Serostim 4 mg-in-vial, 5 mg-in-vial, 6 mg-in-vial, 8.8 mg-in-vial: Indications, Dosage, Precautions, Adverse Effects
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Serostim 4 mg-in-vial, 5 mg-in-vial, 6 mg-in-vial, 8.8 mg-in-vial - Product Information

Manufacture: EMD Serono, Inc
Country: Canada
Condition: AIDS Related Wasting, Cachexia, Prader-Willi Syndrome, Short Stature for Age
Class: Growth hormones
Form: Subcutaneous (SC), Powder
Ingredients: somatropin, sucrose, phosphoric acid

Somatropin for Injection
Lyophilized powder for reconstitution
4 mg/vial, 5 mg/vial, 6 mg/vial, 8.8 mg/vial

Somatropin for injection
Lyophilized powder for reconstitution
8.8 mg (5.83 mg/mL)

Summary Product Information

Route of Administration Dosage Form / Strength Clinically Relevant Nonmedicinal
Ingredients
Subcutaneous injection Lyophilized powder for reconstitution / 4 mg/vial, 5 mg/vial, 6 mg/vial, 8.8 mg/vial For a complete listing see Dosage Forms, Composition and Packaging section.
Subcutaneous injection Lyophilized powder for reconstitution / 8.8 mg (5.83 mg/ml) click.easy

Description

SEROSTIM (somatropin for injection, recombinant human growth hormone) is available in 4 mg/vial, 5 mg/vial, 6 mg/vial and 8.8 mg/vial doses.

SEROSTIM 8.8 mg (5.83 mg/ml) click.easy is an additional presentation of SEROSTIM, pre-assembled with a bacteriostatic solvent cartridge (0.3% (w/v) metacresol in water for injection) in a reconstitution device click.easy.

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.

SEROSTIM is an anabolic and anti-catabolic agent which exerts its influence by interacting 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 by another class of hormones known as somatomedins (IGF-I and IGF-II).

Indications and Clinical Use

SEROSTIM (somatropin for injection) is indicated for the treatment of HIV wasting associated with catabolism, weight loss or cachexia.

Geriatrics

The dosage and administration schedule in the elderly should be the same as for adults (see also Warnings and Precautions).

Pediatrics

There is limited experience with SEROSTIM in patients under 18 years of age. SEROSTIM should not be used in the pediatric age group until further data becomes available.

Contraindications

SEROSTIM (somatropin for injection) is contraindicated and should not be administered in the following cases:

  • In patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or patients having acute respiratory failure. Clinical studies demonstrated that high doses of growth hormone were associated with a significantly increased morbidity and mortality in those patients (see Warnings and Precautions).
  • In the presence of any progression of underlying intracranial tumour. Intracranial tumour should be inactive and anti-malignancy treatment must be completed with evidence of remission prior to instituting therapy. SEROSTIM should be discontinued if there is evidence of recurrent activity. Patients should be examined frequently for progression or recurrence of the underlying disease process.
  • In patients who are hypersensitive to or have a history of previous allergic reaction to somatropin or to any of the excipients or preservatives (benzyl alcohol or metacresol).
  • In patients with active neoplasia (either newly diagnosed or recurrent). Any anti-tumour therapy should be completed prior to starting therapy with SEROSTIM, and should be discontinued if there is evidence of recurrent tumor growth.
  • In patients with diabetes mellitus.
  • In patients with proliferative or preproliferative diabetic retinopathy.

Warnings and Precautions

Serious Warnings and Precautions

  • SEROSTIM (somatropin for injection) therapy should be carried out under the regular guidance of a physician who is experienced in the diagnosis and management of AIDS. Inadequate nutritional intake and hypogonadism, which are common in individuals with AIDS and which may contribute to catabolism and weight loss, should be corrected prior to initiation of SEROSTIM therapy.
  • Any substitution of Growth Hormone products should be made cautiously and only under medical supervision
  • SEROSTIM shall only be used if, once reconstituted, the resulting solution is water-clear and devoid of particulate matter

General

A significant increase in mortality was reported among growth hormone treated patients with acute critical illnesses in intensive care units due to complications following open heart surgery or abdominal surgery, multiple accidental trauma or acute respiratory failure compared with those receiving placebo (see Contraindications and Adverse Reactions).

Fluid retention is expected during growth hormone therapy. Oedema, joint swelling, arthralgias, myalgias, paresthesias may be clinical manifestations of fluid retention. However, these effects are dose dependent, and may resolve spontaneously with analgesic therapy, they usually resolve by reducing the total daily dose by 50% or the number of doses given per week.

SEROSTIM 8.8 mg/vial, reconstituted with the bacteriostatic diluent provided (containing 0.9% benzyl alcohol), should not be administered to patients sensitive to benzyl alcohol.

It is recommended that SEROSTIM 4 mg/vial, 5 mg/vial, 6 mg/vial and 8.8 mg/vial be administered using sterile, disposable syringes and needles. It is recommended that SEROSTIM 8.8 mg (5.83 mg/ml) click.easy after reconstitution be administered with the one-click auto-injector. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes. An appropriate container for the disposal of used needles and syringes should be used. To avoid transmission of disease, cartridge and prefilled syringe shall not be used by more than one person.

When SEROSTIM is administered subcutaneously at the same site over a long period, local tissue atrophy may result. This can be avoided by rotating the injection site daily.

Carcinogenicity and Mutagenesis

Carcinogenicity studies have not been conducted. There is no evidence from animal studies to date of SEROSTIM-induced mutagenicity.

