Somatropin - About a Growth Hormone Replacement

Overview:

Recombinant human growth hormone (Somatropin) is a protein engineered to be almost similar to the natural human growth hormone. This hormone promotes tissue development, linear growth (height), and the metabolism of protein, carbohydrates, fat, and minerals. Its production is pulsatile and is predominantly regulated by GH-releasing hormone (GHRH) (stimulatory), Somatostatin (inhibitory), and, to a lesser extent, ghrelin (inhibitory) (stimulatory). GH secretion is regulated by a complicated feedback system that includes insulin-like growth factor-1 (IGF-1), leptin, ghrelin, free fatty acids, and the central nervous system.

What Are the Indications of Somatropin?

1. Pediatric Patients: Treatment of children with growth failure caused by a lack of endogenous growth hormone (GHD), short stature caused by Noonan syndrome and Turner syndrome, and children born with short height born small for gestational age (SGA) with little or no developmental catch-up by the age of two to four years.

2. Adults Patients: In people with growth hormone deficit (GHD) who fulfill any of the following two criteria, Somatropin injection is advised for the replacement of endogenous GH:

• Adult Onset (AO): Patients who develop GHD due to pituitary illness, hypothalamic disease, surgery, radiation therapy, or trauma, either alone or in combination with a deficiency of multiple hormones in the pituitary gland (hypopituitarism);

• Childhood Onset (CO): Patients who encountered GH deficiency during childhood due to congenital, genetic, acquired, or idiopathic reasons.

Patients treated with Somatropin for GHD as children and who have closed epiphyses should be re-evaluated before continuing Somatropin therapy at the lower dosage level suggested for deficiency of growth hormone in adults.

Dosage and Administration:

Somatropin therapy should be monitored by a physician who has experience in the evaluation and treatment of pediatric patients with short stature due to GHD, Noonan syndrome, Turner syndrome, or SGA, as well as adult patients with either childhood or adult-onset GHD.

• Dosage Formand Strength: Available as per-filled pens for subcutaneous injection and color-coded for easy identification and recognition of the doses.

  • 5 milligrams per 1.5 milliliter (orange).

  • 10 milligrams per 1.5 milliliter (blue).

  • 15 milligrams per 1.5 milliliter (green).

  • 30 milligrams per 3 milliliters (purple).

Dosing of Pediatric Patients:

• General Pediatric Information on Dose Calculation:

  • The dosage and administration of Somatropin should be tailored to each patient depending on the growth response. Serum insulin-like growth factor I (IGF-I) levels may be helpful during the titration of the doses.

  • Responses to Somatropin treatment tend to decline over time, especially in the case of pediatric patients. However, failure to increase the growth rate in pediatric patients, especially within the first year of treatment, suggests the need for close monitoring of compliance and screening for other reasons for growth retardation, such as hypothyroidism, malnutrition, bone age advancement, and antibodies to recombinant human GH.

  • Treatment of short stature should be stopped once both the epiphyseal ends unite.

• Children with Growth Hormone Deficiency (GHD):

  • It is suggested to take 0.024 to 0.034 milligrams per kilogram daily, six to seven times per week.

• Pediatric Patients with Short Stature Due to Noonan Syndrome:

  • Not every child with Noonan syndrome has a short stature; some children will grow to adult height without therapy. As a result, before starting Somatropin treatment for a child with Noonan syndrome, ensure that the child does not have short stature.

  • A daily dose of up to 0.066 micrograms per kilogram is advised.

• Pediatric Patients with Short Stature Due to Turner Syndrome

A daily dose of up to 0.067 micrograms per kilogram is advised.

Dosing of Adult Patients:

• Growth Hormone Deficiency (GHD) In Adults:

There are two ways to take Somatropin dosage in adults:

• Non-weight-Based Regimens - According to current consensus guidelines, a beginning dosage of around 0.2 mg/day (range, 0.15 to 0.30 mg/day) can be taken without regard for body weight. This dose can be progressively increased every one to two months by about 0.1 to 0.2 mg/day, depending on clinical response and serum insulin-like growth factor I (IGF-I) concentrations. The dose should be reduced if adverse effects occur or serum IGF-I concentrations exceed the normal range of age and gender. Maintenance doses differ greatly between individuals and between male and female patients.

