Androxy

Endogenous androgens are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include growth and maturation of prostate, seminal vesicles, penis, and scrotum; development of male hair distribution, such as beard, pubic, chest, and axillary hair; laryngeal enlargement; vocal cord thickening; alterations in body musculature; and fat distribution.

Androgens also cause retention of nitrogen, sodium, potassium, and phosphorus, and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein.

Androgens are responsible for the growth spurt of adolescence and for the eventual termination of linear growth which is brought about by fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rates but may cause a disproportionate advancement in bone maturation. Use over long periods may result in fusion of the epiphyseal growth centers and termination of growth process. Androgens have been reported to stimulate the production of red blood cells by enhancing the production of erythropoietic stimulating factor.

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

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

Pharmacokinetics

Testosterone given orally is metabolized by the gut, and 44 percent is cleared by the liver in the first pass. Oral doses as high as 400 mg per day are needed to achieve clinically effective blood levels for full replacement therapy. The 17-alpha-alkylated derivatives (fluoxymesterone and methyltestosterone) are less extensively metabolized by the liver and have longer half lives. They are more suitable for oral administration than testosterone.

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

About 90 percent of a dose of testosterone is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about six percent of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. Testosterone is metabolized to various 17-keto steroids through two different pathways. There are considerable variations of the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. The half-life of fluoxymesterone is reported to be 10 hours.

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

Male adolescent patients receiving androgens for delayed puberty should have bone development checked every six months.

The physician should instruct patients to report any of the following side effects of androgens:

Adult or adolescent males—too frequent or persistent erections of the penis.

Women—hoarseness, acne, changes in menstrual periods, or more facial hair.

All patients—Any nausea, vomiting, changes in skin color, or ankle swelling.

Half-Life: 9.2 hr, longer t1/2 than natural androgens

Bioavailability: PO: rapidly absorbed

Protein Bound: 98%

Metabolism: liver

Excretion: urine (90%)

Mechanism of Action

Synthetic derivative of testosterone with predominantly androgenic activity; promoting growth and development of male sex organs and maintaining secondary sex characteristics in androgen-deficient males

This medicine can cause birth defects. Do not use fluoxymesterone if you are pregnant.

You should not use fluoxymesterone if you have prostate cancer or male breast cancer.

Fluoxymesterone will not enhance athletic performance and should not be used for that purpose or shared with another person.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• To gain the most benefit, do not miss doses.
• Keep taking Androxy as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of high calcium levels like weakness, confusion, feeling tired, headache, upset stomach and throwing up, hard stools (constipation), or bone pain.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Change in color of skin.
• Low mood (depression).
• A burning, numbness, or tingling feeling that is not normal.
• Upset stomach or throwing up.
• For males, erections (hard penis) that happen often or that last a long time.
• For females, a deep voice, facial hair, pimples, or period changes.
• Very bad and sometimes deadly liver problems have happened with this medicine. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.

Androxy™ (Fluoxymesterone Tablets, USP) 10 mg are round, green, scored compressed tablets debossed with 832 and 86 and are available in bottles of 100.

Dispense in a tight, light-resistant container as defined in the USP.

Store at controlled room temperature 15 – 30°C (59 – 86°F).

Keep out of reach of children.

Manufactured by
UPSHER-SMITH LABORATORIES, INC.
Maple Grove, MN 55369

Rev 0713

• Androderm
• Aveed
• Delatestryl
• Depo-Testosterone
• Fareston
• Halotestin

• Nolvadex
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• Testim
• Testred

© Androxy Patient Information is supplied by Cerner Multum, Inc. and Androxy Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

When administered to pregnant women, androgens can cause virilization of the external genitalia of a female fetus. Virilization effects include clitoromegaly, abnormal vaginal development, and fusion of genital folds to form a scrotal-like structure. The degree of masculinization is related to the drug amount given and the age of the female fetus, and is most likely to occur when the androgen is given in the first trimester. US FDA pregnancy category X: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

This drug is contraindicated in women who are or may become pregnant. US FDA pregnancy category: X Comments: -This drug may cause virilization of the external genitalia of a female fetus; apprise patients of this potential hazard if they become pregnant during treatment. -Oligospermia may occur at high dosages.

