AndroGel

Dosage Form: gel
FULL PRESCRIBING INFORMATION

WARNING: SECONDARY EXPOSURE TO TESTOSTERONE

• Virilization has been reported in children who were secondarily exposed to testosterone gel [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].


• Children should avoid contact with unwashed or unclothed application sites in men using testosterone gel [see Warnings and Precautions (5.2)].


• Healthcare providers should advise patients to strictly adhere to recommended instructions for use [see Warnings and Precautions (5.2) ].

Indications and Usage for AndroGel

Testosterone Replacement Therapy

AndroGel, an androgen, is indicated for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone:

• 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 testosterone levels and gonadotropins (FSH, LH) above the normal range.


• Hypogonadotropic Hypogonadism (Congenital or Acquired) - idiopathic gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum levels but have gonadotropins in the normal or low range.

AndroGel Dosage and Administration

General Dosing

The recommended starting dose of AndroGel is 5 g once daily (preferably in the morning) to clean, dry, intact skin of the shoulders and upper arms and/or abdomen (area of application should be limited to the area that will be covered by the patient's short sleeve t-shirt). AndroGel must not be applied to the genitals. AndroGel is supplied as either a pump or in individual packets. After applying the gel, the application site should be allowed to dry for a few minutes prior to dressing. Avoid fire, flames or smoking until the gel has dried since alcohol based products, including AndroGel, are flammable. Hands should be washed with soap and water after AndroGel has been applied. [see Warnings and Precautions (5.2, 5.10)].

Administration

Multi-Dose Pump

Patients should be instructed to prime the pump before using it for the first time by fully depressing the pump mechanism (actuation) 3 times and discard this portion of the product to assure precise dose delivery. After the priming procedure, patients should completely depress the pump one time (actuation) for every 1.25 g (AndroGel Pump) of product required to achieve the daily prescribed dosage. The product may be delivered directly into the palm of the hand and then applied to the desired application sites, either one pump actuation at a time or upon completion of all pump actuations required for the daily dose. Alternatively, the product can be applied directly to the application sites. Application directly to the sites may prevent loss of product that may occur during transfer from the palm of the hand onto the application sites. Table 1 has specific dosing guidelines for adult males when the 75 g AndroGel Pump is used.

Table 1: Specific Dosing Guidelines for Using the Adult Multi-Dose Pump

Prescribed Daily Dose	Number of Pump Actuations in 75 g Pump
5 g	4 (once daily)
7.5 g	6 (once daily)
10 g	8 (once daily)

Packets

The entire contents should be squeezed into the palm of the hand and immediately applied to the application sites. Alternately, patients may squeeze a portion of the gel from the packet into the palm of the hand and apply to application sites. Repeat until entire contents have been applied.

Dose Adjustment and Patient Assessments

• To ensure proper dosing, serum testosterone levels should be measured at intervals and replaced to serum testosterone levels in the normal range. If the serum testosterone concentration is below the normal range, the daily AndroGel dose may be increased from 5 g to 7.5 g and from 7.5 g to 10 g for adult males as instructed by the physician. If the serum testosterone concentration exceeds the normal range, the daily AndroGel dose may be decreased. If the serum testosterone concentration consistently exceeds the normal range at a daily dose of 5 g, AndroGel therapy should be discontinued.

The following is general advice for treating and monitoring adult patients on AndroGel. No specific recommendations can be made.

• Prescribers should be aware that testosterone is contraindicated in men with known or suspected prostate cancer. Therefore, evaluation for prostate cancer prior to initiation of AndroGel therapy is appropriate [see Contraindications (4)].


• Based on results from controlled studies, serum PSA may rise when taking AndroGel. Therefore, periodic assessment of serum PSA is recommended in patients taking AndroGel [see Adverse Reactions (6.1)].


• Based on results from controlled studies, worsening of BPH may occur in patients taking AndroGel [see Adverse Reactions (6.1)]. Therefore, periodic assessments for signs and symptoms of BPH are recommended in patients taking AndroGel.


• Hematocrit, serum lipid profile, and liver function test should be monitored in patients taking AndroGel [see Warnings and Precautions (5.9)].

Dosage Forms and Strengths

AndroGel (testosterone gel) 1% for topical use is available in either unit-dose packets or multiple-dose pumps. The 75 g (60 metered-dose) pump delivers 1.25 g of product when the pump mechanism is fully depressed once.

AndroGel is available in the following three package containers:

• 2 x 75 g pumps (each pump dispenses 60 metered 1.25 g doses)


• 2.5 g packet


• 5 g packet

Contraindications

AndroGel should not be used in any of the following patients:

• Men with carcinoma of the breast or known or suspected carcinoma of the prostate [see Warnings and Precautions (5.1), Adverse Reactions (6.1), and Nonclinical Toxicology (13.1)].


• Women who are or may become pregnant, or who are breastfeeding. AndroGel can cause fetal harm when administered to a pregnant woman. AndroGel 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. Pregnant women or those who may become pregnant need to be aware of the potential for transfer of testosterone from men treated with AndroGel [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.3)].


• Men with known hypersensitivity to any of its ingredients, including alcohol and soy products.

Warnings and Precautions

Benign Prostatic Hyperplasia and Potential Risk of Prostate Cancer

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


• Patients treated with androgens may be at increased risk for prostate cancer. Evaluation of the patient for prostate cancer prior to initiating and during treatment with androgens is appropriate.


• Increases in serum PSA from baseline values were seen in approximately 18% of individuals in an open label study of 162 hypogonadal men treated with AndroGel for up to 42 months. Most of these increases were seen within the first year of therapy [see Contraindications (4), Warnings and Precautions (5.9), Adverse Reactions (6.1), and Nonclinical Toxicology (13.1)].

Potential for Secondary Exposure to Testosterone

Secondary exposure to testosterone in children and women can occur with testosterone gel use in men [see Clinical Studies (14.3)]. Cases of secondary exposure resulting in virilization of children have been reported in postmarketing surveillance. Signs and symptoms have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases, these signs and symptoms regressed with removal of the exposure to testosterone gel. In a few cases, however, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronological age. The risk of transfer was increased in some of these cases by not adhering to precautions for the appropriate use of testosterone gel.

Inappropriate changes in genital size or development of pubic hair or libido in children, or changes in body hair distribution, significant increase in acne, or other signs of virilization in adult women should be brought to the attention of a physician and the possibility of secondary exposure to testosterone gel should also be brought to the attention of a physician. Testosterone gel should be promptly discontinued until the cause of virilization has been identified.

Testosterone may cause fetal harm in a pregnant woman due to virilization of a female fetus [see Use in Specific Populations (8.1)].

Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to testosterone from AndroGel-treated skin:

• Children and women should avoid contact with unwashed or unclothed application site(s) of men using testosterone gel.


• AndroGel should only be applied to the shoulders, upper arms, and/or abdomen (area of application should be limited to the area that will be covered by the patient's short sleeve t-shirt).


• Patients should wash their hands immediately with soap and water after applying AndroGel.


• Patients should cover the application site(s) with clothing (e.g., a shirt) after the gel has dried.


• Prior to any situation in which skin-to-skin contact with the application site is anticipated, patients should wash the application site(s) thoroughly with soap and water to remove any testosterone residue.


• In the event that unwashed or unclothed skin to which AndroGel has been applied comes in direct contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible. Studies show that residual testosterone is removed from the skin surface by washing with soap and water.

Use in Women

Due to lack of controlled evaluations in women and potential virilizing effects, AndroGel is not indicated for use in women [see Use in Specific Populations (8.1, 8.3)].

Potential for Adverse Effects on Spermatogenesis

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

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 testosterone enanthate has produced multiple hepatic adenomas. AndroGel is not known to produce these adverse effects.

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

Edema

Drugs in the androgen class 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 [see Adverse Reactions (6.2)].

Gynecomastia

Gynecomastia may develop and may persist in patients being treated with androgens, including AndroGel, for hypogonadism.

Sleep Apnea

The treatment of hypogonadal men with testosterone products may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases [see Adverse Reactions (6.2)].

Laboratory Tests

• Increases in hematocrit, reflective of increases in red blood cell mass, may require lowering or discontinuation of testosterone. Increase in red blood cell mass may increase the risk for a thromboembolic event.


• Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy.


• Androgens may decrease levels of thyroxin-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.


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

Flammable Until Dry

• Alcohol Based Products including AndroGel are flammable; therefore avoid fire, flame or smoking until the gel has dried.

Adverse Reactions

Clinical Trial Experience

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

Clinical Trials in Hypogonadal Men

Table 2 shows the incidence of all adverse events judged by the investigator to be at least possibly related to treatment with AndroGel and reported by >1% of patients in a 180 Day, Phase 3 study.

