Full Information of Genotropin Cartridge by Pfizer

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Pharmacodynamic properties of Genotropin by Pfizer

Genotropin contains somatropin, a human growth hormone, synthesized using DNA technologies.

Somatropin is a potent metabolic hormone of importance for the metabolism of lipids, carbohydrates and proteins.

In children with inadequate endogenous growth hormone, somatropin stimulates linear growth and increases growth rate.

In adults, as well as in children, somatropin maintains a normal body composition by increasing nitrogen retention and stimulation of skeletal muscle growth, and by mobilization of body fat.

Visceral adipose tissue is particularly responsive to somatropin.

In addition to enhanced lipolysis, somatropin decreases the uptake of triglycerides into adipose depots.

Serum concentrations of IGF-1 and IGFBP-3 (insulin-like growth factor binding protein 3) are increased by somatropin.

In addition, the following actions have been demonstrated:

Lipid metabolism: Somatropin induces hepatic LDL cholesterol receptors, and affects the profile of serum lipids and lipoproteins.

In general, administration of somatropin to growth hormone deficient patients results in reductions in serum LDL and apolipoprotein B.

A reduction in serum total cholesterol may also be observed.

Carbohydrate metabolism: Somatropin increases insulin, but fasting blood glucose is commonly unchanged.

Children with hypopituitarism may experience fasting hypoglycemia. This condition is reversed by somatropin. Water and mineral metabolism Growth hormone deficiency is associated with decreased plasma and extracellular volumes.

Both are rapidly increased after treatment with somatropin.

Somatropin induces the retention of sodium, potassium and phosphorus.

Bone metabolism Somatropin stimulates the bone turnover. Long-term administration of somatropin to growth hormone deficient patients with osteopenia results in an increase in bone mineral content and density.

Physical capacity: Muscle strength and physical exercise capacity are improved after treatment with somatropin.

Somatropin also increases cardiac output, but the mechanism has yet to be clarified.

A decrease in peripheral vascular resistance may contribute to this effect.

In clinical trials in short children born small for gestational age (SGA) doses of 0.033 and 0.067 mg/kg body weight per day have been used for treatment until final height.

In 56 patients who were continuously treated and have reached (near) final height, the mean change from height at start of treatment was +1.90 SDS (0.033 mg/kg body weight per day) and +2.19 SDS (0.067 mg/kg body weight per day).

Literature data from untreated SGA children without early spontaneous catch-up suggest a late growth of 0.5 SDS.

The data on the safety in long-term administration of the drug are still limited.

Pharmacokinetic properties Absorption The bioavailability of subcutaneously administered Genotropin is approximately 80 % in both healthy subjects and growth hormone deficient patients.

A subcutaneous dose of 0.035 mg/kg of somatropin results in plasma Cmax and tmax values in the range of 13-35 ng/ml and 3-6 hours, respectively.

Elimination The mean terminal half-life of Genotropin after IV administration in growth hormone deficient adults is about 0.4 hours.

However, after SC administration, half-life of 2-3 hours is achieved.

This difference is likely due to slow absorption from the injection site following SC administration. Sub-populations. The absolute bioavailability of somatropin seems to be similar in males and females following SC administration.

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

Preclinical safety data In studies on general toxicity, local tolerance and reproduction toxicity no clinically relevant effects have been observed.

In vitro and in vivo, results of genotoxicity studies on gene mutations and induction of chromosome aberrations were negative.

An increased chromosome fragility has been observed in one in-vitro study on lymphocytes taken from patients after long-term treatment with somatropin and following the addition of the radiomimetic agent bleomycin.

The clinical significance of this finding is unclear. In another study, no increase in chromosomal abnormalities was found in the lymphocytes of patients who had received long-term somatropin therapy.

Therapeutic indications

Children Growth disturbance due to insufficient secretion of growth hormone (growth hormone deficiency, GHD); growth disturbance due to Shereshevsky-Turner syndrome; or growth disturbance during puberty due to chronic renal insufficiency we have described more in this article.

Growth disturbance (current height standard deviation score (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 (height velocity SDS < 0 during the last year] by 4 years of age or later.

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

For Adults Genotropin is indicated as a replacement therapy for adults with pronounced growth hormone deficiency associated with multiple hormone deficiencies as a result of known hypothalamic or pituitary pathology, and for patients who have at least one known deficiency of a pituitary hormone, except for prolactin.

These patients should undergo an appropriate dynamic test in order to diagnose or exclude a growth hormone deficiency.

