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Avodart - Treatment for Benign Prostatic Hyperplasia (BPH)

Avodart - Treatment for Benign Prostatic Hyperplasia (BPH)

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Quick Overview

Avodart (Dutasteride) is a treatment for Prostate Enlargement, a condition that is medically known as Benign Prostatic Hyperplasia, or BPH.


Avodart is also a very effective treatment for Male Pattern Hair Loss.

Product Description

Avodart (Dutasteride) reduces the 2 enzymes responsible for the conversion of testosterone to DHT - which is a primary concern in hair loss.


Where Propecia (Finasteride) only blocks one enzyme, by blocking both Avodart's result could be better. Because of being not approved by the FDA, Avodart officially isn't a hair loss medication.

Additional Information

Manufacturer GlaxoSmithKline
Manufacturer-URL www.avodart.com
Active ingredient Dutasteride

Prescribing Information

AVODART (DUTASTERIDE) TABLETS

DESCRIPTION

Avodart (dutasteride) is a synthetic 4-azasteroid compound that is a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5α-reductase (5AR), an intracellular enzyme that converts testosterone to 5α-dihydrotestosterone (DHT).

Dutasteride is chemically designated as (5α,17β)-N-{2,5 bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide. The empirical formula of dutasteride is C27H30F6N2O2, representing a molecular weight of 528.5 with the following structural formula:

Dutasteride is a white to pale yellow powder with a melting point of 242° to 250°C. It is soluble in ethanol (44 mg/mL), methanol (64 mg/mL), and polyethylene glycol 400 (3 mg/mL), but it is insoluble in water.

Avodart Soft Gelatin Capsules for oral administration contain 0.5 mg of the active ingredient dutasteride in yellow capsules with red print. Each capsule contains 0.5 mg of dutasteride dissolved in a mixture of mono-di-glycerides of caprylic/capric acid and butylated hydroxytoluene. The inactive excipients in the capsule shell are gelatin (from certified BSE-free bovine sources), glycerin, and ferric oxide (yellow). The soft gelatin capsules are printed with edible red ink.

Avodart - Clinical Pharmacology

Pharmacodynamics

Mechanism of Action
Dutasteride inhibits the conversion of testosterone to 5α-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 5α-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 5α-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.

Effect on 5α-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 benign prostatic hyperplasia (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 5α-reductase deficiency also have decreased DHT levels. These 5α-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 5α-reductase deficiency have been observed in these individuals.

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 (DEXA) 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 ACTH stimulation were observed in a subset population (n = 13) of the 1-year healthy volunteer study.

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 study 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 5AR. 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.

Special 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 study, 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 studies, 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 not indicated for use in women (see WARNINGS and PRECAUTIONS). 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 (see PRECAUTIONS: Use in Hepatic Impairment).

Drug Interactions
In vitro drug metabolism studies reveal that dutasteride is metabolized by the human cytochrome P450 isoenzymes CYP3A4 and CYP3A5. In a human mass balance analysis (n = 8), dutasteride was extensively metabolized. Less than 20% of the dose was excreted unchanged in the feces. No clinical drug interaction studies have been performed to evaluate the impact of CYP3A enzyme inhibitors on dutasteride pharmacokinetics. However, based on the 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 is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.

Clinical drug interaction studies have shown no pharmacokinetic or pharmacodynamic interactions between dutasteride and tamsulosin, terazosin, warfarin, digoxin, and cholestyramine (see PRECAUTIONS: Drug Interactions).

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.

Patient Information

AVODART* is for use by men only.

Why is Avodart prescribed?

Avodart is used to treat prostate enlargement, a condition that is medically known as benign prostatic hyperplasia, or BPH.

The prostate is a chestnut-shaped gland that is part of the male reproductive system. It produces a liquid that forms part of the semen. This gland completely encloses the upper part of the urethra, the tube through which urine flows out of the bladder. Many men over age 50 suffer from a benign (noncancerous) enlargement of the prostate. The enlarged gland squeezes the urethra, obstructing the normal flow of urine. Resulting problems may include difficulty in starting urination, weak flow of urine, and the need to urinate urgently or more frequently. Sometimes surgical removal of the prostate is necessary.

By shrinking the enlarged prostate, Avodart may alleviate the various urinary symptoms, making surgery unnecessary. You will need to see your doctor for periodic examinations to assess your response to treatment. It may take several months before you notice an improvement in symptoms.

Most important fact about Avodart

Avodart can be absorbed through the skin. Because the drug could affect a developing baby, pregnant women, women who may become pregnant, and breastfeeding women should strictly avoid skin contact with the drug.

How should you take Avodart?

Take 1 capsule once a day. The capsule should be swallowed whole and can be taken with or without meals.

If you miss a dose...
If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the one you missed and go back to your regular schedule. Do not take 2 doses at once.

Storage instructions...
Store at room temperature.

What side effects may occur?

Side effects cannot be anticipated. If any develop or change in intensity, inform your doctor as soon as possible. Only your doctor can determine if it is safe for you to continue taking Avodart.

More common side effects may include:
Breast tenderness, decreased sex drive, ejaculation problems, enlarged breasts in males, impotence

Why should Avodart not be prescribed?

You should not take Avodart if you have ever had an allergic reaction to it or to similar drugs such as finasteride (Proscar).

Women and children should not use Avodart.

Special warnings about Avodart

If a pregnant or breastfeeding woman is exposed to Avodart, the drug may harm the developing baby (see "Special information if you are pregnant or breastfeeding").

You should not donate blood while taking Avodart or for 6 months after stopping treatment to avoid exposing pregnant or breastfeeding women to blood that contains the drug.

Possible food and drug interactions when taking Avodart

If Avodart is taken with certain other drugs, the effects of either could be increased, decreased, or altered. Check with your doctor before combining Avodart with other medication.

Use Avodart cautiously if you're taking HIV drugs such as ritonavir (Norvir), since there is a theoretical chance of an interaction.

Special information if you are pregnant or breastfeeding

Because Avodart can be absorbed through the skin, pregnant women, women who may become pregnant, and breastfeeding women should strictly avoid skin contact with the drug. If Avodart is accidentally absorbed by a pregnant woman who is carrying a male fetus, the drug could cause abnormal development of the baby's genital organs. Because it's not known if Avodart appears in breast milk, breastfeeding women must also avoid handling the drug.

Recommended dosage

ADULT MEN

Take one 0.5-milligram capsule once a day. The capsule should be swallowed whole.

Avodart has not been evaluated for use in children under 18.

Overdosage

Any medication taken in excess can have serious consequences. If you suspect an overdose, seek medical attention immediately.

 

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