Table 2: Adverse Events Possibly, Probably or Definitely Related to Use of AndroGel in the 180-Day Controlled Clinical Trial

*Lab test abnormal occurred in nine patients with one or more of the following events reported: elevated hemoglobin or hematocrit, hyperlipidemia, elevated triglycerides, hypokalemia, decreased HDL, elevated glucose, elevated creatinine, elevated total bilirubin.
**Prostate disorders included five patients with enlarged prostate, one with BPH, and one with elevated PSA results.
***Testis disorders were reported in two patients: one with left varicocele and one with slight sensitivity of left testis.
Adverse Event	Dose of AndroGel
	5 g	7.5 g	10 g
	N = 77	N = 40	N = 78
Acne	1%	3%	8%
Alopecia	1%	0%	1%
Application Site Reaction	5%	3%	4%
Asthenia	0%	3%	1%
Depression	1%	0%	1%
Emotional Lability	0%	3%	3%
Gynecomastia	1%	0%	3%
Headache	4%	3%	0%
Hypertension	3%	0%	3%
Lab Test Abnormal*	6%	5%	3%
Libido Decreased	0%	3%	1%
Nervousness	0%	3%	1%
Pain Breast	1%	3%	1%
Prostate Disorder**	3%	3%	5%
Testis Disorder***	3%	0%	0%

Other less common adverse reactions, reported in fewer than 1% of patients included: amnesia, anxiety, discolored hair, dizziness, dry skin, hirsutism, hostility, impaired urination, paresthesia, penis disorder, peripheral edema, sweating, and vasodilation.

In this 180 day clinical trial, skin reactions at the site of application were reported with AndroGel, but none was severe enough to require treatment or discontinuation of drug.

Six patients (4%) in this trial had adverse events that led to discontinuation of AndroGel. These events included: cerebral hemorrhage, convulsion (neither of which were considered related to AndroGel administration), depression, sadness, memory loss, elevated prostate specific antigen, and hypertension. No AndroGel patient discontinued due to skin reactions.

In a separate uncontrolled pharmacokinetic study of 10 patients, two had adverse events associated with AndroGel; these were asthenia and depression in one patient and increased libido and hyperkinesia in the other.

In a 3 year, flexible dose, extension study, the incidence of all adverse events judged by the investigator to be at least possibly related to treatment with AndroGel and reported by > 1% of patients is shown in Table 3.

Table 3: Adverse Events Possibly, Probably or Definitely Related to Use of AndroGel in the 3 Year, Flexible Dose, Extension Study

Adverse Event	Percent of Subjects
	(N = 162)
+Lab test abnormal occurred in 15 patients with one or more of the following events reported: elevated AST, elevated ALT, elevated testosterone, elevated hemoglobin or hematocrit, elevated cholesterol, elevated cholesterol/LDL ratio, elevated triglycerides, elevated HDL, elevated serum creatinine.
*Urinary symptoms included nocturia, urinary hesitancy, urinary incontinence, urinary retention, urinary urgency and weak urinary stream.
**Testis disorders included three patients. There were two with a non-palpable testis and one with slight right testicular tenderness.
Lab Test Abnormal+	9.3
Skin dry	1.9
Application Site Reaction	5.6
Acne	3.1
Pruritus	1.9
Enlarged Prostate	11.7
Carcinoma of Prostate	1.2
Urinary Symptoms*	3.7
Testis Disorder**	1.9
Gynecomastia	2.5
Anemia	2.5

Two patients reported serious adverse events considered possibly related to treatment: deep vein thrombosis (DVT) and prostate disorder requiring a transurethral resection of the prostate (TURP).

Discontinuation for adverse events in this study included: two patients with application site reactions, one with kidney failure, and five with prostate disorders (including increase in serum PSA in 4 patients, and increase in PSA with prostate enlargement in a fifth patient).

Increases in Serum PSA Observed in Clinical Trials of Hypogonadal Men

During the initial 6-month study, the mean change in PSA values had a statistically significant increase of 0.26 ng/mL. Serum PSA was measured every 6 months thereafter in the 162 hypogonadal men on AndroGel in the 3-year extension study. There was no additional statistically significant increase observed in mean PSA from 6 months through 36 months. However, there were increases in serum PSA observed in approximately 18% of individual patients. The overall mean change from baseline in serum PSA values for the entire group from month 6 to 36 was 0.11 ng/mL.

Twenty-nine patients (18%) met the per-protocol criterion for increase in serum PSA, defined as >2X the baseline or any single serum PSA >6 ng/mL. Most of these (25/29) met this criterion by at least doubling of their PSA from baseline. In most cases where PSA at least doubled (22/25), the maximum serum PSA value was still <2 ng/mL. The first occurrence of a pre-specified, post-baseline increase in serum PSA was seen at or prior to Month 12 in most of the patients who met this criterion (23 of 29; 79%).

Four patients met this criterion by having a serum PSA >6 ng/mL and in these, maximum serum PSA values were 6.2 ng/mL, 6.6 ng/mL, 6.7 ng/mL, and 10.7 ng/mL. In two of these patients, prostate cancer was detected on biopsy. The first patient's PSA levels were 4.7 ng/mL and 6.2 ng/mL at baseline and at Month 6/Final, respectively. The second patient's PSA levels were 4.2 ng/mL, 5.2 ng/mL, 5.8 ng/mL, and 6.6 ng/mL at baseline, Month 6, Month 12, and Final, respectively.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of AndroGel. 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.

Secondary Exposure to Testosterone in Children

Cases of secondary exposure to testosterone resulting in virilization of children have been reported in postmarket surveillance. Signs and symptoms of these reported cases have included enlargement of the clitoris (with surgical intervention) or the penis, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases with a reported outcome, these signs and symptoms were reported to have regressed with removal of the testosterone gel exposure. In a few cases, however, enlarged genitalia did not fully return to age appropriate normal size, and bone age remained modestly greater than chronological age. In some of the cases, direct contact with the sites of application on the skin of men using testosterone gel was reported. In at least one reported case, the reporter considered the possibility of secondary exposure from items such as the testosterone gel user's shirts and/or other fabric, such as towels and sheets [see Warnings and Precautions (5.2)].

Hypogonadal Men

Table 4 includes adverse reactions that have been identified postmarketing.

Table 4: Adverse Drug Reactions from Postmarketing Experience of AndroGel by MedDRA System Organ Class

Blood and the lymphatic system disorders:	Elevated Hgb, Hct (polycythemia)
Endocrine disorders:	Hirsutism
Gastrointestinal disorders:	Nausea
General disorders and administration site reactions:	Asthenia, edema, malaise
Genitourinary disorders:	Impaired urination
Hepatobiliary disorders:	Abnormal liver function tests (e.g. transaminases, elevated GGTP, bilirubin)
Investigations:	Elevated PSA, electrolyte changes (nitrogen, calcium, potassium, phosphorus, sodium), changes in serum lipids (hyperlipidemia, elevated triglycerides, decreased HDL), impaired glucose tolerance, fluctuating testosterone levels, weight increase
Neoplasms benign, malignant and unspecified (cysts and polyps):	Prostate cancer
Nervous system:	Headache, dizziness, sleep apnea, insomnia
Psychiatric disorders:	Depression, emotional lability, decreased libido, nervousness, hostility, amnesia, anxiety
Reproductive system and breast disorders:	Gynecomastia, mastodynia, prostatic enlargement, testicular atrophy, oligospermia, priapism (frequent or prolonged erections)
Respiratory disorders:	Dyspnea
Skin and subcutaneous tissue disorders:	Acne, alopecia, application site reaction (pruritus, dry skin, erythema, rash, discolored hair, paresthesia), sweating
Vascular disorders:	Hypertension, vasodilation (hot flushes)

Drug Interactions

Insulin

Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirements.

Corticosteroids

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

Oral Anticoagulants

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

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category X: AndroGel is contraindicated during pregnancy or in women who may become pregnant. It is teratogenic and may cause fetal harm [see Contraindications (4)]. Exposure of a female fetus to androgens may result in varying degrees of virilization. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Nursing Mothers

Although it is not known how much testosterone transfers into human milk, AndroGel is contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants [see Contraindications (4)].

Testosterone and other androgens may adversely affect lactation.

Pediatric Use

Safety and efficacy of AndroGel in males < 18 years old has not been established. Improper use may result in acceleration of bone age and premature closure of epiphyses.

Geriatric Use

There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing AndroGel to determine whether efficacy in those over 65 years of age differs from younger subjects. Additionally, there is insufficient long-term safety data in geriatric patients to assess the potential risks of cardiovascular disease and prostate cancer.

Renal or Hepatic Impairment

No formal studies were conducted involving patients with renal or hepatic insufficiencies.

Drug Abuse and Dependence

Controlled Substance

AndroGel contains testosterone, a Schedule III controlled substance as defined by the Anabolic Steroids Control Act.

Oral ingestion of AndroGel will not result in clinically significant serum testosterone concentrations due to extensive first-pass metabolism.

Overdosage

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

AndroGel Description

AndroGel (testosterone gel) 1% is a clear, colorless hydroalcoholic gel containing 1% testosterone. Topical administration of AndroGel 5 g, 7.5 g, or 10 g contains 50 mg, 75 mg, or 100 mg of testosterone, respectively, is to be applied daily to the skin's surface. Approximately 10% of the applied testosterone dose is absorbed across skin of average permeability during a 24-hour period.