Treatment with growth hormone may have an increased risk of developing neoplasm. Patients on SEROSTIM treatment should be monitored for the emergence of any new malignancy and the product discontinued if a new tumour or signs of relapse are detected.

Kaposi's sarcoma, lymphoma, cervical cancer in women and other malignancies are common in AIDS patients. In clinical studies, the risk of developing new Kaposi sarcoma lesions and lymphomas were not found to be increased. The effect of SEROSTIM on the incidence of cervical cancer has not been assessed in clinical trials since the majority of patients included were male. The potential effects of growth hormone on other malignancies are unknown. Evidence is available suggesting the possibility that growth hormone might increase the risk of development of cancers other than lymphoma, in particular colorectal cancer. Although this evidence is not conclusive, the advisability of a regular screening program for colorectal cancer should be discussed with patients having known risk factors for this malignancy.

Intracranial Hypertension (IH)

No cases of intracranial hypertension (IH) have been observed among patients with AIDS wasting treated with SEROSTIM. The syndrome of IH, with papilledema, visual changes, headache, nausea and/or vomiting has been reported in a small number of children with growth failure treated with growth hormone products. Symptoms usually occurred within the first eight weeks of initiation of growth hormone therapy. Nevertheless, funduscopic evaluation of patients is recommended at the initiation and periodically during the course of SEROSTIM therapy.

Idiopathic Intracranial Hypertension

Idiopathic intracranial hypertension has been recognized as a complication (early in treatment usually) of growth hormone treatment. The diagnosis is made on the basis of clinical symptoms such as severe, persistent or recurrent headache, visual problems, nausea and/or vomiting, papilloedema and temporal relationship to growth hormone. Physicians and parents should be attentive to relevant symptoms such as headache and visual problems in patients under growth hormone therapy. Fundoscopic examination should be performed routinely before initiating treatment with growth hormones to exclude pre-existent papilloedema regularly assessed during treatment. If papilloedema is confirmed by fundoscopy, growth hormone 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 recurs. At present, there is insufficient evidence to guide clinical decision making in patients with resolved intracranial hypertension.

Dependence/Tolerance

Inappropriate use of SEROSTIM by individuals who do not have indications for which growth hormone is approved, may result in clinically significant negative health consequences (see Adverse Reactions). SEROSTIM not a drug of dependence.

Endocrine and Metabolism

Hyperglycemia may occur in HIV-infected individuals due to a variety of reasons. SEROSTIM use was associated with a minimal increase of mean blood glucose concentration. Patients with diabetes mellitus or other risk factors for glucose intolerance should be monitored closely during SEROSTIM therapy.

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.

Hypothyroidism may develop during treatment with SEROSTIM. Growth hormone can affect the metabolism of thyroid hormones by increasing the extrathyroidal conversion of T4 to T3. Thyroid function should be evaluated before starting SEROSTIM therapy and regularly assessed during treatment.

During safety surveillance of patients with HIV-associated wasting, cases of new onset impaired glucose tolerance, new onset type 2 diabetes mellitus and exacerbation of preexisting diabetes mellitus have been reported in patients receiving SEROSTIM. Some patients developed diabetic ketoacidosis and diabetic coma. In some patients, these conditions improved when SEROSTIM was discontinued, while in others, the glucose intolerance persisted. Some of these patients required initiation or adjustment of antidiabetic treatment while on SEROSTIM.

Concomitant Medical Conditions

Patients with significant cardiac, hepatic or renal diseases were excluded from clinical studies. Therefore, the potential benefit of SEROSTIM treatment for these patients should be weighed against the possible risks.

Diagnosis and treatment of any identifiable factor attributing to weight loss such as opportunistic infection , malabsorption and inadequate nutritional intake and hypogonadism, which are common in individuals with AIDS disease should be monitored.

Concomitant Antiretroviral Therapy

In some experimental systems, somatropin has been shown to potentiate HIV replication in vitro at concentrations ranging from 50-250 ng/ml. There was no increase in virus production when the antiretroviral agents, zidovudine, didanosine or lamivudine were added to the culture medium. Additional in vitro studies have shown that somatropin does not interfere with the antiviral activity of zalcitabine or stavudine. In the controlled clinical trials, no significant somatropin-associated increase in viral burden was observed. However, the protocol required all participants to be on concomitant antiretroviral therapy for the duration of the study. In view of the potential for acceleration of virus replication, it is recommended that HIV patients be maintained on antiretroviral therapy for the duration of SEROSTIM treatment.

Immune

As for any recombinant product, SEROSTIM is potentially immunogenic. Consequently, if any serious hypersensitivity or allergic reaction occurs, SEROSTIM should be discontinued immediately and appropriate therapy initiated.

Local allergic reactions

With growth hormone therapies SEROSTIM 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).

Rarely, SC administration of growth hormone products can result in lipoatrophy (depression in the skin). Patients should be advised to consult their doctor if they notice any of these conditions. Continuous rotation of the injection site within a given area may help reduce or prevent these reactions. On rare occasion, injection site reactions may require discontinuation of SEROSTIM therapy.

Systemic allergic reactions

Systemic allergic reactions have rarely occurred with SEROSTIM. If any serious hypersensitivity or allergic reactions occurs, SEROSTIM therapy should be discontinued immediately and appropriate therapy initiated as per general guidelines.