Patients who were growth hormone deficient during childhood (as a result of congenital, genetic, acquired, or idiopathic causes) should be re-evaluated for growth hormone secretory capacity after completion of longitudinal growth.

In patients with a high likelihood for persistent GHD, an IGF-I SDS < – 2 without growth hormone treatment for at least 4 weeks should be considered sufficient evidence of GHD. All other patients will require IGF-I assay and one growth hormone stimulation test. 

Posology and method of administration: Genotropin Pfizer

The dosage and administration schedule should be individualized.

The injection should be given subcutaneously and the site varied to prevent lipoatrophy. Growth disturbance due to insufficient secretion of growth hormone in children: Generally a dose of 0.025 – 0.035 mg/kg body weight per day or 0.7 – 1.0 mg/m2 body surface area per day is recommended.

Even higher doses have been used.

Where childhood onset GHD persists into adolescence, treatment should be continued to achieve full somatic development (e.g. body composition, bone mass).

For monitoring, the attainment of a normal peak bone mass defined as a T score >– 1 (i.e. standardized to average adult peak bone mass measured by dual energy X-ray absorptiometry taking into account sex and ethnicity) is one of the therapeutic objectives during the transition period.

For dosing guidelines, see adult section below. Prader-Willi syndrome, for improvement of growth and body composition.

Generally, a dose of 0.035 mg/kg body weight per day or 1.0 mg/m2 body surface area per day is recommended.

Daily doses of 2.7 mg should not be exceeded.

Genotropin should not be used in children with a growth velocity of less than 1 cm per year and near closure of epiphyses.

Growth disturbance due to Shereshevsky-Turner syndrome: A dose of 0.045 – 0.050 mg/kg body weight per day or 1.4 mg/m2 body surface area per day is recommended.

Growth disturbance in chronic renal insufficiency: A dose of 1.4 mg/m2 body surface area per day (0.045 – 0.050 mg/kg body weight per day) is recommended. Higher doses can be needed, if growth velocity is too low.

A dose adjustment can be needed after six months of treatment.

Growth disturbance in short children born small for gestational age: A dose of 0.035 mg/kg body weight per day (1 mg/m2 body surface area per day) is usually recommended until final height is reached.

Treatment should be discontinued after the first year of treatment, if the height velocity SDS is below +1. Treatment should be discontinued, if height velocity is <2 cm/year and bone age is >14 years (girls) or >16 years (boys), corresponding to closure of the epiphyseal growth plates.

Dosage recommendations for pediatric patients

Indication Dose per day, mg/kg body weight.

Dose per day, mg/m2 body surface area Insufficient secretion of growth hormone in children 0.025-0.035 0.07-0.10 Prader-Willi syndrome 0.035 0.10 Shereshevsky – Turner syndrome 0.045-0.050 0.14 Chronic renal insufficiency 0.045-0.050 0.14 Growth disturbance in short children born small for gestational age 0.035 0.10.

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

In patients with adult-onset GHD, therapy should start with a low dose, 0.15–0.3 mg per day.

The dose should be gradually increased according to individual patient needs as determined by the IGF-I concentration.

In both cases treatment goal should be IGF-I concentrations within 2 SDS from the age-corrected mean value.

Patients with normal IGF-I concentrations at the start of the treatment should use such a dose of Genotropin to reach an upper range of normal IGF-I level, but not exceeding 2 SDS.

Clinical response and adverse effects should also be used as guidance for dose titration.

It is recognised that there are patients with GHD who do not normalize IGF-I levels despite a good clinical response, and thus do not require dose escalation.

The maintenance dose seldom exceeds 1.0 mg per day.  Women may require higher doses than men, since men become hypersensitive to IGF-1 over time.

This means that there is a risk that women, especially those on oral estrogen replacement therapy are under-treated, while men are over-treated.

Therefore, the dose of Genotropin should be adjusted every 6 months.

As normal physiological growth hormone production decreases with age, the dose of Genotropin should be reduced.

The minimum effective dose should be used. In patients aged 60 years or above, therapy should start with a dose of 0.1–0.2 mg per day and should be slowly increased according to individual patient needs.

The minimum effective dose should be used. The maintenance dose in these patients seldom exceeds 0.5 mg per day. Introduction. Genotropin 36 IU is administered subcutaneously using the Genotropin Pen injection device.

After the cartridge is inserted into the device, the drug is diluted automatically. When diluting, do not shake the solution, because this can lead to denaturation of the active substances.