The active pharmacologic ingredient in AndroGel is testosterone. Testosterone USP is a white to practically white crystalline powder chemically described as 17-beta hydroxyandrost-4-en-3-one. The structural formula is:

Inactive ingredients in AndroGel are carbomer 980, ethanol 67.0%, isopropyl myristate, purified water, and sodium hydroxide. These ingredients are not pharmacologically active.

AndroGel - Clinical Pharmacology

Mechanism of Action

Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis and scrotum; the development of male hair distribution, such as facial, pubic, chest and axillary hair; laryngeal enlargement, vocal chord thickening, alterations in body musculature and fat distribution. Testosterone and DHT are necessary for the normal development of secondary sex characteristics. Male hypogonadism results from insufficient secretion of testosterone and is characterized by low serum testosterone concentrations. Signs/symptoms associated with male hypogonadism include erectile dysfunction and decreased sexual desire, fatigue and loss of energy, mood depression, regression of secondary sexual characteristics and osteoporosis.

Male hypogonadism 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).

Pharmacokinetics

Adult Males

Absorption

AndroGel delivers physiologic amounts of testosterone, producing circulating testosterone concentrations that approximate normal levels (298 – 1043 ng/dL) seen in healthy men. AndroGel provides continuous transdermal delivery of testosterone for 24 hours following a single application to intact, clean, dry skin of the shoulders, upper arms and/or abdomen.

AndroGel is a hydroalcoholic formulation that dries quickly when applied to the skin surface. The skin serves as a reservoir for the sustained release of testosterone into the systemic circulation. Approximately 10% of the testosterone dose applied on the skin surface from AndroGel is absorbed into systemic circulation. Therefore, 5 g and 10 g of AndroGel systemically deliver approximately 5 mg and 10 mg of testosterone, respectively. In a study with 10 g of AndroGel, all patients showed an increase in serum testosterone within 30 minutes, and eight of nine patients had a serum testosterone concentration within normal range by 4 hours after the initial application. Absorption of testosterone into the blood continues for the entire 24-hour dosing interval. Serum concentrations approximate the steady-state level by the end of the first 24 hours and are at steady state by the second or third day of dosing.

With single daily applications of AndroGel, follow-up measurements 30, 90 and 180 days after starting treatment have confirmed that serum testosterone concentrations are generally maintained within the eugonadal range. Figure 1 summarizes the 24-hour pharmacokinetic profiles of testosterone for hypogonadal men (<300 ng/dL) maintained on 5 g or 10 g of AndroGel for 30 days. The average (± SD) daily testosterone concentration produced by AndroGel 10 g on Day 30 was 792 (± 294) ng/dL and by AndroGel 5 g 566 (± 262) ng/dL.

Figure 1: Mean (± SD) Steady-State Serum Testosterone Concentrations on Day 30 in Patients Applying AndroGel Once Daily

When AndroGel treatment is discontinued after achieving steady state, serum testosterone levels remain in the normal range for 24 to 48 hours but return to their pretreatment levels by the fifth day after the last application.

Distribution

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

Metabolism

There is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. Testosterone is metabolized to various 17-keto steroids through two different pathways. The major active metabolites of testosterone are estradiol and DHT.

DHT concentrations increased in parallel with testosterone concentrations during AndroGel treatment. After 180 days of treatment in adult males, mean DHT concentrations were within the normal range with 5 g AndroGel and were about 7% above the normal range after a 10 g dose. The mean steady-state DHT/T ratio during 180 days of AndroGel treatment remained within normal limits and ranged from 0.23 to 0.29 (5 g/day) and from 0.27 to 0.33 (10 g/day).

Excretion

About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Testosterone 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 testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.

Clinical Studies

Clinical Trials in Adult Hypogonadal Males

AndroGel was evaluated in a multi-center, randomized, parallel-group, active-controlled, 180-day trial in 227 hypogonadal men. The study was conducted in 2 phases. During the Initial Treatment Period (Days 1-90), 73 patients were randomized to AndroGel 5 g daily, 78 patients to AndroGel 10 g daily, and 76 patients to a non-scrotal testosterone transdermal system. The study was double-blind for dose of AndroGel but open-label for active control. Patients who were originally randomized to AndroGel and who had single-sample serum testosterone levels above or below the normal range on Day 60 were titrated to 7.5 g daily on Day 91. During the Extended Treatment Period (Days 91-180), 51 patients continued on AndroGel 5 g daily, 52 patients continued on AndroGel 10 g daily, 41 patients continued on a non-scrotal testosterone transdermal system (5 mg daily), and 40 patients received AndroGel 7.5 g daily. Upon completion of the initial study, 163 enrolled and 162 patients received treatment in an open-label extension study of AndroGel for an additional period of up to 3 years.

Mean peak, trough and average serum testosterone concentrations within the normal range (298-1043 ng/dL) were achieved on the first day of treatment with doses of 5 g and 10 g. In patients continuing on AndroGel 5 g and 10 g, these mean testosterone levels were maintained within the normal range for the 180-day duration of the original study. Figure 2 summarizes the 24-hour pharmacokinetic profiles of testosterone administered as AndroGel for 30, 90 and 180 days. Testosterone concentrations were maintained as long as the patient continued to properly apply the prescribed AndroGel treatment.

Figure 2: Mean Steady-State Testosterone Concentrations in Patients with Once-Daily AndroGel Therapy

Table 5 summarizes the mean testosterone concentrations on Treatment Day 180 for patients receiving 5 g, 7.5 g, or 10 g of AndroGel. The 7.5 g dose produced mean concentrations intermediate to those produced by 5 g and 10 g of AndroGel.

Table 5: Mean (± SD) Steady-State Serum Testosterone Concentrations During Therapy (Day 180)

	5 g	7.5 g	10 g
	N = 44	N = 37	N = 48
Cavg	555 ± 225	601 ± 309	713 ± 209
Cmax	830 ± 347	901 ± 471	1083 ± 434
Cmin	371 ± 165	406 ± 220	485 ± 156

Of 129 hypogonadal men who were appropriately titrated with AndroGel and who had sufficient data for analysis, 87% achieved an average serum testosterone level within the n

Sodium Sulfacetamide 10%/Sulfur 4% Foam

Pronunciation: SO-dee-um SUL-fa-SEET-a-mide/SUL-fur
Generic Name: Sodium Sulfacetamide 10%/Sulfur 4%
Brand Name: Rosula

Sodium Sulfacetamide 10%/Sulfur 4% Foam is used for:

Treating acne, rosacea, and seborrhea. It may also be used for other conditions as determined by your doctor.

Sodium Sulfacetamide 10%/Sulfur 4% Foam is an antibacterial and keratolytic combination. The antibacterial works by killing sensitive bacteria. The keratolytic helps to loosen and shed hard, scaly skin.

Do NOT use Sodium Sulfacetamide 10%/Sulfur 4% Foam if:

• you are allergic to any ingredient in Sodium Sulfacetamide 10%/Sulfur 4% Foam or to a sulfonamide (eg, sulfamethoxazole)


• you have kidney problems

Contact your doctor or health care provider right away if any of these apply to you.

Before using Sodium Sulfacetamide 10%/Sulfur 4% Foam:

Some medical conditions may interact with Sodium Sulfacetamide 10%/Sulfur 4% Foam. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have eczema


• if the skin at the application site is scraped, cut, or damaged

Some MEDICINES MAY INTERACT with Sodium Sulfacetamide 10%/Sulfur 4% Foam. Because little, if any, of Sodium Sulfacetamide 10%/Sulfur 4% Foam is absorbed into the blood, the risk of it interacting with another medicine is low.

Ask your health care provider if Sodium Sulfacetamide 10%/Sulfur 4% Foam may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Sodium Sulfacetamide 10%/Sulfur 4% Foam:

Use Sodium Sulfacetamide 10%/Sulfur 4% Foam as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Wash the affected skin and gently pat dry with a clean towel before each use of Sodium Sulfacetamide 10%/Sulfur 4% Foam.


• Shake well before each use, then gently tap the bottom of the can on a firm surface or in the palm of the hand. Tap 1 to 2 times, then shake and tap again.


• Turn the can upside down. The can may not deliver medicine correctly if it is used in an upright position. Dispense a small amount of the medicine (not larger than the size of a golf ball) onto your fingertips. Gently massage the foam into the affected area.


• If your doctor has told you to leave Sodium Sulfacetamide 10%/Sulfur 4% Foam on, be sure to wipe off any excess medicine after you apply it.


• If your doctor has told you to wash Sodium Sulfacetamide 10%/Sulfur 4% Foam off, wait 1 to 2 minutes after you apply it, then rinse with water and pat dry.


• Wash your hands immediately after using Sodium Sulfacetamide 10%/Sulfur 4% Foam, unless your hands are part of the affected area.


• Use Sodium Sulfacetamide 10%/Sulfur 4% Foam on a regular schedule to get the most benefit from it.


• Continue to use Sodium Sulfacetamide 10%/Sulfur 4% Foam even if your condition improves. Do not miss any doses


• If you miss a dose of Sodium Sulfacetamide 10%/Sulfur 4% Foam, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Sodium Sulfacetamide 10%/Sulfur 4% Foam.