Antibody production

As with all protein pharmaceuticals, a small percentage of patients may develop antibodies during treatment with growth hormones. Patients who have demonstrated an allergic reaction to other growth hormone products may demonstrate an allergic reaction to SEROSTIM (see Adverse Reactions). None of the study participants with AIDS wasting who were treated with SEROSTIM for the first time developed detectable antibodies to SEROSTIM.

Musculoskeletal

Increased tissue turgor (non-edematous swelling, particularly in the hands and feet) and musculoskeletal discomfort (pain, swelling and/or stiffness) may occur during treatment with SEROSTIM, but may resolve spontaneously, with analgesic therapy, or after reducing the frequency of dosing (see Dosage and Administration).

Carpal tunnel syndrome may occur during treatment with SEROSTIM. If the symptoms of carpal tunnel syndrome do not resolve by decreasing the weekly number of doses of SEROSTIM, it is recommended that treatment be discontinued.

Pancreatitis in Children

Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting a greater risk in children compared with adults. Published literature indicates that girls who have Turner syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin treated patient, especially a child, who develops persistent severe abdominal pain.

Renal / Hepatic / Biliary / Pancreatic impairments

A reduction in somatropin clearance has been noted in patients with hepatic dysfunction as compared with normal controls. Whether the clearance of the product is affected in patients with biliary or pancreatic impairment is unknown. The safety of SEROSTIM has not been established in patients with renal, 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.

Sexual Function/Reproduction

Reproduction studies have been performed in rats and rabbits. Doses up to 5 to 10 times the human dose, based on body surface area, have revealed no evidence of impaired fertility or harm to the fetus due to SEROSTIM.

Sensitivity

Sensitivity to diluent (metacresol):

If patients are sensitive or develops sensitivity to the diluents, the drug should be reconstituted with Water for Injection, USP (see Dosage and Administration).

Information for patients

Patients 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

Adult

Experience with prolonged treatment in adults is limited. Adverse events such as peripheral edema, myalgia, arthralgia, and paresthesiae were reported during post-marketing studies (see Adverse Reactions).

Pregnant Women

Reproduction studies have been performed in rats and rabbits. Doses up to 5 to 10 times the human dose, based on body surface area, have revealed no evidence of impaired fertility or harm to the fetus due to SEROSTIM. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be discontinued if pregnancy occurs.

Nursing Women

It is not known whether this drug is excreted in human milk. However, a study done on lactating rats showed that the concentration in milk 24 h after administration were 30 times higher than blood concentration at the same time point. Because many drugs are excreted in human milk, caution should be exercised when somatropin is administered to a nursing mother. SEROSTIM is not recommended for use during lactation.

There have been no studies with somatropin in lactating women. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SEROSTIM is administered to lactating women.

Pediatrics

There is limited experience with SEROSTIM in patients under 18 years of age. SEROSTIM should not be used in the pediatric group until further data becomes available.

Geriatrics

Clinical studies with SEROSTIM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients may be more sensitive to growth hormone action, and may be more prone to develop adverse reactions. Thus, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.

Monitoring and Laboratory Tests

SEROSTIM therapy should be carried out under the regular guidance of a physician who is experienced in the diagnosis and management of AIDS. Monitoring is advisable when SEROSTIM is administered in combination with drugs known to be metabolised by cytochrome 3A4 hepatic enzymes, such as some anti-retroviral drugs.

Thyroid function should be evaluated before starting SEROSTIM therapy and regularly assessed during treatment.

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

With Growth Hormone therapy the need for regular IGF-1 monitoring shall be considered to maintain IGF-1 within the normal range for age and sex. Glucose levels should be determined before starting SEROSTIM therapy and closely monitored during therapy. 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.

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.

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

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

Clinical manifestations of fluid retention are usually transient and dose dependent.

Occupational Hazards

SEROSTIM is not expected to interfere with the patient’s ability to drive or use machinery. No formal studies on the effects on the ability to drive and use machinery have been performed.

Adverse Reactions

Adverse Drug Reaction Overview

The most commonly reported adverse events reported in clinical studies conducted with SEROSTIM (somatropin for injection) were: musculoskeletal discomfort, fever, increased tissue turgor, diarrhoea, neuropathy, nausea, headache, abdominal pain, fatigue, leucopenia and albuminuria. Among these, increased tissue turgor, nausea and musculoskeletal discomfort were more frequent in the SEROSTIM group as compared to the placebo group (statistically significant, p ≤ 0.05).

The most frequently reported adverse reactions resulting in clinical intervention (e.g., discontinuation of SEROSTIM, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction symptom) were increased tissue turgor and musculoskeletal discomfort.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

In two placebo-controlled clinical trials in which 205 patients were treated with SEROSTIM the most common adverse reactions felt to be associated with SEROSTIM were musculoskeletal discomfort and increased tissue turgor (non-edematous swelling, particularly of the hands or feet) (see Warnings and Precautions). These symptoms were generally rated by investigators as mild to moderate in severity and usually subsided with continued treatment. Discontinuations as a result of these events were rare.

Because of the diverse clinical manifestations of AIDS, and the frequent occurrence of adverse events associated with underlying disease process, it was often difficult to distinguish adverse events possibly associated with the administration of SEROSTIM from underlying signs or symptoms of AIDS or associated intercurrent illnesses.

In two small studies, 11 children with HIV-associated failure to thrive were treated subcutaneously with human growth hormone. In one study, five children (age range, 6 to 17 years) were treated with 0.04 mg/kg/day for 26 weeks. In a second study, six children (age range, 8 to 14 years) were treated with 0.07 mg/kg/day for 4 weeks. Treatment appeared to be well tolerated in both studies. These preliminary data collected on a limited number of patients with HIV-associated failure to thrive appear to be consistent with safety observations in growth hormone treated adults with HIV wasting.

