7.5%2.3%
Abdominal pain upper7.5%
Vomiting4.7%
Abdominal distension2.8%
Abdominal pain2.8%
Stomach discomfort2.8%
Abdominal discomfort1.9%
Frequent bowel movements1.9%
Gastrooesophageal reflux disease1.9%
Metabolism and nutrition disordersFluid retention8.4%
Hyperglycaemia3.7%2.3%
Dehydration2.8%
Dyslipidaemia2.8%
Skin and subcutaneous tissue disordersHyperhidrosis4.7%
Rash2.8%2.3%
Skin disorder2.8%
Pruritus1.9%
Nail pigmentation1.9%
Respiratory, thoracic and mediastinal disordersPharyngolaryngeal pain4.7%4.5%
Cough2.8%6.8%
Dyspnoea1.9%4.5%
Nasal congestion2.8%2.3%
Psychiatric disordersInsomnia7.5%
Depression4.7%
Depressive delusion2.8%
Anxiety1.9%
Depressed mood1.9%
Eye disordersConjunctivitis2.8%
Vision blurred2.8%
Eye pain1.9%2.3%
Renal and urinary disordersHaematuria8.4%4.5%
Nephrolithiasis1.9%
Injury, poisoning and procedural complicationsFall1.9%
Joint dislocation1.9%
Joint sprain1.9%
Vascular disordersHypertension3.7%6.8%
Hypotension1.9%
Endocrine disordersHypothyroidism6.5%
Hyperthyroidism1.9%
Reproductive system and breast disordersMetrorrhagia2.8%
Dysmenorrhoea1.9%
Blood and lymphatic system disordersAnaemia1.9%
Lymphadenopathy1.9%
Neoplasms benign, malignant and unspecified (incl cysts and polyps)Pituitary tumour1.9%
Ear and labyrinth disordersEar discomfort1.9%2.3%
Ear pain1.9%

SAIZEN Adult GHD
Number of patients still on treatment by visit since study start.

Month from start of studyTotal # of patientsPatient still on treatment
r-hGHPlacebo°
DBPC start11560 (100%)55 ( 100%)
DBPC end11553 ( 88%)51 ( 93%)
Month 1211549 ( 82%)48 ( 87%)
Month 1811534 ( 57%)34 ( 62%)
Month 24 *4215 ( 68%)13 ( 65%)
Month 30 *4211 ( 50%)11 ( 55%)
Month 36 *426 ( 27%)6 ( 30%)

* Only 2 of the 6 sites scheduled treatment beyond 18 months.
° Treatment with SAIZEN started in month 6.
2 patients had their last visit before one of the presented month and the last after that month.

Withdrawals for this study during both the double-blind, placebo controlled phase and the open-label phase were due to patient decision (7%), protocol violation (0.9%), adverse events (12.2%), lost to follow-up (0.9%) and other (2.6%).

Edema, muscle pain, joint pain, and joint disorders were reported to occur in up to 10% of adult patients receiving growth hormone replacement therapy. These side effects occurred primarily early in therapy and tended to be transient.

Adult patients with growth hormone deficiency, following diagnosis of growth hormone deficiency in childhood, reported side effects less frequently than those with adult onset growth hormone deficiency.

Less Common Clinical Trial Adverse Drug Reactions

Clinical trial adverse drug reactions with a frequency of less than 1% are presented in the following listing:

