Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2023 Publisher: Santen Oy, Niittyhaankatu 20, 33720, Tampere, Finland
Pharmacotherapeutic group: Antiglaucoma preparations and miotics, Carbonic Anhydrase Inhibitors, dorzolamide
ATC code: S01EC03
Carbonic anhydrase (CA) is an enzyme found in many tissues of the body including the eye. In humans, carbonic anhydrase exists as a number of isoenzymes, the most active being carbonic anhydrase II (CA-II) found primarily in red blood cells (RBCs) but also in other tissues. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humour secretion. The result is a reduction in intra-ocular pressure (IOP).
TRUSOPT contains dorzolamide hydrochloride, a potent inhibitor of human carbonic anhydrase II. Following topical ocular administration, dorzolamide reduces elevated intra-ocular pressure, whether or not associated with glaucoma. Elevated intra-ocular pressure is a major risk factor in the pathogenesis of optic nerve damage and visual-field loss. Dorzolamide does not cause pupillary constriction and reduces intra-ocular pressure without side effects such as night blindness, accommodative spasm. Dorzolamide has minimal or no effect on pulse rate or blood pressure.
Topically applied beta-adrenergic blocking agents also reduce IOP by decreasing aqueous humour secretion but by a different mechanism of action. Studies have shown that when dorzolamide is added to a topical beta-blocker, additional reduction in IOP is observed; this finding is consistent with the reported additive effects of beta-blockers and oral carbonic anhydrase inhibitors.
In patients with glaucoma or ocular hypertension, the efficacy of dorzolamide given t.i.d. as monotherapy (baseline IOP ≥23 mmHg) or given b.i.d. as adjunctive therapy while receiving ophthalmic beta-blockers (baseline IOP ≥22 mmHg) was demonstrated in large-scale clinical studies of up to one-year duration. The IOP-lowering effect of dorzolamide as monotherapy and as adjunctive therapy was demonstrated throughout the day and this effect was maintained during long-term administration. Efficacy during long-term monotherapy was similar to betaxolol and slightly less than timolol. When used as adjunctive therapy to ophthalmic beta-blockers, dorzolamide demonstrated additional IOP lowering similar to pilocarpine 2% q.i.d.
A 3-month, double-masked, active-treatment controlled, multicentre study was undertaken in 184 (122 for dorzolamide) paediatric patients from 1 week of age to <6 years of age with glaucoma or elevated intraocular pressure (baseline IOP ≥22 mmHg) to assess the safety of TRUSOPT when administered topically t.i.d. (three times a day). Approximately half the patients in both treatment groups were diagnosed with congenital glaucoma; other common aetiologies were Sturge Weber syndrome, iridocorneal mesenchymal dysgenesis, aphakic patients. The distribution by age and treatments in the monotherapy phase was as follows:
| Dorzolamide 2% | Timolol | |
|---|---|---|
| Age cohort <2 years | N=56 | Timolol GS 0.25% N=27 |
| Age range: 1 to 23 months | Age range: 0.25 to 22 months | |
| Age cohort ≥2 - <6 years | N=66 | Timolol 0.50% N=35 |
| Age range: 2 to 6 years | Age range: 2 to 6 years |
Across both age cohorts approximately 70 patients received treatment for at least 61 days and approximately 50 patients received 81-100 days of treatment.
If IOP was inadequately controlled on dorzolamide or timolol gel-forming solution monotherapy, a change was made to open-label therapy according to the following: 30 patients <2 years were switched to concomitant therapy with timolol gel-forming solution 0.25% daily and dorzolamide 2% t.i.d.; 30 patients ≥2 years were switched to 2% dorzolamide/0.5% timolol fixed combination b.i.d (twice a day).
Overall, this study did not reveal additional safety concerns in paediatric patients: approximately 26% (20% in dorzolamide monotherapy) of paediatric patients were observed to experience drug related adverse affects, the majority of which were local, non-serious ocular effects such as ocular burning and stinging, injection and eye pain. A small percentage <4% was observed to have corneal oedema or haze. Local reactions appeared similar in frequency to comparator. In post marketing data, metabolic acidosis in the very young particularly with renal immaturity/impairment has been reported.
Efficacy results in paediatric patients suggest that the mean IOP decrease observed in the dorzolamide group was comparable to the mean IOP decrease observed in the timolol group even if a slight numeric advantage was observed for timolol.
Longer-term efficacy studies (>12 weeks) are not available.
Unlike oral carbonic anhydrase inhibitors, topical administration of dorzolamide hydrochloride allows for the active substance to exert its effects directly in the eye at substantially lower doses and therefore with less systemic exposure. In clinical trials, this resulted in a reduction in IOP without the acid-base disturbances or alterations in electrolytes characteristic of oral carbonic anhydrase inhibitors.
When topically applied, dorzolamide reaches the systemic circulation. To assess the potential for systemic carbonic anhydrase inhibition following topical administration, active substance and metabolite concentrations in red blood cells (RBCs) and plasma and carbonic anhydrase inhibition in RBCs were measured. Dorzolamide accumulates in RBCs during chronic dosing as a result of selective binding to CA-II while extremely low concentrations of free active substance in plasma are maintained. The parent active substance forms a single N-desethyl metabolite that inhibits CA-II less potently than the parent active substance but also inhibits a less active isoenzyme (CA-I). The metabolite also accumulates in RBCs where it binds primarily to CA-I. Dorzolamide binds moderately to plasma proteins (approximately 33%). Dorzolamide is primarily excreted unchanged in the urine; the metabolite is also excreted in urine. After dosing ends, dorzolamide washes out of RBCs non linearly, resulting in a rapid decline of active substance concentration initially, followed by a slower elimination phase with a half-life of about four months.
When dorzolamide was given orally to simulate the maximum systemic exposure after long-term topical ocular administration, steady state was reached within 13 weeks. At steady state, there was virtually no free active substance or metabolite in plasma; CA inhibition in RBCs was less than that anticipated to be necessary for a pharmacological effect on renal function or respiration. Similar pharmacokinetic results were observed after chronic, topical administration of dorzolamide. However, some elderly patients with renal impairment (estimated CrCl 30-60 ml/min) had higher metabolite concentrations in RBCs, but no meaningful differences in carbonic anhydrase inhibition, and no clinically significant systemic side effects were directly attributable to this finding.
The main findings in animal studies with dorzolamide hydrochloride administered orally were related to the pharmacological effects of systemic carbonic anhydrase inhibition. Some of these findings were species-specific and/or were a result of metabolic acidosis. In rabbits given maternotoxic doses of dorzolamide associated with metabolic acidosis, malformations of the vertebral bodies were observed. In lactating rats, decreases in the body weight gain of offspring were observed. No adverse effects upon fertility were observed in male and female rats given dorzolamide prior to and throughout mating.
In clinical studies, patients did not develop signs of metabolic acidosis or serum electrolyte changes that are indicative of systemic CA inhibition. Therefore, it is not expected that the effects noted in animal studies would be observed in patients receiving therapeutic doses of dorzolamide.
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