Common Clinical Trial Adverse Events

Clinical adverse events which occurred during the first 12 weeks of study in at least 1% of those who received SEROSTIM during the two placebo-controlled trials are listed below by treatment group.

Body System
  Preferred Term
SEROSTIM (n=205)
%
Placebo (n=150)
%
BODY AS A WHOLE - GENERAL
  Fever 31.2 29.3
  Increased Tissue Turgor* 27.3 2.7
  Fatigue 17.1 16.0
  Rigors 9.3 6.7
  Influenza-like Symptoms 5.4 8.0
  Malaise 4.9 3.3
  Asthenia 3.9 4.0
  Carpal Tunnel Syndrome 2.9 0.0
  Tolerance Increased 2.9 0.0
  Death 2.4 2.0
  Chest Pain 2.4 0.7
  Pain 1.0 2.7
  Hot Flashes 1.0 0.7
  Allergic Reaction 1.0 0.0
GASTRO-INTESTINAL SYSTEM
  Diarrhoea 25.9 20.0
  Nausea* 25.9 16.0
  Abdominal Pain 17.1 18.7
  Vomiting 11.7 12.0
  Flatulence 5.9 2.7
  Leukoplakia Oral 5.4 4.0
  Mouth Dry 4.4 1.3
  Constipation 2.9 2.7
  Dyspepsia 2.4 4.7
  Dysphagia 2.0 1.3
  Oesophagitis 2.0 0.7
  Pancreatitis 1.5 0.7
  Stomatitis Ulcerative 1.0 3.3
  Colitis 1.0 1.3
  Rectal Disorder 1.0 1.3
  Gastritis 1.0 0.7
  Tongue Ulceration 1.0 0.7
  Gingivitis 1.0 0.0
  Tongue Disorder 1.0 0.0
MUSCULO-SKELETAL SYSTEM
  Musculoskeletal Discomfort* 53.7 33.3
  Muscle Weakness 2.4 0.7
CENTRAL and PERIPHERAL NERVOUS SYSTEM
  Neuropathy 25.9 17.3
  Headache 19.0 20.7
  Dizziness 3.4 4.7
  Convulsions 1.5 1.3
  Encephalopathy 1.5 0.0
  Tremor 1.0 1.3
  Nystagmus 1.0 0.7
  Meningism 1.0 0.0
RESPIRATORY SYSTEM
  Dyspnoea 9.8 6.0
  Coughing 9.3 13.3
  Sinusitis 8.8 10.0
  Upper Resp Tract Infection 7.8 6.0
  Pharyngitis 5.9 4.7
  Rhinitis 3.9 6.0
  Pneumonia 3.9 2.7
  Bronchitis 2.4 4.0
  Sputum Increased 2.4 0.0
  Respiratory Disorder 2.0 0.7
  Bronchospasm 1.5 2.0
  Pneumonitis 1.5 0.7
  Pleurisy 1.5 0.0
WHITE CELL AND RETICULOENDOTHELIAL SYSTEM DISORDERS
  Lymphadenopathy 14.1 16.0
  Lymphadenopathy Cervical 2.0 3.3
  Eosinophilia 1.0 2.7
SKIN AND APPENDAGES
  Sweating Increased 14.1 8.7
  Rash* 5.9 13.3
  Skin Disorder 5.9 6.0
  Folliculitis 4.9 2.7
  Alopecia 2.0 0.7
  Photosensitivity Reaction 2.0 0.7
  Pigmentation Abnormal 1.5 1.3
  Seborrhoea 1.5 0.7
  Dermatitis 1.0 1.3
  Skin Ulceration 1.0 1.3
  Acne 1.0 0.0
  Skin Discolouration 1.0 0.0
  Verruca 1.0 0.0
SYCHIATRIC
  Anorexia 12.2 9.3
  Insomnia 11.2 9.3
  Depression 8.8 6.0
  Anxiety 5.4 6.0
  Somnolence 2.4 0.7
  Nervousness 2.0 0.7
  Appetite Increased 1,5 2.0
  Amnesia 1.0 0.7
  Thinking Abnormal 1.0 0.0
METABOLIC AND NUTRITIONAL
  Hyperglycaemia 10.2 6.0
  Hypertriglyceridaemia 9.3 7.3
  Dehydration 3.4 4.0
  Cachexia 1.5 2.7
  Hypokalaemia 1.5 0.7
  Glycosuria 1.0 2.0
  Thirst 1.0 0.7
  Acidosis 1.0 0.0
RESISTANCE MECHANISM DISORDERS
  Moniliasis 9.3 8.0
  Infection Bacterial 6.8 2.0
  Pneumocystis Carinii Infection 4.4 5.3
  Infection Viral 4.4 1.3
  Infection 2.9 2.0
  Herpes Simplex 2.4 5.3
  Sepsis 1.5 2.0
  Abscess 1.5 1.3
  Infection Fungal 1.5 0.7
  Herpes Zoster 1.0 0.7
URINARY SYSTEM
  Albuminuria 15.1 9.3
  Haematuria 6.8 4.7
  Urinary Tract Infection 1.0 0.7
  Nocturia 1.0 0.0
LIVER AND BILIARY SYSTEM
  Hepatic Function Abnormal 2.0 0.7
  Hepatomegaly 1.5 2.7
  Hepatitis 1.0 0.0
RED BLOOD CELL
  Anaemia 12.2 8.7
HEART RATE AND RHYTHM
  Tachycardia 11.2 6.0
VISION
  Retinitis 3.4 2.7
  Vision Abnormal 2.9 3.3
  Photophobia 1.0 0.0
PLATELET, BLEEDING and CLOTTING
  Thrombocytopenia 5.9 6.0
  Purpura 1.0 4.7
CARDIOVASCULAR, GENERAL
  ECG Abnormal 1.5 2.7
  Heart Murmur 1.5 1.3
  Hypertension 1.5 0.7
  Hypotension 1.0 1.3
APPLICATION SITE
  Injection Site Pain 2.9 1.3
  Injection Site Reaction 2.0 2.7
NEOPLASMS
  Sarcoma 3.4 2.7
REPRODUCTIVE, MALE
  Epididymitis 1.0 0.7
  Penis Disorder 1.0 0.7
  Hernia Inguinal 1.0 0.0
HEARING AND VESTIBULAR
  Ear Disorder 2.0 2.0
  Earache 2.0 1.3
  Hearing Decreased 1.0 0.0
ENDOCRINE
  Gynaecomastia 2.4 0.7
  Breast Pain Male 1.5 0.0

