Ganfort/Ganfort PF

Ganfort/Ganfort PF

bimatoprost + timolol

Manufacturer:

Allergan

Distributor:

DKSH
Full Prescribing Info
Contents
Bimatoprost, timolol.
Description
Ganfort PF is a clear and colorless to slightly yellow, isotonic and sterile ophthalmic solution.
Each mL contains: 0.3 mg bimatoprost and 5 mg timolol equivalent to 6.8 mg of timolol maleate, sodium chloride, dibasic sodium phosphate heptahydrate, citric acid monohydrate, hydrochloric acid or sodium hydroxide (to adjust pH), purified water.
Action
Pharmacotherapeutic Group: Ophthalmological–beta-blocking agents–timolol, combinations.
ATC Code:
SO1ED 51.
Pharmacology: Pharmacodynamics: Mechanism of Action: Ganfort/Ganfort PF consists of two active substances: Bimatoprost and timolol maleate. These two components decrease elevated intraocular pressure (IOP) by complementary mechanisms of action and the combined effect results in additional IOP reduction compared to either compound administered alone. Ganfort/Ganfort PF has a rapid onset of action.
Bimatoprost is a potent ocular hypotensive agent. It is a synthetic prostamide, structurally related to prostaglandin F (PGF) that acts through an identified prostamide receptor.
Ganfort: Bimatoprost selectively mimics the effects of newly discovered biosynthesised substances called prostamides. The prostamide receptor, however, has not yet been structurally identified.
Ganfort PF: The efficacy of bimatoprost may be related to a dual mechanism of action on aqueous humor outflow that involves uveoscleral and trabecular meshwork Schlemm's canal pathways. Bimatoprost reduces IOP in humans by increasing aqueous humor outflow through the trabecular meshwork and enhancing uveoscleral outflow.
Timolol is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic (membrane-stabilising) activity. Timolol lowers IOP by reducing aqueous humour formation.
Ganfort: The precise mechanism of action is not clearly established, but inhibition of the increased cyclic AMP synthesis caused by endogenous beta-adrenergic stimulation is probable.
Clinical Effects: Bimatoprost lowers IOP with a peak ocular hypotensive effect at approximately 12 hours; timolol reaches peak ocular hypotensive effect at approximately 1 to 2 hours. Both bimatoprost and timolol significantly lower IOP following the first dose. The IOP-lowering effect of Ganfort PF is non-inferior to that achieved by adjunctive therapy of bimatoprost (once daily) and timolol (twice daily).
There are no studies with evening dosing of GANFORT. Morning dosing of GANFORT is therefore recommended to ensure maximal IOP-lowering effect at the time of the physiological IOP rise. However, if necessary for patient compliance, an evening dosing may be considered. Once-daily dosing of timolol 0.5% has a rapid onset of maximal effect, corresponding with the time of this rise, and maintains clinically meaningful IOP-lowering over the 24-hour period. Bimatoprost studies show comparable IOP control regardless of moring or evening dosing.
Pharmacokinetics: Ganfort Medicinal Product: Plasma bimatoprost and timolol concentrations were determined in a crossover study comparing the monotherapy treatments to Ganfort treatment in healthy subjects. Systemic absorption of the individual components was minimal and not affected by co-administration in a single formulation.
In two 12-month studies where systemic absorption was measured, no accumulation was observed with either of the individual components.
Bimatoprost:
Bimatoprost penetrates the human cornea and sclera well in vitro. After ocular administration, the systemic exposure of bimatoprost is very low with no accumulation over time. After once daily ocular administration of one drop of 0.03% bimatoprost to both eyes for two weeks, blood concentrations peaked within 10 minutes after dosing and declined to below the lower limits of detection (0.025 ng/ml) within 1.5 hours after dosing. Mean Cmax and AUC0-24hrs values were similar on days 7 and 14 at approximately 0.08 ng/ml and 0.09 ng∙hr/ml respectively, indicating that a steady drug concentration was reached during the first week of ocular dosing.
