Apfecto (Drops) Instructions for Use

Marketing Authorization Holder

World Medicine İlaç San. ve Tic. A.Ş. (Turkey)

Contact Information

World Medicine İlaç San. ve Tic. A.Ş. (Turkey)

ATC Code

S01BC10 (Nepafenac)

Active Substance

Nepafenac (Rec.INN registered by WHO)

Dosage Form

Apfecto

Eye drops 1 mg/1 ml: 5 ml bottle.

Dosage Form, Packaging, and Composition

Eye drops in the form of a yellow suspension.

Excipients: boric acid, propylene glycol, carbomer 974P, sodium chloride, guar gum, sodium carboxymethylcellulose, disodium edetate, benzalkonium chloride, sodium hydroxide, hydrochloric acid, purified water.

5 ml – low-density polyethylene bottles (1) with a dropper cap – cardboard boxes.

Clinical-Pharmacological Group

NSAIDs for topical use in ophthalmology

Pharmacotherapeutic Group

Agents used in ophthalmology; anti-inflammatory agents; nonsteroidal anti-inflammatory agents

Pharmacological Action

Mechanism of action

Nepafenac is a prodrug of an active NSAID with anti-inflammatory and analgesic effects. When applied topically, Nepafenac penetrates the cornea, where it is converted by hydrolases into its active form, amfenac. Amfenac inhibits the action of prostaglandin H synthase (cyclooxygenase), an enzyme necessary for prostaglandin production.

When applied topically, Nepafenac reduces eye tissue swelling and pain and does not have a significant effect on intraocular pressure.

It has been shown in rabbits that Nepafenac reduces the permeability of the blood-retinal barrier while inhibiting PGE2 synthesis. Ex vivo studies confirmed that a single topical dose of nepafenac suppresses prostaglandin synthesis in the iris/ciliary body (85-95%) and retina/choroid (55%) for up to 6 hours and 4 hours, respectively.

Pharmacodynamic effects

Most hydrolytic conversion occurs in the retina/choroid, as well as in the iris/ciliary body and cornea, depending on the degree of tissue vascularization.

Results from clinical studies indicate that Nepafenac does not have a significant effect on intraocular pressure.

Clinical efficacy and safety

Prevention and treatment of pain and inflammation associated with cataract surgery

Three main studies were conducted to evaluate the efficacy and safety of nepafenac administered 3 times/day compared with placebo and/or ketorolac in the prevention and treatment of postoperative pain and inflammation in patients who underwent cataract surgery. In these studies, the study drug was started 1 day before surgery, continued on the day of surgery, and for 2-4 weeks postoperatively. Additionally, almost all patients received prophylactic antibiotic treatment according to the clinical practice at each study center.

In two double-blind, randomized, placebo-controlled studies, patients treated with Nepafenac had significantly less inflammation (cells and aqueous flare) from the early postoperative period until the end of treatment compared to patients receiving placebo.

In one double-blind, randomized study with placebo and active controls, patients treated with Nepafenac had significantly less inflammation than patients receiving placebo. Furthermore, Nepafenac was non-inferior to ketorolac 5 mg/ml in reducing ocular inflammation and pain and was significantly more comfortable upon instillation.

A significantly greater percentage of patients in the nepafenac group experienced no ocular pain following cataract surgery compared to patients in the placebo group.

Reduction of the risk of macular edema in diabetic patients following cataract surgery

Four studies (two in diabetic patients and two in non-diabetic patients) were conducted to evaluate the efficacy and safety of nepafenac for the prevention of postoperative macular edema associated with cataract surgery. In these studies, the study drug was started 1 day before surgery, continued on the day of surgery, and for up to 90 days postoperatively.

In one double-blind, randomized, placebo-controlled study involving patients with diabetic retinopathy, a significantly greater percentage of patients in the placebo group developed macular edema (16.7%) compared to patients receiving Nepafenac (3.2%). A greater percentage of patients receiving placebo experienced a reduction in best-corrected visual acuity of more than 5 letters from day 7 to day 90 (or premature discontinuation in the placebo group) (11.5%) compared to patients receiving Nepafenac (5.6%). An improvement of 15 letters in best-corrected visual acuity was observed in a greater proportion of patients receiving Nepafenac compared to patients receiving placebo, 56.8% versus 41.9%, respectively, p = 0.019.