• Weight-Based Regimens - Based on the dosing regimen adopted in the initial adult GHD registration studies, the suggested starting dose is less than 0.004 micrograms per kilogram per day. After around six weeks, the dose can be raised to less than 0.016 micrograms per kilogram daily, depending on the patient's needs. Clinical response, side effects, age, and gender-based titrations of serum IGF-I concentrations should be utilized as dosage titration guidelines.

• For elderly patients, who are more susceptible to the side effects of Somatropin than younger people, a lower beginning dose and increments in small doses should be considered. Furthermore, obese people are more prone to experience negative side effects when managed with a weight-based strategy. To achieve the therapy aim, estrogen-replete women may require larger doses than males. In women, oral estrogen treatment may raise the dosage needs.

Contraindications:

• Acute Critical Illness: Patients with an acute critical illness due to complications from open heart surgery, abdominal surgery, multiple accidental injuries, or those with severe respiratory failure should not be treated.

• Prader-Willi Syndrome in Children: Individuals with Prader-Willi syndrome who are extremely obese, with a history of upper airway obstruction or sleep apnea, or have significant respiratory dysfunction should not use Somatropin. It is not approved for treating pediatric children with genetically proven Prader-Willi syndrome growth failure.

• Active Malignancy: Somatropin is generally contraindicated in the presence of ongoing cancer. Before starting Somatropin therapy, any pre-existing cancer should be cured, and treatment should be completed. If there are any indications of recurring activity, Somatropin should be withdrawn. Because GHD can be an early indicator of a pituitary tumor (or, in rare cases, other brain cancers), the presence of such tumors should be checked before starting therapy. Somatropin should not be administered in individuals with signs of an underlying brain tumor, either progressing or recurrence of tumors.

• Hypersensitivity: Somatropin is not recommended for those allergic to the drug or its active ingredients. The usage of Somatropin drugs has been associated with systemic hypersensitivity responses.

• Diabetic Retinopathy: Somatropin is not recommended for individuals with active proliferative or severe non-proliferative diabetic retinopathy.

• Closed Epiphyses: Somatropin should not be administered in pediatric patients to promote growth after the closure of epiphyses.

Warnings and Precautions:

• Acute Critical Illness: Following therapy with pharmacologic quantities of Somatropin, there has been a gradual increase in mortality (death) rates in patients with acute critical illness due to problems following open heart surgery, abdominal surgery, multiple accidental injuries, or acute respiratory failure. The safety of continuing Somatropin therapy in patients getting replacement doses for specified conditions who acquire these diseases simultaneously has not been demonstrated. As a result, the possible benefit of continuing Somatropin medication in patients with acute critical diseases should be balanced against the potential danger.

• Prader-Willi Syndrome in Children: There have been instances of deaths after starting Somatropin medication in pediatric patients with Prader-Willi syndrome who had one or more of the risk factors listed below: extreme obesity, history of upper airway obstruction or sleep apnea, or unexplained respiratory infection. Male patients are at a higher risk than female patients. Before starting Somatropin medication, patients with Prader-Willi syndrome should be checked for upper airway obstruction and sleep apnea symptoms. Medication should be discontinued if patients exhibit indicators of upper airway obstruction (including the development or worsening of snoring) and new onset sleep apnea while on Somatropin. All individuals with Prader-Willi syndrome who receive Somatropin should maintain a healthy weight and be evaluated for disease symptoms.

• Neoplasms: A higher risk of a second neoplasm has been documented in childhood cancer survivors who had undergone radiation to the brain or head for their first neoplasm, developed later GHD, and were treated with Somatropin. The most prevalent of these second neoplasms were intracranial tumors, particularly meningiomas. Therefore, if Somatropin medication is started, the doctor or the staff should closely follow these individuals for the development of neoplasms.

• Impaired Glucose Tolerance and Diabetes Mellitus: Somatropin therapy may reduce insulin sensitivity, especially at larger dosages in susceptible individuals. Therefore, previously undetected decreased glucose tolerance and overt diabetes mellitus may become apparent with Somatropin therapy. In addition, patients have been diagnosed with the onset of type 2 diabetes mellitus. As a result, glucose levels should be evaluated regularly in all patients using Somatropin, particularly those with a risk for diabetes like obesity, Turner syndrome, or a family history of diabetes mellitus. In addition, patients with type 1 or type 2 diabetes or impaired glucose tolerance should be regularly monitored throughout Somatropin treatment. When Somatropin therapy is initiated in these individuals, the dosages of antihyperglycemic medicines (for example- Insulin or oral medication) need to be adjusted.

