PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

200 MG/ML - VIAL LABEL

NDC 71225-127-01
1 mL Single-Dose Vial
Testosterone Cypionate Injection, USP
CIII

For intramuscular use only
Rx only


Prinicipal Display Panel - 200 MG/ML - VIAL CARTON

NDC 71225-127-01
1 mL Single-Dose Vial

Testosterone Cypionate Injection, USP
CIII

For intramuscular use only
Rx only


1 INDICATIONS & USAGE

Testosterone Cypionate Injection is indicated for testosterone replacement therapy in males in conditions associated with a deficiency or absence of endogenous testosterone:

• Primary hypogonadism (congenital or acquired): testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome; or orchiectomy, Klinefelter’s syndrome, or toxic damage from alcohol or heavy metals, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (follicle stimulating hormone (FSH), luteinizing hormone (LH)) above the normal range [see Dosage and Administration (2.2)].

• 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 testosterone serum concentrations but have gonadotropins in the normal or low range [see Dosage and Administration (2.2)].

Limitations of Use
• Safety and efficacy of Testosterone Cypionate Injection in men with “age- related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.
• Safety and efficacy of Testosterone Cypionate Injection in pediatric patients below the age of 12 years have not been established [see Use in Specific Populations (8.4)].

4 CONTRAINDICATIONS

Testosterone Cypionate Injection is contraindicated in:

• Known hypersensitivity to Testosterone Cypionate Injection or to any of its components [see Description (11)]. Hypersensitivity, including skin manifestations and anaphylactoid reactions have been reported [see Adverse Reactions (6.2)].

• Men with carcinoma of the breast or known or suspected carcinoma of the prostate gland [see Warnings and Precautions (5.2)].

• Women who are pregnant. Testosterone can cause virilization of the female fetus when administered to a pregnant woman [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are discussed elsewhere in the labeling:
• Polycythemia [see Warnings and Precautions (5.1)]
• Cardiovascular Risk [see Warnings and Precautions (5.2)]
• Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer [see Warnings and Precautions (5.3)]
• Venous Thromboembolism [see Warnings and Precautions (5.4)]
• Hepatic Adverse Effects [see Warnings and Precautions (5.8)]
• Edema [see Warnings and Precautions (5.9)]
• Sleep Apnea [see Warnings and Precautions (5.10)]
• Gynecomastia [see Warnings and Precautions (5.11)]
• Lipid Changes [see Warnings and Precautions (5.12)]
• Hypercalcemia [see Warnings and Precautions (5.13)]
• Decreased Thyroxine-binding Globulin [see Warnings and Precautions (5.14)]
• Increases in Prolactin [see Warnings and Precautions (5.15)]
• Adverse Effects on Bone Maturation [see Warnings and Precautions (5.16)]

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 practice.

The safety of Testosterone Cypionate Injection was evaluated, in Study 1, a randomized, single-dose, open-label study conducted in 27 adult males with hypogonadism. Patients were 18 to 65 years of age with a body mass index of 18 to 35 kg/m2. Patients received a single intramuscular dose Testosterone Cypionate Injection 200 mg or comparator intramuscular testosterone replacement therapy product and were observed for adverse reactions and injection site reactions over 31 days.

The most common adverse reactions in patients who received Testosterone Cypionate Injection were injection site erythema (26%) and injection site reaction (4%). All cases of injection site erythema and injection site reaction were categorized as mild based on a pre-defined injection site assessment scale that defined injection site reactions as mild if they were slight or barely perceptible.

6.2 Other Adverse Reactions

The following adverse reactions associated with the use of testosterone were identified in clinical studies or postmarketing reports. Because some of these reactions were 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.

Administration site reactions: Inflammation and pain at the site of intramuscular injection.

Allergic: Hypersensitivity, including skin manifestations and anaphylactoid reactions.

Cardiovascular disorders: myocardial infarction, stroke.

Endocrine and urogenital: Gynecomastia premature closure of bony epiphyses with termination of growth, precocious puberty.

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.

Reproductive system: Excessive frequency and duration of penile erections, oligospermia, and priapism

Vascular disorders: Venous thromboembolism.

Skin and appendages: Male pattern baldness, seborrhea, and acne.

Special senses: Rare cases of central serous chorioretinopathy (CSCR).

7 DRUG INTERACTIONS

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, insulin requirements.

