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Drugs used in ocular treatment
J.S.A.G. Schouten
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Drugs used in ocular treatment
DRUGS USED IN THE MANAGEMENT OF AGE-RELATED MACULAR DEGENERATION (SEDA-30, 545; SEDA-31, 739)
Bevacizumab (SEDA-30, 545) Sensory systems Bevacizumab eye-drops, 5 mg/ml, used five times a day for 0.5–6 months in five patients, mean age 42 years, to reduce corneal neovasculari zation, did not have any epithelial adverse effects (1c).
Pegaptanib
(SEDA-31, 739)
Systematic reviews The adverse events in two trials of pegaptanib have been summarized in a systematic review (2M). Adverse effects were common, but most were transient mild to moderate events, and serious events were rare. There was endophthalmitis in 1.3% of patients in the first year, but in none of those who continued to use pegaptanib for a second year. Significantly, more of the patients who received pegaptanib than those who received sham injections had vitreous floaters (33% versus 8%), vitreous opacities (18% versus 10%), and anterior Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32047-2 2010 Elsevier B.V. All rights reserved.
chamber inflammation (14% versus 6%) in the first year of the VISION study. Observational studies Pegaptanib has been investigated in a combined study, including open administration in 37 patients, who were given 3 mg in 0.09 ml, and a randomized, double-masked, uncontrolled, multi center study in 110 patients, who were given 1 or 3 mg in 0.09 ml (3C). The dose of pegaptanib was three or ten times higher than the normal dose and was given every 6 weeks for 54 weeks. The mean number of injections was 9.6. No patients were lost to follow-up. Although there were urine abnormalities (proteinuria, hematuria, or altered albumin-to-creatinine ratio), these normalized after 60 weeks, or had not changed after 60 weeks, or were attributed to a disease. There were no important changes in hematological parameters, liver function, renal function, or electrolytes. There were no important changes from mean or median baseline measurements in vital signs, including blood pressure, and no changes in electrocardiography. All but two patients had at least one adverse event and 28 of 147 (19%) had serious adverse events, most often cardiac disorders. No patient withdrew because of adverse events, and there were no differences between the groups in overall adverse event rates. Nonocular adverse events were uncommon and there was no evidence of systemic toxicity. Five patients died before week 60 and within 60 days of the previous dose, but no deaths were considered to be related to the study treatment. There were ocular adverse events in the study eye in 138 of 147 patients
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(94%); most were mild to moderate in intensity. Only one ocular adverse event was reported as serious (moderate retinal hemorrhage); it was reported on day 245 and was considered to be unrelated to the treatment. There were no cases of endophthalmitis, retinal detachment, or traumatic cataract. The most common ocular adverse events were eye pain (69/147; 47%), vitreous floaters (63/147; 43%), punctate keratitis (60/147; 41%), visual disturbances (37/147; 25%), eye irritation (33/147; 22%), and increased intraocular pressure (31/147; 21%); 11 patients (7%) had mild anterior chamber inflammation. Most events occurred with similar frequencies across the treatment groups, but the incidence of increased intraocular pressure was greater with pegaptanib 3 mg. Most of the ocular adverse events were attributed by the investigators to the injection procedure, and few were attributed to the study drug. As expected, the incidence of ocular adverse events in the fellow eye was much lower than that in the study eye (35% versus 94%). Fluorescein angiography showed no retinal vascular or choroidal abnormalities in the study eye that were not expected during the natural progression of neovascular agerelated macular degeneration. There were no notable delays in arteriovenous transit time, abnormalities in choroidal perfusion or arteriolar occlusions. Sensory systems Intravitreal injections of 0.09 ml pegaptanib cause increased intraocular pressure (4c). Of 75 patients 77% had received prophylactic pressurelowering medications 1 hour before treatment. Immediately after the injection, pressure was exerted on the globe to lower intraocular pressure. Vision was also evaluated immediately after injection. Four patients had no light perception after the injection and the initial pressure was over 55 mmHg; immediate anterior chamber paracentesis was conducted. The mean preinjection pressure for the first injection was 14 mmHg, at 1 minute after injection
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38 mmHg, at 3–10 minutes 34 mmHg, and at 11–20 minutes 26 mmHg. In most cases the pressure fell significantly by 30 minutes after injection. There was no difference between patients with and without glaucoma. The increase in intraocular pressure was related to the volume injected, which in the case of pegaptanib is 0.09 ml. The pressure even increases in patients who received pressure-lowering drugs before treatment, and anterior chamber paracentesis before injection or use of a smaller volume (with another anti-VEGF drug) could be the best way to prevent the pressure increase. Immunologic In two cases systemic allergic reactions were associated with intravitreous administration of pegaptanib (5A).
Autacoids A patient with occult choroidal neovascularization had a prolonged anaphylactoid reaction 35 minutes after a first dose of intraocular pegaptanib sodium 0.3 mg. The reaction included oral angioedema and generalized urticaria. Later skin tests with several medications that the patient had been given, including pegaptanib, were negative, except for intradermal histamine. IgE antibodies for latex were also negative. Six weeks later the patient received an injection of bevacizumab uneventfully. Another patient received four injections of pegaptanib over 6 months, and 12 hours after each injection, he developed mild lip angioedema that lasted for hours and an urticarial rash that lasted for days. He had these adverse events after each of four injections, but reported them only after the fourth injection. No other changes in his medical regimen or environment explained his symptoms. Bevacizumab was used for subsequent injections without adverse events. The authors described this as an anaphylactoid reaction (i.e. a non-IgE mediated anaphylactic reaction), since it occurred after the first injection and skin tests were negative. They hypothesized that the reactions could have been related to the polyethylene glycol moieties in
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pegaptanib, since polyethylene glycol-con taining products have been associated with cutaneous contact sensitivity, urticarial reactions, angioedema, and anaphylactoid reactions. Drug–drug interactions Warfarin The safety of intravitreal injections in patients with age-related macular degeneration using warfarin has been investigated in 31 patients who received 102 injections of pegaptanib (6c). There were no intraoperative or immediate postoperative hemorrhagic complications. One patient had an acute submacular hemorrhage 35 days after the third injection. There were no other hemorrhagic events. Submacular bleeding can also occur in patients with macular degeneration without intravitreal injections. Patients with exudative disease (‘wet’ degeneration) are at risk of massive macular bleeding when using anticoagulants and in many patients this therapy should be withdrawn (7c).
Ranibizumab
(SEDA-30, 545;
SEDA-31, 739) Comparative studies Adverse events have been reported in the 2-year results of a randomized, single-masked, controlled trial of ranibizumab 0.5 mg þ verteporfin photo dynamic therapy (n = 106) versus verte porfin photodynamic therapy alone (n = 56) in neovascular age-related macular degen eration (FOCUS study) (8C). Serious ocular adverse events occurred more often in those who received ranibizumab þ photodynamic therapy (17% versus 14%). This was due to endophthalmitis (2.9%, 3/105, versus 0%) and ocular inflammation (12%, 13/105, ver sus 0%). Serious systemic vascular events occurred more often with ranibizu mab þ photodynamic therapy (14/105, 13% versus 6/56, 11%). The authors reported that the cumula tive rates of serious non-ocular adverse events were similar in the two groups at 2 years (17/56 versus 30/105). Of the serious
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non-ocular adverse vascular events, which might plausibly have been due to systemic VEGF inhibition, the cumulative rates were 6/56 (11%) versus 14/105 (13%). Hypertension among patients who were not hypertensive at study entry emerged as a serious adverse event in only one patient who received ranibizumab. The rates of non-ocular hemorrhage were balanced between the groups (4/56 versus 7/105), and none was reported as serious. Arterial thromboembolic events as defined using the Antiplatelet Trialists’ Collabora tion (APTC) criteria (i.e. vascular death or death from an unknown cause, non-fatal myocardial infarction, non-fatal ischemic or hemorrhagic stroke, or stroke of unknown cause) were slightly more com mon in those who received photodynamic therapy alone (4/56 versus 5/105). Placebo-controlled studies In a multi center, randomized, double-masked, sham injection-controlled trial in patients with predominantly or minimally classic or occult with no classic lesions due to age-related macular degeneration, 184 patients were randomized to ranibizumab 0.3 or 0.5 mg or to sham treatment (9C). Ranibizumab was given monthly for 3 months and then quarterly. Assessment of serious or non-ser ious non-ocular adverse events showed no overall difference between the groups. There were no deaths during the first year of treatment. Hypertension in subjects who were not hypertensive at baseline was reported as an adverse event in 8.1% of sham-treated subjects, 6.8% of those who received ranibizumab 0.3 mg and 8.2% of those who received 0.5 mg. Routinely mea sured systolic and diastolic blood pressures were very similar among groups at baseline and at 12 months. Proteinuria was not reported during the first year. The rates of non-ocular hemorrhage were 2.4 and 6.6% with ranibizumab 0.3 and 0.5 mg respec tively, and 4.8% in the sham group. There was only one case of serious non-ocular hemorrhage (hemorrhage at the site of an intravenous catheter in a subject who received ranibizumab 0.5 mg). There were
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no cases of gastrointestinal perforation. There were no arterial thromboembolic events. The only serious or non-serious arterial thromboembolic event during the first year was ischemic cardiomyopathy in a sham-treated subject. Immunoreactivity to ranibizumab was assessed at screening and at month 12 or at early termination. During screening, one subject randomized to sham treatment tested positive, possibly because of pre-existing anti-Fab anti bodies. None of those who received rani bizumab tested positive before study treatment, but two of those who received 0.5 mg group tested positive at month 12; neither of these two subjects had any severe or serious adverse events during the study. Systematic reviews The adverse events in three trials of ranibizumab have been summarized in a systematic review (2M) Endophthalmitis occurred in 1.4 and 1.9% of patients receiving 0.5 mg ranibizumab in the ANCHOR and FOCUS trials, respectively. The rate per injection was 0.05% in the MARINA trial. Sensory systems In a review of three large clinical trials of ranibizumab in the treatment of age-related macular degeneration, serious adverse ocular events occurred in association with <0.1% of intravitreal injections (10M). They included retinal detachment and endophthalmitis. Less serious adverse ocular reactions occurred in <2% of patients, including intraocular inflammation and increased intraocular pressure. Retinal pigment epithelial tears have been reported after intravitreal injection of rani bizumab. One patient already had a pigment epithelial detachment and the symptoms appeared only after the third injection, with no adverse events after the previous two dosages (11A). Six other patients with age-related macular degenera tion, four of whom had a pigment epithelial detachment, developed a retinal pigment epithelial tear after intravitreous injections of ranibizumab (12A, 13A). In other cases
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this adverse event occurred within 2–6 weeks after the injections (14A–16A). Ocular hypertension can complicate intra vitreal injections. Four patients without a history of glaucoma or ocular hypertension had sustained ocular hypertension after intravitreal injections of ranibizumab (17A). The intraocular pressure rose as high as 30, 34, 46, and 50 mmHg, but only in the injected eye. All four were treated with topical anti-glaucoma medications. The importance of this observation is that the ocular pressure can be high and remain high after intravitreal injections of ranibizumab. In a retrospective chart review study in 50 patients, there was a short-term increase in ocular hypertension after intravitreal injec tion of ranibizumab from a mean of 14 (range 9–22) mmHg to 21 (range 10–31) mmHg (18c). There was no increase 1–4 weeks after injection. Hematologic Arterial thromboses at distant sites, in particular strokes, have been reported with intravitreous ranibizumab, at a higher frequency with 0.5 mg per injection (about 1%) than with 0.3 mg per injection (19r).
