Avodart

Avodart is the brand name of the generic drug dutasteride, prescribed to manage symptoms caused by an enlarged prostate, or benign prostatic hyperplasia (BPH).

Avodart belongs to a class of drugs known as 5-alpha-reductase inhibitors. The medication stops the conversion of testosterone into dihydrotestosterone (DHT) in the body.

In doing this, Avodart helps shrink prostate tissue and prevent further prostate enlargement.

DHT is the hormone responsible for prostate tissue growth. When too much prostate tissue develops, you have trouble urinating and may have some urine dribbling.

Lowering the level of dihydrotestosterone helps reduce and manage these symptoms.

The Food and Drug Administration (FDA) approved Avodart in 2001, and GlaxoSmithKline manufactures it.

Avodart and Hair Growth

Abnormally high DHT levels cause hair loss, especially male pattern baldness.

Because Avodart lowers DHT levels, it’s not unusual to see hair growth along the hairline, the crown of the head, and even the eyebrows.

A 2006 study comparing Avodart to a similar drug, finasteride (Propecia, Proscar), and a placebo, showed that men taking 2.5 milligrams (mg) of Avodart had more hair growth at 5, 12, and 24 weeks than those taking 5 mg of finasteride or a placebo.

Avodart Warnings

Don’t take Avodart if you are:

• Allergic to Avodart or any other ingredient in the drug
• Female
• Pregnant
• A child

If you have liver problems, talk to your doctor about Avodart before taking it.

Wait at least six months after you’ve stopped taking Avodart to donate blood.

The delay is necessary because Avodart may linger in your system and your blood for months and may affect women, unborn babies of pregnant women, and children who receive that blood.

Pregnancy and Avodart

Avodart causes birth defects, so pregnant women should not take it.

Doctors don’t consider Avodart safe to take while breastfeeding, either.

Tell your doctor if you’re pregnant, might become pregnant, or are breastfeeding.

Avodart Coupons

As with many prescription medications, there are several coupon and rebate programs offering discounts on Avodart, both online and from various pharmacies.

Such programs can help make treatment more affordable.

However, a prescription from your doctor is still required to use Avodart, and the drug may or may not be the best option for your symptoms.

The decision on which medication to use should be based on your specific symptoms and needs, and not on available financial incentives.

Talk to your doctor to see if Avodart is right for you before exploring discount options.

Avodart may cause rare and serious allergic reactions including:

• swelling of your face, tongue, or throat
• serious skin reactions, such as skin peeling

The most common side effects of Avodart include:

• trouble having or maintaining an erection (impotence)
• a decrease in sex drive (libido)
• ejaculation problems
• enlarged or painful breasts. If you notice breast lumps or nipple discharge, you should talk to your healthcare provider.

Taking Avodart may increase the risk that you will develop a type of cancer that spreads and grows more quickly than other types of prostate cancer. Talk to your doctor about the risks of taking Avodart.

This is not a complete list of Avodart side effects. Ask your doctor or pharmacist for more information.

If you take too much Avodart call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If Avodart is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Dosage Forms & Strengths

capsule

• 0.5mg

Benign Prostatic Hyperplasia

0.5 mg PO qDay

Dosing Modifications

Renal impairment: Dose adjustment not necessary

Hepatic impairment: Dose adjustment not necessary

Safety and efficacy not established

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Tell your doctor about all other medicines you use, especially:

• conivaptan (Vaprisol);

• imatinib (Gleevec);

• isoniazid (for treating tuberculosis);

• an antibiotic such as clarithromycin (Biaxin), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin, Pediazole), or telithromycin (Ketek);

• an antifungal medication such as itraconazole (Sporanox), ketoconazole (Nizoral), miconazole (Oravig), or voriconazole (Vfend);

• an antidepressant such as nefazodone;

• heart or blood pressure medication such as nicardipine (Cardene) or quinidine (Quin-G); or

• HIV/AIDS medicine such as atazanavir (Reyataz), delavirdine (Rescriptor), indinavir (Crixivan), nelfinavir (Viracept), saquinavir (Invirase), or ritonavir (Norvir, Kaletra).