• Intracranial Hypertension: Few individuals treated with Somatropin drugs, intracranial hypertension (IH) with papilledema, visual abnormalities, headache, nausea, and vomiting have been recorded. Symptoms commonly appeared within the first eight weeks of starting Somatropin treatment. In all documented cases, IH-related signs and symptoms improved quickly once the medication or even the Somatropin dose was reduced. To rule out previous papilledema, a funduscopic evaluation should be conducted routinely before starting Somatropin medication and regularly following treatment if papilledema is detected during Somatropin administration. Patients with Turner syndrome may be at a higher risk of developing IH.

• Hypersensitivity: Somatropin drugs have been associated with serious systemic hypersensitivity responses, particularly anaphylactic reactions and angioedema. Patients and carers should be aware of such responses and seek medical help as early as possible if an allergic reaction develops.

• Fluid Retention: Retention of fluid with Somatropin treatment in adults is common. Fluid retention clinical symptoms of fluid retention (edema, arthralgia, myalgia, nerve compression of the nerves syndromes like carpal tunnel syndrome or paraesthesias) are often temporary and dosage dependent.

• Hypoadrenalism: Patients undergoing Somatropin treatment at risk for pituitary hormone deficiency have lower blood cortisol levels, or the central (secondary) hypoadrenalism gets unmasked.

• Hypothyroidism: Hypothyroidism, underdiagnosed or not treated, may impair an adequate response to Somatropin. Patients with Turner syndrome are predisposed to develop autoimmune thyroid disease and primary hypothyroidism. Central hypothyroidism may appear or worsen in GHD patients with Somatropin administration. Individuals using Somatropin should have frequent thyroid function testing, and thyroid hormone replacement treatment should be started or altered.

• Slipped Capital Femoral Epiphysis in Pediatric Patients: Slipped capital femoral epiphysis is more common in individuals with endocrine abnormalities (such as GHD and Turner syndrome) or rapidly growing children. Any pediatric patient who develops a limp or complains of pain in the hip or knee while on Somatropin treatment should be carefully checked.

• Progression of Preexisting Scoliosis in Pediatric Patients: Patients with a history of scoliosis managed with Somatropin should be evaluated for scoliosis advancement. Somatropin has not been demonstrated to enhance the occurrence of scoliosis. Skeletal problems are frequent in untreated Turner syndrome, Noonan syndrome, and Prader-Willi syndrome individuals. Physicians should monitor these anomalies, which can occur with Somatropin administration.

• Otitis Media and Cardiovascular Disorders in Turner Syndrome: Children with Turner syndrome should be thoroughly checked for otitis media and other ear disorders because they are at a greater risk of ear and hearing problems. Treatment with Somatropin may raise the likelihood of otitis media in Turner syndrome patients. Furthermore, people with Turner syndrome should be continuously watched for cardiovascular problems (stroke, aneurysm of the aorta or dissection, hypertension), as they are at risk for these conditions.

• Confirmation of Childhood Onset Adult GHD: Patients with epiphyseal closure who had Somatropin replacement treatment as a child should be re-assessed using the criteria.

• Lipoatrophy: Atrophy of the tissues may occur when Somatropin is injected subcutaneously at the same place for a prolonged period. Can rotate the injection to avoid this.

• Laboratory Tests: After treatment with Somatropin, inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH), and IGF-I, serum levels may rise.

• Pancreatitis: Cases of pancreatitis have been observed in children and adults undergoing Somatropin therapy, with some data suggesting that children are at a higher risk than adults. According to published research, females with Turner syndrome may be more vulnerable than other Somatropin-treated children. Any Somatropin-treated patient, particularly a child, who experiences chronic severe stomach discomfort should be evaluated for pancreatitis.

For Patients:

What Is a Growth Hormone?

Growth hormone (GH), also known as Somatotropin or human growth hormone, is a peptide hormone released by the pituitary gland's anterior lobe. It promotes the development of most of the body's tissues, including bone.

What Is Somatropin and Its Uses?

Human growth hormone (HGH), commonly known as Somatotropin, is a single polypeptide chain containing 191 amino acids synthesized by somatotropic cells in the anterior pituitary gland. The primary activity of Somatropin is to promote growth and development in children and adolescents and treat adults with growth hormone deficiency. Somatropin is nearly identical to human natural growth hormone, except that it is produced outside the body by a method known as "recombinant DNA technology" (genetic engineering).

What Are the Possible Side Effects?

