Ganfort: drug to reduce intraocular pressure

2021-06-07 04:10 PM

Ganfort consists of 2 active ingredients: bimatoprost and timolol maleate. These two components lower intraocular pressure (IOP) through a complementary and synergistic mechanism of action, resulting in further reductions in intraocular pressure compared with the individual components.

Producer

Allergan.

Ingredient

Per mL: Bimatoprost 0.3mg, timolol 5mg.

Pharmacodynamic properties

Pharmacotherapeutic group

Combination drug of Timolol - beta-blocking agent used in ophthalmology.

ATC code: S01ED 51.

Mechanism of action

Ganfort consists of 2 active ingredients: bimatoprost and timolol maleate. These two components lower intraocular pressure (IOP) through a complimentary and synergistic mechanism of action, resulting in further reductions in intraocular pressure compared with the individual components. Ganfort has a rapid onset of action.

Bimatoprost is a potent intraocular pressure lowering agent. It is a synthetic prostamide, which is molecularly related to prostaglandin F2α (PGF2α) and acts through the identified prostamide receptor.

Bimatoprost lowers intraocular pressure in humans by increasing drainage of aqueous humor through the trabecular and uveo-scleral networks (via Schlemm channels).

Timolol is a beta1 and beta2 adrenergic receptor blocker (non-selective), with no significant intrinsic sympathomimetic or direct inhibitory effects on myocardial activity, and no anabolic effects. local sensitization (membrane-stabilizing action). Timolol lowers intraocular pressure by reducing the formation of aqueous humor.

Clinical effects

Bimatoprost lowers intraocular pressure with its IOP-lowering effect peaking at about 12 hours; timolol has an effect on lowering intraocular pressure that peaks in about 1-2 hours. Both bimatoprost and timolol significantly lower intraocular pressure after the first dose.

The intraocular pressure-lowering effect of Ganfort was not less than that achieved by adjuvant treatment with bimatoprost (1 time/day) and timolol (2 times/day).
 
Some of the available literature on Ganfort suggest that evening administration may be more effective in lowering IOP than morning administration. However, the possibility of adherence should be considered when considering morning or evening dosing.

Use in children

The efficacy and safety of Ganfort in children aged 0-18 years have not been established.

Pharmacokinetic properties

Drugs Ganfort

Plasma concentrations of bimatoprost and timolol have been determined in a crossover study comparing monotherapy with Ganfort treatment in healthy subjects. The systemic absorption of each drug is minimal and unaffected by the combination in a single formulation.

In two 12-month studies evaluating systemic absorption, no drug accumulation was observed for the individual components.

Bimatoprost

Bimatoprost penetrates well into the cornea and sclera of humans in the laboratory. After ophthalmic administration, systemic exposure of bimatoprost was very low and did not accumulate over time. Following instillation of 1 drop of bimatoprost 0.03% once daily in both eyes for 2 weeks, peak blood concentrations were reached within 10 minutes of instillation and fell below the detectable limit ( 0.025 ng/mL) within 1.5 hours of instillation. The mean values ​​of peak concentration (Cmax) and area under the concentration curve (AUC0-24 hours) were similar between day 7 and day 14 at approximately 0.08 ng/mL and 0 respectively. .09 ng•hour/mL respectively. This indicates that steady-state drug concentrations are achieved within the first week of dosing.

Bimatoprost is moderately distributed into body tissues, with a steady-state human volume of distribution of 0.67 l/kg. In human blood, bimatoprost is mainly in plasma. Bimatoprost is approximately 88% bound to plasma proteins.

Bimatoprost is the predominant circulating form in the blood once it enters the systemic circulation following ophthalmic administration. Bimatoprost then undergoes oxidation, N-deethylation, and glucuronide to form various metabolites.

Bimatoprost is eliminated mainly by renal excretion, up to 67% of an intravenous dose administered to healthy volunteers is excreted in the urine, 25% of the dose is excreted in the feces. The half-life was determined after intravenous administration to be approximately 45 minutes, and the total blood clearance was 1.5 L/hr/kg.