Verteporfin and photodynamic therapy (SEDA-30, 545; SEDA-31, 739); see also chapter 45 Observational studies After 12 months of photodynamic therapy with verteporfin in 64 patients with neovascular age-related macular degeneration, 51 received treat ment for a further 12 months (20c). In all, 118 adverse events were reported during the 12-month extension, of which 14 were considered possibly or probably related to the treatment. This compares with 47 (26%) of 180 adverse events that were considered possibly or probably related to the treatment during the first 12 months of the study in the 51 patients who enrolled in the extension. Most of the adverse events were mild to moderate in
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intensity. Three patients withdrew because of an adverse event during the first 12 months, and three did so during the extension. The adverse events during the extension phase were similar to those during the first 12 months, but a further seven patients had reduced vision, none related to the drug. One patient had an injection-site hemorrhage during the extension. There were no photosensitivity reactions at any time. Comparative studies Photodynamic ther apy with verteporfin has been compared with anecortave 15 mg under Tenon’s capsule at baseline and at 6 months as a periocular posterior juxtascleral depot (21C). There were no differences between the groups. The most common adverse event was reduced visual acuity, but there was no differ ence between the groups. There were 15 deaths, which were assessed as being un related to the treatment. There were non fatal serious adverse events in 97 patients (18%) during 12 months, of whom 45 (17%) received verteporfin. These were thought to be unrelated to the therapy or the injection procedure. Treatment had to be withdrawn because of adverse events in 13 patients (5%) who received verteporfin. Sensory systems Profound choroidal hypoperfusion occurred after verteporfin photodynamic therapy and intravitreal triam cinolone acetonide for age-related macular degeneration in 15 out of 108 patients with 155 treatments (22C). No susceptibility factors were identified. It occurred after the first treatment in some cases (n = 7) and after retreatment in others. If profound hypoperfu sion had occurred after several treatments, mild hypoperfusion had occurred after earlier treatments. Three patients with profound hypoperfusion were re-treated because of recurrence of the neovascularization. In all three the severity of hypoperfusion increased. Five patients with profound choroidal hypoperfusion had a pretreatment visual acuity of 20/80. The visual acuity worsened to 20/100 in two patients and to counting fingers in two;
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it increased by one line in one patient. Chor oidal hypoperfusion has been reported in patients with age-related macular degenera tion who were treated with verteporfin photo dynamic therapy, but the rate in this study (15/108) was higher than previously reported. Intravitreal triamcinolone may have contrib uted to the risk by preventing the inflamma tory response to photodynamic therapy and re-perfusion of normal vessels afterwards. Dosage regimens When verteporfin photodynamic therapy is used for choroidal neovascularization in age-related macular degeneration, adverse events include atrophy of the retinal pigment epithelium, choroidal ischemia, secondary choroidal neovascularization and transiently reduced macular function. Because of these adverse events, and since patients with acute central serous chorioretinopathy generally have a fairly good vision and a good prognosis, the effect of half-dose verteporfin has been investigated. Verteporfin 3 mg/m2 was infused over 8 minutes and indocyanine green angiography guided photodynamic therapy with 50 J/cm2 light energy was used to treat 43 eyes in 43 patients with acute central serous chorioretinopathy (23c). There were no ocular or systemic adverse events.
ADRENOCEPTOR AGONISTS (SEDA-28, 569; SEDA-31, 740)
Apraclonidine Susceptibility factors Children In five infants suspected of having Horner’s syndrome, apraclonidine eye-drops were used diagnostically (24Ac). The main adverse event was drowsiness in three cases; two required emergency admission for unresponsiveness. In one case there was bradycardia, hypertension, and reduced oxygen saturation. Based on these observations, apraclonidine eye-drops should not be used in infants.
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Brimonidine Sensory systems Brimonidine was reported to have caused granulomatous anterior uveitis and granulomatous papillary conjunctivitis after 2 years of treatment in a 78-year-old man (25A). Extensive additional investiga tions did not reveal an underlying cause. Withdrawal of brimonidine led to improve ment in 2 days and complete resolution within 1 month. Skin In 13 patients with periorbital dermatitis, ectropion was presumed to have been due to one or more of the drugs that they were using: brimonidine, betaxolol, dorzolamide, latanoprost, preservatives, timolol, or travoprost; the drugs were withdrawn and the patients were assessed again, with rechallenge after the last assessment (26c). The ectropion resolved partly or completely after the eye-drops had been withheld, and there was recurrence after rechallenge. Dorzolamide (seven cases) was the most common offender, followed by brimonidine (three cases). In six cases more than one drug was implicated, and in five cases the preservative in which the drug was formulated was blamed.
BETA-ADRENOCEPTOR ANTAGONISTS (SEDA-26, 525; SEDA-27, 509; SEDA-31, 740)
Carteolol Observational studies Carteolol is a non selective beta-adrenoceptor antagonist used in the treatment of glaucoma and ocular hypertension. During trials of carteolol 1–2% two patients had serious cardiac events, including bradycardia, congestive heart failure, and myocardial infarction; one had hypotension, which required drug withdrawal. Withdrawal was also necessary in one patient who developed bronchoconstriction and in five who developed breathlessness;
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patients with pulmonary disease had been excluded. These reactions act as a reminder that beta-blocker eye-drops can cause systemic adverse effects. Cardiovascular There are few if any differences between carteolol and other beta-adrenoceptor antagonists in terms of their effects on heart rate, blood pressure, or FEV1 in patients with glaucoma or ocular hypertension. However, in one study there was a significantly lower incidence of cardiovascular adverse events overall and a significantly lower incidence of bradycardia with carteolol than with timolol; in particular, carteolol seemed less likely to induce nocturnal bradycardia. Standard carteolol and long-acting carteolol did not differ in their effects on blood pressure or heart rate. Sensory systems The effects of carteolol eye-drops 1 and 2% have been reviewed (27R). The most common ocular symptoms were burning/stinging at the time of instillation, tearing, ocular pain, blurred vision, itching, and conjunctival hyperemia. In general, there were no significant differences in the incidence of ocular symptoms between patients who used carteolol and those who used other beta-adrenoceptor antagonists, such as timolol, metipranolol, or levobunolol. However, several studies have shown better ocular tolerability of carteolol versus timolol for certain end-points (e.g. fewer ocular symptoms overall and less burning and eye pain). The long-acting formulation of carteolol was associated with blurred vision in under 2% of patients.
Timolol
(SED-15, 3428; SEDA-31, 741)
Sensory systems In a retrospective study of 209 eyes (178 patients) with primary acquired nasolacrimal duct obstruction and 183 control eyes in patients who underwent cataract surgery, the prevalence of primary openangle glaucoma was significantly higher in the former (48/209 versus 11/183) (28C).
