Apart from ocular irritation and conjunctival hyperaemia, no other ocular side effects are known if Oftal-Mix eye drops is overdosed.
If Oftal-Mix eye drops is accidentally ingested the following information may be useful: One bottle contains 125 micrograms Oftal-Mix. More than 90% is metabolised during the first pass through the liver. Intravenous infusion of 3 micrograms/kg in healthy volunteers induced no symptoms, but a dose of 5.5-10 micrograms/kg caused nausea, abdominal pain, dizziness, fatigue, hot flushes and sweating. In monkeys, Oftal-Mix has been infused intravenously in doses of up to 500 micrograms/kg without major effects on the cardiovascular system.
Intravenous administration of Oftal-Mix in monkeys has been associated with transient bronchoconstriction. However, in patients with moderate bronchial asthma, bronchoconstriction was not induced by Oftal-Mix when applied topically on the eyes in a dose of seven times the clinical dose of Oftal-Mix.
If overdosage with Oftal-Mix eye drops occurs, treatment should be symptomatic.
Apart from ocular irritation and conjunctival hyperaemia, no other ocular side effects are known if Oftal-Mix is overdosed.
If Oftal-Mix is accidentally ingested the following information may be useful: One bottle contains 125 micrograms latanoprost. More than 90% is metabolised during the first pass through the liver. Intravenous infusion of 3 micrograms/kg in healthy volunteers induced no symptoms, but a dose of 5.5-10 micrograms/kg caused nausea, abdominal pain, dizziness, fatigue, hot flushes and sweating. In monkeys, latanoprost has been infused intravenously in doses of up to 500 micrograms/kg without major effects on the cardiovascular system.
Intravenous administration of latanoprost in monkeys has been associated with transient bronchoconstriction. However, in patients with moderate bronchial asthma, bronchoconstriction was not induced by latanoprost when applied topically on the eyes in a dose of seven times the clinical dose of Oftal-Mix.
If overdosage with Oftal-Mix occurs, treatment should be symptomatic.
Intravenous infusion of up to 3 mcg/kg in healthy volunteers produced mean plasma concentrations 200 times higher than during clinical treatment and no adverse reactions were observed. Intravenous dosages of 5.5 to 10 mcg/kg caused abdominal pain, dizziness, fatigue, hot flushes, nausea, and sweating. If overdosage with XALATAN occurs, treatment should be symptomatic.
Known hypersensitivity to latanoprost, benzalkonium chloride, or any other ingredients in this product.
In vitro studies have shown that precipitation occurs when eye drops containing thiomersal are mixed with Oftal-Mix. If such drugs are used, the eye drops should be administered with an interval of at least five minutes.
In vitro studies have shown that precipitation occurs when eye drops containing thiomersal are mixed with Oftal-Mix. If such medicinal products are used, the eye drops should be administered with an interval of at least five minutes.
a. Summary of the safety profile
The majority of adverse events relate to the ocular system. In an open 5-year Oftal-Mix safety study, 33% of patients developed iris pigmentation. Other ocular adverse events are generally transient and occur on dose administration.
b. Tabulated list of adverse reactions
Adverse events are categorized by frequency as follows: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000) and very rare (<1/10,000). Not known (cannot be estimated from the available data).
| Infections and Infestations | Not known: | Herpetic keratitis |
| Nervous System Disorders | Not known: | Headache, Dizziness |
| Eye Disorders | Very common: | Increased iris pigmentation; mild to moderate conjunctival hyperaemia, eye irritation (burning, grittiness, itching, stinging and foreign body sensation); eyelash and vellus hair changes (increased length, thickness, pigmentation and number) (vast majority of reports in Japanese population). |
| Common: | Transient punctate epithelial keratitis, mostly without symptoms; blepharitis; eye pain, photophobia. | |
| Uncommon: | Eyelid oedema, dry eye; keratitis; vision blurred; conjunctivitis. | |
| Rare: | Iritis/uveitis (the majority of reports in patients with concomitant predisposing factors); macular oedema; symptomatic corneal oedema and erosions; periorbital oedema; misdirected eyelashes sometimes resulting in eye irritation; extra row of cilia at the aperture of the meibomian glands (distichiasis). | |
| Very rare: | Periorbital and lid changes resulting in deepening of the eyelid sulcus. | |
| Not known: | Iris cyst | |
| Cardiac Disorders: | Very rare: | Unstable angina. |
| Not known: | Palpitations. | |
| Respiratory, Thoracic and Mediastinal Disorders: | Rare: | Asthma, asthma exacerbation and dyspnoea. |
| Skin and Subcutaneous Tissue Disorders: | Uncommon: | Skin rash. |
| Rare: | Localised skin reaction on the eyelids; darkening of the palpebral skin of the eyelids. | |
| Musculoskeletal and Connective Tissue Disorders: | Not known: | Myalgia; Arthralgia. |
| General Disorders and Administration Site Conditions: | Very rare: | Chest pain. |
c. Description of selected adverse reactions
No information is provided.