Bimatoprost is moderately distributed into body tissues and the systemic volume of distribution in humans at steady-state was 0.67 L/kg. In human blood, bimatoprost resides mainly in the plasma. The plasma protein binding of bimatoprost is approximately 88%.
Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing. Bimatoprost then undergoes oxidation, N-deethylation and glucuronidation to form a diverse variety of metabolism.
Bimatoprost is eliminated primarily by renal excretion, up to 67% of an intravenous dose administered to healthy volunteers was excreted in the urine, 25% of the dose was excreted via the faeces. The elimination half-life, determined after intravenous administration, was approximately 45 minutes; the total blood clearance was 1.5 L/hr/kg.
Characteristics in Elderly patients: After twice daily dosing, the mean AUC0-24hrs values of 0.0634 ng∙hr/mL bimatoprost in the elderly (subjects 65 years or older) were significantly higher than 0.0218 ng∙hr/mL in young healthy adults. However, this finding is not clinically relevant as systemic exposure for both elderly and young subjects remained very low from ocular dosing. There was no accumulation of bimatoprost in the blood over time and the safety profile was similar in elderly and young patients.
Timolol: After ocular administration of a 0.5% eye drops solution in humans undergoing cataract surgery, peak timolol concentration was 898 ng/mL in the aqueous humour at one hour post-dose. Part of the dose is absorbed systemically where it is extensively metabolized in the liver. The half-life of timolol in plasma is about 4 to 6 hours. Timolol is partially metabolized by the liver with timolol and its metabolites excreted by the kidney. Timolol is not extensively bound to plasma.
Toxicology: Preclinical Safety data: Ganfort: Repeated dose ocular toxicity studies on GANFORT showed no special hazard for humans. The ocular and systemic safety profile of the individual components is well establised.
Bimatoprost:  Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential. Studies in rodents produced species-specific abortion at systemic exposure levels 33- to 97-times that achieved in humans after ocular administration.
Monkeys administered ocular bimatoprost concentrations of ≥0.03% daily for 1 year had an increase in iris pigmentation and reversible dose-related periocular effects characterised by a prominent upper and/or lower sulcus and widening of the palpebral fissure. The increased iris pigmentation appears to be caused by increased stimulation of melanin production in melanocytes and not by an increase in melanocyte number. No functional or microscopic changes related to the periocular effects have been observed, and the mechanism of action for the periocular changes is unknown.
Timolol: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
Ganfort PF: Ocular Toxicology: Preclinical repeated dose ocular toxicity studies of the bimatoprost 0.03%/timolol 0.5% combination demonstrated an ocular safety profile similar to that of bimatoprost (alone) or timolol (alone).
Bimatoprost: The toxicity of bimatoprost (alone) has been assessed in ocular instillation studies up to 1 month duration in New Zealand White rabbits (NZW), up to 6 months duration in Dutch belted (DB) rabbits, up to 1 month duration in dogs, and up to 1 year duration in monkeys.
Slight, transient ocular discomfort and conjunctival hyperemia were noted in NZW rabbits in both 3-day and 1-month studies at bimatoprost concentrations as low as 0.001%. However, rabbits administered placebo solutions exhibited the same response. Dogs exhibited ocular discomfort and transient slight conjunctival erythema at concentrations as low as 0.001% bimatoprost, and in placebo controls. Administration of bimatoprost or placebo to DB rabbits did not cause ocular irritation in any study. Since slight, transient ocular irritation was observed in NZW rabbits and dogs QID, but not in DB rabbits given the same formulation of bimatoprost and placebo BID, these effects may be due to the higher frequency of dosing. No systemic effects were noted in the 6-month ocular rabbit study which achieved a maximal AUCde that was approximately 360-fold higher than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen.