Preclinical safety data

Preclinical studies of pharmacological safety, repeated-dose toxicity, and genotoxicity of nepafenac did not reveal any special hazard to humans.

Long-term carcinogenicity studies of nepafenac have not been conducted.

In reproductive toxicity studies, the effect of nepafenac on reproductive function in rats at maternally toxic doses ≥ 10 mg/kg was associated with dystocia, increased post-implantation loss, decreased fetal weight and growth, and reduced fetal survival. In pregnant rabbits, administration of nepafenac at a dose of 30 mg/kg, which caused mild maternal toxicity, showed a statistically significant increase in the incidence of litter malformations.

Pharmacokinetics

Absorption

After three times daily instillation of nepafenac into both eyes, low but quantifiable concentrations of nepafenac and amfenac were observed in plasma at 2 and 3 hours after administration, respectively. The C_max of nepafenac in plasma is 0.310 ± 0.104 ng/ml; the C_max of amfenac is 0.422 ± 0.121 ng/ml.

Distribution

After a single instillation of nepafenac in 25 patients who underwent cataract surgery, nepafenac concentration in the aqueous humor was measured at 15, 30, 45, and 60 minutes after dose administration. C_max in the aqueous humor was observed at 1 hour (Nepafenac – 177 ng/ml, amfenac – 44.8 ng/ml).

These data indicate rapid penetration of nepafenac into the cornea.

Amfenac has a high affinity for serum albumin. In vitro binding to rat albumin, human albumin, and human serum was 98.4%, 95.4%, and 99.1%, respectively.

Studies in rats have shown that radiolabeled substances associated with the active substance are widely distributed in the body after single and repeated oral doses of ¹⁴C-nepafenac.

Studies in rabbits have shown that topically applied Nepafenac distributes from the anterior part of the eye to the posterior segments of the eye (retina and choroid).

Metabolism

When applied topically, under the action of intraocular hydrolases, Nepafenac undergoes rapid hydrolysis to amfenac.

Further metabolism of amfenac proceeds via hydroxylation of the aromatic ring, leading to the formation of glucuronic acid conjugates. Radiochromatographic analysis performed before and after hydrolysis with β-glucuronidase showed that all metabolites were present as glucuronic acid conjugates, except for amfenac. Amfenac was the major metabolite in plasma, accounting for about 13% of the total radioactivity detected in plasma. The second most common metabolite in plasma was identified as 5-hydroxynepafenac, representing 9% of the total radioactivity at C_max.

Excretion

Nepafenac is excreted primarily by the kidneys (approximately 85% of the radioactive label after oral administration of ¹⁴C-nepafenac is found in urine, about 6% in feces).

Indications

Adults from 18 years of age

• Prevention and treatment of pain and inflammation associated with cataract surgery;
• To reduce the risk of macular edema in diabetic patients following cataract surgery.

ICD codes

Dosage Regimen

Prevention and treatment of pain and inflammation associated with cataract surgery

Apfecto is instilled as 1 drop into the conjunctival sac of the eye 3 times/day. Treatment is started 1 day before cataract surgery and continued for the first 2 weeks of the postoperative period (including the day of surgery). As prescribed by the doctor, treatment may be extended up to 21 days after surgery. An additional drop of the drug should be instilled 30-120 minutes before surgery.

To reduce the risk of macular edema in diabetic patients following cataract surgery

Apfecto is instilled as 1 drop into the conjunctival sac of the eye 3 times/day, starting 1 day before cataract removal, then continued on the day of surgery and postoperatively for up to 60 days as prescribed by the doctor. An additional drop of the drug should be instilled 30-120 minutes before surgery.

Special patient groups

Dosage adjustment in elderly patients (>65 years) is not required.

The use of nepafenac has not been studied in patients with renal or hepatic impairment. Nepafenac is eliminated from the body mainly by biotransformation, and systemic exposure after topical application is negligible. There is no need for dose adjustment for this group of patients.

The safety and efficacy of nepafenac in children aged 0 to 18 years have not been established. No data are available.

