Testosterone Cypionate Injection USP 100 mg/mL Sterile Solution Androgens Cytex Pharmaceuticals Inc. 5545 Macara Street Halifax, Nova Scotia B3K 1W1
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 9 DOSAGE AND ADMINISTRATION 9 OVERDOSAGE. 10 ACTION AND CLINICAL PHARMACOLOGY. 10 STORAGE AND STABILITY. 12 DOSAGE FORMS, COMPOSITION AND PACKAGING. 12
PHARMACEUTICAL INFORMATION 13 CLINICAL TRIALS 13 TOXICOLOGY. 13 REFERENCES. 14
Testosterone Cypionate Injection USP | ||
|---|---|---|
| Route of | Dosage Form/ | Clinically Relevant Nonmedical |
| Administration | Strength | Ingredients |
| Intramuscular | Injection 100 mg/mL | Benzyl alcohol, ethyl oleate |
Testosterone Cypionate Injection USP is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone (hypogonadism). Testosterone Cypionate Injection USP should not be used to treat non-specific symptoms suggestive of hypogonadism if testosterone deficiency has not been demonstrated and if other etiologies responsible for the symptoms have not been excluded. Testosterone deficiency should be clearly demonstrated by clinical features and confirmed by two separate validated biochemical assays (morning testosterone) before initiating therapy with any testosterone replacement, including Testosterone Cypionate Injection USP treatment. Geriatrics (>65 years of age): There are no controlled clinical trial data to support the use of Testosterone Cypionate Injection USP in the geriatric population (see WARNINGS AND PRECAUTIONS and CLINICAL TRIALS). Pediatrics (<18 years of age): Testosterone Cypionate Injection USP is not indicated for children <18 years of age since safety and efficacy have not been established in this patient population. (See WARNINGS AND PRECAUTIONS, SPECIAL POPULATIONS).
(see
). Testosterone may cause fetal harm. Testosterone exposure during pregnancy has been reported to be associated with fetal abnormalities.
Androgens are contraindicated in men with known or suspected carcinoma of the prostate or breast. Testosterone Cypionate Injection USP should not be used in patients with known hypersensitivity to any of its ingredients, including testosterone that is chemically synthesized from soy. For a complete listing, see AVAILABILITY OF DOSAGE FORMS section of the Prescribing Information.
There are no controlled clinical trial data with Testosterone Cypionate Injection USP in the geriatric male (>65 years of age) to support the efficacy and safety of prolonged use. Impacts to prostate and cardiovascular event rates and patient important outcomes are unknown. Testosterone Cypionate Injection USP should not be used to attempt to improve body composition, bone and muscle mass, increase lean body mass and decrease total fat mass. Efficacy and safety have not been established. Serious long-term deleterious health issues may arise. Testosterone Cypionate Injection USP has not been shown to be safe and effective for the enhancement of athletic performance. Because of the potential risk of serious adverse health effects, this drug should not be used for such purpose. If testosterone deficiency has not been established, testosterone replacement therapy should not be used for the treatment of sexual dysfunction. Clinical studies have not established testosterone replacement therapy as a treatment for male infertility. Testosterone Cypionate Injection USP contains benzyl alcohol. Benzyl alcohol has been reported to be associated with fatal "Gasping Syndrome" in premature infants. Testosterone cypionate should not be used interchangeably with testosterone propionate because of differences in the duration of action.
Testosterone Cypionate Injection USP should not be used in pregnant or nursing women. Testosterone may cause fetal harm. Testosterone exposure during pregnancy has been reported to be associated with fetal abnormalities.
Androgen therapy should be used cautiously in males with hypogonadism causing delayed puberty. Androgens can accelerate bone maturation without producing compensatory gain in linear growth. This adverse effect may result in compromised adult stature. The younger the child the greater the risk of compromising final mature height. The effect of androgens on bone maturation should be monitored closely by assessing bone age of the wrist and hand on a regular basis.
There are very limited controlled clinical study data supporting the use of testosterone in the geriatric population and virtually no controlled clinical studies on subjects aged 75 years and over.
Geriatrics patients treated with androgens may be at an increased risk for the development of prostatic hyperplasia and prostatic carcinoma. Geriatric patients and other patients with clinical or demographic characteristics that are recognized to be associated with an increased risk of prostate cancer should be evaluated for the presence of prostate cancer prior to initiation of testosterone replacement therapy. In men receiving testosterone replacement therapy, surveillance for prostate cancer should be consistent with current practices for eugonadal men.
