Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2022 Publisher: Upjohn UK Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom
Pharmacotherapeutic group: Ophthalmologicals; Antiglaucoma preparations and miotics, prostaglandin analogues
ATC code: S01EE01
The active substance latanoprost, a prostaglandin F2α analogue, is a selective prostanoid FP receptor agonist which reduces the IOP by increasing the outflow of aqueous humour. Reduction of the IOP in man starts about three to four hours after administration and maximum effect is reached after eight to twelve hours. Pressure reduction is maintained for at least 24 hours.
Studies in animals and man indicate that the main mechanism of action is increased uveoscleral outflow, although some increase in outflow facility (decrease in outflow resistance) has been reported in man.
Pivotal studies have demonstrated that Xalatan is effective as monotherapy. In addition, clinical trials investigating combination use have been performed. These include studies that show that latanoprost is effective in combination with beta-adrenergic antagonists (timolol). Short-term (1 or 2 weeks) studies suggest that the effect of latanoprost is additive in combination with adrenergic agonists (dipivalyl epinephrine), oral carbonic anhydrase inhibitors (acetazolamide) and at least partly additive with cholinergic agonists (pilocarpine).
Clinical trials have shown that latanoprost has no significant effect on the production of aqueous humour. Latanoprost has not been found to have any effect on the blood-aqueous barrier.
Latanoprost has no or negligible effects on the intraocular blood circulation when used at the clinical dose and studied in monkeys. However, mild to moderate conjunctival or episcleral hyperaemia may occur during topical treatment.
Chronic treatment with latanoprost in monkey eyes, which had undergone extracapsular lens extraction, did not affect the retinal blood vessels as determined by fluorescein angiography.
Latanoprost has not induced fluorescein leakage in the posterior segment of pseudophakic human eyes during short-term treatment.
Latanoprost in clinical doses has not been found to have any significant pharmacological effects on the cardiovascular or respiratory system.
The efficacy of Xalatan in paediatric patients ≤18 years of age was demonstrated in a 12-week, double-masked clinical study of latanoprost compared with timolol in 107 patients diagnosed with ocular hypertension and paediatric glaucoma. Neonates were required to be at least 36 weeks gestational age. Patients received either latanoprost 50 mcg/mL once daily or timolol 0.5% (or optionally 0.25% for subjects younger than 3 years old) twice daily. The primary efficacy endpoint was the mean reduction in IOP from baseline at Week 12 of the study. Mean IOP reductions in the latanoprost and timolol groups were similar. In all age groups studied (0 to <3 years, 3 to <12 years and 12 to 18 years of age) the mean IOP reduction at Week 12 in the latanoprost group was similar to that in the timolol group. Nevertheless, efficacy data in the age group 0 to <3 years were based on only 13 patients for latanoprost and no relevant efficacy was shown from the 4 patients representing the age group 0 to <1 year old in the clinical paediatric study. No data are available for preterm infants (less than 36 weeks gestational age).
IOP reductions among subjects in the PCG subgroup were similar between the latanoprost group and the timolol group. The non-PCG (e.g. juvenile open angle glaucoma, aphakic glaucoma) subgroup showed similar results as the PCG subgroup.
The effect on IOP was seen after the first week of treatment (see table) and was maintained throughout the 12 week period of study, as in adults.
Table. IOP reduction (mmHg) at week 12 by active treatment group and baseline diagnosis:
| Latanoprost N=53 | Timolol N=54 | |||
|---|---|---|---|---|
| Baseline Mean (SE) | 27.3 (0.75) | 27.8 (0.84) | ||
| Week 12 Change from Baseline Mean†(SE) | -7.18 (0.81) | -5.72 (0.81) | ||
| p-value vs. timolol | 0.2056 | |||
| PCG N=28 | Non-PCG N=25 | PCG N=26 | Non-PCG N=28 | |
| Baseline Mean (SE) | 26.5 (0.72) | 28.2 (1.37) | 26.3 (0.95) | 29.1 (1.33) |
| Week 12 Change from Baseline Mean†(SE) | -5.90 (0.98) | -8.66 (1.25) | -5.34 (1.02) | -6.02 (1.18) |
| p-value vs. timolol | 0.6957 | 0.1317 | ||
SE: standard error.
