Dutasteride/Silodosin

Monotherapy

Dutasteride® (dutasteride) soft gelatin capsules are indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:

Combination with Alpha-adrenergic Antagonist

Dutasteride in combination with the alpha-adrenergic antagonist, tamsulosin, is indicated for the treatment of symptomatic BPH in men with an enlarged prostate.

Limitations of Use

Dutasteride is not approved for the prevention of prostate cancer.

Silodosin capsules, a selective alpha-1 adrenergic receptor antagonist, are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Silodosin capsules are not indicated for the treatment of hypertension.

Note: Women of childbearing potential should not use or handle dutasteride capsules. Dutasteride can cause birth defects in male fetuses.

Dutasteride is used alone or in combination with tamsulosin (Flomax®) to treat men who have symptoms of an enlarged prostate gland, which is also known as benign prostatic hyperplasia (BPH). Benign enlargement of the prostate is a problem that can occur in men as they get older. The prostate gland is located below the bladder. As the prostate gland enlarges, certain muscles in the gland may become tight and get in the way of the tube that drains urine from the bladder. This can cause problems with urinating, such as a need to urinate often, a weak stream when urinating, or a feeling of not being able to empty the bladder completely.

Dutasteride blocks the action of an enzyme called 5-alpha-reductase. This enzyme changes testosterone to another hormone that causes the prostate to grow. As a result, the size of the prostate is decreased. The effect of dutasteride lasts only as long as the medicine is taken. If it is stopped, the prostate begins to grow again.

dutasteride is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, dutasteride is used in certain patients with the following medical conditions:

• Male pattern alopecia.

Silodosin is used to treat men who have symptoms of an enlarged prostate gland, which is also known as benign enlargement of the prostate (benign prostatic hyperplasia or BPH). Benign enlargement of the prostate is a problem that can occur in men as they get older. The prostate gland is located below the bladder. As the prostate gland gets larger, certain muscles in the gland may become tight and get in the way of the tube that drains urine from the bladder. This can cause problems in urinating, such as a need to urinate often, a weak stream when urinating, or a feeling of not being able to empty the bladder completely.

Silodosin helps relax the muscles in the prostate and in the opening to the bladder. This may help increase the flow of urine or decrease the symptoms.

Silodosin should not be given to women.

silodosin is available only with your doctor's prescription.

The recommended dose of Dutasteride (dutasteride) is 1 capsule (0.5 mg) taken orally once a day. The capsules should be swallowed

whole. Dutasteride (dutasteride) may be administered with or without food.

No dosage adjustment is necessary for subjects with renal impairment or for the elderly. Due to the absence of data in patients with hepatic impairment, no dosage recommendation can be made.

How supplied

Dutasteride (dutasteride) Soft Gelatin Capsules 0.5 mg are oblong, opaque, dull yellow, gelatin capsules imprinted with "GX CE2" in red ink on one side packaged in bottles of 100 (NDC 0173-0712-00) with child-resistant closures and unit dose blister packs of 70 capsules (NDC 0173-0712-01).

Storage and Handling: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

Dutasteride is absorbed through the skin. Dutasteride (dutasteride) Soft Gelatin capsules should not be handled by women who are pregnant or who may become pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus.

Manufactured by:

RP Scherer Beinheim, France for

GlaxoSmithKline

GlaxoSmithKline

Research Triangle Park, NC 27709

©2001,GlaxoSmithKline All rights reserved.

(Updated Sep 05, 2003)

Dosing Information

The recommended dose is 8 mg orally once daily with a meal.

Patients who have difficulty swallowing pills and capsules may carefully open the Silodosin capsule and sprinkle the powder inside on a tablespoonful of applesauce. The applesauce should be swallowed immediately (within 5 minutes) without chewing and followed with an 8 oz glass of cool water to ensure complete swallowing of the powder. The applesauce used should not be hot, and it should be soft enough to be swallowed without chewing. Any powder/applesauce mixture should be used immediately (within 5 minutes) and not stored for future use. Subdividing the contents of a Silodosin capsule is not recommended [seeClinical Pharmacology (12.3)].