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In those who had primary open-angle glaucoma, the duration was longer in the former (14 years versus 9.63 years) and the average number of topical anti-glaucoma drugs per treated eye was higher (1.58 versus 0.73). Significantly more patients with glaucoma and nasolacrimal duct obstruction (69% versus 18%) were using timolol. There were no statistically significant differences for other topical glaucoma drugs. The authors concluded that chronic use of timolol eyedrops in patients with glaucoma is associated with an increased risk of nasolacrimal duct obstruction. However, a causal effect of timolol can not be based on this study and the mechanism is speculative.
CARBONIC ANHYDRASE INHIBITORS See Chapter 21.
GLUCOCORTICOSTEROIDS (SED-15, 906; SEDA-30, 548; SEDA-31, 741) Observational studies Intralesional gluco corticoids are used to treat periocular capil lary hemangiomas. Adverse events in 13 infants were adrenal suppression, transient reductions in linear growth, and localized eyelid necrosis (29c).
PROSTAGLANDIN ANALOGUES (SEE ALSO CHAPTER 39) Comparative studies Bimatoprost and latanoprost Bimatoprost (0.03%) and latanoprost have been compared in 129 patients with exfoliative glaucoma in a 3-month crossover observer-masked study
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(30C). There were no serious adverse events. More patients reported at least one adverse event with bimatoprost than with latanoprost (58 patients versus 34 patients). Conjunctival hyperemia and hypertrichosis were more common with bimatoprost than with latanoprost (32 versus 9 and 14 versus 2, respectively). There were no significant differences in other adverse events (lid dermatitis, itching, stinging, ocular pain, foreign body sensation, blurred vision, headache, change in iris color, and periocular pigmentation). The number of adverse events at the end of the trial was independent of treatment order. The incidence of periocular pigmenta tion in patients using bimatoprost (0.03%) or latanoprost has been studied retrospectively (31c). The 12-month inci dence was 0.8% (2/263) in patients who used latanoprost and 5.8% (8/137) in those who used bimatoprost. The pig mentation disappeared without withdra wal of treatment in some patients. The pigmentation ranged from deep red to brown. Latanoprost and travoprost In an observer-masked, crossover comparison of latanoprost and travoprost in 40 patients with exfoliative glaucoma, travoprost more often led to conjunctival hyperemia than latanoprost (15 versus 6) (32c).
Latanoprost Observational studies The adverse events that occurred after at least 6 months (mean 2.2 years) during latanoprost monotherapy in 353 patients have been reported (33c). Ocular adverse event occurred in 24%, including conjunctival hyperemia (21%), burning and stinging (5.9%), a foreign body sensation (3.7%), and allergic reactions (0.8%). Systemic adverse events occurred in 3.7% and included fatigue (3.1%), headache (1.4%), and nausea (0.3%). It is difficult to assess whether some of these common systemic adverse events were due to the drug.
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Sensory systems An iris pigment epithelial cyst has been associated with topical prostaglandin F2a analogues in a 76-year-old woman (34A). The cyst disappeared after withdrawal of latanoprost and recurred after rechallenge with latanoprost or bimatoprost, supporting a causal effect. The cyst did not disappear completely after drug withdrawal. It is therefore uncertain whether the cyst itself was caused by the prostaglandin analogues or whether it caused an increase in its size due to accumulation of fluid in the cyst. Choroidal detachment is a well-recognized early complication of trabeculectomy, if the eye is hypotonic in the early postoperative period. Delayed choroidal detachment and hypotony have been reported in association with the use of topical prostaglandin analo gues. Late-onset choroidal detachment after combined cataract and glaucoma surgery (phacoemulsification and trabeculectomy) has been associated with the use of topical latanoprost in the fellow eye (35A). • An 89-year-old white woman developed gra dually reduced vision in her left eye after combined phacoemulsification and trabecu lectomy 11 months before. She was using topical latanoprost 0.005% once daily in her right eye only. Examination of the left eye showed visual acuity of hand movements, an intraocular pressure of 0 mmHg, a deep ante rior chamber and a non-leaking trabeculect omy bleb. Gonioscopy showed an open anterior chamber angle, Schaeffer grade III. There was no cyclodialysis. Left fundoscopy showed extensive choroidal detachment in all quadrants, confirmed by B-scan ultrasono graphy. Intraocular pressure in the right eye was 10 mmHg. Latanoprost was withdrawn. Over the next 6 weeks, the choroidal detach ment in the left eye resolved completely, the intraocular pressure rose to 12 mmHg and Snellen visual acuity improved to 6/9. The intraocular pressure in the right eye remained within the reference range without treatment. The Naranjo causality scale suggested that the adverse reaction was possibly due to lata noprost. The choroidal detachment had not recurred at 1 year follow-up after withdrawal of latanoprost.
Late choroidal detachment after trabecu lectomy is rare in the absence of a leaking bleb. It has been reported up to 5 years after trabeculectomy in association with topical latanoprost in the involved eye. In
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this patient, latanoprost 0.005% was being used once daily in only the fellow eye. The eye takes up about 1% of topical latanoprost and the remainder is absorbed into the sys temic circulation. In studies in which patients have been treated with latanoprost in one eye only, intraocular pressure in the fellow eye was reduced by only 0.4–1.2 mmHg. However, previous glaucoma surgery is likely to alter dose-responsiveness to intraocular pressure-lowering agents. In addition, indivi dual patient sensitivity is likely to vary. The authors suggested that the patient’s sensitiv ity to systemically absorbed latanoprost, combined with the altered intraocular milieu after previous surgery, had been sufficient to cause chronic hypotony and choroidal detachment. Sensory systems The histological and cytological changes in the irises of 15 patients who had used latanoprost and had photographically demonstrated darkening of the iris have been compared to the irises of 15 controls who had never been exposed to latanoprost (36c). The specimens of iris were taken during trabeculectomy. A masked observer conducted extensive histological, cytological, and electron microscopic examinations. The darkening effect of latanoprost was not associated with either proliferative or generative iris changes, nor with increases in the number of granules. Instead, it appeared to be due to small increases in the size of mature melanin granules, particularly in the anterior border region. In a prospective observer-masked study of the effect of patient age on the incidence of latanoprost-induced increases in iris pigmen tation in unilaterally treated eyes in 36 patients under 60 years and 36 patients older than 75 years with primary open-angle glaucoma, heterochromia was assessed by means of photographs of both eyes at base line and after 6 months of follow-up (37c). Age was an important susceptibility factor for latanoprost-induced iris color change, because 28 of the older patients developed an increase in iris pigmentation (78%) com pared with 8 of the younger (22%).
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Macular edema can occur during the use of latanoprost and has been reported in a phakic patient with idiopathic juxtafoveal retinal telangiectasis using latano prost (38A). Patients with idiopathic juxtafoveal retinal telangiectasis are at risk of macular edema. Skin Latanoprost can cause hyper pigmentation of the periocular skin and has also been reported to darken a facial skin graft (39A). The darkening abated after withdrawal.
Travoprost
(SED-15, 3481; SEDA-31, 742)
Sensory systems Acute iritis and corneal edema developed after only two doses of travoprost (40A). • A 70-year-old Caucasian woman with primary open-angle glaucoma developed redness, discomfort, and blurring of vision in her left eye. She had used timolol and dorzolamide combination therapy for 1 year, and then travoprost was added to the left eye. Her symptoms began after only two doses. She stopped using travoprost and 10 days later the discomfort resolved. Latanoprost was then added without adverse effects.
In a before-and-after study in 379 patients with glaucoma or ocular hyperten sion, central corneal thickness was reduced by a mean of 6.9 µm, but without a signifi cant effect on intraocular pressure (41c). A control group was not included in this study, limiting a causal interpretation. If the thin ning is causative, based on a presumed effect on extra matrix remodelling, the effect is small (about a 1% change in cor neal thickness). Uveitis is rare in patients who use latano prost or travoprost, but drug withdrawal should be considered in patients who develop uveitis while using these drugs. In one patient, corneal edema and anterior uveitis occurred after two doses of travo prost and resolved 10 days after withdrawal of travoprost (40A). The intraocular was
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controlled with latanoprost, which did not cause uveitis in this patient. Hair Prostaglandins cause growth of lashes and ancillary hairs around the eye lids. Manifestations include greater thick ness and length of lashes, additional rows, and conversion of vellus to terminal hairs in canthal areas as well as in regions adja cent to the rows. Vellus hairs of the lower eyelids also undergo increased growth and pigmentation. Eyelash hypertrichosis has been reported in 75% of patients in clinical trials of travoprost in ocular hypertension. Prostaglandin analogues are thought to prolong the anagen phase of eyelash growth. Travoprost has therefore been proposed as a possible treatment for alope cia areata involving the eyelashes. Periocular skin pigmentation developed in three patients during treatment with topical travoprost for alopecia areata involving the eyelashes (42A).
