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Saizen (somatropin) injection, for subcutaneous use

Summary about Saizen

Saizen (somatropin) is a human growth hormone produced by recombinant DNA technology. It is a type of treatment called growth hormone replacement therapy and is available by prescription only. The structure of the growth hormone used in treatment is identical to the growth hormone produced by the pituitary gland.

Saizen is used for growth hormone therapy to replace the hormone that the body fails to produce on its own. It works to stimulate skeletal growth, increase the number and size of skeletal muscle cells, influence the size and function of internal organs, and has important effects on metabolism.

Treatment may not only help a body grow in height, but will also play an important role in stimulating the liver and other tissues to secrete IGF-1, a protein which supports muscle growth and metabolic functions.

 

Figure 1: Saizen product (Sourcehttps://www.saizenus.com/)

Saizen is indicated for the treatment of:

  • Pediatric patients with growth failure due to growth hormone deficiency (GHD) and
  • Adults with either adult onset or childhood onset GHD.

The goal of GH therapy in pediatric patients is to sustain normal linear growth and achieve a normal adult height. In addition to promoting linear growth, GH has favourable effects on muscle accretion and bone mineral density. GH stimulates osteoblast and osteoclast differentiation and promotes the accretion of bone mass. GH stimulates the proliferation of adipose precursor cells, restricts their differentiation into mature adipocytes, and limits deposition of fat in the abdominal visceral area. Consequently, children with growth hormone deficiency (GHD) demonstrate reduced linear growth, reduced lean body mass, increased body fat with disproportionate deposition of visceral and truncal fat, subnormal bone mineral density and lipid abnormalities. Untreated patients with adult onset GHD demonstrate all the pediatric consequences with the exception of a linear growth effect. Untreated adults with GHD have also decreased muscle strength, impaired cardiac function, and decreased quality of life.

Saizen is available in following forms:

  • Saizen® lyophilized powder in vial: 5 mg and 8.8 mg
  • Saizen® click.easy® reconstitution device: One vial Saizen® containing 8.8 mg somatropin and one cartridge diluent containing 1.51 ml 0.3% (w/v) metacresol in Sterile Water for Injection

 

 

Saizen is contrainidicated in following cases:

  • Acute critical illness
  • Children with Prader-Willi Syndrome who are severely obese or have severe respiratory impairment – reports of sudden death
  • Active malignancy
  • Hypersensitivity to somatropin or its excipients
  • Active proliferative or severe non-proliferative diabetic retinopathy
  • Children with closed epiphyses
  • Known hypersensitivity to somatropin or excipients
  • Diabetic retinopathy.

 

Saizen (somatropin)

Active Ingredient

Somatropin

Administration Route

Subcutaneous

Alcohol Warning

No data about interaction

Available Strength

 

·       Saizen® lyophilized powder in vial: 5 mg and 8.8 mg

·      Saizen® click.easy® reconstitution device: One vial Saizen® containing 8.8 mg somatropin and one cartridge diluent containing 1.51 ml 0.3% (w/v) metacresol in Sterile Water for Injection

Breastfeeding Warning

Caution is recommended. Excretion into human milk is unknown.

Following subcutaneous administration of radiolabelled medication in animal studies, radioactivity was transferred to milk reaching four  times the concentration found in maternal plasma. However, absorption of the intact protein in the gastrointestinal tract of the infant is considered extremely unlikely.

Clinical Pharmacology

Pharmacodynamics

Tissue Growth:
The primary and most intensively studied action of somatropin is the stimulation of linear growth. This effect is demonstrated in children with GHD.

Skeletal Growth:
The measurable increase in bone length after administration of somatropin results from its effect on the cartilaginous growth areas of long bones. Studies in vitro have shown that the incorporation of sulfate into proteoglycans is not due to a direct effect of somatropin, but rather is mediated by the somatomedins or insulin-like growth factors (IGFs). The somatomedins, among them IGF-I, are polypeptide hormones which are synthesized in the liver, kidney, and various other tissues. IGF-I levels are low in the serum of hypopituitary dwarfs and hypophysectomized humans or animals, and increase after treatment with somatropin.

Cell Growth:
It has been shown that the total number of skeletal muscle cells is markedly decreased in children with short stature lacking endogenous GH compared with normal children, and that treatment with somatropin results in an increase in both the number and size of muscle cells.

Organ Growth:
Somatropin influences the size of internal organs, and it also increases red cell mass.