List of adverse events (preferred terms) with a frequency of less than 1% in clinical trials performed with SAIZEN in registered indications:
IndicationSystem Organ ClassPreferred Terms
PediatricAdult
GHDBlood and lymphatic system disordersIron deficiency anaemia, Neutrophilia, PlasmacytosisMicrocytic anaemia, Neutropenia, Neutrophilia
Cardiac disordersAngina pectoris, Aortic valve stenosis, PalpitationsAtrial fibrillation, Coronary artery disease, Left ventricular failure
Congenital, familial and genetic disordersAtrial septal defect, Epidermal naevus, Facial dysmorphism, Foetal alcohol syndrome, Lymphangioma, Pigmented naevus, Turner's syndrome-
Ear and labyrinth disordersDeafness, Deafness bilateral, Ear congestion, Ear discomfort, Motion sickness, Tinnitus, Tympanic membrane hyperaemia, Tympanic membrane perforation-
Endocrine disordersAdrenocortical insufficiency chronic, Empty sella syndrome, HyperthyroidismAdrenocortical insufficiency acute, Pituitary cyst, Toxic nodular goitre
Eye disordersBlepharitis, Blindness, Diplopia, Eye haemorrhage, Eye irritation, Eyelid oedema, Eyelid ptosis, Lacrimal cyst, Optic atrophy, Papilloedema, Vision blurred, Visual acuity reduced, Visual disturbanceAccommodation disorder, Asthenopia, Cataract, Conjunctivitis allergic, Dry eye, Eyelid cyst, Eyelid oedema, Optic discs blurred
Gastrointestinal disordersAbdominal pain lower, Aphthous stomatitis, Dyspepsia, Faeces hard, Flatulence, Gingival bleeding, Gingival hypertrophy, Irritable bowel syndrome, Mouth ulceration, Oral mucosal blistering, Pancreatitis, Salivary gland hypertrophy, Tooth disorderAnal fissure, Colitis ulcerative, Constipation, Diverticulum, Dysphagia, Food poisoning, Gastritis, Gastrointestinal haemorrhage, Haemorrhoids, Intestinal polyp, Tooth disorder, Toothache
General disorders and administration site conditionsAdverse drug reaction, Adverse event, Application site pain, Chills, Cyst rupture, Feeling cold, Feeling hot, Hernia, Influenza like illness, Infusion site bruising, Injection site atrophy, Injection site haemorrhage, Injection site hypertrophy, Injection site induration, Injection site irritation, Injection site mass, Injection site rash, Injection site scar, Injection site swelling, Instillation site pruritus, Irritability, Local swelling, Malaise, Mucosal ulceration, No adverse effect, Oedema peripheral, PainApplication site reaction, Chest discomfort, Discomfort, Facial pain, Injection site pain, Injection site reaction, Malaise
Hepatobiliary disordersLiver disorderCholelithiasis, Gallbladder polyp, Hepatic function abnormal
Immune system disordersDrug hypersensitivity, Multiple allergies, Selective IgG subclass deficiencyHypersensitivity, Seasonal allergy
Infections and infestationsAcarodermatitis, Appendicitis, Bacteriuria Body tinea, Conjunctivitis infective, Cystitis, Enterobiasis, Erythema infectiosum, Eye infection, Febrile infection, Fungal infection, Furuncle, Gastric infection, Genital infection, Hepatitis B, Herpes zoster, Herpetic stomatitis, Infectious mononucleosis, Injection site infection, Kidney infection, Lice infestation, Localised infection, Lower respiratory tract infection, Lymph gland infection, Measles, Meningitis viral, Molluscum contagiosum, Nail infection, Oral candidiasis, Orchitis, Otitis externa, Paronychia, Pertussis, Pharyngotonsillitis, Postoperative wound infection, Pyelonephritis, Skin infection, Staphylococcal infection, Streptococcal infection, Tinea capitis, Tinea infection, Tooth abscess, Tooth infection, Vaginal infection, Viraemia, Viral upper respiratory tract infection, Vulvitis, Vulvovaginal mycotic infection, Wound infectionBreast infection, Cystitis, Eye infection, Gastroenteritis viral, Gingival infection, Helicobacter infection, Herpes zoster oticus, Hordeolum, Infected sebaceous cyst, Labyrinthitis, Pharyngitis, Sinusitis, Viral infection, Vulvovaginal mycotic infection
Injury, poisoning and procedural complicationsAnimal scratch, Arthropod sting, Concussion, Confusion postoperative, Contusion, Exposure to toxic agent, Fibula fracture, Head injury, Heat exhaustion, Humerus fracture, Joint ligament rupture, Limb injury, Lower limb fracture, Medical device discomfort, Mouth injury, Multiple fractures, Muscle strain, Soft tissue injury, Splinter, Sunburn, Superficial injury of eye, Thermal burn, Tibia fracture, Vaccination complication, WoundAnkle fracture, Back injury, Contusion, Laceration, Muscle strain, Procedural pain, Wrist fracture
InvestigationsBlood corticotrophin decreased, Blood cortisol decreased, Blood gonadotrophin decreased, Blood iron decreased, Blood sodium decreased, Catheterisation cardiac, Diagnostic procedure, Glucose tolerance test abnormal, Glucose urine, Head circumference abnormal, Hepatic enzyme increased, Iodine uptake abnormal, Lipids increased, Platelet count decreased, Transaminases increased, Weight decreased, White blood cell count decreased, White blood cells urine positiveBlood calcium increased, Blood creatinine increased, Blood glucose decreased, Blood potassium decreased, Body temperature decreased, Gammaglutamyltransferase increased, Haemoglobin increased, Heart rate increased, Hepatic enzyme increased, High density lipoprotein decreased, Liver function test abnormal, Low density lipoprotein increased, Lymph node palpable, Monocyte count decreased, Prostate examination abnormal, Semen volume decreased, Weight increased
