Adverse reactions : תופעות לוואי

4.8. Undesirable effects

For latanoprost, the majority of adverse reactions relate to the ocular system. In data from the extension phase of the Xalacom pivotal trials, 16 - 20% of patients developed increased iris pigmentation, which may be permanent. In an open 5 year latanoprost safety study, 33% of patients developed iris pigmentation (see section 4.4). Other ocular adverse reactions are generally transient and occur on dose administration. For timolol, the most serious adverse reactions are systemic in nature, including bradycardia, arrhythmia, congestive heart failure, bronchospasm and allergic reactions.

Like other topically applied ophthalmic drugs, timolol is absorbed into the systemic circulation. This may cause similar undesirable effects as seen with systemic beta blocking agents. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers.

Treatment related adverse reactions seen in clinical trials with Xalacom are listed below.

Adverse reactions are categorized by frequency as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to<1/100), rare (≥1/10,000 to <1/1000) and very rare (<1/10,000), not known (frequency cannot be estimated from the available data).

Table 1: Adverse reactions seen in Xalacom trials

System Organ Class            Very common (≥1/10)          Common               Uncommon ≥ 1/100 to < 1/10    ≥ 1/1,000 to
< 1/100

Nervous system                                                                  Headache disorders
Eye disorders                 Iris hyperpigmentation       Eye pain, eye        Corneal disorders, irritation           conjunctivitis, blepharitis,
(including           eye hyperaemia, vision stinging, burning,   blurred, lacrimation itching, foreign     increased body sensation)
Skin and                                                                        Rash, pruritus subcutaneous tissue disorders

Additional adverse reactions have been reported specific to the use of the individual components of Xalacom in either clinical studies, spontaneous reports or in the available literature.

For latanoprost, these are:

Table 2: Adverse Reaction for Latanoprost
System Organ Class                  Adverse Reactions
Infections and infestations                 Herpetic keratitis
Table 2: Adverse Reaction for Latanoprost
System Organ Class                  Adverse Reactions

Nervous system disorders                Dizziness
Eye disorders                           Eyelash and vellus hair changes of the eyelid (increased length, thickness, pigmentation, and number of eyelashes);
punctate keratitis, periorbital oedema; iritis; uveitis; macular oedema including cystoid macular oedema; dry eye; keratitis;
corneal oedema; corneal erosion; trichiasis; iris cyst;
photophobia; periorbital and lid changes resulting in deepening of the eyelid sulcus; eyelid oedema; localised skin reaction on the eyelids; pseudopemphigoid of the ocular conjunctiva+; darkening of the palpebral skin
Cardiac disorders                       Angina; angina unstable; palpitations Respiratory, thoracic and mediastinal   Asthma; asthma aggravation; dyspnoea disorders
Gastrointestinal disorders              Nausea*; vomiting*
Musculoskeletal and connective           Myalgia; arthralgia tissue disorders
General disorders and administration Chest pain site conditions
*Identified post marketing with an estimated frequency of uncommon
+
May be potentially related to the preservative benzalkonium chloride

For timolol, these are:

Table 3: Adverse Reaction for Timolol Maleate (ocular administration) System Organ Class                  Adverse Reactions

Immune system disorders                 Systemic allergic reactions including anaphylactic reaction, angioedema, urticaria, localised and generalised rash,
pruritus
Metabolism and nutrition disorders      Hypoglycaemia

Psychiatric disorders                   Memory loss, insomnia, depression, nightmares, hallucinations

Nervous system disorders                Cerebrovascular accident, cerebral ischaemia, dizziness, increases in signs and symptoms of myasthenia gravis,
paraesthesia, headache, syncope

Eye disorders                         Choroidal detachment following filtration surgery (see section 4.4), corneal erosion, keratitis, diplopia, decreased corneal sensitivity, signs and symptoms of ocular irritation
(e.g., burning, stinging, itching, tearing and redness), dry eyes, ptosis, blepharitis, blurred vision
Ear and labyrinth disorders           Tinnitus
Cardiac disorders                     Cardiac arrest, cardiac failure, atrioventricular block, congestive heart failure, chest pain, arrhythmia,
bradycardia, oedema, palpitations
Vascular disorders                    Cold hands and feet, hypotension, Raynaud’s phenomenon Respiratory, thoracic and mediastinal Bronchospasm (predominately in patients with pre-existing disorders                             bronchospastic disease), cough, dyspnoea Gastrointestinal disorders            Abdominal pain, vomiting, diarrhoea, dry mouth, Table 3: Adverse Reaction for Timolol Maleate (ocular administration) System Organ Class                  Adverse Reactions
 dysgeusia, dyspepsia, nausea
Skin and subcutaneous tissue             Skin rash, psoriasiform rash, exacerbation of psoriasis, disorders                                alopecia
Musculoskeletal and connective           Myalgia tissue disorders
Reproductive system and breast           Sexual dysfunction, decreased libido disorders
General disorders and administration     Asthenia, fatigue site conditions

Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas.

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