DRUGS & SUPPLEMENTS
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WARNING: SERIOUS PULMONARY OIL MICROEMBOLISM (POME) REACTIONS AND ANAPHYLAXIS
See full prescribing information for complete boxed warning
Warnings and Precautions (5.7) 10/2016
Testoderm TTS is indicated for Testoderm TTS replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous Testoderm TTS.
Testoderm TTS should only be used in patients who require Testoderm TTS replacement therapy and in whom the benefits of the product outweigh the serious risks of pulmonary oil microembolism and anaphylaxis.
Limitations of use:
Testoderm TTS (testosterone undecanoate) injection is an androgen indicated for Testoderm TTS replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous Testoderm TTS:
o Primary hypogonadism (congenital or acquired) (1)
o Hypogonadotropic hypogonadism (congenital or acquired) (1)
Testoderm TTS should only be used in patients who require Testoderm TTS replacement therapy and in whom the benefits of the product outweigh the serious risks of pulmonary oil microembolism and anaphylaxis (1).
Limitations of use:
Prior to initiating Testoderm TTS, confirm the diagnosis of hypogonadism by ensuring that serum Testoderm TTS concentrations have been measured in the morning on at least two separate days and that these serum Testoderm TTS concentrations are below the normal range.
Testoderm TTS is for intramuscular use only. Dosage titration is not necessary.
Inject Testoderm TTS deeply into the gluteal muscle following the usual precautions for intramuscular administration; care must be taken to avoid intravascular injection . Intravascular injection of Testoderm TTS 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.
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 Testoderm TTS 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.
The site for injection for Testoderm TTS 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 Testoderm TTS, 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).
750 mg/3 mL (250 mg/mL) Testoderm TTS undecanoate sterile injectable solution is provided in an amber glass, single use vial with silver-colored crimp seal and gray plastic cap.
Testoderm TTS should not be used in any of the following patients:
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 Testoderm TTS 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 Testoderm TTS, 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 Testoderm TTS undecanoate.
Both serious POME reactions and anaphylaxis can occur after any injection of Testoderm TTS undecanoate during the course of therapy, including after the first dose. Patients with suspected hypersensitivity reactions to Testoderm TTS should not be re-treated with Testoderm TTS.
Following each injection of Testoderm TTS, 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.
Testoderm TTS is available only through a restricted program called the Testoderm TTS REMS Program because of the risk of serious POME and anaphylaxis.
Notable requirements of the Testoderm TTS REMS Program include the following:
Further information is available at www. AveedREMS.com or call 1-855-755-0494.
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 .
Increases in hematocrit, reflective of increases in red blood cell mass, may require discontinuation of Testoderm TTS.
Check hematocrit prior to initiating Testoderm TTS treatment. It would be appropriate to re-evaluate the hematocrit 3 to 6 months after starting Testoderm TTS 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.
There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis and pulmonary embolism (PE), in patients using Testoderm TTS products, such as Testoderm TTS. 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 Testoderm TTS and initiate appropriate workup and management.
Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of Testoderm TTS 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 Testoderm TTS compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of Testoderm TTS replacement therapy in men. Patients should be informed of this possible risk when deciding whether to use or to continue to use Testoderm TTS.
Testoderm TTS 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 Testoderm TTS abuse is suspected, check serum Testoderm TTS concentrations to ensure they are within therapeutic range. However, Testoderm TTS levels may be in the normal or subnormal range in men abusing synthetic Testoderm TTS derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of Testoderm TTS and anabolic androgenic steroids. Conversely, consider the possibility of Testoderm TTS and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.
Due to lack of controlled evaluations in women and potential virilizing effects, Testoderm TTS is not indicated for use in women.
With large doses of exogenous androgens, including Testoderm TTS, 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.
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 Testoderm TTS enanthate, which elevates blood levels for prolonged periods, has produced multiple hepatic adenomas. Testoderm TTS 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 Testoderm TTS while the cause is evaluated.
Androgens, including Testoderm TTS, 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.
Gynecomastia occasionally develops and occasionally persists in patients being treated for hypogonadism .
