Adverse reactions : תופעות לוואי

4.8 Undesirable effects

In a 3 month clinical study, approximately 29% of patients treated with bimatoprost experienced adverse reactions. The most frequently reported adverse reactions were conjuctival hyperaemia (mostly trace to mild and of a non-inflammatory nature) occurring in 24% of patients, and eye pruritis occurring in 4% of patients.
Approximately 0.7% of patients in the bimatoprost group discontinued due to any adverse event in the 3 month study.
The following adverse reactions were reported during clinical trials with bimatoprost or in the post- marketing period. Most were ocular, mild and none was serious:
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) adverse reactions are presented according to System Organ Class in Table 1. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1


System Organ class                              Frequency                            Adverse reaction 
Nervous system disorders                   uncommon                               headache  not known                              dizziness

Eye disorders                              very common                            conjunctival hyperaemia, prostaglandin analogue periorbitopathy
 common                                 punctate keratitis, eye irritation, foreign body sensation, dry eye, eye pain, eye pruritus, growth of eyelashes, eyelid erythema
 uncommon                               asthenopia, conjunctival oedema, photophobia, lacrimation increased, iris hyperpigmentation, blurred vision,
eyelid pruritus, eyelid oedema
 not known                              eye discharge, ocular discomfort 
Respiratory, thoracic and mediastinal      not known                              asthma, asthma exacerbation, COPD disorders                                                                         exacerbation and dyspnoea 
Skin and subcutaneous tissue               common                                 skin hyperpigmentation (periocular) disorders uncommon                               hair growth abnormal
 not known                              skin discoloration (periocular) 
Immune system disorders                    not known                              Hypersensitivity reaction including signs and symptoms of eye allergy and allergic dermatitis

Vascular disorders                         not known                              hypertension 
Description of selected adverse reactions
Prostaglandin analogue periorbitopathy (PAP)
Prostaglandin analogues including bimatoprost can induce periorbital lipodystrophic changes which can lead to deepening of the eyelid sulcus, ptosis, enophthalmos, eyelid retraction, involution of dermatochalasis and inferior scleral show.
Changes are typically mild, can occur as early as one month after initiation of treatment with BIMATOPROST S.K, and may cause impaired field of vision even in the absence of patient recognition. PAP is also associated with periocular skin hyperpigmentation or discoloration and hypertrichosis. All changes have been noted to be partially or fully reversible upon discontinuation or switch to alternative treatments.
Iris hyperpigmentation
Increased iris pigmentation is likely to be permanent. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. The long term effects of increased iris pigmentation are not known. Iris colour changes seen with ophthalmic administration of bimatoprost may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts become more brownish. Neither naevi nor freckles of the iris appear to be affected by the treatment. At 3 months, the incidence of iris hyperpigmentation with bimatoprost 0.3 mg/mL single dose was 0.3%. At 12 months, the incidence of iris pigmentation with bimatoprost 0.3 mg/mL (multi-dose formulation) was 1.5% (see section 4.8) and did not increase following 3 years treatment.
In clinical studies, over 1800 patients have been treated with bimatoprost 0.3 mg/mL (multi-dose formulation). On combining the data from phase III monotherapy and adjunctive bimatoprost 0.3 mg/mL (multi-dose formulation) usage, the most frequently reported adverse reactions were:
• growth of eyelashes in up to 45% in the first year with the incidence of new reports decreasing to 7% at 2 years and 2% at 3 years
• conjunctival hyperaemia (mostly trace to mild and thought to be of a non-inflammatory nature) in up to 44% in the first year with the incidence of new reports decreasing to 13% at 2 years and 12% at 3 years
• ocular pruritus in up to 14% of patients in the first year with the incidence of new reports decreasing to 3% at 2 years and 0% at 3 years.
Less than 9% of patients discontinued due to any adverse event in the first year with the incidence of additional patient discontinuations being 3% at both 2 and 3 years.
Table 2 lists adverse reactions that were seen in a 12 month clinical study with bimatoprost 0.3 mg/mL (multi-dose formulation), but were reported at a higher frequency than with bimatoprost 0.3 mg/mL (single-dose). Most were ocular, mild to moderate, and none were serious.
Table 2


System Organ class                             Frequency                               Adverse Reaction 
Nervous system disorders                  common                                    headache 
Eye disorders                             very common                               ocular pruritus, growth of eyelashes  common                                    asthenopia, conjunctival oedema, photophobia, tearing, increased iris pigmentation; blurred vision

Skin and subcutaneous tissue              common                                    eyelid pruritus disorders

In addition to the adverse reactions seen with bimatoprost , Table 3 lists additional adverse reactions that were seen with bimatoprost 0.3 mg/mL (multi-dose formulation). Most were ocular, mild to moderate, and none were serious.
Table 3


System Organ class                             Frequency                               Adverse Reaction 
Nervous system disorders                  uncommon                                  dizziness 
Eye disorders                             common                                    corneal erosion, ocular burning, allergic conjunctivitis, blepharitis, worsening of visual acuity, eye discharge, visual disturbance, eyelash darkening
 uncommon                                  retinal haemorrhage, uveitis, cystoid macular oedema, iritis, blepharospasm,
eyelid retraction

Vascular disorders                        common                                    hypertension 
Gastrointestinal disorders                uncommon                                  nausea 
Skin and subcutaneous tissue              not known                                 periobital erythema disorders

General disorders and administration      uncommon                                  asthenia site conditions

Investigations                            common                                    liver function test abnormal 
Adverse reactions reported in phosphate containing eye drops:
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. Healthcare professionals are asked to report any suspected adverse reactions via:
: https://sideeffects.health.gov.il