Characteristics of elderly patients

After twice-daily dosing, the mean area under the concentration curve (AUC0-24 hours) for bimatoprost 0.0634 ng•h/mL in the elderly (those 65 years of age or older) was high. significantly more than 0.0218 ng•hr/mL in healthy young adults. However, this finding is not clinically relevant because systemic exposure in both the elderly and the young remains very low after ocular administration. There is no accumulation of bimatoprost in the blood over time, and the safety profile is similar between the elderly and younger patients.

Timolol

After ophthalmic administration of 0.5% solution to cataract surgery, peak timolol concentrations were 898 ng/mL in aqueous humor 1 hour after administration. Part of this dose is absorbed systemically, from which the drug is extensively metabolized in the liver. The half-life of timolol in plasma is approximately 4-6 hours. Timolol is partially metabolized in the liver and then excreted with its metabolites by the kidneys. Timolol is not strongly bound to plasma.

Preclinical safety

Toxicity in the eyes

Preclinical studies of ocular toxicity with repeated dosing of the combination bimatoprost 0.03%/timolol 0.5% showed ocular safety data similar to those of bimatoprost (alone) or timolol (used alone).

Ganfort (multiple doses)

No significant adverse effects of ocular or systemic toxicity were observed in rabbits when bimatoprost 0.03% was administered by topical eye drops as well as supported by 0.5% timolol twice daily. for 3 months or in combination with timolol 0.5%, 3 times/day for 1 month. Ocular administration of the combination bimatoprost 0.03%/timolol 0.5% twice daily for 6 months in monkeys did not produce significant systemic toxicity effects. The ocular effects in monkeys, when administered in combination, were limited to periocular changes, characterized by a prominent increase in the eyelid sulcus, widening of the eyelid slit, and increased pigmentation in the iris.

These periocular effects may be related to the class of prostaglandin compounds, as similar results have been observed in previous long-term ocular studies with bimatoprost in monkeys and with other prostaglandin analogs.

The ocular safety of bimatoprost 0.03% (alone) and timolol 0.5% (alone) has been demonstrated by preclinical studies (described below) used to support the approval of LUMIGAN and Timoptic, respectively, and by the documented safe clinical use of these products.

Bimatoprost

Toxicity of bimatoprost (alone) has been evaluated in ophthalmic studies of up to 1-month duration in New Zealand white rabbits (NZW), up to 6 months duration in Dutch belted rabbits (DB), time to 1 month in dogs, and up to 1 year in monkeys.

Eye discomfort and mild, transient conjunctival congestion were observed in NZW rabbits in both the 3-day and 1-month studies at bimatoprost concentrations as low as 0.001%. However, rabbits using the placebo solution showed a similar response. Dogs showed mild, transient ocular discomfort and conjunctival erythema at concentrations as low as 0.001% bimatoprost and in the placebo control group. Administration of bimatoprost or placebo to DB rabbits did not cause eye irritation in any of the studies. As mild, transient eye irritation was observed in NZW rabbits and dogs administered 4 times a day but not in DB rabbits given the same bimatoprost and placebo formulations twice daily, these effects may be possible. due to higher frequency of drug use. No systemic effects were observed in the 6-month rabbit eye study, which achieved a maximum AUCde 360 ​​times higher than the human value receiving the bimatoprost 0 combination clinical regimen. 0.03%/ timolol 0.5%.

Monkeys receiving 1 drop of bimatoprost 0.03% once daily or twice daily or bimatoprost 0.1% twice daily for 52 weeks showed a dose-dependent increase in prominence of the leading eyelid sulcus. to wide eyelid slit of the eye being treated. The severity and incidence of this effect is transiently dose-related. No functional or microscopic changes were observed in association with periocular changes. Iris hyperpigmentation was noted in several animals in all treated groups. No increase in the number of melanocytes associated with pigmentation was observed. It appears that the mechanism of iris hyperpigmentation is due to increased stimulation of melanin production in the melanocytes and not to an increased number of melanocytes. The highest dose (0.1%, twice daily) produced a maximum AUCde approximately 440 times higher than that in humans receiving the clinical combination regimen of bimatoprost 0,03%/ timolol 0,5%.

Timolol

Administration of timolol 1.5% (alone) to rabbits and dogs in one eye, 3 times/day for up to 12 months (5 days/week) resulted in only mild, treatment-related eye irritation.

