Cristerone T

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Cristerone T uses

• Warning: serious pulmonary oil microembolism (pome) reactions and anaphylaxis
• Recent major changes
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Drug abuse and dependence
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Cristerone T reviews

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 Cristerone T undecanoate injection. These reactions can occur after any injection of Cristerone T undecanoate during the course of therapy, including after the first dose [see Warnings and Precautions (5.1)].
• Following each injection of Cristerone T, 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, Cristerone T is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Cristerone T 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 Cristerone T undecanoate injection. These reactions can occur after any injection of Cristerone T undecanoate during the course of therapy, including after the first dose (5.1).
• Following each injection of Cristerone T, 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).
• Cristerone T is available only through a restricted program called the Cristerone T REMS Program (5.2).

RECENT MAJOR CHANGES

Warnings and Precautions (5.7) 10/2016

1 INDICATIONS AND USAGE

Cristerone T is indicated for Cristerone T replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous Cristerone T.

• 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 Cristerone T 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 Cristerone T serum concentrations but have gonadotropins in the normal or low range.

Cristerone T should only be used in patients who require Cristerone T 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 Cristerone T in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.
• Safety and efficacy of Cristerone T in males less than 18 years old have not been established [see Use in Specific Populations ( 8.4 )].

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

o Primary hypogonadism (congenital or acquired) (1)

o Hypogonadotropic hypogonadism (congenital or acquired) (1)

Cristerone T should only be used in patients who require Cristerone T 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 Cristerone T in men with “age-related hypogonadism” have not been established (1).
• Safety and efficacy of Cristerone T in males less than 18 years old have not been established (1, 8.4).

2 DOSAGE AND ADMINISTRATION

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

• Prior to initiating Cristerone T, confirm the diagnosis of hypogonadism by ensuring that serum Cristerone T has been measured in the morning on at least two separate days and that these concentrations are below the normal range.
• 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 Cristerone T, 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 Cristerone T deeply into the gluteal muscle following the usual precautions for intramuscular administration of oily solutions (2.3).

2.1 Dosage

Cristerone T is for intramuscular use only. Dosage titration is not necessary.

Inject Cristerone T deeply into the gluteal muscle following the usual precautions for intramuscular administration; care must be taken to avoid intravascular injection . Intravascular injection of Cristerone T 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 Cristerone T 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 Cristerone T 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 Cristerone T, 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) Cristerone T 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) Cristerone T 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

Cristerone T 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. Cristerone T can cause fetal harm when administered to a pregnant woman. Cristerone T 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 Cristerone T 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 Cristerone T 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 Cristerone T 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 Cristerone T 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 Cristerone T 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 Cristerone T, 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 Cristerone T undecanoate.

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

Following each injection of Cristerone T, 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 Cristerone T Risk Evaluation and Mitigation Strategy Program

Cristerone T is available only through a restricted program called the Cristerone T REMS Program because of the risk of serious POME and anaphylaxis.

Notable requirements of the Cristerone T REMS Program include the following:

• Healthcare providers who prescribe Cristerone T must be certified with the REMS Program before ordering or dispensing Cristerone T.
• Healthcare settings must be certified with the REMS Program and have healthcare providers who are certified before ordering or dispensing Cristerone T. 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 Cristerone T.

Check hematocrit prior to initiating Cristerone T treatment. It would be appropriate to re-evaluate the hematocrit 3 to 6 months after starting Cristerone T 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 and pulmonary embolism (PE), in patients using Cristerone T products, such as Cristerone T. 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 Cristerone T 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 Cristerone T 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 Cristerone T compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of Cristerone T replacement therapy in men. Patients should be informed of this possible risk when deciding whether to use or to continue to use Cristerone T.

5.7 Abuse of Cristerone T and Monitoring of SerumTestosterone Concentrations

Cristerone T 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 Cristerone T abuse is suspected, check serum Cristerone T concentrations to ensure they are within therapeutic range. However, Cristerone T levels may be in the normal or subnormal range in men abusing synthetic Cristerone T derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of Cristerone T and anabolic androgenic steroids. Conversely, consider the possibility of Cristerone T 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, Cristerone T is not indicated for use in women.

