4.1. Therapeutic indications

• Treatment of moderate to severe symptoms of benign prostatic hyperplasia (BPH).

• Reduction in the risk of acute urinary retention (AUR) and surgery in patients with moderate to severe symptoms of BPH.

For information on effects of treatment and patient populations studied in clinical trials please see section 5.1.

4.2. Posology and method of administration

Posology

Adults (including elderly)

The recommended dose of Dutrozen is 1 capsule (0.5 mg / 0.4 mg) once daily.

Where appropriate, Dutrozen may be used to substitute concomitant dutasteride and tamsulosin hydrochloride in existing dual therapy to simplify treatment.

Where clinically appropriate, direct change from dutasteride or tamsulosin hydrochloride monotherapy to Dutrozen may be considered.

Renal impairment

The effect of renal impairment on dutasteride-tamsulosin pharmacokinetics has not been studied. No adjustment in dosage is anticipated for patients with renal impairment (see section 4.4 and 5.2).

Hepatic impairment

The effect of hepatic impairment on dutasteride-tamsulosin pharmacokinetics has not been studied so caution should be used in patients with mild to moderate hepatic impairment (see section 4.4 and section 5.2). In patients with severe hepatic impairment, the use of Dutrozen is contraindicated (see section 4.3).

Paediatric population

Dutasteride-tamsulosin is contraindicated in the paediatric population (under 18 years of age) (see section 4.3).

Method of administration

For oral use.

Patients should be instructed to swallow the capsules whole, approximately 30 minutes after the same meal each day. The capsules should not be chewed or opened. Contact with the contents of the dutasteride capsule contained within the hard-shell capsule may result in irritation of the oropharyngeal mucosa.

4.3. Contraindications

Dutrozen is contraindicated in:

• Women and children and adolescents (see section 4.6).

• Patients with hypersensitivity to dutasteride, other 5-alpha reductase inhibitors, tamsulosin (including tamsulosin induced angioedema), soya, peanut (soya lecithin) or any of other the excipients listed in section 6.1.

• Patients with a history of orthostatic hypotension.

• Patients with severe hepatic impairment

4.4. Special warnings and precautions for use

Combination therapy should be prescribed after careful benefit risk assessment due to the potential increased risk of adverse events (including cardiac failure) and after consideration of alternative treatment options including monotherapies.

Prostate cancer and high grade tumours

The REDUCE study, a 4-year, multicentre, randomised, double-blind, placebo controlled study investigated the effect of dutasteride 0.5 mg daily on patients with a high risk for prostate cancer (including men 50 to 75 years of age with PSA levels of 2.5 to 10 ng/ml and a negative prostate biopsy 6 months before study enrolment) compared to placebo. Results of this study revealed a higher incidence of Gleason 8 – 10 prostate cancers in dutasteride treated men (n = 29, 0.9%) compared to placebo (n = 19, 0.6%). The relationship between dutasteride and Gleason 8 – 10 prostate cancers is not clear. Thus, men taking dutasteride-tamsulosin should be regularly evaluated for prostate cancer (see section 5.1).

Prostate specific antigen (PSA)

Serum prostate-specific antigen (PSA) concentration is an important component in the detection of prostate cancer. Dutasteride-tamsulosin causes a decrease in mean serum PSA levels by approximately 50%, after 6 months of treatment.

Patients receiving dutasteride-tamsulosin should have a new PSA baseline established after 6 months of treatment with dutasteride-tamsulosin. It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from lowest PSA level while on dutasteride-tamsulosin may signal the presence of prostate cancer or noncompliance to therapy with dutasteride-tamsulosin and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5-alpha reductase inhibitor (see section 5.1). In the interpretation of a PSA value for a patient taking dutasteride, previous PSA values should be sought for comparison.

Treatment with dutasteride-tamsulosin 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.

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-tamsulosin. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing dutasteride-tamsulosin therapy, no adjustment to its value appears necessary.

