Consumer medicine information

APO-Dutasteride

Dutasteride

BRAND INFORMATION

Brand name

APO-Dutasteride Capsules

Active ingredient

Dutasteride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Dutasteride.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about dutasteride. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

The name of your medicine is APO-DUTASTERIDE Soft Capsules. It contains the active ingredient dutasteride.

This medicine belongs to a group of medicines called 5 alpha reductase enzyme inhibitors which are used in men who have a condition known as benign prostatic hyperplasia (BPH).

BPH is a non-cancerous enlargement of the prostate gland which is located at the lower portion of the urinary bladder surrounding the urethra (urine carrying tube). In men with BPH, the prostate gland becomes large enough to squeeze the urine tube running through it. If the urine tube is squeezed it narrows, making it more difficult for you to pass urine normally and you may have some or all of the following symptoms:

  • difficulty in starting to urinate
  • an interrupted, weak urinary stream
  • more frequent urination, especially at night
  • feeling that you need to urinate right away
  • leaking or dribbling
  • a feeling that you cannot empty your bladder completely

As the disease progresses, untreated BPH can lead to an increased risk of complete blockage of urine flow (acute urinary retention) and/or the need for surgery.

Dutasteride may also be taken in combination with another type of medicine called an alpha blocker in order to treat symptoms of an enlarged prostate.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

How it works

Prostate growth is caused by a hormone in the blood called dihydrotestosterone (DHT). Dutasteride lowers DHT production in the body, leading to shrinkage of the enlarged prostate in most men. Just as your prostate became large over a long period of time, reducing the size of your prostate and improving your symptoms may take time.

There is no evidence that this medicine is addictive.

Use in children

This medicine should not be used in children.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You are a woman or child.
  • You are hypersensitive to, or have had an allergic reaction to, dutasteride, other 5 alpha reductase enzyme inhibitors or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You suffer from liver disease and/or other medical conditions. :
  2. You are planning to have surgery or an anaesthetic.
  3. You are currently receiving or are planning to receive dental treatment.
  4. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Women (who are pregnant or may be pregnant) and children must avoid handling punctured or leaking capsules. Wash the affected area immediately with soap and water if there is any contact with the skin.

If dutasteride is absorbed through the skin by a woman who is pregnant with a male baby, it may cause the male baby to be born with abnormalities of the genital organs. Dutasteride has been found in the semen of men taking dutasteride. If your partner is or may be pregnant, you must avoid exposing her to your semen as dutasteride may affect the normal development of a male baby. You must use a condom during sex. You must not donate blood until 6 months after you've stopped taking dutasteride.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

How to take it

Each capsule must be swallowed whole and not chewed or opened. Contact with the contents of the capsule may make your mouth or throat sore.

When to take it

Take this medicine at the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

It does not matter if you take it before, with or after food.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time. Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses.

This may increase the chance of you experiencing side effects.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects. Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking dutasteride or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Tell your doctor if you notice any of the following:

  • impotence (inability to achieve or maintain an erection).
  • decrease in libido (sex drive).
  • difficulty with ejaculation.
  • breast swelling or tenderness.
  • dizziness when taken with an alpha blocker.
  • hair loss (usually from the body) or hair growth
  • depressed mood
  • testicular pain and testicular swelling
  • decrease in sperm count and semen volume.

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to dutasteride, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-DUTASTERIDE Soft Capsules looks like

Dutasteride 500 micrograms: An oily, colourless to pale yellow liquid absent of any visible particles and/or crystals within a pale yellow, oblong gelatin capsule printed with red ink. Logo is "A 0.5".

Ingredients

Each soft capsule contains 500 micrograms of dutasteride as the active ingredient.

It also contains the following inactive ingredients:

  • mono- and di- glycerides
  • butylated hydroxytoluene
  • gelatin
  • glycerol
  • water – purified
  • iron oxide yellow CI77499
  • titanium dioxide
  • OPACODE monogramming ink S-1-15095 Red (PI#12470).

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

APO-Dutasteride 500 micrograms soft capsules (blister pack 30): AUST R 212047.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO is a registered trade mark of Apotex Inc.

This leaflet was last updated in: November 2017

BRAND INFORMATION

Brand name

APO-Dutasteride Capsules

Active ingredient

Dutasteride

Schedule

S4

 

Name of the medicine

Dutasteride.

Excipients.

Glyceryl caprylate/caprate, butylated hydroxytoluene, gelatin, glycerol, iron oxide yellow, titanium dioxide, Opacode monogramming ink S-1-15095 Red (PI#12470).

Description

The chemical name of dutasteride is 4-azaandrost-1-ene-17-carboxamide, N-[2,5-bis(trifluoromethyl)phenyl]-3-oxo-, (5 alpha, 17 beta).
Molecular formula: C27H30F6N2O2. Molecular weight: 528.5. CAS Registry Number: 164656-23-9.
Dutasteride is a white to pale yellow powder. It is insoluble in water, and soluble in organic solvents, dimethyl sulfoxide, acetone, methanol, ethanol and isopranol. Dutasteride has a partition coefficient [in terms of log10P (1-octonol layer/aqueous layer)] of 2.65.
Each soft capsule contains 500 microgram of dutasteride as the active ingredient. In addition, each soft capsule contains the following inactive ingredients: glyceryl caprylate/caprate, butylated hydroxytoluene, gelatin, glycerol, iron oxide yellow, titanium dioxide, Opacode monogramming ink S-1-15095 Red (PI#12470).