Systemic toxicity

Systemic toxicity studies have not been performed with the combination bimatoprost 0.03%/timolol 0.5% due to the well-understood and clear mechanism of action of the individual compounds and toxicity assessment. extensive systemic exposure of individual compounds in the following studies.

Bimatoprost

Effects in nonclinical studies were observed only at exposures considered sufficient in excess of maximum human exposure to indicate little significance for clinical use.

No effects were observed in mice receiving bimatoprost 4 mg/kg/day orally for 3 months. This dose produced a maximum AUCde approximately 1000-fold higher than that observed in humans receiving the combined clinical regimen of bimatoprost 0.03%/timolol 0.5%. Female mice given an oral dose of 8 mg/kg/day showed reversible thymic lymphocyte proliferation. This result was observed only in mice and the maximum AUCde was approximately 3000 times higher than the human values ​​given the combined clinical regimen of bimatoprost 0.03%/timolol 0.5%.

Decreased feed intake and increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed in male rats given ≥8 mg/kg/day for 13 weeks. Reversible body weight loss and weight gain were observed in both cultivars with doses ≥4 mg/kg/day. Reversible ovarian weight gain with delayed luteal degeneration was observed only in female rats administered ≥4 mg/kg/day. Effects on the ovary were observed only in studies with unborn rats and as these effects were not seen in other species or pregnant rats it is suggested that bimatoprost may only affect the cycle luteal phase in unborn rats. These results were observed at AUCde at least 11,000-fold higher than those in humans receiving the combined clinical regimen of bimatoprost 0.03%/timolol 0.5%. Species specificity and significant exposure limits indicate that the risk of human ovarian effects is negligible. There were no drug-related effects at either dose of 0.1 mg/kg/day. A slight (9%) reduction in body weight was observed in female rats (2 mg/kg/day) compared with controls in a 1-year rat study. There was a slight increase in transaminase activity (approximately 3-fold) in male rats in all dose groups but these changes were not associated with any histopathological damage and reversibility was evident. The effects on the ovaries and liver were reversible and were considered species-specific as these changes were not observed in mice and monkeys with systemic exposures up to 8500 to 99,000-fold higher respectively. respectively, compared with values ​​in humans receiving a combination clinical regimen of bimatoprost 0.03%/timolol 0.5%.

Periocular effects were also observed with 0.01 mg/kg/day intravenous injection in monkeys for 17 weeks. Intravenous administration of 0.01 mg/kg/day produced an AUCde approximately 1600 times higher than values ​​in humans receiving the clinical regimen of bimatoprost 0.03%/timolol 0.5%. The periocular effects disappeared after discontinuation of treatment. No functional or anatomical abnormalities of the eye were detected. The underlying cause of the prominence of the eyelid sulcus and the widening of the eyelid fissure observed with intraocular and intravenous administration to monkeys is unknown. Since periocular changes were observed with both ocular and intravenous bimatoprost, these studies suggest that there are local receptor-specific effects underlying the periocular effects in monkeys.

Timolol

Timolol maleate given orally to rats or dogs at doses up to 50 mg/kg/day for up to 4 months did not cause drug-related toxicity.

Carcinogenicity and genotoxicity studies

Bimatoprost was not carcinogenic in mice or rats when administered by nasogastric tube at doses up to 2 mg/kg/day in mice and 1 mg/kg/day in rats. The 104-week treatment resulted in AUC values ​​that were approximately 1300-fold and 2000-fold higher than those in humans receiving the combined clinical regimen of bimatoprost 0.03%/timolol 0.5%.

In a 2-year study with timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of pheochromocytoma in male rats given 300 mg/kg/day. This dose is approximately 510,000 times the daily dose of bimatoprost 0.03%/timolol 0.5% in humans.

Neither bimatoprost nor timolol maleate is considered to pose a genotoxicity risk, based on the results of a comprehensive series of genotoxicity tests. Bimatoprost was not mutagenic or chromosomal fracture in the Ames test, the mouse lymphoma test, or the in vivo mouse micronucleus test. Timolol maleate had no mutagenic potential when tested in vivo (mice), in micronucleus and cytogenetic tests (doses up to 800 mg/kg), and in cytotoxicity assays. neoplastic tumor cells in vitro (up to 100 μg/mL). In the Ames trial, the highest concentration of timolol used was 5,000 or 10,000 μg/plate, which was associated with a statistically significant increase in revertants observed with the test strain TA. 100 (in 7 replicate trials) but not in the other 3 strains. In the trial with the test strain TA 100, no dose-matching relationship was observed and the regression sample to control ratio did not reach 2. A ratio of 2 is generally considered to be Criteria for a positive Ames test.