Visually inspect the reconstituted solution for injection before use. Use only a clear solution without visible particles.

To prevent lipoatrophy, it is necessary to change the injection site.

Contraindications: Genotropin Go quick

Genotropin must not be used when there is any evidence of activity of a tumor.

Anti-tumor therapy must be completed prior to starting growth hormone therapy.

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

Patients with acute critical illness suffering from complications following open-heart surgery, abdominal surgery, multiple accidental trauma, or acute respiratory should not be treated with Genotropin.

Hypersensitivity to the active substance or to any of the excipients.

Overdose of Genotropin (Somatropin):

For each group, the frequency of adverse effects is ranked by severity. Patients with growth hormone deficiency are characterized by extracellular volume deficit.

When treatment with Genotropin is started, this deficit is rapidly corrected.

In adult patients, adverse effects related to fluid retention, such as edema peripheral, face edema, musculoskeletal stiffness, arthralgia, myalgia and paraesthesia are common.

In general, these adverse effects are mild to moderate, arise within the first months of treatment and resolved spontaneously or with dose reduction.

The incidence of these adverse effects is related to the administered dose, the age of patients, and possibly inversely related to the age of patients at the onset of growth hormone deficiency.

In children, such adverse effects are uncommon (≥1/1,000 to <1/100). Children may have transient skin reactions at the injection site.

There were single case reports on type 2 diabetes mellitus.

Rarely, benign intracranial hypertension develops. In adults, carpal tunnel syndrome may rarely be diagnosed. In some patients who were treated with Genotropin, the formation of antibodies to it was noted.

Their binding activity was low and not clinically significant at all.

There were reports on reduction of serum cortisol levels, possibly by affecting carrier proteins with somatropin or by increased hepatic clearance.

The clinical significance of this finding is unclear.

Despite this, GCS replacement therapy should be adjusted before starting treatment with Genotropin.

Leukemia has been reported in a small number of growth hormone deficient patients, some of whom have been treated with somatropin; however, the incidence of leukemia does not differ from that in children without growth hormone deficiency.

In the post-marketing experience, rare cases of sudden death have been reported in patients with Prader-Willi syndrome treated with somatropin, although no causal relationship has been demonstrated (here you can learn more).

System organ class Common ≥1/100 to <1/10 Uncommon ≥1/1,000 to <1/100 Rare ≥1/10,000 to <1/1,000 Very Rare <1/10,000 Neoplasms (benign and malignant).

Diagnosis and therapy with Genotropin should be initiated and monitored by physicians who are appropriately qualified and experienced in the diagnosis and management of diseases specified in the THERAPEUTIC INDICATIONS section.

Myositis is a very rare adverse event that may be related to the preservative m-cresol which is part of Genotropin.

In the case of myalgia or increased soreness at the injection site, myositis should be suspected.

If confirmed, a form of Genotropin without m-cresol should be used. Somatropin can cause insulin resistance and hyperglycemia in some patients, and therefore patients should be tested for a low glucose tolerance.

Sometimes the appearance of signs of type II diabetes mellitus may be a consequence of the use of somatropin, therefore it must be borne in mind that in most cases in diabetes mellitus there are risk factors such as obesity (including obesity in patients with Prader-Willi syndrome), family history, steroid therapy or a pre-existing low glucose tolerance.

In patients with diabetes mellitus, after the prescription of Genotropin, it may be necessary to correct antidiabetic therapy.

Somatropin increases the conversion of T4 to T3, which may result in a reduction in serum T4 and an increase in serum T3 concentrations.

Usually, the peripheral thyroid hormone levels have remained within the reference ranges, but hypothyroidism may develop in patients with subclinical hypothyroidism.

By contrast, in patients receiving thyroxine as a replacement therapy, moderate hyperthyroidism may develop.

In this regard, it is recommended to examine the thyroid gland after starting treatment with somatropin and after adjusting its dose.

In growth hormone deficiency secondary to treatment of malignant disease, it is recommended to pay attention to signs of relapse of the malignancy.

In patients with endocrine disorders, including growth hormone deficiency, slipped epiphyses of the hip may occur more frequently than in the general population.

Children limping during treatment with somatropin, should be examined clinically. In case of severe or recurrent headache, visual problems, nausea and/or vomiting, a funduscopy for papilledema is recommended.

If papilledema is confirmed, a diagnosis of benign intracranial hypertension should be considered. If necessary, growth hormone treatment should be discontinued.