This list is not complete and other drugs may interact with dutasteride. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Metabolized by CYP isoenzymes 3A4 and 3A5 to active metabolites; not metabolized by CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1.1

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction with inhibitors of CYP3A4 and CYP3A5 (decreased clearance and increased serum concentrations of dutasteride).1 14 Use with caution in patients receiving chronic therapy with potent CYP3A4 inhibitors.1 14

Specific Drugs and Laboratory Tests

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 this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine 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

Dutasteride is not indicated for use in the pediatric population. 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 dutasteride in the elderly.

Pregnancy

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 this medicine, 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 this medicine 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.

• Ceritinib
• Clarithromycin
• Idelalisib

Using this medicine 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.

• Cimetidine
• Ciprofloxacin
• Diltiazem
• Ketoconazole
• Ritonavir
• Verapamil

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 this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Effects on Prostate-specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection

In clinical trials, Avodart reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. This decrease was predictable over the entire range of PSA values in subjects with symptomatic BPH, although it may vary in individuals. Avodart may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men taking Avodart, a new PSA baseline should be established at least 3 months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on Avodart may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5 alpha-reductase inhibitor. Noncompliance with Avodart may also affect PSA test results.

To interpret an isolated PSA value in a man treated with Avodart for 3 months or more, the PSA value should be doubled for comparison with normal values in untreated men.The free-to-total PSA ratio (percent free PSA) remains constant, even under the influence of Avodart. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving Avodart, no adjustment to its value appears necessary.

Coadministration of dutasteride and tamsulosin resulted in similar changes to serum PSA as dutasteride monotherapy.

Increased Risk of High-grade Prostate Cancer

In men aged 50 to 75 years with a prior negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/mL and 10.0 ng/mL taking Avodart in the 4-year Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, there was an increased incidence of Gleason score 8-10 prostate cancer compared with men taking placebo (Avodart 1.0% versus placebo 0.5%) [see Indications and Usage (1.3), Adverse Reactions (6.1)]. In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR®), similar results for Gleason score 8-10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%).

5 alpha-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5 alpha-reductase inhibitors to reduce prostate volume or trial-related factors impacted the results of these trials has not been established.

Evaluation for Other Urological Diseases

Prior to initiating treatment with Avodart, consideration should be given to other urological conditions that may cause similar symptoms. In addition, BPH and prostate cancer may coexist.

Exposure of WomenRisk to Male Fetus

Avodart Capsules should not be handled by a woman who is pregnant or who could become pregnant. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a woman who is pregnant or who could become pregnant comes in contact with leaking dutasteride capsules, the contact area should be washed immediately with soap and water [see Use in Specific Populations (8.1)].

Blood Donation

Men being treated with Avodart should not donate blood until at least 6 months have passed following their last dose. The purpose of this deferred period is to prevent administration of dutasteride to a pregnant female transfusion recipient.

Effect on Semen Characteristics

The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal volunteers aged 18 to 52 (n = 27 dutasteride, n = 23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reductions from baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all semen parameters at all time-points remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), 2 subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of dutasteride’s effect on semen characteristics for an individual patient’s fertility is not known.

In volunteer trials, single doses of dutasteride up to 40 mg (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns. In a clinical trial, daily doses of 5 mg (10 times the therapeutic dose) were administered to 60 subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg.

There is no specific antidote for dutasteride. Therefore, in cases of suspected overdosage, symptomatic and supportive treatment should be given as appropriate, taking the long half-life of dutasteride into consideration.

Mechanism of Action

Dutasteride inhibits the conversion of testosterone to dihydrotestosterone (DHT). DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5 alpha-reductase, which exists as 2 isoforms, type 1 and type 2. The type 2 isoenzyme is primarily active in the reproductive tissues, while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver.

Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5 alpha-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human androgen receptor.

Pharmacodynamics

Effect on 5 Alpha-dihydrotestosterone and Testosterone

The maximum effect of daily doses of dutasteride on the reduction of DHT is dose dependent and is observed within 1 to 2 weeks. After 1 and 2 weeks of daily dosing with dutasteride 0.5 mg, median serum DHT concentrations were reduced by 85% and 90%, respectively. In patients with BPH treated with dutasteride 0.5 mg/day for 4 years, the median decrease in serum DHT was 94% at 1 year, 93% at 2 years, and 95% at both 3 and 4 years. The median increase in serum testosterone was 19% at both 1 and 2 years, 26% at 3 years, and 22% at 4 years, but the mean and median levels remained within the physiologic range.