Metabolism and nutrition disordersAnorexia, Decreased appetite Dehydration, Fluid overload Fluid retention, Glucose tolerance impaired, Hypercholesterolaemia, Hyperinsulinaemia, Hyponatraemia, Increased appetite, Polydipsia, Weight gain poorDecreased appetite, Diabetes mellitus, Hypercholesterolaemia, Hyperkalaemia, Hypertriglyceridaemia, Hypoglycaemia, Increased appetite, Iron deficiency, Polydipsia
Musculoskeletal and connective tissue disordersArthropathy, Chondropathy Flank pain, Groin pain, Growth retardation, Joint effusion, Joint range of motion decreased, Juvenile arthritis, Limb discomfort, Muscle contracture, Musculoskeletal pain, Myopathy, Neck pain, Osteochondrosis, Rickets, Scoliosis, Shoulder pain, Spinal disorder, Temporomandibular joint syndrome, TorticollisArthritis, Arthropathy, Axillary mass, Bone pain, Bursitis, Ganglion, Limb deformity, Muscle fatigue, Muscle tightness, Musculoskeletal chest pain, Musculoskeletal pain, Myopathy, Sacral pain, Synovitis, Tendon disorder
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)Astrocytoma, Glioma, Metastases to spine, Neoplasm progression, Pinealoma, Pituitary tumour, Skin papilloma, Tumour flareAcrochordon, Basal cell carcinoma, Glioma, Haemangioma, Uterine leiomyoma
Nervous system disordersAmnesia, Brain oedema, Carpal tunnel syndrome, Cerebral atrophy, Clonus, Coordination abnormal, Depressed level of consciousness, Encephalitis, Grand mal convulsion, Hemiparesis, Hyperreflexia, Hypoaesthesia, Hipotonía, Intracranial pressure increased, Memory impairment, Mental retardation severity unspecified, Migraine, Paraesthesia, Psychomotor hyperactivity, Reflexes abnormal, Somnolence, Status epilepticus, Syncope Tonic convulsion, Transient ischaemic attack, TremorCerebellar infarction, Cerebrovascular accident, Disturbance in attention, Drooling, Hyperaesthesia, Lethargy, Syncope, Syncope vasovagal, Tremor, Trigeminal neuralgia, Visual field defect
Psychiatric disordersAbnormal behaviour, Aggression, Attention deficit/hyperactivity disorder, Crying, Emotional disorder, Personality change, Personality disorder, Restlessness, Stress, TicAggression, Early morning awakening, Mood altered, Mood swings, Stress
Renal and urinary disordersBladder spasm, Dysuria, Glycosuria, Haematuria, Leukocyturia, Nocturia, Polyuria, ProteinuriaMicturition urgency, Proteinuria, Renal colic, Urinary incontinence
Reproductive system and breast disordersBilateral breast buds, Breast pain, Breast swelling, Dysmenorrhoea, Epididymal cyst, Female genitaldigestive tract fistula, Menstruation irregular, Metrorrhagia, Priapism, Pruritus genital, Testicular retraction, Testicular swelling, Vaginal erythema, Vaginal haemorrhage, Vaginal ulcerationBreast pain, Breast tenderness, Gynaecomastia Menorrhagia, Menstruation irregular, Withdrawal bleed, Withdrawal bleeding irregular
Respiratory, thoracic and mediastinal disordersDyspnoea, Dyspnoea exertional, Hyperventilation, Pharyngeal erythema, Pharyngeal ulceration, Rhinalgia, Tonsillar hypertrophyAsthma, Nasal dryness, Rhinitis allergic, Sinus disorder, Sleep apnoea syndrome
Skin and subcutaneous tissue disordersAlopecia, Angioneurotic oedema, Dandruff, Dermatitis Dermatitis allergic, Dermatitis contact, Dry skin, Hair growth abnormal, Hyperhidrosis, Hyperkeratosis, Keloid scar, Lipoatrophy, Lipodystrophy acquired, Neurodermatitis, Periorbital oedema, Pigmentation disorder, Rash erythematous, Rash maculo-papular, Rash papular, Rash pruritic, Scar, Seborrhoea, Skin discolouration, Skin hyperpigmentation, Skin hypopigmentation, Skin lesionAcne, Alopecia, Dermatitis, Dermatitis contact, Erythema, Hypertrichosis, Parapsoriasis, Petechiae, Photosensitivity reaction, Rash generalised, Rash pruritic, Scar, Seborrhoeic dermatitis, Skin inflammation, Skin nodule, Sweat gland disorder, Urticaria
Social circumstancesFamily stress-
Surgical and medical proceduresAbscess drainage, Adenoidectomy, Adenotonsillectomy, Adhesiolysis, Allergenic desensitisation procedure, Astrocytoma surgery, Brain tumour operation, Dental disorder prophylaxis, Dental treatment, Drug therapy, Ear operation, Ear tube insertion, Explorative laparotomy, Eye muscle tenotomy, Foot operation, Hernia repair, Hormone replacement therapy, Intraaortic balloon placement, Medical device implantation, Mineral supplementation, Mole excision, Orchidopexy, Surgery, Testicular operation, Urethral operation, Urethral repair, Wart excision-
Vascular disordersFlushing, Poor peripheral circulationHot flush, Lymphoedema, Orthostatic hypotension
TS, CRF, SGANo patients experienced AEs on treatment with a frequency of less than 1%.*