Fertility studies

In infertility and early embryo development studies in rats, there were no drug-related effects of bimatoprost at doses up to 0.6 mg/kg/day on reproductive performance in rats. male or female rats, maternal or paternal toxicity, sperm analysis parameters, uterine implantation parameters, or embryo viability. The highest dose produced a Cmax that was 160-fold higher than in humans receiving the combined clinical regimen of bimatoprost 0.03%/timolol 0.5%. Although the AUCde for a dose of 0.6 mg/kg/day was not determined in this particular study, in this study it could be inferred to be 710 times higher than the value in humans given the regimen. clinical treatment from drug exposure data in embryonic development studies.

Reproduction and fertility studies with timolol in rats revealed no adverse effects on male or female fertility at doses up to 5100 times the daily dose of the combination. bimatoprost 0.03%/ timolol 0.5% in humans.

Studies on embryo-foetal development

In an embryo-foetal development study in CD-1 mice treated with bimatoprost 0.3 and 0.6 mg/kg/day orally, maternal toxicity was evident in the form of one billion small percentage of late miscarriage (days 16-17) and preterm delivery. No maternal toxicity occurred at the dose of bimatoprost 0.1 mg/kg/day (Cmax was 28 times higher than in humans given the 0.03% bimatoprost/timolol 0 combination clinical regimen). 5%). The lowest dose showing maternal toxicity (bimatoprost 0.3 mg/kg/day) had an AUCde 220 times higher than in humans given the clinical regimen. The embryo-foetal concentration of no known adverse effects (NOAEL) was 0.6 mg/kg/day bimatoprost, which produced a 490-fold higher AUCde than in subjects receiving the clinical regimen.

Teratogenicity studies with timolol were performed in mice, rats and rabbits at oral doses up to 50 mg/kg/day (8,600 times the daily dose of bimatoprost 0.03%/timolol 0.5% in humans) showed no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, no adverse effects on postnatal development were observed. A dose of 1000 mg/kg/day (170,000 times the daily dose of bimatoprost 0.03%/timolol 0.5% in humans) was maternally toxic in mice and resulted in an increased number of abortions.

Prenatal and postnatal studies

In prenatal and postnatal development studies, treatment of F0 generation rats with bimatoprost ≥0.3 mg/kg/day affected pregnancy and prenatal development, expressed as prolonged gestation period, late abortion, fetal death, postpartum mortality and decreased body weight of pups. At a dose of bimatoprost 0.6 mg/kg/day, a reduction in the number of parities in the mother, the pregnancy index, and the number of parities were breastfed. No effect on the postnatal development and mating performance of the F1 progeny was observed at a dose of 0.1 mg/kg/day bimatoprost, which produced exposure 94 times the human exposure. AUCde). These parameters were slightly affected at a dose of 0.3 mg/kg/day which produced an exposure 280 times the human exposure with the 0.03% bimatoprost/timolol 0.5% combination. Neurobehavioral function, hysterotomy, and parity in F1-generation rats were not affected by high doses of bimatoprost 0.3 mg/kg/day.

Indications and uses

Lowers intraocular pressure (IOP) in patients with open-angle glaucoma or glaucoma who have not responded adequately to topical beta-blockers or prostaglandin analogs.

Dosage and Administration

Eye drops

Ganfort is indicated for topical use in the eyes.

As with any eye drops, to reduce systemic absorption, it is recommended to press on the lacrimal sac at the inner corner of the eye (tear occlusion) for at least 1 minute. This should be done immediately after instillation into each eye (Standard Medical Practice).

The recommended dose for Ganfort is 1 drop in the affected eye once a day, either in the morning or in the evening. The medicine should be taken at the same time each day.

Some of the available literature on Ganfort suggest that evening administration may be more effective in lowering IOP than morning administration. However, the possibility of adherence should be considered when considering morning or evening dosing.