Pharmacology

Mode 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 two isoforms, type 1 and type 2. Studies in vitro have shown that dutasteride is a competitive inhibitor of both type 1 and type 2 5α-reductase isoenzymes.

Effects on DHT/testosterone.

The maximum effect of daily doses of dutasteride on the reduction on DHT is dose dependent and is observed within 1-2 weeks. After 1 week and 2 weeks of daily dosing of dutasteride 500 microgram, median serum DHT concentrations were reduced by 85% and 90% respectively.
In BPH patients treated with 500 microgram of dutasteride daily, the median decrease in DHT was 94% at 1 year and 93% at 2 years, and the median increase in serum testosterone was 19% at both 1 and 2 years. This is an expected consequence of 5α-reductase inhibition and did not result in any known adverse events.

Pharmacokinetics.

Absorption.

Dutasteride is administered orally in solution as a soft gelatin capsule. Following administration of a single 500 microgram dose, peak serum concentrations of dutasteride occur within 1-3 hours. Absolute bioavailability in man is approximately 60% relative to a 2 hour intravenous infusion. The bioavailability of dutasteride is not affected by food.

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 proteins (> 99.5%).
Following daily dosing, dutasteride serum concentrations achieve 65% of steady state concentration after 1 month and approximately 90% after 3 months.
Steady state serum concentrations (Css) of approximately 40 nanogram/mL are achieved after 6 months of dosing 500 microgram once a day. Similarly to serum, dutasteride concentrations in semen achieved steady state at 6 months. After 52 weeks of therapy, semen dutasteride concentrations averaged 3.4 nanogram/mL (range 0.4 to 14 nanogram/mL). Dutasteride partitioning from serum into semen averaged 11.5%.

Metabolism.

Dutasteride is extensively metabolised in humans. While not all metabolic pathways have been identified, in vitro studies show that dutasteride is metabolised by the CYP3A4 isoenzyme to 2 minor mono-hydroxylated metabolites. Dutasteride is not metabolised in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 and CYP2D6.
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), have been detected. In vitro, 4'-hydroxydutasteride and 1,2-dihydrodutasteride metabolites are much less potent than dutasteride against both isoforms of human 5α-reductase. The activity of 6β-hydroxydutasteride is comparable to that of dutasteride.

Excretion.

Dutasteride is extensively metabolised. Following oral dosing of dutasteride 500 microgram/day to steady state in humans, 1.0% to 15.4% (mean of 5.4%) of the administered dose is excreted as dutasteride in the faeces. The remainder is excreted in the faeces as 4 major metabolites comprising 39%, 21%, 7%, and 7% each of drug-related material and 6 minor metabolites (less than 5% each). Only trace amounts of unchanged dutasteride (less than 0.1% of the dose) are detected in human urine.
At therapeutic concentrations, the terminal half-life of dutasteride is 3 to 5 weeks. Serum concentrations remain detectable (greater than 0.1 nanogram/mL) for up to 4 to 6 months after discontinuation of treatment.

Linearity/non-linearity.

The elimination of dutasteride 500 microgram appears to occur by two parallel, elimination pathways; one that is saturable at low concentrations and one that is not saturable. At serum levels greater than 3 nanogram/mL, including therapeutic concentrations, the slower, nonsaturable elimination pathway dominates and dutasteride total clearance is linear with a half-life of 3 to 5 weeks.

Elderly.

Dutasteride pharmacokinetics and pharmacodynamics were evaluated in 36 healthy male subjects between the ages of 24 and 87 years following administration of a single 5 mg dose of dutasteride. Exposure to dutasteride, represented by AUC, was calculated to be higher in the middle age (50-69 years of age) and older age group (≥ 70 years of age), compared to subjects 20-49 years of age. This difference was not statistically significant and no differences in drug effect as measured by DHT reduction were observed between age groups. On this basis no dose adjustment based on age is necessary.

Renal impairment.

The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 500 microgram dose of dutasteride is recovered in human urine, so no adjustment in dosage is anticipated for patients with renal impairment.

Hepatic impairment.

The effect on the pharmacokinetics of dutasteride in hepatic impairment has not been studied (see Precautions). The use of dutasteride in patients with severe hepatic impairment is contraindicated.

Clinical Trials

Dutasteride monotherapy.

