Combodart 0.5 mg / 0.4 mg hard capsules

1.       NAME OF THE MEDICINAL PRODUCT

Duodart 0.5 mg / 0.4 mg hard capsules

4.4     Special warnings and precautions for use

Duodart 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.

Cardiac failure

In twoa 4-year clinical studiesy, 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, than it was among subjects not taking the combination.  In these two trials, the incidence of cardiac failure was low (≤1%) and variable between the studies  No causal relationship between dutasteride (alone or in combination with an alpha blocker) and cardiac failure has been established (see section 5.1).

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

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 with BPH prior to initiating therapy with Duodart and periodically thereafter.

Serum prostate-specific antigen (PSA) concentration is an important component in the detection of prostate cancer.  Generally, a total serum PSA concentration greater than 4 ng/mL (Hybritech) requires further evaluation and consideration of prostate biopsy.  Physicians should be aware that a baseline PSA less than 4 ng/mL in patients taking Duodart does not exclude a diagnosis of prostate cancer.  Duodart causes a decrease in mean serum PSA levels by approximately 50%, after 6 months of treatment., in patients with BPH, even in the presence of prostate cancer. 

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.  Although there may be individual variation, the reduction in PSA by approximately 50% is predictable as it was observed over the entire range of baseline PSA values (1.5 to 10 ng/mL).  Therefore to interpret an isolated PSA value in a man treated with Duodart for six months or more, PSA values should be doubled for comparison with normal ranges in untreated men.  This adjustment preserves the sensitivity and specificity of the PSA assay and maintains its ability to detect prostate cancer.  Any sustained confirmed increases from lowest in PSA levels while on Duodart may signal the presence of prostate cancer (particularly high grade cancer) or should be carefully evaluated, including consideration of 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 5a‑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 (see section 5.1).

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.

Prostate cancer and high grade tumours

Results of one clinical study (the REDUCE study) in men at increase risk of prostate cancer revealed a higher incidence of Gleason 8 – 10 prostate cancers in dutasteride treated men compared to placebo.  The relationship between dutasteride and high grade prostate cancer is not clear.  Men taking Duodart should be regularly evaluated for prostate cancer risk including PSA testing (see section 5.1). 

Renal impairment

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

Orthostatic hypotension

As with other alpha-blockers, 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.

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 lead to increased procedural complications during 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 capsules

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.

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.

Breast neoplasia

Breast cancer has been reported in men taking dutasteride in clinical trials (see section 5.1) and during the post-marketing period.  Physicians 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.

4.6     Fertility, pregnancy and lactation

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. Based on studies in animals, it is unlikely that 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). However, a

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.

4.8         Undesirable effects

Clinical Trial Data

<>Nervous system disorders

<>   Combinationa

   Dutasteride

   Tamsulosin

^a           Combination = dutasteride 0.5 mg once daily plus tamsulosin 0.4 mg once daily.
^b           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.

^c         Includes breast tenderness and breast enlargement.

TAMSULOSIN MONOTHERAPY

Clinical Trial Data and Postmarketing Data

The adverse reactions and frequency categories listed in the table below are based on information available in the public domain. Common and uncommon reactions are consistent with those identified in a clinical trial setting and the frequency categories generally reflect incidence over placebo. Rare and very rare reactions are consistent with those identified from post marketing reports and the frequency categories reflect reporting rates.

During postmarketing surveillance, reports of Intraoperative Floppy Iris Syndrome (IFIS), a variant of small pupil syndrome, during cataract surgery have been associated with alpha-1 blocker therapy, including tamsulosin (see section 4.4).

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).

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

Cardiac failure:

In this 4 year BPH 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%) (see section 4.4).

DUTASTERIDE

Cardiac failure:

In a 4 year BPH study of dutasteride in combination with tamsulosin in 4844 men (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%).

In a separate 4-year study in 8231 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL in the case of men 50 to 60 years of age, or 3 ng/mL and 10.0 ng/mL in the case of men older than 60 years of age) (the REDUCE study), there was a higher incidence of the composite term cardiac failure in subjects taking dutasteride 0.5 mg once daily (30/4105, 0.7%) compared to subjects taking placebo (16/4126, 0.4%).  A post-hoc analysis of this study showed 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 taking dutasteride and no alpha blocker (18/2953, 0.6%), placebo and an alpha blocker (1/1399, <0.1%), or placebo and no alpha blocker (15/2727, 0.6%).

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 ng/mL and 10.0 ng/mL in the case of men 50 to 60 years of age, or 3 ng/mL and 10.0 ng/mL in the case of men older than 60 years of age) (the REDUCE study), 6,706 subjects had prostate needle biopsy (primarily protocol mandated) 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, 70%).

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) (see section 4.4). There was no difference in the incidence of Gleason 7-10 cancers (p=0.81).

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.

The relationship between dutasteride and high grade prostate cancer is not clear.  

5.3     Preclinical safety data

Non-clinical studies have not been conducted with Duodart. Dutasteride and tamsulosin hydrochloride individually have been extensively evaluated in animal toxicity tests and findings were consistent with the known pharmacological actions of 5 alpha‑reductase inhibitors and alpha-adrenergic blockers. The following statements reflect the information available on the individual components.

Dutasteride

Current studies of general toxicity, genotoxicity and carcinogenicity did not show any particular risk to humans.

Reproduction toxicity studies in male rats have shown a decreased weight of the prostate and seminal vesicles, decreased secretion from accessory genital glands and a reduction in fertility indices (caused by the pharmacological effect of dutasteride). The clinical relevance of these findings is unknown.

As with other 5 alpha reductase inhibitors, feminisation of male foetuses in rats and rabbits has been noted when dutasteride was administered during gestation. Dutasteride has been found in blood from female rats after mating with dutasteride treated males. When dutasteride was administered during gestation to primates, no feminisation of male foetuses was seen at blood exposures sufficiently in excess of those likely to occur via human semen. It is unlikely that a male foetus will be adversely affected following seminal transfer of dutasteride.

Tamsulosin

Studies of general toxicity and genotoxicity did not show any particular risk to humans other than those related to the pharmacological properties of tamsulosin.

In carcinogenicity studies in rats and mice, tamsulosin hydrochloride produced an increased incidence of proliferative changes of the mammary glands in females.  These findings, which are probably mediated by hyperprolactinaemia and only occurred at high dose levels, are regarded as not clinically relevant

High doses of tamsulosin hydrochloride resulted in a reversible reduction in fertility in male rats considered possibly due to changes of semen content or impairment of ejaculation.  Effects of tamsulosin on sperm counts or sperm function have not been evaluated.

Administration of tamsulosin hydrochloride to pregnant female rats and rabbits at higher than the therapeutic dose showed no evidence of foetal harm.

Updates to SPC -

Section 4.3 - Addition of hypersentitity to excipient including soya & peanut

Section 4.5 - CORRECTION of 'Administration of 12 g cholestyramine one hour AFTER instead of BEFORE a 5 mg single dose of dutasteride

Section 4.8 - addition of Postmarketing Data, AE's