If a dose is missed, treatment should be continued with the next scheduled dose. Do not exceed the daily dose of one drop in the affected eye.

If more than one eye medication is to be used, the different drugs should be instilled at least 5 minutes apart.

Use in children

The safety and effectiveness of Ganfort have not been established in pediatric patients.

Use in the elderly

No overall differences in safety and efficacy were observed between elderly and other adult patients.

Patients with liver or kidney failure

Ganfort has not been studied in patients with hepatic or renal impairment. Therefore, caution should be exercised in treating these patients.

Warning

Ganfort should be used with caution in patients with active endophthalmitis (eg, uveitis) because inflammation may be exacerbated.

Macular edema, including cystic macular edema, has been reported during treatment with Ganfort. Ganfort should be used with caution in lens-agnostic patients, patients with artificial lenses with a ruptured posterior vitreous capsule, or patients with known risk factors for macular edema (eg. : surgery in the eye, retinal vein occlusion, inflammatory eye disease, and diabetic retinopathy).

An increase in iris pigmentation has been observed after treatment with Ganfort. Patients should be informed of the possibility of brown pigmentation in the iris, which may be permanent. The pigmentation change is due to an increase in the melanin content in the melanocytes, rather than an increase in the number of melanocytes.

The long-term effects of iris hyperpigmentation are unknown. Changes in iris color observed with ocular bimatoprost may go unnoticed for months to years. Neither the nevus nor the freckle in the iris appears to be affected by the treatment.

Ganfort has been reported to cause changes to pigmented tissue.

The most commonly reported pigmentary changes are hyperpigmentation of the skin around the eyes and darkening of the eyelashes. Periorbital pigmentation has been reported to be reversible in some patients.

There is a possibility of hair growth in areas where Ganfort solution comes into repeated contact with the skin surface. Therefore, it is important to apply Ganfort as directed and to avoid letting it run on the cheeks or other areas of the skin.

In studies of 0.03% bimatoprost ophthalmic solution in patients with glaucoma or glaucoma, it has been shown that routine eye exposure to more than 1 daily dose of bimatoprost can reduce the effects of bimatoprost. lower intraocular pressure. Intraocular pressure should be monitored in patients receiving bimatoprost ophthalmic solution with other prostaglandin analogs.

Ganfort has not been studied in patients with ocular inflammatory conditions, neovascular glaucoma, inflammatory glaucoma, angle-closure glaucoma, congenital glaucoma, or narrow-angle glaucoma.

As with topical ophthalmic drugs, the active ingredients bimatoprost and timolol in Ganfort can be absorbed systemically. An increase in systemic absorption of the individual active ingredients has not been observed.

Because the beta-adrenergic component is timolol, side effects typical of systemic beta-adrenergic receptor blockers may occur, including the following:

Anaphylaxis

While taking beta-blockers, patients with a history of allergies or a history of severe anaphylactic reactions to multiple allergens may be more reactive to repeated administration of the above allergens.

These patients may not respond to the usual doses of epinephrine used to treat anaphylaxis.

Heart disorder

Although rare, cardiovascular effects have been reported, including death from heart failure. Ganfort should be used with caution in patients with cardiovascular disease (eg, coronary artery disease, Prinzmetal's angina, first-degree heart block, and heart failure) and hypotension.

Patients with a history of cardiovascular disease should be monitored for signs of worsening of these conditions.

Respiratory disorders

Although rare, respiratory reactions have been reported, including death, due to bronchospasm.

Ganfort should be prescribed with caution in patients with mild and moderate chronic obstructive pulmonary disease.

Diabetes

Beta-adrenergic blockers should be used with caution in patients with spontaneous hypoglycemia or in patients with diabetes mellitus (especially those with unstable diabetes mellitus) because beta-adrenergic receptor blockers may mask the signs and symptoms of acute hypoglycemia.

Hyperthyroidism

Beta-adrenergic blockers may mask the signs of hyperthyroidism.

Corneal disease

Beta-blockers used in the eyes can cause dry eyes. Caution should be exercised when treating patients with corneal disease.

Choroidal aneurysm

Angioplasty after dialysis has been reported with the use of hydrosuppressive therapy (eg, timolol).