d. Paediatric Population
In two short term clinical trials (≤ 12 weeks), involving 93 (25 and 68) paediatric patients the safety profile was similar to that in adults and no new adverse events were identified. The short term safety profiles in the different paediatric subsets were also similar. Adverse events seen more frequently in the paediatric population as compared to adults are: nasopharyngitis and pyrexia.
Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.
a. Summary of the safety profile
The majority of adverse reactions relate to the ocular system. In an open 5-year latanoprost safety study, 33% of patients developed iris pigmentation. Other ocular adverse reactions are generally transient and occur on dose administration.
b. Tabulated list of adverse reactions
Adverse reactions are categorized by frequency as follows: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000) and very rare (<1/10,000). not known (frequency cannot be estimated from the available data).
| System Organ Class | Very Common >1/10 | Common >1/100 to < 1/10 | Uncommon >1/1,000 to <1/100 | Rare >1/10,000 to <1/1,000 | Very Rare <1/10,000 | |
| Infections and infestations | Herpetic keratitis*§ | |||||
| Nervous system disorders | Headache*; dizziness* | |||||
| Eye disorders | Iris hyperpigmentation; mild to moderate conjunctival hyperaemia; eye irritation (burning grittiness, itching, stinging and foreign body sensation); eyelash and vellus hair changes of the eyelid (increased length, thickness, pigmentation and number of eyelashes) | Punctate keratitis, mostly without symptoms; blepharitis; eye pain; photophobia; conjunctivitis* | Eyelid oedema; dry eye; keratitis*; vision blurred; macular oedema including cystoid macular oedema*; uveitis* | Iritis*; corneal oedema*; corneal erosion; periorbital oedema; trichiasis*; distichiasis; iris cyst*§; localised skin reaction on the eyelids; darkening of the palpebral skin of the eyelids; pseudopemphigoid of ocular conjunctiva*§ | Periorbital and lid changes resulting in deepening of the eyelid sulcus | |
| Cardiac disorders | Angina; palpitations* | Angina unstable | ||||
| Respiratory, thoracic and mediastinal disorders | Asthma*; dyspnoea* | Asthma exacerbation | ||||
| Skin and subcutaneous tissue disorders | Rash | Pruritus | ||||
| Musculoskeletal and connective tissue disorders | Myalgia*; arthralgia* | |||||
| General disorders and administration site conditions | Chest pain* | |||||
*ADR identified post-marketing
§ADR frequency estimated using “The Rule of 3â€
c. Description of selected adverse reactions
No information is provided.
d. Paediatric population
In two short term clinical trials (≤ 12 weeks), involving 93 (25 and 68) paediatric patients the safety profile was similar to that in adults and no new adverse events were identified. The short term safety profiles in the different paediatric subsets were also similar. Adverse events seen more frequently in the paediatric population as compared to adults are: nasopharyngitis and pyrexia.
Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
The following adverse reactions were reported in postmarketing experience and are discussed in greater detail in other sections of the label:
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
XALATAN was studied in three multicenter, randomized, controlled clinical trials. Patients received 50 mcg/mL XALATAN once daily or 5 mg/mL active-comparator (timolol) twice daily. The patient population studied had a mean age of 65±10 years. Seven percent of patients withdrew before the 6-month endpoint.
