Adverse reactions : תופעות לוואי

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 Avodart and Tamsulosin) study, a comparison of dutasteride 0.5mg and tamsulosin 0.4mg once daily for four years as co-administration or as monotherapy. Bioequivalence of Duodart 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 Duodart 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 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; ≥1/1000 to <1/100, Rare; ≥1/10,000 to <1/1000, Very rare; <1/10,000. Within each SOC grouping, undesirable effects are presented in order of decreasing seriousness.
System organ class         Adverse reactions           Dutasteride+     Dutasteride         Tamsulosinc tamsulosina
Nervous system        Syncope disorders                                                      -              -                 Rare Dizziness                           Common              -               Common Headache                             -                  -              Uncommon Cardiac disorders       Cardiac failure (Composite      Uncommon          Uncommond                 - term1)


Palpitations                         -                  -              Uncommon 
Vascular disorders      Orthostatic hypotension              -                  -              Uncommon 

Respiratory, thoracic   Rhinitis                             -                  -              Uncommon and mediastinal disorders
Gastrointestinal        Constipation                         -                  -               Uncommon disorders
Diarrhoea                            -                  -              Uncommon 

Nausea                               -                  -              Uncommon Vomiting                             -                  -              Uncommon Skin and                Angioedema                           -                  -                Rare subcutaneous disorders               Stevens-Johnson syndrome             -                  -               Very rare 

Urticaria                            -                  -              Uncommon 
Rash                                 -                  -              Uncommon Pruritus                             -                  -              Uncommon 


Reproductive system      Priapism                               -                   -               Very rare and breast disorders
Impotence3                         Common             Commonb                   - Altered (decreased) libido3        Common             Commonb                   - 

Ejaculation disorders3^            Common             Commonb               Common 
Breast disorders2                  Common             Commonb                   - 
General disorders         Asthenia                               -                    -              Uncommon and administration site disorders 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
Immune system disorders
Not known: Allergic reactions, including rash, pruritus, urticaria, localised oedema, and 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 postmarketing 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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il
Additionally, you should also report to GSK Israel (il.safety@gsk.com).