Digital rectal examination, as well as other evaluations for prostate cancer or other conditions which can cause the same symptoms as BPH, must be performed on patients prior to initiating therapy with dutasteride-tamsulosin and periodically thereafter.

Cardiovascular adverse events

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 marginally higher among subjects taking the combination of dutasteride and an alpha1-adrenoceptor antagonist, primarily tamsulosin, than it was among subjects not taking the combination. However, the incidence of cardiac failure in these trials was lower in all actively treated groups compared to the placebo group, and other data available for dutasteride or alpha1-adrenoceptor antagonists do not support a conclusion on increased cardiovascular risks (see section 5.1).

Breast neoplasia

There have been rare reports of male breast cancer reported in men taking dutasteride in clinical trials and during the post-marketing period. However, epidemiological studies showed no increase in the risk of developing male breast cancer with the use of 5-alpha reductase inhibitors (see section 5.1). Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps or nipple discharge.

Renal impairment

The treatment of patients with severe renal impairment (creatinine clearance of less than 10 ml/min) should be approached with caution as these patients have not been studied.

Hypotension

Orthostatic: As with other alpha1-adrenoceptor antagonists, a reduction in blood pressure can occur during treatment with tamsulosin, as a result of which, rarely, syncope can occur. Patients beginning treatment with dutasteride-tamsulosin should be cautioned to sit or lie down at the first signs of orthostatic hypotension (dizziness, weakness) until the symptoms have resolved.

In order to minimise the potential for developing postural hypotension the patient should be haemodynamically stable on an alpha1-adrenoceptor antagonist prior to initiating use of PDE5 inhibitors.

Symptomatic: Caution is advised when alpha-adrenergic blocking agents including tamsulosin are co-administered with PDE5 inhibitors (e.g. sildenafil, tadalafil, vardenafil). Alpha1-adrenoceptor antagonists and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these 2 drug classes can potentially cause symptomatic hypotension (see section 4.5).

Intraoperative floppy iris syndrome

Intraoperative floppy iris syndrome (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients on or previously treated with tamsulosin. IFIS may increase the risk of eye complications during and after the operation. The initiation of therapy with dutasteride-tamsulosin in patients for whom cataract surgery is scheduled is therefore not recommended.

During pre-operative assessment, cataract surgeons and ophthalmic teams should consider whether patients scheduled for cataract surgery are being or have been treated with dutasteride-tamsulosin in order to ensure that appropriate measures will be in place to manage the IFIS during surgery.

Discontinuing tamsulosin 1 – 2 weeks prior to cataract surgery is anecdotally considered helpful, but the benefit and duration of stopping therapy prior to cataract surgery has not yet been established.

Inhibitors of CYP3A4 and CYP2D6

Concomitant administration of tamsulosin hydrochloride with strong inhibitors of CYP3A4 (e.g. ketoconazole), or to a lesser extent, with strong inhibitors of CYP2D6 (e.g. paroxetine) can increase tamsulosin exposure (see section 4.5). Tamsulosin hydrochloride is therefore not recommended in patients taking a strong CYP3A4 inhibitor and should be used with caution in patients taking a moderate CYP3A4 inhibitor, a strong or moderate CYP2D6 inhibitor, a combination of both CYP3A4 and CYP2D6 inhibitors, or in patients known to be poor metabolisers of CYP2D6.

Hepatic impairment

Dutasteride-tamsulosin has not been studied in patients with liver disease. Caution should be used in the administration of dutasteride-tamsulosin to patients with mild to moderate hepatic impairment (see section 4.2, section 4.3 and section 5.2).

Leaking capsule

Dutasteride is absorbed through the skin, therefore, women, children and adolescents must avoid contact with leaking capsules (see section 4.6). If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.

Mood alterations and depression

Mood alterations including depressed mood, depression and, less frequently, suicidal ideation have been reported in patients treated with another oral 5-alpha reductase inhibitor. Patients should be advised to seek medical advice if any of these symptoms occur.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially “sodium-free”.