Table 1: Ocular Adverse Reactions and Ocular Signs/Symptoms Reported by 5-15% of Patients Receiving Latanoprost
| Symptom/Finding | Adverse Reactions (incidence (%)) | |
| Latanoprost (n=460) | Timolol (n=369) | |
| Foreign body sensation | 13 | 8 |
| Punctate keratitis | 10 | 9 |
| Stinging | 9 | 12 |
| Conjunctival hyperemia | 8 | 3 |
| Blurred vision | 8 | 8 |
| Itching | 8 | 8 |
| Burning | 7 | 8 |
| Increased pigmentation of the Iris | 7 | 0 |
Less than 1% of the patients treated with XALATAN required discontinuation of therapy because of intolerance to conjunctival hyperemia.
Table 2: Adverse Reactions That Were Reported in 1-5% of Patients Receiving Latanoprost
| Adverse Reactions (incidence (%)) | ||
| Latanoprost (n=460) | Timolol (n=369) | |
| Ocular Events/Signs and Symptoms | ||
| Excessive tearing | 4 | 6 |
| Eyelid discomfort/pain | 4 | 2 |
| Dry eye | 3 | 3 |
| Eye pain | 3 | 3 |
| Eyelid margin crusting | 3 | 3 |
| Erythema of the eyelid | 3 | 2 |
| Photophobia | 2 | 1 |
| Eyelid edema | 1 | 3 |
| Systemic Events | ||
| Upper respiratory tract infection/nasopharyngitis/influenza | 3 | 3 |
| Myalgia/arthralgia/back pain | 1 | 0.5 |
| Rash/allergic skin reaction | 1 | 0.3 |
The ocular event/signs and symptoms of blepharitis have been identified as “commonly observed” through analysis of clinical trial data.
Postmarketing ExperienceThe following reactions have been identified during postmarketing use of XALATAN in clinical practice. Because they are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to XALATAN, or a combination of these factors, include:
Nervous System disorders: Dizziness; headache; toxic epidermal necrolysis
Eye Disorders: Eyelash and vellus hair changes of the eyelid (increased length, thickness, pigmentation, and number of eyelashes); keratitis; corneal edema and erosions; intraocular inflammation (iritis/uveitis); macular edema, including cystoid macular edema; trichiasis; periorbital and lid changes resulting in deepening of the eyelid sulcus; iris cyst; eyelid skin darkening; localised skin reaction on the eyelids; conjunctivitis; pseudopemphigoid of the ocular conjunctiva
Respiratory, Thoracic and Mediastinal Disorders: Asthma and exacerbation of asthma; dyspnea
Skin and Subcutaneous Tissue Disorders: Pruritus
Infections and Infestations: Herpes keratitis
Cardiac Disorders: Angina; palpitations; angina unstable
General Disorders and Administration Site Conditions: Chest pain
The ocular as well as systemic toxicity of Oftal-Mix has been investigated in several animal species. Generally, Oftal-Mix is well tolerated with a safety margin between clinical ocular dose and systemic toxicity of at least 1000 times. High doses of Oftal-Mix, 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, Oftal-Mix 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, Oftal-Mix 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 Oftal-Mix 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.
Oftal-Mix 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 Oftal-Mix does not have mutagenic potency. Carcinogenicity studies in mice and rats were negative.
Oftal-Mix 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 Oftal-Mix. However, Oftal-Mix 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 embryofetal toxicity characterised by increased incidence of late resorption and abortion and by reduced fetal weight.
No teratogenic potential has been detected.
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 1000 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.
Reduction of elevated intraocular pressure in patients with open angle glaucoma and ocular hypertension.
Reduction of elevated intraocular pressure in paediatric patients with elevated intraocular pressure and paediatric glaucoma.
Reduction of elevated intraocular pressure in patients with open angle glaucoma and ocular hypertension.
Reduction of elevated intraocular pressure in paediatric patients with elevated intraocular pressure and paediatric glaucoma.
XALATAN is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
Pharmacotherapeutic group: Prostaglandin analogues
ATC code: S01EE01
The active substance Oftal-Mix, a prostaglandin F2α analogue, is a selective prostanoid FP receptor agonist which reduces the intraocular pressure by increasing the outflow of aqueous humour. Reduction of the intraocular pressure 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 Oftal-Mix is effective as monotherapy. In addition, clinical trials investigating combination use have been performed. These include studies that show that Oftal-Mix is effective in combination with beta-adrenergic antagonists (timolol). Short-term (1 or 2 weeks) studies suggest that the effect of Oftal-Mix 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 Oftal-Mix has no significant effect on the production of aqueous humour. Oftal-Mix has not been found to have any effect on the blood-aqueous barrier.