7.2 Oral Anticoagulants

Changes in anticoagulant activity may be seen with androgens. Frequent monitoring of INR and prothrombin time may be necessary in patients taking anticoagulants, especially at the initiation and termination of androgen therapy.

7.3 Corticosteroids

The concurrent use of testosterone with corticosteroids may result in increased fluid retention and should be monitored cautiously, particularly in patients with cardiac, renal or hepatic disease.

2 DOSAGE & ADMINISTRATION

2.1 Important Dosage Information

• Injectable testosterone products may have different doses, strengths, or administration instructions and they are not substitutable on a milligram-per- milligram basis.

• Administer Testosterone Cypionate Injection by deep gluteal intramuscular injection only.

2.2 Confirmation of Hypogonadism before Initiation of Testosterone

Cypionate

Prior to initiating Testosterone Cypionate Injection, 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.

2.3 Recommended Dosage and Administration

The recommended dosage of Testosterone Cypionate Injection is 50 mg to 400 mg administered every two to four weeks as a deep intramuscular injection in the gluteal muscle.

Individualize the dose and schedule of Testosterone Cypionate Injection based on the patient’s age, diagnosis, response to treatment, and the appearance of adverse reactions.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard any unused portions of drug remaining in the single-dose vial.

3 DOSAGE FORMS & STRENGTHS

Injection: 200 mg/mL available as 1 mL of clear colorless to pale yellow solution filled in a single-dose glass vial.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
Testosterone Cypionate Injection is contraindicated in pregnant women and not indicated for use in females [see Contraindications (4)]. Testosterone is teratogenic and may cause fetal harm when administered to a pregnant woman based on data from animal studies (see Data) and its mechanism of action [see Clinical Pharmacology (12.1)]. Exposure of a female fetus to androgens may result in varying degrees of virilization. In animal developmental studies, exposure to testosterone in utero resulted in hormonal and behavioral changes in offspring and structural impairments of reproductive tissues in female and male offspring. These studies did not meet current standards for nonclinical development toxicity studies.

Data
Animal Data
In developmental studies conducted in rats, rabbits, pigs, sheep and rhesus monkeys, pregnant animals received intramuscular injection of testosterone during the period of organogenesis. Testosterone treatment at doses that were comparable to those used for testosterone replacement therapy resulted in structural impairments in both female and male offspring. Structural impairments observed in females included increased anogenital distance, phallus development, empty scrotum, no external vagina, intrauterine growth retardation, reduced ovarian reserve, and increased ovarian follicular recruitment. Structural impairments seen in male offspring included increased testicular weight, larger seminal tubular lumen diameter, and higher frequency of occluded tubule lumen. Increased pituitary weight was seen in both sexes.

Testosterone exposure in utero also resulted in hormonal and behavioral changes in offspring. Hypertension was observed in pregnant females and offspring in rats exposed to doses approximately twice those used for testosterone replacement therapy.

8.2 Lactation

Risk Summary
Testosterone Cypionate Injection is not indicated for use in females.

8.3 Females and Males of Reproductive Potential

Infertility
Males
During treatment with large doses of exogenous androgens, including testosterone cypionate injection, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular-axis [see Warnings and Precautions (5.7)]. Reduced fertility is observed in some men taking testosterone replacement therapy. The impact on fertility may be irreversible. Testicular atrophy, subfertility, and infertility have also been reported in men who abuse anabolic androgenic steroids [see Drug Abuse and Dependence (9.2)].

8.4 Pediatric Use

Improper use may result in acceleration of bone age and premature closure of epiphyses. 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. Precocious puberty has also been reported with use of testosterone.

The safety and effectiveness of Testosterone Cypionate Injection have not been established in pediatric patients young than 12 years of age.

8.5 Geriatric Use

Geriatric patients treated with androgens may be at an increased risk of developing BPH and prostatic carcinoma [see Warnings and Precautions (5.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Testosterone Cypionate Injection contains testosterone, a Schedule III controlled substance.

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 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.

9.3 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.

10 OVERDOSAGE

There is one report of acute overdosage with use of an approved injectable testosterone product: this subject had serum testosterone levels of up to 11,400 ng/dL with a cerebrovascular accident. Treatment of overdosage consists of discontinuation of Testosterone Cypionate Injection and appropriate symptomatic and supportive care.

