Saizen^® 3.33 mg powder and solvent for solution for injection

Each vial of Saizen 3.33 mg contains Somatropin* (recombinant human growth hormone).

*produced by recombinant DNA technology in mammalian cells

For excipients, see section 6.1.

Powder and solvent for solution for injection.

White lyophilised powder and clear, colourless solvent.

Saizen is indicated in the 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.

• growth failure in prepubertal children due to chronic renal failure (CRF).

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

• replacement therapy in adults with pronounced growth hormone deficiency as diagnosed by a single dynamic test for growth hormone deficiency. Patients must also fulfil the following criteria:

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 one other hormone deficiency diagnosed (except for prolactin) and adequate replacement therapy instituted, before replacement therapy using growth hormone may begin.

Saizen 3.33 mg is intended for multiple dose 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:

0.7-1.0 mg/m² body surface area (BSA) per day or 0.025-0.035 mg/kg body weight (BW) per day by subcutaneous or intramuscular administration.

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

1.4 mg/m² body surface area (BSA) per day or 0.045-0.050 mg/kg body weight (BW) per day by subcutaneous administration.

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

Growth failure in prepubertal children due to chronic renal failure (CRF):

1.4 mg/m² body surface area (BSA), approximately equal to 0.045-0.050 mg/kg body weight (BW), per day by subcutaneous administration.

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

The recommended daily dose is 0.035 mg/kg body weight (or 1 mg/m²/day, equal to 0.1 IU/kg/day or 3 IU/m²/day) per day, by subcutaneous administration.

Duration of treatment

Treatment should be discontinued when the patient has reached a satisfactory adult height, or the epiphyses are fused.

For growth disturbance in short children born SGA, treatment is usually recommended until final height is reached. Treatment should be discontinued after the first year if height velocity SDS is below +1. Treatment should be discontinued when final height is reached (defined as height velocity < 2 cm/year), and if confirmation is required if bone age is> 14 years (girls) or> 16 years (boys), corresponding to closure of the epiphyseal growth plates.

Growth Hormone Deficiency in adults:

At the start of somatropin therapy, low doses of 0.15-0.3mg are recommended, given as a daily subcutaneous injection. The dose should be adjusted stepwise, controlled by Insulin-like Growth Factor 1 (IGF-1) values. The recommended final GH dose seldom exceeds 1.0mg/day. In general the lowest efficacious dose should be administered. In older or overweight patients, lower doses may be necessary.

Saizen should not be used in children in whom epiphyseal fusion occurred.

Saizen is contraindicated in patients known to be hypersensitive to Somatropin and any of the excipients in the powder for solution for injection or the solvent.

Saizen is contraindicated in patients with active neoplasia.Any anti-tumor therapy must be completed prior to starting treatment with Somatropin.

Saizen should not be used in cases with evidence of any progression or recurrence of an underlying intra-cranial lesion.

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 4.4 “Special warnings and special precautions for use“.)

Treatment should be carried out under the regular guidance of a physician who is experienced in the diagnosis and management of patients with growth hormone deficiency.

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

Some cases of leukaemia 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 been established.

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. Somatropin may induce a state of insulin resistance which can result in hyperinsulinism and in some patients hyperglycemia.To detect insulin resistance, patients should be monitored for evidence of glucose intolerance.

Saizen should be used with caution in patients with diabetes mellitus or with a family history of diabetes mellitus. Patients with diabetes mellitus may require adjustment of their antidiabetic therapy.

Stable background retinopathy should not lead to discontinuation of Somatropin replacement therapy. In case of development of preproliferative changes and the presence of proliferative retinopathy Somatropin replacement therapy should be discontinued.

During treatment with Somatropin an enhanced T4 to T3 conversion has been found which may result in a reduction in serum T4 and an increase in serum T3 concentrations. In general, the peripheral thyroid hormone levels have remained within the reference ranges for healthy subjects. The effects of Somatropin on thyroid hormone levels may be of clinical relevance in patients with central subclinical hypothyroidism in whom overt hypothyroidism theoretically may develop. Conversely, in patients receiving replacement therapy with thyroxine mild hyperthyroidism may occur. It is therefore particularly advisable to test thyroid function after starting treatment with Somatropin and after dose adjustments.

Fluid retention is expected during growth hormone replacement therapy in adults.

In case of persistent oedema or severe paraesthesia the dosage should be decreased in order to avoid the development of carpal tunnel syndrome.