Oftal-Mix 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 Oftal-Mix in monkey eyes, which had undergone extracapsular lens extraction, did not affect the retinal blood vessels as determined by fluorescein angiography.
Oftal-Mix has not induced fluorescein leakage in the posterior segment of pseudophakic human eyes during short-term treatment.
Oftal-Mix in clinical doses has not been found to have any significant pharmacological effects on the cardiovascular or respiratory system.
Paediatric population
The efficacy of Oftal-Mix in paediatric patients ≤ 18 years of age was demonstrated in a 12-week, double-masked clinical study of Oftal-Mix 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 at random either Oftal-Mix 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 intraocular pressure (IOP) from baseline at Week 12 of the study. Mean IOP reductions in the Oftal-Mix 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 Oftal-Mix 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 Oftal-Mix 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 primary congenital/infantile glaucoma (PCG) subgroup were similar between the Oftal-Mix 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 | ||||
| Oftal-Mix 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.
Pharmacotherapeutic group: Antiglaucoma preparations and miotics, prostaglandin analogues ATC code: S 01 E E 01
The active substance latanoprost, a prostaglandin F2α analogue, is a selective prostanoid FP receptor agonist which reduces the intraocular pressure by increasing the outflow of aqueous humour. Reduction of the intraocular pressure 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 Oftal-Mix 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.
Paediatric population
The efficacy of Oftal-Mix 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 intraocular pressure (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 primary congenital/infantile glaucoma (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.
Reduction of the IOP in man starts about 3-4 hours after administration and maximum effect is reached after 8-12 hours. IOP reduction is present for at least 24 hours.
Oftal-Mix (mw 432.58) is an isopropyl ester prodrug which per se is inactive, but after hydrolysis to the acid of Oftal-Mix 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, Oftal-Mix 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 Oftal-Mix 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.
Paediatric population
An open-label pharmacokinetic study of plasma Oftal-Mix 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 Oftal-Mix 50 mcg/ml, one drop daily in each eye for a minimum of 2 weeks. Oftal-Mix 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. 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 Oftal-Mix acid in the systemic circulation under steady-state conditions.
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.
Paediatric population
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. 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.
AbsorptionLatanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to the acid form to become biologically active.
DistributionThe distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of latanoprost can be measured in aqueous humor during the first 4 hours, and in plasma only during the first hour after local administration. Studies in man indicate that the peak concentration in the aqueous humor is reached about two hours after topical administration.
MetabolismLatanoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to the biologically active acid. The active acid of latanoprost reaching the systemic circulation is primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid β-oxidation.
ExcretionThe elimination of the acid of latanoprost from human plasma is rapid (t½ = 17 min) after both intravenous and topical administration. Systemic clearance is approximately 7 mL/min/kg. Following hepatic β-oxidation, the metabolites are mainly eliminated via the kidneys. Approximately 88% and 98% of the administered dose are recovered in the urine after topical and intravenous dosing, respectively.
Oftal-Mix eye drops may gradually change eye colour by increasing the amount of brown pigment in the iris. Before treatment is instituted, patients should be informed of the possibility of a permanent change in eye colour. Unilateral treatment can result in permanent heterochromia.
This change in eye colour has predominantly been seen in patients with mixed coloured irides, i.e. blue-brown, grey-brown, yellow-brown and green-brown. In clinical studies with Oftal-Mix, the onset of the change is usually within the first 8 months of treatment, rarely during the second or third year, and has not been seen after the fourth year of treatment. The rate of progression of iris pigmentation decreases with time and is stable for five years. The effect of increased pigmentation beyond five years has not been evaluated. In an open 5-year Oftal-Mix safety study, 33% of patients developed iris pigmentation. The iris colour change is slight in the majority of cases and often not observed clinically. The incidence in patients with mixed colour irides ranged from 7 to 85%, with yellow-brown irides having the highest incidence. In patients with homogeneously blue eyes, no change has been observed and in patients with homogeneously grey, green or brown eyes, the change has only rarely been seen.
