Testex

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Testex uses

Testex consists of Testosterone Cypionate, Testosterone Propionate.

Testosterone Cypionate:


DESCRIPTION

Testex (Testosterone Cypionate) Injection, for intramuscular injection, contains Testex (Testosterone Cypionate) which is the oil-soluble 17 (beta)- cyclopentylpropionate ester of the androgenic hormone testosterone.

Testex (Testosterone Cypionate) is a white or creamy white crystalline powder, odorless or nearly so and stable in air. It is insoluble in water, freely soluble in alcohol, chloroform, dioxane, ether, and soluble in vegetable oils.

The chemical name for Testex (Testosterone Cypionate) is androst-4-en-3-one, 17-(3-cyclopentyl-1-oxopropoxy)-, (17β)-. Its molecular formula is C27H40O3, and the molecular weight 412.61.

The structural formula is represented below:

Testex (Testosterone Cypionate) Injection is available in two strengths, 100 mg/mL and 200 mg/mL Testex (Testosterone Cypionate).

Each mL of the 100 mg/mL solution contains:
Testosterone cypionate 100 mg
Benzyl benzoate 0.1 mL
Cottonseed oil 736 mg
Benzyl alcohol (as preservative) 9.45 mg
Each mL of the 200 mg/mL solution contains:
Testosterone cypionate 200 mg
Benzyl benzoate 0.2 mL
Cottonseed oil 560 mg
Benzyl alcohol (as preservative) 9.45 mg
Chemical Structure
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CLINICAL PHARMACOLOGY

Endogenous androgens are responsible for normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include growth and maturation of the prostate, seminal vesicles, penis, and scrotum; development of male hair distribution, such as beard, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat distribution. Drugs in this class also cause retention of nitrogen, sodium, potassium, and phosphorous, 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 are responsible for the growth spurt of adolescence and for eventual termination of linear growth, brought about by fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rates, but may cause disproportionate advancement in bone maturation. Use over long periods may result in fusion of the epiphyseal growth centers and termination of the growth process. Androgens have been reported to stimulate production of red blood cells by enhancing production of erythropoietic stimulation factor.

During exogenous administration of androgens, endogenous testosterone release is inhibited through feedback inhibition of pituitary luteinizing hormone. At large doses of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle stimulating hormone (FSH).

There is a lack of substantial evidence that androgens are effective in fractures, surgery, convalescence, and functional uterine bleeding.

Pharmacokinetics

Testosterone esters are less polar than free testosterone. Testosterone esters in oil injected intramuscularly are absorbed slowly from the lipid phase; thus, Testex (Testosterone Cypionate) can be given at intervals of two to four weeks.

Testosterone in plasma is 98 percent bound to a specific testosterone-estradiol binding globulin, and about 2 percent is free. Generally, the amount of this sex-hormone binding globulin in the plasma will determine the distribution of testosterone between free and bound forms, and the free testosterone concentration will determine its half-life.

About 90 percent of a dose of testosterone is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6 percent of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. Testosterone is metabolized to various 17-keto steroids through two different pathways.

The half-life of Testex (Testosterone Cypionate) when injected intramuscularly is approximately eight days.

In many tissues the activity of testosterone appears to depend on reduction to dihydrotestosterone, which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcription events and cellular changes related to androgen action.

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INDICATIONS AND USAGE

Testex (Testosterone Cypionate) Injection is indicated for replacement therapy in the male in conditions associated with symptoms of deficiency or absence of endogenous testosterone.

1. Primary hypogonadism (congenital or acquired)-testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome; or orchidectomy.

2. Hypogonadotropic hypogonadism (congenital or acquired)- gonadotropin or LHRH deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation.

Safety and efficacy of Testex (Testosterone Cypionate) (testosterone cypionate) in men with "age-related hypogonadism" (also referred to as "late-onset hypogonadism") have not been established.

CONTRAINDICATIONS

  • Known hypersensitivity to the drug
  • Males with carcinoma of the breast
  • Males with known or suspected carcinoma of the prostate gland
  • Women who are or who may become pregnant
  • Patients with serious cardiac, hepatic or renal disease

WARNINGS

Hypercalcemia may occur in immobilized patients. If this occurs, the drug should be discontinued.

Prolonged use of high doses of androgens (principally the 17-α alkyl-androgens) has been associated with development of hepatic adenomas, hepatocellular carcinoma, and peliosis hepatis -all potentially life-threatening complications.

Geriatric patients treated with androgens may be at an increased risk of developing prostatic hypertrophy and prostatic carcinoma although conclusive evidence to support this concept is lacking.

There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products, such as Testex (Testosterone Cypionate). Evaluate patients who report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a venous thromboembolic event is suspected, discontinue treatment with Testex (Testosterone Cypionate) and initiate appropriate workup and management.

Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. To date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events (MACE), such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of testosterone compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of testosterone replacement therapy in men. Patients should be informed of this possible risk when deciding whether to use or to continue to use Testex (Testosterone Cypionate) (testosterone cypionate).

Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions.

If testosterone abuse is suspected, check serum testosterone concentrations to ensure they are within therapeutic range. However, testosterone levels may be in the normal or subnormal range in men abusing synthetic testosterone derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids. Conversely, consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.

Edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal or hepatic disease.

Gynecomastia may develop and occasionally persists in patients being treated for hypogonadism.

The preservative benzyl alcohol has been associated with serious adverse events, including the "gasping syndrome", and death in pediatric patients. Although normal therapeutic doses of this product ordinarily deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome", the minimum amount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity administered and the liver and kidneys' capacity to detoxify the chemical. Premature and low-birth weight infants may be more likely to develop toxicity.

Androgen therapy should be used cautiously in healthy males with delayed puberty. The effect on bone maturation should be monitored by assessing bone age of the wrist and hand every 6 months. In children, androgen treatment may 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.

This drug 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.

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PRECAUTIONS

General

Patients with benign prostatic hypertrophy may develop acute urethral obstruction. Priapism or excessive sexual stimulation may develop. Oligospermia may occur after prolonged administration or excessive dosage. If any of these effects appear, the androgen should be stopped and if restarted, a lower dosage should be utilized.

Testex should not be used interchangeably with testosterone propionate because of differences in duration of action.

Testex (Testosterone Cypionate) is not for intravenous use.

Information for patients

Patients should be instructed to report any of the following: nausea, vomiting, changes in skin color, ankle swelling, too frequent or persistent erections of the penis.

Laboratory tests

Hemoglobin and hematocrit levels should be checked periodically in patients receiving long-term androgen administration.

Serum cholesterol may increase during androgen therapy.

Drug interactions

Androgens may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may require reduction in order to maintain satisfactory therapeutic hypoprothrombinemia.

Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone.

In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirements.

Drug/Laboratory test Interferences

Androgens may decrease levels of thyroxine-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.

Carcinogenesis

Animal data

Testosterone has been tested by subcutaneous injection and implantation in mice and rats. The implant induced cervical-uterine tumors in mice, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.

Human data

There are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumors in all cases.

Geriatric patients treated with androgens may be at an increased risk of developing prostatic hypertrophy and prostatic carcinoma although conclusive evidence to support this concept is lacking.

Pregnancy

Teratogenic Effects

Pregnancy Category X

Benzyl alcohol can cross the placenta. See WARNINGS.

Nursing mothers

Testex (Testosterone Cypionate) is not recommended for use in nursing mothers.

Pediatric use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

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ADVERSE REACTIONS

The following adverse reactions in the male have occurred with some androgens:

Endocrine and urogenital: Gynecomastia and excessive frequency and duration of penile erections. Oligospermia may occur at high dosages.