Method of administration

The drug is intended for topical use only as instillations into the conjunctival sac.

The patient should be warned that the bottle should be shaken well before use.

After opening the bottle, before using the drug, the tamper-evident ring ensuring control of the first opening should be removed.

If necessary, the drug can be used in combination with other topical ophthalmic drugs. In this case, the interval between their applications should be at least 5 minutes. Eye ointments should be applied last.

To prevent contamination of the drug, the tip of the dropper should not be touched to any surface.

After use, the bottle should be kept tightly closed.

If a dose is missed, the dose should not be doubled to make up for the missed dose.

If a dose is missed, one drop should be instilled as soon as possible, then return to the regular dosing schedule.

Adverse Reactions

In clinical studies involving 2314 patients treated with Nepafenac 1 mg/ml, the most frequent adverse reactions (ARs) were punctate keratitis, foreign body sensation in the eye, and eyelid margin crusting, which were observed in 0.2-0.4% of patients.

The following ARs are classified by frequency: very common (≥ 1/10), common (from ≥ 1/100 to <1/10), uncommon (from ≥ 1/1,000 to <1/100), rare (from ≥ 1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). Within each of these groups, ARs are presented in order of decreasing severity. Data on ARs were obtained from clinical studies and during post-marketing use.

Diabetic patients

In two clinical studies, diabetic patients (n=209) received treatment with nepafenac for 60 days or more to prevent macular edema after cataract removal. The most frequently reported AR was punctate keratitis, which was noted in 3% of patients (frequency category – common). Other ARs were corneal epithelial defect, which was noted in 1% of patients, and allergic dermatitis, noted in 0.5% of patients (frequency category – uncommon).

Description of selected adverse reactions

Clinical trial data on the long-term use of nepafenac for the prevention of macular edema after cataract extraction in diabetic patients are limited. Ocular adverse reactions in diabetic patients may occur more frequently than observed in the general population (see the “Special Precautions” section).

In patients with signs of corneal epithelial damage, including corneal perforation, the use of nepafenac should be discontinued immediately, and the condition of the cornea should be carefully monitored (see the “Special Precautions” section).

Cases of corneal epithelial defect have been reported during the post-marketing use of nepafenac. The severity of such cases ranges from minor impact on corneal epithelial integrity to more serious events requiring surgical intervention and/or additional medication to restore visual clarity.

Post-marketing experience with topical NSAIDs has shown that patients who have undergone complicated eye surgery or repeated surgery within a short time, with corneal defects, corneal denervation, diabetes, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, have an increased risk of corneal adverse reactions that may threaten vision. If it is necessary to prescribe nepafenac to diabetic patients for the prevention of macular edema after cataract extraction, and they have any additional risk factor, a reassessment of the expected benefit/risk ratio should be performed and particularly careful monitoring of this patient should be carried out.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to nepafenac or any of the excipients included in the drug;
• Hypersensitivity to other NSAIDs;
• Bronchial asthma, urticaria, acute rhinitis caused by taking acetylsalicylic acid or other NSAIDs.

Use in Pregnancy and Lactation

Pregnancy

Adequate data on the use of nepafenac in pregnant women are not available. Animal studies have revealed reproductive toxicity. The potential risk to humans is unknown. Since systemic exposure to nepafenac in non-pregnant women is negligible, it can be assumed that the risk during pregnancy is also low. However, inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development, and/or labor, and/or postnatal development, therefore Nepafenac is not recommended for use during pregnancy.

Breastfeeding period

It is not known whether Nepafenac passes into human breast milk. Studies in rats have shown that Nepafenac passes into breast milk. However, Nepafenac is not expected to affect breastfed infants because systemic exposure to nepafenac in breastfeeding women is negligible. Nepafenac can be used by women during lactation.

Fertility

Data on the effect of nepafenac on fertility are not available.

Women of childbearing potential

Nepafenac is not recommended for women of childbearing potential who are not using contraception.

Use in Hepatic Impairment

The use of nepafenac has not been studied in patients with hepatic impairment. Nepafenac is eliminated from the body mainly by biotransformation, and systemic exposure after topical application is negligible. There is no need for dose adjustment for this group of patients.