The colour change is due to increased melanin content in the stromal melanocytes of the iris and not to an increase in number of melanocytes. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery in affected eyes, but the entire iris or parts of it may become more brownish. No further increase in brown iris pigment has been observed after discontinuation of treatment. It has not been associated with any symptom or pathological changes in clinical trials to date.
Neither naevi nor freckles of the iris have been affected by treatment. Accumulation of pigment in the trabecular meshwork or elsewhere in the anterior chamber has not been observed in clinical trials. Based on 5 years clinical experience, increased iris pigmentation has not been shown to have any negative clinical sequelae and Oftal-Mix eye drops can be continued if iris pigmentation ensues. However, patients should be monitored regularly and if the clinical situation warrants, Oftal-Mix eye drops treatment may be discontinued.
There is limited experience of Oftal-Mix in chronic angle closure glaucoma, open angle glaucoma of pseudophakic patients and in pigmentary glaucoma. There is no experience of Oftal-Mix in inflammatory and neovascular glaucoma or inflammatory ocular conditions. Oftal-Mix eye drops has no or little effect on the pupil, but there is no experience in acute attacks of closed angle glaucoma. Therefore, it is recommended that Oftal-Mix eye drops should be used with caution in these conditions until more experience is obtained.
There are limited study data on the use of Oftal-Mix during the peri-operative period of cataract surgery. Oftal-Mix eye drops should be used with caution in these patients.
Oftal-Mix eye drops should be used with caution in patients with a history of herpetic keratitis, and should be avoided in cases of active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues.
Reports of macular oedema have occurred mainly in aphakic patients, in pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema (such as diabetic retinopathy and retinal vein occlusion). Oftal-Mix eye drops should be used with caution in aphakic patients, in pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema.
In patients with known predisposing risk factors for iritis/uveitis, Oftal-Mix eye drops can be used with caution.
There is limited experience from patients with asthma, but some cases of exacerbation of asthma and/or dyspnoea were reported in post marketing experience.).
Periorbital skin discolouration has been observed, the majority of reports being in Japanese patients. Experience to date shows that periorbital skin discolouration is not permanent and in some cases has reversed while continuing treatment with Oftal-Mix.
Oftal-Mix may gradually change eyelashes and vellus hair in the treated eye and surrounding areas; these changes include increased length, thickness, pigmentation, number of lashes or hairs and misdirected growth of eyelashes. Eyelash changes are reversible upon discontinuation of treatment.
Oftal-Mix eye drops contains benzalkonium chloride, which is commonly used as a preservative in ophthalmic products. Benzalkonium chloride has been reported to cause punctuate keratopathy and/or toxic ulcerative keratopathy, may cause eye irritation and is known to discolour soft contact lenses. Close monitoring is required with frequent or prolonged use of Oftal-Mix eye drops in dry eye patients, or in conditions where the cornea is compromised. Contact lenses may absorb benzalkonium chloride and these should be removed before applying Oftal-Mix eye drops but may be reinserted after 15 minutes.
Paediatric population
Efficacy and safety data in the age group < 1 year (4 patients) are very limited. No data are available for preterm infants (less than 36 weeks gestational age).
In children from 0 to < 3 years old that mainly suffer from PCG (primary congenital glaucoma), surgery (e.g. trabeculotomy/goniotomy) remains the first line treatment.
Long-term safety in children has not yet been established.
Oftal-Mix may gradually change eye colour by increasing the amount of brown pigment in the iris. Before treatment is instituted, patients should be informed of the possibility of a permanent change in eye colour. Unilateral treatment can result in permanent heterochromia.
This change in eye colour has predominantly been seen in patients with mixed coloured irides, i.e. blue-brown, grey-brown, yellow-brown and green-brown. In studies with latanoprost, the onset of the change is usually within the first 8 months of treatment, rarely during the second or third year, and has not been seen after the fourth year of treatment. The rate of progression of iris pigmentation decreases with time and is stable for five years. The effect of increased pigmentation beyond five years has not been evaluated. In an open 5-year latanoprost safety study, 33% of patients developed iris pigmentation. The iris colour change is slight in the majority of cases and often not observed clinically. The incidence in patients with mixed colour irides ranged from 7 to 85%, with yellow-brown irides having the highest incidence. In patients with homogeneously blue eyes, no change has been observed and in patients with homogeneously grey, green or brown eyes, the change has only rarely been seen.
