Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

Peripheral oedema (37%) and headache (28%)were the most common adverse reactions observed with ambrisentan. The higher dose (10 mg) was associated with a higher incidence of these adverse 
reactions, and peripheral oedema tended to be more severe in patients ≥65 years in short-term clinical studies (see section 4.4).

Serious adverse reactions associated with ambrisentan use include anaemia (decreased haemoglobin, decreased haematocrit) and hepatotoxicity.

Reductions in haemoglobin concentrations and haematocrit (10%) have been associated with ERAs including ambrisentan. Most of these decreases were detected during the first 4 weeks of treatment and haemoglobin generally stabilised thereafter (see section 4.4).

Hepatic enzyme elevations (2%), hepatic injury and autoimmune hepatitis (including exacerbation of underlying disease) have been observed with ambrisentan (see sections 4.4 and 5.1).

Tabulated list of adverse reactions

Frequencies are defined as: very common (≥ 1/10); 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) and not known (cannot be estimated from available data). For dose-related adverse reactions the frequency category reflects the higher dose of ambrisentan. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.


System organ class               Frequency          Adverse reaction(s) Blood and lymphatic system       Very common        Anaemia (decreased haemoglobin, disorders                                           decreased haematocrit)1 Immune system disorders          Common             Hypersensitivity reactions (e.g. angioedema, rash, pruritus)
Nervous system disorders         Very common        Headache (including sinus headache, migraine)2, dizziness
Eye disorders                    Common             Blurred vision,
visual impairment
Ear and labyrinth disorders      Common             Tinnitus3
Uncommon           Sudden hearing loss3
Cardiac disorders                Very common        Palpitation
Common             Cardiac failure4
Vascular disorders               Very common        Flushing5
Common             Hypotension,
syncope
Respiratory, thoracic and        Very common        Dyspnoea6,
mediastinal disorders                               upper respiratory (e.g. nasal, sinus) congestion7, nasopharyngitis7
Common             Epistaxis,
rhinitis7,
sinusitis7



Gastrointestinal disorders       Very common       Nausea,
diarrhoea,
vomiting5
Common            Abdominal pain,
constipation
Hepatobiliary disorders          Common            Hepatic transaminases increased Uncommon          Hepatic injury (see section 4.4),
autoimmune hepatitis (see section 4.4)
Skin and subcutaneous tissue     Common            Rash8 disorders
General disorders and            Very common       Peripheral oedema, administration site conditions                     fluid retention,
chest pain/discomfort5,
fatigue
Common            Asthenia

1
See section ‘Description of selected adverse reactions’.
2
The frequency of headache appeared higher with 10 mg ambrisentan.
3
Cases were only observed in a placebo-controlled clinical study of ambrisentan in combination with tadalafil.
4
Most of the reported cases of cardiac failure were associated with fluid retention.
5
Frequencies were observed in a placebo-controlled clinical study of ambrisentan in combination with tadalafil. Lower incidence was observed with ambrisentan monotherapy..
6
Cases of worsening dyspnoea of unclear aetiology have been reported shortly after starting ambrisentan therapy.
7
The incidence of nasal congestion was dose related during ambrisentan therapy.
8
Rash includes rash erythematous, rash generalised, rash papular and rash pruritic.

Description of selected adverse reactions

Decreased haemoglobin
In the post-marketing period, cases of anaemia requiring blood cell transfusion have been reported (see section 4.4). The frequency of decreased haemoglobin (anaemia) was higher with 10 mg ambrisentan. Across the 12 week placebo controlled Phase 3 clinical studies, mean haemoglobin concentrations decreased for patients in the ambrisentan groups and were detected as early as week 4 (decrease by 0.83 g/dL); mean changes from baseline appeared to stabilise over the subsequent 8 weeks. A total of 17 patients (6.5%) in the ambrisentan treatment groups had decreases in haemoglobin of ≥15% from baseline and which fell below the lower limit of normal.


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).