Please also see PART II - Toxicology
Geriatric patients treated with androgen may be at an increased risk for the development of prostatic hyperplasia and prostatic carcinoma (see
).
Breast: Patients using long-term testosterone replacement therapy may be at increased risk for the development of breast cancer2. Hepatic: Prolonged use of high doses of orally active 17-a-alkyl-androgens (e.g. methyltestosterone) has been associated with serious hepatic effects (peliosis hepatic, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatis can be a life-threatening or fatal complication. Long-term therapy with testosterone enanthate, which elevates blood levels for prolonged periods, has produced multiple hepatic adenomas.
Patients with skeletal metastases are at risk of exacerbating hypercalcemia/hypercalciuria with concomitant androgen therapy.
Testosterone may increase blood pressure and should be used with caution in patients with hypertension. Edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease. Diuretic therapy may be required, in addition to discontinuation of the drug.
Testosterone Cypionate Injection USP contains testosterone, a Schedule G controlled substance as defined by the Food and Drugs Act.
Androgens have been shown to alter glucose tolerance tests. Diabetics should be followed
carefully and the insulin or oral hypoglycemic dosage adjusted accordingly (see
).
Hypercalciuria/hypercalcemia (caused by malignant tumours) may be exacerbated by androgen treatment. Androgens should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria). Regular monitoring of serum calcium concentrations is recommended in patients at risk of hypercalciuria/hypercalcemia. Hypercalcemia may occur in immobilized patients. If this occurs, the drug should be discontinued.
Hemoglobin and hematocrit levels should be checked periodically (to detect polycythemia) in patients on long-term androgen therapy (see
).
Alkylated derivatives of testosterone such as methandrostenolone, have been reported to decrease the anticoagulant requirement of patients receiving oral anticoagulants (e.g. warfarin). Patients receiving oral anticoagulant therapy require close monitoring especially when androgens are started and stopped (see
).
The treatment of hypogonadal men with testosterone may potentiate sleep apnea in some patients, particularly for those with risk factors such as obesity or chronic lung diseases.
Gynecomastia may frequently develop and occasionally persists in patients being treated for hypogonadism. Priapism or excessive sexual stimulation may develop. Oligospermia may occur after prolonged administration or excessive dosage.
Inflammation and pain at the site of intramuscular injection may occur.
The patients should be monitored (including serum testosterone levels) on a regular basis to ensure adequate response to treatment. Currently there is no consensus about age specific testosterone levels. The normal serum testosterone level for young eugonadal men is generally accepted to be approximately 10.4-34.6 nmol/L (300-1000 ng/dL). It should be taken into account that physiological testosterone levels (mean and range) are lower with increasing age. The following laboratory tests, performed routinely, are recommended to ensure that adverse effects possibly caused by or related to testosterone replacement therapy is detected and addressed: hemoglobin and hematocrit levels should be checked periodically (to detect polycythemia); liver function tests; to detect hepatoxicity associated with the use of 17-a- alkylated androgens; prostate specific antigen (PSA) levels, Digital Rectal Examination (DRE), especially if the patient presents with progressive difficulty with urination or a change in voiding habits; lipid profile, total cholesterol, LDL, HDL, and triglycerides;
diabetics should be followed carefully and the insulin or oral hypoglycemic dosage adjusted accordingly (see
).
ADVERSE DRUG REACTION OVERVIEW
The following adverse reactions in the male have occurred with some androgens:
Blood and the Lymphatic System Disorders
: Suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, and polycythemia.
Gastrointestinal Disorders
: Nausea.
General Disorders and Administration Site Conditions
: Inflammation and pain at the site of intramuscular injection.
Hepatobiliary Disorders
: Cholestatic jaundice, alterations in liver function tests, hepatocellular neoplasms and peliosis hepatis.
Immune System Disorders
: Hypersensitivity, including skin manifestations and anaphylactoid reactions.
Metabolism and Nutrition Disorders
: Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates.
Nervous System Disorders
: Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia.
Reproductive System and Breast Disorders
: Gynecomastia, excessive frequency and duration of penile erections, and oligospermia.
Skin and Subcutaneous Tissue Disorders
: Hirsutism, male pattern of baldness, seborrhea and acne.