The efficacy and safety of dutasteride 500 microgram/day in the treatment and prevention of progression of BPH in 4325 males (aged 47 to 94 years with BPH who had enlarged prostates (greater than 30 mL) and a PSA value within the range 1.5-10 nanogram/mL) was demonstrated in three pivotal, randomised, double-blind, placebo-controlled, 2-year multicentre studies (ARIA3001, ARIA3002 and ARIB3003). Of the 4325 males enrolled in the studies, 2167 received dutasteride and 2158 received placebo.
Pooled data from the three pivotal studies show that, in men with BPH, dutasteride reduces the risk of both acute urinary retention (AUR) and the need for surgical intervention (SI). Improvements in BPH related symptoms, increased maximum urinary flow rates, and decreasing prostate volume suggest dutasteride reverses the progression of BPH in men with an enlarged prostate.
Pooled efficacy data from the three pivotal studies is summarised below.

Acute urinary retention (AUR) and surgical intervention.

Relative to placebo dutasteride significantly reduces both the risk and incidence of AUR by 57% (4.2% for placebo versus 1.8% for dutasteride) and the need for BPH-related surgical intervention by 48% (4.1% for placebo versus 2.2% for dutasteride) over 24 months. See Table 1.

Lower urinary tract symptoms (LUTS) assessed by AUA-SI.

Symptoms were quantified using the AUA-SI (American Urological Association Symptom Index), a seven-item questionnaire that evaluates urinary symptoms (incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia) by rating on a 0 to 5 scale with a maximum score of 35. Entry criteria included a screening score of ≥ 12 (moderate to severe symptoms). A reduction in score signifies an improvement in symptoms.
The AUA-SI results at each of the scheduled visits, pooled across the three pivotal studies (ARIA3001, ARIA3002, and ARIB3003), are presented in Figure 1. The baseline AUA-SI score across the three studies was approximately 17 units in both treatment groups. Statistically significant improvements in symptom score in patients treated with dutasteride compared to placebo were noted from Month 6 through to Month 24 (p < 0.001). At Month 24, the mean decrease from baseline in AUA-SI symptom scores was -4.8 units for dutasteride and -2.4 units for placebo.

Maximum urinary flow (Qmax).

The Qmax results at each of the scheduled visits, pooled across the three pivotal studies (ARIA3001, ARIA3002, and ARIB3003), are presented in Figure 2. Baseline Qmax was approximately 10 mL/sec (normal Qmax ≥ 15 mL/sec) in both treatment groups across the three studies. Statistically significant improvement in Qmax in patients treated with dutasteride compared to placebo was noted from Month 1 through to Month 24. At Month 24, treatment urinary flow had improved by 0.8 mL/sec and 2.4 mL/sec in the placebo and dutasteride groups respectively.

Prostate volume.

In patients treated with dutasteride, prostate volume was shown to reduce as early as one month after initiation of treatment and reductions continued through to Month 24 (p < 0.001). Dutasteride led to a mean reduction of prostate volume of 23.6% (from 54.9 mL at baseline to 42.1 mL) at Month 12 compared with a mean reduction of 0.5% (from 54.0 mL to 53.7 mL) in the placebo group. At 24 months, dutasteride decreased prostate volume by 25.7% (from 54.9 mL at baseline to 41.2 mL) compared with an increase of 1.7% (from 54.0 mL to 54.1 mL) in the placebo group.
Pooled safety data from the three pivotal studies show that the adverse reaction profile of dutasteride (500 microgram/day for 24 months) was similar to that of placebo (see Adverse Reactions).

Dutasteride and tamsulosin combination therapy.

