Prior to initiating treatment with Duodart the patient should be examined to rule out other causes of the symptoms.
Duodart should only be prescribed after a careful benefit/risk assessment due to the risk of adverse events from both active components, and after careful consideration of alternative treatment options (e.g. monotherapies).
Patients with large residual urinary volume and/or severely impaired urine flow should be monitored carefully for acute or chronic urinary retention.
As the active principle dutasteride is absorbed through the skin, contact with leaking capsules should be avoided. In the event of contact with leaking capsules the area affected should be washed thoroughly with soap and water at once. Women should not handle crushed or broken Duodart capsules if they are pregnant or could become pregnant, due to the possibility of absorption of dutasteride and the possible risk to a male foetus (see Use in Pregnancy & Lactation).
Effects on prostate-specific antigen (PSA) and the detection of prostate cancers: Before initiating treatment with Duodart tests to rule out prostate cancer including a digital rectal examination should be carried out. These tests should be repeated at regular intervals during the treatment.
The PSA serum level is an important parameter for early detection of prostate cancer. Treatment with Duodart leads to an average reduction of 50% in PSA serum levels within 6 months (with great inter-individual fluctuations, standard deviation 30%). This is why PSA levels within the normal range in patients taking Duodart do not rule out prostate cancer.
For this reason, after six months of treatment with Duodart, PSA levels must be assessed again and the result of this measurement used as the baseline value for future measurements. Any confirmed rise in PSA levels compared to the lowest value determined during treatment with Duodart may indicate the presence of prostate cancer (particularly high grade tumour) or lack of compliance and must therefore be evaluated carefully, even if values are still within the normal range for men who have not been treated with 5α-reductase inhibitors. A comparison with previous PSA values should be used to interpret the PSA value in patients treated with dutasteride.
After discontinuation of the treatment the PSA levels return to baseline values within 6 months.
The ratio of free to total PSA remains unchanged by Duodart. If the doctor uses the percentage of free PSA as a marker to detect prostate cancer, no adjustment of the value is necessary during treatment with Duodart.
Prostate cancer (in particular high grade tumours): Results of two long-term clinical studies (REDUCE dutasteride study and PCPT finasteride study) in men at increased risk of prostate cancer revealed a higher incidence of Gleason 8 – 10 prostate cancers in men treated with 5α-reductase inhibitors (dutasteride or finasteride) compared to placebo (see Pharmacology under Actions). The relationship between 5α-reductase inhibitors and higher grade prostate cancer is not clear yet. Men taking Duodart should be regularly evaluated for the manifestation of prostate cancer, including PSA testing.
Breast cancer in men: Data on a possible relationship between long-term therapy with dutasteride and the occurrence of breast cancer in men are currently inadequate. In two-year clinical trials with single-agent dutasteride therapy, in which exposure to dutasteride totaling 3,374 patient-years was achieved, and in the two-year open-label extension phase, two cases of breast cancer were reported in patients treated with dutasteride and one case in the placebo group up to the time of registration. In the 4-year CombAT and REDUCE studies there were no cases of breast cancer reported in any treatment groups. Integration of these 2 studies results in exposure of 17,489 patient-years to dutasteride monotherapy and 5,027 patient-years to the combination of dutasteride and tamsulosin.
Prescribers should instruct their patients to promptly report any changes in their breast tissue such as lumps or nipple discharge. Currently it is not clear if there is a causal relationship between the occurrence of male breast cancer and long term use of dutasteride.
Hypotension: During treatment with an adrenergic alpha-1 receptor blocker such as tamsulosin orthostatic hypotension may occur which in rare cases can result in syncope. Caution is advised in particular in patients who exhibited an excessive haemodynamic reaction during previous treatment with an alpha-1 receptor blocker and in patients receiving antihypertensive therapy. In theory, when tamsulosin hydrochloride is co-administered with anaesthetics, PDE5 inhibitors or other adrenergic alpha-1 receptor blockers, there is a risk of potentiation of hypotensive effects. Duodart must not therefore be used in combination with other adrenergic alpha-1 receptor blockers, and should only be used with caution in combination with PDE5 inhibitors.
Patients beginning treatment with Duodart should be cautioned to sit or lie down at the first signs of orthostatic hypotension (dizziness) until the symptoms have resolved.
Cardiac failure under combined therapy with tamsulosin: In two studies, both of which were over a four years period, cases of (acute or chronic) cardiac failure under combined therapy with dutasteride and an alpha blocker (mainly tamsulosin) were observed more frequently than under a monotherapy with dutasteride or an alpha blocker (incidence under dutasteride 0.1%, under alpha blocker 0.2%, under combined therapy 0.6%). However, there was no difference between the three treatment groups for all of the undesirable effects in the cardiovascular system. Up until now there have been no grounds to suspect a causal connection between the medication and the manifestation of cardiac failure, especially since the majority of the patients affected presented predisposing illnesses such as arterial hypertonia or coronary heart disease.
