Ganfort^® (Drops) Instructions for Use

Marketing Authorization Holder

AbbVie, LLC (Russia)

Manufactured By

Allergan Pharmaceuticals Ireland (Ireland)

ATC Code

S01ED51 (Timolol in combination with other drugs)

Active Substances

Timolol (Rec.INN registered by WHO)

Bimatoprost (Rec.INN registered by WHO)

Dosage Forms

	Ganfort®	Eye drops (with preservative) 0.3 mg/1 ml+5 mg/1 ml: dropper bottle 3 ml 1 pc..
		Eye drops (preservative-free) 0.3 mg/1 ml+5 mg/1 ml: containers 0.4 ml 30 pcs.

Dosage Form, Packaging, and Composition

Eye drops as a colorless or light yellow, clear solution.

Excipients: benzalkonium chloride, citric acid monohydrate, sodium phosphate heptahydrate, sodium chloride, hydrochloric acid, sodium hydroxide, water.

3 ml – dropper bottles made of white polyethylene with a capacity of 5 ml (1) – cardboard packs.

Eye drops as a colorless or light yellow, clear solution.

Excipients: citric acid monohydrate, sodium phosphate heptahydrate, sodium chloride, hydrochloric acid, sodium hydroxide, water.

0.4 ml – single-dose containers made of polyethylene with a capacity of 0.9 ml (10*) – bags made of aluminum foil (3) – cardboard packs.

* as two strips of 5 pcs.

Clinical-Pharmacological Group

Antiglaucoma drug

Pharmacotherapeutic Group

Drugs used in ophthalmology; antiglaucoma drugs and miotic agents; beta-adrenergic blockers

Pharmacological Action

Ganfort^® is a combined drug, its components Bimatoprost and timolol reduce intraocular pressure through combined interaction, leading to a significantly more pronounced hypotensive effect compared to the effect of each component separately.

Bimatoprost belongs to synthetic prostatamides, its chemical structure is similar to prostaglandin F2a (PGF2a). Bimatoprost does not affect any of the known types of prostaglandin receptors. The hypotensive action of bimatoprost is achieved by enhancing the outflow of intraocular fluid through the trabecula and the uveoscleral pathway of the eye.

Timolol is a non-selective beta-blocker, it does not possess intrinsic sympathomimetic and membrane-stabilizing activity.

Timolol reduces intraocular pressure by reducing the production of intraocular fluid. The exact mechanism of action is not established, it may be associated with the inhibition of cyclic adenosine monophosphate (cAMP) synthesis and is caused by endogenous stimulation of beta-adrenergic receptors.

Pharmacokinetics

Ganfort^®

Systemic absorption of the drug is minimal, it does not differ either during combined treatment or during instillation of each of the drug components separately.

In two studies lasting 12 months, no systemic accumulation of any of the active substances was noted.

Bimatoprost

In vitro studies have shown that Bimatoprost penetrates the iris and sclera of the eye. When instilling 0.03% bimatoprost solution, 1 drop in both eyes once a day for 2 weeks, the C_max of bimatoprost in blood plasma is reached within 10 minutes after application, and within 1.5 hours its concentration in blood plasma decreases to the lower limit of quantification (0.025 ng/ml). The mean values of C_max and the area under the concentration-time curve (AUC_{0-24 h}) of bimatoprost were similar on day 7 and day 14 of application, and were 0.08 ng/ml and 0.09 ng×h/ml respectively, indicating that the steady-state concentration of bimatoprost is reached within the first week of application.

Bimatoprost is moderately distributed in tissues, and the systemic volume of distribution at steady-state concentration of the drug is 0.67 L/kg. Bimatoprost is predominantly in the blood plasma. The binding of bimatoprost to plasma proteins is approximately 88%. Bimatoprost undergoes oxidation, N-deethylation and glucuronidation to form various metabolites.

Bimatoprost is excreted primarily by the kidneys. About 67% of the drug administered intravenously to healthy volunteers was excreted in the urine, and 25% through the gastrointestinal tract (GIT). The T_1/2 of bimatoprost, determined after its intravenous administration, was approximately 45 minutes; and the total clearance was 1.5 L/h/kg.

In elderly patients

When using bimatoprost twice a day, the mean AUC_{0-24 h} value in elderly patients is 0.0634 ng×h/ml, which significantly exceeds the value of this indicator in healthy young individuals – 0.0218 ng×h/ml.