In patients with BPH treated with 5 mg/day of dutasteride or placebo for up to 12 weeks prior to transurethral resection of the prostate, mean DHT concentrations in prostatic tissue were significantly lower in the dutasteride group compared with placebo (784 and 5,793 pg/g, respectively, P<0.001). Mean prostatic tissue concentrations of testosterone were significantly higher in the dutasteride group compared with placebo (2,073 and 93 pg/g, respectively, P<0.001).

Adult males with genetically inherited type 2 5 alpha-reductase deficiency also have decreased DHT levels. These 5 alpha-reductase deficient males have a small prostate gland throughout life and do not develop BPH. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to 5 alpha-reductase-deficiency have been observed in these individuals.

Effects on Other Hormones

In healthy volunteers, 52 weeks of treatment with dutasteride 0.5 mg/day (n = 26) resulted in no clinically significant change compared with placebo (n = 23) in sex hormone-binding globulin, estradiol, luteinizing hormone, follicle-stimulating hormone, thyroxine (free T4), and dehydroepiandrosterone. Statistically significant, baseline-adjusted mean increases compared with placebo were observed for total testosterone at 8 weeks (97.1 ng/dL, P<0.003) and thyroid-stimulating hormone at 52 weeks (0.4 mcIU/mL, P<0.05). The median percentage changes from baseline within the dutasteride group were 17.9% for testosterone at 8 weeks and 12.4% for thyroid-stimulating hormone at 52 weeks. After stopping dutasteride for 24 weeks, the mean levels of testosterone and thyroid-stimulating hormone had returned to baseline in the group of subjects with available data at the visit. In subjects with BPH treated with dutasteride in a large randomized, double-blind, placebo-controlled trial, there was a median percent increase in luteinizing hormone of 12% at 6 months and 19% at both 12 and 24 months.

Other Effects

Plasma lipid panel and bone mineral density were evaluated following 52 weeks of dutasteride 0.5 mg once daily in healthy volunteers. There was no change in bone mineral density as measured by dual energy x-ray absorptiometry compared with either placebo or baseline. In addition, the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins, and triglycerides) was unaffected by dutasteride. No clinically significant changes in adrenal hormone responses to adrenocorticotropic hormone (ACTH) stimulation were observed in a subset population (n = 13) of the 1-year healthy volunteer trial.

Pharmacokinetics

Absorption

Following administration of a single 0.5-mg dose of a soft gelatin capsule, time to peak serum concentrations (Tmax) of dutasteride occurs within 2 to 3 hours. Absolute bioavailability in 5 healthy subjects is approximately 60% (range: 40% to 94%). When the drug is administered with food, the maximum serum concentrations were reduced by 10% to 15%. This reduction is of no clinical significance.

Distribution

Pharmacokinetic data following single and repeat oral doses show that dutasteride has a large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha-1 acid glycoprotein (96.6%).

In a trial of healthy subjects (n = 26) receiving dutasteride 0.5 mg/day for 12 months, semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) at 12 months and, similar to serum, achieved steady-state concentrations at 6 months. On average, at 12 months 11.5% of serum dutasteride concentrations partitioned into semen.

Metabolism and Elimination

Dutasteride is extensively metabolized in humans. In vitro studies showed that dutasteride is metabolized by the CYP3A4 and CYP3A5 isoenzymes. Both of these isoenzymes produced the 4′-hydroxydutasteride, 6-hydroxydutasteride, and the 6,4′-dihydroxydutasteride metabolites. In addition, the 15-hydroxydutasteride metabolite was formed by CYP3A4. Dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In human serum following dosing to steady state, unchanged dutasteride, 3 major metabolites (4′-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and 2 minor metabolites (6,4′-dihydroxydutasteride and 15-hydroxydutasteride), as assessed by mass spectrometric response, have been detected. The absolute stereochemistry of the hydroxyl additions in the 6 and 15 positions is not known. In vitro, the 4′-hydroxydutasteride and 1,2-dihydrodutasteride metabolites are much less potent than dutasteride against both isoforms of human 5 alpha-reductase. The activity of 6β-hydroxydutasteride is comparable to that of dutasteride.

Dutasteride and its metabolites were excreted mainly in feces. As a percent of dose, there was approximately 5% unchanged dutasteride (~1% to ~15%) and 40% as dutasteride-related metabolites (~2% to ~90%). Only trace amounts of unchanged dutasteride were found in urine (<1%). Therefore, on average, the dose unaccounted for approximated 55% (range: 5% to 97%).