Dosage Adjustment in Special Populations

Renal impairment: Silodosin capsules are contraindicated in patients with severe renal impairment (CCr < 30 mL/min). In patients with moderate renal impairment (CCr 30 mL/min to 50 mL/min), the dose should be reduced to 4 mg once daily taken with a meal. No dosage adjustment is needed in patients with mild renal impairment (CCr 50 mL/min to 80 mL/min).

Hepatic impairment: Silodosin capsules have not been studied in patients with severe hepatic impairment (Child-Pugh score ≥ 10) and is therefore contraindicated in these patients. No dosage adjustment is needed in patients with mild or moderate hepatic impairment.

See also:
What is the most important information I should know about Dutasteride?

Hypersensitivity to dutasteride, other 5α-reductase inhibitors or any component of Dutasteride; severe hepatic impairment.

Impairment of Fertility: The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal volunteers aged 18-52 years (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 reduction 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 >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.

Use in pregnancy: Dutasteride is contraindicated for use in women. Dutasteride has not been studied in women because preclinical data suggests that the suppression of circulating levels of DHT may inhibit the development of the external genital organs in a male foetus carried by a woman exposed to dutasteride.

Use in lactation: It is not known whether dutasteride is excreted in breast milk.

Use in children: Dutasteride is contraindicated for use in children and adolecent.

See also:
What is the most important information I should know about Silodosin?

You should not take silodosin if you have severe kidney or liver disease, or if you are also using ketoconazole (Extina, Ketozole, Nizoral, Xolegal), itraconazole (Sporanox), or ritonavir (Norvir).

Do not take silodosin with other similar medicines such as alfuzosin (Uroxatral), doxazosin (Cardura), prazosin (Minipress), tamsulosin (Flomax), or terazosin (Hytrin).

Silodosin may cause dizziness or fainting, especially when you first start taking it. Be careful if you drive or do anything that requires you to be alert. Avoid standing for long periods of time or becoming overheated during exercise and in hot weather. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy.

Silodosin can affect your pupils during cataract surgery. Tell your eye surgeon ahead of time that you are using this medication. Do not stop using silodosin before surgery unless your surgeon tells you to.

There are many other drugs that can interact with silodosin. Tell your doctor about all medications you use.

Use dutasteride as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with dutasteride. Talk to your pharmacist if you have questions about this information.
• Take dutasteride by mouth with or without food.
• Swallow dutasteride whole. Do not break, crush, chew, or open before swallowing. Do not take capsules that are cracked, deformed, discolored, or leaking. Dutasteride can irritate your lips, mouth, and throat.
• Take dutasteride on a regular schedule to get the most benefit from it. Taking dutasteride at the same time each day will help you remember to take it.
• Continue to take dutasteride even if you feel well. Do not miss any doses.
• If you miss a dose of dutasteride, take it as soon as possible if you remember the same day. Skip the missed dose if you do not remember until the next day. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use dutasteride.

Use silodosin as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take silodosin by mouth with a meal.
• Swallow silodosin whole. Do not break, crush, or chew before swallowing. If you cannot swallow the capsule whole, you may open it and sprinkle the contents over a spoonful of applesauce. Mix the medicine with the applesauce and swallow the mixture right away, followed by a glass of water. Do not crush or chew the medicine before swallowing. Do not store the mixture for future use.
• If you miss a dose of silodosin, take 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 take 2 doses at once.

Ask your health care provider any questions you may have about how to use silodosin.

Use: Labeled Indications

Benign prostatic hyperplasia: Treatment of symptomatic benign prostatic hyperplasia (BPH) as monotherapy (to improve symptoms, reduce the risk of acute urinary retention, and to reduce the risk of need for BPH-related surgery) or combination therapy with tamsulosin

Limitations of use: Not approved for the prevention of prostate cancer.

Off Label Uses

Male pattern baldness

Two randomized, placebo-controlled trials demonstrated efficacy of dutasteride in increased hair growth compared to placebo, with the most common side effect reported was decreased libido or sexual dysfunction. Additional trials may be necessary to further define the role of dutasteride in the treatment of this condition.