Monkeys given ocular administration of 1 drop of bimatoprost 0.03% QD or BID or bimatoprost 0.1% BID for 52 weeks exhibited a dose-related increase in the prominence of the periocular sulci, resulting in a widening of the palpebral fissure of the treated eye. The severity and incidence of this effect was temporally related to dose. No functional or microscopic change related to the periocular change was observed. An increase in iris pigmentation was noted in some animals in all treated groups. No associated increase in melanocyte number was observed with the pigmentation. It appears that the mechanism of increased iris pigmentation is due to increased stimulation of melanin production in melanocytes and not to an increase in melanocyte number. The highest dose (0.1% twice daily) produced a maximal AUCde that was approximately 440-fold higher than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen.
Timolol: Timolol 1.5% (alone) administered to rabbits and dogs into one eye, 3 times daily for up to 12 months (5 days/week) resulted in only minor, treatment-related, ocular irritation.
Systemic Toxicology: Systemic toxicity studies were not carried out with the combination 0.03% bimatoprost/ 0.5% timolol because of the distinct and well-understood mechanisms of action of the individual compounds and the extensive systemic toxicology evaluation of the individual compounds in the following studies.
Bimatoprost: Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
No effects were observed in mice given 4 mg/kg/day bimatoprost orally for 3 months. This dose produced a maximal AUCde that was approximately 1000-fold higher than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen. Female mice given oral doses of 8 mg/kg/day showed a reversible thymic lymphoid proliferation. This finding was only observed in mice and a maximal AUCde that was approximately 3000-fold higher than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen.
A decrease in food consumption and an increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed in male rats given ≥8 mg/kg/day for 13 weeks. Reversible decreases in body weight and body weight gain were observed in both genders at ≥4 mg/kg/day. A reversible increase in ovarian weight accompanied by delayed regression of corpora lutea was noted in females ≥4 mg/kg/day. The ovarian effects were observed only in studies with nulliparous rats and since these effects were not seen in other species or pregnant rats suggesting that bimatoprost may uniquely affect the luteal cycle in nulliparous rats. These findings were observed at an AUCde that was at least 11,000-fold higher than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen. The species-specificity and considerable exposure margins indicate that risk of ovarian effects is negligible in humans. There were no drug related effects in either gender at 0.1 mg/kg/day. A slight decrease (9%) in body weight in females (2 mg/kg/day) versus control was observed in the 1-year study in rats. There was a slight increase in transaminase activity (~3-fold) in males of all dose groups but these changes were not associated with any histopathological lesions and reversibility was apparent. Ovarian and hepatic effects were reversible, and considered species specific since these changes had not been observed in mice and monkeys at systemic exposures up to 8500 to 99000-fold higher, respectively, than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen.
Periocular effects were also observed with IV administration of 0.01 mg/kg/day in monkeys for 17 weeks. IV administration of 0.01 mg/kg/day produced an AUCde of 1600-fold greater than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen. The periocular effects were resolved following cessation of treatment. No functional or anatomic abnormalities of the eye were detected. The underlying cause of the prominence of the sulci and widening of the palpebral fissures observed with ocular and IV administration in monkeys is unknown. Since periocular changes were observed with both ocular and IV administration of bimatoprost, these studies suggest there are local receptor-specific effects underlying the periocular effects in monkeys.
Timolol: Timolol maleate administered orally to rats or dogs at doses up to 50 mg/kg/day for up to 4 months produced no drug-related toxicity.
Carcinogenicity and Genotoxicity Studies: Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses up to 2 mg/kg/day and 1 mg/kg/day, respectively, for 104 weeks, giving AUC values approximately 1300 and 2000-times greater than the human value resulting from the 0.03% bimatoprost/0.5% timolol combination clinical regimen.
In a 2-year study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day. This dose was approximately 510,000-times the daily dose of bimatoprost 0.03%/timolol 0.5% in humans.