Dutasteride 500 microgram/day (n=1,623), tamsulosin 400 microgram/day (n=1,611) or the combination of dutasteride 500 microgram plus tamsulosin 400 microgram (n=1,610) administered once daily [total number of patients = 4844] were evaluated in men with moderate to severe symptoms of BPH who had prostates ≥ 30 mL and a PSA values within the range 1.5-10 nanogram/mL in a multicentre, multinational, randomized double-blind, parallel group study (CombAT). Approximately 52% of subjects had previous exposure to 5α-reductase inhibitor or alpha-blocker treatment.
The primary efficacy endpoint at 2 years of treatment was the level of improvement from baseline in the international prostate symptom score (IPSS).
After 2 years of treatment, combination therapy showed a statistically significant adjusted mean improvement in symptom scores from baseline of -6.2 units. The adjusted mean improvements in symptom scores observed with the individual therapies were -4.9 units for dutasteride and -4.3 units for tamsulosin. The adjusted mean improvement in flow rate from baseline was 2.4 mL/sec for the combination, 1.9 mL/sec for dutasteride and 0.9 mL/sec for tamsulosin. The adjusted mean improvement in BPH Impact Index (BII) from baseline was -2.1 units for the combination, -1.7 for dutasteride and -1.5 for tamsulosin.
The reduction in total prostate volume and transition zone volume after 2 years of treatment was statistically significant for combination therapy compared to tamsulosin monotherapy alone (see Table 2).
The primary efficacy endpoint at 4 years of treatment was time to first event of AUR or BPH-related surgery. The study was powered to show a statistical difference between combination therapy and tamsulosin, but not between combination therapy and dutasteride or between tamsulosin and dutasteride. After 4 years of treatment, combination therapy statistically significantly reduced the risk of AUR or BPH-related surgery (65.8% reduction in risk p < 0.001 [95% CI 54.7% to 74.1%]) compared to tamsulosin monotherapy. The incidence of AUR or BPH-related surgery by Year 4 was 4.2% for combination therapy and 11.9% for tamsulosin (p < 0.001). Compared to dutasteride monotherapy, combination therapy reduced the risk of AUR or BPH-related surgery by 19.6%; the difference between treatment groups was not significant (p=0.18 [95% CI -10.9% to 41.7%]). The incidence of AUR or BPH-related surgery by Year 4 was 4.2% for combination therapy and 5.2% for dutasteride.
Clinical progression was defined as a composite of worsening symptoms (IPSS), and BPH-related events of AUR, incontinence, UTI, and renal insufficiency. Combination therapy was associated with a statistically significantly lower rate of clinical progression compared with tamsulosin (p < 0.001, 44.1% risk reduction [95% CI: 33.6% to 53.0%]) after 4 years. The rates of clinical progression for combination therapy, tamsulosin, and dutasteride were: 12.6%, 21.5%, and 17.8%, respectively.
The statistically significant adjusted mean improvement in symptom scores (IPSS) from baseline was maintained from year 2 to year 4. At 4 years, the adjusted mean improvements in symptom scores observed were -6.3 units for combination therapy, -5.3 units for dutasteride monotherapy and -3.8 units for tamsulosin monotherapy.
After 4 years of treatment, the adjusted mean improvement in flow rate (Qmax) from baseline was 2.4 mL/sec for combination therapy, 2.0 mL/sec for dutasteride monotherapy and 0.7 mL/sec for tamsulosin monotherapy. Compared with tamsulosin, the adjusted mean improvement from baseline in Qmax was statistically significantly greater with combination therapy at each 6-month assessment from Month 6 to Month 48 (p < 0.001). Compared with dutasteride, the adjusted mean improvement from baseline in Qmax was not statistically significantly different than with combination therapy (p=0.050 at Month 48).
Combination therapy was significantly superior (p < 0.001) to tamsulosin monotherapy and to dutasteride monotherapy for the improvement in health outcome parameters BII and BPH-related Health Status (BHS) at 4 years. The adjusted mean improvement in BII from baseline was -2.2 units for the combination, -1.8 units for dutasteride and -1.2 units for tamsulosin. The adjusted mean improvement in BHS from baseline was -1.5 units for the combination, -1.3 units for dutasteride and -1.1 units for tamsulosin.
The reduction in total prostate volume and transition zone volume after 4 years of treatment was statistically significant for combination therapy compared to tamsulosin monotherapy alone (see Table 3).

Cardiac failure.

In a 4 year comparison of dutasteride coadministered with tamsulosin and dutasteride or tamsulosin monotherapy in men with BPH (the CombAT study), the incidence of the composite term cardiac failure in the combination group (14/1610, 0.9%) was higher than in either monotherapy group: dutasteride, 4/1623 (0.2%) and tamsulosin, 10/1611, (0.6%). The relative risk estimate for time to first cardiac failure event was 3.57 [95% CI 1.17, 10.8] for combination treatment compared to dutasteride monotherapy and 1.36 [95% CI 0.61, 3.07] compared to tamsulosin monotherapy. The reason for the observed imbalance is not known. There was no difference between treatment groups in incidence of overall cardiovascular events. No causal relationship between dutasteride (alone or in combination with an alpha blocker) and cardiac failure has been established (see Precautions).
In REDUCE (a 4 year, double-blind, randomised parallel group study comparing dutasteride 500 microgram/day or placebo in men at increased risk of developing prostate cancer), there was a higher incidence of the composite term cardiac failure in subjects taking dutasteride (30/4105, 0.7%) versus placebo (16/4126, 0.4%) for a relative risk estimate for time to first cardiac failure event of 1.91 [95% CI 1.04, 3.50]. In a post-hoc analysis of concomitant alpha blocker use (primarily tamsulosin, alfuzosin, doxazosin and terazosin), there was a higher incidence of the composite term cardiac failure in subjects taking dutasteride and an alpha blocker concomitantly (12/1152, 1.0%), compared to subjects not taking dutasteride and an alpha blocker concomitantly: dutasteride and no alpha blocker (18/2953, 0.6%), placebo and an alpha blocker (1/1399, < 0.1%), placebo and no alpha blocker (15/2727, 0.6%). The reason for the observed imbalance is not known. There was no difference between treatment groups in incidence of overall cardiovascular events. No causal relationship between dutasteride (alone or in combination with an alpha blocker) and cardiac failure has been established (see Precautions).

Prostate cancer and high grade tumours.