Dutrozen contains 299.46 mg propylene glycol monocaprylate (equivalent to 112.80 mg propylene glycol) in each capsule and traces of propylene glycol in the black ink.

This medicine may contain traces of soya lecithin. If you are allergic to peanut or soya, do not use this medicinal product (see section 4.3).

4.5. Interaction with other medicinal products and other forms of interaction

There have been no drug interaction studies for dutasteride-tamsulosin. The following statements reflect the information available on the individual components.

Dutasteride

For information on the decrease of serum PSA levels during treatment with dutasteride and guidance concerning prostate cancer detection, please see section 4.4.

Effects of other drugs on the pharmacokinetics of dutasteride

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 to 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 (e.g. ritonavir, indinavir, nefazodone, itraconazole, ketoconazole administered orally) may increase serum concentrations of dutasteride. Further inhibition of 5-alpha 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 half-life may be further prolonged and it can take more than 6 months of concurrent therapy before a new steady state is reached.

Administration of 12 g cholestyramine 1 hour after a 5 mg single dose of dutasteride did not affect the pharmacokinetics of dutasteride.

Effects of dutasteride on the pharmacokinetics of other drugs

In a small study (n = 24) of 2 weeks duration in healthy men, dutasteride (0.5 mg daily) had no effect on the pharmacokinetics of tamsulosin or terazosin. There was also no indication of a pharmacodynamic interaction in this study.

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.

Tamsulosin

Concomitant administration of tamsulosin hydrochloride with drugs which can reduce blood pressure, including anaesthetic agents, PDE5 inhibitors and other alpha1-adrenoceptor antagonists could lead to enhanced hypotensive effects. Dutasteride-tamsulosin should not be used in combination with other alpha1-adrenoceptor antagonists.

Concomitant administration of tamsulosin hydrochloride and ketoconazole (a strong CYP3A4 inhibitor) resulted in an increase of the Cmax and AUC of tamsulosin hydrochloride by a factor of 2.2 and 2.8, respectively. Concomitant administration of tamsulosin hydrochloride and paroxetine (a strong CYP2D6 inhibitor) resulted in an increase of the Cmax and AUC of tamsulosin hydrochloride by a factor of 1.3 and 1.6, respectively. A similar increase in exposure is expected in CYP2D6 poor metabolisers as compared to extensive metabolisers when co-administered with a strong CYP3A4 inhibitor. The effects of co-administration of both CYP3A4 and CYP2D6 inhibitors with tamsulosin hydrochloride have not been evaluated clinically, however there is a potential for significant increase in tamsulosin exposure (see section 4.4).

Concomitant administration of tamsulosin hydrochloride (0.4 mg) and cimetidine (400 mg every 6 hours for 6 days) resulted in a decrease in the clearance (26%) and an increase in the AUC (44%) of tamsulosin hydrochloride. Caution should be used when dutasteride-tamsulosin is used in combination with cimetidine.

A definitive drug-drug interaction study between tamsulosin hydrochloride and warfarin has not been conducted. Results from limited in vitro and in vivo studies are inconclusive. Diclofenac and warfarin, however, may increase the elimination rate of tamsulosin. Caution should be exercised with concomitant administration of warfarin and tamsulosin hydrochloride.

No interactions have been seen when tamsulosin hydrochloride was given concomitantly with either atenolol, enalapril, nifedipine or theophylline. Concomitant furosemide brings about a fall in plasma levels of tamsulosin, but as levels remain within the normal range posology need not be adjusted.

In vitro neither diazepam nor propranolol, trichlormethiazide, chlormadinon, amitryptyline, diclofenac, glibenclamide and simvastatin change the free fraction of tamsulosin in human plasma. Neither does tamsulosin change the free fractions of diazepam, propranolol, trichlormethiazide, and chlormadinon.