However, this difference has no clinical significance, since the systemic exposure of bimatoprost during its topical application in elderly patients and healthy young individuals remains very low. No accumulation of bimatoprost in the systemic circulation is observed, the safety profile does not differ in elderly patients and young individuals.

Timolol

In patients who underwent surgical treatment for cataracts, after instillation of eye drops in the form of a 0.5% solution, the C_max of timolol in the intraocular fluid after 1 hour was 898 ng/ml. Some amount of the drug enters the systemic circulation and undergoes metabolism in the liver. The T_1/2 of timolol is about 4-6 hours. Part of timolol metabolized in the liver is excreted through the gastrointestinal tract, and another part of it and metabolites are excreted by the kidneys. Timolol binds to plasma proteins to a small extent.

Indications

• Reduction of intraocular pressure in patients with open-angle glaucoma and ocular hypertension with insufficient effectiveness of topical application of drugs from the group of beta-blockers and prostaglandin analogs.

ICD codes

Dosage Regimen

Recommended doses for adults (including elderly patients): 1 drop is instilled into the conjunctival sac of the affected eye once a day in the morning.

If the drug administration is missed once, the drug is administered the next day. It is not recommended to exceed the dose – 1 administration once a day. If more than 2 drugs are used, it is necessary to take a 5-minute break between each instillation.

Adverse Reactions

The frequency of side effects identified during studies was assessed as follows: very common (>1/10), common (>1/100, <1/10); uncommon (>1/1000, <1/100).

The following side effects were identified in clinical studies of the drug Ganfort^®

From the central nervous system uncommon – headache;

From the organ of vision very common – conjunctival hyperemia, eyelash growth; common — superficial keratitis, corneal erosion, burning sensation, itching, burning pain in the eyes, foreign body sensation, dryness of the eye mucosa, eyelid redness, eye pain, photophobia, eye discharge, visual impairment, eyelid skin itching; uncommon – iridocyclitis, eye mucosa irritation, conjunctival edema, blepharitis, epiphora, eyelid swelling, eyelid tenderness, decreased visual acuity, asthenopia, trichiasis; frequency unknown: cystoid macular edema.

From the respiratory system uncommon – rhinitis;

From the skin and subcutaneous tissue common — eyelid skin pigmentation; uncommon – hirsutism.

Other side effects that were observed with the use of one of the drug components and are potentially possible during treatment with the drug Ganfort^®

Bimatoprost

From the cardiovascular system increased blood pressure.

General disorders and administration site conditions asthenia, peripheral edema.

From the organ of vision allergic conjunctivitis, cataract, darkening of eyelashes, increased iris pigmentation, blepharospasm, eyelid retraction, retinal hemorrhage, uveitis.

Laboratory parameters changes in liver enzyme activity.

Timolol

Mental disorders insomnia, nightmares, decreased libido.

From the central nervous system myasthenia gravis, paresthesia, cerebral ischemia.

From the organ of vision decreased corneal sensitivity, diplopia, ptosis, retinal detachment (after surgical treatment), change in refraction (due to withdrawal of miotic therapy in some cases), keratitis.

From the hearing and vestibular system tinnitus.

From the cardiovascular system heart block, cardiac arrest, cardiac arrhythmias, loss of consciousness, bradycardia, heart failure, congestive heart failure; decreased blood pressure, chest pain, cerebrovascular accident, intermittent claudication, Raynaud’s syndrome, cold extremities, palpitations.

From the respiratory system bronchospasm (mainly in persons with a history of bronchospasm episodes), dyspnea, cough.

From the gastrointestinal tract nausea, diarrhea, dyspepsia, dry oral mucosa.

From the skin and subcutaneous tissue alopecia, psoriasis-like rashes, exacerbation of psoriasis.

From the musculoskeletal and connective tissue systemic lupus erythematosus.

From the urinary system Peyronie’s disease.

Others edema, chest pain, fatigue.

Contraindications

• Hypersensitivity to the components of the drug;
• Increased reactivity of the respiratory tract syndrome, including bronchial asthma in the acute stage and past episodes in the history, severe chronic obstructive pulmonary disease (COPD);
• Sinus bradycardia, atrioventricular block II and III degree, clinically significant heart failure, cardiogenic shock;
• Age under 18 years;
• Pregnancy, breastfeeding period.

With caution impaired liver and kidney function (the drug has not been sufficiently studied in this category of patients). In patients with risk factors for macular edema (for example, with aphakia, pseudophakia, lens rupture).