5.9 Potential for Adverse Effects on Spermatogenesis

With large doses of exogenous androgens, including Cristerone T, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle- stimulating hormone 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 (e.g., methyltestosterone) 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 Cristerone T enanthate, which elevates blood levels for prolonged periods, has produced multiple hepatic adenomas. Cristerone T 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 Cristerone T while the cause is evaluated.

5.11 Edema

Androgens, including Cristerone T, 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 Cristerone T 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 Cristerone T therapy.

5.15 Hypercalcemia

Androgens, including Cristerone T, should be used with caution in cancer patients at risk of hypercalcemia. Regular monitoring of serum calcium concentrations is recommended in these patients.

5.16 Decreased Thyroxine-binding Globulin

Androgens, including Cristerone T, 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.

Cristerone T 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 Cristerone T

* 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 Cristerone T undecanoate in a total of 7 controlled clinical trials. In these clinical trials, the dose and dose frequency of intramuscular Cristerone T 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 Cristerone T, 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 Cristerone T 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 Cristerone T 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 Cristerone T. 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 Cristerone T 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 Cristerone T 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 Cristerone T 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 Cristerone T 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 Cristerone T decreased, blood Cristerone T 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 Cristerone T 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 Cristerone T 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. Cristerone T is teratogenic and may cause fetal harm. Exposure of a fetus to androgens, such as Cristerone T, 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 Cristerone T transfers into human milk, Cristerone T is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants.

8.4 Pediatric Use

Safety and effectiveness of Cristerone T 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 Cristerone T 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 Cristerone T, 26 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

Cristerone T contains Cristerone T, 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 Cristerone T are seen in male and female adults and adolescents. Testosterone, often in combination with other anabolic androgenic steroids, 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 Cristerone T than prescribed and continuing Cristerone T 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 Cristerone T 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 Cristerone T 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 Cristerone T for approved indications has not been documented.

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10 OVERDOSAGE

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

Treatment of overdosage would consist of discontinuation of Cristerone T together with appropriate symptomatic and supportive care.

11 DESCRIPTION

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

Cristerone T undecanoate is a white to off-white crystalline substance. The empirical formula of Cristerone T undecanoate is C₃₀H₄₈O₃ and a molecular weight of 456.7. The structural formula is:

FIGURE 2: Cristerone T Undecanoate

C₃₀H₄₈O₃ MW: 456.7

Cristerone T is a clear, yellowish, sterile oily solution containing Cristerone T undecanoate, a Cristerone T ester, for intramuscular injection. Each single use vial contains 3 mL of 250 mg/mL Cristerone T 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 Cristerone T and dihydrotestosterone 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 Cristerone T, 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

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

Cristerone T esters in oil injected intramuscularly are absorbed from the lipid phase. Cleavage of the undecanoic acid side chain of Cristerone T by tissue esterases releases Cristerone T.

Following intramuscular injection of 750 mg of Cristerone T, serum Cristerone T concentrations reach a maximum after a median of

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

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

FIGURE 3: Mean (SD) Serum Total Cristerone T

Concentrations (ng/dL) at 14-24 Weeks

Distribution

Circulating Cristerone T is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin.

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

Metabolism

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

Cristerone T is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of Cristerone T are estradiol and DHT.

DHT concentrations increased in parallel with Cristerone T concentrations during Cristerone T 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 Cristerone T as reported in the literature, ranging from 10 to 100 minutes. About 90% of a Cristerone T dose given intramuscularly is excreted in the urine as glucuronic and sulfuric acid-conjugates of Cristerone T or as metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of Cristerone T occurs primarily in the liver.

Effect of Body Weight and Body Mass Index (BMI)

Analysis of serum Cristerone T concentrations from 117 hypogonadal men in the 84-week clinical study of Cristerone T indicated that serum Cristerone T 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 Cristerone T average concentration was 426 ± 104 ng/dL. A higher serum Cristerone T 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 Cristerone T concentrations.

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

445 ± 116 ng/dL. Higher serum Cristerone T 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 Cristerone T concentrations.

Figure3

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility

Carcinogenicity

Cristerone T 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 Cristerone T into some strains of female mice increases their susceptibility to hepatoma. Cristerone T 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 Cristerone T undecanoate were not detected in a battery of in vitro tests including bacterial mutation assays (Ames test) and chromosomal aberration tests in human lymphocytes. Cristerone T undecanoate was also negative in an in vivo bone marrow micronucleus assay in mice. Cristerone T was negative in the in vitro Ames and in the in vivo mouse micronucleus assays.