*CRF, TS, SGA: clinical trials included a subject number inferior or equal to 100 patients.

Drug Interactions

Thyroid Hormones

Growth hormone administration in healthy normal adult subjects acutely increases serum T3, leading to reciprocal decreases in Free Thyroxine (FT4) and Thyroid-Stimulating Hormone (TSH) with a consequent increase in the T3 to the T4 ratio. This GH effect may as such unmask incipient hypothyroidism.
Therefore, the importance of evaluating thyroid function in GHD children prior to commencing therapy is emphasized.

Growth Hormone Affecting the Metabolism of Glucocorticoids

Several clinical studies report an impact of GH administration on glucorticoid secretion, even if its mode of action remains unclear. There is evidence to suggest that GH lowers the levels of cortisol binding globulin and increases the net conversion of cortisol to cortisone, thus reducing bioactivity of glucocorticoids during GH replacement.

Initiation of GH replacement may unmask secondary adrenal insufficiency in some patients by reducing the activity of 11β-hydroxysteroid dehydrogenase, type 1 (11β-HSD1), an enzyme converting inactive cortisone to cortisol. In a patient with central adrenal failure, initiation of GH treatment may require an increase in hydrocortisone dose. Careful monitoring of patients’ symptoms such as weight, appetite, and mood are required to assess the need for glucocorticoid dose modification.

Glucocorticoid Effects on Growth Hormone Response

Concomitant glucorticoid therapy may reduce the growth promoting effect of somatropin. If glucocorticoid replacement is required, the dose should be carefully adjusted to avoid either adrenal insufficiency or inhibition of growth promoting effects.

Antidiabetic

It is well documented that GH in the basal state increases plasma free fatty levels, even in the presence of insulin stimulation, thus counteracting the antilipolytic action of insulin. Given the anti-insulin effects of GH, SAIZEN patients should be monitored for evidence of glucose intolerance in patients with diabetes mellitus or with a family history of diabetes mellitus. The care of diabetes in GH-replaced adults should follow standard guidelines, but intensified monitoring of metabolic control is advocated in the early phase of GH replacement of such patients. Patients with diabetes mellitus may require adjustment of their antidiabetic therapy.

Growth Hormone as Inducer of Cytochrome P450 34A

Published in vitro data indicate that growth hormone may be an inducer of CYP34A, a cytochrome P450 enzyme involved in glucocorticoid catabolism. Therefore, growth hormone therapy may both unmask unsuspected adrenocorticotropic hormone (ACTH) deficiencies and negate low replacement glucocorticoid doses used in secondary adrenal insufficiency (AI) by decreasing the availability of cortisol. Patients starting growth hormone therapy may require adjustments in their glucocorticoid replacement doses, and stress doses. Caution is recommended when administering SAIZEN with compounds that are metabolized by the CP450 or CY3A4 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine and others). When SAIZEN is administered in combination with drugs known to be metabolized by CYP P450 or CYP3A4 hepatic enzymes, it is advisable to monitor clinical effectiveness of such drugs.

Oral Estrogen

Because oral estrogens may reduce the serum IGF-1 response to somatropin treatment, girls and women receiving oral estrogen replacement may require greater somatropin dosages. However, the maximum recommended weekly dose should not be exceeded.

Interactions with food, herbal products or laboratory tests have not been established.

Dosage and Administration

Dosing Consideration

Before initiating a patient on SAIZEN therapy, please review completely the CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS sections.

SAIZEN dosage should be individualized for each patient according to body weight.

SAIZEN treatment should be carried out under regular guidance of a physician experienced in the diagnosis and management of growth disorders.

The patient’s medical history for hypersensitivity reactions should be carefully evaluated prior to performing the injection (see WARNINGS AND PRECAUTIONS – Allergic Reactions).
For SAIZEN 1.33 mg, 3.33 mg, 5 mg and 8.8 mg , once the appropriate dose for a patient has been determined, reconstitute each vial of SAIZEN with the diluent supplied. For use in patients sensitive to benzyl alcohol, see WARNINGS and PRECAUTIONS.