† Adjusted estimate based on an analysis of covariance (ANCOVA) model
Latanoprost (mw 432.58) is an isopropyl ester prodrug which per se is inactive, but after hydrolysis to the acid of latanoprost becomes biologically active.
The prodrug is well absorbed through the cornea and all drug that enters the aqueous humour is hydrolysed during the passage through the cornea.
Studies in man indicate that the peak concentration in the aqueous humour is reached about two hours after topical administration. After topical application in monkeys, latanoprost is distributed primarily in the anterior segment, the conjunctivae and the eyelids. Only minute quantities of the drug reach the posterior segment.
There is practically no metabolism of the acid of latanoprost in the eye. The main metabolism occurs in the liver. The half-life in plasma is 17 minutes in man. The main metabolites, the 1,2-dinor and 1,2,3,4-tetranor metabolites, exert no or only weak biological activity in animal studies and are excreted primarily in the urine.
An open-label pharmacokinetic study of plasma latanoprost acid concentrations was undertaken in 22 adults and 25 paediatric patients (from birth to <18 years of age) with ocular hypertension and glaucoma. All age groups were treated with latanoprost 50 mcg/mL, one drop daily in each eye for a minimum of 2 weeks. Latanoprost acid systemic exposure was approximately 2-fold higher in 3 to <12 year olds and 6-fold higher in children <3 years old compared with adults, but a wide safety margin for systemic adverse effects was maintained (see section 4.9). Median time to reach peak plasma concentration was 5 minutes post-dose across all age groups. The median plasma elimination half-life was short (<20 minutes), similar for paediatric and adult patients, and resulted in no accumulation of latanoprost acid in the systemic circulation under steady-state conditions.
The ocular as well as systemic toxicity of latanoprost has been investigated in several animal species. Generally, latanoprost is well tolerated with a safety margin between clinical ocular dose and systemic toxicity of at least 1,000 times. High doses of latanoprost, approximately 100 times the clinical dose/kg body weight, administered intravenously to unanaesthetised monkeys have been shown to increase the respiration rate probably reflecting bronchoconstriction of short duration. In animal studies, latanoprost has not been found to have sensitising properties.
In the eye, no toxic effects have been detected with doses of up to 100 micrograms/eye/day in rabbits or monkeys (clinical dose is approximately 1.5 micrograms/eye/day). In monkeys, however, latanoprost has been shown to induce increased pigmentation of the iris.
The mechanism of increased pigmentation seems to be stimulation of melanin production in melanocytes of the iris with no proliferative changes observed. The change in iris colour may be permanent.
In chronic ocular toxicity studies, administration of latanoprost 6 micrograms/eye/day has also been shown to induce increased palpebral fissure. This effect is reversible and occurs at doses above the clinical dose level. The effect has not been seen in humans.
Latanoprost was found negative in reverse mutation tests in bacteria, gene mutation in mouse lymphoma and mouse micronucleus test. Chromosome aberrations were observed in vitro with human lymphocytes. Similar effects were observed with prostaglandin F2α, a naturally occurring prostaglandin, and indicates that this is a class effect.
Additional mutagenicity studies on in vitro/in vivo unscheduled DNA synthesis in rats were negative and indicate that latanoprost does not have mutagenic potency. Carcinogenicity studies in mice and rats were negative.
Latanoprost has not been found to have any effect on male or female fertility in animal studies. In the embryotoxicity study in rats, no embryotoxicity was observed at intravenous doses (5, 50 and 250 micrograms/kg/day) of latanoprost. However, latanoprost induced embryolethal effects in rabbits at doses of 5 micrograms/kg/day and above.
The dose of 5 micrograms/kg/day (approximately 100 times the clinical dose) caused significant embryofoetal toxicity characterised by increased incidence of late resorption and abortion and by reduced foetal weight.
No teratogenic potential has been detected.
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