Skin and appendages: Hirsutism, male pattern of baldness, seborrhea, and acne.

Cardiovascular Disorders: myocardial infarction, stroke.

Fluid and electrolyte disturbances: Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates.

Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function tests, rarely hepatocellular neoplasms and peliosis hepatis.

Hematologic: Suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, and polycythemia.

Nervous system: Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia.

Allergic: Hypersensitivity, including skin manifestations and anaphylactoid reactions.

Vascular disorders: Venous thromboembolism.

Miscellaneous: Inflammation and pain at the site of intramuscular injection.

DRUG ABUSE AND DEPENDENCE

Controlled Substance

Testex Injection contains testosterone, a Schedule III controlled substance in the Controlled Substances Act.

Abuse

Drug abuse is intentional non-therapeutic use of a drug, even once, for its rewarding psychological and physiological effects. Abuse and misuse of testosterone are seen in male and female adults and adolescents. Testosterone, often in combination with other anabolic androgenic steroids (AAS), and not obtained by prescription through a pharmacy, may be abused by athletes and bodybuilders. There have been reports of misuse by men taking higher doses of legally obtained testosterone than prescribed and continuing testosterone despite adverse events or against medical advice.

Abuse-Related Adverse Reactions

Serious adverse reactions have been reported in individuals who abuse anabolic androgenic steroids and include cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and serious psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression.

The following adverse reactions have also been reported in men: transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility.

The following additional adverse reactions have been reported in women: hirsutism, virilization, deepening of voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities.

The following adverse reactions have been reported in male and female adolescents: premature closure of bony epiphyses with termination of growth, and precocious puberty.

Because these reactions are reported voluntarily from a population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dependence

Behaviors Associated with Addiction

Continued abuse of testosterone and other anabolic steroids, leading to addiction is characterized by the following behaviors:

  • Taking greater dosages than prescribed
  • Continued drug use despite medical and social problems due to drug use
  • Spending significant time to obtain the drug when supplies of the drug are interrupted
  • Giving a higher priority to drug use than other obligations
  • Having difficulty in discontinuing the drug despite desires and attempts to do so
  • Experiencing withdrawal symptoms upon abrupt discontinuation of use

Physical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or a significant dose reduction of a drug. Individuals taking supratherapeutic doses of testosterone may experience withdrawal symptoms lasting for weeks or months which include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism.

Drug dependence in individuals using approved doses of testosterone for approved indications has not been documented.

OVERDOSAGE

There have been no reports of acute overdosage with the androgens.

DOSAGE AND ADMINISTRATION

Prior to initiating Testex (Testosterone Cypionate) (testosterone cypionate), confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days and that these serum testosterone concentrations are below the normal range.

Testex (Testosterone Cypionate) Injection is for intramuscular use only.

It should not be given intravenously. Intramuscular injections should be given deep in the gluteal muscle.

The suggested dosage for Testex (Testosterone Cypionate) Injection varies depending on the age, sex, and diagnosis of the individual patient. Dosage is adjusted according to the patient's response and the appearance of adverse reactions.

Various dosage regimens have been used to induce pubertal changes in hypogonadal males; some experts have advocated lower dosages initially, gradually increasing the dose as puberty progresses, with or without a decrease to maintenance levels. Other experts emphasize that higher dosages are needed to induce pubertal changes and lower dosages can be used for maintenance after puberty. The chronological and skeletal ages must be taken into consideration, both in determining the initial dose and in adjusting the dose.

For replacement in the hypogonadal male, 50400 mg should be administered every two to four weeks.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Warming and shaking the vial should redissolve any crystals that may have formed during storage at temperatures lower than recommended.

HOW SUPPLIED

Testex (Testosterone Cypionate) Injection is available as follows:

100 mg/mL
10 mL vials NDC 0009-0347-02
200 mg/mL
1 mL vials NDC 0009-0417-01
10 mL vials NDC 0009-0417-02

Store at 20° to 25°C (68° to 77°F). Protect from light.

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com

Rx only

LAB-0245-12.0

September 2017

Logo

NDC 0009-0347-02

10 mL Vial

Multiple-Dose

Depo®-

Testosterone

Testex (Testosterone Cypionate)

injection, USP

100 mg/mL

CIII

For intramuscular use only

Pfizer Injectables

Rx only

Testosterone Propionate:


WARNING: SERIOUS PULMONARY OIL MICROEMBOLISM REACTIONS AND ANAPHYLAXIS

  • Serious POME reactions, involving urge to cough, dyspnea, throat tightening, chest pain, dizziness, and syncope; and episodes of anaphylaxis, including life-threatening reactions, have been reported to occur during or immediately after the administration of Testex (Testosterone Propionate) undecanoate injection. These reactions can occur after any injection of Testex (Testosterone Propionate) undecanoate during the course of therapy, including after the first dose [see Warnings and Precautions (5.1)].
  • Following each injection of Testex (Testosterone Propionate), observe patients in the healthcare setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions or anaphylaxis .
  • Because of the risks of serious POME reactions and anaphylaxis, Testex (Testosterone Propionate) is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Testex (Testosterone Propionate) REMS Program [see Warnings and Precautions (5.2)].

WARNING: SERIOUS PULMONARY OIL MICROEMBOLISM (POME) REACTIONS AND ANAPHYLAXIS

See full prescribing information for complete boxed warning

  • Serious POME reactions, involving urge to cough, dyspnea, throat tightening, chest pain, dizziness, and syncope; and episodes of anaphylaxis, including life-threatening reactions, have been reported to occur during or immediately after the administration of Testex (Testosterone Propionate) undecanoate injection. These reactions can occur after any injection of Testex (Testosterone Propionate) undecanoate during the course of therapy, including after the first dose (5.1).
  • Following each injection of Testex (Testosterone Propionate), observe patients in the healthcare setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions or anaphylaxis (5.1).
  • Testex (Testosterone Propionate) is available only through a restricted program called the Testex (Testosterone Propionate) REMS Program (5.2).

RECENT MAJOR CHANGES

Warnings and Precautions (5.7) 10/2016

1 INDICATIONS AND USAGE

Testex (Testosterone Propionate) is indicated for Testex (Testosterone Propionate) replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous Testex (Testosterone Propionate).

  • Primary hypogonadism (congenital or acquired): testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter"s syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum Testex (Testosterone Propionate) concentrations and gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) above the normal range.
  • Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low Testex (Testosterone Propionate) serum concentrations but have gonadotropins in the normal or low range.

Testex (Testosterone Propionate) should only be used in patients who require Testex (Testosterone Propionate) replacement therapy and in whom the benefits of the product outweigh the serious risks of pulmonary oil microembolism and anaphylaxis.

Limitations of use:

  • Safety and efficacy of Testex (Testosterone Propionate) in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.
  • Safety and efficacy of Testex (Testosterone Propionate) in males less than 18 years old have not been established [see Use in Specific Populations ( 8.4 )].

Testex (Testosterone Propionate) (testosterone undecanoate) injection is an androgen indicated for Testex (Testosterone Propionate) replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous Testex (Testosterone Propionate):

o Primary hypogonadism (congenital or acquired) (1)

o Hypogonadotropic hypogonadism (congenital or acquired) (1)

Testex (Testosterone Propionate) should only be used in patients who require Testex (Testosterone Propionate) replacement therapy and in whom the benefits of the product outweigh the serious risks of pulmonary oil microembolism and anaphylaxis (1).