In a 4-year comparison of placebo and dutasteride in 8231 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 nanogram/mL and 10.0 nanogram/mL (the REDUCE study), 6,706 subjects had prostate needle biopsy data available for analysis to determine Gleason Scores. There were 1517 subjects diagnosed with prostate cancer in the study. The majority of biopsy-detectable prostate cancers in both treatment groups were diagnosed as low grade (Gleason 5-6). There was no difference in the incidence of Gleason 7-10 cancers (p=0.81).
There was a higher incidence of Gleason 8-10 prostate cancers in the dutasteride group (n=29, 0.9%) compared to the placebo group (n=19, 0.6%) (p=0.15). In Years 1-2, the number of subjects with Gleason 8-10 cancers was similar in the dutasteride group (n=17, 0.5%) and the placebo group (n=18, 0.5%). In Years 3-4, more Gleason 8-10 cancers were diagnosed in the dutasteride group (n=12, 0.5%) compared with the placebo group (n=1, < 0.1%) (p=0.0035). There are no data available on the effect of dutasteride beyond 4 years in men at risk of prostate cancer. The percentage of subjects diagnosed with Gleason 8-10 cancers was consistent across study time periods (Years 1-2 and Years 3-4) in the dutasteride group (0.5% in each time period), while in the placebo group, the percentage of subjects diagnosed with Gleason 8-10 cancers was lower during Years 3-4 than in Years 1- 2 (< 0.1% versus 0.5%, respectively). In a 4 year BPH study (CombAT) where there were no protocol-mandated biopsies and all diagnoses of prostate cancer were based on for-cause biopsies, the rates of Gleason 8-10 cancer were (n=8, 0.5%) for dutasteride, (n=11, 0.7%) for tamsulosin and (n=5, 0.3%) for combination therapy (see Precautions).

Effects on prostate specific antigen (PSA) and prostate cancer detection.

In a 4-year comparison of placebo and dutasteride in 8231 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 nanogram/mL and 10.0 nanogram/mL (the REDUCE study), dutasteride treatment caused a decrease in mean serum PSA by approximately 50% after six months of treatment with a large variability (standard deviation of 30%) among patients. The PSA suppression observed at six months was similar in men who did or who did not develop biopsy-detectable prostate cancer during the study. (see Precautions).

Breast neoplasia.

In dutasteride BPH monotherapy clinical trials, providing 3374 patient years of exposure to dutasteride, there were 2 cases of breast cancer reported in dutasteride-treated patients, one after 10 weeks and one after 11 months of treatment, and 1 case in a patient who received placebo. In subsequent clinical trials in BPH and 8231 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 nanogram/mL and 10.0 nanogram/mL providing 17489 patient years exposure to dutasteride and 5027 patient years exposure to dutasteride and tamsulosin combination there were no additional cases in any of the treatment groups. The relationship between long-term use of dutasteride and male breast cancer is unknown.

Indications

Dutasteride is indicated for use as monotherapy for the management of symptomatic benign prostatic hyperplasia (BPH) or as combination therapy with an alpha blocker which is approved for use in BPH and which has been dose titrated in accordance with the relevant recommendations in the product information for that alpha blocker.

Contraindications

Dutasteride is contraindicated in:
patients with known hypersensitivity to dutasteride, other 5-alpha-reductase inhibitors, or any component of the preparation;
women and children (see Precautions, Use in pregnancy and Use in lactation);
patients with severe hepatic impairment.

Precautions

Dutasteride is absorbed through the skin, therefore, women and children must avoid contact with leaking capsules. If contact is made with leaking capsules the contact area should be washed immediately with soap and water (see Use in pregnancy and Use in lactation).
The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Dutasteride is extensively metabolised and has a half-life of 3 to 5 weeks, therefore caution should be used in the administration of dutasteride to patients with liver disease (see Dosage and Administration, and Pharmacology, Pharmacokinetics).

Effects on prostate specific antigen (PSA) and prostate cancer detection.

Digital rectal examination, as well as other evaluations for prostate cancer, should be performed on patients with BPH prior to initiating therapy with dutasteride and periodically thereafter.
Serum prostate-specific antigen (PSA) concentration is an important component of the screening process to detect prostate cancer.
Dutasteride causes a decrease in mean serum PSA levels by approximately 50%, after 6 months of treatment.
Patients receiving dutasteride should have a new PSA baseline established after 6 months of treatment with dutasteride. It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from lowest PSA level while on dutasteride may signal the presence of prostate cancer (particularly high grade cancer) or non-compliance to therapy with dutasteride and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5α-reductase inhibitor (see Clinical Trials). In the interpretation of a PSA value for a patient taking dutasteride, previous PSA values should be sought for comparison.
Treatment with dutasteride does not interfere with the use of PSA as a tool to assist in the diagnosis of prostate cancer after a new baseline has been established (see Clinical Trials).
Total serum PSA levels return to baseline within 6 months of discontinuing treatment. The ratio of free to total PSA remains constant even under the influence of dutasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing dutasteride therapy, no adjustment to its value is necessary.

Prostate cancer and high grade tumours.