Combinations of anti-glaucoma drugs Observational studies In 3333 patients using anti-glaucoma drugs, satisfaction, ocular adverse events, and the probability of changing eye-drops because of adverse events have been studied (43C). Although there were differences between drugs, they were not statistically significant for tolerability or the chance of discontinuing a drug. There was a statistically significant difference for the sum scores of adverse ocular events, because of a lower rate in those who used timolol gellans and a higher rate in those who used other combination of three or more medications. Comparative studies Brimonidine and lata noprost In a meta-analysis of randomized controlled comparisons of brimonidine and latanoprost, fatigue was more common with brimonidine (RR = 3.7; 95% CI = 1.14, 13); the risks were 5% (11/211) in those who
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used brimonidine and 1% (3/247) in those who used latanoprost (44M). There were no differences in other adverse events between the two groups. Brimonidine and brinzolamide Brimoni dine 0.15% (n = 79) and brinzolamide 1% (n = 84) added to travoprost have been compared in a 3-month, randomized, double-masked, parallel-group design (45C). The most frequent adverse events were allergy, eye pain, headache, hyperemia, and taste disturbances. The incidences were not significantly different between the groups, but that does not mean that the two drugs are equivalent in terms of the incidences of adverse effects. Brinzolamide and levobetaxolol Adverse events in a randomized, double-masked study of brinzolamide (n = 32) and levobe taxolol (n = 46) have been evaluated in children aged under 6 years with congeni tal glaucoma, with a follow-up of 12 weeks (46C). Adverse events that were judged to be related to the drugs were hyperemia, discharge, discomfort, tearing, foreign body sensations, hordeolum, pruritus of the eye, fatigue, and bradycardia. No con cerns arose with regard to visual acuity, the adnexae, anterior segment, posterior seg ment, or vitreous, patient alertness, or car diovascular parameters. Eight patients (five using brinzolamide and three using levobetaxolol) had increased corneal dia meter of at least 1 mm in at least one eye. In two patients (using brinzolamide) this was considered to be clinically relevant, but these patients also had increased intraocular pressure. The adverse events in the overall population were predomi nately non-serious and were generally mild to moderate in intensity. No patient had a serious adverse event that was related to a study drug. There were no withdrawals because of adverse events. Dorzolamide and timolol Dorzolamide 2% and timolol 0.5% either alone (n = 70) or added to latanoprost (n = 280) have been compared in an open
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non-randomized study (47c). There were 116 predominantly mild non-serious adverse events reported by 86 patients (25%). The most frequent were eye irritation (n = 42; 12%) and a bad taste in the mouth (n = 15; 4%). There were five treatment-related non-serious adverse events of severe intensity (eye irritation, diarrhea, nausea, gout, and headache). There were no serious adverse events. Systematic reviews In a systematic review of seven randomized controlled trials, there were no differences in adverse events between fixed combinations compared with the non-fixed components administered concomitantly (48M). The rates were 8–43%, and there were more overall drug-related adverse events in the non-fixed group in five of the seven studies. More patients withdrew because of intolerance or adverse events in the non-fixed combination groups in one of the seven studies; the rates were 1–6% and 13% in one study. Three main ocular adverse effects were reported: hyperemia, ocular irritation, and keratitis. Hyperemia was reported in all of the studies, and in three studies of prostaglandins there were more cases in the fixed than in the nonfixed groups; this difference was significant in one study. The systemic effect with the highest rate was bitter taste with dorzolamide, with equal rates in the fixed and non-fixed therapies.
PROCEDURES Intravitreal injection (SEDA-29, 581) Sensory systems Endophthalmitis after intravitreal injection has been reviewed (49R). Infectious endophthalmitis is most probably related to the procedure, and sterile endophthalmitis (uveitis) can also be due to the drug used.
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References 1. Bock F, Konig Y, Kruse F, Baier M, Cursie fen C. Bevacizumab (Avastin) eye drops inhibit corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 2008; 246:281–4. 2. Takeda AL, Colquitt J, Clegg AJ, Jones J. Pegaptanib and ranibizumab for neovascular age-related macular degeneration: a sys tematic review. Br J Ophthalmol 2007; 91:1177–82. 3. Macugen AMD, Group S, Apte RS, Modi M, Masonson H, Patel M, Whitfield L, Adamis AP. Pegaptanib 1-year systemic safety results from a safety-pharmacokinetic trial in patients with neovascular age-related macular degen eration. Opthalmology 2007; 114:1702–12. 4. Frenkel REP, Mani L, Toler AR, Frenkel MPC. Intraocular pressure effects of pegap tanib (macugen) injections in patients with and without glaucoma. Am J Ophthalmol 2007; 143:1034–5. 5. Steffensmeier ACG, Azar AE, Fuller JJ, Muller BA, Russell SR. Vitreous injections of pegaptanib sodium triggering allergic reactions. Am J Ophthalmol 2007; 143:512–3. 6. Dayani PN, Siddiqi OK, Holekamp NM. Safety of intravitreal injections in patients receiving warfarin anticoagulation. Am J Ophthalmol 2007; 144:452–3. 7. Tilanus MA, Vaandrager W, Cuypers MH, Verbeek AM, Hoyng CB. Relationship between anticoagulant medication and mas sive intraocular hemorrhage in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2000; 238:482–5. 8. Antoszyk AN, Tuomi L, Chung CY, Singh A. Ranibizumab combined with verteporfin photodynamic therapy in neovascular agerelated macular degeneration (FOCUS): year 2 results. Am J Ophthalmol 2008; 145:862–74. 9. Regillo CD, Brown DM, Abraham P, Yue H, Ianchulev T, Schneider S, Shams N. Randomi zed, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol 2008; 145:239–48. 10. Kourlas H, Abrams P. Ranibizumab for the treatment of neovascular age-related macu lar degeneration: a review. Clin Ther 2007; 29(9):1850–61.
11. Lee GKY, Lai TYY, Chan W, Lam DSC. Retinal pigment epithelial tear following intravitreal ranibizumab injections for neo vascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2007; 45:1225–7. 12. Carvounis PE, Kopel AC, Benz MS. Retinal pigment epithelium tears following rani bizumab for exudative age-related macular degeneration. Am J Ophthalmol 2007; 143:504–5. 13. Bakri SJ, Kitzmann AS. Retinal pigment epithelial tear after intravitreal ranibizumab. Am J Ophthalmol 2007; 143:505–7. 14. Chan CK, Lin SG. Retinal pigment epithelial tear after ranibizumab therapy for subfoveal fibrovascular pigment epithelial detachment. Eur J Ophthalmol 2007; 17(4):674–6. 15. Apte RS. Retinal pigment epithelial tear after intravitreal ranibizumab for subfoveal CNV secondary to AMD. Int Ophthalmol 2007; 27(1):59–61. 16. Kiss C, Michels S, Prager F, Geitzenauer W, Schmidt-Erfurth U. Retinal pigment epithe lium tears following intravitreal ranibizumab therapy. Acta Ophthalmol Scand 2007; 85:902–3. 17. Bakri SJ, McCannel CA, Edwards AO, Moshfeghi DM. Persisent ocular hypertension following intravitreal ranibizumab. Graefes Arch Clin Exp Ophthalmol 2008; 246:955–8. 18. Mojica G, Hariprasad SM, Jager RD, Mieler WF. Short-term intraocular pressure trends following intravitreal injections of ranibizu mab (Lucentis) for the treatment of wet agerelated macular degeneration. Br J Ophthal mol 2008; 92:584. 19. Anonymous. Ranibizumab: new drug. Macu lar degeneration: second-line use due to risks. Prescrire Int 2008; 17(93):3–6. 20. Ohji M, Tano Y, Bressler NM, Ishibashi T, Shiraga F, Takahashi K, Weisberger A, Yuzawa M, Japanese Age-Related Macu lar Degeneration Trial (JAT) Study Group. Photodynamic therapy with verte porfin in Japanese patients with subfoveal choroidal neovascularization secondary to age-related macular. Jpn J Ophthalmol 2008; 52:1049–61.
876 21. Slakter JS, Bochow T, Amico D’, Marks B, Jerdan J, Sullivan K; Anecortave Acetate Clinical Study Group. Anecortave acetate (15 milligrams) versus photodynamic ther apy for treatment of subfoveal neovascular ization in age-related macular degeneration. Ophthalmology 2006; 113:3–13. 22. Blaha GR, Wertz III FD, Marx JL. Profound choroidal hypoperfusion after combined photodynamic therapy and intravitreal triam cinolone acetonide. Ophthal Surg Lasers Ima ging 2008; 39:6–11. 23. Chan W-M, Lai TYY, Lai RYK, Liu DTL, Lam DSC. Half-dose verteporfin photo dynamic therapy for acute central serous chorioretinopathy. One-year results of a ran domized controlled trial. Ophthalmology 2008; 115:1756–65. 24. Watts P, Satterfield D, Lim MK. Adverse effects of apraclonidine used in the diagnosis of Horner syndrome in infants. J AAPOS 2007; 11:282–3. 25. Nguyen EV, Azar D, Papalkar D, McClus key P. Brimonidine-induced anterior uveitis and conjunctivitis: clinical and histologic fea tures. J Glaucoma 2008; 17:40–2. 26. Hegde V, Robinson R, Dean F, Mulvihill HA, Ahluwalia H. Drug-induced ectropion. What is best practice? Ophthalmology 2007; 114:362–6. 27. Henness S, Harrison TS, Keating GM. Ocu lar carteolol: a review of its use in the management of glaucoma and ocular hyper tension. Drugs Aging 2007; 24:509–28. 28. Seider N, Miller B, Beiran I. Topical glau coma therapy as a risk factor for nasolacri mal duct obstruction. Am J Ophthalmol 2008; 145(1):120–3. 29. Weiss AH, Kelly JP. Reappraisal of astigma tism induced by periocular capillary heman gioma and treatment with intralesional corticosteroid injection. Ophthalmology 2008; 115:228–30. 30. Konstas AGP, Holló G, Irkec M, Tsironi S, Durukan I, Goldenfeld M, Diurnal MS. IOP control with bimatoprost versus latanoprost in exfoliative glaucoma: a crossover, obser ver-masked, three-centre study. Br J Ophthalmol 2007; 91:757–60. 31. Sharpe ED, Reynolds AC, Skuta GL, Jen kins JN, Stewart WC. The clinical impact and incidence of periocular pigmentation
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33.