Limitations of use:

  • Safety and efficacy of Testex (Testosterone Propionate) in men with “age-related hypogonadism” have not been established (1).
  • Safety and efficacy of Testex (Testosterone Propionate) in males less than 18 years old have not been established (1, 8.4).

2 DOSAGE AND ADMINISTRATION

Prior to initiating Testex, confirm the diagnosis of hypogonadism by ensuring that serum Testex (Testosterone Propionate) concentrations have been measured in the morning on at least two separate days and that these serum Testex (Testosterone Propionate) concentrations are below the normal range.

  • Prior to initiating Testex (Testosterone Propionate), confirm the diagnosis of hypogonadism by ensuring that serum Testex (Testosterone Propionate) has been measured in the morning on at least two separate days and that these concentrations are below the normal range (2).
  • For intramuscular use only (2.1).
  • 3 mL (750 mg) is to be injected intramuscularly at initiation, at 4 weeks, and every 10 weeks thereafter (2.1).
  • Following each injection of Testex (Testosterone Propionate), observe patients in the healthcare setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions or anaphylaxis (2.3).
  • Inject Testex (Testosterone Propionate) deeply into the gluteal muscle following the usual precautions for intramuscular administration of oily solutions (2.3).

2.1 Dosage

Testex (Testosterone Propionate) is for intramuscular use only. Dosage titration is not necessary.

Inject Testex (Testosterone Propionate) deeply into the gluteal muscle following the usual precautions for intramuscular administration; care must be taken to avoid intravascular injection . Intravascular injection of Testex (Testosterone Propionate) may lead to pulmonary oil microembolism .

The recommended dose of Aveed is 3 mL (750 mg) injected intramuscularly, followed by 3 mL (750 mg) injected after 4 weeks, then 3 mL (750 mg) injected every 10 weeks thereafter.

2.2 Preparation Instructions

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Carefully remove the gray plastic cap from the top of the vial by lifting it up from the edges with your fingers or by pushing the bottom edge of the cap upward using the top of your thumb. Remove only the gray plastic cap while leaving the aluminum metal ring and crimp seal around the gray rubber stopper in place. To facilitate the removal of medication from the vial, you can draw 3 mL of air into the syringe and inject it through the gray rubber stopper into the vial to create positive pressure within the vial chamber.

Withdraw 3 mL of Testex (Testosterone Propionate) solution from the vial. Expel excess air bubbles from the syringe. Replace the syringe needle used to draw up the solution from the vial with a new intramuscular needle and inject. Discard any unused portion in the vial.

2.3 Administration Instructions

The site for injection for Testex (Testosterone Propionate) is the gluteus medius muscle site located in the upper outer quadrant of the buttock. Care must be taken to avoid the needle hitting the superior gluteal arteries and sciatic nerve. Between consecutive injections, alternate the injection site between left and right buttock.

Figure 1: Identifying the injection site


Following antiseptic skin preparation, enter the muscle and maintain the syringe at a 90° angle with the needle in its deeply imbedded position. Grasp the barrel of the syringe firmly with one hand. With the other hand, pull back on the plunger and aspirate for several seconds to ensure that no blood appears. If any blood is drawn into the syringe, immediately withdraw and discard the syringe and prepare another dose.

If no blood is aspirated, reinforce the current needle position to avoid any movement of the needle and slowly (over 60 to 90 seconds) depress the plunger carefully and at a constant rate, until all the medication has been delivered. Be sure to depress the plunger completely with sufficient controlled force. Withdraw the needle.

Immediately upon removal of the needle from the muscle, apply gentle pressure with a sterile pad to the injection site. If there is bleeding at the site of injection, apply a bandage.

Following each injection of Testex (Testosterone Propionate), observe patients in the healthcare setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions or anaphylaxis (5.1).

Figure1

3 DOSAGE FORMS AND STRENGTHS

750 mg/3 mL (250 mg/mL) Testex (Testosterone Propionate) undecanoate sterile injectable solution is provided in an amber glass, single use vial with silver-colored crimp seal and gray plastic cap.

  • 750 mg/3 mL (250 mg/mL) Testex (Testosterone Propionate) undecanoate sterile injectable solution is provided in an amber glass, single use vial with silver-colored crimp seal and gray plastic cap (3).

4 CONTRAINDICATIONS

Testex (Testosterone Propionate) should not be used in any of the following patients:

  • Men with carcinoma of the breast or known or suspected carcinoma of the prostate .
  • Women who are or may become pregnant, or who are breastfeeding. Testex (Testosterone Propionate) can cause fetal harm when administered to a pregnant woman. Testex (Testosterone Propionate) may cause serious adverse reactions in nursing infants. Exposure of a female fetus or nursing infant to androgens may result in varying degrees of virilization.
  • Men with known hypersensitivity to Testex (Testosterone Propionate) or any of its ingredients (testosterone undecanoate, refined castor oil, benzyl benzoate).
  • Men with carcinoma of the breast or known or suspected carcinoma of the prostate (4, 5.3).
  • Pregnant or breastfeeding women. Testosterone may cause fetal harm (4, 8.1, 8.3).
  • Known hypersensitivity to Testex (Testosterone Propionate) or its ingredients (testosterone undecanoate, refined castor oil, benzyl benzoate) (4).

5 WARNINGS AND PRECAUTIONS

  • Monitor patients with benign prostatic hyperplasia for worsening of signs and symptoms of BPH (5.3).
  • Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients using Testex (Testosterone Propionate) products. Evaluate patients with signs or symptoms consistent with DVT or PE. (5.5)
  • Some postmarketing studies have shown an increased risk of myocardial infarction and stroke associated with use of Testex (Testosterone Propionate) replacement therapy. (5.6)
  • Exogenous administration of androgens may lead to azoospermia (5.9).
  • Edema with or without congestive heart failure may be a complication in patients with preexisting cardiac, renal, or hepatic disease (5.11).
  • Sleep apnea may occur in those with risk factors (5.13).
  • Monitor prostatic specific antigen (PSA), hemoglobin, hematocrit, and lipid concentrations periodically (5.3, 5.4, 5.14).

5.1 Serious Pulmonary Oil Microembolism (POME) Reactions and Anaphylaxis

Serious POME reactions, involving cough, urge to cough, dyspnea, hyperhidrosis, throat tightening, chest pain, dizziness, and syncope, have been reported to occur during or immediately after the injection of intramuscular Testex (Testosterone Propionate) undecanoate 1000 mg (4 mL). The majority of these events lasted a few minutes and resolved with supportive measures; however, some lasted up to several hours and some required emergency care and/or hospitalization. To minimize the risk of intravascular injection of Testex (Testosterone Propionate), care should be taken to inject the preparation deeply into the gluteal muscle, being sure to follow the recommended procedure for intramuscular administration .

In addition to serious POME reactions, episodes of anaphylaxis, including life-threatening reactions, have also been reported to occur following the injection of intramuscular Testex (Testosterone Propionate) undecanoate.

Both serious POME reactions and anaphylaxis can occur after any injection of Testex (Testosterone Propionate) undecanoate during the course of therapy, including after the first dose. Patients with suspected hypersensitivity reactions to Testex (Testosterone Propionate) should not be re-treated with Testex (Testosterone Propionate).

Following each injection of Testex (Testosterone Propionate), observe patients in the healthcare setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions and anaphylaxis.

5.2 Testex Risk Evaluation and Mitigation Strategy (REMS) Program

Testex (Testosterone Propionate) is available only through a restricted program called the Testex (Testosterone Propionate) REMS Program because of the risk of serious POME and anaphylaxis.