In a 4-year study of over 8,000 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 nanogram/mL and 10.0 nanogram/mL (the REDUCE study), 1,517 men were diagnosed with prostate cancer. There was a higher incidence of Gleason 8-10 prostate cancers in the dutasteride group (n=29, 0.9%) compared to the placebo group (n=19, 0.6%). There was no increased incidence in Gleason 5-6 or 7-10 prostate cancers. No causal relationship between dutasteride and high grade prostate cancer has been established. The clinical significance of the numerical imbalance is unknown. Men taking dutasteride should be regularly evaluated for prostate cancer risk including PSA testing (see Clinical Trials).

Breast cancer in men.

Breast cancer has been reported in men taking dutasteride in clinical trials (see Clinical Trials) and during the post-marketing period. Prescribers should instruct their patients to promptly report any changes in their breast tissue such as lumps or nipple discharge. It is not clear if there is a causal relationship between the occurrence of male breast cancer and long term use of dutasteride.

Combination use with an alpha blocker and cardiac failure.

Implementation of the combination therapy of dutasteride and an alpha blocker requires consideration of the combined side-effect profiles. Cardiovascular function should be stabilised prior to initiating combination therapy or adding an alpha blocker to dutasteride monotherapy. When initiating less selective alpha blockers such as doxazosin, terazosin and prazosin, careful and measured titration of the dose is required to minimise the risk of alpha blocker-related adverse events such as postural hypotension, dizziness, and syncope. Dose titration is normally not required for the selective alpha blockers such as tamsulosin and alfuzosin. Please see the recommendations in the product information of the relevant alpha blocker for full safety information.
In two 4 year clinical studies, the incidence of cardiac failure (a composite term of reported events, primarily cardiac failure and congestive cardiac failure) was higher among subjects taking the combination of dutasteride and an alpha blocker, (primarily tamsulosin, alfuzosin, doxazosin and terazosin) than it was among subjects not taking the combination. In these two trials, the incidence of cardiac failure was ≤ 1%. The reason for the imbalance of cardiac failure in the two trials is not known. No imbalance was observed in the incidence of cardiovascular adverse events overall in either trial. No causal relationship between dutasteride (alone or in combination with an alpha blocker) and cardiac failure has been established (see Clinical Trials).

Blood donation.

Men being treated with dutasteride 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.

Carcinogenicity.

In a 2-year carcinogenicity study in B6C3F1 mice, at doses up to 500 mg/kg/day for males and 250 mg/kg/day for females, an increased incidence of benign hepatocellular adenomas was noted at 250 mg/kg/day (278-fold the expected clinical exposure to a 0.5 mg daily dose) in females only. Two of the three major human metabolites have been detected in mice. The exposure to these metabolites in mice is either lower than in humans or is not known.
In a 2-year carcinogenicity study in Han Wistar rats, at doses up to 53 mg/kg/day for males and 15 mg/kg/day for females, there was an increase in Leydig cell adenomas in the testes at doses of 53 mg/kg/day (160-fold the expected clinical exposure). An increased incidence of Leydig cell hyperplasia was present at doses of 7.5 mg/kg/day (79-fold the expected clinical exposure) and above in male rats. A positive correlation between proliferative changes in the Leydig cells and an increase in circulating luteinizing hormone levels has been demonstrated with 5α-reductase inhibitors and is consistent with an effect on the hypothalamic-pituitary-testicular axis following 5α-reductase inhibition. At tumourigenic doses in rats, luteinising hormone levels in rats were increased by 167%. In this study, there may have been limited exposure to the major human metabolites.

Genotoxicity.

Dutasteride was not genotoxic in assays for gene mutations (in vitro tests for bacterial gene mutation) and chromosomal damage (chromosomal aberration in CHO cells in vitro and a micronucleus test in rats). Two of the major human metabolites were also negative in bacterial gene mutation assays.

Effects on fertility.

The effects of dutasteride 500 microgram/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 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%), two 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.
Treatment of sexually mature male rats with dutasteride at doses up to 500 mg/kg/day (110-fold the expected clinical exposure of parent drug) for up to 31 weeks resulted in dose- and time-dependent decreases in fertility, reduced cauda epididymal (absolute) sperm counts (at 50 and 500 mg/kg/day), reduced weights of the epididymis, prostate and seminal vesicles, and microscopic changes in the male reproductive organs. The fertility effects were reversed by recovery week 6 at all doses and sperm counts were normal at the end of a 14-week recovery period. The 5α-reductase-related changes consisted of cytoplasmic vacuolation of tubular epithelium in the epididymides and decreased cytoplasmic content of epithelium, consistent with decreased secretory activity in the prostate and seminal vesicles. The microscopic changes were no longer present at recovery week 14 in the low dose group and were partly recovered in the remaining treatment groups. Low levels of dutasteride were detected in the serum of untreated female rats mated to males dosed at 10 mg/kg/day and above for 29 weeks.
In rats and dogs, repeated oral administration of dutasteride resulted in some animals showing signs of non-specific, reversible, centrally mediated toxicity, without associated changes at exposures 207 and 314 fold the expected clinical exposure of the dutasteride, respectively.

Use in pregnancy.