* statistically significant difference, p<0.05

The table above displays all adverse events reported in clinical studies, regardless of causality assessment and severity. Among the adverse events, several can be considered as adverse reactions to SEROSTIM, either by analyzing the difference in frequency as compared to placebo, or by evaluating their plausibility in relationship to the known mechanism of action of SEROSTIM. Carpal tunnel syndrome, peripheral neuropathies and hyperglycaemia were more frequent than in the placebo group and are known effects of somatropin (see Warnings and Precautions).

Less Common Clinical Trial Adverse Drug Reactions

Adverse events which occurred in less than 1% of study participants receiving SEROSTIM in the two placebo-controlled clinical efficacy studies are listed below by body system. The list of adverse events has been compiled regardless of causal relationship to SEROSTIM.

Body as a Whole - General : Syncope, chest pain substernal, hypovolaemia
Gastro-intestinal System : abdomen enlarged, eructation, haemorrhoids, melaena, oesophageal ulceration, duodenitis, enanthema, gastric ulcer, gastro-intestinal disorder, haemorrhage rectum, haemorrhoids thrombosed, hiccup, intestinal obstruction, peptic ulcer, periodontal destruction, stomatitis aphthous, tooth disorder
Musculo-skeletal System : bursitis
Central and Peripheral Nervous System : cerebral atrophy, migraine, gait abnormal, neuritis cranial, sensory disturbance, dysphonia, hyperkinesias, hyperreflexia, vertigo
Respiratory System: chest x-ray abnormal, hypoxia, pneumothorax, respiratory insufficiency
White Cell and Reticuloendothelial System Disorders : leukocytosis
Skin and Appendages : skin dry, eczema, rash maculo-papular, hypertrichosis, psoriasis
Psychiatric : agitation, confusion, concentration impaired, libido decreased, libido increased, neurosis
Metabolic and Nutritional : Hypoglycaemia, hyperkalaemia, hypophosphataemia, serum iron decreased, diabetes mellitus, hyperglobulinaemia, hypocalcaemia, hyponatraemia, oedema pharynx, serum iron increased
Resistance Mechanism Disorders : toxoplasmosis
Urinary System : dysuria, nephropathy toxic, renal calculus, urine abnormal, polyuria, renal cyst
Liver and Biliary System : cholecystitis, hepatitis cholestatic, hepatosplenomegaly, jaundice
Red Blood Cell : splenomegaly
Heart Rate and Rhythm : bradycardia, qt prolonged, palpitation
Vision : conjunctivitis, conjunctival discolouration, glaucoma, miosis, retinal oedema
Platelet, Bleeding and Clotting : prothrombin increased
Cardiovascular, General : hypotension postural, cardiomegaly, cyanosis
Application Site : otitis externa
Neoplasms : lymphoma malignant
Reproductive, Male : Prostatic disorder, genital eruption male, orchitis
Hearing and Vestibular tinnitus
Endocrine : adrenal hypercorticism, hypothyroidism
Vascular (extracardiac) : peripheral ischaemia, atherosclerosis, flushing, purpura, telangiectasis

The types and incidences of adverse events reported in an open-label, extension trial and in a single, foreign trial, for up to one year, were not different from, or greater in frequency, than those observed in the primary, placebo-controlled, clinical trials.

Abnormal Hematologic and Clinical Chemistry Findings

Adverse Event SEROSTIM
(n=205)
%
Placebo
(n=150)
%
Leukopenia* 15.1 24.7
Albuminuria 15.1 9.3
Granulocytopenia 14.1 21.3
Lymphadenopathy 14.1 16.0
Anemia 12.2 8.7
SGOT increased 11.7 6.0
Tachycardia 11.2 6.0
Hyperglycemia 10.2 6.0
SGPT increased 10.2 5.3
Phosphatase alkaline increased 7.3 4.7
Creatinine Phosphokinase increased 2.0 0.7
LDH increased 2.0 0.7
Amylase increased 1.5 2.0

* statistically significant difference, p < 0.05

Post-Market Adverse Drug Reactions

During post-marketing surveillance, the following adverse reactions have been reported. The indicated frequency is an estimate based on reporting rates.