Notable requirements of the Testex (Testosterone Propionate) REMS Program include the following:

  • Healthcare providers who prescribe Testex (Testosterone Propionate) must be certified with the REMS Program before ordering or dispensing Testex (Testosterone Propionate).
  • Healthcare settings must be certified with the REMS Program and have healthcare providers who are certified before ordering or dispensing Testex (Testosterone Propionate). Healthcare settings must have on-site access to equipment and personnel trained to manage serious POME and anaphylaxis.

Further information is available at www. AveedREMS.com or call 1-855-755-0494.

5.3 Worsening of Benign Prostatic Hyperplasia and Potential Risk of Prostate Cancer

Patients with BPH treated with androgens are at an increased risk of worsening of signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms.

Patients treated with androgens may be at an increased risk for prostate cancer. Evaluate patients for prostate cancer prior to initiating and during treatment with androgens .

5.4 Polycythemia

Increases in hematocrit, reflective of increases in red blood cell mass, may require discontinuation of Testex.

Check hematocrit prior to initiating Testex (Testosterone Propionate) treatment. It would be appropriate to re-evaluate the hematocrit 3 to 6 months after starting Testex (Testosterone Propionate) treatment, and then annually. If hematocrit becomes elevated, stop therapy until hematocrit decreases to an acceptable level. An increase in red blood cell mass may increase the risk of thromboembolic events.

5.5 Venous Thromboembolism

There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using Testex (Testosterone Propionate) products, such as Testex (Testosterone Propionate). Evaluate patients who report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a venous thromboembolic event is suspected, discontinue treatment with Testex (Testosterone Propionate) and initiate appropriate workup and management.

5.6 Cardiovascular Risk

Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of Testex replacement therapy in men. To date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events (MACE), such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of Testex (Testosterone Propionate) compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of Testex (Testosterone Propionate) replacement therapy in men. Patients should be informed of this possible risk when deciding whether to use or to continue to use Testex (Testosterone Propionate).

5.7 Abuse of Testex (Testosterone Propionate) and Monitoring of SerumTestosterone Concentrations

Testex (Testosterone Propionate) has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions .

If Testex (Testosterone Propionate) abuse is suspected, check serum Testex (Testosterone Propionate) concentrations to ensure they are within therapeutic range. However, Testex (Testosterone Propionate) levels may be in the normal or subnormal range in men abusing synthetic Testex (Testosterone Propionate) derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of Testex (Testosterone Propionate) and anabolic androgenic steroids. Conversely, consider the possibility of Testex (Testosterone Propionate) and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.

5.8 Use in Women

Due to lack of controlled evaluations in women and potential virilizing effects, Testex is not indicated for use in women.

5.9 Potential for Adverse Effects on Spermatogenesis

With large doses of exogenous androgens, including Testex (Testosterone Propionate), spermatogenesis may be suppressed through feedback inhibition of pituitary follicle- stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count.

5.10 Hepatic Adverse Effects

Prolonged use of high doses of orally active 17-alpha-alkyl androgens has been associated with serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatis can be a life-threatening or fatal complication. Long-term therapy with intramuscular Testex (Testosterone Propionate) enanthate, which elevates blood levels for prolonged periods, has produced multiple hepatic adenomas. Testex (Testosterone Propionate) is not known to produce these adverse effects. Nonetheless, patients should be instructed to report any signs or symptoms of hepatic dysfunction (e.g., jaundice). If these occur, promptly discontinue Testex (Testosterone Propionate) while the cause is evaluated.

5.11 Edema

Androgens, including Testex (Testosterone Propionate), may promote retention of sodium and water. Edema with or without congestive heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required.

5.12 Gynecomastia

Gynecomastia occasionally develops and occasionally persists in patients being treated for hypogonadism .

5.13 Sleep Apnea

The treatment of hypogonadal men with Testex (Testosterone Propionate) products may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases.

5.14 Lipids

Changes in serum lipid profile may require dose adjustment of lipid lowering drugs or discontinuation of Testex therapy.

5.15 Hypercalcemia

Androgens, including Testex (Testosterone Propionate), should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria). Regular monitoring of serum calcium concentrations is recommended in these patients.

5.16 Decreased Thyroxine-binding Globulin

Androgens, including Testex (Testosterone Propionate), may decrease concentrations of thyroxine-binding globulin, resulting in decreased total T4 serum concentrations and increased resin uptake of T3 and T4. Free thyroid hormone concentrations remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

6 ADVERSE REACTIONS

The most commonly reported adverse reactions are acne, injection site pain, prostatic specific antigen (PSA) increased, estradiol increased, hypogonadism, fatigue, irritability, hemoglobin increased, insomnia, and mood swings (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Endo Pharmaceuticals at 1-800-462-3636 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Testex (Testosterone Propionate) was evaluated in an 84-week clinical study using a dose regimen of 750 mg (3 mL) at initiation, at 4 weeks, and every 10 weeks thereafter in 153 hypogonadal men. The most commonly reported adverse reactions (>2%) were: acne (5.2%), injection site pain (4.6%), prostate specific antigen increased (4.6%), hypogonadism (2.6%) and estradiol increased (2.6%).

Table 1 presents adverse reactions reported by 1% of patients in the 84-week clinical study.

Table 1

Adverse Reactions Reported in at Least 1% of Patients in the 84-Week Clinical Study of Testex (Testosterone Propionate)



MedDRA Preferred term


Number of patients (%)


Aveed 750 mg

(N=153)


Acne


8 (5.2%)


Injection site pain


7 (4.6%)


Prostatic specific antigen increased*


7 (4.6%)


Estradiol increased


4 (2.6%)


Hypogonadism


4 (2.6%)


Fatigue


3 (2%)


Irritability


3 (2%)


Hemoglobin increased


3 (2%)


Insomnia


3 (2%)


Mood swings


3 (2%)


Aggression


2 (1.3%)


Ejaculation disorder


2 (1.3%)


Injection site erythema


2 (1.3%)


Hematocrit increased


2 (1.3%)


Hyperhidrosis


2 (1.3%)


Prostate Cancer


2 (1.3%)


Prostate induration


2 (1.3%)


Weight increased


2 (1.3%)


* Prostate specific antigen increased defined as a serum PSA concentration >4 ng/mL.

In the 84-week clinical trial, 7 patients (4.6%) discontinued treatment because of adverse reactions. Adverse reactions leading to discontinuation included: hematocrit increased, estradiol increased, prostatic specific antigen increased, prostate cancer, mood swings, prostatic dysplasia, acne, and deep vein thrombosis.

During the 84-week clinical trial, the average serum PSA increased from 1.0 ± 0.8 ng/mL at baseline to 1.5 ± 1.3 ng/mL at the end of study. Fourteen patients (10.9%) in whom the baseline PSA was < 4 ng/mL had a post-baseline serum PSA of > 4 ng/mL during the 84-week treatment period.

A total of 725 hypogonadal men received intramuscular Testex (Testosterone Propionate) undecanoate in a total of 7 controlled clinical trials. In these clinical trials, the dose and dose frequency of intramuscular Testex (Testosterone Propionate) undecanoate varied from 750 mg to 1000 mg, and from every 9 weeks to every 14 weeks. Several of these clinical trials incorporated additional doses upon initiation of therapy (e.g., loading doses). In addition to those adverse reactions noted in Table 1, the following adverse events were reported by at least 3% of patients in these trials, irrespective of the investigator’s assessment of relationship to study medication: sinusitis, prostatitis, arthralgia, nasopharyngitis, upper respiratory tract infection, bronchitis, back pain, hypertension, diarrhea and headache.