The terminal elimination half-life of dutasteride is approximately 5 weeks at steady state. The average steady-state serum dutasteride concentration was 40 ng/mL following 0.5 mg/day for 1 year. Following daily dosing, dutasteride serum concentrations achieve 65% of steady-state concentration after 1 month and approximately 90% after 3 months. Due to the long half-life of dutasteride, serum concentrations remain detectable (greater than 0.1 ng/mL) for up to 4 to 6 months after discontinuation of treatment.

Specific Populations

Pediatric: Dutasteride pharmacokinetics have not been investigated in subjects younger than 18 years.

Geriatric: No dose adjustment is necessary in the elderly. The pharmacokinetics and pharmacodynamics of dutasteride were evaluated in 36 healthy male subjects aged between 24 and 87 years following administration of a single 5-mg dose of dutasteride. In this single-dose trial, dutasteride half-life increased with age (approximately 170 hours in men aged 20 to 49 years, approximately 260 hours in men aged 50 to 69 years, and approximately 300 hours in men older than 70 years). Of 2,167 men treated with dutasteride in the 3 pivotal trials, 60% were age 65 and over and 15% were age 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients.

Gender: Avodart is contraindicated in pregnancy and women of childbearing potential and is not indicated for use in other women [see Contraindications (4), Warnings and Precautions (5.1)]. The pharmacokinetics of dutasteride in women have not been studied.

Race: The effect of race on dutasteride pharmacokinetics has not been studied.

Renal Impairment: The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 0.5-mg dose of dutasteride is recovered in human urine, so no adjustment in dosage is anticipated for patients with renal impairment.

Hepatic Impairment: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients.

Drug Interactions 

Cytochrome P450 Inhibitors: No clinical drug interaction trials have been performed to evaluate the impact of CYP3A enzyme inhibitors on dutasteride pharmacokinetics. However, based on in vitro data, blood concentrations of dutasteride may increase in the presence of inhibitors of CYP3A4/5 such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, troleandomycin, and ciprofloxacin.

Dutasteride does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at a concentration of 1,000 ng/mL, 25 times greater than steady-state serum concentrations in humans.

Alpha-adrenergic Antagonists: In a single-sequence, crossover trial in healthy volunteers, the administration of tamsulosin or terazosin in combination with Avodart had no effect on the steady-state pharmacokinetics of either alpha-adrenergic antagonist. Although the effect of administration of tamsulosin or terazosin on dutasteride pharmacokinetic parameters was not evaluated, the percent change in DHT concentrations was similar for Avodart alone compared with the combination treatment.

Calcium Channel Antagonists: In a population pharmacokinetics analysis, a decrease in clearance of dutasteride was noted when coadministered with the CYP3A4 inhibitors verapamil (-37%, n = 6) and diltiazem (-44%, n = 5). In contrast, no decrease in clearance was seen when amlodipine, another calcium channel antagonist that is not a CYP3A4 inhibitor, was coadministered with dutasteride (+7%, n = 4).

The decrease in clearance and subsequent increase in exposure to dutasteride in the presence of verapamil and diltiazem is not considered to be clinically significant. No dose adjustment is recommended.

Cholestyramine: Administration of a single 5-mg dose of Avodart followed 1 hour later by 12 g cholestyramine did not affect the relative bioavailability of dutasteride in 12 normal volunteers.

Digoxin: In a trial of 20 healthy volunteers, Avodart did not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks.

Warfarin: In a trial of 23 healthy volunteers, 3 weeks of treatment with Avodart 0.5 mg/day did not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time when administered with warfarin.

Other Concomitant Therapy: Although specific interaction trials were not performed with other compounds, approximately 90% of the subjects in the 3 randomized, double-blind, placebo-controlled safety and efficacy trials receiving Avodart were taking other medications concomitantly. No clinically significant adverse interactions could be attributed to the combination of Avodart and concurrent therapy when Avodart was coadministered with anti-hyperlipidemics, angiotensin-converting enzyme (ACE) inhibitors, beta-adrenergic blocking agents, calcium channel blockers, corticosteroids, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), phosphodiesterase Type V inhibitors, and quinolone antibiotics.

Using dutasteride may increase your risk of developing prostate cancer. Your doctor will perform tests to make sure you do not have other conditions that would prevent you from safely using dutasteride.

Before taking dutasteride, tell your doctor if you have ever had an allergic reaction to this medication, or to a similar medicine called finasteride (Propecia, Proscar).