Neither bimatoprost nor timolol maleate are considered genotoxic hazards, based on results of comprehensive genotoxicity test batteries. Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo mouse micronucleus tests. Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 μg/mL). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 μg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA 100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain TA 100, no consistent dose response relationship was observed, and the ratio of test to control revertants did not reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test.
Fertility Studies: In the fertility and early embryonic development study in rats, there were no drug-related effects of bimatoprost at up to 0.6 mg/kg/day on male or female reproductive performance, paternal or maternal toxicity, sperm analysis parameters, uterine implantation parameters, or embryo viability. The highest dose produced a Cmax 160 times higher than in humans given the 0.03% bimatoprost/0.5% timolol combination clinical regimen. Although an AUCde for 0.6 mg/kg/day was not determined in this particular study for this study, it can be inferred as 710 times the value in humans given the clinical regimen from the exposure data in an embryofetal developmental study.
Reproduction and fertility studies of timolol in rats demonstrated no adverse effect on male or female fertility at doses up to 5100 times the daily dose of 0.03% bimatoprost/ 0.5% timolol combination in humans.
Embryo Fetal Development Studies: In an embryofetal developmental study in CD-1 mice given 0.3 and 0.6 mg/kg/day bimatoprost orally, maternal toxicity was apparent as a small percentage of late gestational abortions (days 16-17) and early delivery. No maternal toxicity occurred at 0.1 mg/kg/day bimatoprost (Cmax was 28-fold higher than humans given the 0.03% bimatoprost/ 0.5% timolol combination clinical regimen). The lowest dose showing maternal toxicity (0.3 mg/kg/day bimatoprost) had an AUCde that was 220 times higher than humans given the clinical regimen. The embryofetal no-observed-adverse-effect level (NOAEL) was 0.6 mg/kg/day bimatoprost, which produced an AUCde that was 490 times higher than humans given the clinical regimen.
Teratogenicity studies with timolol 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) demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1000 mg/kg/day (170,000-times the daily dose of bimatoprost 0.03%/timolol 0.5% in humans) were maternally toxic in mice and resulted in an increased number of fetal resorptions.
Prenatal and Postnatal Studies: In the prenatal and postnatal developmental study, treatment of F0 rats with ≥0.3 mg/kg/day of bimatoprost affected gestation and prenatal development, manifest as reduced gestation length, late resorption and fetal death, postnatal mortality, and reduced pup body weight. At 0.6 mg/kg/day bimatoprost, reductions in the number of dams delivering litters, gestation index, and number of nursed litters were observed. No effects on postnatal development and mating performance of the F1 offspring were observed at 0.1 mg/kg/day bimatoprost, which produced 94-times the human exposure (AUCde). These parameters were affected slightly at 0.3 mg/kg/day which produced 280-times the human exposure to 0.03% bimatoprost/0.5% timolol combination. Neurobehavioral function, Caesarean sections, and litters in F1 rats were unaffected by dosages as high as 0.3 mg/kg/day of bimatoprost.
Indications/Uses
Reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta-blocker or prostaglandin analogues.
Dosage/Direction for Use
Ganfort: Recommended dosage in adults (including the elderly): The recommended dose is one drop of GANFORT in the affected eye(s) once daily, administered in the morning.
If one dose is missed, treatment should continue with the next dose as planned. The dose should not exceed one drop in the affected eye(s) daily.
If more than one topical ophthalmic product is to be used, the different products should be instilled at least 5 minutes apart.
Use in renal and hepatic impairment: GANFORT has not been studied in patients with hepatic or renal impairment. Therefore caution should be used in treating such patients.
Use in children and adolescents: GANFORT has only been studied in adults and therefore its use is not recommended in children or adolescents.
Ganfort PF: Ganfort PF is administered topically to the eye.
The recommended dose is one drop of Ganfort PF in the affected eye(s) once daily, administered either in the morning or in the evening. It should be administered at the same time each day.