Inform the physician immediately if the patient suffers from severe and recurring headaches accompanied by nausea, vomiting, or eye problems. These are symptoms of benign intracranial hypertension, a rare side effect.

Certain Frequencies May Have Side Effects, Which Are Defined as Follows:

• Highly Common: More than one out of every ten persons may be affected.

• Common: May impact up to one out of every ten persons.

• Uncommon: May impact up to one in every hundred persons.

• Rare: May impact up to one in every 1,000 persons.

• Very rare: Up to one in 10,000 persons may be affected.

• Unknown: The frequency cannot be calculated based on the given data.

Common Side Effects:

• Reactions at the site of injection include redness, itching, swelling, rash, hives, discomfort, inflammation, bleeding, and abnormal blood collection outside of a blood vessel (hematoma). If this happens to be extremely painful, then talk to the physician.

• Loss of fat tissue locally beneath the skin, which can be prevented by changing the site of injection.

• Carpal tunnel syndrome in adults is characterized by chronic stinging, burning, discomfort, and numbness in the fingers, primarily the thumb, index, and occasionally the middle and ring finger.

• Fluid retention in adults causes peripheral edema (swelling), muscular discomfort, numbness and tingling sensation, joint pain, and joint problems. These adverse effects generally emerge soon after the treatment, are temporary, and are dose-dependent.

• Isolated headaches.

Uncommon Side Effects:

• Benign hypertension intracranially (headache, nausea, vomiting, double vision, and other visual symptoms caused by elevated intracranial pressure surrounding the brain).

• Carpal tunnel syndrome and fluid retention.

• Enlargement of the breasts (one or both sides may be affected).

Very Rare Side Effects:

• Slipped capital femoral epiphysis (a hip condition that occurs when the developing end of the thigh bone slides away from the ball of the hip joint) and femoral head avascular necrosis. Please consult the doctor if the child has an unexplainable limp and hip or knee discomfort.

• Growth hormone therapy may lower thyroid hormone levels. Therefore, the doctor can periodically examine the thyroid hormone levels and, if necessary, prescribe the appropriate therapy.

Side Effects with an Unknown Frequency

• Due to treatment with Somatropin, the child may have allergic reactions.

• As the muscle, fat, and liver cells may not respond appropriately to insulin during growth hormone treatment, the child may suffer elevated insulin levels (hyperinsulinism) (insulin resistance). In addition, this disease can cause elevated blood sugar levels (hyperglycemia).

• Rarely has pancreatic inflammation been recorded in individuals receiving growth hormone treatment.

• Leukemia has been recorded in a limited number of people with growth hormone insufficiency; some have had Somatropin treatment. However, there is no indication that growth hormone recipients are more likely to develop leukemia without predisposing circumstances.

• Very infrequently, a patient may develop antibodies against Somatropin. However, these are typically not connected with any negative effects and do not impede growth.

What if an Overdose of Somatropin Occurs?

• Short-Term: Overdosage for a short duration may result in hypoglycemia, followed by hyperglycemia. Moreover, Somatropin overdose probably results in fluid retention of the fluid.

• Long-Term: Overdosage for a long duration may cause gigantism and acromegaly, which is consistent with the recognized consequences of excess growth hormone.

For Doctors:

What Is Somatropin?

Somatropin is a polypeptide hormone derived from recombinant DNA. The hormone is produced by a strain of E. coli bacteria that has been altered by inserting a plasmid containing the human growth hormone gene. Somatropin includes a sequence of 191 amino acids similar to the pituitary human growth hormone, which has a molecular weight of approximately 22,000 Daltons.

Dosage and Administration:

Somatropin is a sterile solution for subcutaneous injection in 1.5 mL or 3 mL ready-to-use prefilled pens.

What Is the Clinical Pharmacology of Somatropin?

• Mechanism of Action: Somatropin (an endogenous GH) binds to a dimeric receptor of GH in the membrane of the target cells, leading to intracellular signal transmission and various pharmacological actions. Some of these pharmacodynamic actions are predominantly regulated by IGF-I generated in the liver and locally (for example- skeletal growth, synthesis of the proteins), whereas others are essentially a result of Somatropin's direct actions (for example - lipolysis).

• Pharmacodynamics:

  • Tissue Growth: Somatropin's primary and most extensively researched action is the promotion of linear growth. This outcome has been observed in children with GHD.