The colour change is due to increased melanin content in the stromal melanocytes of the iris and not to an increase in number of melanocytes. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery in affected eyes, but the entire iris or parts of it may become more brownish. No further increase in brown iris pigment has been observed after discontinuation of treatment. It has not been associated with any symptom or pathological changes in clinical trials to date.
Neither naevi nor freckles of the iris have been affected by treatment. Accumulation of pigment in the trabecular meshwork or elsewhere in the anterior chamber has not been observed in clinical trials. Based on 5 years clinical experience, increased iris pigmentation has not been shown to have any negative clinical sequelae and Oftal-Mix can be continued if iris pigmentation ensues. However, patients should be monitored regularly and if the clinical situation warrants, Oftal-Mix treatment may be discontinued.
There is limited experience of Oftal-Mix in chronic angle closure glaucoma, open angle glaucoma of pseudophakic patients and in pigmentary glaucoma. There is no experience of Oftal-Mix in inflammatory and neovascular glaucoma or inflammatory ocular conditions. Oftal-Mix has no or little effect on the pupil, but there is no experience in acute attacks of closed angle glaucoma. Therefore, it is recommended that Oftal-Mix should be used with caution in these conditions until more experience is obtained.
There are limited study data on the use of Oftal-Mix during the peri-operative period of cataract surgery. Oftal-Mix should be used with caution in these patients.
Oftal-Mix should be used with caution in patients with a history of herpetic keratitis, and should be avoided in cases of active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues.
Reports of macular oedema have occurred mainly in aphakic patients, in pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema (such as diabetic retinopathy and retinal vein occlusion). Oftal-Mix should be used with caution in aphakic patients, in pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema.
In patients with known predisposing risk factors for iritis/uveitis, Oftal-Mix can be used with caution.
There is limited experience from patients with asthma, but some cases of exacerbation of asthma and/or dyspnoea were reported in post marketing experience.
Periorbital skin discolouration has been observed, the majority of reports being in Japanese patients. Experience to date shows that periorbital skin discolouration is not permanent and in some cases has reversed while continuing treatment with Oftal-Mix.
Latanoprost may gradually change eyelashes and vellus hair in the treated eye and surrounding areas; these changes include increased length, thickness, pigmentation, number of lashes or hairs and misdirected growth of eyelashes. Eyelash changes are reversible upon discontinuation of treatment.
Oftal-Mix contains benzalkonium chloride, which is commonly used as a preservative in ophthalmic products. Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy, may cause eye irritation and is known to discolour soft contact lenses. Close monitoring is required with frequent or prolonged use of Oftal-Mix in dry eye patients, or in conditions where the cornea is compromised. Contact lenses may absorb benzalkonium chloride and these should be removed before applying Oftal-Mix but may be reinserted after 15 minutes.
Paediatric population
Efficacy and safety data in the age group < 1 year (4 patients) are very limited. No data are available for preterm infants (less than 36 weeks gestational age).
In children from 0 to < 3 years old that mainly suffer from PCG (primary congenital glaucoma), surgery (e.g. trabeculotomy/goniotomy) remains the first line treatment.
Long-term safety in children has not yet been established.
WARNINGSIncluded as part of the PRECAUTIONS section.
PRECAUTIONS PigmentationXALATAN has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid), and eyelashes. Pigmentation is expected to increase as long as latanoprost is administered.
The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of latanoprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. Beyond 5 years the effects of increased pigmentation are not known.
Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with XALATAN can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly.
Eyelash ChangesXALATAN may gradually change eyelashes and vellus hair in the treated eye; these changes include increased length, thickness, pigmentation, the number of lashes or hairs, and misdirected growth of eyelashes. Eyelash changes are usually reversible upon discontinuation of treatment.
Intraocular InflammationXALATAN should be used with caution in patients with a history of intraocular inflammation (iritis/uveitis) and should generally not be used in patients with active intraocular inflammation because inflammation may be exacerbated.
Macular EdemaMacular edema, including cystoid macular edema, has been reported during treatment with XALATAN. XALATAN should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.