Existing literature data for Ganfort PF suggest that evening dosing may be more effective in IOP lowering than morning dosing. However, consideration should be given to the likelihood of compliance when considering either morning or evening dosing.
Administration: Ganfort PF: If one dose is missed, treatment should continue with the next dose as planned. The dose should not exceed one drop in the affected eye(s) daily.
As with any eye drops, to reduce possible systemic absorption, it is recommended that the lacrimal sac be compressed at the medial canthus (punctal occlusion) for at least 1 minute. This should be performed immediately following the instillation of each drop.
If more than one topical ophthalmic product is to be used, the different products should be instilled at least 5 minutes apart.
Overdosage
Ganfort: No case of overdose has been reported, and is unlikely to occur after ocular administration.
Bimatoprost: If GANFORT is accidentally ingested, the following information may be useful: in two-week oral rat and mouse studies, doses of bimatoprost up to 100 mg/kg/day did not produce any toxicity. This dose expressed as mg/m2 is at least 70-times higher than the accidental dose of one bottle of GANFORT in a 10 kg child.
Timolol: Symptoms of systemic timolol overdose are: bradycardia, hypotension, bronchospasm, headache, dizziness, shortness of breath, and cardiac arrest. A study of patients showed that timolol did not dialyse readily.
If overdose occurs treatment should be symptomatic and suppprtive.
Ganfort PF: No information is available on overdosage with Ganfort PF in humans. If overdosage occurs, treatment should be symptomatic and supportive; a patient airway should be maintained.
If Ganfort PF is accidentally ingested, the following information may be useful: in 2-week oral rat and mouse studies, doses of bimatoprost up to 100 mg/kg/day did not produce any toxicity.
This dose is at least 22 times higher than the amount of bimatoprost to which a 10 kg child would be exposed were it to accidentally ingest the entire content of a package (30 unit dose vials; 0.4 mL per vial; 12 mL) of bimatoprost 0.03% ophthalmic solution.
There have been reports of inadvertent overdosage with timolol ophthalmic solution resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, hypotension, 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 of patients with renal failure showed that timolol did not dialyze readily.
Contraindications
Ganfort/Ganfort PF is contraindicated in patients with the following conditions: Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.
Sinus bradycardia, sick sinus syndrome, sino-atrial nodal block, second or third degree atrioventricular block not controlled with a pacemaker, overt cardiac failure, cardiogenic shock.
Hypersensitivity to the active substances or to any of the excipients.
Special Precautions
Ganfort: Like other topically applied opthalmic agents, GANFORT may be absorbed systemically. No enhancement of the systemic absorption of the individual active substances has been observed.
Due to the beta-adrenergic component, timolol, the same types of cardiovascular and pulmonary adverse reactions as seen with systemic beta-blockers may occur.
Cardiac failure should be adequately controlled before beginning GANFORT therapy. Patients with a history of severe cardiac disease should be watched for signs and symptoms watched for signs of cardiac failure and have their pulse rates checked. Cardiac and respiratory reactions, including death due to bronchospasm in patients with asthma, and, rarely, death in association with cardiac failures have been reported following administration of timolol maleate.
Beta-blockers may also mask the signs of hyperthyroidism and cause worsening of Prinzmetal angina, severe peripheral and central central circulatory disorders and hypotension.
Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) as beta-blockers may mask the signs and symptoms of acute hypoglycemia.
While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be unresponsive to the usual dose of adrenaline used to treat anaphylactic reactions.
In patients with a history of mild liver disease or abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin at baseline, bimatoprost had no adverse effects on liver function over 24 months. There are no known adverse reactions of ocular timolol on liver function.
Before treatment is initiated, patients should be informed of the possibility of eyelash growth, darkening of the eyelid skin and and increased iris pigmentation since these have been observed during treatment with bimatoprost and GANFORT. Some of these changes may be permanent, and may lead to differences in appearance between the eyes if only one eye is treated.