11 DESCRIPTION

Testosterone Cypionate Injection, USP for intramuscular injection, contains testosterone cypionate which is the oil-soluble 17 (beta)-cyclopentylpropionate ester of the androgenic hormone testosterone.
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 testosterone cypionate is androst-4-en-3-one, 17-(3-cyclopentyl-1-oxopropoxy)-, (17ß)-. Its molecular formula is C27H40O3, and the molecular weight 412.61. The structural formula is shown in the following figure:


Testosterone Cypionate Injection, USP is provided as sterile, clear colorless to pale yellow solution containing 200 mg/mL testosterone cypionate in vials.

Each mL of solution contains:
Testosterone cypionate………………………………………..200 mg
Benzyl alcohol………………………………………………….20 mg
Benzyl benzoate……………………………………………….0.2 mL
Cottonseed oil…………………………………………………542 mg

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Endogenous androgens, including testosterone and dihydrotestosterone (DHT), 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; 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, a clinical syndrome resulting from insufficient secretion of testosterone, 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).

12.2 Pharmacodynamics

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of testosterone have not been fully characterized.

12.3 Pharmacokinetics

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

Pharmacokinetic parameters of baseline-corrected testosterone obtained following a single-dose intramuscular administration of testosterone cypionate 200 mg in prefilled syringe in 26 hypogonadal adult males are summarized in Table 1 below.****

** Table 1: Mean (±SD) Baseline-corrected Testosterone Pharmacokinetic Parameters**

Following a Single-dose Intramuscular Administration of Testosterone Cypionate 200 mg

in Hypogonadal Males (N=26)

a Reported in median (min, max).

** Distribution**
Circulating testosterone is primarily bound in serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is bound to albumin and other proteins.

Elimination
The half-life of testosterone cypionate when injected intramuscularly is approximately eight days.

Metabolism
Inactivation of testosterone occurs primarily in the liver. Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are dihydrotestosterone (DHT) and estradiol.

Excretion
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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
****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.

** Mutagenicity**
Testosterone was negative in the in vitro Ames and in the in vivo mouse micronucleus assays.

** Impairment of Fertility**
****The administration of exogenous testosterone suppresses spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment.

16 HOW SUPPLIED/STORAGE AND HANDLING

Testosterone Cypionate Injection is supplied as a sterile, clear colorless to pale yellow solution in single-dose vials as 200 mg/mL testosterone cypionate.

Store at 15°C to 25°C (59°F to 77°F); excursions permitted to 2°C to 30°C (36°F to 86°F). Store product in carton to protect contents from light.

17 PATIENT COUNSELING INFORMATION

Polycythemia
Advise patients that Testosterone Cypionate Injection can cause an increase in hematocrit levels that may increase the risk of thromboembolic events. Advise patients about the importance of completing laboratory testing as instructed by their health care provider while on Testosterone Cypionate Injection [see Warnings and Precautions (5.1)].

Cardiovascular Risk
Advise patients that Testosterone Cypionate Injection may increase in the risk of major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular death. [see Warnings and Precautions (5.2)].

Worsening of Benign Prostatic Hyperplasia (BPH) and Potential Risk of Prostate Cancer
Advise patients that Testosterone Cypionate Injection can cause increased symptoms of BPH and can increase the risk for prostate cancer. Advise patients to contact their health care provider if they have any prostate-related symptoms [see Warnings and Precautions (5.3)].

Edema
Advise patients with preexisting cardiac, renal, or hepatic disease that Testosterone Cypionate Injection can cause edema. Advise patients to notify their health care provider if edema develops or worsens [see Warnings and Precautions (5.9)].

Sleep Apnea
Advise patients that Testosterone Cypionate Injection can worsen sleep apnea especially in patients with risk factors such as obesity or chronic lung diseases [see Warnings and Precautions (5.10)].

Gynecomastia
Advise patients that Testosterone Cypionate Injection can cause gynecomastia [see Warnings and Precautions (5.11)].

Manufactured for:
Slayback Pharma LLC,
Princeton, NJ 08540

Manufactured by:
LSNE-LEON SLU
Calle nicostrato vela
(pq. Tecchnologico leon),
S/N – M1.1-M1.2, Leon, 24009,
Spain (ESP)

Revised:6/2022

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 6/2022