Protein Metabolism:
Linear growth is facilitated in part by increased cellular protein synthesis. This synthesis and growth are reflected by nitrogen retention which can be quantitated by observing the decline in urinary nitrogen excretion and blood urea nitrogen following the initiation of somatropin therapy.

Carbohydrate Metabolism:
Hypopituitary children sometimes experience fasting hypoglycemia that may be improved by treatment with somatropin. In healthy subjects, large doses of somatropin may impair glucose tolerance. Although the precise mechanism of the diabetogenic effect of somatropin is not known, it is attributed to blocking the action of insulin rather than blocking insulin secretion. Insulin levels in serum actually increase as somatropin levels increase. Administration of human growth hormone to normal adults and patients with growth hormone deficiency results in increases in mean serum fasting and postprandial insulin levels, although mean values remain in the normal range. In addition, mean fasting and postprandial glucose and hemoglobin A1c levels remain in the normal range.

Lipid Metabolism:
Somatropin stimulates intracellular lipolysis, and administration of somatropin leads to an increase in plasma free fatty acids and triglycerides. Untreated GHD is associated with increased body fat stores, including increased abdominal visceral and subcutaneous adipose tissue. Treatment of growth hormone deficient patients with somatropin results in a general reduction of fat stores, and decreased serum levels of low density lipoprotein (LDL) cholesterol.

Mineral Metabolism:
Administration of somatropin results in an increase in total body potassium and phosphorus and to a lesser extent sodium. This retention is thought to be the result of cell growth. Serum levels of phosphate increase in children with GHD after somatropin therapy due to metabolic activity associated with bone growth. Serum calcium levels are not altered. Although calcium excretion in the urine is increased, there is a simultaneous increase in calcium absorption from the intestine. Negative calcium balance, however, may occasionally occur during somatropin treatment.

Connective Tissue Metabolism:
Somatropin stimulates the synthesis of chondroitin sulfate and collagen, and increases the urinary excretion of hydroxyproline.

Pharmacokinetics

Absorption 

The absolute bioavailability of somatropin after subcutaneous administration ranges between 70 to 90%.

Distribution

The steady-state volume of distribution (mean ±SD) of somatropin following intravenous administration in healthy volunteers was estimated to be 12.0 ± 1.08 L.

Metabolism 

The metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products is returned to the systemic circulation. The mean half-life of intravenous somatropin in normal males is around 0.6 hours, whereas subcutaneously and intramuscularly administered somatropin has a half-life of around 2 hours. The longer half-life observed after subcutaneous or intramuscular administration is due to slow absorption from the injection site.

Excretion

The clearance (mean ±SD) of intravenously administered somatropin in six normal male volunteers was 14.6 ± 2.8 L/hr.

Specific Populations

Pediatric – The pharmacokinetics of somatropin is similar in children and adults. However, no pharmacokinetic studies of SAIZEN have been conducted in pediatric patients.

Gender – No gender studies have been performed in children for somatropin. In adults, the clearance of somatropin in both men and women tends to be similar. However, no studies have been conducted to evaluate the effect of gender on pharmacokinetics of SAIZEN.

Race – No studies have been conducted to determine the effect of race on the pharmacokinetics of SAIZEN.

Renal Impairment Children and adults with chronic renal failure tend to have decreased somatropin clearance compared to those with normal renal function. However, no studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of SAIZEN.

Hepatic Impairment – A reduction in somatropin clearance has been noted in patients with hepatic dysfunction as compared with normal controls.

Cost

Approximate Retail Price

from  http://www.goodrx.com/Saizen

lyophilisate for solution for injection:

  • 5 mg (1 vial, 5 mg): $674.16

lyophilisate for solution for injection:

  • 5.83 mg/mL (1 cartridge, 8.8 mg): $2,836.07

Dosage Form

Injection for subcutaneous use

Dose Schedule

Pediatric GHD: 0.18 mg/kg/week, divided into equal doses given either on 3 alternate days, 6 times per week or daily

Adult GHD: Either a non-weight based or a weight based dosing regimen may be followed, with doses adjusted based on treatment response and IGF-1 concentrations.

Non-weight-based dosing: A starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) may be used without consideration of body weight, and increased gradually every 1 to 2 months by increments of approximately 0.1 to 0.2 mg/day.

Weight-based dosing: The recommended initial dose is not more than 0.005 mg/kg/day; the dose may be increased as tolerated to not more than 0.01 mg/kg/day after 4 weeks.