Reactions reported at frequency >1%

Body as a Whole - General Disorders:
  Oedema (mainly peripheral)
  Carpal tunnel syndrome
Musculo-skeletal Disorders:
  Arthralgia, myalgia
Central and Peripheral Nervous System Disorders:
  Paresthesia, hypoesthesia
Metabolism Disorders:
  Increase in blood glucose levels
Endocrine Disorders:
  Gynecomastia
Heart Rate and Rhythm Disorders:
  Tachycardia

Reactions reported at frequency <1%

Central and Peripheral Nervous System Disorders:
  Idiopathic intracranial hypertension has been reported with somatropin in children
  Diabetes - During postmarketing surveillance, cases of new onset glucose intolerance, diabetes mellitus and exacerbation of pre-existing diabetes mellitus have been reported in patients receiving SEROSTIM. Some patients developed diabetic ketoacidosis. In some patients, these conditions improved when SEROSTIM was discontinued while in others the glucose intolerance persisted.
Neoplasms:
  Some cases of malignancies (mainly lymphoma) have been reported in post-marketing surveillance (see Warnings and Precautions).

Drug Interactions

During clinical trials in which all patients received concomitant anti-retroviral therapy there were no detectable increases in plasma viral load following SEROSTIM (somatropin for injection) therapy, as measured by quantitative HIV-RNA analysis. Patients with AIDS wasting considered for treatment with SEROSTIM should also receive concomitant approved anti-retroviral therapy.

No formal interaction studies have been performed in patients treated with SEROSTIM. Published in vitro data indicate that growth hormone treatment may increase cytochrome P 450 3A4 mediated antipyrine clearance in man. Caution is recommended when administering SEROSTIM with compounds that are metabolized by the CP450 or CY3A4 liver enzymes (e.g corticosteroids, sex steroids, anticonvulsants, cyclosporine and others.

Concomitant glucocorticoid treatment may inhibit the human growth hormone. If glucocorticoid replacement therapy is required, glucocorticoid dosage and compliance should be monitored carefully to avoid either adrenal insufficiency or inhibition of growth promoting effects. In patients treated with somatropin, previously undiagnosed secondary hypoadrenalism may be unmasked requiring glucocorticoid replacement therapy. In addition patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses.

Growth hormone therapy may affect the metabolism of glucocorticoids, by inhibiting the microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) which is required for the conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Introduction of Growth hormone therapy may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. In consequence, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with Growth Hormones.

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 and laboratory tests have not been established.

Dosage and Administration

Dosing Considerations

Before initiating a patient on SEROSTIM (somatropin for injection) therapy, please review completely the Contraindications and Warnings and Precautions. The patient’s medical history for hypersensitivity reactions should be carefully evaluated prior to performing the injection.

SEROSTIM treatment should be carried out under regular guidance of a physician experienced in the diagnosis and management of HIV and wasting.

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

SEROSTIM 8.8 mg/vial and 8.8 mg (5.83 mg/ml) click.easy once reconstituted is intended for subcutaneous multiple dose administration.

Recommended Dose and Dosage Adjustment

SEROSTIM should be administered subcutaneously daily at bedtime according to the following dosage recommendations:

Weight Range Dose*
>55 kg 6 mg SC daily
45-55 kg 5 mg SC daily
35-45 kg 4 mg SC daily

* Based on an approximate daily dosage of 0.1 mg/kg

In patients who weigh less than 35 kg, SEROSTIM should be administered at a dose of 0.1 mg/kg subcutaneously daily at bedtime.

Missed Dose

For patients who miss a dose, it is not recommended to double the next dose. The patients should be reminded to contact the physician monitoring their treatment.

Administration

Administer subcutaneously daily at bedtime. Dose reductions for side effects felt to be related to treatment with SEROSTIM, which are unresponsive to symptomatic treatment, may be effected by reducing the number of doses given per week. In controlled trials, dose reductions were accomplished by reducing the frequency of dosing to five or three times a week.

Injection sites should be rotated.

Serostim 4 mg/vial, 5 mg/vial, 6 mg/vial, and 8.8 mg/vial

SEROSTIM once reconstituted should be administered using sterile, disposable syringes and needles. The syringe used should be of appropriately small volume to ensure accurate dose withdrawal. The calculated dose should be withdrawn for subcutaneous administration.

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

SEROSTIM 8.8 mg (5.83 mg/ml) click.easy once reconstituted, should be administered using the one.click auto-injector. The route of injection using the auto-injector is subcutaneous.

The calculated dose should be set on the one.click device. Follow the instructions given in PART III: CONSUMER INFORMATION.

Although SEROSTIM 8.8 mg (5.83 mg/ml) in the click.easy device is intended for the one.click auto-injector, SEROSTIM 8.8 mg (5.83 mg/ml) click.easy, once reconstituted, can also be accessed with a conventional syringe for a subcutaneous injection.

Serostim 4 mg/vial, 5 mg/vial, 6 mg/vial, 8.8 mg/vial

Once the appropriate dose for a patient has been determined, reconstitute each vial of SEROSTIM with the diluent supplied.

Once SEROSTIM 4mg/vial, 5 mg/vial or 6 mg/vial is reconstituted with the diluent supplied (Sterile Water for Injection, USP), the reconstituted solution should be used immediately (within 3 hours). Although not recommended, it may be stored for up to 24 hours at 2-8 °C. As there is no preservative in this reconstituted solution, any unused solution should be discarded once the dose is given.

Once SEROSTIM 8.8 mg/vial is reconstituted with the diluent supplied (Bacteriostatic Water for Injection, USP), the reconstituted solution may be stored for up to 14 days at 2-8 °C.