Important safety information:

• Sodium Sulfacetamide 10%/Sulfur 4% Foam is for external use only. Do not get it in your eyes or on the inside of your nose or mouth. If you get Sodium Sulfacetamide 10%/Sulfur 4% Foam in any of these areas, rinse them immediately with cool water.


• Talk with your doctor before you use any other medicines or cleansers on your skin.


• Do not apply Sodium Sulfacetamide 10%/Sulfur 4% Foam over large areas of the body or to open wounds or scraped, infected, or burned skin without first checking with your doctor.


• Do not use Sodium Sulfacetamide 10%/Sulfur 4% Foam for other skin conditions at a later time.


• Sodium Sulfacetamide 10%/Sulfur 4% Foam may cause harm if it is swallowed. If you may have taken it by mouth, contact your poison control center or emergency room right away.


• Sodium Sulfacetamide 10%/Sulfur 4% Foam should be used with extreme caution in CHILDREN younger than 12 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: It is not known if Sodium Sulfacetamide 10%/Sulfur 4% Foam can cause harm to the fetus. If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Sodium Sulfacetamide 10%/Sulfur 4% Foam while you are pregnant. It is not known if Sodium Sulfacetamide 10%/Sulfur 4% Foam is found in breast milk after topical use. If you are or will be breast-feeding while you use Sodium Sulfacetamide 10%/Sulfur 4% Foam, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Sodium Sulfacetamide 10%/Sulfur 4% Foam:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Mild redness or peeling of the skin.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); fever, chills, or sore throat; red, swollen, blistered, or peeling skin; severe or persistent skin irritation; symptoms of liver problems (eg, dark urine, loss of appetite, pale stools, severe or persistent stomach pain or nausea, yellowing of the skin or eyes); unusual bruising or bleeding; unusual tiredness or weakness; unusually pale skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Sodium Sulfacetamide0%/Sulfur 4% side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Sodium Sulfacetamide 10%/Sulfur 4% Foam may be harmful if swallowed. Symptoms of ingestion may include change in the amount of urine; nausea; vomiting.

Proper storage of Sodium Sulfacetamide 10%/Sulfur 4% Foam:

Store Sodium Sulfacetamide 10%/Sulfur 4% Foam at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Do not freeze. Avoid temperatures above 120 degrees F (49 degrees C). Store the can upright, away from heat and direct sunlight. Do not puncture, break, or burn the canister even if it appears to be empty. Keep Sodium Sulfacetamide 10%/Sulfur 4% Foam out of the reach of children and away from pets.

General information:

• If you have any questions about Sodium Sulfacetamide 10%/Sulfur 4% Foam, please talk with your doctor, pharmacist, or other health care provider.


• Sodium Sulfacetamide 10%/Sulfur 4% Foam is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Sodium Sulfacetamide 10%/Sulfur 4% Foam. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Sodium Sulfacetamide 10%/Sulfur 4% resources

• Sodium Sulfacetamide 10%/Sulfur 4% Side Effects (in more detail)
• Sodium Sulfacetamide 10%/Sulfur 4% Use in Pregnancy & Breastfeeding
• Sodium Sulfacetamide 10%/Sulfur 4% Drug Interactions
• Sodium Sulfacetamide 10%/Sulfur 4% Support Group
• 18 Reviews for Sodium Sulfacetamide0%/Sulfur 4% - Add your own review/rating

Compare Sodium Sulfacetamide 10%/Sulfur 4% with other medications

• Acne
• Rosacea
• Seborrheic Dermatitis

testosterone Topical application

tes-TOS-ter-one

Topical application route(Gel/Jelly)

Virilization has been reported in children who were secondarily exposed to testosterone gel. Healthcare providers should advise patients to adhere strictly to instructions for use. Children should avoid contact with unwashed or unclothed testosterone application sites .

Topical application route(Solution)

Virilization has been reported in children who were secondarily exposed to topical testosterone products. Healthcare providers should advise patients to adhere strictly to instructions for use. Children should avoid contact with unwashed or unclothed testosterone application sites .

Commonly used brand name(s)

In the U.S.

• Androgel


• Axiron


• First-Testosterone


• First-Testosterone MC


• Fortesta


• Testim

Available Dosage Forms:

• Gel/Jelly


• Solution


• Kit

Therapeutic Class: Endocrine-Metabolic Agent

Pharmacologic Class: Androgen

Uses For testosterone

Testosterone topical gel is used for the treatment of males whose bodies do not make enough natural testosterone, a condition called hypogonadism. Testosterone is a male hormone responsible for the growth and development of the male sex organs and maintenance of secondary sex characteristics.

testosterone is available only with your doctor's prescription.

Before Using testosterone

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For testosterone, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to testosterone or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of testosterone topical gel in children. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of testosterone topical gel in the elderly. However, elderly patients may be at an increased risk for developing heart and blood vessel problems, or prostate problems (including prostate cancer), which may require caution in patients receiving testosterone topical gel.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	X	Studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. This drug should not be used in women who are or may become pregnant because the risk clearly outweighs any possible benefit.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking testosterone, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using testosterone with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Anisindione


• Bupropion


• Dicumarol


• Paclitaxel


• Paclitaxel Protein-Bound


• Phenprocoumon


• Warfarin

Using testosterone with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Licorice

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of testosterone. Make sure you tell your doctor if you have any other medical problems, especially:

• Allergy to alcohol or soy products or


• Breast cancer (males) or


• Prostate cancer, known or suspected—Should not be used in patients with these conditions.

• Diabetes or


• Enlarged prostate or


• Lung disease or breathing problems (e.g., sleep apnea) or


• Problems with passing urine—Use with caution. May make these conditions worse.

• Heart disease or


• Kidney disease or


• Liver disease—Use with caution. Testosterone may cause edema (fluid retention) in patients with these conditions.

Proper Use of testosterone

testosterone comes with a Medication Guide and patient instructions. Read and follow these instructions carefully. Ask your doctor if you have any questions.

testosterone is available in two forms: individual packets or multi-dose pump. If you are using the pump gel for the first time, prime the pump before measuring out your first dose. Hold the pump over a sink and press the pump all the way down at least 3 times or until the gel begins to flow freely. Rinse the medicine discarded into the sink down the drain. Place the palm of your hand under the pump and press the pump the proper number of times to measure out your correct dose.

If you are using the gel in foil packets, tear the packet completely open along the perforation. Squeeze the entire contents directly onto the skin where you will apply the gel. You may also empty the packet into the palm of your hand and then apply the medicine. Throw away the empty foil packet in a place where children and pets cannot reach it.

To use the gel:

• Make sure that you wash your hands with soap and water before and after applying the gel.


• Apply the gel to a clean, dry, intact skin of the shoulders, upper arms, or abdomen (stomach), unless your doctor tells you to use it on another part of your body. Do not apply testosterone to your scrotum or your penis. Do not use the medicine on skin that has a cut, scrape, or other type of injury.


• Allow the gel to dry on your skin before you cover it with clothing (e.g., t-shirt).


• Wait for 5 hours after applying testosterone before showering or swimming.

The gel form can be transferred to another person if they touch or rub the skin where the gel was placed or if some of the gel remains on your hands. To keep this from happening, wash your hands again after applying the gel. Also, wash the area where you applied the gel with soap and water if you expect to have a skin-to-skin contact with another person.

testosterone is flammable until it dries on the skin. Do not use it near heat, an open flame, or while smoking.

Dosing

The dose of testosterone will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of testosterone. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For topical dosage form (gel):
  
  • For hormone replacement:
    
    • Adults—At first, apply 5 grams to a clean, dry, intact skin once a day (usually in the morning). Your doctor may increase your dose as needed. However, the dose is usually not more than 10 grams.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of testosterone, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using testosterone

It is very important that your doctor check your progress at regular visits to see if the medicine is working properly. Blood tests may be needed to check for any problems or unwanted effects.

testosterone should not be used by women. Testosterone may cause birth defects if a pregnant woman comes in contact with the medicine. Make sure your doctor knows if your sexual partner is pregnant. If a pregnancy occurs while you are using testosterone, tell your doctor right away.

Children and women should avoid contact with the unwashed or unclothed area where the testosterone gel has been applied. If another person does accidentally get testosterone on the skin, wash the area with soap and water as soon as possible.

Tell your doctor if your female partner or child starts to have male-like body changes while you are using testosterone. Such changes may include hair growth on the face, a deeper voice, or a significant increase in acne. The changes may also include an enlarged penis or clitoris, early development of pubic hair, increased erections or sexual desire, aggressive behavior, and bone problems.

In some cases, testosterone may decrease the amount of sperm men make and affect their ability to have children. If you plan to have children, talk with your doctor before using testosterone.

testosterone may cause fluid retention (edema) in some patients. Tell your doctor right away if you have bloating or swelling of face, arms, hands, lower legs, or feet; tingling of hands or feet; or unusual weight gain or loss.

testosterone may affect the results of the prostate specific antigen (PSA) test, which may be used to detect prostate cancer. Make sure you tell all of your doctors that you are using testosterone.