General

• Individualize dosage according to condition being treated, severity of symptoms, and patient age, gender, and history of prior androgenic therapy.a b

• Adjust dosage carefully according to individual therapeutic response and appearance of adverse effects.c

Delayed Puberty

• Take into consideration the chronological and skeletal ages of the patient, both in determining the initial dosage and in adjusting the dosage.a c

• Perform radiographic examination of the hand and wrist at 6-month intervals to determine the rate of bone maturation and to assess the effect of therapy on the epiphyseal centers.a b c (See Pediatric Use under Cautions.)

Breast Cancer

• Administer only under the supervision of a qualified clinician experienced in the treatment of breast cancer.a c

• Occasionally, may appear to accelerate progression of the disease; monitor patients closely.c

Administration

Oral Administration

Administer orally, usually as a single daily dose or in 3 or 4 divided doses.a b c

Dosage

Pediatric Patients

For development of secondary sexual characteristics during adolescence: 5–20 mg daily.a b c Generally, therapy initiated at a higher level within the range (e.g., 10 mg daily).a b c Prolonged therapy is required to maintain sexual characteristics.a c

Use dosages in the lower end of the usual range for replacement (i.e., 10 mg daily) for 4–6 months.a b c Usual range: 2.5–20 mg daily; however, most patients respond to 2.5–10 mg daily.a c Titrate carefully using low doses.a b c

Some clinicians recommend lower dosages initially, followed by gradual increases in dosage as puberty progresses;a b subsequently, the dosage may be decreased to maintenance levels.a Other clinicians state that higher dosages are required initially to induce pubertal changes and lower dosages can then be used for maintenance therapy after puberty.a c

Adults

Usual dosage: 5–20 mg daily;a b c prolonged therapy is required to maintain sexual characteristics.a c

Usual dosage: 10–40 mg daily in divided doses.a b c

Generally, ≥1 month of therapy is necessary to obtain a satisfactory subjective response; ≥2–3 months of continuous therapy is required to obtain a satisfactory objective response.a b c

Special Populations

No special population dosage recommendations at this time.b c

Contraindications

• Males with breast cancer or known or suspected prostate cancer.a b c

• Known or suspected pregnancy.b c

• Some manufacturers state that fluoxymesterone is contraindicated in patients with serious cardiac, hepatic, or renal disease.a b

• Known hypersensitivity to fluoxymesterone or any ingredient in the formulation.a b

Warnings/Precautions

Warnings

May cause fetal harm; dose-related virilization of the external genitalia (e.g., clitoral hypertrophy, labial fusion of the external genital fold to form a scrotal-like structure, abnormal vaginal development, persistence of a urogenital sinus) of female fetus reported, particularly when exposure to androgens occurs during the first trimester.a c If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard;c contraindicated in pregnant women.a b c (See Contraindications under Cautions.)

Potentially serious and/or life-threatening adverse hepatic effects (e.g., peliosis hepatis, hepatic adenomas, hepatocellular carcinoma) associated with prolonged use of high dosages of androgens.a b c Discontinuance of androgen therapy following development of hepatocellular carcinoma dose not always result in regression of the tumor.a

If cholestatic hepatitis or jaundice occurs, or if liver function test results become abnormal during therapy, discontinue the drug and investigate the etiology of these disorders.a b c Drug-induced jaundice usually is reversible following discontinuance of the drug.a b c

Periodic liver function evaluation recommended.a b c

Priapism or excessive sexual stimulation possible, especially in geriatric men.a b Oligospermia and decreased ejaculatory volume also may occur in men receiving excessive dosage or prolonged administration.a b Acute urethral obstruction possible in patients with benign prostatic hypertrophy.b If any of these adverse effects occur, discontinue the drug temporarily.a b If therapy is restarted, use lower dosages.a b