Use in Renal Impairment

The use of nepafenac has not been studied in patients with renal impairment. Nepafenac is eliminated from the body mainly by biotransformation, and systemic exposure after topical application is negligible. There is no need for dose adjustment for this group of patients.

Pediatric Use

The safety and efficacy of nepafenac in children aged 0 to 18 years have not been established. No data are available.

Geriatric Use

Dosage adjustment in elderly patients (> 65 years) is not required.

Special Precautions

Apfecto is not intended for injection. Patients should be warned that Apfecto should not be taken orally.

Patients should be warned to avoid sunlight during treatment with nepafenac.

Effects on the eye

Topical application of NSAIDs may lead to the development of keratitis. In some susceptible patients, prolonged topical use of NSAIDs may lead to epithelial damage, corneal thinning, corneal erosion, ulceration, or perforation (see the “Adverse Reactions” section). Such adverse reactions may threaten vision. Patients who develop signs of corneal damage should immediately discontinue the use of Apfecto, and the condition of the cornea must be carefully monitored.

Topical application of NSAIDs may slow down or delay healing. It is also known that topical corticosteroids contribute to slowing down or delaying healing. Concurrent topical application of NSAIDs and topical corticosteroids may slow down the healing processes. Therefore, caution is recommended when using nepafenac concurrently with corticosteroids, especially in patients at high risk of adverse corneal reactions described below.

Post-marketing experience with ophthalmic NSAIDs suggests that patients who have undergone complicated ocular surgery, have corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, or have had repeated ocular surgeries within a short period of time may have an increased risk of corneal adverse effects which may become sight-threatening. Topical NSAIDs should be used with caution in these patients. Prolonged ophthalmic use of NSAIDs may increase the risk and severity of corneal adverse reactions.

There are reports that ophthalmic use of NSAIDs in conjunction with eye surgery may cause intensive bleeding in the eye tissues, including hyphema (hemorrhage into the anterior chamber of the eye). Apfecto should be used with caution in patients with bleeding tendencies or those receiving other medications that may prolong bleeding time.

Ophthalmic use of NSAIDs may mask the course of an acute ocular infection. NSAIDs do not possess antimicrobial activity. In case of development of an ocular infection, these drugs should be used concurrently with antibacterial agents with caution.

Benzalkonium Chloride

Apfecto contains benzalkonium chloride, which may cause eye irritation and discoloration of soft contact lenses. Furthermore, wearing contact lenses is not recommended postoperatively after cataract removal. Therefore, patients are advised not to wear contact lenses during the use of Apfecto.

Studies have shown that benzalkonium chloride can cause punctate and/or ulcerative toxic keratopathy. Therefore, with frequent or prolonged use of the drug, careful patient monitoring is necessary.

Cross-Sensitivity

When using nepafenac, there is a possibility of developing cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, as well as other NSAIDs.

Effect on Ability to Drive and Operate Machinery

Nepafenac affects the ability to drive and operate machinery.

After application of nepafenac, temporary blurring of vision may occur, and until it clears, it is not recommended to drive vehicles or engage in activities requiring increased attention and rapid reactions.

Overdose

Symptoms of nepafenac overdose, both with topical ophthalmic instillation and oral administration, the occurrence of toxic effects is unlikely.

Data on nepafenac overdose are not available.

Treatment if an excessive amount of the drug gets into the eyes, it is recommended to rinse the eyes with warm water.

Drug Interactions

In in vitro studies, neither nepafenac at concentrations up to 3000 ng/mL nor amfenac at concentrations up to 1000 ng/mL inhibited the metabolic activity of human cytochrome P450 (isoenzymes CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4). Therefore, when used concurrently with other drugs, interactions involving cytochrome P450 isoenzymes are unlikely. Interactions mediated by plasma protein binding are also unlikely.

Concurrent topical application of NSAIDs and topical corticosteroids may slow down or delay the healing process.

Concurrent use of nepafenac with drugs that increase bleeding time may increase the risk of bleeding.

Data on the concurrent use of prostaglandin analogs and nepafenac are not available. Given their mechanisms of action, concurrent use is not recommended.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

After opening the bottle, the drug should be used within 28 days.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.