Opatanol

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OPATANOL® (OPATANOL®)

Composition:

Active substance: olopatadine;

1 ml of solution contains olopatadine 1 mg (as hydrochloride);

Excipients: benzalkonium chloride, sodium chloride, sodium hydrogen phosphate dodecahydrate, hydrochloric acid and/or sodium hydroxide (for pH adjustment), purified water.

Pharmaceutical form. Eye drops.

Main physicochemical properties: sterile, clear solution ranging from colorless to light yellow.

Pharmacotherapeutic group.

Agents for ophthalmic use. Anti-inflammatory and antiallergic agents.

ATC code S01GX09.

Pharmacological properties.

Pharmacodynamics.

Olopatadine is a potent, selective antiallergic/antihistamine agent with multiple distinct mechanisms of action. It counteracts the release of histamine (the primary mediator of allergic reactions in humans) and prevents histamine-induced stimulation of cytokine production by human conjunctival epithelial cells. In vitro studies indicate that the drug acts on conjunctival mast cells, inhibiting the release of inflammatory mediators. It has been observed that topical ophthalmic administration of OPATANOL® in patients with patent nasolacrimal ducts reduces nasal signs and symptoms frequently associated with seasonal allergic conjunctivitis. The drug does not cause clinically significant changes in pupil diameter.

Preclinical data obtained from standard safety, pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity studies revealed no hazard to humans.

Animal studies showed delayed pup development during lactation in females administered systemic doses of olopatadine exceeding the maximum recommended ophthalmic dose in humans. Olopatadine was detected in the milk of lactating rats following oral administration.

Pharmacokinetics.

Olopatadine is systemically absorbed, as are other topically applied medicinal products. However, with topical application, systemic absorption of olopatadine is minimal, and plasma concentrations range from below the limit of quantification (< 0.5 ng/mL) to 1.3 ng/mL. These plasma concentrations are 50–200 times lower than those observed after oral administration of well-tolerated doses of the drug.

Pharmacokinetic studies following oral administration showed that the plasma half-life of olopatadine is approximately 8–12 hours, and the drug is primarily excreted by the kidneys. Approximately 60–70% of the administered dose was recovered in urine as unchanged active substance. Two metabolites, mono-desmethyl and N-oxide, were detected in urine at low concentrations.

Since olopatadine is excreted in urine predominantly as unchanged active substance, its pharmacokinetics are altered in patients with impaired renal function. Peak plasma concentrations in patients with severe renal impairment (mean creatinine clearance of 13 mL/min) are 2–3 times higher than in healthy adult volunteers. In patients receiving hemodialysis after a 10 mg oral dose, plasma olopatadine concentrations were significantly lower on dialysis days compared to non-dialysis days, suggesting that olopatadine is removed during hemodialysis.

Comparative pharmacokinetic studies of a 10 mg oral dose in young individuals (mean age 21 years) and elderly individuals (mean age 74 years) showed no significant differences in plasma concentrations, protein binding, urinary excretion of unchanged drug, or metabolites.

Studies of olopatadine following oral administration in patients with severe renal impairment have been conducted. Results indicate that somewhat higher plasma concentrations may be expected in this patient group when using OPATANOL®. However, since plasma concentrations after topical ophthalmic administration of olopatadine are 50–200 times lower than those achieved with well-tolerated oral doses, dosage adjustment is not necessary for elderly individuals or patients with renal impairment. Hepatic metabolism is not a major elimination pathway for the drug; therefore, dosage adjustment is not required for patients with hepatic impairment.

Clinical characteristics.

Indications.

Treatment of seasonal allergic conjunctivitis.

Contraindications.

Hypersensitivity to olopatadine or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

No studies on interactions between OPATANOL® and other medicinal products have been conducted.

In vitro studies showed that olopatadine does not inhibit metabolic reactions mediated by cytochrome P450 isoenzymes 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. These results indicate that olopatadine does not cause metabolic interactions with other active substances when used concomitantly.

Special precautions for use

OPATANOL® is a topical antiallergic/antihistamine agent that is absorbed systemically. The drug should be discontinued at the first signs of serious reactions or increased sensitivity.

OPATANOL® contains benzalkonium chloride, which may cause ocular irritation.

Benzalkonium chloride has also been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Patients with dry eye syndrome or corneal damage who use the product frequently or over prolonged periods should be closely monitored.

Contact lenses

Benzalkonium chloride is known to discolour contact lenses. Contact with soft contact lenses should be avoided. Patients should be advised to remove contact lenses before instilling the drops and to wait at least 15 minutes after instillation before reinserting the lenses.

Use during pregnancy or breastfeeding

Pregnancy

Data on the ophthalmic use of olopatadine in pregnant women are lacking or limited in quantity. Animal studies have shown reproductive toxicity following systemic administration (see section "Pharmacological properties"). Olopatadine is not recommended for use in pregnant women or in women of childbearing potential who are not using contraceptive measures.