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associated with either latanoprost or bimatoprost therapy. Curr Eye Res 2007; 32:1037–43. Konstas AG, Kozobolis VP, Katsimpris IE, Boboridis K, Koukoula S, Jenkins JN, Stew art WC. Efficacy and safety of latanoprost versus travoprost in exfoliative glaucoma patients. Ophthalmology 2007; 114:653–7. Thelen U, Christ T, Schnober D, Hofstetter H-J, Stewart WC. Midterm response with latanoprost therapy in German ocular hyper tension patients. Curr Eye Res 2007; 32:51–6. Krohn J, Hove VK. Recurring iris pigment epithelial cyst induced by topical prostaglan din F2a analogues. Arch Ophthalmol 2008; 126:867–8. Horgan N, Kirwan RP, O’Brien CJ. Choroi dal detachment associated with latanoprost use in the fellow eye. Ann Pharmacother 2007; 41(1):161–2. Cracknell KPB, Grierson I, Hogg P. Morphometric effects of long-term exposure to latanoprost. Ophthalmology 2007; 114: 938–48. Arranz-Marquez E, Teus MA. Effect of age on the development of a latanoprost-induced increase in iris pigmentation. Ophthalmology 2007; 114(7):1255–8. Baba T, Nagayama M, Ohtsuki H, Hirooka K, Shiraga F. Macular edema associated with latanoprost use in a patient with idiopathic juxtafoveal retinal telangiectasis. Jpn J Ophthalmol 2008; 52:68–70. Calladine D, Harrison RJ. Severe darkening of a facial skin graft from latanoprost. Arch Ophthalmol 2007; 125:1427–8. Aydin S, Ozcura F. Corneal oedema and acute anterior uveitis after two doses of tra voprost. Acta Ophthalmol Scand 2007; 85 (6):693–4. Harasymowycz PJ, Papamatheakis DG, Ennis M, Brady M, Gordon KD, Archam bault P, Bazin G, Boucher S, Brochu J, Char bonneau A, Chehade N, Cohen S, Deschenes C, Gelinas G, Gosselin M, Hase gawa N, Isabelle N, Kavalec C, Krauss D, Lalonde G, Lalonde L, Lapointe A, Mayer J, Noel F, Podtetenev M, Robrerge M, Simard M, Weldon C. Relationship between travoprost and central corneal thickness in ocular hypertension and open-angle glau coma. Cornea 2007; 26:34–41.
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42. Feletti F, Vincenzi C, Pazzaglia M, Tosti A. Periocular pigmentation associated with use of travoprost for the treatment of alopecia areata of the eyelashes. J Eur Acad Derma tol Venereol 2007; 21(3):421–3. 43. Beckers HJM, Schouten JSAG, Webers CAB, Valk R, Hendrikse F. Side effects of commonly used glaucoma medications: comparison of tolerability, chance of dis continuation, and patient satisfaction. Graefes Arch Clin Exp Ophthalmol 2008; 246:1485–90. 44. Fung AT, Reid SE, Jones MP, Healey PR, McCluskey PJ, Craig JC. Meta-analysis of randomised controlled trials comparing lata noprost with brimonidine in the treatment of open-angle glaucoma, ocular hypertension or normal-tension glaucoma. Br J Ophthalmol 2007; 91:62–8. 45. Feldman RM, Tanna AP, Gross RL, Chuang AZ, Baker L, Reynolds A, Prager TC. Comparison of the ocular hypotensive efficacy of adjunctive brimonidine 0.15% or
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47.
48.
49.
brinzolamide 1% in combination with travo prost 0.004%. Ophthalmology 2007; 114: 1248–54. Whitson JT, Roarty JD, Vijaya L, Robin AL, Gross RD, Landry TA, Dickerson JE, Scheib SA, Scott H, Hua SY, Woodside AM, Berga mini MVW. Efficacy of brinzolamide and levobetaxolol in pediatric glaucomas: a rando mized clinical trial. J AAPOS 2008; 12:239–46. Lesk MR, Koulis T, Sampalis F, Sampalis JS, Bastien NR. Effectiveness and safety of dor zolamide–timolol alone or combined with latanoprost in open-angle glaucoma or ocu lar hypertension. Ann Pharmacother 2008; 42:498–504. Cox JA, Mollan SP, Bankart J, Robinson R. Efficacy of antiglaucoma fixed combination therapy versus unfixed components in redu cing intraocular pressure: a systematic review. Br J Ophthalmol 2008; 92:729–34. Ho J, Loewenstein JI. Endophthalmitis asso ciated with intravitreal injections. Int Ophthalmol Clin 2007; 47:199–208.
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Drugs used in ocular treatment
DRUGS USED IN THE MANAGEMENT OF AGE-RELATED MACULAR DEGENERATION (SEDA-30, 545; SEDA-31, 739)
Bevacizumab (SEDA-30, 545) Sensory systems Bevacizumab eye-drops, 5 mg/ml, used five times a day for 0.5–6 months in five patients, mean age 42 years, to reduce corneal neovasculari zation, did not have any epithelial adverse effects (1c).
Pegaptanib
(SEDA-31, 739)
Systematic reviews The adverse events in two trials of pegaptanib have been summarized in a systematic review (2M). Adverse effects were common, but most were transient mild to moderate events, and serious events were rare. There was endophthalmitis in 1.3% of patients in the first year, but in none of those who continued to use pegaptanib for a second year. Significantly, more of the patients who received pegaptanib than those who received sham injections had vitreous floaters (33% versus 8%), vitreous opacities (18% versus 10%), and anterior Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32047-2 2010 Elsevier B.V. All rights reserved.
chamber inflammation (14% versus 6%) in the first year of the VISION study. Observational studies Pegaptanib has been investigated in a combined study, including open administration in 37 patients, who were given 3 mg in 0.09 ml, and a randomized, double-masked, uncontrolled, multi center study in 110 patients, who were given 1 or 3 mg in 0.09 ml (3C). The dose of pegaptanib was three or ten times higher than the normal dose and was given every 6 weeks for 54 weeks. The mean number of injections was 9.6. No patients were lost to follow-up. Although there were urine abnormalities (proteinuria, hematuria, or altered albumin-to-creatinine ratio), these normalized after 60 weeks, or had not changed after 60 weeks, or were attributed to a disease. There were no important changes in hematological parameters, liver function, renal function, or electrolytes. There were no important changes from mean or median baseline measurements in vital signs, including blood pressure, and no changes in electrocardiography. All but two patients had at least one adverse event and 28 of 147 (19%) had serious adverse events, most often cardiac disorders. No patient withdrew because of adverse events, and there were no differences between the groups in overall adverse event rates. Nonocular adverse events were uncommon and there was no evidence of systemic toxicity. Five patients died before week 60 and within 60 days of the previous dose, but no deaths were considered to be related to the study treatment. There were ocular adverse events in the study eye in 138 of 147 patients
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(94%); most were mild to moderate in intensity. Only one ocular adverse event was reported as serious (moderate retinal hemorrhage); it was reported on day 245 and was considered to be unrelated to the treatment. There were no cases of endophthalmitis, retinal detachment, or traumatic cataract. The most common ocular adverse events were eye pain (69/147; 47%), vitreous floaters (63/147; 43%), punctate keratitis (60/147; 41%), visual disturbances (37/147; 25%), eye irritation (33/147; 22%), and increased intraocular pressure (31/147; 21%); 11 patients (7%) had mild anterior chamber inflammation. Most events occurred with similar frequencies across the treatment groups, but the incidence of increased intraocular pressure was greater with pegaptanib 3 mg. Most of the ocular adverse events were attributed by the investigators to the injection procedure, and few were attributed to the study drug. As expected, the incidence of ocular adverse events in the fellow eye was much lower than that in the study eye (35% versus 94%). Fluorescein angiography showed no retinal vascular or choroidal abnormalities in the study eye that were not expected during the natural progression of neovascular agerelated macular degeneration. There were no notable delays in arteriovenous transit time, abnormalities in choroidal perfusion or arteriolar occlusions. Sensory systems Intravitreal injections of 0.09 ml pegaptanib cause increased intraocular pressure (4c). Of 75 patients 77% had received prophylactic pressurelowering medications 1 hour before treatment. Immediately after the injection, pressure was exerted on the globe to lower intraocular pressure. Vision was also evaluated immediately after injection. Four patients had no light perception after the injection and the initial pressure was over 55 mmHg; immediate anterior chamber paracentesis was conducted. The mean preinjection pressure for the first injection was 14 mmHg, at 1 minute after injection
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J.S.A.G. Schouten
38 mmHg, at 3–10 minutes 34 mmHg, and at 11–20 minutes 26 mmHg. In most cases the pressure fell significantly by 30 minutes after injection. There was no difference between patients with and without glaucoma. The increase in intraocular pressure was related to the volume injected, which in the case of pegaptanib is 0.09 ml. The pressure even increases in patients who received pressure-lowering drugs before treatment, and anterior chamber paracentesis before injection or use of a smaller volume (with another anti-VEGF drug) could be the best way to prevent the pressure increase. Immunologic In two cases systemic allergic reactions were associated with intravitreous administration of pegaptanib (5A).