Before you have any medical tests, tell the medical doctor in charge that you are using testosterone. The results of some tests may be affected by testosterone.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

testosterone Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Blood in the urine


• difficulty urinating


• feeling need to urinate often


• frequent urination

Less common

• Bloating or swelling of the face, arms, hands, lower legs, or feet


• blurred vision


• dizziness


• feeling faint, dizzy, or lightheaded


• feeling of warmth or heat


• flushing or redness of the skin, especially on the face and neck


• frequent strong or increased urge to urinate


• headache


• increased urge to urinate during the night


• nervousness


• pain, redness, or swelling in the arm or leg


• pounding in the ears


• rapid weight gain


• slow or fast heartbeat


• sweating


• swelling of the breasts or breast soreness in both females and males


• tingling of the hands or feet


• unusual weight gain or loss


• waking to urinate at night

Incidence not known

• Aggressive behavior


• bluish lips or skin


• decrease in testicle size


• development of pubic hair


• difficult or labored breathing


• enlargement of the clitoris or penis


• not breathing


• painful or prolonged erection of the penis


• shortness of breath


• tightness in the chest


• wheezing

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Blemishes on the skin


• burning, itching, redness, skin rash, swelling, or soreness at the application site


• pimples

Less common

• Anxiety


• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings


• crying


• decreased interest in sexual intercourse


• depersonalization


• depression


• discoloration of the hair


• dry skin


• dysphoria


• euphoria


• hair loss


• inability to have or keep an erection


• lack or loss of strength


• loss in sexual ability, desire, drive, or performance


• loss of memory


• paranoia


• problems with memory


• quick to react or overreact emotionally


• rapidly changing moods


• thinning of the hair

Incidence not known

• Increased in sexual ability, desire, drive, or performance


• increased interest in sexual intercourse


• sleeplessness


• trouble with sleeping


• unable to sleep

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

See also: testosterone Topical application side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More testosterone Topical application resources

• Testosterone Topical application Side Effects (in more detail)
• Testosterone Topical application Use in Pregnancy & Breastfeeding
• Testosterone Topical application Drug Interactions
• Testosterone Topical application Support Group
• 146 Reviews for Testosterone Topical application - Add your own review/rating

Compare testosterone Topical application with other medications

• Breast Cancer, Palliative
• Delayed Puberty, Male
• Hypogonadism, Male
• Postpartum Breast Pain

Visipaque

iodixanol

Dosage Form: injection

PHARMACY BULK PACKAGE–NOT FOR DIRECT INFUSION

NOT FOR INTRATHECAL USE

Visipaque Description

Visipaque™ (iodixanol) Injection, 5,5'-[(2-hydroxy-1,3-propanediyl)bis (acetylimino)]bis[N,N'-bis(2,3-dihydroxypropyl)-2,4,6- triiodo-1,3- benzenedicarboxamide], is a dimeric, isosmolar, nonionic, water-soluble, radiographic contrast medium with a molecular weight of 1550.20 (iodine content 49.1%). It is administered by intravascular injection.

Visipaque (C35H44I6N6O15) has the following chemical structure:

Visipaque Injection is provided as a ready-to-use sterile, pyrogen-free, colorless to pale yellow solution, in Pharmacy Bulk Package, in concentrations of 270 and 320 mg of organically bound iodine per mL (550 and 652 mg of iodixanol per mL, respectively). A Pharmacy Bulk Package is used to dispense multiple single doses, utilizing a suitable transfer device. Sodium chloride and calcium chloride have been added, resulting in an isotonic solution for injection. Visipaque 270 (270 mgI/mL) contains 0.074 mg calcium chloride dihydrate per mL and 1.87 mg sodium chloride per mL, and Visipaque 320 (320 mgI/mL) contains 0.044 mg calcium chloride dihydrate per mL and 1.11 mg sodium chloride per mL, providing for both concentrations a sodium/calcium ratio equivalent to blood. In addition, each milliliter contains 1.2 mg tromethamine and 0.1 mg edetate calcium disodium. The pH is adjusted to 7.4 with hydrochloric acid and/or sodium hydroxide to achieve a range between pH 6.8 and 7.7 at 22°C. All solutions are terminally sterilized by autoclaving and contain no preservatives.

The two concentrations of Visipaque Injection (270 mgI/mL and 320 mgI/mL) have the following physical properties:

PHYSICAL PROPERTIES of Visipaque

Parameter		Concentration (mgI/mL)
		320	270
Osmolality (mOsmol/kg water)		290	290
Viscosity (cP)	@ 20°C	26.6	12.7
	@ 37°C	11.8	6.3
Density (g/mL)	@ 20°C	1.369	1.314
	@ 37°C	1.356	1.303

Visipaque - Clinical Pharmacology

GENERAL

Iodixanol is a dimeric, isosmolar, nonionic, water soluble, iodinated x-ray contrast agent for intravascular administration.

Intravascular injection of iodixanol opacifies those vessels in the path of flow of the contrast agent, permitting radiographic visualization of the internal structures until significant dilution and elimination occurs.

PHARMACOKINETICS

Distribution

In an in vitro human plasma study, iodixanol did not bind to protein. The volume of distribution was 0.26 L/kg body weight, consistent with distribution to extracellular space.

Metabolism

Iodixanol metabolites have not been demonstrated.

Excretion

Plasma and urine levels suggest that body clearance of iodixanol is primarily due to renal clearance. In adults, approximately 97% of the injected dose of iodixanol is excreted unchanged in urine within 24 hours, with less than 2% excreted in feces within five days post-injection. In 40 healthy, young male volunteers receiving a single intravenous administration of Visipaque Injection in doses of 0.3 to 1.2 gI/kg body weight, the elimination half-life was 2.1 hr (± 0.1); and renal clearance was 110 mL/min (±14), equivalent to glomerular filtration (108 mL/min). These values were independent of the dose administered.

Special Populations

Pediatric

Forty pediatric patients ≤12 years old, with renal function that is normal for their age, received multiple intra-arterial administrations of Visipaque Injection in doses of 0.32 to 3.2 gI/kg body weight. The elimination half-lives for these patients are shown in the following table and are derived from the mean terminal elimination rate constants (Kel): 0.185 hr -1 (newborn to 2 months old), 0.256 hr -1 (2 to <6 months old), 0.299 hr -1 (6 months to<1 year), 0.322 hr -1 (1 to<2 years), and 0.307 hr -1 (2 to ≤12 years old). The adult mean terminal elimination rate constant is 0.336 hr-1. The actual Visipaque clearance and volume of distribution in pediatric patients were not determined. Pharmacodynamic dose adjustments to account for differences in elimination half-life in pediatric patients under 6 months of age have not been studied. (For pediatric dosing see the Dosage and Administration section; for age adjusted adverse events see the Pediatric Use section).

MEAN ELIMINATION HALF-LIFE* IN PEDIATRIC PATIENTS

Age Range	Number of Patients	Elimination half-life
		(hr ± SD)
* Calculated from the elimination rate constant. Actual clearance and volume of distribution were not measured.
Newborn - < 2 months	8	4.1 ± 1.4
2 - 6 months	8	2.8 ± 0.6
6 - 12 months	9	2.4 ± 0.4
1 - 2 years	5	2.3 ± 0.6
2 - 12 years	10	2.3 ± 0.5
Adults	40	2.1 ± 0.1

Renal Insufficiency

In patients with significantly impaired renal function, the total clearance of iodixanol is reduced and the half-life in plasma phase is prolonged. In a study of 16 adult patients who were scheduled for renal transplant, the elimination of iodixanol 320 mgI/mL was studied. The patients' baseline mean creatinine levels were 6.3 mg/dL (±1.5) and mean creatinine clearances were 13.61 mL/min (±4.67). In these patients, the plasma half-life was increased to 23 hours (normal t1/2 = 2 hours). In these patients, levels of iodixanol were detected 5 days after dosing. Contrast enhancement time in kidneys increased from 6 hours to at least 24 hours. Dose adjustments in patients with renal impairment have not been studied. (See PHARMACODYNAMICS section for renal failure and blood-brain barrier interactions.)

Visipaque has been shown to be dialyzable. In an in vitro hemodialysis study, after 4 hours of dialysis with a cellulose membrane, approximately 36% of iodixanol was removed from the plasma. After 4 hours of dialysis with polysulfone membranes, approximately 49% of iodixanol was removed.

Drug-Drug Interactions

Not known.

PHARMACODYNAMICS

As with other iodinated contrast agents, following administration of Visipaque Injection, the degree of enhancement is directly related to the iodine content in an administered dose; peak iodine plasma levels occur immediately following rapid intravascular injection. Iodine plasma levels fall rapidly within 5 to 10 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid compartments.

Intravascular Contrast

Contrast enhancement with iodinated contrast agents appears to be greatest immediately after bolus injections (15 seconds to 120 seconds). Thus, greatest enhancement may be detected by a series of consecutive two-to-three second scans performed within 30 to 90 seconds after injection (i.e., dynamic computed tomographic imaging).