4.6. Fertility, pregnancy and lactation

Dutasteride-tamsulosin is contraindicated for use by women. There have been no studies to investigate the effect of dutasteride-tamsulosin on pregnancy, lactation and fertility. The following statements reflect the information available from studies with the individual components (see section 5.3).

Pregnancy

As with other 5-alpha 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 (see section 4.4). Small amounts of dutasteride have been recovered from the semen in subjects receiving dutasteride. It is not known whether 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).

As with all 5-alpha 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.

Administration of tamsulosin hydrochloride to pregnant female rats and rabbits showed no evidence of foetal harm.

For information on preclinical data, see section 5.3.

Breast-feeding

It is not known whether dutasteride or tamsulosin are excreted in human milk.

Fertility

Dutasteride has been reported to affect semen characteristics (reduction in sperm count, semen volume, and sperm motility) in healthy men (see section 5.1). The possibility of reduced male fertility cannot be excluded.

Effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated.

4.7. Effects on ability to drive and use machines

No studies on the effects of dutasteride-tamsulosin on the ability to drive and use machines have been performed. However, patients should be informed about the possible occurrence of symptoms related to orthostatic hypotension such as dizziness when taking dutasteride-tamsulosin.

4.8. Undesirable effects

The data presented here relate to the co-administration of dutasteride and tamsulosin from the 4-year analysis of the CombAT (Combination of dutasterid and tamsulosin) study, a comparison of dutasteride 0.5 mg and tamsulosin 0.4 mg once daily for 4 years as co-administration or as monotherapy. Bioequivalence of dutasteride-tamsulosin with co-administered dutasteride and tamsulosin has been demonstrated (see section 5.2). Information on the adverse event profiles of the individual components (dutasteride and tamsulosin) is also provided. Note that not all the adverse events reported with the individual components have been reported with dutasteride-tamsulosin and these are included for information for the prescriber.

Data from the 4-year CombAT study have shown that the incidence of any investigator-judged drug-related adverse event during the first, second, third and fourth years of treatment respectively was 22%, 6%, 4% and 2% for dutasteride-tamsulosin co-administration therapy, 15%, 6%, 3% and 2% for dutasteride monotherapy and 13%, 5%, 2% and 2% for tamsulosin monotherapy. The higher incidence of adverse events in the co-administration therapy group in the first year of treatment was due to a higher incidence of reproductive disorders, specifically ejaculation disorders, observed in this group.

The investigator-judged drug-related adverse events have been reported with an incidence of greater than or equal to 1% during the first year of treatment in the CombAT Study, BPH monotherapy clinical studies and REDUCE study are as shown in the table below.

In addition the undesirable effects for tamsulosin below are based on information available in the public domain. The frequencies of adverse events may increase when the combination therapy is used.

The frequency of adverse reactions identified from clinical trials: Common: ≥ 1/100 to < 1/10, uncommon: ≥ 1/1,000 to < 1/100, rare: ≥ 1/10,000 to < 1/1,000, very rare: < 1/10,000. Within each SOC grouping, undesirable effects are presented in order of decreasing seriousness.

System organ class

Adverse reactions

Dutasteride-tamsulosina

Dutasteride

Tamsulosinc

Nervous system disorders

Syncope

-

-

Rare

Dizziness

Common

-

Common

Headache

-

-

Uncommon

Cardiac disorders

Cardiac failure (composite term1)

Uncommon

Uncommond

-

Palpitations

-

-

Uncommon

Vascular disorders

Orthostatic hypotension

-

-

Uncommon

Respiratory, thoracic and mediastinal disorders

Rhinitis

-

-

Uncommon

Gastrointestinal disorders

Constipation

-

-

Uncommon

Diarrhoea

-

-

Uncommon

Nausea

-

-

Uncommon

Vomiting

-

-

Uncommon

Skin and subcutaneous tissue disorders

Angioedema

-

-

Rare

Stevens-Johnson syndrome

-

-

Very rare

Urticaria

-

-

Uncommon

Rash

-

-

Uncommon

Pruritus

-

-

Uncommon

Reproductive system and breast disorders

Priapism

-

-

Very rare

Impotence3

Common

Commonb

-

Altered (decreased) libido3

Common

Commonb

-

Ejaculation disorders3^

Common

Commonb

Common

Breast disorders2

Common

Commonb

General disorders and administration site disorders

Asthenia

-

-

Uncommon

a Dutasteride-tamsulosin: From CombAT study – the frequencies of these adverse events decrease over time of treatment, from year 1 to year 4.