(Category X)
Dutasteride is contraindicated for use in women. Dutasteride has not been studied in women because pre-clinical data suggests that the suppression of circulating levels of dihydrotestosterone may inhibit the development of the external genital organs in a male foetus carried by a woman exposed to dutasteride.
In an intravenous embryo-foetal development study in the rhesus monkey, administration of dutasteride at doses up to 2010 nanogram/day on gestation days 20 to 100 did not adversely affect development of male external genitalia. Reduction of foetal adrenal weights, reduction of foetal prostate weights, and increases in foetal ovarian and testes weights were observed in monkeys treated with the highest doses. Based on the highest measured semen concentration of dutasteride in treated men (14 nanogram/mL), these doses are approximately 16 times (based on blood levels of parent drug; 186-fold based on daily dose in nanogram/kg of body weight) the potential maximum exposure of a human female to 5 mL semen daily from a dutasteride treated man, assuming 100% absorption. Dutasteride is highly bound to proteins in human semen (> 96%), potentially reducing the amount of dutasteride available for vaginal absorption.
In an embryo-foetal development study In female rats, oral administration of dutasteride at doses up to 30 mg/kg/day resulted in feminisation of male foetuses (decreased anogenital distance) and male offspring (nipple development, hypospadias, and distended preputial glands) at all doses (0.09- to 143-fold) the expected male clinical exposure). An increase in stillborn pups was observed at 30 mg/kg/day, and reduced foetal body weight was observed at doses ≥ 2.5 mg/kg/day (18- to 143-fold) the expected clinical exposure). Increased incidences of skeletal variations considered to be delays in ossification associated with reduced body weight were observed at doses of 12.5 and 30 mg/kg/day (70- to 143-fold the expected clinical exposure).
In an oral pre- and post-natal development study in rats, dutasteride doses up to 30 mg/kg/day were administered. Feminisation of the genitalia (i.e. decreased anogenital distance, increased incidence of hypospadias, nipple development) of F1 generation male offspring occurred at doses ≥ 2.5 mg/kg/day (15- to 109-fold the expected clinical exposure in men). At a daily dose of 0.05 mg/kg/day (0.06-fold the expected clinical exposure), evidence of feminisation was limited to a small, but statistically significant, decrease in anogenital distance. Doses of 2.5 to 30 mg/kg/day resulted in prolonged gestation in the parental females and a decrease in time to vaginal patency for female offspring and decreased prostate and seminal vesicle weights in male offspring. Effects on newborn startle response were noted at doses greater than or equal to 12.5 mg/kg/day. Increased stillbirths were noted at 30 mg/kg/day. Feminisation of male foetuses is an expected physiological consequence of inhibition of the conversion of testosterone to DHT by 5α-reductase deficiency.
In the rabbit, embryo-foetal study doses up to 200 mg/kg/day (31- to 95-fold the expected clinical exposure in men) were administered orally on days 7 to 29 of pregnancy to encompass the late period of external genitalia development. Histological evaluation of the genital papilla of foetuses revealed evidence of feminisation of the male foetus at all doses. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites.

Warnings.

Exposure of women, risk to male foetus.

Dutasteride is absorbed through the skin. Therefore, women who are pregnant or may be pregnant should not handle dutasteride soft gelatin capsules because of the possibility of absorption of dutasteride and the potential risk of a foetal anomaly to a male foetus (see Contraindications). As with other 5α-reductase inhibitors, dutasteride inhibits the conversion of testosterone to dihydrotestosterone and may, if administered to a woman carrying a male foetus, inhibit the development of the external genitalia of the foetus. Small amounts of dutasteride have been recovered from the semen in subjects receiving dutasteride 500 microgram day. Based on studies in animals, it is unlikely that a male foetus will be adversely affected if his mother is exposed to the semen of a patient being treated with dutasteride (the risk of which is greatest during the first 16 weeks of pregnancy). However, as with all 5α-reductase inhibitors, when the patient's partner is or may potentially be pregnant it is recommended that the patient avoids exposure of his partner to semen by use of a condom.

Use in lactation.

Dutasteride is contraindicated for use in women. It is not known if dutasteride is excreted in animal or human milk.

Use in children.

The use of dutasteride is contraindicated in children. Dutasteride has not been studied in children.

Effects on ability to drive and use machines.

Based on the pharmacokinetic and pharmacodynamic properties of dutasteride, treatment with dutasteride would not be expected to interfere with the ability to drive or operate machinery.