Iodinated contrast agents may be visualized in the renal parenchyma within 30-60 seconds following rapid intravenous injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1-3 minutes, with optimum contrast occurring within 5-15 minutes.

Contrast Enhanced Computerized Tomography (CECT)

AS WITH OTHER IODINATED CONTRAST AGENTS, THE USE OF Visipaque INJECTION CONTRAST ENHANCEMENT MAY OBSCURE SOME LESIONS WHICH WERE SEEN ON PREVIOUSLY UNENHANCED CT SCANS.

In CECT some performance characteristics are different in the brain and body. In CECT of the body, iodinated contrast agents diffuse rapidly from the vascular into the extravascular space. Following the administration of iodinated contrast agents, the increase in tissue density to x-rays is related to blood flow, the concentration of the contrast agent, and the extraction of the contrast agent by various interstitial tissues. Contrast enhancement is thus due to relative differences in extravascular diffusion between adjacent tissues.

In normal brain with an intact blood-brain barrier, contrast enhancement is generally due to the presence of iodinated contrast agent within the intravascular space. The radiographic enhancement of vascular lesions, such as arteriovenous malformations and aneurysms, depends on the iodine content of the circulating blood pool.

In tissues with a break in the blood-brain barrier, contrast agent accumulates within interstitial spaces of the brain. The time to maximum contrast enhancement can vary from the time that peak blood iodine levels are reached to one hour after intravenous bolus administration. This delay suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine-containing medium within the lesion and outside the blood pool. The mechanism by which this occurs is not clear.

IN PATIENTS WITH NORMAL BLOOD-BRAIN BARRIERS and RENAL FAILURE, iodinated contrast agents have been associated with blood-brain barrier DISRUPTION and ACCUMULATION OF CONTRAST IN THE BRAIN. (See PRECAUTIONS.)

The usefulness of contrast enhancement for the investigation of the retrobulbar space and of low grade or infiltrative glioma has not been demonstrated. Calcified lesions are less likely to enhance. The enhancement of tumors after therapy may decrease. The opacification of the inferior vermis following contrast agent administration has resulted in false-positive diagnosis. Cerebral infarctions of recent onset may be better visualized with contrast enhancement. Older infarctions may be obscured by the contrast agent.

For information on coagulation parameters, platelets, erythrocytes and complement system, please refer to the LABORATORY TEST FINDINGS section.

Clinical Trials

Visipaque (iodixanol) Injection was administered to 1244 adult patients. The comparators administered to 861 adult patients included low osmolar nonionic, and high and low osmolar ionic contrast media. Approximately one-half (590) of the Visipaque patients were 60 years of age or older; the mean age was 56 years (range 18-90). Of the 1244 patients, 806 (65%) were male and 438 (35%) were female. The racial distribution was: Caucasian-85%, Black-12%, Oriental <1%, and other or unknown-3%. The demographic information for the pool of patients who received a comparison contrast agent was similar.

There were 1235 patients given Visipaque and 855 patients given other contrast agents were evaluated for efficacy. Efficacy assessment was based on quality of the radiographic diagnostic visualization (i.e., either excellent, good, poor, or none) and on the ability to make a diagnosis (i.e., either confirmed a previous diagnosis, found normal, or diagnosed new findings). Results were compared to those of active controls (ioxaglate, iohexol, iopromide, and meglumine-sodium diatrizoate) at concentrations which were similar to those of Visipaque Injection.

INTRA-ARTERIAL ADMINISTRATION

Angiocardiography, cerebral arteriography, peripheral arteriography, and visceral arteriography were studied with either one or both concentrations of Visipaque Injection (270 mgI/mL or 320 mgI/mL). In these intra-arterial studies, diagnostic visualization ratings were good or excellent in 100% of the patients and a radiologic diagnosis was made in all (100%) of the patients given Visipaque Injection. In additional intra-arterial studies, overall quality of diagnostic visualization was rated optimal in the majority of patients and a radiologic diagnosis was made in all (100%) of the patients administered Visipaque Injection. Results were compared to those of active controls (ioxaglate, iohexol, iopromide). The number of patients studied in each indication is provided below.

Angiocardiography was evaluated in two randomized, double-blind clinical trials in 101 adult patients given Visipaque Injection 320 mgI/mL and 97 given iohexol 350 mgI/mL. Seven additional angiocardiography studies were performed in 217 adult patients given Visipaque Injection 320 mgI/mL, 37 given iohexol 350 mgI/mL, 40 given meglumine-sodium diatrizoate 370 mgI/mL, and 96 given ioxaglate 320 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given Visipaque; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Cerebral arteriography was evaluated in two randomized, double-blind clinical trials in 51 adult patients given Visipaque Injection 320 mgI/mL and 48 given iohexol 300 mgI/mL. Two additional cerebral arteriography studies were performed in 15 adult patients given Visipaque Injection 270 mgI/mL, 40 patients given Visipaque Injection 320 mgI/mL, and 40 patients given ioxaglate 320 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given Visipaque a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Peripheral arteriography was evaluated in two randomized, double-blind clinical trials in 49 adult patients given Visipaque Injection 320 mgI/mL, 25 given iohexol 350 mgI/mL, and 25 given ioxaglate 320 mgI/mL. Four additional peripheral arteriography studies were performed in 41 adult patients given Visipaque Injection 270 mgI/mL, 85 patients given Visipaque Injection 320 mgI/mL, 37 given iohexol 300 mgI/mL, and 47 given iopromide 300 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given Visipaque; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Visceral arteriography was evaluated in two randomized, double-blind clinical trials in 55 adult patients given Visipaque Injection 320 mgI/mL, 26 given iohexol 350 mgI/mL, and 25 given ioxaglate 320 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given Visipaque; a radiologic diagnosis was made in the majority of the patients. The results were similar to iohexol. Confirmation of the radiologic findings by other diagnostic methods was not obtained. The risk added to renal arteriography by giving Visipaque could not be analyzed.

Similar studies with digital subtraction angiography (DSA) were completed with comparable findings noted in cerebral arteriography, peripheral arteriography, and visceral arteriography. Studies have not been conducted to determine the lowest effective concentration.

INTRAVENOUS ADMINISTRATION

Excretory urography, contrast-enhanced computed tomography (CECT) of the head, CECT of the body, and peripheral venography were studied with either one or both Visipaque Injection concentrations (270 mgI/mL or 320 mgI/mL). In these intravenous studies, diagnostic visualization ratings were good or excellent in 96-100% of the patients and a radiologic diagnosis was made in all (100%) of the patients given Visipaque Injection. Results were compared to those of the active control. The number of patients studied in each indication is provided below.

Excretory urography was evaluated in one uncontrolled, unblinded clinical trial in 40 patients, 20 given Visipaque Injection 270 mgI/mL and 20 given Visipaque Injection 320 mgI/mL, and in two randomized, double-blind clinical trials in 50 adult patients given Visipaque Injection 270 mgI/mL, 50 patients given Visipaque Injection 320 mgI/mL, and 50 patients given iohexol 300 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given Visipaque; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active control. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

CECT of the head was evaluated in two randomized, double-blind clinical trials in 49 adult patients given Visipaque Injection 270 mgI/mL, in 50 patients given Visipaque Injection 320 mgI/mL, and in 49 patients given iohexol 300 mgI/mL. CECT of the body was evaluated in three randomized, double-blind clinical trials in 104 adult patients given Visipaque Injection 270 mgI/mL, in 109 patients given Visipaque Injection 320 mgI/mL, and in 101 patients given iohexol 300 mgI/mL. In both CECT of the head and body, visualization ratings were good or excellent in 100% of the patients given Visipaque; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Peripheral venography was evaluated in two randomized, double-blind clinical trials in 46 adult patients given Visipaque Injection 270 mgI/mL and in 50 patients given iohexol 300 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given Visipaque; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active control. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Indications and Usage for Visipaque

INTRA-ARTERIAL1

Visipaque Injection (270 mgI/mL) is indicated for intra-arterial digital subtraction angiography.

Visipaque Injection (320 mgI/mL) is indicated for angiocardiography (left ventriculography and selective coronary arteriography), peripheral arteriography, visceral arteriography, and cerebral arteriography.

INTRAVENOUS1

Visipaque Injection (270 mgI/mL) is indicated for CECT imaging of the head and body, excretory urography, and peripheral venography.

Visipaque Injection (320 mgI/mL) is indicated for CECT imaging of the head and body, and excretory urography.

1

For information on the concentrations and doses for the pediatric population see the Precautions–Pediatric Use, Clinical Pharmacology–Special Populations, and Dosage and Administration sections.

Contraindications

Visipaque Injection is not indicated for intrathecal use.

In the pediatric population prolonged fasting and the administration of a laxative before Visipaque injection are contraindicated.

Warnings

SERIOUS ADVERSE EVENTS—INADVERTENT INTRATHECAL ADMINISTRATION

Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use. These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Special attention must be given to insure that this drug product is not administered intrathecally.

Nonionic, iodinated contrast media inhibit blood coagulation in vitro less than ionic contrast media. Clotting has been reported when blood remains in contact with syringes containing nonionic contrast media. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting.

Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiocardiographic procedures with both ionic and nonionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events. Numerous factors, including length of procedure, catheter and syringe material, underlying disease state, and concomitant medications, may contribute to the development of thromboembolic events. For these reasons, meticulous angiographic techniques are recommended, including close attention to guidewire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing with heparinized saline solutions, and minimizing the length of the procedure.

Serious or rare fatal reactions have been associated with the administration of iodine-containing radiopaque media. It is of utmost importance to be completely prepared to treat any reaction associated with the use of any contrast agent.

Caution must be exercised in patients with severely impaired renal function, combined renal and hepatic disease, combined renal and cardiac disease, severe thyrotoxicosis, myelomatosis, or anuria, particularly when large doses are administered. (See PRECAUTIONS.)

Intravascularly administered iodine-containing radiopaque media are potentially hazardous in patients with multiple myeloma or other paraproteinaceous diseases, who are prone to disease induced renal insufficiency and/or renal failure. Although neither the contrast agent nor dehydration has been proven to be the cause of renal insufficiency (or worsening renal insufficiency) in myelomatous patients, it has been speculated that the combination of both may be causative. Special precautions, including maintenance of normal hydration and close monitoring, are required. Partial dehydration in the preparation of these patients is not recommended since it may predispose the patient to precipitation of the myeloma protein.

Reports of thyroid storm following the intravascular use of iodinated radiopaque contrast agents in patients with hyperthyroidism, or with an autonomously functioning thyroid nodule, suggest that this additional risk be evaluated in such patients before use of any contrast agent.

Administration of radiopaque materials to patients known to have, or suspected of having, pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the procedures may be performed; however, the amount of radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure, and measures for the treatment of hypertensive crisis should be readily available. These patients should be monitored very closely during contrast-enhanced procedures.

Contrast agents may promote sickling in individuals who are homozygous for sickle cell disease when the agents are administered intravascularly.

Precautions

GENERAL

CONTRAST AGENTS ARE ASSOCIATED WITH RISK AND INCREASED RADIATION EXPOSURE, AND THE DECISION TO USE ENHANCEMENT SHOULD BE BASED UPON A CAREFUL EVALUATION OF CLINICAL, OTHER RADIOLOGIC DATA, AND THE RESULTS OF UNENHANCED CT FINDINGS.

Patients receiving contrast agents, and especially those who are medically unstable, must be closely supervised. Diagnostic procedures which involve the use of iodinated intravascular contrast agents should be carried out under the direction of personnel skilled and experienced in the particular procedure to be performed. A fully equipped emergency cart, or equivalent supplies and equipment, and personnel competent in recognizing and treating adverse reactions of all types should always be available. Since severe delayed reactions have been known to occur, emergency facilities and competent personnel should be available for at least 30 to 60 minutes.

Pediatrics

Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent may include those with asthma, hypersensitivity to other medication and/or allergens, cyanotic and acyanotic heart disease, congestive heart failure, or a serum creatinine greater than 1.5 mg/dL. Pediatric patients with immature renal function or dehydration may be at increased risk for adverse events due to prolonged elimination of iodinated contrast agents.

The injection rates in small vascular beds, and the relationship of the administered volume or concentration of iodinated contrast agents in small neonates, infants and small pediatric patients, have not been established. Caution should be exercised in selecting the volume.

Dehydration, Renal Insufficiency, Congestive Heart Failure

Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with advanced vascular disease, congestive heart disease, diabetic patients, and other patients such as those on medications which alter renal function and the elderly with age-related renal impairment. Patients should be adequately hydrated prior to and following intravascular administration of iodinated contrast agent. Dose adjustments in renal impairment have not been studied.

Iodinated contrast agents may cross the blood-brain barrier. In patients where the blood-brain barrier is known or suspected to be disrupted, or in patients with normal blood-brain barrier and associated renal impairment, CAUTION MUST BE EXERCISED IN THE USE OF AN IODINATED CONTRAST AGENT. (See PHARMACODYNAMICS.)

Patients with congestive heart failure receiving concurrent diuretic therapy may have relative intravascular volume depletion, which may affect the renal response to the contrast agent osmotic load. These patients should be observed following the procedure to detect delayed hemodynamic renal function disturbances.

Immunologic Reactions

The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid or cardiovascular reactions, should always be considered. Increased risk is associated with a history of a previous reaction to contrast agent, a known sensitivity to iodine and known allergies (i.e., bronchial asthma, drug, or food allergies), other hypersensitivities, and underlying immune disorders, autoimmunity or immunodeficiencies that predispose to specific or nonspecific mediator release. If during administration there is evidence of an allergy-like reaction, the injection should be discontinued and appropriate treatment initiated.

Skin testing cannot be relied upon to predict severe reactions and may itself be hazardous to the patient. A thorough medical history with emphasis on allergy and hypersensitivity, immune, autoimmune and immunodeficiency disorders, and prior receipt of and response to the injection of any contrast agent may be more accurate than pretesting in predicting potential adverse reactions.

Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions does not prevent serious life-threatening reactions, but may reduce both their incidence and severity. Extreme caution should be exercised in considering the use of iodinated contrast agents in patients with these histories or disorders. Patients with a history of allergy or drug reaction should be observed for several hours after drug administration.

Anesthesia

General anesthesia may be indicated in the performance of some procedures in selected patients; however, a higher incidence of adverse reactions have been reported in these patients. It is not clear if this is due to the inability of the patient to identify untoward symptoms or to the hypotensive effect of anesthesia, which can prolong the circulation time and increase the duration of exposure to a contrast agent.

Angiocardiography

In angiographic procedures, the possibility of dislodging plaques, or damaging or perforating the vessel wall with resultant pseudoaneurysms, hemorrhage at puncture site, dissection of coronary artery, etc., should be considered during catheter manipulations and contrast agent injection. Angiography may be associated with local and distal organ damage, ischemia, thrombosis and organ failure (e.g., brachial plexus palsy, chest pain, myocardial infarction, sinus arrest, hepatorenal function abnormalities, etc.). Test injections to ensure proper catheter placement are suggested. During these procedures, increased thrombosis and activation of the complement system has also occurred. (See WARNINGS.)

Angiocardiography should be avoided whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and embolism. (See PHARMACODYNAMICS.)

In an uncontrolled study of 204 patients who received Visipaque Injection and who had cardiovascular disease associated with either Class II-IV congestive failure, angina, recent myocardial infarction, left ventricular ejection fraction of < 35% or valvular disease, the patients were evaluated for the types of interventions needed for treatment of adverse events. The reported type and frequency of adverse events were comparable to those in all clinical intra-arteriographic studies. Of 204 patients, 63 (31%) of patients had 99 adverse events. Of the 99 events, 68 (68%) required medical intervention of some type. Patients with 17 (17%) of these adverse events required treatment with cardioversion, multiple medications, prolonged hospitalization or intensive care. These interventions were not compared to a control group of similar patients who did not have coronary arteriography.

Selective coronary arteriography should be performed only in patients for whom the expected benefits outweigh the procedural risk. Also, the inherent risks of angiocardiography in patients with chronic pulmonary emphysema must be weighed against the necessity for performing this procedure.

Venography

In addition to the general precautions previously described, special care is required when venography is performed in patients with suspected thrombosis, phlebitis, severe ischemic disease, local infection, venous thrombosis or a totally obstructed venous system.

Extreme caution during injection of a contrast agent is necessary to avoid extravasation. This is especially important in patients with severe arterial or venous disease.

GENERAL ADVERSE REACTIONS WITH CONTRAST AGENTS

The following adverse reactions are possible with any parenterally administered iodinated contrast agent. Severe life-threatening reactions and fatalities, mostly of cardiovascular origin, have occurred. Most deaths occur during injection or five to ten minutes later, the main feature being cardiac arrest, with cardiovascular disease as the main aggravating factor. Isolated reports of hypotensive collapse and shock are found in the literature. Based upon clinical literature reported deaths from the administration of other iodinated contrast agents range from 6.6 per million (0.00066%) to 1 in 10,000 (0.01%).

The reported incidence of adverse reactions to contrast agents in patients with a history of allergy is twice that of the general population. Patients with a history of a previous reaction to a contrast agent are three times more susceptible than other patients. However, sensitivity to contrast media does not appear to increase with repeated examinations.

Adverse reactions to injectable contrast agents fall into two categories: chemotoxic reactions and idiosyncratic reactions. Chemotoxic reactions result from the physicochemical properties of the contrast agent, the dose and the speed of injection. All hemodynamic disturbances and injuries to organs or vessels perfused by the contrast agent are included in this category.

Idiosyncratic reactions include all other reactions. They occur more frequently in patients 20 to 40 years old. Idiosyncratic reactions may or may not be dependent on the dose injected, the speed of injection, the mode of injection and the radiographic procedure. Idiosyncratic reactions are subdivided into minor, intermediate, and severe. The minor reactions are self-limited and of short duration; the severe reactions are life-threatening, and treatment is urgent and mandatory.

INFORMATION FOR PATIENTS

Patients receiving an iodinated intravascular contrast agent should be instructed to:

1. Inform your physician if you are pregnant (see PRECAUTIONS - Pregnancy Category B).


2. Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease, or known thyroid disorder (see WARNINGS).