Pulmonary Oil Microembolism (POME) and Anaphylaxis in Controlled Clinical Studies

Adverse events attributable to pulmonary oil microembolism and anaphylaxis were reported in a small number of patients in controlled clinical trials. In the 84-week clinical trial of Testex (Testosterone Propionate), 1 patient experienced a mild coughing fit lasting 10 minutes after his third injection, which was retrospectively attributed to POME. In another clinical trial of intramuscular Testex (Testosterone Propionate) undecanoate (1000 mg), a hypogonadal male patient experienced the urge to cough and respiratory distress at 1 minute after his tenth injection, which was also retrospectively attributed to POME.

During a review that involved adjudication of all cases meeting specific criteria, 9 POME events in 8 patients and 2 events of anaphylaxis among 3,556 patients treated with intramuscular Testex (Testosterone Propionate) undecanoate in 18 clinical trials were judged to have occurred.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Testex (Testosterone Propionate). Because the 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.

Pulmonary Oil Microembolism (POME) and Anaphylaxis

Serious pulmonary oil microembolism (POME) reactions, involving cough, urge to cough, dyspnea, hyperhidrosis, throat tightening, chest pain, dizziness, and syncope, have been reported to occur during or immediately after the injection of intramuscular Testex (Testosterone Propionate) undecanoate 1000 mg (4 mL) in post-approval use outside the United States. The majority of these events lasted a few minutes and resolved with supportive measures; however, some lasted up to several hours and some required emergency care and/or hospitalization.

In addition to serious POME reactions, episodes of anaphylaxis, including life-threatening reactions, have also been reported to occur following the injection of intramuscular Testex (Testosterone Propionate) undecanoate in post-approval use outside of the United States.

Both serious POME reactions and anaphylaxis have been reported to occur after any injection of Testex (Testosterone Propionate) undecanoate during the course of therapy, including after the first dose.

Other Events

The following treatment emergent adverse events or adverse reactions have been identified during post-marketing clinical trials and during post-approval use of intramuscular Testex (Testosterone Propionate) undecanoate. In most cases, the dose being used was 1000 mg.

Blood and Lymphatic System Disorders: polycythemia, thrombocytopenia

Cardiac Disorders: angina pectoris, cardiac arrest, cardiac failure, coronary artery disease, coronary artery occlusion, myocardial infarction, tachycardia

Ear and Labyrinth Disorders: sudden hearing loss, tinnitus

Endocrine Disorders: hyperparathyroidism, hypoglycemia

Gastrointestinal Disorders: abdominal pain upper, diarrhea, vomiting

General Disorders and Administrative Site Conditions: chest pain, edema peripheral, injection site discomfort, injection site hematoma, injection site irritation, injection site pain, injection site reaction, malaise, paresthesia, procedural pain

Immune System Disorders: anaphylactic reaction, anaphylactic shock, asthma, dermatitis allergic, hypersensitivity, leukocytoclastic vasculitis

Infections and Infestations: injection site abscess, prostate infection

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, blood glucose increased, blood pressure increased, blood prolactin increased, blood Testex (Testosterone Propionate) decreased, blood Testex (Testosterone Propionate) increased, blood triglycerides increased, gamma-glutamyltransferase increased, hematocrit increased, intraocular pressure increased, liver function test abnormal, prostate examination abnormal, prostatic specific antigen increased, transaminases increased

Metabolism and Nutrition Disorders: diabetes mellitus, fluid retention, hyperlipidemia, hypertriglyceridemia

Musculoskeletal and Connective Tissue Disorders: musculoskeletal chest pain, musculoskeletal pain, myalgia, osteopenia, osteoporosis, systemic lupus erythematosus

Neoplasms Benign, Malignant and Unspecified (including cysts and polyps): prostate cancer, prostatic intraepithelial neoplasia

Nervous System Disorders: stroke, cerebrovascular insufficiency, reversible ischemic neurological deficiency, transient ischemic attack

Psychiatric Disorders: aggression, anxiety, depression, insomnia, irritability, Korsakoff’s psychosis non-alcoholic, male orgasmic disorder, nervousness, restlessness, sleep disorder

Renal and Urinary Disorders: calculus urinary, dysuria, hematuria, nephrolithiasis, pollakiuria, renal colic, renal pain, urinary tract disorder

Reproductive System and Breast Disorders: azoospermia, benign prostatic hyperplasia, breast induration, breast pain, erectile dysfunction, gynecomastia, libido decreased, libido increased, prostate induration, prostatitis, spermatocele, testicular pain

Respiratory, Thoracic and Mediastinal Disorders: asthma, chronic obstructive pulmonary disease, cough, dysphonia, dyspnea, hyperventilation, obstructive airway disorder, pharyngeal edema, pharyngolaryngeal pain, pulmonary microemboli, pulmonary embolism, respiratory distress, rhinitis, sleep apnea syndrome, snoring

Skin and Subcutaneous Tissue Disorders: acne, alopecia, angioedema, angioneurotic edema, dermatitis allergic, erythema, hyperhidrosis, pruritus, rash

Vascular Disorders: cerebral infarction, cerebrovascular accident, circulatory collapse, deep venous thrombosis, hot flush, hypertension, syncope, thromboembolism, thrombosis, venous insufficiency.

7 DRUG INTERACTIONS

  • Androgens may decrease blood glucose, and therefore may decrease insulin requirements in diabetic patients .
  • Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of international normalized ratio (INR) and prothrombin time is recommended in patients taking warfarin (7.2).
  • Use of Testex (Testosterone Propionate) with corticosteroids may result in increased fluid retention. Use with caution, particularly in patients with cardiac, renal, or hepatic disease (7.3).

7.1 Insulin

Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, may necessitate a decrease in the dose of anti-diabetic medication.

7.2 Oral Anticoagulants

Changes in anticoagulant activity may be seen with androgens, therefore more frequent monitoring of international normalized ratio and prothrombin time are recommended in patients taking warfarin, especially at the initiation and termination of androgen therapy.

7.3 Corticosteroids

The concurrent use of Testex (Testosterone Propionate) with corticosteroids may result in increased fluid retention and requires careful monitoring, particularly in patients with cardiac, renal or hepatic disease.

8 USE IN SPECIFIC POPULATIONS

Geriatric Patients: There are insufficient long-term safety data to assess the potential risks of cardiovascular disease and prostate cancer.

8.1 Pregnancy

Pregnancy Category X: Aveed is contraindicated in pregnant women or in women who may become pregnant. Testex (Testosterone Propionate) is teratogenic and may cause fetal harm. Exposure of a fetus to androgens, such as Testex (Testosterone Propionate), may result in varying degrees of virilizations. If this drug is used in pregnancy or if the patient becomes pregnant while taking this drug, the patient should be made aware of the potential hazard to the fetus.

8.3 Nursing Mothers

Although it is not known how much Testex transfers into human milk, Testex (Testosterone Propionate) is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants.

8.4 Pediatric Use

Safety and effectiveness of Testex (Testosterone Propionate) in pediatric patients less than 18 years old have not been established. Improper use may result in acceleration of bone age and premature closure of epiphyses.

8.5 Geriatric Use

There have not been sufficient numbers of geriatric patients in controlled clinical studies with Testex to determine whether efficacy or safety in those over 65 years of age differs from younger subjects. Of the153 patients enrolled in the pivotal clinical study utilizing Testex (Testosterone Propionate), 26 (17.0%) were over 65 years of age. Additionally, there are insufficient long-term safety data in geriatric patients to assess the potentially increased risk of cardiovascular disease and prostate cancer.

Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of BPH .