  • Skeletal Growth: The significant increase in bone length following Somatropin treatment is due to its effect on the growth of the cartilaginous regions of long bones. In vitro, studies have revealed that including sulfate in proteoglycans is not a direct effect of Somatropin but is regulated by somatomedins or insulin-like growth factors (IGFs). Somatomedins, including IGF-I, are polypeptide hormones generated in the liver, kidney, and several other organs. IGF-I levels are low in the serum of hypopituitary dwarfism and hypophysectomized individuals or animals but rise following Somatropin administration.

  • Cell Growth: It has been demonstrated that children with short stature who lack endogenous GH have a significantly lesser total number of skeletal muscle cells than normal children and that Somatropin therapy increases both the size and number of cells in the muscles.

  • Organ Growth: Somatropin regulates internal organ growth and boosts red cell mass.

  • Protein Metabolism: Enhanced protein synthesis of the cells aids in linear growth. Nitrogen retention, which can be quantified by monitoring the drop in urinary nitrogen excretion and blood urea nitrogen upon the beginning of Somatropin treatment, reflects the synthesis and growth.

  • Carbohydrate Metabolism: Fasting hypoglycemia in hypopituitary children can occasionally be addressed with Somatropin therapy. Large doses of Somatropin may compromise glucose tolerance in healthy persons. Even though the actual mechanism of Somatropin's diabetogenic impact is unknown, it is believed to be due to inhibiting insulin action rather than inhibiting insulin secretion. Insulin levels in the blood rise as Somatropin levels rise. Human growth hormone administration to normal people and individuals with growth hormone deficiency causes a rise in mean serum fasting and postprandial insulin levels despite mean values maintained within the normal range. Furthermore, mean fasting and postprandial glucose and hemoglobin A1c levels were maintained within acceptable limits.

  • Lipid Metabolism: Somatropin increases lipolysis intracellularly, resulting in a rise in plasma-free fatty acids and triglycerides. Untreated GHD is associated with increased body fat reserves, particularly visceral and subcutaneous adipose tissue in the abdomen. Somatropin therapy of growth hormone deficient individuals gradually decreased fat deposits and lowered blood levels of low-density lipoprotein (LDL) cholesterol.

  • Mineral Metabolism: Administration of Somatropin causes a rise in total body potassium, phosphorus, and sodium to a lesser extent. Cell proliferation is believed to be the cause of this retention. Phosphate levels in children with GHD rise following Somatropin medication, owing to metabolic activity connected with bone expansion. Serum calcium levels remain unchanged. Although calcium output in the urine is raised, calcium absorption from the gut is also enhanced. Therefore, negative calcium balance may develop on rare occasions with Somatropin administration.

  • Connective Tissue Metabolism: Somatropin enhances the production of chondroitin sulfate and collagen and promotes the excretion of hydroxyproline in the urine.

• Pharmacokinetics:

  • Nine patients with growth hormone deficiency received a 180-minute IV infusion of Somatropin (33 ng/kg/min). At 150 minutes, achieved a mean human GH steady-state serum level of about 23.1 (±15.0) ng/mL and a mean clearance rate of about 2.3 (±1.8) mL/min/kg or 139 (±105) mL/min for hGH was recorded. Following infusion, serum human GH levels decayed exponentially, with a final elimination half-life (T1/2) of about 21.1 (±5.1) min.

  • In an investigation of Eighteen GHD adult patients, a subcutaneous dosage of 0.024 mg/kg or 3 IU/m2 was administered in the thigh, and mean Cmax values of 13.8 (±5.7) and 17.1 (±10.1) ng/mL were recorded for the four and eight milligrams Somatropin vials, respectively, at around four to five-hour post-treatment.

  • The average final T1/2 values were calculated to be between seven and ten hours. Therefore, the absolute bioavailability of Somatropin following subcutaneous dosing is still unknown.

Use in Specific Populations:

• Pregnancy: In pregnancy, Somatropin comes under the C category drug. Somatropin has not been studied in animal reproduction. Therefore, it is unknown whether Somatropin can cause fetal damage or alter reproductive capability when given to a pregnant woman. Therefore, Somatropin should only be administered to a pregnant woman if necessary.

• Nursing Mothers: It is unknown whether Somatropin is secreted in breast milk. Because many medications are excreted in human milk, Somatropin should be given with caution to a breastfeeding mother.

• Geriatric Use: Somatropin safety and efficacy in individuals over 65 have not been studied in clinical trials. Older people are more susceptible to Somatropin activity, and hence, more likely to suffer negative effects. Therefore, lower initial dosage and fewer dose increases are recommended.