For use of SEROSTIM 8.8 mg/vial in patients sensitive to benzyl alcohol, SEROSTIM 8.8 mg/vial should be reconstituted with Sterile Water for Injection, USP, and used immediately (within 3 hours). Although not recommended, it may be stored for up to 24 hours at 2-8 °C. As there is no preservative in this reconstituted solution, any unused solution should be discarded once the dose is given.

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

Once SEROSTIM 8.8 mg (5.83 mg/ml) click.easy is reconstituted, the solution may be stored for 28 days at 2-8 C. Do not freeze.

Overdosage

Glucose intolerance can occur with overdosage. Long-term overdosage with growth hormone could results in signs and symptoms of acromegaly.

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

Action and Clinical Pharmacology

Mechanism of Action

HIV-associated wasting is a metabolic disorder characterized by specific abnormalities of intermediary metabolism resulting in weight loss, inappropriate depletion of lean body mass (LBM), and paradoxical preservation of body fat. LBM includes primarily skeletal muscle, organ tissue, blood and blood constituents. LBM depletion results in muscle weakness, organ failure, immune deficiency, general inanition and death. Unlike nutritional intervention for HIV-associated wasting, in which supplemental calories are converted predominantly to body fat which is essentially inert in day-to- day metabolic balance, the anabolic and anti-catabolic effects of somatropin treatment resulted in a prompt and sustained increase in LBM and a decrease in body fat with a significant increase in body weight due to the dominant effect of LBM gain.

Pharmacodynamics

Effects on Protein, Lipid, and Carbohydrate Metabolism

A one-week study in 6 patients with HIV-associated wasting has shown that treatment with somatropin improves nitrogen balance, increases protein-sparing lipid oxidation, and has little effect on overall carbohydrate metabolism.

Lean Body Mass Accrual

In the same study, treatment with somatropin resulted in the retention of phosphorous, potassium, nitrogen, and sodium. The ratio of retained potassium and nitrogen during somatropin therapy was consistent with retention of these elements in lean tissue. In clinical studies (12 weeks), somatropin significantly increased lean body mass. There was also a proportionate increase in intracellular and extracellular fluid during somatropin therapy suggesting accretion of normally hydrated lean body tissue.

Physical Performance

Treadmill performance was examined in a 12-week placebo-controlled study. Work output improved significantly in the somatropin-treated group after 12 weeks of therapy and was correlated with LBM. No such correlation was seen with body fat. Isometric muscle performance, as measured by grip strength dynamometry, declined, probably as a result of a transient increase in tissue turgor known to occur with r-hGH therapy.

Pharmacokinetics

Subcutaneous Absorption

The absolute bioavailability of somatropin after subcutaneous administration of a formulation not equivalent to the marketed formulation was determined to be 70-90%. The t½ (Mean ± SD) after subcutaneous administration is significantly longer than that seen after intravenous administration to normal male volunteers, down-regulated with somatostatin (3.94 ± 3.44 hrs. vs. 0.58 ± 0.08 hrs.), indicating that the subcutaneous absorption of the clinically tested formulation of the compound is slow and rate-limiting.

Distribution

The steady-state volume of distribution (Mean ± SD) following IV administration of somatropin in healthy volunteers is 12.0 ± 1.08 L.

Metabolism

Although the liver plays a role in the metabolism of growth hormone (GH), GH is primarily cleaved in the kidney. GH undergoes glomerular filtration and after cleavage within the renal cells, the peptides and amino acids are returned to the systemic circulation.

Elimination

The t½ (Mean ± SD) in nine patients with AIDS-related wasting with an average weight of 56.7 ± 6.8 kg, given a fixed dose of 6.0 mg r-hGH subcutaneously was 4.28 ± 2.15 hrs. The renal clearance of r-hGH after subcutaneous administration in nine patients with AIDS-related wasting was 0.0015 ± 0.0037 L/h. No significant accumulation of r-hGH appears to occur after 6 weeks of dosing as indicated.

Summary of SEROSTIM Pharmacokinetics Parameters in healthy volunteers
Parameters Cmax
(mIU/mL)
AUClast
(mIU/mL)
AUC
(mIU/mL)
AUC
extrapolated
(%)
tmax
(h)
median values
SEROSTIM Mean (Min-max) 146 (92 - 244) 1090 (706-1440) 1150 (867-1490) 4.37 (0.9-12.2) 3.05 (2.00-6.00)

1 mg = approx. 3 IU

Special Populations and Conditions

Pediatric

Available evidence suggests that r-hGH clearances are similar in adults and children, but no clinical studies were conducted in children with acquired immune deficiency syndrome or AIDS-related complex.

Gender

Biomedical literature indicates that a gender-related difference in the mean clearance of r-hGH could exist (clearance of r- hGH in males > clearance of r-hGH in females). However, no gender-based analysis is available on SEROSTIM (somatropin for injection) in normal volunteers or patients infected with HIV.

Renal Insufficiency

It has been reported that individuals with chronic renal failure tend to have decreased hGH clearance compared to normals, but there are no data on SEROSTIM use in the presence of renal insufficiency.

Hepatic Insufficiency

A reduction in r-hGH clearance has been noted in patients with severe liver dysfunction. However, the clinical significance of this in HIV+ patients is unknown.

Storage and Stability

Serostim 4 mg/vial, 5 mg/vial, 6 mg/vial, 8.8 mg/vial

Storage Recommendations

Serostim 4 mg, 5 mg, 6 mg and 8.8 mg Vials

Store SEROSTIM (somatropin for injection) lyophilized product at or below 25 °C. Do not use SEROSTIM after the expiry date shown on the label.