After discontinuation of GANFORT, pigmentation of iris may be permanent. After 12 months treatment with bimatoprost eye drops alone, the incidence was 1.5% and did not increase following 3 years treatment.
Cystoid macular oedema has not been reported with GANFORT, however, it has been uncommonly reported (>0.1% to <1%) following treatment with bimatoprost. Therefore, GANFORT, should be used with caution in patients with known risk factors for mauclar oedema (e.g. aphakic patients, pseudopakic patients with a torn posterior lens capsule).
The preservative in GANFORT, benzalkonium chloride, may cause eye irritation. Contact lenses must not be removed prior to application, with at least a 15-minute wait before reinsertion. Benzalkonium chloride is known to discolour soft contact lenses.
Contact lenses with soft contact lenses must be avoided.
Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic keratopathy. Therefore monitoring is required with frequent or prolonged use of GANFORT in dry eye patients or where the cornea is compromised.
GANFORT has not been studied in patients with inflammatory ocular conditions, neovascular, inflammatory, angle-closure glaucoma, congenital glaucoma or narrow-angle glaucoma.
Ganfort PF: Ganfort PF should be used with caution in patients with active intraocular inflammation (e.g. uveitis) because the inflammation may be exacerbated.
Ganfort PF 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 (e.g. intraocular surgery, retinal vein occlusions, ocular inflammatory disease and diabetic retinopathy).
Patients should be advised about the potential for increased brown iris pigmentation which is likely to be permanent. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. The long term effects of increased iridial pigmentation are not known. Iris color changes seen with ophthalmic administration of bimatoprost may not be noticeable for several months to years. Neither nevi nor freckles of the iris appear to be affected by treatment.
Ganfort PF has been reported to cause changes to pigmented tissues. The most frequently reported pigmentary changes have been increased pigmentation of periocular skin and eyelash darkening. Periorbital tissue pigmentation has been reported to be reversible in some patients.
There is the potential for hair growth to occur in areas where Ganfort PF solution comes repeatedly in contact with the skin surface. Thus, it is important to apply Ganfort PF as instructed and to avoid it running onto the cheek or other skin areas.
In bimatoprost ophthalmic solution 0.03% studies in patients with glaucoma or ocular hypertension, it has been shown that more frequent exposure of the eye to more than 1 dose of bimatoprost daily may decrease the IOP-lowering effect. Patients using bimatoprost ophthalmic solutions with other prostaglandin analogs should be monitored for changes to their intraocular pressure.
Ganfort PF has not been studied in patients with inflammatory ocular conditions, neovascular glaucoma, inflammatory glaucoma, angle-closure glaucoma, congenital glaucoma or narrow-angle glaucoma.
As with other topically applied ophthalmic drugs, the active substances, bimatoprost and timolol, in Ganfort PF may be absorbed systemically. No enhancement of the systemic absorption of the individual active substances have been observed. Due to the betaadrenergic component, timolol, adverse reactions typical of systemic beta-adrenoceptor blocking agents may occur.
Respiratory and cardiac reactions have been reported including, rarely, death due to bronchospasm or associated with cardiac failure.
Cardiac Disorders: Ganfort PF should be used with caution in patients with cardiovascular disease (e.g. coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension. Patients with a history of cardiovascular diseases should be watched for signs of deterioration of these diseases.
Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.
Vascular Disorders: Patients with severe peripheral circulatory disturbance/disorders (i.e. Raynaud's phenomenon) should be treated with caution.
Obstructive Pulmonary Disease: Patients with chronic obstructive pulmonary disease of mild or moderate severity, should, in general, not receive products containing beta blockers, including Ganfort PF; however, if Ganfort PF is deemed necessary in such patients, it should be administered with caution.
Anaphylaxis: While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.
Diabetes Mellitus: Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) as beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.
Hyperthyroidism: Beta-adrenergic blocking agents may mask signs of hyperthyroidism.
Corneal diseases: Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.
Choroidal Detachment: Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g., timolol).