In some cases the symptoms of heart failure did not occur until after more than one year of treatment.
Caution is advised in patients with coronary heart disease owing to the possible antihypertensive effects of tamsulosin (see as follows).
Intraoperative floppy iris syndrome: Intraoperative floppy iris syndrome (IFIS) has been observed during ophthalmological interventions (cataract and glaucoma surgery) in some patients treated with adrenergic alpha-1 receptor blockers, such as tamsulosin. IFIS is characterised by a flaccid iris, progressive intraoperative miosis despite premedication with standard mydriatics, and potential prolapse of the iris towards the incisions for phacoemulsification. IFIS may increase the risk of intraoperative and postoperative ophthalmological complications, and the surgeon should be prepared, if necessary, to adjust his surgical techniques accordingly.
It is recommended that treatment with tamsulosin is not initiated in patients who are about to undergo eye surgery. However, it has not been proven that discontinuation of tamsulosin 1-2 weeks prior to the intervention is beneficial. There have been some reports on IFIS in patients who discontinued tamsulosin some time prior to the operation.
Effects on the reproductive system: In a fertility study with dutasteride in 50 volunteers there was a reduction in total sperm count, total sperm volume and sperm motility although mean values remained within the normal range. Sperm concentration and morphology were normal. There were major fluctuations in the individual results. In two volunteers there was a 90% reduction in sperm count after 52 weeks, which had partially recovered by the follow-up 24 weeks later. The relevance of the effects of dutasteride on semen characteristics for an individual patient's fertility is not known (see also Pharmacology: Toxicology: Preclinical data under Actions).
The effects of tamsulosin hydrochloride on sperm count or function have not been examined.
In the case of combined administration of dutasteride and tamsulosin there was an increased incidence of undesirable effects in the organ system "reproductive system and breast", particularly at the start of the treatment (i.e. during the first 6-12 months) compared to therapy with dutasteride or tamsulosin alone.
Hepatic impairment: The effects of hepatic impairment on the pharmacokinetics of dutasteride have not been investigated. As dutasteride undergoes extensive metabolism and has a half-life of 3-5 weeks, Duodart should be used with caution in patients with mild to moderate hepatic impairment (see Dosage & Administration and Contraindications). Since also for tamsulosin there are no data regarding severe hepatic impairment available, Duodart is contraindicated for severe liver impairment.
CYP3A4 inhibitors (see Interactions): Co-administration of tamsulosin and CYP3A4 inhibitors may increase tamsulosin exposure. In particular, there is a risk for significantly increased tamsulosin exposure in the case of CYP2D6 slow metabolisers who are being treated concurrently with potent CYP3A4 inhibitors. As polymorphism for CYP2D6 is generally unknown outside clinical studies, Duodart should basically not be co-administered with potent CYP3A4 inhibitors (e.g. ketoconazole‚ itraconazole, voriconazole, clarithromycin, indinavir, nelfinavir, ritonavir, saquinavir).
Duodart should only be co-administered with caution with moderate CYP3A4 inhibitors (e.g. erythromycin, fluconazole, verapamil, diltiazem). This applies in particular if the patient is being concurrently treated with a potent or moderate CYP2D6 inhibitor (such as paroxetine) or if concurrent treatment is with a CYP3A4 inhibitor that also inhibits CYP2D6 (such as amiodarone, cimetidine, imatinib).
Renal impairment: The effects of renal impairment on the pharmacokinetics of tamsulosin have not been investigated in patients with creatinine clearance <10 ml/min. Duodart should therefore be used with caution in such patients. For dutasteride no pharmacokinetic data are available in patients with impaired renal function. Due to the minimal renal elimination, there is no meaningful impact expected.
Swallowing disorders: Duodart has not been studied in patients with swallowing disorders (e.g. stenosing oesophageal changes or neurological disorders accompanied by impaired oesophageal motility). Caution is therefore advised in such patients.
Discontinuation of Duodart: On discontinuing Duodart the prostate can go back to the size it was prior to the treatment. Patients should therefore be suitably monitored for the recurrence of symptomatic BPH.
Effect on diagnostic methods: Within 6 months dutasteride leads to a reduction in the PSA serum level by about 50% in BPH patients; this also applies in the presence of prostate cancer.
Effects on ability to drive vehicles and use machines: Studies to investigate the effect of Duodart on the ability to perform tasks that require judgement, motor or cognitive skills have not been conducted. However, patients should be informed about the possible occurrence of symptoms related to orthostatic hypotension (such as dizziness) and visual disturbances when taking Duodart that could impair the ability to drive and to use machines.