Dutasteride should never be taken by a woman or a child. Dutasteride can be absorbed through the skin, and women or children should not be permitted to handle dutasteride capsules.

Although dutasteride is not for use by women, this medication can cause birth defects if a woman is exposed to it during pregnancy. Dutasteride capsules should not be handled by a woman who is pregnant or who may become pregnant.

If a woman accidentally comes into contact with this medication from a leaking capsule, wash the area with soap and water right away.

Clinical Trials 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 with rates in the clinical trial of another drug and may not reflect the rates observed in practice.

From clinical trials with AVODART as monotherapy or in combination with tamsulosin:

• The most common adverse reactions reported in subjects receiving AVODART were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), and ejaculation disorders. The most common adverse reactions reported in subjects receiving combination therapy (AVODART plus tamsulosin) were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders, and dizziness. Ejaculation disorders occurred significantly more in subjects receiving combination therapy (11%) compared with those receiving AVODART (2%) or tamsulosin (4%) as monotherapy.
• Trial withdrawal due to adverse reactions occurred in 4% of subjects receiving AVODART, and 3% of subjects receiving placebo in placebo-controlled trials with AVODART. The most common adverse reaction leading to trial withdrawal was impotence (1%).
• In the clinical trial evaluating the combination therapy, trial withdrawal due to adverse reactions occurred in 6% of subjects receiving combination therapy (AVODART plus tamsulosin) and 4% of subjects receiving AVODART or tamsulosin as monotherapy. The most common adverse reaction in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%).

Monotherapy

Over 4,300 male subjects with BPH were randomly assigned to receive placebo or 0.5-mg daily doses of AVODART in 3 identical 2-year, placebo-controlled, double-blind, Phase 3 treatment trials, each followed by a 2-year open-label extension. During the double-blind treatment period, 2,167 male subjects were exposed to AVODART, including 1,772 exposed for 1 year and 1,510 exposed for 2 years. When including the open-label extensions, 1,009 male subjects were exposed to AVODART for 3 years and 812 were exposed for 4 years. The population was aged 47 to 94 years (mean age: 66 years) and greater than 90% were white. Table 1 summarizes clinical adverse reactions reported in at least 1% of subjects receiving AVODART and at a higher incidence than subjects receiving placebo.

Table 1. Adverse Reactions Reported in ≥1% of Subjects over a 24-Month Period and More Frequently in the Group Receiving AVODART than the Placebo Group (Randomized, Double- blind, Placebo-controlled Trials Pooled) by Time of Onset

Long-Term Treatment (Up To 4 Years)

The REDUCE trial was a randomized, double-blind, placebo-controlled trial that enrolled 8,231 men aged 50 to 75 years with a serum PSA of 2.5 ng/mL to 10 ng/mL and a negative prostate biopsy within the previous 6 months. Subjects were randomized to receive placebo (n = 4,126) or 0.5-mg daily doses of AVODART (n = 4,105) for up to 4 years. The mean age was 63 years and 91% were white. Subjects underwent protocol-mandated scheduled prostate biopsies at 2 and 4 years of treatment or had “for-cause biopsies” at non-scheduled times if clinically indicated. There was a higher incidence of Gleason score 8-10 prostate cancer in men receiving AVODART (1.0%) compared with men on placebo (0.5%) [see INDICATIONS AND USAGE, WARNINGS AND PRECAUTIONS]. In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR), similar results for Gleason score 8-10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%).

No clinical benefit has been demonstrated in patients with prostate cancer treated with AVODART.

In the 3 pivotal placebo-controlled BPH trials with AVODART, each 4 years in duration, there was no evidence of increased sexual adverse reactions (impotence, decreased libido, and ejaculation disorder) or breast disorders with increased duration of treatment. Among these 3 trials, there was 1 case of breast cancer in the dutasteride group and 1 case in the placebo group. No cases of breast cancer were reported in any treatment group in the 4-year CombAT trial or the 4-year REDUCE trial.

The relationship between long-term use of dutasteride and male breast neoplasia is currently unknown.