POSTMARKET ADVERSE DRUG REACTIONS
The following adverse reactions have been identified during postmarketing use of testosterone replacement therapy in general. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Table 1.
Adverse Drug Reactions from Postmarketing Experience of Testosterone Replacement Therapy
| MedDRA System Organ Class (SOC) | Adverse Drug Reaction |
| Blood and the Lymphatic System Disorders: | Polycythemia, erythropoiesis abnormal. |
| Endocrine Disorders: | Abnormal accelerated growth |
| Gastrointestinal Disorders: | Nausea, vomiting, diarrhea, abdominal pain, gastrointestinal bleeding |
| General Disorders and Administration Site Conditions: | Edema, malaise, fatigue, application site burning, application site induration, application site rash, application site dermatitis, application site blister, application site erythema. |
| Hepatobiliary Disorder: | Hepatic neoplasms, peliosis hepatis |
| Immune System Disorders: | Allergic reaction, hypersensitivity reaction |
| Investigations: | Weight increase, fluctuating testosterone levels, testosterone decreased, abnormal liver function tests (eg. elevated GGTP), lipids abnormalities. |
| Metabolism and Nutrition Disorders: | Increased appetite, electrolyte changes (nitrogen, potassium, phosphorus, sodium), urine calcium decrease, glucose tolerance impaired, elevated cholesterol. |
| Musculoskeletal and Connective Tissue Disorders: | Myalgia, arthralgia. |
| Nervous System Disorders: | Insomnia, headache, dizziness. |
| Psychiatric Disorders: | Personality disorder, confusion, anger, aggression, depression, anxiety, decreased libido, cognitive disturbance. |
| Reproductive System and Breast Disorder: | Prostate carcinoma, enlarged prostate (benign), free prostate-specific antigen increased, testicular atrophy, epididymitis, oligospermia, priapism, impotence, precocious puberty, gynecomastia, mastodynia. |
| Renal and Urinary Disorders: | Dysuria, hematuria, incontinence, bladder irritability. |
| Respiratory, Thoracic and Mediastinal Disorder: | Dyspnea, sleep apnea. |
| Skin and Subcutaneous Tissue Disorders: | Pruritus, rash, urticaria, vesiculo-bullous rash, seborrhoea, acne, alopecia, male pattern baldness, hirsuitism. |
| Vascular Disorders: | Hypertension. |
In diabetic patients, the metabolic effects of androgens may decrease blood glucose and therefore, insulin requirements.
: In a published pharmacokinetic study of an injectable testosterone product, administration of testosterone cypionate led to an increased clearance of propranolol in the majority of men tested.
The concurrent administration of testosterone with ACTH or corticosteroids may enhance edema formation; thus these drugs should be administered cautiously, particularly in patient with cardiac or hepatic disease.
: Androgens may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may require reduction in order to maintain satisfactory therapeutic hypoprothrombinemia.
Interactions with food have not been established.
It was found that some herbal products (e.g. St. John's Wort) which are available as over the counter (OTC) products might interfere with steroid metabolism and therefore may decrease plasma testosterone levels.
Androgens may decrease levels of thyroxin-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.
Testosterone Cypionate Injection USP is to be administered by a health care professional only. Testosterone Cypionate Injection USP is for intramuscular use only and should not be given intravenously. Intramuscular injections should be given deep in the gluteal muscle. Testosterone Cypionate Injection USP should be used only in patients available for re-evaluation at periodic intervals. Dosage should be adjusted according to the patient's response and appearance of adverse reactions.
For replacement therapy in the hypogonadal male, 200 mg should be administered intramuscularly every two weeks.
400 mg per month.
If a dose of this medication has been missed, it should be taken as soon as possible. However if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not double doses.
Parenteral drug products, such as Testosterone Cypionate Injection USP, should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Warming and shaking the vial should redissolve any crystals that may have formed during storage.
Testosterone Cypionate Injection USP is to be administered by a health care professional. All used injection equipment must be safely disposed of. All disposable syringes and needles should be disposed of immediately following use in a designated safety box or puncture-proof container. The needle should not be recapped or removed from the syringe, the whole combination should be inserted into the safety box directly after use. Additional waste from injections (syringe packaging, cotton, etc.) should be disposed of appropriately.
Symptoms of testosterone overdose are not known. No specific antidote is available. Symptomatic and supportive treatment should be given.