Recommended Dose and Dosage Adjustment

Growth failure due to inadequate endogenous growth hormone secretion

It is recommended that SAIZEN be administered subcutaneously at a dose of 0.2 mg/kg body weight per week. The dosage can be increased to 0.27 mg/kg per week if there is insufficient response to treatment.

Growth failure in girls due to gonadal dysgenesis (Turner’s Syndrome)

It is recommended that SAIZEN be administered subcutaneously at a dose of 0.375 mg/kg body weight per week (optimal dosing 0.32 – 0.375 mg/kg/week).

Concomitant therapy with non-androgenic anabolic steroids in patients with Turner’s syndrome can enhance the growth response.

Growth failure in children with Chronic Renal Failure

It is recommended that SAIZEN be administered subcutaneously at a dose of 0.35 mg/kg body weight per week.

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

It is recommended that SAIZEN be administered subcutaneously at a dose of 0.47 mg/kg body weight/week.

Adult Growth Hormone Deficiency

It is recommended that SAIZEN be administered subcutaneously at a dose of 0.005 mg/kg/day at the start of therapy. This dose may be increased after 4 weeks to 0.01 mg/kg/day if well tolerated. The minimum effective dose should be used and dose requirements may decline with age.

Missed Dose

For patients who miss a dose, it is not recommended to double the next dose. Administer the regular dose at the next scheduled dosage time.

Administration

Saizen 8.8 mg (8.0 mg/mL) click.easy, 8.8 mg (5.83 mg/mL) click.easy, 4 mg (1.5 mg/mL) click.easy

SAIZEN, once reconstituted, should be administered using the one.click auto-injector or the easypod electromechanical auto-injector. The route of injection, using either device, is subcutaneous.

The calculated dose should be set on the one.click device.

Although SAIZEN in the click.easy device is intended for the one.click auto-injector or the easypod electromechanical auto-injector, SAIZEN, once reconstituted, can also be accessed with a conventional syringe for a subcutaneous injection.

Saizen 1.33 mg, 3.33 mg, 5 mg, 8.8 mg

SAIZEN should be administered using sterile, disposable syringes and needles. The syringe used should be of appropriately small volume to ensure the accurate dose withdrawal. The calculated dose should be withdrawn for either subcutaneous or intramuscular injection.

Saizen 6 mg (5.83 mg/mL), 12 mg (8 mg/mL), 20 mg (8 mg/mL) Cartridges

The cartridge containing the solution of SAIZEN is for use with the easypod electromechanical auto-injector. The route of injection is subcutaneous.

Paediatric Indications

Growth failure due to inadequate endogenous growth hormone secretion

  1. Subcutaneous injection:
    The weekly dose can be divided into 3 single doses (corresponding to 0.067 mg/kg per injection) or into 6 or 7 single daily doses (corresponding to 0.033 or 0.028 mg/kg per injection, respectively). The injection site should be altered to prevent lipoatrophy. For subcutaneous injections, the use of a needle which is 1.25 cm long is recommended.
  2. Intramuscular injection:
    The weekly dose should be divided into 3 single injections (corresponding to 0.0067 mg/kg). For intramuscular injections, the use of a needle which is at least 2.5 cm long is recommended to ensure the injection reaches the intramuscular layer.

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

The weekly dose can be divided into 3 single doses (corresponding to 0.137 - 0.161 mg/kg per injection) or into 7 single daily doses (corresponding to 0.045 - 0.054 mg/kg per injection).

Growth failure in children with Chronic Renal Failure

The daily subcutaneous injection consists of a single injection of 0.05 mg/kg body weight. The injection site should be altered to prevent lipoatrophy. A needle 1.25 cm long should be used for subcutaneous injections.

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

For SGA patients, SAIZEN should be administered as a daily subcutaneous injection consisting of a single injection of 0.067 mg/kg body weight. The injection site should be altered to prevent lipoatrophy. A needle 1.25 cm long should be used for subcutaneous injections.

Adult Indication

Adult Growth Hormone Deficiency

At the start of somatropin therapy, a low dose of 0.005 mg/kg/day is recommended, given as a daily subcutaneous injection. The dose should be adjusted stepwise, controlled by Insulin-like Growth Factor 1 (IGF-1) age-adjusted normal values, to 0.01 mg/kg/day if well tolerated. The recommended final GH dose seldom exceeds 1.0 mg/day. In general, the lowest efficacious dose should be administered. In older or overweight patients, lower doses may be necessary.