Diluents for Reconstitution

The recommended diluents for reconstitution are:

Serostim 4 mg, 5 mg and 6 mg Vials: Sterile Water for Injection, USP
Serostim 8.8 mg Vials: Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol)

Incompatibility

SEROSTIM 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.

To reconstitute SEROSTIM, inject 1 mL of diluent into the vial of SEROSTIM, aiming the liquid against the vial wall. Swirl the vial with a GENTLE rotary motion until the contents are dissolved completely. DO NOT SHAKE. Because SEROSTIM is a protein, shaking can result in a cloudy solution; 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.

Stability and Storage of Solution

Serostim 4 mg, 5mg and 6 mg Vials

When reconstituted with the diluent provided (Sterile Water for Injection,USP), the reconstituted solution should be used immediately (within 3 hours). Although not recommended, it may be stored for up to 24 hours at 2-8 °C. As there is no preservative in this reconstituted solution, any unused solution should be discarded once the dose is given.

Serostim 8.8 mg Vials

When reconstituted with the diluent provided (Bacteriostatic Water for Injection, USP), the reconstituted solution may be stored at 2-8 °C for up to 14 days.

When reconstituted with Sterile Water for Injection, the reconstituted solution should be used immediately (within 3 hours). Although not recommended, solution reconstituted with Sterile Water for Injection may be stored for up to 24 hours at 2-8 °C. As there is no preservative in this reconstituted solution, any unused solution should be discarded once the dose is given.

Serostim 8.8 mg (5.83 mg/mL) Click.easy

Storage Recommendations

Store SEROSTIM 8.8 mg (5.83 mg/ml) click.easy at room temperature (25 C or below) in original package. Do not use after expiry date on label.

Stability and Storage of Reconstituted Product

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.

Special Handling Instructions

The SEROSTIM (somatropin for injection) 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 Forms and Composition

Serostim 4 mg/vial, 5 mg/vial, 6 mg/vial, 8.8 mg/vial

SEROSTIM (somatropin for injection) is available as a sterile, non-pyrogenic, lyophilized powder.

SEROSTIM 4 mg/vial: Each vial contains 4 mg somatropin, 0.9 mg phosphoric acid, 0.6 mg sodium hydroxide, 27.4 mg sucrose; sodium hydroxide and/or phosphoric acid for pH adjustment to pH 7.5 ± 0.1.
SEROSTIM 5 mg/vial: Each vial contains 5 mg somatropin, 1.2 mg phosphoric acid, 0.7 mg sodium hydroxide, 34.2 mg sucrose; sodium hydroxide and/or phosphoric acid for pH adjustment to pH 7.5 ± 0.1.
SEROSTIM 6 mg/vial: Each vial contains 6 mg somatropin, 1.4 mg phosphoric acid, 0.8 mg sodium hydroxide, 41 mg sucrose; sodium hydroxide and/or phosphoric acid for pH adjustment to pH 7.5 ± 0.1.
SEROSTIM 8.8 mg/vial: Each vial contains 8.8 mg somatropin, 2.1 mg phosphoric acid, 1.2 mg sodium hydroxide, 60.2 mg sucrose; sodium hydroxide and/or phosphoric acid for pH adjustment to pH 7.5 ± 0.1.

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

SEROSTIM is available as a sterile, non-pyrogenic, lyophilized powder in vials for reconstitution.

Each vial of SEROSTIM 8.8 mg (5.83 mg/ml) click.easy contains the following: Somatropin 8.8mg, sucrose 60.2mg, phosphoric acid 2.1mg, sodium hydroxide 1.2mg.

Packaging

Serostim 4 mg/vial, 5 mg/vial, 6 mg/vial, 8.8 mg/vial

The following vial sizes are available:

SEROSTIM 4 mg/vial: Cartons containing 1 vial of 4 mg somatropin for injection together with diluent (Sterile Water for Injection, USP).

Cartons containing 7 vials of 4 mg somatropin for injection together with diluent (Sterile Water for Injection, USP).
SEROSTIM 5 mg/vial: Cartons containing 1 vial of 5 mg somatropin for injection together with diluent (Sterile Water for Injection, USP).

Cartons containing 7 vials of 5 mg somatropin for injection together with diluent (Sterile Water for Injection, USP).
SEROSTIM 6 mg/vial: Cartons containing 1 vial of 6 mg somatropin for injection together with diluent (Sterile Water for Injection, USP).

Cartons containing 7 vials of 6 mg somatropin for injection together with diluent (Sterile Water for Injection, USP).
SEROSTIM 8.8 mg/vial: Cartons containing 1 vial of 8.8 mg somatropin for injection together with diluent (Bacteriostatic Water for Injection, USP).

Cartons containing 7 vials of 8.8 mg somatropin for injection together with diluent (Bacteriostatic Water for Injection, USP).

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

The DIN 2R 3 ml vials of SEROSTIM 8.8 mg product and the cartridges of the solvent are of neutral glass (Type I).

SEROSTIM 8.8 mg (5.83 mg/ml) click.easy is available in the following pack sizes:

1 vial of SEROSTIM 8.8 mg product and 1 cartridge of bacteriostatic solvent pre-assembled in 1 reconstitution device (click.easy) comprising of the main body, the cap assembly and the sterile transfer cannula.

5 vials of SEROSTIM 8.8 mg product and 5 cartridges of bacteriostatic solvent preassembled 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.