Autacoids A patient with occult choroidal neovascularization had a prolonged anaphylactoid reaction 35 minutes after a first dose of intraocular pegaptanib sodium 0.3 mg. The reaction included oral angioedema and generalized urticaria. Later skin tests with several medications that the patient had been given, including pegaptanib, were negative, except for intradermal histamine. IgE antibodies for latex were also negative. Six weeks later the patient received an injection of bevacizumab uneventfully. Another patient received four injections of pegaptanib over 6 months, and 12 hours after each injection, he developed mild lip angioedema that lasted for hours and an urticarial rash that lasted for days. He had these adverse events after each of four injections, but reported them only after the fourth injection. No other changes in his medical regimen or environment explained his symptoms. Bevacizumab was used for subsequent injections without adverse events. The authors described this as an anaphylactoid reaction (i.e. a non-IgE mediated anaphylactic reaction), since it occurred after the first injection and skin tests were negative. They hypothesized that the reactions could have been related to the polyethylene glycol moieties in
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Chapter 47
pegaptanib, since polyethylene glycol-con taining products have been associated with cutaneous contact sensitivity, urticarial reactions, angioedema, and anaphylactoid reactions. Drug–drug interactions Warfarin The safety of intravitreal injections in patients with age-related macular degeneration using warfarin has been investigated in 31 patients who received 102 injections of pegaptanib (6c). There were no intraoperative or immediate postoperative hemorrhagic complications. One patient had an acute submacular hemorrhage 35 days after the third injection. There were no other hemorrhagic events. Submacular bleeding can also occur in patients with macular degeneration without intravitreal injections. Patients with exudative disease (‘wet’ degeneration) are at risk of massive macular bleeding when using anticoagulants and in many patients this therapy should be withdrawn (7c).
Ranibizumab
(SEDA-30, 545;
SEDA-31, 739) Comparative studies Adverse events have been reported in the 2-year results of a randomized, single-masked, controlled trial of ranibizumab 0.5 mg þ verteporfin photo dynamic therapy (n = 106) versus verte porfin photodynamic therapy alone (n = 56) in neovascular age-related macular degen eration (FOCUS study) (8C). Serious ocular adverse events occurred more often in those who received ranibizumab þ photodynamic therapy (17% versus 14%). This was due to endophthalmitis (2.9%, 3/105, versus 0%) and ocular inflammation (12%, 13/105, ver sus 0%). Serious systemic vascular events occurred more often with ranibizu mab þ photodynamic therapy (14/105, 13% versus 6/56, 11%). The authors reported that the cumula tive rates of serious non-ocular adverse events were similar in the two groups at 2 years (17/56 versus 30/105). Of the serious
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non-ocular adverse vascular events, which might plausibly have been due to systemic VEGF inhibition, the cumulative rates were 6/56 (11%) versus 14/105 (13%). Hypertension among patients who were not hypertensive at study entry emerged as a serious adverse event in only one patient who received ranibizumab. The rates of non-ocular hemorrhage were balanced between the groups (4/56 versus 7/105), and none was reported as serious. Arterial thromboembolic events as defined using the Antiplatelet Trialists’ Collabora tion (APTC) criteria (i.e. vascular death or death from an unknown cause, non-fatal myocardial infarction, non-fatal ischemic or hemorrhagic stroke, or stroke of unknown cause) were slightly more com mon in those who received photodynamic therapy alone (4/56 versus 5/105). Placebo-controlled studies In a multi center, randomized, double-masked, sham injection-controlled trial in patients with predominantly or minimally classic or occult with no classic lesions due to age-related macular degeneration, 184 patients were randomized to ranibizumab 0.3 or 0.5 mg or to sham treatment (9C). Ranibizumab was given monthly for 3 months and then quarterly. Assessment of serious or non-ser ious non-ocular adverse events showed no overall difference between the groups. There were no deaths during the first year of treatment. Hypertension in subjects who were not hypertensive at baseline was reported as an adverse event in 8.1% of sham-treated subjects, 6.8% of those who received ranibizumab 0.3 mg and 8.2% of those who received 0.5 mg. Routinely mea sured systolic and diastolic blood pressures were very similar among groups at baseline and at 12 months. Proteinuria was not reported during the first year. The rates of non-ocular hemorrhage were 2.4 and 6.6% with ranibizumab 0.3 and 0.5 mg respec tively, and 4.8% in the sham group. There was only one case of serious non-ocular hemorrhage (hemorrhage at the site of an intravenous catheter in a subject who received ranibizumab 0.5 mg). There were
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no cases of gastrointestinal perforation. There were no arterial thromboembolic events. The only serious or non-serious arterial thromboembolic event during the first year was ischemic cardiomyopathy in a sham-treated subject. Immunoreactivity to ranibizumab was assessed at screening and at month 12 or at early termination. During screening, one subject randomized to sham treatment tested positive, possibly because of pre-existing anti-Fab anti bodies. None of those who received rani bizumab tested positive before study treatment, but two of those who received 0.5 mg group tested positive at month 12; neither of these two subjects had any severe or serious adverse events during the study. Systematic reviews The adverse events in three trials of ranibizumab have been summarized in a systematic review (2M) Endophthalmitis occurred in 1.4 and 1.9% of patients receiving 0.5 mg ranibizumab in the ANCHOR and FOCUS trials, respectively. The rate per injection was 0.05% in the MARINA trial. Sensory systems In a review of three large clinical trials of ranibizumab in the treatment of age-related macular degeneration, serious adverse ocular events occurred in association with <0.1% of intravitreal injections (10M). They included retinal detachment and endophthalmitis. Less serious adverse ocular reactions occurred in <2% of patients, including intraocular inflammation and increased intraocular pressure. Retinal pigment epithelial tears have been reported after intravitreal injection of rani bizumab. One patient already had a pigment epithelial detachment and the symptoms appeared only after the third injection, with no adverse events after the previous two dosages (11A). Six other patients with age-related macular degenera tion, four of whom had a pigment epithelial detachment, developed a retinal pigment epithelial tear after intravitreous injections of ranibizumab (12A, 13A). In other cases
Chapter 47
J.S.A.G. Schouten
this adverse event occurred within 2–6 weeks after the injections (14A–16A). Ocular hypertension can complicate intra vitreal injections. Four patients without a history of glaucoma or ocular hypertension had sustained ocular hypertension after intravitreal injections of ranibizumab (17A). The intraocular pressure rose as high as 30, 34, 46, and 50 mmHg, but only in the injected eye. All four were treated with topical anti-glaucoma medications. The importance of this observation is that the ocular pressure can be high and remain high after intravitreal injections of ranibizumab. In a retrospective chart review study in 50 patients, there was a short-term increase in ocular hypertension after intravitreal injec tion of ranibizumab from a mean of 14 (range 9–22) mmHg to 21 (range 10–31) mmHg (18c). There was no increase 1–4 weeks after injection. Hematologic Arterial thromboses at distant sites, in particular strokes, have been reported with intravitreous ranibizumab, at a higher frequency with 0.5 mg per injection (about 1%) than with 0.3 mg per injection (19r).