Overdosage

No cases of acute overdosage have been reported. However, exceeding the recommended doses can cause side effects. Overdosage can lead to hypoglycemia followed by hyperglycemia. Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess human growth hormone. If any signs of overdosage occur, treatment should be discontinued. Moreover, somatropin overdose is likely to cause manifestations of fluid retention.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Actions and Clinical Pharmacology

General

Somatropin is a polypeptide hormone consisting of 191 amino acid residues and its structure is identical to that of growth hormone extracted from human pituitary glands. It is produced by recombinant (rDNA) technology in a mammalian cell expression system. Somatropin is also therapeutically equivalent to human growth hormone of pituitary origin.

SAIZEN provides an exogenous supply of human growth hormone for those patients lacking the ability to produce adequate endogenous supplies.

Pharmacology

Linear growth

Somatropin stimulates linear growth in patients with pituitary growth hormone deficiency, Turner’s syndrome and chronic renal failure. Treatment of these patients with SAIZEN results in increased growth rates and IGF-1 levels similar to those seen for children treated with growth hormone of pituitary origin.

Skeletal growth

The measurable increase in growth (body length) after somatropin treatment results from its effect on cartilaginous growth areas of the long bones. It is known that somatropin's effect is mediated by a sulfation factor, IGF-1, which permits the incorporation of sulfate into cartilage. IGF-1 is present in low concentration in the serum of growth hormone deficient patients and increases during somatropin therapy.

Cell growth

Somatropin brings about cellular growth as demonstrated by an increase in the muscular, visceral and red cell mass. In muscle tissue, the increase in mass is associated with a corresponding increase in both number and dimension of muscular fibre cells.

Carbohydrate metabolism

Somatropin has an effect on carbohydrate metabolism. The diabetogenic effect of somatropin is well-known in clinical medicine. Acromegalic patients often suffer from diabetes mellitus while hypopituitary children experience hypoglycemia. In healthy patients, very large doses of somatropin may interfere with glucose tolerance. A simultaneous increase in the plasma insulin level is observed upon somatropin administration.

The diabetogenic activity of somatropin is perhaps due to several concomitant factors:

  1. Reduced transport of glucose into peripheral tissues.
  2. Increased release of glucose from the liver.
  3. Reduced concentration of insulin at the muscular level.
  4. Reduced glycolysis from the block of the enzyme triose phosphate dehydrogenase, mediated by non-esterified fatty acids.

Protein metabolism

Somatropin has an effect on protein metabolism. Somatropin is an anabolic agent that stimulates intracellular transport of amino acids, net retention of nitrogen and protein synthesis which can be quantified by observing the decline in urinary nitrogen excretion and BUN.

Lipid metabolism

Lipid metabolism is also affected by somatropin. This occurs when intracellular lipolysis is stimulated, thus increasing the plasma concentration of free fatty acids and stimulating the oxidation of fatty acids. In the diabetic patient, somatropin has been shown to accentuate ketogenesis.

Connective tissue metabolism

Connective tissue metabolism is affected by somatropin's ability to stimulate the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline.

Mineral metabolism

Somatropin affects mineral metabolism by inducing the net retention of phosphorus and potassium and to a lesser degree sodium. Somatropin induces the increased intestinal absorption of calcium and the increased renal tubular reabsorption of phosphorus with increased serum and inorganic phosphate. Increased serum alkaline phosphatase may also be observed during somatropin therapy.

Pharmacokinetics

The pharmacokinetics of SAIZEN are linear at least up to doses of 8 IU (2.67 mg). At higher doses (60 IU/20 mg) some degree of non-linearity cannot be ruled out, however with no clinical relevance.

Following IV administration in healthy volunteers the volume of distribution at steady-state is around 7 L, total metabolic clearance is around 15 L/h while the renal clearance is negligible, and the drug exhibits an elimination half-life of 20 to 35 min.

Following single-dose SC and IM administration of SAIZEN, the apparent terminal half-life is much longer, around 1 to 6 hours (median 2.7 hours). This is due to a rate limiting absorption process.

Maximum serum growth hormone (GH) concentrations following injection are reached after approximately 4 hours (range 2 to 7 hours) and serum GH levels return to baseline within 24 hours, indicating that no accumulation of injected GH will occur during repeated administrations.

The absolute bioavailability of both routes is 70-90 %.

Summary of Somatropin’s Pharmaceutical Parameters
Distribution
Steady State
Metabolic
Clearance
Terminal half-
life (range)
Time to CmaxBioavailability
Single dose7L15L/h4 hours (1 to 6 hours)4 hours70-90%

Special Populations and Conditions

SAIZEN is indicated for children with growth failure due to chronic renal failure (see INDICATIONS AND CLINICAL USE). No other studies have been conducted with special populations and conditions.