Testosterone Cypionate Injection USP delivers testosterone in the form of testosterone cypionate intramuscularly to produce circulating testosterone levels that approximate normal levels (e.g. 10.4-34.6 nmol/L [300-1000 ng/dL]) seen in healthy young men.
Testosterone and dihydrotestosterone (DHT), endogenous androgens, are responsible for normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest and axillary hair; laryngeal enlargement; vocal cord thickening; alterations in body musculature; and fat distribution.
Male hypogonadism results from insufficient secretion of testosterone and is characterized by low serum testosterone concentrations. Symptoms associated with male hypogonadism include decreased sexual desire with or without impotence, fatigue, and loss of energy, mood depression, regression of secondary sexual characteristics, and osteoporosis. Hypogonadism is a risk factor for osteoporosis in men.
Drugs in the androgen class also promote retention of nitrogen, sodium, potassium, phosphorus, and decreased urinary excretion of calcium.
Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein. Androgens have been reported to stimulate the production of red blood cells by enhancing erythropoietin production. Androgens are responsible for the growth spurt of adolescence and for the eventual termination of linear growth brought about by fusion of the epiphyseal growth centres. In children, exogenous androgens accelerate linear growth rates but may cause a disproportionate advancement in bone maturation. Use over long periods may result in fusion of the epiphyseal growth centres and termination of the growth process. During exogenous administration of androgens, endogenous testosterone release may be inhibited through feedback inhibition of pituitary luteinizing hormone (LH). At large doses of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH).
Testosterone cypionate is a testosterone ester. Esterification of testosterone at position 17 increases the lipid solubility of the testosterone molecule and prolongs the activity of the molecule by increasing its residence time. Following intramuscular administration in an oily vehicle, testosterone ester is slowly absorbed into the general circulation and then rapidly hydrolyzed in plasma to testosterone.
In a randomized crossover study of six healthy males aged 20-29 years of age, the pharmacokinetics of a single injection of 200 mg testosterone cypionate was compared to that of a single injection of 194 mg testosterone enanthate. Mean serum testosterone concentrations increased sharply to 3 times the basal levels (approximately 1350 ng/dl) at 24 hours and declined gradually to basal levels (approximately 500 ng/dl) by day 10 . A similar observation was noted in a clinical study of replacement therapy with a single intramuscular dose of 200 mg testosterone cypionate in 11 hypogonadal males aged 28-74. Pharmacokinetic analysis showed a threefold mean increase in serum testosterone concentrations by day 2 (1108 +- 440 ng/dl) and a progressive decline to basal serum levels (360 +- 166 ng/dl) by day 14 for the group. These pharmacokinetic studies demonstrated the dosing regimen of 200 mg testosterone cypionate every 2 weeks led to initial elevation of serum testosterone into the supraphysiological range and then a gradual decline into the hypogonadal range by the end of the dosing interval.
Circulating testosterone is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin. The albumin-bound fraction of testosterone easily dissociates from albumin and is presumed to be bioactive. The portion of testosterone bound to SHBG is not considered biologically active. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins. The amount of SHBG in the serum and the total testosterone level will determine the distribution of bioactive
and nonbioactive androgen.
There is considerable variation in the half-life of testosterone as reported in the literature ranging from ten to 100 minutes.
Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and dihydrotestosterone (DHT). Testosterone is metabolised to DHT by steroid 5a reductase located in the skin, liver and the urogenital tract of the male. Estradiol is formed by an aromatase enzyme complex in the brain, fat and testes. DHT binds with greater affinity to SHBG than does testosterone. In many tissues, the activity of testosterone depends on its reduction to DHT, which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcription and cellular changes related to androgen action. In reproductive tissues, DHT is further metabolised to 3-a and 3-b androstanediol.
About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulphuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.
Store between 15 and 30degC. Protect from light. Keep in a safe place out of reach of children and pets.
Testosterone Cypionate Injection USP is available in one strength, 100 mg testosterone cypionate/mL. Testosterone Cypionate Injection USP (100 mg/mL) is available in the following packaging:
- In single dose ampoules of 2 mL each, with 5 ampoules per carton.
Each mL of the 100 mg/mL solution contains:
Testosterone Cypionate ..................................................................................100 mg Benzyl Alcohol............................................................................................. 2% v/v Ethyl Oleate (oil) ..........................................................................................q.s.