In case of severe or recurrent headache, visual problems, nausea and/or vomiting, funduscopy for papilloedema is recommended. If papilloedema is confirmed a diagnosis of benign intracranial hypertension (or pseudotumor cerebri) should be considered and Saizen treatment should be discontinued. At present there is insufficient evidence to guide clinical decision-making in patients with resolved intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary and treatment should be discontinued if intracranial hypertension recurs.

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 the treatment. Growth spurts may increase the risk of joint-related problems, the hip joint being under particular strain during the prepubertal growth spurt. Physicians and parents should be alert to the development of a limp or complaints of hip or knee pain in children treated with Saizen.

Patients with growth failure due to chronic renal failure should be examined periodically for evidence of progression of renal osteodystrophy. Slipped capitalfemoral epiphysis or avascular necrosis of the femoral head may be seen in children with advanced renal osteodystrophy and it is uncertain whether these problems are affected by growth hormone therapy. X-rays of the hip should be obtained prior to initiating therapy.

In children with chronic renal failure, renal function should have decreased to below 50% of normal before therapy is instituted. To verify the growth disturbance, growth should have been followed for a year before institution of therapy. Conservative treatment for renal insufficiency (which includes control of acidosis, hyperparathyroidism and nutritional status for one year prior to the treatment) should have been established and should be maintained during treatment. Treatment should be discontinued at the time of renal transplantation.

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 fasting insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g. familial history of diabetes, obesity, increased body mass index, severe insulin resistance, acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs, growth hormone should not be administered.

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

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

The injection site should be varied to prevent lipoatrophy.

Benzyl alcohol as a preservative in bacteriostatic sodium chloride solution may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old and must not be given to premature babies or neonates. Saizen may be reconstituted with Sodium Chloride Injection BP or Sterile Water for Injections for immediate use when administering to children under 3 years of age.

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

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

Cases of sleep apnoea and sudden death in patients with Prader-Willi-Syndrome under treatment with Somatropin have been reported. Saizen is not indicated for the treatment of patients with Prader-Willi-Syndrome.

Concomitant corticosteroid therapy may inhibit the response to Saizen.

Somatropin has been reported to induce a modest reduction of serum cortisol levels in GH deficient patients receiving adrenal substitution treatment. Therefore, it is recommended to monitor serum cortisol levels in patients on corticosteroid replacement therapy in whom Somatropin therapy is started and adjust the dose of corticosteroids if necessary.

Published in vitro data indicate that growth hormone may be an inducer of cytochrome P450 3A4. The clinical significance of this observation is unknown. However, when Somatropin is administered in combination with drugs known to be metabolised by CYP P450 3A4 hepatic enzymes, it is advisable to monitor the clinical effectiveness of such drugs.

Pregnancy: For Saizen no clinical data on exposed pregnancies are available. Thus, the risk for humans is unknown. Although animal studies do not point to a potential risk during pregnancy, Saizen should be discontinued if pregnancy occurs.

Lactation: 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.

Saizen does not interfere with the patient's ability to drive or use machinery.

Up to 10 % of patients may experience redness and itching at the site of injection, particularly when the subcutaneous route is used.

Fluid retention is expected during growth hormone replacement therapy in adults. Oedema, joint swelling, arthralgias, myalgias and paresthesias may be clinical manifestations of fluid retention. However, these symptoms / signs are usually transient and dose dependent.

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.

Antibodies to Somatropin can form in some patients; 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 attenuation except in patients with gene deletions. In very rare instances, where short stature is due to deletion of the growth hormone gene complex, treatment with growth hormone may induce growth attenuating antibodies.

The adverse reactions reported below are classified according to frequency of occurrence as follows:

Application site disorders

Common

Injection site reactions

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

Body as a whole – General disorders

Common (in adults) Uncommon (in children)

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

Uncommon

Carpal tunnel syndrome

CNS

Uncommon

Idiopathic intracranial hypertension (benign intracranial hypertension)

Endocrine Disorders

Very rare

Hypothyroidism

Musculo-skeletal disorders

Very rare

Slipped capital femoral epiphysis (Epiphysiolysis capitis femoris), or avascular necrosis of the femoral head

Metabolism disorders

Insulin resistance can result in hyperinsulinism and in rare cases in hyperglycemia.

No cases of acute overdosage have been reported. However, exceeding the recommended doses can cause side effects. Overdosage can lead to hypoglycaemia and subsequently to hyperglycaemia. Moreover, Somatropin overdose is likely to cause manifestations of fluid retention.