At present, there is insufficient evidence to give specific advice on the continuation of growth hormone treatment in patients with clinical manifestations of intracranial hypertension.

However, clinical experience shows that the re-initiation of therapy in most cases did not cause an occurrence of signs of intracranial hypertension.

If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary. Experience in the use of Genotropin in patients aged 80 years or above is limited.

Elderly patients may be more sensitive to the action of Genotropin, and therefore may be more prone to develop adverse reactions.

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

There have been reports of fatalities associated with the use of growth hormone in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity (those patients exceeding a weight/height ratio of 200%), history of respiratory failure or sleep apnea, or unidentified respiratory infection.

Patients with one or more of these factors may be at increased risk.

Before initiation of treatment with somatropin in patients with Prader-Willi syndrome, signs for upper airway obstruction, sleep apnea, or respiratory infections should be assessed.

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

Sleep apnea should be assessed before onset of growth hormone treatment by polysomnography or overnight oxymetry, and monitored if sleep apnea is suspected.

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

All patients with Prader-Willi syndrome should be monitored, if sleep apnea is suspected. Patients should be monitored for signs of respiratory infections, which should be diagnosed as early as possible and treated aggressively.

All patients with Prader-Willi syndrome should also have effective weight control before and during growth hormone treatment.

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

The incidence and severity of scoliosis did not increase with the use of growth hormone.

Experience with long-term treatment in adults and in patients with Prader-Willi syndrome is limited. In short children born SGA, the reasons that could explain growth disturbance should be ruled out before starting treatment.

In SGA children, 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. family history of diabetes, obesity, severe insulin resistance, or acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If diabetes is confirmed, growth hormone should not be administered. In SGA children, it is recommended to measure the IGF-I level before start of treatment and twice a year thereafter. 

If on repeated measurements IGF-I levels exceed +2 SD compared to references for age and pubertal status, the IGF-I / IGFBP-3 ratio could be taken into account to consider dose adjustment.

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

Experience in patients with Silver-Russell syndrome is limited. Sometimes, in early termination, the success of treatment in short SGA children before they reach their final height, may be lost. In chronic renal insufficiency, renal function should be below 50% of normal before starting the therapy of Genotropin.

To confirm growth disturbance, this parameter should be monitored for a year preceding institution of therapy.

During this period and treatment with somatropin, conservative treatment for renal insufficiency (which includes control of acidosis, hyperparathyroidism and nutritional status) should be continued.

The treatment should be discontinued at renal transplantation. To date, no data on final height in patients with chronic renal insufficiency treated with Genotropin are available.

The efficacy of Genotropin was studied in two placebo-controlled trials involving 522 critically-ill patients suffering from complications following open-heart surgery, abdominal surgery, multiple accidental trauma or acute respiratory failure.

Mortality was higher in patients treated with 16 or 24 IU (5.3 or 8 mg) of Genotropin daily compared to patients receiving placebo (41.9% and 19.3%, respectively).

Based on this information, this group of patients should not be treated with Genotropin.

For rationale of the use of Genotropin in patients developing other or similar acute critical illness, the possible benefit of treatment must be weighed against the potential risk.

Pregnancy and lactation. Clinical experience in pregnant women is limited. Animal studies are not finished yet. If pregnancy is diagnosed, the use of Genotropin should be discontinued.

During the course of normal pregnancy, the level of pituitary-derived growth hormone drops significantly after week 20 and is replaced almost completely by placental one by week 30.

Therefore, it is unlikely to continue growth hormone replacement therapy in the III trimester of pregnancy in women with deficiency.

It is not known whether peptide hormones are excreted in human milk, but absorption of intact protein from the gastrointestinal tract of the infant is extremely unlikely.

Children The drug is used in pediatric practice. Effects on ability to drive and use machines.

There were no signs of influence on the ability to drive and use machines.

Genotropin can increase the clearance of compounds metabolized by cytochrome P450 3A4 (e.g. sex steroids, corticosteroids, anticonvulsants and cyclosporine).

The clearance of compounds metabolized by cytochrome P 450 3A4 may be especially increased resulting in low plasma levels of these compounds.

The clinical significance of this effect is unknown.

Overdose and intoxication are not described. Acute overdose could lead initially to hypoglycemia and subsequently to hyperglycemia.

Therapy is symptomatic.

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

Storage conditions: Store in a dark place at a temperature of 2 to 8 °C.   The reconstituted solution may be stored at a temperature of 2 to 8 °C for 28 days.

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