The treatment of hypogonadal men with Testoderm TTS products may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases.
Changes in serum lipid profile may require dose adjustment of lipid lowering drugs or discontinuation of Testoderm TTS therapy.
Androgens, including Testoderm TTS, should be used with caution in cancer patients at risk of hypercalcemia. Regular monitoring of serum calcium concentrations is recommended in these patients.
Androgens, including Testoderm TTS, 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.
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 .
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.
Testoderm TTS 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.
Adverse Reactions Reported in at Least 1% of Patients in the 84-Week Clinical Study of Testoderm TTS
MedDRA Preferred term
Number of patients (%)
Aveed 750 mg
Injection site pain
Prostatic specific antigen increased*
Injection site erythema
* 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 Testoderm TTS undecanoate in a total of 7 controlled clinical trials. In these clinical trials, the dose and dose frequency of intramuscular Testoderm TTS 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 Testoderm TTS, 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 Testoderm TTS 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 Testoderm TTS undecanoate in 18 clinical trials were judged to have occurred.
The following adverse reactions have been identified during post-approval use of Testoderm TTS. 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 Testoderm TTS 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 Testoderm TTS 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 Testoderm TTS undecanoate during the course of therapy, including after the first dose.
The following treatment emergent adverse events or adverse reactions have been identified during post-marketing clinical trials and during post-approval use of intramuscular Testoderm TTS 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 Testoderm TTS decreased, blood Testoderm TTS 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.
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.
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.
The concurrent use of Testoderm TTS with corticosteroids may result in increased fluid retention and requires careful monitoring, particularly in patients with cardiac, renal or hepatic disease.
Geriatric Patients: There are insufficient long-term safety data to assess the potential risks of cardiovascular disease and prostate cancer.
Pregnancy Category X: Aveed is contraindicated in pregnant women or in women who may become pregnant. Testoderm TTS is teratogenic and may cause fetal harm. Exposure of a fetus to androgens, such as Testoderm TTS, 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.
Although it is not known how much Testoderm TTS transfers into human milk, Testoderm TTS is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants.
Safety and effectiveness of Testoderm TTS 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.
There have not been sufficient numbers of geriatric patients in controlled clinical studies with Testoderm TTS 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 Testoderm TTS, 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 .
No studies were conducted in patients with renal impairment.
No studies were conducted in patients with hepatic impairment.
Testoderm TTS contains Testoderm TTS, a Schedule III controlled substance in the Controlled Substances Act.
Drug abuse is intentional non-therapeutic use of a drug, even once, for its rewarding psychological and physiological effects. Abuse and misuse of Testoderm TTS 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 Testoderm TTS than prescribed and continuing Testoderm TTS 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.
Behaviors Associated with Addiction
Continued abuse of Testoderm TTS and other anabolic steroids, leading to addiction is characterized by the following behaviors:
Physical dependence is characterized by withdrawal symptoms after abrupt drug discontinuation or a significant dose reduction of a drug. Individuals taking supratherapeutic doses of Testoderm TTS 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 Testoderm TTS for approved indications has not been documented.
There have been no reports of overdosage in the Testoderm TTS clinical trials. There is one report of acute overdosage with use of an approved injectable Testoderm TTS product: this subject had serum Testoderm TTS levels of up to 11,400 ng/dL with a cerebrovascular accident.
Treatment of overdosage would consist of discontinuation of Testoderm TTS together with appropriate symptomatic and supportive care.
Testoderm TTS (testosterone undecanoate) injection contains Testoderm TTS undecanoate (17β-undecanoyloxy-4-androsten-3-one) which is an ester of the androgen, Testoderm TTS. Testoderm TTS is formed by cleavage of the ester side chain of Testoderm TTS undecanoate.
Testoderm TTS undecanoate is a white to off-white crystalline substance. The empirical formula of Testoderm TTS undecanoate is C30H48O3 and a molecular weight of 456.7. The structural formula is:
FIGURE 2: Testoderm TTS Undecanoate
C30H48O3 MW: 456.7
Testoderm TTS is a clear, yellowish, sterile oily solution containing Testoderm TTS undecanoate, a Testoderm TTS ester, for intramuscular injection. Each single use vial contains 3 mL of 250 mg/mL Testoderm TTS undecanoate solution in a mixture of 1500 mg of benzyl benzoate and 885 mg of refined castor oil.