Storage and Stability

Saizen 1.33 mg/vial, 3.33 mg/vial, 5 mg/vial, 8.8 mg/vial

1.33 & 3.33 mg Vials: Store SAIZEN lyophilized product under refrigeration at 2-8 °C.
5 & 8.8 mg Vials: Store SAIZEN lyophilized product at room temperature.

Do not use SAIZEN after the expiry date shown on label.

Reconstitution

The recommended diluents for reconstitution are:

1.33 mg Vial: Sodium Chloride Injection, USP
3.33 mg Vial: Sodium Chloride Injection, USP and Bacteriostatic Sodium Chloride Injection, USP
5 & 8.8 mg Vials: Water for Injection, USP and Bacteriostatic Water for Injection, USP

Incompatibility

SAIZEN should not be mixed with other drugs.

Preparation of Solution

To prevent possible contamination of the vial, wipe the rubber stopper with an antiseptic solution before puncturing it with the needle.

After determining appropriate patient dose, reconstitute each 5 and 8.8 mg vial of SAIZEN with 1-3.5 mL of Bacteriostatic Water for Injection, USP (Benzyl Alcohol preserved), each 3.33 mg vial of SAIZEN with up to 5 mL of Bacteriostatic Sodium Chloride Injection, USP (Benzyl Alcohol preserved), and each 1.33 mg vial of SAIZEN with up to 1 mL of Sodium Chloride Injection, USP.

To reconstitute SAIZEN, inject the diluent into the vial of SAIZEN aiming the liquid against the glass vial wall. Swirl the vial with a GENTLE rotary motion until contents are dissolved completely. DO NOT SHAKE. If shaken, the solution will appear opalescent; however, this opalescence does not indicate any decrease in potency. Parenteral drug products should be inspected visually prior to administration. Do not inject if the reconstituted product contains particulate matter or is discoloured. For use in patients sensitive to the diluent see WARNINGS.

Stability of Solution and Storage

Saizen 1.33 mg/vial

When reconstituted with Sodium Chloride Injection, USP, the reconstituted solution should be administered immediately (within 3 hours). Any unused solution should be discarded.

Saizen 3.33 mg/vial

When reconstituted with Bacteriostatic Sodium Chloride Injection, USP, the reconstituted solution may be stored at 2-8 °C for up to 21 days.

When reconstituted with Sodium Chloride Injection, USP, the reconstituted solution should be administered immediately (within 3 hours). Any unused solution should be discarded.

Saizen 5 mg/vial and 8.8 mg/vial

When reconstituted with 1 mL to 3.5 mL Bacteriostatic Water for Injection, USP, the reconstitutedsolution may be stored at 2-8 °C for up to 14 days.

When reconstituted with Water for Injection, USP, the reconstituted solution should be administered immediately (within 3 hours). Any unused solution should be discarded.

Saizen 8.8 mg (5.83 mg/mL) click.easy

Store at room temperature (25 °C or below) in original package. Do not freeze. Store reconstituted product at 2-8 °C in the cartridge for up to 28 days. Keep in a safe place out of the reach of children. Do not use after expiry date.

Saizen 8.8 mg (8.0 mg/mL) click.easy and Saizen 4 mg (1.5 mg/mL) click.easy

Store at room temperature (25 °C or below) in original package. Do not freeze. Store reconstituted product at 2-8 °C in the cartridge for up to 21 days. Keep in a safe place out of the reach of children. Do not use after expiry date.

Saizen 6 mg (5.83 mg/mL), 12 mg (8 mg/mL), 20 mg (8 mg/mL) cartridges

Store cartridges in a refrigerator (2-8oC) in the original package. Do not freeze. Use within 28 days after first injection.

When containing a cartridge of SAIZEN, the easypod electromechanical auto-injector has to be stored in a refrigerator (2-8oC).

Special Handling Instructions

SAIZEN solution should not be administered if it contains particles or is not clear.

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

Dosage Forms, Composition and Packaging

Dosage Form and Composition

Saizen 1.33 mg/vial, 3.33 mg/vial, 5 mg/vial, 8.8 mg/vial

SAIZEN is a sterile, non-pyrogenic, lyophilized powder.

1.33 mg Vial: Each vial contains 1.33 mg somatropin, 20 mg mannitol, 2.0-2.4 mg disodium hydrogen phosphate dihydrate, 0.3-0.4 mg sodium dihydrogen phosphate monohydrate and 1.0 mg sodium chloride.
3.33 mg Vial: Each vial contains 3.33 mg somatropin, 5 mg mannitol, 2.8-3.2 mg disodium phosphate dihydrate and 0.4-0.5 mg sodium dihydrogen phosphate monohydrate.
5 mg Vial: Each vial contains 5 mg somatropin, 1.2 mg phosphoric acid, 0.7 mg of sodium hydroxide and 34.2 mg sucrose.
8.8 mg Vial: Each vial contains 8.8 mg of somatropin, 2.1 mg of phosphoric acid, 1.2 mg of sodium hydroxide and 60.2 mg of sucrose.