Possible increased risk for the development of prostatic hyperplasia and prostate cancer, particularly in geriatric patients.a b c

Possible increased or decreased libido.b c

Gynecomastia frequently develops and occasionally persists in patients being treated for hypogonadism.a b c

Edema, with or without CHF, possible as a result of sodium and water retention and may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease.a b c (See Contraindications under Cautions.) If edema occurs and is considered a serious complication, discontinue drug and, if necessary, initiate diuretic therapy.a c If therapy is restarted, use lower dosages.c

Retention of potassium and inorganic phosphates also has occurred.a b c

Possible hypercalcemia resulting from osteolysis, especially in immobile patients and those with metastatic breast cancer.a b c In patients with cancer, hypercalcemia may indicate progression of metastases to the bone.a c Monitor urine and serum calcium concentrations frequently during the course of androgen therapy in women with metastatic breast cancer.b c If hypercalcemia occurs, discontinue the druga b c and institute appropriate measures.c

Serious adverse effects (e.g., increased aggression, antisocial behavior, manic episode, hostility, depression, changes in libido, increased risk of cardiovascular events, hepatotoxicity, testicular atrophy, sperm abnormalities) associated with misuse and abuse of androgens (see Misuse, Abuse, and Dependence under Uses);135 193 194 fluoxymesterone preparations currently subject to control as schedule III (C-III) drugs.a b c d

Manifestations of withdrawal (e.g., depressed mood, major depression, fatigue, cravings, restlessness, irritability, anorexia, insomnia, decreased libido, hypogonadotropic hypogonadism) may occur if androgens discontinued abruptly or dosage substantially reduced in physically dependent patients or in those taking supratherapeutic dosages of such drugs; withdrawal symptoms may persist for weeks or months.135

General Precautions

Virilization, including deepening of the voice, hirsutism, acne, menstrual irregularities, and clitoral enlargement, occurs commonly in females receiving high-dose fluoxymesterone therapy;a b c changes may not be reversible following discontinuance of the drug.a

Monitor women receiving fluoxymesterone therapy for signs of virilization.a b c If virilization occurs, discontinue therapy.a b c

Possible polycythemia, especially with high dosages of androgens.b c Perform periodic hemoglobin and hematocrit determinations in patients receiving high dosagesa c or long-term administration of fluoxymesterone.a b

Androgens may alter serum cholesterol concentration;b c therefore, administer with caution in patients with history of MI or CAD.c

Monitor serum cholesterol throughout therapy; adjust therapy accordinglyc .

Specific Populations

Category X.b c f (See Fetal/Neonatal Morbidity and also Contraindications, under Cautions.)

Not known whether fluoxymesterone is distributed into milk.a c Discontinue nursing or the drug.a b c

May accelerate bone maturation without producing compensatory gain in linear growth, possibly resulting in compromised adult stature.a b c The younger the child, the greater the risk of fluoxymesterone compromising final mature stature.a c Use with extreme caution in children and only under the supervision of a specialist who is aware of the adverse effects of fluoxymesterone on bone maturation.a Perform radiographic examination of the hand and wrist every 6 months to determine the rate of bone maturation and to assess the effect of treatment on the epiphyseal centers.a b c

Possible risk of developing prostatic hypertrophy and carcinoma during androgen therapy.a b c

Males, especially geriatric patients, may become overly sexually stimulated during therapy and such stimulation may be a sign of excessive dosage.a Carefully monitor males for the development of excessive sexual stimulation.a

Common Adverse Effects

Males: Gynecomastia,a b c frequent or persistent penile erections.b c

Females: Amenorrhea,a b c other menstrual irregularities,a b c inhibition of gonadotropin secretion,a b c virilization (e.g., deepening of the voice, clitoral enlargement).a b c