8.6 Renal Impairment

No studies were conducted in patients with renal impairment.

8.7 Hepatic Impairment

No studies were conducted in patients with hepatic impairment.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Testex contains Testex (Testosterone Propionate), a Schedule III controlled substance in the Controlled Substances Act.

9.2 Abuse

Drug abuse is intentional non-therapeutic use of a drug, even once, for its rewarding psychological and physiological effects. Abuse and misuse of Testex (Testosterone Propionate) are seen in male and female adults and adolescents. Testosterone, often in combination with other anabolic androgenic steroids (AAS), and not obtained by prescription through a pharmacy, may be abused by athletes and bodybuilders. There have been reports of misuse of men taking higher doses of legally obtained Testex (Testosterone Propionate) than prescribed and continuing Testex (Testosterone Propionate) despite adverse events or against medical advice.

Abuse-Related Adverse Reactions

Serious adverse reactions have been reported in individuals who abuse anabolic androgenic steroids, and include cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure, cerebrovascular accident, hepatotoxicity, and serious psychiatric manifestations, including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression.

The following adverse reactions have also been reported in men: transient ischemic attacks, convulsions, hypomania, irritability, dyslipidemias, testicular atrophy, subfertility, and infertility.

The following additional adverse reactions have been reported in women: hirsutism, virilization, deepening of voice, clitoral enlargement, breast atrophy, male-pattern baldness, and menstrual irregularities.

The following adverse reactions have been reported in male and female adolescents: premature closure of bony epiphyses with termination of growth, and precocious puberty.

Because these reactions are reported voluntarily from a population of uncertain size and may include abuse of other agents, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

9.3 Dependence

Behaviors Associated with Addiction

Continued abuse of Testex (Testosterone Propionate) and other anabolic steroids, leading to addiction is characterized by the following behaviors:

  • Taking greater dosages than prescribed
  • Continued drug use despite medical and social problems due to drug use
  • Spending significant time to obtain the drug when supplies of the drug are interrupted
  • Giving a higher priority to drug use than other obligations
  • Having difficulty in discontinuing the drug despite desires and attempts to do so
  • Experiencing withdrawal symptoms upon abrupt discontinuation of use

Physical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or a significant dose reduction of a drug. Individuals taking supratherapeutic doses of Testex (Testosterone Propionate) may experience withdrawal symptoms lasting for weeks or months which include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism.

Drug dependence in individuals using approved doses of Testex (Testosterone Propionate) for approved indications has not been documented.

.

10 OVERDOSAGE

There have been no reports of overdosage in the Testex (Testosterone Propionate) clinical trials. There is one report of acute overdosage with use of an approved injectable Testex (Testosterone Propionate) product: this subject had serum Testex (Testosterone Propionate) levels of up to 11,400 ng/dL with a cerebrovascular accident.

Treatment of overdosage would consist of discontinuation of Testex (Testosterone Propionate) together with appropriate symptomatic and supportive care.

11 DESCRIPTION

Testex (Testosterone Propionate) (testosterone undecanoate) injection contains Testex (Testosterone Propionate) undecanoate (17β-undecanoyloxy-4-androsten-3-one) which is an ester of the androgen, Testex (Testosterone Propionate). Testex (Testosterone Propionate) is formed by cleavage of the ester side chain of Testex (Testosterone Propionate) undecanoate.

Testex (Testosterone Propionate) undecanoate is a white to off-white crystalline substance. The empirical formula of Testex (Testosterone Propionate) undecanoate is C30H48O3 and a molecular weight of 456.7. The structural formula is:

FIGURE 2: Testex (Testosterone Propionate) Undecanoate


C30H48O3 MW: 456.7

Testex (Testosterone Propionate) is a clear, yellowish, sterile oily solution containing Testex (Testosterone Propionate) undecanoate, a Testex (Testosterone Propionate) ester, for intramuscular injection. Each single use vial contains 3 mL of 250 mg/mL Testex (Testosterone Propionate) undecanoate solution in a mixture of 1500 mg of benzyl benzoate and 885 mg of refined castor oil.

Figure2

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Endogenous androgens, including Testex and dihydrotestosterone (DHT) are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of 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, and alterations in body musculature and fat distribution.

Male hypogonadism, a clinical syndrome resulting from insufficient secretion of Testex (Testosterone Propionate), has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

12.3 Pharmacokinetics

Absorption

Testex (Testosterone Propionate) 750 mg delivers physiologic amounts of Testex (Testosterone Propionate), producing circulation Testex (Testosterone Propionate) concentrations that approximate normal concentrations (300-1000 ng/dL) seen in healthy men.

Testex (Testosterone Propionate) esters in oil injected intramuscularly are absorbed from the lipid phase. Cleavage of the undecanoic acid side chain of Testex (Testosterone Propionate) by tissue esterases releases Testex (Testosterone Propionate).

Following intramuscular injection of 750 mg of Testex (Testosterone Propionate), serum Testex (Testosterone Propionate) concentrations reach a maximum after a median of

7 days (range 4 – 42 days) then slowly decline (Figure 3). Steady state serum Testex (Testosterone Propionate) concentration was achieved with the 3rd injection of Testex (Testosterone Propionate) at 14 weeks.

Figure 3 shows the mean serum total Testex (Testosterone Propionate) concentration-time profile during the 3rd injection interval (at steady state, 14-24 weeks) for hypogonadal men (less than 300 ng/dL) given 750 mg Testex (Testosterone Propionate) at initiation, at 4 weeks, and every 10 weeks thereafter. Intramuscular injection of 750 mg of Testex (Testosterone Propionate) generates mean steady state serum total Testex (Testosterone Propionate) concentrations in the normal range for 10 weeks.

FIGURE 3: Mean (SD) Serum Total Testex (Testosterone Propionate)

Concentrations (ng/dL) at 14-24 Weeks


Distribution

Circulating Testex (Testosterone Propionate) is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin.

Approximately 40% of Testex (Testosterone Propionate) in plasma is bound to SHBG, 2% remains unbound (free), and the rest is loosely bound to albumin and other proteins.

Metabolism

Testex (Testosterone Propionate) undecanoate is metabolized to Testex (Testosterone Propionate) via ester cleavage of the undecanoate group. The mean (SD) maximum concentration of Testex (Testosterone Propionate) undecanoate was 90.9 (68.8) ng/dL on Day 4 following injection of Testex (Testosterone Propionate). Testex (Testosterone Propionate) undecanoate was nearly undetectable 42 days following injection of Testex (Testosterone Propionate).

Testex (Testosterone Propionate) is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of Testex (Testosterone Propionate) are estradiol and DHT.

DHT concentrations increased in parallel with Testex (Testosterone Propionate) concentrations during Testex (Testosterone Propionate) treatment. Average DHT concentrations during a dosing interval ranged from 244 to 451 ng/dL. The mean DHT:T ratios ranged from 0.05 to 0.07.

Excretion

There is considerable variation in the half-life of Testex (Testosterone Propionate) as reported in the literature, ranging from 10 to 100 minutes. About 90% of a Testex (Testosterone Propionate) dose given intramuscularly is excreted in the urine as glucuronic and sulfuric acid-conjugates of Testex (Testosterone Propionate) or as metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of Testex (Testosterone Propionate) occurs primarily in the liver.