Verteporfin and photodynamic therapy (SEDA-30, 545; SEDA-31, 739); see also chapter 45 Observational studies After 12 months of photodynamic therapy with verteporfin in 64 patients with neovascular age-related macular degeneration, 51 received treat ment for a further 12 months (20c). In all, 118 adverse events were reported during the 12-month extension, of which 14 were considered possibly or probably related to the treatment. This compares with 47 (26%) of 180 adverse events that were considered possibly or probably related to the treatment during the first 12 months of the study in the 51 patients who enrolled in the extension. Most of the adverse events were mild to moderate in
Drugs used in ocular treatment
Chapter 47
intensity. Three patients withdrew because of an adverse event during the first 12 months, and three did so during the extension. The adverse events during the extension phase were similar to those during the first 12 months, but a further seven patients had reduced vision, none related to the drug. One patient had an injection-site hemorrhage during the extension. There were no photosensitivity reactions at any time. Comparative studies Photodynamic ther apy with verteporfin has been compared with anecortave 15 mg under Tenon’s capsule at baseline and at 6 months as a periocular posterior juxtascleral depot (21C). There were no differences between the groups. The most common adverse event was reduced visual acuity, but there was no differ ence between the groups. There were 15 deaths, which were assessed as being un related to the treatment. There were non fatal serious adverse events in 97 patients (18%) during 12 months, of whom 45 (17%) received verteporfin. These were thought to be unrelated to the therapy or the injection procedure. Treatment had to be withdrawn because of adverse events in 13 patients (5%) who received verteporfin. Sensory systems Profound choroidal hypoperfusion occurred after verteporfin photodynamic therapy and intravitreal triam cinolone acetonide for age-related macular degeneration in 15 out of 108 patients with 155 treatments (22C). No susceptibility factors were identified. It occurred after the first treatment in some cases (n = 7) and after retreatment in others. If profound hypoperfu sion had occurred after several treatments, mild hypoperfusion had occurred after earlier treatments. Three patients with profound hypoperfusion were re-treated because of recurrence of the neovascularization. In all three the severity of hypoperfusion increased. Five patients with profound choroidal hypoperfusion had a pretreatment visual acuity of 20/80. The visual acuity worsened to 20/100 in two patients and to counting fingers in two;
869
it increased by one line in one patient. Chor oidal hypoperfusion has been reported in patients with age-related macular degenera tion who were treated with verteporfin photo dynamic therapy, but the rate in this study (15/108) was higher than previously reported. Intravitreal triamcinolone may have contrib uted to the risk by preventing the inflamma tory response to photodynamic therapy and re-perfusion of normal vessels afterwards. Dosage regimens When verteporfin photodynamic therapy is used for choroidal neovascularization in age-related macular degeneration, adverse events include atrophy of the retinal pigment epithelium, choroidal ischemia, secondary choroidal neovascularization and transiently reduced macular function. Because of these adverse events, and since patients with acute central serous chorioretinopathy generally have a fairly good vision and a good prognosis, the effect of half-dose verteporfin has been investigated. Verteporfin 3 mg/m2 was infused over 8 minutes and indocyanine green angiography guided photodynamic therapy with 50 J/cm2 light energy was used to treat 43 eyes in 43 patients with acute central serous chorioretinopathy (23c). There were no ocular or systemic adverse events.
ADRENOCEPTOR AGONISTS (SEDA-28, 569; SEDA-31, 740)
Apraclonidine Susceptibility factors Children In five infants suspected of having Horner’s syndrome, apraclonidine eye-drops were used diagnostically (24Ac). The main adverse event was drowsiness in three cases; two required emergency admission for unresponsiveness. In one case there was bradycardia, hypertension, and reduced oxygen saturation. Based on these observations, apraclonidine eye-drops should not be used in infants.
870
Brimonidine Sensory systems Brimonidine was reported to have caused granulomatous anterior uveitis and granulomatous papillary conjunctivitis after 2 years of treatment in a 78-year-old man (25A). Extensive additional investiga tions did not reveal an underlying cause. Withdrawal of brimonidine led to improve ment in 2 days and complete resolution within 1 month. Skin In 13 patients with periorbital dermatitis, ectropion was presumed to have been due to one or more of the drugs that they were using: brimonidine, betaxolol, dorzolamide, latanoprost, preservatives, timolol, or travoprost; the drugs were withdrawn and the patients were assessed again, with rechallenge after the last assessment (26c). The ectropion resolved partly or completely after the eye-drops had been withheld, and there was recurrence after rechallenge. Dorzolamide (seven cases) was the most common offender, followed by brimonidine (three cases). In six cases more than one drug was implicated, and in five cases the preservative in which the drug was formulated was blamed.
BETA-ADRENOCEPTOR ANTAGONISTS (SEDA-26, 525; SEDA-27, 509; SEDA-31, 740)
Carteolol Observational studies Carteolol is a non selective beta-adrenoceptor antagonist used in the treatment of glaucoma and ocular hypertension. During trials of carteolol 1–2% two patients had serious cardiac events, including bradycardia, congestive heart failure, and myocardial infarction; one had hypotension, which required drug withdrawal. Withdrawal was also necessary in one patient who developed bronchoconstriction and in five who developed breathlessness;
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J.S.A.G. Schouten
patients with pulmonary disease had been excluded. These reactions act as a reminder that beta-blocker eye-drops can cause systemic adverse effects. Cardiovascular There are few if any differences between carteolol and other beta-adrenoceptor antagonists in terms of their effects on heart rate, blood pressure, or FEV1 in patients with glaucoma or ocular hypertension. However, in one study there was a significantly lower incidence of cardiovascular adverse events overall and a significantly lower incidence of bradycardia with carteolol than with timolol; in particular, carteolol seemed less likely to induce nocturnal bradycardia. Standard carteolol and long-acting carteolol did not differ in their effects on blood pressure or heart rate. Sensory systems The effects of carteolol eye-drops 1 and 2% have been reviewed (27R). The most common ocular symptoms were burning/stinging at the time of instillation, tearing, ocular pain, blurred vision, itching, and conjunctival hyperemia. In general, there were no significant differences in the incidence of ocular symptoms between patients who used carteolol and those who used other beta-adrenoceptor antagonists, such as timolol, metipranolol, or levobunolol. However, several studies have shown better ocular tolerability of carteolol versus timolol for certain end-points (e.g. fewer ocular symptoms overall and less burning and eye pain). The long-acting formulation of carteolol was associated with blurred vision in under 2% of patients.
Timolol
(SED-15, 3428; SEDA-31, 741)
Sensory systems In a retrospective study of 209 eyes (178 patients) with primary acquired nasolacrimal duct obstruction and 183 control eyes in patients who underwent cataract surgery, the prevalence of primary openangle glaucoma was significantly higher in the former (48/209 versus 11/183) (28C).
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In those who had primary open-angle glaucoma, the duration was longer in the former (14 years versus 9.63 years) and the average number of topical anti-glaucoma drugs per treated eye was higher (1.58 versus 0.73). Significantly more patients with glaucoma and nasolacrimal duct obstruction (69% versus 18%) were using timolol. There were no statistically significant differences for other topical glaucoma drugs. The authors concluded that chronic use of timolol eyedrops in patients with glaucoma is associated with an increased risk of nasolacrimal duct obstruction. However, a causal effect of timolol can not be based on this study and the mechanism is speculative.
CARBONIC ANHYDRASE INHIBITORS See Chapter 21.
GLUCOCORTICOSTEROIDS (SED-15, 906; SEDA-30, 548; SEDA-31, 741) Observational studies Intralesional gluco corticoids are used to treat periocular capil lary hemangiomas. Adverse events in 13 infants were adrenal suppression, transient reductions in linear growth, and localized eyelid necrosis (29c).
PROSTAGLANDIN ANALOGUES (SEE ALSO CHAPTER 39) Comparative studies Bimatoprost and latanoprost Bimatoprost (0.03%) and latanoprost have been compared in 129 patients with exfoliative glaucoma in a 3-month crossover observer-masked study
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(30C). There were no serious adverse events. More patients reported at least one adverse event with bimatoprost than with latanoprost (58 patients versus 34 patients). Conjunctival hyperemia and hypertrichosis were more common with bimatoprost than with latanoprost (32 versus 9 and 14 versus 2, respectively). There were no significant differences in other adverse events (lid dermatitis, itching, stinging, ocular pain, foreign body sensation, blurred vision, headache, change in iris color, and periocular pigmentation). The number of adverse events at the end of the trial was independent of treatment order. The incidence of periocular pigmenta tion in patients using bimatoprost (0.03%) or latanoprost has been studied retrospectively (31c). The 12-month inci dence was 0.8% (2/263) in patients who used latanoprost and 5.8% (8/137) in those who used bimatoprost. The pig mentation disappeared without withdra wal of treatment in some patients. The pigmentation ranged from deep red to brown. Latanoprost and travoprost In an observer-masked, crossover comparison of latanoprost and travoprost in 40 patients with exfoliative glaucoma, travoprost more often led to conjunctival hyperemia than latanoprost (15 versus 6) (32c).
Latanoprost Observational studies The adverse events that occurred after at least 6 months (mean 2.2 years) during latanoprost monotherapy in 353 patients have been reported (33c). Ocular adverse event occurred in 24%, including conjunctival hyperemia (21%), burning and stinging (5.9%), a foreign body sensation (3.7%), and allergic reactions (0.8%). Systemic adverse events occurred in 3.7% and included fatigue (3.1%), headache (1.4%), and nausea (0.3%). It is difficult to assess whether some of these common systemic adverse events were due to the drug.