Other beta-blockers

Caution should be exercised when co-administered with systemic beta-adrenergic blockers due to the potential for a synergistic effect on systemic beta-blockade. The response of these patients should be closely monitored. The use of 2 topical beta-adrenergic blockers is not recommended.

Surgical anesthesia

Ophthalmic beta-blockers may decrease compensatory tachycardia and increase the risk of hypotension when used in combination with anesthetics. The anesthesiologist must be informed if the patient is using Ganfort.

Liver and kidney function

Ganfort has not been studied in patients with hepatic or renal impairment; Caution should be exercised when treating these patients.

Vascular disorder

Caution should be exercised when treating patients with severe peripheral circulatory disorders (ie, Raynaud's phenomenon).

Use contact lenses

Patients who are wearing soft (hydrophilic) contact lenses should be instructed to remove their contact lenses prior to using Ganfort solution and to wait at least 15 minutes after instillation of Ganfort before wearing soft contact lenses.

General warnings and cautions

Patients should be instructed to avoid contact of the tip of the vial with the eye or surrounding structures to avoid eye injury and eye drop contamination.

The benzalkonium chloride in Ganfort (multiple doses) can be absorbed and cause discoloration of soft contact lenses.

Benzalkonium chloride in Ganfort has been determined to be safe for the eyes by two preclinical studies of ocular toxicity using Ganfort and placebo containing 0.005% benzalkonium chloride. These studies have revealed no adverse effects in the conjunctiva or cornea by ocular examination and microscopic histopathology.

Use for children

The safety and efficacy of Ganfort have not been established in pediatric patients.

Use in geriatrics

No overall differences in safety and efficacy were observed between elderly and other adult patients.

Effects on ability to drive and use machines

Ganfort has no significant influence on the ability to drive and use machines. As with any ophthalmic medication, if transient blurred vision occurs with eye drops, the patient should wait until clear vision is restored before driving or using machines.

Overdose

There is no information on Ganfort overdose in humans. If Overdosage occurs, treatment should be symptomatic and supportive; need to maintain a clear airway.

If Ganfort is accidentally ingested, the following information may be helpful: in 2-week studies in rats and mice administered orally, doses of bimatoprost up to 100 mg/kg/day did not cause any toxicity. This dose was 36 times higher than the accidental ingestion of a 7.5 mL bottle of 0.03% bimatoprost ophthalmic solution in a 10 kg infant.

Inadvertent overdose of timolol ophthalmic solution has been reported resulting in systemic effects similar to those observed with systemic beta-adrenergic blockers such as dizziness, headache, shortness of breath, bradycardia, hypotension, and hypotension. pressure, bronchospasm, and cardiac arrest. An in vitro hemodialysis study, using 14C timolol added to human plasma or whole blood showed that timolol was readily dialyzed from these fluids, however, a study in patients with renal impairment showed timolol is not readily dialyzable.

Contraindications

Ganfort is contraindicated in patients with the following conditions:

Hypersensitivity to the active substance or to any of the excipients.

Reactivated respiratory disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.

Sinus bradycardia, sick sinus syndrome, sinoatrial block, second or third-degree atrioventricular block not controlled by a pacemaker, marked heart failure, cardiogenic shock.

Use in pregnant and lactating women

Pregnant

There are no adequate data on the use of Ganfort in pregnant women.

Ganfort is used during pregnancy only if the possible benefit to the mother outweighs the possible risk to the fetus.

Breastfeeding

Timolol has been detected in breast milk following oral and ophthalmic administration. Studies in rats have shown that bimatoprost is excreted in the milk of lactating rats.

Ganfort should not be used by women who are breastfeeding.

Interactive

No drug interaction studies have been performed with Ganfort.

Beta-adrenergic blocking drugs

Patients receiving a systemic beta-adrenergic blocker (e.g., orally or intravenously) and Ganfort should be monitored because of the potential for an additive beta-blocker effect on both systemic blood pressure and pressure. intraocular.

Antihypertensives/cardiac glycosides

There is potential for additive effects leading to hypotension, and/or marked bradycardia when timolol-containing eye drops are used concomitantly with oral calcium channel blockers, guanethidine, and antiarrhythmics. , digitalis glycosides, drugs with parasympathetic effects, and other antihypertensive agents.

Pupil dilators

Although timolol has little or no effect on pupil size, there have been occasional reports of mydriasis when timolol is administered with a pupillary dilator such as adrenaline.