b Dutasteride: From BPH monotherapy clinical studies.

c Tamsulosin: From EU core safety profile for tamsulosin.

d REDUCE study (see section 5.1).

1 Cardiac failure composite term comprised of cardiac failure congestive, cardiac failure, left ventricular failure, cardiac failure acute, cardiogenic shock, left ventricular failure acute, right ventricular failure, right ventricular failure acute, ventricular failure, cardiopulmonary failure, congestive cardiomyopathy.

2 Includes breast tenderness and breast enlargement.

3 These sexual adverse events are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse events may persist after treatment discontinuation. The role of dutasteride in this persistence is not known.

^ Includes semen volume decreased.

Other data

The REDUCE study revealed a higher incidence of Gleason 8 – 10 prostate cancers in dutasteride treated men compared to placebo (see sections 4.4 and 5.1). Whether the effect of dutasteride to reduce prostate volume, or study related factors, impacted the results of this study has not been established.

The following has been reported in clinical trials and post-marketing use: male breast cancer (see section 4.4).

Post-marketing data

Adverse events from world-wide post-marketing experience are identified from spontaneous post-marketing reports; therefore the true incidence is not known.

Dutasteride

System organ class

Frequency

Adverse reaction

Immune system disorders

Not known

Allergic reactions, including rash, pruritus, urticaria, localised oedema, angioedema

Psychiatric disorders

Not known

Depression

Skin and subcutaneous tissue disorders

Uncommon

Alopecia (primarily body hair loss), hypertrichosis

Reproductive system and breast disorders

Not known

Testicular pain and testicular swelling

Tamsulosin

During post-marketing surveillance, reports of intraoperative floppy iris syndrome (IFIS), a variant of small pupil syndrome, during cataract surgery have been associated with alpha1-adrenoceptor antagonists, including tamsulosin (see section 4.4).

In addition atrial fibrillation, arrhythmia, tachycardia, dyspnoea, epistaxis, vision blurred, visual impairment, erythema multiforme, dermatitis exfoliative, ejaculation disorder, retrograde ejaculation, ejaculation failure and dry mouth have been reported in association with tamsulosin use. The frequency of events and the role of tamsulosin in their causation cannot be reliably determined.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store..

4.9. Overdose

No data are available with regard to overdosage of dutasteride-tamsulosin. The following statements reflect the information available on the individual components.

Dutasteride

In volunteer studies, single daily doses of dutasteride up to 40 mg/day (80 times the therapeutic dose) have been administered for 7 days without significant safety concerns. In clinical studies, doses of 5 mg daily have been administered to subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg. There is no specific antidote for dutasteride, therefore, in suspected overdosage symptomatic and supportive treatment should be given as appropriate.

Tamsulosin

Acute overdose with 5 mg tamsulosin hydrochloride has been reported. Acute hypotension (systolic blood pressure 70 mm Hg), vomiting and diarrhoea were observed which were treated with fluid replacement and the patient could be discharged the same day. In case of acute hypotension occurring after overdosage cardiovascular support should be given. Blood pressure can be restored and heart rate brought back to normal by lying the patient down. If this does not help then volume expanders, and when necessary, vasopressors could be employed. Renal function should be monitored and general supportive measures applied. Dialysis is unlikely to be of help as tamsulosin is very highly bound to plasma proteins.

Measures, such as emesis, can be taken to impede absorption. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulphate, can be administered.