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Sensory systems An iris pigment epithelial cyst has been associated with topical prostaglandin F2a analogues in a 76-year-old woman (34A). The cyst disappeared after withdrawal of latanoprost and recurred after rechallenge with latanoprost or bimatoprost, supporting a causal effect. The cyst did not disappear completely after drug withdrawal. It is therefore uncertain whether the cyst itself was caused by the prostaglandin analogues or whether it caused an increase in its size due to accumulation of fluid in the cyst. Choroidal detachment is a well-recognized early complication of trabeculectomy, if the eye is hypotonic in the early postoperative period. Delayed choroidal detachment and hypotony have been reported in association with the use of topical prostaglandin analo gues. Late-onset choroidal detachment after combined cataract and glaucoma surgery (phacoemulsification and trabeculectomy) has been associated with the use of topical latanoprost in the fellow eye (35A). • An 89-year-old white woman developed gra dually reduced vision in her left eye after combined phacoemulsification and trabecu lectomy 11 months before. She was using topical latanoprost 0.005% once daily in her right eye only. Examination of the left eye showed visual acuity of hand movements, an intraocular pressure of 0 mmHg, a deep ante rior chamber and a non-leaking trabeculect omy bleb. Gonioscopy showed an open anterior chamber angle, Schaeffer grade III. There was no cyclodialysis. Left fundoscopy showed extensive choroidal detachment in all quadrants, confirmed by B-scan ultrasono graphy. Intraocular pressure in the right eye was 10 mmHg. Latanoprost was withdrawn. Over the next 6 weeks, the choroidal detach ment in the left eye resolved completely, the intraocular pressure rose to 12 mmHg and Snellen visual acuity improved to 6/9. The intraocular pressure in the right eye remained within the reference range without treatment. The Naranjo causality scale suggested that the adverse reaction was possibly due to lata noprost. The choroidal detachment had not recurred at 1 year follow-up after withdrawal of latanoprost.
Late choroidal detachment after trabecu lectomy is rare in the absence of a leaking bleb. It has been reported up to 5 years after trabeculectomy in association with topical latanoprost in the involved eye. In
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this patient, latanoprost 0.005% was being used once daily in only the fellow eye. The eye takes up about 1% of topical latanoprost and the remainder is absorbed into the sys temic circulation. In studies in which patients have been treated with latanoprost in one eye only, intraocular pressure in the fellow eye was reduced by only 0.4–1.2 mmHg. However, previous glaucoma surgery is likely to alter dose-responsiveness to intraocular pressure-lowering agents. In addition, indivi dual patient sensitivity is likely to vary. The authors suggested that the patient’s sensitiv ity to systemically absorbed latanoprost, combined with the altered intraocular milieu after previous surgery, had been sufficient to cause chronic hypotony and choroidal detachment. Sensory systems The histological and cytological changes in the irises of 15 patients who had used latanoprost and had photographically demonstrated darkening of the iris have been compared to the irises of 15 controls who had never been exposed to latanoprost (36c). The specimens of iris were taken during trabeculectomy. A masked observer conducted extensive histological, cytological, and electron microscopic examinations. The darkening effect of latanoprost was not associated with either proliferative or generative iris changes, nor with increases in the number of granules. Instead, it appeared to be due to small increases in the size of mature melanin granules, particularly in the anterior border region. In a prospective observer-masked study of the effect of patient age on the incidence of latanoprost-induced increases in iris pigmen tation in unilaterally treated eyes in 36 patients under 60 years and 36 patients older than 75 years with primary open-angle glaucoma, heterochromia was assessed by means of photographs of both eyes at base line and after 6 months of follow-up (37c). Age was an important susceptibility factor for latanoprost-induced iris color change, because 28 of the older patients developed an increase in iris pigmentation (78%) com pared with 8 of the younger (22%).
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Macular edema can occur during the use of latanoprost and has been reported in a phakic patient with idiopathic juxtafoveal retinal telangiectasis using latano prost (38A). Patients with idiopathic juxtafoveal retinal telangiectasis are at risk of macular edema. Skin Latanoprost can cause hyper pigmentation of the periocular skin and has also been reported to darken a facial skin graft (39A). The darkening abated after withdrawal.
Travoprost
(SED-15, 3481; SEDA-31, 742)
Sensory systems Acute iritis and corneal edema developed after only two doses of travoprost (40A). • A 70-year-old Caucasian woman with primary open-angle glaucoma developed redness, discomfort, and blurring of vision in her left eye. She had used timolol and dorzolamide combination therapy for 1 year, and then travoprost was added to the left eye. Her symptoms began after only two doses. She stopped using travoprost and 10 days later the discomfort resolved. Latanoprost was then added without adverse effects.
In a before-and-after study in 379 patients with glaucoma or ocular hyperten sion, central corneal thickness was reduced by a mean of 6.9 µm, but without a signifi cant effect on intraocular pressure (41c). A control group was not included in this study, limiting a causal interpretation. If the thin ning is causative, based on a presumed effect on extra matrix remodelling, the effect is small (about a 1% change in cor neal thickness). Uveitis is rare in patients who use latano prost or travoprost, but drug withdrawal should be considered in patients who develop uveitis while using these drugs. In one patient, corneal edema and anterior uveitis occurred after two doses of travo prost and resolved 10 days after withdrawal of travoprost (40A). The intraocular was
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controlled with latanoprost, which did not cause uveitis in this patient. Hair Prostaglandins cause growth of lashes and ancillary hairs around the eye lids. Manifestations include greater thick ness and length of lashes, additional rows, and conversion of vellus to terminal hairs in canthal areas as well as in regions adja cent to the rows. Vellus hairs of the lower eyelids also undergo increased growth and pigmentation. Eyelash hypertrichosis has been reported in 75% of patients in clinical trials of travoprost in ocular hypertension. Prostaglandin analogues are thought to prolong the anagen phase of eyelash growth. Travoprost has therefore been proposed as a possible treatment for alope cia areata involving the eyelashes. Periocular skin pigmentation developed in three patients during treatment with topical travoprost for alopecia areata involving the eyelashes (42A).
Combinations of anti-glaucoma drugs Observational studies In 3333 patients using anti-glaucoma drugs, satisfaction, ocular adverse events, and the probability of changing eye-drops because of adverse events have been studied (43C). Although there were differences between drugs, they were not statistically significant for tolerability or the chance of discontinuing a drug. There was a statistically significant difference for the sum scores of adverse ocular events, because of a lower rate in those who used timolol gellans and a higher rate in those who used other combination of three or more medications. Comparative studies Brimonidine and lata noprost In a meta-analysis of randomized controlled comparisons of brimonidine and latanoprost, fatigue was more common with brimonidine (RR = 3.7; 95% CI = 1.14, 13); the risks were 5% (11/211) in those who
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used brimonidine and 1% (3/247) in those who used latanoprost (44M). There were no differences in other adverse events between the two groups. Brimonidine and brinzolamide Brimoni dine 0.15% (n = 79) and brinzolamide 1% (n = 84) added to travoprost have been compared in a 3-month, randomized, double-masked, parallel-group design (45C). The most frequent adverse events were allergy, eye pain, headache, hyperemia, and taste disturbances. The incidences were not significantly different between the groups, but that does not mean that the two drugs are equivalent in terms of the incidences of adverse effects. Brinzolamide and levobetaxolol Adverse events in a randomized, double-masked study of brinzolamide (n = 32) and levobe taxolol (n = 46) have been evaluated in children aged under 6 years with congeni tal glaucoma, with a follow-up of 12 weeks (46C). Adverse events that were judged to be related to the drugs were hyperemia, discharge, discomfort, tearing, foreign body sensations, hordeolum, pruritus of the eye, fatigue, and bradycardia. No con cerns arose with regard to visual acuity, the adnexae, anterior segment, posterior seg ment, or vitreous, patient alertness, or car diovascular parameters. Eight patients (five using brinzolamide and three using levobetaxolol) had increased corneal dia meter of at least 1 mm in at least one eye. In two patients (using brinzolamide) this was considered to be clinically relevant, but these patients also had increased intraocular pressure. The adverse events in the overall population were predomi nately non-serious and were generally mild to moderate in intensity. No patient had a serious adverse event that was related to a study drug. There were no withdrawals because of adverse events. Dorzolamide and timolol Dorzolamide 2% and timolol 0.5% either alone (n = 70) or added to latanoprost (n = 280) have been compared in an open
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non-randomized study (47c). There were 116 predominantly mild non-serious adverse events reported by 86 patients (25%). The most frequent were eye irritation (n = 42; 12%) and a bad taste in the mouth (n = 15; 4%). There were five treatment-related non-serious adverse events of severe intensity (eye irritation, diarrhea, nausea, gout, and headache). There were no serious adverse events. Systematic reviews In a systematic review of seven randomized controlled trials, there were no differences in adverse events between fixed combinations compared with the non-fixed components administered concomitantly (48M). The rates were 8–43%, and there were more overall drug-related adverse events in the non-fixed group in five of the seven studies. More patients withdrew because of intolerance or adverse events in the non-fixed combination groups in one of the seven studies; the rates were 1–6% and 13% in one study. Three main ocular adverse effects were reported: hyperemia, ocular irritation, and keratitis. Hyperemia was reported in all of the studies, and in three studies of prostaglandins there were more cases in the fixed than in the nonfixed groups; this difference was significant in one study. The systemic effect with the highest rate was bitter taste with dorzolamide, with equal rates in the fixed and non-fixed therapies.
PROCEDURES Intravitreal injection (SEDA-29, 581) Sensory systems Endophthalmitis after intravitreal injection has been reviewed (49R). Infectious endophthalmitis is most probably related to the procedure, and sterile endophthalmitis (uveitis) can also be due to the drug used.
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