Breastfeeding

Animal studies have shown that olopatadine passes into breast milk following oral administration (see "Pharmacological properties" for details). A risk to newborns/infants cannot be excluded. OPATANOL® should not be used during breastfeeding.

Reproductive function

No studies have been conducted on the effect of olopatadine on human reproductive function following topical ophthalmic administration.

Ability to affect reaction speed when driving or operating machinery

OPATANOL® has no or negligible influence on the ability to drive or operate machinery. However, as with the use of any eye drops, transient visual blurring or other visual disturbances may affect the ability to drive or operate machinery. If visual blurring occurs after instillation, patients should wait until vision clears before driving or operating machinery.

Method of Administration and Dosage.

For ophthalmic use only.

One drop of OPATANOL® should be instilled into the conjunctival sac of the affected eye(s) twice daily (with an interval of 8 hours). If necessary, treatment may continue for up to 4 months.

Use in elderly patients.

No dosage adjustment is required for this patient population.

Use in children and adolescents.

OPATANOL® can be used in pediatric practice for children aged 3 years and older at the same dosage as in adults. Safety and efficacy of OPATANOL® in children under 3 years of age have not been established. Data for this age group are lacking.

Use in patients with hepatic or renal impairment.

Studies with olopatadine in the form of ophthalmic solution (OPATANOL®) have not been conducted in patients with hepatic or renal impairment. However, no dosage adjustment is necessary in cases of hepatic or renal dysfunction (see section "Pharmacokinetics").

After the first opening of the bottle, remove the tamper-evident ring designed for control of first opening.

To prevent contamination of the dropper tip and the contents of the bottle, care must be taken not to touch the eyelids, adjacent areas, or other surfaces with the tip of the dropper bottle. The bottle should be tightly closed after each use.

If more than one ophthalmic agent is used locally, an interval of at least 5 minutes should be maintained between applications. Ophthalmic ointments should be applied last.

Children.

OPATANOL® can be used in children aged 3 years and older at the same dosage as in adults.

Overdose.

There are no data on overdose in humans following accidental or intentional ingestion. Olopatadine has shown a low level of acute toxicity in animals. Accidental ingestion of the entire contents of one bottle of OPATANOL® would result in a maximum systemic exposure of 5 mg of olopatadine. This exposure would correspond to a dose of 0.5 mg/kg in a child weighing 10 kg assuming 100% absorption.

Prolongation of the QT interval in dogs was observed only at doses significantly exceeding the maximum human dose, indicating a low likelihood of QT prolongation during clinical use. In a study involving 102 healthy volunteers, including young men and women as well as elderly individuals, who received 5 mg of the drug orally twice daily for 2.5 days, a slight QT interval prolongation was observed compared to placebo. In this study, peak plasma concentrations of olopatadine (ranging from 35 to 127 ng/mL) were at least 70 times higher than those achieved with topical olopatadine administration, indicating minimal risk regarding cardiac repolarization effects.

In case of overdose, appropriate patient evaluation and treatment should be initiated.

Adverse reactions.

In clinical studies involving 1680 patients, OPATANOL® was administered from once to four times daily in both eyes for up to four months, either as monotherapy or as add-on therapy to loratadine 10 mg. Adverse effects associated with the use of OPATANOL® were observed in approximately 4.5% of patients; however, only 1.6% were withdrawn from clinical studies due to these adverse effects. During clinical studies, there were no reports of any serious ocular or systemic adverse events related to the use of the drug. The most common adverse effect with OPATANOL® was ocular pain, occurring at a frequency of 0.7%.

The following adverse reactions have been reported during clinical studies and in the post-marketing period, and are classified according to frequency: very common (≥1/10), common (>1/100, <1/10), uncommon (>1/1000, ≤1/100), rare (>1/10,000, ≤1/1000), very rare (≤1/10,000), or frequency not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

In patients with significant corneal involvement, very rare cases of corneal calcification have been reported with the use of ophthalmic solutions containing phosphates.

Reporting of suspected adverse reactions following administration of a registered medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report, according to the applicable legislation, any suspected adverse reactions that occur in patients during therapy.

Shelf life. 3 years.

Do not use more than 4 weeks after first opening the bottle.

Storage conditions.

No special storage conditions are required. Keep out of reach and sight of children.

Packaging. 5 ml in dropper bottles, 1 or 3 dropper bottles per cardboard box. Not all pack sizes may be marketed.

Prescription status. Prescription only.

Manufacturer.

1. Alcon-Couvreur, Belgium
2. Novartis Farmaceutica, S.A., Spain

Manufacturer's name and address.

1. Rijksweg 14, B-2870 Puurs, Belgium
2. Gran Via de les Corts Catalanes 764, Barcelona, 08013, Spain