Silodosin is used by men to treat the symptoms of an enlarged prostate (benign prostatic hyperplasia-BPH). It does not shrink the prostate, but it works by relaxing the muscles in the prostate and the bladder. This helps to relieve symptoms of BPH such as difficulty in beginning the flow of urine, weak stream, and the need to urinate often or urgently (including during the middle of the night).

Silodosin belongs to a class of drugs known as alpha blockers.

Do not use this medication to treat high blood pressure.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

Silodosin may also be used to help your body "pass," or get rid of, kidney stones through urination.

How to use Silodosin

Take this medication by mouth as directed by your doctor, usually once daily with a meal.

If you have difficulty swallowing this medication whole, you may sprinkle the entire contents of a capsule on a small amount (such as a tablespoon) of cool soft applesauce just before taking. Swallow the mixture right away (within 5 minutes). Do not chew the mixture, and do not save it for future use. Do not use hot applesauce. Drink a glass of cool water after each dose.

Silodosin may cause a sudden drop in your blood pressure, which could lead to dizziness or fainting. This risk is higher when you first start taking this drug, after your doctor increases your dose, or if you restart treatment after you stop taking it. During these times, avoid situations where you may be injured if you faint.

To avoid injury from dizziness or fainting, your doctor may tell you to take your first dose of silodosin with food at bedtime so that your body can get used to its effects.

The dosage is based on your medical condition and response to treatment.

Take this medication regularly to get the most benefit from it. To help you remember, take it with the same meal each day.

Tell your doctor if your condition does not improve or if it worsens.

See also:
What other drugs will affect Dutasteride?

For information on the decrease of serum PSA levels during treatment with dutasteride and guidance concerning prostate cancer detection, see Precautions.

Effects of Other Drugs on the Pharmacokinetics of Dutasteride: Concomitant Administration with CYP3A4 and/or P-Glycoprotein Inhibitors: Dutasteride is mainly eliminated via metabolism. In vitro studies indicate that this metabolism is catalysed by CYP3A4 and CYP3A5. No formal interaction studies have been performed with potent CYP3A4 inhibitors. However, in a population pharmacokinetic study, dutasteride serum concentrations were on average 1.6-1.8 times greater, respectively, in a small number of patients treated concurrently with verapamil or diltiazem (moderate inhibitors of CYP3A4 and inhibitors of P-glycoprotein) than in other patients.

Long-term combination of dutasteride with drugs that are potent inhibitors of the enzyme CYP3A4 (eg, ritonavir, indinavir, nefazodone, itraconazole, ketoconazole administered orally) may increase serum concentrations of dutasteride. Further inhibition of 5α-reductase at increased dutasteride exposure, is not likely. However, a reduction of the dutasteride dosing frequency can be considered if side effects are noted. It should be noted that in the case of enzyme inhibition, the long t_½ may be further prolonged and it can take >6 months of concurrent therapy before a new steady state is reached.

Administration of cholestyramine 12 g 1 hr before a 5-mg single dose of dutasteride did not affect the pharmacokinetics of dutasteride.

Effects of Dutasteride on the Pharmacokinetics of Other Drugs: Dutasteride has no effect on the pharmacokinetics of warfarin or digoxin. This indicates that dutasteride does not inhibit/induce CYP2C9 or the transporter P-glycoprotein. In vitro interaction studies indicate that dutasteride does not inhibit the enzymes CYP1A2, CYP2D6, CYP2C9, CYP2C19 or CYP3A4.

In a small study (N=24) of 2 weeks duration in healthy men, no pharmacokinetic or pharmacodynamic interaction was observed between dutasteride and tamsulosin or terazosin.

There was no evidence of an interaction when dutasteride was co-administered with tamsulosin in a clinical trial of 327 patients for up to 9 months.

Incompatibilities: Not applicable.

See also:
What other drugs will affect Silodosin?

Moderate and Strong CYP3A4 Inhibitors

In a clinical metabolic inhibition study, a 3.8-fold increase in silodosin maximum plasma concentrations and 3.2-fold increase in silodosin exposure were observed with concurrent administration of a strong CYP3A4 inhibitor, 400 mg ketoconazole. Use of strong CYP3A4 inhibitors such as itraconazole or ritonavir may cause plasma concentrations of silodosin to increase. Concomitant administration of strong CYP3A4 inhibitors and Silodosin is contraindicated.