Pharmaco-therapeutic group: Anterior pituitary lobe hormones and analogues, ATC code: HO1A.

Saizen contains recombinant human growth hormone produced by genetically engineered mammalian cells.

It is a peptide of 191 amino acids identical to human pituitary growth hormone with respect to aminoacid sequence and composition as well as peptide map, isoelectric point, molecular weight, isomeric structure and bioactivity.

Growth hormone is synthesised in a transformed murine cell line that has been modified by the addition of the gene for pituitary growth hormone.

Saizen is an anabolic and anticatabolic agent, which exerts effects not only on growth but also on body composition and metabolism. It interacts with specific receptors on a variety of cell types including myocytes, hepatocytes, adipocytes, lymphocytes and hematopoietic cells. Some, but not all of its effects are mediated through another class of hormones known as somatomedins (IGF-1 and IGF-2).

Depending on the dose, the administration of Saizen elicits a rise in IGF-1, IGFBP-3, non-esterified fatty acids and glycerol, a decrease in blood urea, and decreases in urinary nitrogen, sodium and potassium excretion. The duration of the increase in GH levels may play a role in determining the magnitude of the effects. A relative saturation of the effects of Saizen at high doses is probable. This is not the case for glycemia and urinary C-peptide excretion, which are significantly elevated only after high doses (20 mg).

In a randomised clinical trial, three years treatment of pre-pubertal short children born SGA with a dose of 0.067 mg/kg/day resulted in a mean gain of +1.8 height-SDS. In those children who did not receive treatment beyond 3 years, part of the treatment benefit was lost, but the patients retained a significant gain of +0.7 height-SDS at final height (p<0.01 compared to baseline). Patients who received a second treatment course after a variable period of observation experienced a total gain of +1.3 height-SDS (p=0.001 compared to baseline) at final height. (The mean cumulative treatment duration in the latter group was 6.1 years). The gain in height-SDS (+1.3 ± 1.1) at final height in this group was significantly (p<0.05) different from the gain in height-SDS obtained in the first group (+0.7±0.8) that received only 3.0 years of treatment on average.

A second clinical trial investigated two different dose regimens over four years. One group was treated with 0.067 mg/kg/day for 2 years and then observed without treatment for 2 years. The second group received 0.067mg/kg/day in the first and third year and no treatment in the second and fourth year. Either treatment regimen resulted in a cumulative administered dose of 0.033/mg/kg/day over the four-year study period. Both groups showed a comparable acceleration of growth and a significant improvement of +1.55 (p<0.0001) and + 1.43 (p<0.0001) height-SDS respectively at the end of the four year study period. Long-term safety data are still limited.

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 2 to 4 hours. This is due to a rate limiting absorption process.

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

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

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. 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.

Powder for solution for injection

Mannitol, Disodium phosphate dihydrate, Sodium dihydrogen phosphate monohydrate

Solvent for parenteral use

0.9 % w/v sodium chloride in water for injections and 0.9 % w/v benzyl alcohol

No incompatibilities of Saizen with other pharmaceutical preparations are known at present.

2 years.

After reconstitution, the product may be stored for a maximum of 7 days in a refrigerator (2°C to 8°C).

Store in a refrigerator (2°C to 8°C) in the original package.

Store the reconstituted product in a refrigerator (2°C to 8°C) in the original package.

Do not freeze.

The 10 ml vials containing 3.33 mg of powder and the 5 ml vials containing 5 ml of solvent are of neutral glass (Type I). The vials are closed by rubber stoppers.

Saizen 3.33 mg is available in the following pack sizes:

1 vial of Saizen 3.33 mg product and 1 vial of bacteriostatic solvent.

5 vials of Saizen 3.33 mg product and 5 vials of bacteriostatic solvent.

Not all pack sizes may be marketed.

Reconstitution :

The 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 1 ml of the bacteriostatic solvent into the vial of Saizen 3.33 mg aiming the liquid against the glass wall. Swirl the vial with a GENTLE rotary motion until the content is dissolved completely. Avoid vigorous shaking.

Discard any unused solvent.

Serono Ltd.

Bedfont Cross, Stanwell Road

Feltham, Middlesex.

TW14 8NX

Telephone: +44(0)20 8818 7200

Product Licence Numbers

Saizen 3.33 mg PL 03400/0034

Bacteriostatic solvent PL 03400/0035

First authorisation in UK: 27th August 1991

Renewed: 19 April 2005

April 2005

POM