Effect of Body Weight and Body Mass Index (BMI)

Analysis of serum Testex (Testosterone Propionate) concentrations from 117 hypogonadal men in the 84-week clinical study of Testex (Testosterone Propionate) indicated that serum Testex (Testosterone Propionate) concentrations achieved were inversely correlated with the patient’s body weight. In 60 patients with pretreatment body weight of ≥100 kg, the mean (±SD) serum Testex (Testosterone Propionate) average concentration was 426 ± 104 ng/dL. A higher serum Testex (Testosterone Propionate) average concentration (568 ± 139 ng/dL) was observed in 57 patients weighing 65 to 100 kg. A similar trend was also observed for maximum serum Testex (Testosterone Propionate) concentrations.

In 70 patients with pretreatment body mass index of >30 kg/m2, the mean (±SD) serum Testex (Testosterone Propionate) average concentration was

445 ± 116 ng/dL. Higher serum Testex (Testosterone Propionate) average concentrations (579 ± 101 ng/dL and 567± 155ng/dL) were observed in patients with BMIs <26 kg/m2 and 26 to 30 kg/m2,respectively. A similar trend was also observed for maximum serum Testex (Testosterone Propionate) concentrations.

Figure3

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility

Carcinogenicity

Testex (Testosterone Propionate) has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors, which metastasized in some cases. There is suggestive evidence that injection of Testex (Testosterone Propionate) into some strains of female mice increases their susceptibility to hepatoma. Testex (Testosterone Propionate) is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.

Mutagenicity

Mutagenic effects of Testex (Testosterone Propionate) undecanoate were not detected in a battery of in vitro tests including bacterial mutation assays (Ames test) and chromosomal aberration tests in human lymphocytes. Testex (Testosterone Propionate) undecanoate was also negative in an in vivo bone marrow micronucleus assay in mice. Testex (Testosterone Propionate) was negative in the in vitro Ames and in the in vivo mouse micronucleus assays.

Impairment of Fertility

The administration of exogenous Testex (Testosterone Propionate) has been reported to suppress spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment.

14 CLINICAL STUDIES

14.1 Testex Replacement Therapy

Testex (Testosterone Propionate) was evaluated for efficacy in an 84-week, single-arm, open-label, multicenter study of 130 hypogonadal men. Eligible patients weighed at least 65 kg, were 18 years of age and older (mean age 54.2 years), and had a morning serum total Testex (Testosterone Propionate) concentrations <300 ng/dL (mean screening Testex (Testosterone Propionate) concentration 215 ng/dL). Patients were Caucasian (74.6%), Black (12.3%), Hispanic (10.8%) and of Other ethnicities (2.3%). The mean body mass index was 32 kg/m2.

All patients received injections of Testex (Testosterone Propionate) 750 mg at baseline, at 4 weeks, and then every 10 weeks thereafter.

The primary endpoint was the percentage of patients with average serum total Testex (Testosterone Propionate) concentration (Cavg) within the normal range (300-1000 ng/dL) after the third injection, at steady state.

The secondary endpoint was the percentage of patients with maximum total Testex (Testosterone Propionate) concentration (Cmax) above three pre-determined limits: greater than 1500 ng/dL, between 1800 and 2499 ng/dL, and greater than 2500 ng/dL.

A total of 117 out of 130 hypogonadal men completed study procedures through Week 24 and were included in the evaluation of Testex (Testosterone Propionate) pharmacokinetics after the third Testex (Testosterone Propionate) injection. Ninety-four percent (94%) of patients maintained a Cavg within the normal range (300 to 1000 ng/dL). The percentages of patients with Cavg below the normal range (less than 300 ng/dL) and above the normal range (greater than 1000 ng/dL) were 5.1% and 0.9%, respectively.

Table 2 summarizes the mean (SD) serum total Testex (Testosterone Propionate) pharmacokinetic parameters at steady state for these 117 patients.

TABLE 2

Mean (SD) Serum Total Testex (Testosterone Propionate) Concentrations at Steady State


Pharmacokinetics at Steady State


Testex (Testosterone Propionate) 750 mg

(N=117)


Cavg (0 to 10 weeks) (ng/dL)


495 (142)


Cmax (ng/dL)


891 (345)


Cmin (ng/dL)


324 (99)


Cavg = average concentration; Cmax = maximum concentration; Cmin = minimum concentration

The percentage of patients with Cmax >1500 ng/dL was 7.7%. No patient had a Cmax >1800 ng/dL.

16 HOW SUPPLIED/STORAGE AND HANDLING

Testex (Testosterone Propionate), NDC 67979-511-43: 750 mg/3 mL (250 mg/mL) Testex (Testosterone Propionate) undecanoate sterile injectable solution is provided in an amber glass vial with silver-colored crimp seal and gray plastic cap. Each vial is individually packaged in a carton box.

Store at controlled room temperature 25 ºC (77 ºF); excursions permitted to 15 - 30 ºC (59 - 86 ºF) in its original carton until the date indicated.

Before use, each vial should be visually inspected. Only vials free from particles should be used.

Single Use Vial. Discard unused portion.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Medication Guide

Advise patients of the following:

17.1 Risks of Serious Pulmonary Oil Microembolism and Anaphylaxis

  • Serious pulmonary oil microembolism (POME) reactions, involving cough, urge to cough, shortness of breath, sweating, throat tightening, chest pain, dizziness, and syncope, have been reported to occur during or immediately after the injection of intramuscular Testex (Testosterone Propionate) undecanoate. The majority of these events lasted a few minutes and resolved with supportive measures; however, some lasted up to several hours and some required emergency care and/or hospitalization.
  • Episodes of anaphylaxis, including life-threatening reactions, have also been reported to occur following the injection of intramuscular Testex (Testosterone Propionate) undecanoate.
  • Both serious POME reactions and anaphylaxis can occur after any injection of Testex (Testosterone Propionate) undecanoate during the course of therapy, including after the first dose.
  • Advise the patient to read the Testex (Testosterone Propionate) REMS information sheet titled "What You Need to Know About Testex (Testosterone Propionate)® Treatment: A Patient Guide.
  • Instruct patients to remain at the healthcare setting for 30 minutes after each Testex (Testosterone Propionate) injection.

17.2 Men with Known or Suspected Carcinoma of the Prostate or Breast

Men with known or suspected prostate or breast cancer should not use Testex .

17.3 Potential Adverse Reactions to Androgens

Patients should be informed that treatment with androgens may lead to adverse reactions which include:

  • Changes in urinary habits, such as increased urination at night, trouble starting the urine stream, passing urine many times during the day, having an urge to go the bathroom right away, having a urine accident, or being unable to pass urine or weak urine flow
  • Breathing disturbances, including those associated with sleep or excessive daytime sleepiness
  • Too frequent or persistent erections of the penis
  • Nausea, vomiting, changes in skin color, or ankle swelling

17.4 Patients Should be Advised of the Following Instructions for Use

  • Read the Medication Guide before starting Testex (Testosterone Propionate) therapy and reread the Guide before each injection.
  • Adhere to all recommended monitoring.
  • Report any changes in their state of health, such as changes in urinary habits, breathing, sleep, and mood.

Distributed by:

Endo Pharmaceuticals Solutions Inc.

Malvern, PA 19355

Testex (Testosterone Propionate) is a registered trademark of Endo Pharmaceuticals Inc.

© 2017 Endo Pharmaceuticals Solutions Inc. All rights reserved.

Revised: July 2017

Testex (Testosterone Propionate)® (Uh-Veed)

(testosterone undecanoate)

injection

Read this Medication Guide before you receive Testex (Testosterone Propionate) and before each injection. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about Testex (Testosterone Propionate)?