Endogenous androgens, including Testoderm TTS 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 Testoderm TTS, 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).
Testoderm TTS 750 mg delivers physiologic amounts of Testoderm TTS, producing circulation Testoderm TTS concentrations that approximate normal concentrations (300-1000 ng/dL) seen in healthy men.
Testoderm TTS esters in oil injected intramuscularly are absorbed from the lipid phase. Cleavage of the undecanoic acid side chain of Testoderm TTS by tissue esterases releases Testoderm TTS.
Following intramuscular injection of 750 mg of Testoderm TTS, serum Testoderm TTS concentrations reach a maximum after a median of
7 days (range 4 – 42 days) then slowly decline (Figure 3). Steady state serum Testoderm TTS concentration was achieved with the 3rd injection of Testoderm TTS at 14 weeks.
Figure 3 shows the mean serum total Testoderm TTS 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 Testoderm TTS at initiation, at 4 weeks, and every 10 weeks thereafter. Intramuscular injection of 750 mg of Testoderm TTS generates mean steady state serum total Testoderm TTS concentrations in the normal range for 10 weeks.
FIGURE 3: Mean (SD) Serum Total Testoderm TTS
Concentrations (ng/dL) at 14-24 Weeks
Circulating Testoderm TTS is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin.
Approximately 40% of Testoderm TTS in plasma is bound to SHBG, 2% remains unbound (free), and the rest is loosely bound to albumin and other proteins.
Testoderm TTS undecanoate is metabolized to Testoderm TTS via ester cleavage of the undecanoate group. The mean (SD) maximum concentration of Testoderm TTS undecanoate was 90.9 (68.8) ng/dL on Day 4 following injection of Testoderm TTS. Testoderm TTS undecanoate was nearly undetectable 42 days following injection of Testoderm TTS.
Testoderm TTS is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of Testoderm TTS are estradiol and DHT.
DHT concentrations increased in parallel with Testoderm TTS concentrations during Testoderm TTS 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.
There is considerable variation in the half-life of Testoderm TTS as reported in the literature, ranging from 10 to 100 minutes. About 90% of a Testoderm TTS dose given intramuscularly is excreted in the urine as glucuronic and sulfuric acid-conjugates of Testoderm TTS or as metabolites. About 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of Testoderm TTS occurs primarily in the liver.
Effect of Body Weight and Body Mass Index (BMI)
Analysis of serum Testoderm TTS concentrations from 117 hypogonadal men in the 84-week clinical study of Testoderm TTS indicated that serum Testoderm TTS 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 Testoderm TTS average concentration was 426 ± 104 ng/dL. A higher serum Testoderm TTS 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 Testoderm TTS concentrations.
In 70 patients with pretreatment body mass index of >30 kg/m2, the mean (±SD) serum Testoderm TTS average concentration was
445 ± 116 ng/dL. Higher serum Testoderm TTS 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 Testoderm TTS concentrations.
Testoderm TTS 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 Testoderm TTS into some strains of female mice increases their susceptibility to hepatoma. Testoderm TTS is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.
Mutagenic effects of Testoderm TTS undecanoate were not detected in a battery of in vitro tests including bacterial mutation assays (Ames test) and chromosomal aberration tests in human lymphocytes. Testoderm TTS undecanoate was also negative in an in vivo bone marrow micronucleus assay in mice. Testoderm TTS was negative in the in vitro Ames and in the in vivo mouse micronucleus assays.
Impairment of Fertility
The administration of exogenous Testoderm TTS has been reported to suppress spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment.
Testoderm TTS 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 Testoderm TTS concentrations <300 ng/dL (mean screening Testoderm TTS 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 Testoderm TTS 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 Testoderm TTS 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 Testoderm TTS 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 Testoderm TTS pharmacokinetics after the third Testoderm TTS 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 Testoderm TTS pharmacokinetic parameters at steady state for these 117 patients.