CYP2D6. Inhibitors

Increased systemic beta-blocking effects (eg, decreased heart rate, depression) have been reported during co-administration with CYP2D6 inhibitors [eg, quinidine, selective serotonin reuptake inhibitors. (SSRI)] and timolol.

Side effects

Experience from Clinical Studies - Studies 192024-018T and 192024-021T with Ganfort (multiple doses)

In the pivotal clinical studies 192024-018T and 192024-021T with Ganfort, most adverse events were transient and were not to the extent of requiring discontinuation of therapy. Adverse reactions were coded, using the COSTART dictionary available at the time of the study. Presents 12-month pooled data from the pivotal studies and reflects adverse events in the Ganfort arm as reported. Presents adverse events with incidence <1% in 12-month pooled data from pivotal studies 192024-018T and 192024-021T. The ordering of adverse reactions is based on the MedDRA system organ class (SOC) in an internationally agreed order.

After-sales experience - Ganfort (multiple dose)

The following adverse reactions have been identified during post-marketing use of Ganfort (multiple doses) in clinical practice. Since these reactions were reported voluntarily from a population of unknown size, frequency estimates cannot be made.

Eye disorders: Cystic macular edema, deepening of eyelid grooves (concave), iris hyperpigmentation, eye swelling, blurred vision.

Skin and Subcutaneous Tissue Disorders: Hyperpigmentation (around the eyes), alopecia.

Cardiovascular disorders: Slow heart rate.

General disorders and administration site: Fatigue, immune system disorders, hypersensitivity reactions including signs or symptoms of atopic dermatitis, angioedema, eye allergy.

Nervous system disorders: Dizziness, taste disturbances.

Psychiatric disorders: Insomnia, nightmares.

Respiratory, thoracic, and mediastinal disorders: Asthma, dyspnea.

Additional side effects

The additional side effects listed below have been reported with the active ingredients bimatoprost and timolol and are likely to occur with Ganfort:

Bimatoprost 0.03% multiple-dose (for eye drops)

Eye disorders: Eye fatigue, darkening of eyelashes, iritis.

Gastrointestinal disorders: Nausea.

Vascular disorders: Hypertension.

Timolol (for eye drops)

Eye Disorders: Corneal desensitization, diplopia, pseudo-pemphigus, ptosis, refractive changes, ocular irritation signs and symptoms including conjunctivitis and keratitis.

Cardiac disorders: Arrhythmia, atrioventricular block, cardiac arrest, heart failure, chest pain, congestive heart failure, edema, heart block, palpitations, pulmonary edema, worsening angina.

Ear and labyrinth disorders: Tinnitus.

Digestive disorders: Abdominal pain, loss of appetite, diarrhea, dry mouth, dyspepsia, nausea, vomiting.

Systemic disorders and administration site conditions: Asthenia.

Immune system disorders: Systemic allergic reactions including anaphylaxis, systemic lupus erythematosus.

Metabolic and nutritional disorders: Hypoglycemia (in patients with diabetes mellitus.

Musculoskeletal and connective tissue disorders: Myalgia.

Nervous system disorders: Cerebral ischemia, cerebrovascular accident, increased signs and symptoms of severe myasthenia gravis, paresthesia, syncope.

Psychiatric Disorders: Behavioral changes and mental disorders including anxiety, confusion, depression, disorientation, hallucinations, restlessness, amnesia, somnolence.

Reproductive system and mammary gland disorders: Decreased libido, Peyronie's disease, retroperitoneal fibrosis, sexual dysfunction.

Respiratory, Thoracic, and Mediastinal Disorders: Bronchospasm (mainly in patients with pre-existing bronchospasm, cough, nasal congestion, respiratory distress, upper respiratory tract infection).

Skin and Subcutaneous Tissue Disorders: Acute exacerbation of psoriasis, psoriatic rash, skin rash.

Vascular disturbances (partially cardiovascular): intermittent claudication, cold hands, and feet, hypotension, Raynaud's phenomenon.

Preservation

Store below 30°C. Keep the vial in the carton box.

Do not use the medicine more than 4 weeks after opening.

Presentation and packaging

Eye drops solution: box of 1 bottle of 3ml.