Herpetic KeratitisReactivation of Herpes Simplex keratitis has been reported during treatment with XALATAN. XALATAN should be used with caution in patients with a history of herpetic keratitis. XALATAN should be avoided in cases of active herpes simplex keratitis because inflammation may be exacerbated.
Bacterial KeratitisThere have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.
Use With Contact LensesContact lenses should be removed prior to the administration of XALATAN, and may be reinserted 15 minutes after administration.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityLatanoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 170 mcg/kg/day (approximately 2800 times the recommended maximum human dose) for up to 20 and 24 months, respectively.
Latanoprost was not mutagenic in bacteria, in mouse lymphoma, or in mouse micronucleus tests. Chromosome aberrations were observed in vitro with human lymphocytes. Additional in vitro and in vivo studies on unscheduled DNA synthesis in rats were negative.
Latanoprost has not been found to have any effect on male or female fertility in animal studies.
Use In Specific Populations Pregnancy Teratogenic EffectsPregnancy Category C.
Reproduction studies have been performed in rats and rabbits. In rabbits, an incidence of 4 of 16 dams had no viable fetuses at a dose that was approximately 80 times the maximum human dose, and the highest nonembryocidal dose in rabbits was approximately 15 times the maximum human dose.
There are no adequate and well-controlled studies in pregnant women. XALATAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing MothersIt is not known whether this drug or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when XALATAN is administered to a nursing woman.
Pediatric UseSafety and effectiveness in pediatric patients have not been established.
Geriatric UseNo overall differences in safety or effectiveness have been observed between elderly and younger patients.
In common with other eye preparations, instillation of eye drops may cause transient blurring of vision. Until this has resolved, patients should not drive or use machines.
Posology
Recommended dosage for adults (including the elderly):
Recommended therapy is one eye drop in the affected eye(s) once daily. Optimal effect is obtained if Oftal-Mix eye drops is administered in the evening.
The dosage of Oftal-Mix eye drops should not exceed once daily since it has been shown that more frequent administration decreases the intraocular pressure lowering effect.
If one dose is missed, treatment should continue with the next dose as normal.
Method of administration
As with any eye drops, to reduce possible systemic absorption, it is recommended that the lachrymal sac be compressed at the medial canthus (punctal occlusion) for one minute. This should be performed immediately following the instillation of each drop.
Contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes.
If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.
Paediatric population
Oftal-Mix eye drops may be used in paediatric patients at the same posology as in adults. No data are available for preterm infants (less than 36 weeks gestational age). Data in the age group < 1 year (4 patients) are limited.
Posology
Adults (including the elderly):
Recommended therapy is one eye drop in the affected eye(s) once daily. Optimal effect is obtained if Oftal-Mix is administered in the evening.
The dosage of Oftal-Mix should not exceed once daily since it has been shown that more frequent administration decreases the intraocular pressure lowering effect.
If one dose is missed, treatment should continue with the next dose as normal.
As with any eye drops, to reduce possible systemic absorption, it is recommended that the lachrymal sac be compressed at the medial canthus (punctal occlusion) for one minute. This should be performed immediately following the instillation of each drop.
Contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes.
If more than one topical ophthalmic medicinal product is being used, the medicinal products should be administered at least five minutes apart.
Paediatric population:
Oftal-Mix eye drops may be used in paediatric patients at the same posology as in adults. No data are available for preterm infants (less than 36 weeks gestational age). Data in the age group < 1 year (4 patients) are limited.
The recommended dosage is one drop in the affected eye(s) once daily in the evening. If one dose is missed, treatment should continue with the next dose as normal.
The dosage of XALATAN should not exceed once daily; the combined use of two or more prostaglandins, or prostaglandin analogs including XALATAN is not recommended. It has been shown that administration of these prostaglandin drug products more than once daily may decrease the intraocular pressure (IOP) lowering effect or cause paradoxical elevations in IOP.
Reduction of the IOP starts approximately 3 to 4 hours after administration and the maximum effect is reached after 8 to 12 hours.
XALATAN may be used concomitantly with other topical ophthalmic drug products to lower IOP. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. Contact lenses should be removed prior to the administration of XALATAN, and may be reinserted 15 minutes after administration
No special requirements.