Saizen 8.8 mg (8.0 mg/mL) click.easy, 8.8 mg (5.83 mg/mL) click.easy, 4 mg (1.5 mg/mL) click.easy

SAIZEN is a sterile, non-pyrogenic, lyophilized powder in vials for reconstitution.

Each vial of SAIZEN 8.8 mg contains the following: 8.8 mg somatropin, 60.2 mg sucrose, 2.1 mg phosphoric acid, 1.2 mg sodium hydroxide.

Each vial of SAIZEN 4 mg contains the following: 4 mg somatropin, 27.4 mg sucrose, 0.9 mg phosphoric acid, 0.6 mg sodium hydroxide.

Saizen 6 mg (5.83 mg/mL), 12 mg (8 mg/mL), 20 mg (8 mg/mL) cartridges

6 mg (5.83 mg/mL) Cartridge: Each cartridge contains 6 mg of somatropin, 77.3 mg sucrose, 2.1 mg Poloxamer 188, 3.8 mg phenol and citric acid (pH 6.1 ± 0.1).
12 mg (8 mg/mL) Cartridge: Each cartridge contains 12 mg somatropin, 112.5 mg sucrose, 3.0 mg Poloxamer-188, 5.6 mg phenol and citric acid (pH 6.1 ± 0.1).
20 mg (8 mg/mL) Cartridge: Each cartridge contains 20 mg somatropin, 187.5 mg sucrose, 5.0 mg Poloxamer 188, 9.3 mg phenol and citric acid (pH 6.1 ± 0.1).

Packaging

Saizen 1.33 mg/vial, 3.33 mg/vial, 5 mg/vial, 8.8 mg/vial

SAIZEN is available as a sterile, non-pyrogenic, lyophilized powder. The following vial sizes are available:

SAIZEN 1.33 mg: Cartons containing 1 vial of 1.33 mg somatropin for Injection together with diluent (1 mL Sodium Chloride Injection, USP).

Cartons containing 10 vials of 1.33 mg somatropin for Injection together with diluent (1 mL Sodium Chloride Injection, USP).
SAIZEN 3.33 mg: Cartons containing 1 vial of 3.33 mg somatropin for Injection together with diluent (5 mL bacterostatic Sodium Chloride Injection, USP).

Cartons containing 10 vials of 3.33 mg somatropin for Injection together with diluent (5 mL bacterostatic Sodium Chloride Injection, USP).
SAIZEN 5 mg: Cartons containing 1 vial of 5 mg somatropin for injection together with 1 vial of diluent (3.5 mL or 10 mL bacteriostatic Water for Injection, USP).

Cartons containing 2 vials of 5 mg somatropin for injection together with 2 vials of diluent (3.5 mL or 10 mL bacteriostatic Water for Injection, USP).
SAIZEN 8.8 mg: Cartons containing 1 vial of 8.8 mg somatropin for injection together with 1 vial of diluent (3.5 mL or 10 mL bacteriostatic Water for Injection, USP)

The recommended route of administration is subcutaneous or intramuscular.

Saizen 8.8 mg (8.0 mg/mL) click.easy, 8.8 mg (5.83 mg/mL) click.easy, 4 mg (1.5 mg/mL) click.easy

The DIN 2R 3 mL vials of SAIZEN and the cartridges of the solvent are of neutral glass (Type I).

SAIZEN 8.8 mg (8.0 mg/mL) click.easy, 8.8 mg (5.83 mg/mL) click.easy and 4 mg (1.5 mg/mL) click.easy are available in the following pack sizes:

1 vial of SAIZEN product and 1 cartridge of pre-assembled in 1 reconstitution device (click.easy) comprising of the main body, the cap assembly and the sterile transfer cannula.

5 vials of SAIZEN product and 5 cartridges of bacteriostatic solvent pre-assembled in 5 reconstitution devices (click.easy) comprising each of the main body, the cap assembly and sterile transfer cannula.

There is no latex in the components of the vial, cartridge or reconstitution device.

The recommended route of administration is subcutaneous.

Saizen 6 mg (5.83 mg/mL), 12 mg (8 mg/mL) and 20 mg (8 mg/mL) Cartridges

SAIZEN, solution for injection in a cartridge is supplied in a standard 3 mL nominal capacity glass cartridge (Type I).

They are available in pack sizes of 1 and 5 cartridges.

The recommended route of administration is subcutaneous.