Testex (Testosterone Propionate) may cause serious side effects, including:

  • A serious lung problem. Testex (Testosterone Propionate) can cause a serious lung problem called a pulmonary oil microembolism (POME) reaction. POME is caused by tiny droplets of oil that have traveled to the lungs. Symptoms of a POME reaction may include:

o cough or urge to cough

o difficulty breathing

o sweating

o tightening of your throat

o chest pain

o dizziness

o fainting

  • Serious allergic reactions (anaphylaxis). Testex (Testosterone Propionate) can cause a serious allergic reaction right after receiving the injection. Some of these allergic reactions may be life threatening.

These reactions can happen after you receive your first dose of Testex (Testosterone Propionate) or may happen after receiving more than 1 dose.

You may need emergency treatment in a hospital, especially if these symptoms get worse over the 24 hours after

your AVEED injection.

These side effects may happen during or right after each injection. To be sure that you are not having one

of these reactions:

o You need to stay in the doctor’s office, clinic, or hospital for 30 minutes after having your Testex (Testosterone Propionate) injection so

that your doctor can watch you for symptoms of POME or a serious allergic reaction.

o You can only get Testex (Testosterone Propionate) at your doctor’s office, clinic, or hospital.

Testex (Testosterone Propionate) is only available through a restricted program called the Testex (Testosterone Propionate) Risk Evaluation and Mitigation Strategy (REMS) Program. For more information about the Testex (Testosterone Propionate) REMS Program go to www. AveedREMS.com or call 1-855-755-0494.

What is Testex (Testosterone Propionate)?

Testex (Testosterone Propionate) is a prescription medicine that contains Testex (Testosterone Propionate). Testex (Testosterone Propionate) is used to treat adult males who have low or no Testex (Testosterone Propionate) due to certain medical conditions.

Testex (Testosterone Propionate) is only for adult males who need Testex (Testosterone Propionate) replacement therapy and when the benefit of receiving Testex (Testosterone Propionate) is more than the risk of POME and anaphylaxis.

Your healthcare provider will test your blood before you start and while you are taking Testex (Testosterone Propionate).

It is not known if AVEEDis safe or effective to treat men who have low Testex (Testosterone Propionate) due to aging.

It is not known if Testex (Testosterone Propionate) is safe and effective for use in children younger than 18 years old. Improper use of Testex (Testosterone Propionate) may affect bone growth in children.

Testex (Testosterone Propionate) is a controlled substance (CIII) because it contains Testex (Testosterone Propionate) that can be a target for people who abuse prescription medicines.

Testex (Testosterone Propionate) is not meant for use in women.

Who should not receive Testex (Testosterone Propionate)?

Do not receive Testex (Testosterone Propionate) if you:

  • have breast cancer
  • have or might have prostate cancer
  • are pregnant or may become pregnant or are breastfeeding. Testex (Testosterone Propionate) may harm your unborn or breastfeeding baby.
  • are allergic to Testex (Testosterone Propionate) or to any of the ingredients in Testex (Testosterone Propionate). See the end of this leaflet for a complete list of ingredients in Testex (Testosterone Propionate).

Talk to your doctor before receiving this medicine if you have any of the above conditions.

What should I tell my doctor before receiving Testex (Testosterone Propionate)?

Before receiving Testex (Testosterone Propionate), tell your doctor if you:

  • have breast cancer
  • have or might have prostate cancer
  • have urinary problems due to an enlarged prostate
  • have heart problems
  • have liver or kidney problems
  • have problems breathing while you sleep (sleep apnea)
  • have any other medical conditions

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Receiving Testex (Testosterone Propionate) with certain other medicines can affect each other. Especially tell your doctor if you take:

  • insulin
  • medicines that decrease blood clotting
  • corticosteroids

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of your medicines and show them to your doctor and pharmacist when you get a new medicine.

How will I receive Testex (Testosterone Propionate)?

See “What is the most important information I should know about Testex (Testosterone Propionate)?

Your doctor will inject Testex (Testosterone Propionate) deep into the muscle of your buttock. You will get 1 injection when you start, 1 injection 4 weeks later and then 1 injection every 10 weeks.

Your doctor will test your blood before you receive and while you are receiving Testex (Testosterone Propionate).

What are the possible side effects of Testex (Testosterone Propionate)?

Testex (Testosterone Propionate) can cause serious side effects including:

  • see “What is the most important information I should know about Testex (Testosterone Propionate)?”
  • if you already have enlargement of your prostate gland, your signs and symptoms can get worse while receiving Testex (Testosterone Propionate). This can include:

o increased urination at night

o trouble starting your urine stream

o having to pass urine many times during the day

o having an urge that you have to go to the bathroom right away

o having a urine accident

o being unable to pass urine or weak urine flow

  • changes in certain blood tests
  • possible increased risk of prostate cancer. Your doctor should check you for prostate cancer or any other prostate problems before you receive and while you are receiving Testex (Testosterone Propionate).
  • blood clots in the legs or lungs. Signs and symptoms of a blood clot in your leg can include leg pain, swelling or redness. Signs and symptoms of a blood clot in your lungs can include difficulty breathing or chest pain.
  • possible increased risk of heart attack or stroke.
  • in large doses Testex (Testosterone Propionate) may lower your sperm count.
  • liver problems. Symptoms of liver problems may include:

o nausea or vomiting

o yellowing of your skin or whites of your eyes

o dark urine

o pain on the right side of your stomach area (abdominal pain)

  • swelling of your ankles, feet, or body, with or without heart failure. This may cause serious problems for people who have heart, kidney, or liver disease.
  • enlarged or painful breasts.
  • have problems breathing while you sleep (sleep apnea).

Call your doctor right away if you have any of the serious side effects listed above.

The most common side effects of Testex (Testosterone Propionate) include:

  • acne
  • pain at the injection site
  • increased prostate specific antigen (a test used to screen for prostate cancer)
  • increased estradiol level
  • low Testex (Testosterone Propionate) level
  • feeling tired
  • irritability
  • increased red blood cell count
  • difficulty sleeping
  • mood swings

Other side effects include more erections than are normal for you or erections that last for a long time.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects with Testex (Testosterone Propionate). For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about Testex (Testosterone Propionate)

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

This Medication Guide summarizes the most important information about Testex (Testosterone Propionate). If you would like more information, talk with your doctor. You can ask your doctor or nurse for information about Testex (Testosterone Propionate) that is written for health professionals. For more information, go to www. AVEEDUSA.com or call 1-800-462-3636.

What are the ingredients in Testex (Testosterone Propionate)?

Active ingredient: Testex (Testosterone Propionate) undecanoate

Inactive ingredients: refined castor oil, benzyl benzoate

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by:

Endo Pharmaceuticals Solutions Inc.

Malvern, PA 19355

Testex (Testosterone Propionate) is a registered trademark of Endo Pharmaceuticals Inc.

© 2016 Endo Pharmaceuticals Solutions Inc. All rights reserved.

Approved: 10/2016

85534041



carton

Testex pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Testex available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Testex destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Testex Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Testex pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."DEPO-TESTOSTERONE (TESTOSTERONE CYPIONATE) INJECTION, SOLUTION [PHARMACIA AND UPJOHN COMPANY LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."TESTOSTERONE PROPIONATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."TESTOSTERONE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Testex?

Depending on the reaction of the Testex after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Testex not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Testex addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Testex, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Testex consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

Visitor reported frequency of use

No survey data has been collected yet

One visitor reported doses

What is the dose of Testex drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 51-100mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
51-100mg1
100.0%

Visitor reported time for results

No survey data has been collected yet

Visitor reported administration

No survey data has been collected yet

One visitor reported age

Visitors%
46-601
100.0%

Visitor reviews


There are no reviews yet. Be the first to write one!


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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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