3. Inform your physician if you are allergic to any drugs or food, or if you have immune, autoimmune or immune deficiency disorders. Also inform your physician if you had any reactions to previous injections of dyes used for x-ray procedures (see PRECAUTIONS, General).


4. Inform your physician about all medications you are currently taking, including nonprescription (over-the-counter) drugs, before you have this procedure.

DRUG INTERACTIONS

Renal toxicity has been reported in a few patients with liver dysfunction who were given an oral cholecystographic agent followed by intravascular contrast agents. Administration of any intravascular contrast agent should therefore be postponed in patients who have recently received an oral cholecystographic contrast agent.

Other drugs should not be mixed with Visipaque Injection.

DRUG/LABORATORY TEST INTERACTIONS

The results of protein bound iodine and radioactive iodine uptake studies, which depend on iodine estimation, will not accurately reflect thyroid function for at least 16 days following administration of iodinated contrast agents. However, thyroid function tests which do not depend on iodine estimations (e.g., T3 resin uptake and total or free thyroxine T4 assays) are not affected.

As reported with other contrast agents, Visipaque may produce a false-positive result for protein in the urine using Multistix®. However, the Coomassie blue method has been shown to give accurate results for the measurement of urine protein in the presence of Visipaque. In addition, care should be used in interpreting the results of urine specific gravity measurements in the presence of high levels of Visipaque and other contrast agents in the urine. Refractometry or urine osmolality may be substituted.

LABORATORY TEST FINDINGS

Coagulation, platelets, erythrocytes and complement activation were evaluated with standard citrated human plasma or whole blood in the following assays: thrombin generation time, platelet aggregation and activation, red blood cell rigidification and aggregation, and complement activation. Data on reversibility, thrombin time, PTT and clotting factors are not available.

In vitro human blood studies showed that with 5 mL of iodixanol 320 mgI/mL, the thrombin generation time was increased to a mean of 46 minutes (saline control = 14 minutes). An in vitro study of platelet enriched plasma after incubation with iodixanol 320 mgI/mL, the platelet aggregation response to collagen was inhibited to 63% of normal (range 30-98% with iodixanol concentrations of 16 to 64 mgI/mL); these findings were comparable to those of a tested nonionic comparators; platelet degranulation did not occur. Erythrocyte rigidification (measured by half conductance of the Mynipore sieve with hematocrit adjusted to 8%) was comparable for iodixanol and the tested nonionic comparators. Also, the red cell aggregation decrease was comparable to that of other nonionic comparators. In a CH-50 hemolytic complement activation assay after 11 hours of incubation with 320 mgI/mL, the remaining complement activity was approximately 15 % (± 3) of normal.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

Long-term animal studies have not been performed with iodixanol to evaluate carcinogenic potential. Iodixanol was not genotoxic in a series of studies including the Ames test, the CHO/HGPRT assay, a chromosome aberration assay in CHO cells, and a mouse micronucleus assay. Iodixanol did not impair the fertility of male or female rats when administered at doses up to 2.0 gI/kg (1.3 times the maximum recommended dose for a 50 kg human, or approximately 0.2 times the maximum recommended dose for a 50 kg human following normalization of the data to body surface area estimates).

PREGNANCY

Teratogenic Effects: Pregnancy Category B

Reproduction studies performed in rats and rabbits at doses up to 2.0 gI/kg [1.3 times the maximum recommended dose for a 50 kg human, or approximately 0.2 (rat) and 0.4 (rabbit) times the maximum recommended dose for a 50 kg human following normalization of the data to body surface estimates] have not revealed evidence of impaired fertility or harm to the fetus due to iodixanol. Adequate and well-controlled studies in pregnant women have not been conducted. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

NURSING MOTHERS

It is not known whether Visipaque Injection is excreted in human milk. However, many injectable contrast agents are excreted unchanged in human milk. Although it has not been established that serious adverse reactions occur in nursing infants, caution should be exercised when intravascular contrast agents are administered to nursing women because of the potential for adverse reactions, and consideration should be given to temporarily discontinue nursing.

PEDIATRIC USE

The safety and efficacy of Visipaque has been established in the pediatric population over 1 year of age for arterial studies and for intravenous procedures. Use of Visipaque in these age groups is supported by evidence from adequate and well controlled studies of Visipaque in adults and additional safety data obtained in pediatric studies. Although Visipaque has been administered to pediatric patients less than 1 year of age, the relative safety of the volumes injected, the optimal concentrations, and the potential need for dose adjustment because of prolonged elimination half-lives have not been systematically studied. (See Clinical Pharmacology–Special Populations section).

Visipaque (iodixanol) Injection was administered to 459 pediatric patients. There were 26 patients administered Visipaque Injection in the birth to <29 day age range, 148 from 29 days to 2 years, 263 from 2 to <12 years, and 22 from 12 to 18 years. The mean age was 4.4 years (range <1 day to 17.4 years). Of the 459 patients, 252 (55%) were male and 207 (45%) were female. The racial distribution was: Caucasian-81%, Black-14%, Oriental-2%, and other or unknown-4%. The demographic information for the pool of patients who received a comparison contrast agent was similar.

In pediatric patients who received intravenous injection for computerized tomography or excretory urography, a concentration of 270 mgI/mL was used in 144 patients, and a concentration of 320 mgI/mL in 154 patients. All patients received one intravenous injection of 1-2 mL/kg.

In pediatric patients who received intra-arterial and intracardiac studies, a concentration of 320 mgI/mL was used in 161 patients. Of the 161 patients in the intra-arterial studies, the mean age was 2.6 years. Twenty-two patients were < 29 days of age; 78 were 29 days to 2 years of age; and 61 were over 2 years. Most of these pediatric patients received initial volumes of 1-2 mL/kg and most patients had a maximum of 3 injections.

Optimal volumes, concentrations or injection rates of Visipaque have not been established because different injection volumes, concentrations, and injection rates were not studied. The relationship of the volume of injection with respect to the size of the target vascular bed has not been established. The potential need for dose adjustment to maximize efficacy of computerized tomography, or to minimize the toxicity to other immature body tissues, has not been studied in neonates or infants with immature renal function.

In the above patients, adverse events were associated with decreasing age and intra-arterial procedures. In general the type of adverse events reported are similar to those of adults. Although the frequency of events appears to be comparable, the percentages cannot be confirmed because of the different ability of pediatric and adult patients to report adverse events.

ADVERSE EVENTS REPORTED IN PEDIATRIC PATIENTS WHO RECEIVED Visipaque (BY AGE, ROUTE OF ADMINISTRATION, AND CONCENTRATION OF IODINE)

Age Range	Number of Patients with Adverse Events
(For additional information see the Clinical Pharmacology–Special Populations, and Dosage and Administration sections.)
< 29 days	8/24 (33%)	P< 0.05 between the < 29 day and 1-2 year patient groups.
> 29 days - 6 months	9/43 (20%)
> 6 months - 12 months	26/91 (28%)
1 year - 2 year	8/49 (17%)
> 2 years	40/263 (15%)
Intra-arterial injections	42/161 (26%)	P< 0.05
Intravenous injections	32/298 (10%)
270 mgI/mL	11/144 (8%)	P< 0.05
320 mgI/mL	53/315 (17%)

GERIATRIC USE

Of the total number of patients in clinical studies of Visipaque in the U.S., 254/757 (34%) were 65 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

ADVERSE EVENTS

Visipaque (iodixanol) injection was administered to 1244 patients. The comparators administered to 861 patients included low osmolar nonionic, and high and low osmolar ionic contrast media. For complete demographics, see CLINICAL TRIALS section.

Serious, life-threatening and fatal reactions have been associated with the administration of iodine-containing contrast media, including Visipaque Injection. In clinical trials, 3/1244 patients given Visipaque Injection and 1/861 patients given a comparator died within 5 days or later after drug administration. Also, 7/1244 patients given Visipaque Injection and 8/861 given a comparator had serious adverse events. Rare reports of anaphylaxis have been documented during postmarket surveillance.

As with other contrast agents, Visipaque is often associated with sensations of discomfort, warmth or pain. In a subgroup of 1259 patients, for whom data are available; similar percentages of patients (30%) who received Visipaque or a comparator had application site discomfort, pain, warmth or cold. Visipaque had a trend toward fewer patient reports of moderate or severe pain or warmth; however, whether or not this related to the dose, rate of administration, site of injection or concentration has not been determined.

The following table of incidence of events is based upon blinded, controlled clinical trials with Visipaque Injection in controlled clinical studies in which Visipaque (1244 patients) was compared with low osmolar nonionic (iohexol, iopromide), a low osmolar ionic (ioxaglate), and a high osmolar ionic (diatrizoate) contrast agents. This listing includes all reported adverse events regardless of attribution. Adverse events (AEs) are listed by body system and in decreasing order of occurrence greater than 0.5% in the Visipaque group.

As the table shows, one or more adverse events were recorded in 248 of 1244 (20%) patients during the clinical trials, with the administra