Impairment of Fertility

The administration of exogenous Cristerone T 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 Cristerone T Replacement Therapy

Cristerone T 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 Cristerone T concentrations <300 ng/dL (mean screening Cristerone T 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 Cristerone T 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 Cristerone T concentration (C_avg) 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 Cristerone T concentration (C_max) 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 Cristerone T pharmacokinetics after the third Cristerone T injection. Ninety-four percent (94%) of patients maintained a C_avg within the normal range (300 to 1000 ng/dL). The percentages of patients with C_avg 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 Cristerone T pharmacokinetic parameters at steady state for these 117 patients.

TABLE 2

Mean (SD) Serum Total Cristerone T Concentrations at Steady State

C_avg = average concentration; C_max = maximum concentration; C_min = minimum concentration

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Cristerone T, NDC 67979-511-43: 750 mg/3 mL (250 mg/mL) Cristerone T 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 Cristerone T 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 Cristerone T undecanoate.
• Both serious POME reactions and anaphylaxis can occur after any injection of Cristerone T undecanoate during the course of therapy, including after the first dose.
• Advise the patient to read the Cristerone T REMS information sheet titled "What You Need to Know About Cristerone T^® Treatment: A Patient Guide.
• Instruct patients to remain at the healthcare setting for 30 minutes after each Cristerone T 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 Cristerone T .

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 Cristerone T 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

Cristerone T is a registered trademark of Endo Pharmaceuticals Inc.

© 2017 Endo Pharmaceuticals Solutions Inc. All rights reserved.

Revised: July 2017

Cristerone T^® (Uh-Veed)

(testosterone undecanoate)

injection

Read this Medication Guide before you receive Cristerone T 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 Cristerone T?

Cristerone T may cause serious side effects, including:

• A serious lung problem. Cristerone T 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). Cristerone T 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 Cristerone T 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 Cristerone T injection so

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

o You can only get Cristerone T at your doctor’s office, clinic, or hospital.

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

What is Cristerone T?

Cristerone T is a prescription medicine that contains Cristerone T. Cristerone T is used to treat adult males who have low or no Cristerone T due to certain medical conditions.

Cristerone T is only for adult males who need Cristerone T replacement therapy and when the benefit of receiving Cristerone T is more than the risk of POME and anaphylaxis.

Your healthcare provider will test your blood before you start and while you are taking Cristerone T.

It is not known if AVEEDis safe or effective to treat men who have low Cristerone T due to aging.

It is not known if Cristerone T is safe and effective for use in children younger than 18 years old. Improper use of Cristerone T may affect bone growth in children.

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

Cristerone T is not meant for use in women.

Who should not receive Cristerone T?

Do not receive Cristerone T if you:

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

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

What should I tell my doctor before receiving Cristerone T?

Before receiving Cristerone T, 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 Cristerone T 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 Cristerone T?

See “What is the most important information I should know about Cristerone T?”

Your doctor will inject Cristerone T 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 Cristerone T.

What are the possible side effects of Cristerone T?

Cristerone T can cause serious side effects including:

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

• acne
• pain at the injection site
• increased prostate specific antigen (a test used to screen for prostate cancer)
• increased estradiol level
• low Cristerone T 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 Cristerone T. 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 Cristerone T

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

This Medication Guide summarizes the most important information about Cristerone T. If you would like more information, talk with your doctor. You can ask your doctor or nurse for information about Cristerone T 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 Cristerone T?

Active ingredient: Cristerone T 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

Cristerone T is a registered trademark of Endo Pharmaceuticals Inc.

© 2016 Endo Pharmaceuticals Solutions Inc. All rights reserved.

Approved: 10/2016

85534041

carton

Cristerone T pharmaceutical active ingredients containing related brand and generic drugs:

• Testosterone

Cristerone T available forms, composition, doses:

• N/A

Cristerone T destination | category:

• Human:
• Androgens

Cristerone T Anatomical Therapeutic Chemical codes:

• G03BA03 - Testosterone

Cristerone T pharmaceutical companies:

• Gador

References

1. Dailymed."TESTOPEL (TESTOSTERONE) PELLET [ENDO PHARMACEUTICALS, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. 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).
3. "testosterone". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Cristerone T after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Cristerone T 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.

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