Interactions

No drug interactions of clinical significance have been identified.
In vitro drug metabolism studies show that dutasteride is metabolised by human cytochrome P450 isoenzyme CYP3A4. Therefore blood concentrations of dutasteride may increase in the presence of inhibitors of CYP3A4.
Phase II data showed a decrease in clearance of dutasteride when co-administered with the CYP3A4 inhibitors verapamil (37%) and diltiazem (44%). In contrast no decrease in clearance was seen when amlodipine, another calcium channel antagonist, was coadministered with dutasteride.
A decrease in clearance and subsequent increase in exposure to dutasteride, in the presence of CYP3A4 inhibitors, is unlikely to be clinically significant due to the wide margin of safety (up to 10 times the recommended dose has been given to patients for up to six months), therefore no dose adjustment is necessary.
In vitro, dutasteride is not metabolised by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 and CYP2D6.
Dutasteride neither inhibits the in vitro metabolism of model substrates for the major human cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), nor induces cytochrome P450 isoenzymes CYP1A, CYP2B, and CYP3A in rats and dogs in vivo.
In vitro studies demonstrate that dutasteride does not displace warfarin, acenocoumorol, phenprocoumon, diazepam, or phenytoin from plasma protein nor do these model compounds displace dutasteride. Compounds that have been tested for drug interactions in man include tamsulosin, terazosin, warfarin, digoxin, and cholestyramine, and no clinically significant pharmacokinetic or pharmacodynamic interactions have been observed.
Although specific interaction studies were not performed with other compounds, approximately 90% of the subjects in large Phase III studies receiving dutasteride were taking other medications concomitantly. No clinically significant adverse interactions were observed in clinical trials when dutasteride was co-administered with anti-hyperlipidaemics, 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.

Adverse Effects

Dutasteride monotherapy for BPH.

Dutasteride is well tolerated in men with BPH.
The nature and frequency of adverse reactions reported in the pivotal efficacy studies (ARIA3001, ARIA3002 and ARIB3003) were generally similar in patients treated with dutasteride or with placebo. Investigator-judged drug-related adverse events (with incidence more than or equal to 1%) reported more commonly in these studies on dutasteride treatment compared to placebo are presented in Table 4. A higher incidence of reproductive adverse reactions was reported in the dutasteride group, which was an expected class effect of 5α-reductase inhibitors. Overall, fewer adverse reactions were reported during the second year of treatment compared with the first year.

Dutasteride and tamsulosin combination therapy for BPH.

The following investigator-judged drug-related adverse events (with a cumulative incidence of greater than or equal to 1%) have been reported in the CombAT (Combination of Dutasteride and Tamsulosin) Study, a comparison of dutasteride 500 microgram and tamsulosin 400 microgram once daily for four years in combination or as monotherapy (see Table 5).

Post-marketing data.

Adverse drug reactions are listed below by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000) and very rare (< 1/10,000) including isolated reports.
Frequency categories determined from post-marketing data refer to reporting rate rather than true frequency.

Immune system disorders.

Very rare: allergic reaction, including rash, pruritus, urticaria, localised oedema and angioedema.

Psychiatric disorders.

Very rare: depressed mood.

Skin and subcutaneous tissue disorders.

Rare: alopecia (primarily body hair loss), hypertrichosis.

Reproductive system and breast disorders.

Very rare: testicular pain and testicular swelling.

Dosage and Administration

Dutasteride can be administered alone or in combination with an alpha blocker.

Adult males (including elderly).

The recommended dose is one 500 microgram capsule daily. The capsules should be swallowed whole and not chewed or opened, as contact with the capsule contents may result in irritation of the oropharyngeal mucosa. Dutasteride may be taken with or without food.
Although early improvements in symptoms may be seen in some patients, treatment for at least 6 months is generally necessary to assess whether a beneficial response in symptom relief has been achieved.

Dosage in renal impairment.

The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, no adjustment in dosage is anticipated for patients with renal impairment (see Pharmacology, Pharmacokinetics).

Dosage in hepatic impairment.

The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied (see Precautions, and Pharmacology, Pharmacokinetics). The use of dutasteride in patients with severe hepatic impairment is contraindicated.

Combination use with an alpha blocker.

Implementation of the combination therapy of dutasteride and an alpha blocker requires consideration of the combined side-effect profiles. Cardiovascular function should be stabilised prior to initiating combination therapy or adding an alpha blocker to dutasteride monotherapy. When initiating less selective alpha blockers such as doxazosin, terazosin and prazosin, careful and measured titration of the dose is required to minimise the risk of alpha blocker-related adverse events such as postural hypotension, dizziness, and syncope. Dose titration is normally not required for the selective alpha blockers such as tamsulosin and alfuzosin. Please see the recommendations in the product information of the relevant alpha blocker for full safety information.

Overdosage

In volunteer studies single doses of dutasteride up to 40 mg/day (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns. In clinical studies doses of 5 mg daily have been administered to patients for 6 months with no additional adverse effects to those seen at therapeutic doses of 500 microgram. There is no specific antidote for dutasteride therefore, in cases of suspected overdosage symptomatic and supportive treatment should be given as appropriate.
For information on the management of overdose, contact the Poison Information Centre on 131 126 (Australia).

Presentation

APO-Dutasteride 500 microgram soft gel capsules are intended for oral administration.
An oily colourless to pale yellow liquid absent of visible particles and/or crystals in a pale yellow oblong gelatin capsule printed with 'A 0.5' on one side in red ink.
Blister pack (White PVC/PVdC Aluminium silver foil) of 30 soft capsules (AUST R 212047).

Storage

Store below 25°C.

Poison Schedule

S4.