Mean (SD) Serum Total Testoderm TTS Concentrations at Steady State
Pharmacokinetics at Steady State
Testoderm TTS 750 mg
Cavg (0 to 10 weeks) (ng/dL)
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.
Testoderm TTS, NDC 67979-511-43: 750 mg/3 mL (250 mg/mL) Testoderm TTS 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.
See FDA-Approved Medication Guide
Advise patients of the following:
Men with known or suspected prostate or breast cancer should not use Testoderm TTS .
Patients should be informed that treatment with androgens may lead to adverse reactions which include:
Endo Pharmaceuticals Solutions Inc.
Malvern, PA 19355
Testoderm TTS is a registered trademark of Endo Pharmaceuticals Inc.
© 2017 Endo Pharmaceuticals Solutions Inc. All rights reserved.
Revised: July 2017
Testoderm TTS® (Uh-Veed)
Read this Medication Guide before you receive Testoderm TTS 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 Testoderm TTS?
Testoderm TTS may cause serious side effects, including:
o cough or urge to cough
o difficulty breathing
o tightening of your throat
o chest pain
These reactions can happen after you receive your first dose of Testoderm TTS 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 Testoderm TTS injection so
that your doctor can watch you for symptoms of POME or a serious allergic reaction.
o You can only get Testoderm TTS at your doctor’s office, clinic, or hospital.
Testoderm TTS is only available through a restricted program called the Testoderm TTS Risk Evaluation and Mitigation Strategy (REMS) Program. For more information about the Testoderm TTS REMS Program go to www. AveedREMS.com or call 1-855-755-0494.
What is Testoderm TTS?
Testoderm TTS is a prescription medicine that contains Testoderm TTS. Testoderm TTS is used to treat adult males who have low or no Testoderm TTS due to certain medical conditions.
Testoderm TTS is only for adult males who need Testoderm TTS replacement therapy and when the benefit of receiving Testoderm TTS is more than the risk of POME and anaphylaxis.
Your healthcare provider will test your blood before you start and while you are taking Testoderm TTS.
It is not known if AVEEDis safe or effective to treat men who have low Testoderm TTS due to aging.
It is not known if Testoderm TTS is safe and effective for use in children younger than 18 years old. Improper use of Testoderm TTS may affect bone growth in children.
Testoderm TTS is a controlled substance (CIII) because it contains Testoderm TTS that can be a target for people who abuse prescription medicines.
Testoderm TTS is not meant for use in women.
Who should not receive Testoderm TTS?
Do not receive Testoderm TTS if you:
Talk to your doctor before receiving this medicine if you have any of the above conditions.
What should I tell my doctor before receiving Testoderm TTS?
Before receiving Testoderm TTS, tell your doctor if you:
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Receiving Testoderm TTS with certain other medicines can affect each other. Especially tell your doctor if you take:
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 Testoderm TTS?
See “What is the most important information I should know about Testoderm TTS?”
Your doctor will inject Testoderm TTS 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 Testoderm TTS.
What are the possible side effects of Testoderm TTS?
Testoderm TTS can cause serious side effects including:
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
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)
Call your doctor right away if you have any of the serious side effects listed above.
The most common side effects of Testoderm TTS include:
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 Testoderm TTS. 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 Testoderm TTS
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
This Medication Guide summarizes the most important information about Testoderm TTS. If you would like more information, talk with your doctor. You can ask your doctor or nurse for information about Testoderm TTS 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 Testoderm TTS?
Active ingredient: Testoderm TTS undecanoate
Inactive ingredients: refined castor oil, benzyl benzoate
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Endo Pharmaceuticals Solutions Inc.
Malvern, PA 19355
Testoderm TTS is a registered trademark of Endo Pharmaceuticals Inc.
© 2016 Endo Pharmaceuticals Solutions Inc. All rights reserved.
Depending on the reaction of the Testoderm TTS after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Testoderm TTS 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 Testoderm TTS 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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The information was verified by Dr. Rachana Salvi, MD Pharmacology