The effect of moderate CYP3A4 inhibitors on the pharmacokinetics of silodosin has not been evaluated. Concomitant administration with moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil) may increase concentration of Silodosin. Exercise caution and monitor patients for adverse events when co-administering Silodosin with moderate CYP3A4 inhibitors.

Strong P-glycoprotein (P-gp) Inhibitors

In vitro studies indicated that silodosin is a P-gp substrate. Ketoconazole, a CYP3A4 inhibitor that also inhibits P-gp, caused significant increase in exposure to silodosin. Inhibition of P-gp may lead to increased silodosin concentration. Silodosin is therefore not recommended in patients taking strong P-gp inhibitors such as cyclosporine.

Alpha-Blockers

The pharmacodynamic interactions between silodosin and other alpha-blockers have not been determined. However, interactions may be expected, and Silodosin should not be used in combination with other alpha-blockers.

Digoxin

The effect of co-administration of Silodosin and digoxin 0.25 mg/day for 7 days was evaluated in a clinical trial in 16 healthy males, aged 18 to 45 years. Concomitant administration of Silodosin and digoxin did not significantly alter the steady state pharmacokinetics of digoxin. No dose adjustment is required.

PDE5 Inhibitors

Co-administration of Silodosin with a single dose of 100 mg sildenafil or 20 mg tadalafil was evaluated in a placebo-controlled clinical study that included 24 healthy male subjects, 45 to 78 years of age. Orthostatic vital signs were monitored in the 12-hour period following concomitant dosing. During this period, the total number of positive orthostatic test results was greater in the group receiving Silodosin plus a PDE5 inhibitor compared with Silodosin alone. No events of symptomatic orthostasis or dizziness were reported in subjects receiving Silodosin with a PDE5 inhibitor.

Other Concomitant Drug Therapy

Antihypertensives

The pharmacodynamic interactions between silodosin and antihypertensives have not been rigorously investigated in a clinical study. However, approximately one-third of the patients in clinical studies used concomitant antihypertensive medications with Silodosin. The incidence of dizziness and orthostatic hypotension in these patients was higher than in the general silodosin population (4.6% versus 3.8% and 3.4% versus 3.2%, respectively). Exercise caution during concomitant use with antihypertensives and monitor patients for possible adverse events.

Metabolic Interactions

In vitro data indicate that silodosin does not have the potential to inhibit or induce cytochrome P450 enzyme systems.

Food Interactions

The effect of a moderate fat, moderate calorie meal on silodosin pharmacokinetics was variable and decreased silodosin maximum plasma concentration (Cmax) by approximately 18 - 43% and exposure (AUC) by 4 - 49% across three different studies. Safety and efficacy clinical trials for Silodosin were always conducted in the presence of food intake. Patients should be instructed to take silodosin with a meal to reduce risk of adverse events.

See also:
What are the possible side effects of Dutasteride?

Adverse reactions were generally mild and transient. The most common adverse events leading to withdrawal in both treatment groups were associated with the reproductive system.

The data described below reflect exposure to Dutasteride (dutasteride) in 2166 male subjects, including 1772 exposed for one year. Over 4300 male subjects with BPH were randomly assigned to receive placebo or 0.5-mg daily doses of Dutasteride (dutasteride) in three identical, placebo-controlled Phase in treatment studies. The population was aged 47 to 94 years (mean age 66 years) and greater than 90% Caucasian. A total of 267 subjects (6% of each treatment group) were withdrawn from the studies due to adverse experiences, usually associated with the reproductive system. Withdrawals due to adverse events considered by the investigator to have a reasonable possibility of being caused by the study medication occurred in 3% of the subjects receiving Dutasteride (dutasteride) and in 2% of the subjects receiving placebo. Table 1 summarizes clinical adverse reactions that were reported by the investigator as drug-related in at least 1% of subjects receiving Dutasteride (dutasteride) and at a higher incidence than subjects receiving placebo.