Drug Class

H01AC – Somatropin and somatropin agonists

Drug Unit

mg/ml

Food Warning

No known interactions

Included In
Health Insurance Plan

Saizen sometimes is covered by health insurance if considered medically necessary, but some patients have had coverage denied. The Magic Foundation offers help making the case for coverage or appealing a denial, and outlines patients’ experiences getting approval.

Interacting Drug

Inhibitors of 11ß-Hydroxysteroid Dehydrogenase Type 1:
May require the initiation of glucocorticoid replacement therapy. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance dosesGlucocorticoid Replacement Therapy:
Should be carefully adjustedCytochrome P450-Metabolized Drugs:
Monitor carefully if used with somatropinOral Estrogen:
Larger doses of somatropin may be required in womenInsulin and/or Oral/Injectable Hypoglycemic Agents:
May require adjustment

Is Available Generically

No. There is currently no therapeutically equivalent version of Saizen available.

Is Proprietary

Yes

Label Details

https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019764s072lbl.pdf

Legal Status

Legal.

Is not subject to the Controlled Substances Act.

Manufacturer

EMD Serono, Inc.

Maximum Intake

0.0125 mg/kg/day

Mechanism of Action

Somatropin binds to the human growth hormone receptor (GHR). Upon binding, soatropin causes dimerization of GHR, activation of the GHR-associated JAK2 tyrosine kinase, and tyrosyl phosphorylation of both JAK2 and GHR. These events recruit and/or activate a variety of signaling molecules, including MAP kinases, insulin receptor substrates, phosphatidylinositol 3′ phosphate kinase, diacylglycerol, protein kinase C, intracellular calcium, and Stat transcription factors. These signaling molecules contribute to the GH-induced changes in enzymatic activity, transport function, and gene expression that ultimately culminate in changes in growth and metabolism.

Non Proprietary Name

Somatropin

Overdosage

Short-term overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Furthermore, overdose with somatropin is likely to cause fluid retention.

Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone

Pregnancy Category

 

AU TGA pregnancy category B2: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.

US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Pregnancy Warning

Use is not recommended unless clearly needed.

Animal studies did not show any teratogenicity or adverse effects on gestation, morphogenesis, parturition, lactation, postnatal development, or reproductive capacity of the offspring; a slight increase in fetal death and increased body weight of pups, and reduced pregnancy rate, increased litter size, irregular estrus cycles, and decreased sperm motility in the parents were seen. There are no controlled data in human pregnancy.

Prescribing Info

https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019764s072lbl.pdf

Prescription Status

Prescription drug

Proprietary Name

Saizen

Related Drugs

Tesamorelin, Mecasermin rinfabate, Sermorelin, Mecasermin, Somatrem

RxCUI

202830

Warning

 

Acute Critical Illness: Potential benefit of treatment continuation should be weighed against the potential risk.

Prader-Willi Syndrome in Children: Evaluate for signs of upper airway obstruction and sleep apnea before initiation of treatment for GHD. Discontinue treatment if these signs occur.

Neoplasm: Monitor patients with preexisting tumors for progression or recurrence. Increased risk of a second neoplasm in childhood cancer survivors treated with somatropin – in particular meningiomas in patients treated with radiation to the head for their first neoplasm.

Impaired Glucose Tolerance and Diabetes Mellitus: May be unmasked. Periodically monitor glucose levels in all patients. Doses of concurrent antihyperglycemic drugs in diabetics may require adjustment.

Intracranial Hypertension: Exclude preexisting papilledema. May develop and is usually reversible after discontinuation or dose reduction.

Hypersensitivity: Serious hypersensitivity reactions may occur. In the event of an allergic reaction, seek prompt medical attention.

Fluid Retention (i.e., edema, arthralgia, carpal tunnel syndrome – especially in adults): May occur frequently. Reduce dose as necessary.

Hypoadrenalism: Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism.

Hypothyroidism: May first become evident or worsen.

Slipped Capital Femoral Epiphysis: May develop. Evaluate children with the

onset of a limp or hip/knee pain.

Progression of Preexisting Scoliosis: May develop.

Pancreatitis: Consider pancreatitis in patients with persistent severe abdominal pain.

 

Links:

https://www.saizenus.com/
https://www.drugs.com/mtm/saizen.html
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ab750de2-3eda-411a-924e-00c499eda39b
https://www.drugbank.ca/drugs/DB00052

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