Combination With Alpha-Blocker Therapy (CombAT)

Over 4,800 male subjects with BPH were randomly assigned to receive 0.5-mg AVODART, 0.4-mg tamsulosin, or combination therapy (0.5-mg AVODART plus 0.4-mg tamsulosin) administered once daily in a 4-year double-blind trial. Overall, 1,623 subjects received monotherapy with AVODART; 1,611 subjects received monotherapy with tamsulosin; and 1,610 subjects received combination therapy. The population was aged 49 to 88 years (mean age: 66 years) and 88% were white. Table 2 summarizes adverse reactions reported in at least 1% of subjects in the combination group and at a higher incidence than subjects receiving monotherapy with AVODART or tamsulosin.

Table 2. Adverse Reactions Reported over a 48-Month Period in ≥1% of Subjects and More Frequently in the Coadministration Therapy Group than the Groups Receiving Monotherapy with AVODART or Tamsulos in (CombAT) by Time of Onset

In CombAT, after 4 years of treatment, the incidence of the composite term cardiac failure in the combination therapy group (12/1,610; 0.7%) was higher than in either monotherapy group: AVODART, 2/1,623 (0.1%) and tamsulosin, 9/1,611 (0.6%). Composite cardiac failure was also examined in a separate 4-year placebo-controlled trial evaluating AVODART in men at risk for development of prostate cancer. The incidence of cardiac failure in subjects taking AVODART was 0.6% (26/4,105) compared with 0.4% (15/4,126) in subjects on placebo. A majority of subjects with cardiac failure in both trials had comorbidities associated with an increased risk of cardiac failure. Therefore, the clinical significance of the numerical imbalances in cardiac failure is unknown. No causal relationship between AVODART alone or in combination with tamsulosin and cardiac failure has been established. No imbalance was observed in the incidence of overall cardiovascular adverse events in either trial.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of AVODART. Because these 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. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to AVODART.

Hypersensitivity reactions, including rash, pruritus, urticaria, localized edema, serious skin reactions, and angioedema.

Male breast cancer.

Depressed mood.

Testicular pain and testicular swelling.

Read the entire FDA prescribing information for Avodart (Dutasteride)

Avodart should never be taken by a woman or a child. Dutasteride can be absorbed through the skin, and women or children should not be permitted to handle the capsules. Although Avodart is not for use by women, this medication can cause birth defects if a woman is exposed to it during pregnancy. Avodart capsules should not be handled by a woman who is pregnant or who may become pregnant.

Do not chew, crush, or open a Avodart capsule. Swallow the capsule whole. Dutasteride can irritate your lips, mouth, or throat if the capsule has been broken or opened before you swallow it. If a woman accidentally comes into contact with this medication from a leaking capsule, wash the area with soap and water right away.

Before taking Avodart, tell your doctor if you have ever had an allergic reaction to dutasteride, or to a similar medicine called finasteride (Propecia, Proscar). Using Avodart may increase your risk of developing prostate cancer. Your doctor will perform tests to make sure you do not have other conditions that would prevent you from safely using Avodart.

Do not donate blood while taking Avodart and for at least 6 months after your treatment ends. Avodart can be carried in the blood and could cause birth defects if a pregnant women receives a transfusion with blood that contains dutasteride.

Applies to dutasteride: oral capsule

Other

Common (1% to 10%): Impotence, decreased libido, ejaculation disorders, breast disorders
Postmarketing reports: Testicular pain and swelling[Ref]

-Impotence, decreased libido, and ejaculation disorders may persist after treatment discontinuation; this drug's role in this persistence is unknown.
-Ejaculation disorders included anorgasmia, retrograde ejaculation, decreased semen volume, decreased orgasmic sensation, abnormal orgasm, delayed ejaculation, ejaculation failure, and premature ejaculation.
-Breast disorders include breast enlargement, gynecomastia, breast swelling, breast pain, breast tenderness, nipple pain, and nipple swelling.[Ref]

Oncologic

Common (1% to 10%): High-grade prostate cancer
Frequency not reported: Male breast cancer[Ref]

Cardiovascular

Uncommon (0.1% to 1%): Cardiac failure[Ref]

Dermatologic

Uncommon (0.1% to 1%): Alopecia (primarily body hair loss), hypertrichosis[Ref]

Nervous system

Uncommon (0.1% to 1%): Dizziness, nervous system disorders[Ref]

Hypersensitivity

Postmarketing reports: Hypersensitivity reactions (e.g., rash, pruritus, urticaria, localized edema, serious skin reactions, angioedema)[Ref]

Psychiatric

Postmarketing reports: Depressed mood[Ref]

Some side effects of Avodart may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.