Table 1: Drug-related Adverse Events* Reported in >1% Subjects and More Frequently in the

Dutasteride (dutasteride) Group than the Placebo Group Pivotal Studies Pooled

* A drug-related adverse event is one considered by the investigator to have a reasonable possibility of being caused by the study medication. In assessing causality, investigators were asked to select from one of two options: reasonably related to study medication or unrelated to study medication.

Includes breast tenderness and breast enlargement

Long-Term Treatment: The incidence of sexual adverse events considered by the investigator to have a reasonable possibility of being drug-related decreased with duration of treatment; after the first 6 months of treatment the incidence of onset of impotence, decreased libido, ejaculation disorders or gynecomastia was <1% for subjects receiving either Dutasteride (dutasteride) or placebo.

The adverse event profile for 677 subjects who were maintained on Dutasteride (dutasteride) 0.5 mg/day for 24 months in one pivotal study was consistent with that observed after 12 months of treatment in the three studies combined. The incidence of onset of drug-related events was lower during the second year of treatment compared with the first year of treatment, with the exception of gynecomastia (onset in 1 % during first year and 2% during second year).

See also:
What are the possible side effects of Silodosin?

6.1 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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In U.S. clinical trials, 897 patients with BPH were exposed to 8 mg Silodosin daily. This includes 486 patients exposed for 6 months and 168 patients exposed for 1 year. The population was 44 to 87 years of age, and predominantly Caucasian. Of these patients, 42.8% were 65 years of age or older and 10.7% were 75 years of age or older.

In double-blind, placebo controlled, 12-week clinical trials, 466 patients were administered Silodosin and 457 patients were administered placebo. At least one treatment-emergent adverse reaction was reported by 55.2% of Silodosin treated patients (36.8% for placebo treated). The majority (72.1%) of adverse reactions for the Silodosin treated patients (59.8% for placebo treated) were qualified by the investigator as mild. A total of 6.4% of Silodosin treated patients (2.2% for placebo treated) discontinued therapy due to an adverse reaction (treatment-emergent), the most common reaction being retrograde ejaculation (2.8%) for Silodosin treated patients. Retrograde ejaculation is reversible upon discontinuation of treatment.

Adverse Reactions observed in at least 2% of patients:

The incidence of treatment-emergent adverse reactions listed in the following table were derived from two 12-week, multicenter, double-blind, placebo-controlled clinical studies of Silodosin 8 mg daily in BPH patients. Adverse reactions that occurred in at least 2% of patients treated with Silodosin and more frequently than with placebo are shown in Table 1.

In the two 12-week, placebo-controlled clinical trials, the following adverse events were reported by between 1% and 2% of patients receiving Silodosin and occurred more frequently than with placebo: insomnia, PSA increased, sinusitis, abdominal pain, asthenia, and rhinorrhea. One case of syncope in a patient taking prazosin concomitantly and one case of priapism were reported in the Silodosin treatment group.

In a 9-month open-label safety study of Silodosin, one case of Intraoperative Floppy Iris Syndrome (IFIS) was reported.

6.2 Postmarketing Experience

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

Skin and subcutaneous tissue disorders: toxic skin eruption, purpura, skin rash, pruritus, and urticaria

Hepatobiliary disorders: jaundice, impaired hepatic function associated with increased transaminase values

Immune system disorders: allergic-type reactions, not limited to skin reactions including swollen tongue and pharyngeal edema resulting in serious outcomes

Dutasteride belongs to a class of drugs called 5-alpha-reductase inhibitors, which block the action of the 5-alpha-reductase enzymes that convert testosterone into dihydrotestosterone (DHT). Finasteride also belongs to this group, but while dutasteride inhibits both isoforms of 5-alpha reductase, finasteride inhibits only one. Even so, a clinical study done by GlaxoSmithKline, the EPICS trial, did not find dutasteride to be more effective than finasteride in treating BPH. [Wikipedia]

Silodosin is an α1-adrenoceptor antagonist that is selective for the prostate. Silodosin is for symptomatic treatment of benign prostatic hyperplasia. FDA approved Oct 9, 2008.