In patients with diabetes mellitus (unstable course) and impaired glucose tolerance, since the beta-blocker timolol, which is part of the drug Ganfort^®, can mask the signs of hypoglycemia. In patients with inflammatory changes in the eyes, neovascular, inflammatory, closed-angle glaucoma, congenital glaucoma or narrow-angle glaucoma (no data on the study of efficacy and safety).

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Use with caution in case of impaired liver function.

Use in Renal Impairment

Use with caution in case of impaired kidney function.

Pediatric Use

Contraindicated in children under 18 years of age.

Special Precautions

Just like other ophthalmic drugs, Ganfort^® can penetrate into the systemic bloodstream.

Symptoms of heart failure must be compensated before starting the use of the drug Ganfort^®. Regular monitoring of the condition of patients with severe heart failure and determination of heart rate is necessary. When using timolol, there were reports of side effects from the cardiovascular system and respiratory organs, including fatal outcomes due to bronchospasm in patients with bronchial asthma, and less often due to heart failure.

Beta-blockers can mask the symptoms of hypoglycemia, hyperthyroidism and cause worsening of Prinzmetal’s angina, severe peripheral and central vascular disorders, as well as arterial hypotension.
In patients with a history of atopic manifestations and severe anaphylactic reactions to various allergens, the doses of epinephrine (adrenaline) that are usually used to stop anaphylactic reactions may be ineffective against the background of the use of beta-blockers. In patients with mild liver disease or initially elevated activity of liver enzymes ALT (ALT), AST (AST) and/or total bilirubin, Bimatoprost did not affect liver function during the study period of 4 hours lasting more than 24 months.

Before starting treatment, patients must be informed about the possible growth of eyelashes, increased pigmentation of the eyelid skin and pigmentation of the iris of the eyes, since these side effects have been established during studies of bimatoprost and the drug Ganfort^®. Some changes may be permanent, and may be accompanied by the occurrence of differences between the eyes if instillations of the drug were carried out in only one eye. After discontinuation of the drug Ganfort^®, iris pigmentation may remain permanent. After 12 months of treatment with the drug Ganfort^®, the frequency of iris pigmentation was noted in 0.2% of patients. And after 12 months of treatment with only bimatoprost in the form of eye drops 1.5%, no further increase in the frequency of this effect was observed during therapy lasting 3 years. Increased pigmentation of the iris is due to increased production of melanocytes, and not just an increase in their number.

The excipient benzalkonium chloride, which is part of the drug Ganfort^®, can cause irritation of the eye mucosa and discoloration of soft contact lenses. Contact lenses must be removed before administering the drug, they can be put on 15 minutes after instillation. Benzalkonium chloride can cause acute keratitis and/or toxic corneal ulcer. In this regard, it is necessary to monitor the patient’s condition during frequent or prolonged treatment with the drug Ganfort^® in persons with dry eye syndrome and with corneal changes.

After opening the bottle, the possibility of microbial contamination of its contents cannot be excluded, which can lead to inflammatory eye lesions. The shelf life of the drug after the first opening of the bottle is 28 days. After the specified time has elapsed, the bottle should be discarded, even if the solution has not been completely used.

It is recommended to write the date of opening the bottle on the cardboard pack of the medicinal product.

Effect on the ability to drive vehicles and mechanisms

Transient visual impairment after drug administration is possible, so the patient should wait until vision is fully restored before driving a car or operating machinery.

Overdose

No cases of overdose of the drug Ganfort^® have been reported; when administered as eye drops, overdose is unlikely.

Bimatoprost

In case of unintentional oral intake of the drug Ganfort^®, the following information may be useful: no symptoms of toxic effects of bimatoprost in doses up to 100 mg/kg/day were noted during 2-week oral administration in an experiment on rats and mice. The dose used in the study, expressed in mg/m, exceeds by 70 times the possible dose of bimatoprost in case of accidental oral intake of the contents of a bottle of the drug Ganfort^® by a child weighing 10 kg.

Timolol

In case of timolol overdose, the following symptoms may be observed: bradycardia, decreased blood pressure, bronchospasm, headache, dizziness, shortness of breath, cardiac arrest. Studies have shown that timolol is not completely removed by hemodialysis. If an overdose occurs, symptomatic therapy should be carried out.

Storage Conditions

At a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 2 years.

Dispensing Status

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.