Special Warning : אזהרת שימוש

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 Duodart 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. Duodart causes a decrease in mean serum PSA levels by approximately 50%, after 6 months of treatment.

Patients receiving Duodart should have a new PSA baseline established after 6 months of treatment with Duodart. It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from lowest PSA level while on Duodart may signal the presence of prostate cancer or noncompliance to therapy with Duodart 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 Duodart 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 Duodart. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing Duodart 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 Duodart 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 Duodart 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 two 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 Duodart 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 Duodart 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.

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.

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

Excipients
This medicinal product contains the colouring agent Sunset Yellow (E110), which may cause allergic reactions.

Effects on Driving

4.7     Effects on ability to drive and use machines
No studies on the effects of Duodart 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 Duodart.