Other Beta-blocking Agents: Caution should be exercised when used concomitantly with systemic beta-adrenergic blocking agents because of the potential for additive effects on systemic beta-blockade. The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking agents is not recommended.
Surgical Anesthesia: Ophthalmic beta-blockers may impair compensatory tachycardia and increase risk of hypotension when used in conjunction with anesthetics. The anesthetist must be informed if the patient is using Ganfort PF.
Liver and Renal Function: Ganfort PF has not been studied in patients with hepatic or renal impairment; caution should be used in treating such patients.
General: Patients wearing soft (hydrophilic) contact lenses should be instructed to remove contact lenses prior to administration of the Ganfort PF solution and wait at least 15 minutes after instilling Ganfort PF before reinserting soft contact lenses.
Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures to avoid eye injury and contamination of eye drops.
Each vial is intended only for a single treatment in the affected eye(s). Discard any remaining solution in the vial immediately after use.
Effects on Ability to Drive and Use Machines: Ganfort/Ganfort PF has negligible influence on the ability to drive and use machines. As with any ocular treatment, if transient blurred vision occurs at instillation, the patient should wait until the vision clears before driving or using machinery.
Use in Children: Safety and effectiveness have not been demonstrated with Ganfort PF in pediatric patients.
Use in Elderly: No overall differences in safety and effectiveness have been observed between elderly and other adult patients.
Use In Pregnancy & Lactation
Use in Pregnancy: Ganfort: There are no adequate data from the use of GANFORT in pregnant women.
Bimatoprost: No adequate clinical data in exposed pregnancies are available. Animal studies have shown reproductive toxicity at high maternotoxic doses.
Timolol: Epidemiological studies have not revealed malformative effects but shown a risk for intra uterine growth retardation when beta-blockers are administered by the oral-route. In addition, signs and symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycemia) have been administered until delivery. If GANFORT is administered until delivery, the neonate should be carefully monitored during the first days of life: Animal studies with timolol have shown reproductive toxicity at doses significantly higher than would be used in clinical practice.
Consequently, GANFORT should not be used during pregnancy unless clearly necessary.
Ganfort PF: There are no adequate data from the use of the bimatoprost/timolol fixed combination in pregnant women. Ganfort PF should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Use in Lactation: Ganfort: Timolol is excreted in breast milk. It is not known if brimatoprost is excreted in human breast milk but it is excreted in the milk of the lactating rat. GANFORT should not be used by breast-feeding women.
Ganfort PF: Timolol has been detected in human milk following oral and ophthalmic drug administration. Studies in rats have indicated bimatoprost is excreted in the milk of the lactating rat. Ganfort PF should not be used by breast-feeding women.
Adverse Reactions
Ganfort: No adverse drug reactions (ADRs) specific for GANFORT have been observed in clinical studies. The ADRs have been limited to those earlier reported for bimatoprost and timolol.
The majority of ADRs were ocular, mild in severity and none were serious. Based on 12-month clinical data, the most commonly reported ADR was conjunctival hyperaemia (mostly trace to mild and thought to be a non-inflammatory nature) in approximately 26% of patients and led to discontinuation in 1.5% of patients.
The following ADRs were reported during clinical trials with GANFORT (within each frequency grouping, undesirable effects are presented in order of decreasing seriousness): Nervous system disorders: Uncommon (>1/1000, <1/100): headache.
Eye disorders: Very common: (>1/10): conjunctival hyperaemia, growth of eyelashes.
Common: (>1/100, <1/10): superficial punctuate keratitis, corneal erosion, burning sensation, eye pruritus, stinging sensation in the eye, foreign body sensation, eye dryness, eyelid erythema, eye pain, photophobia, eye discharge, visual disturbance, eyelid pruritus.
Uncommon (>1/1000, <1/100): iritis, eye irritation, conjunctival oedema, blepharitis, epiphora, eyelid oedema, eyelid pain, visual acuity worsened, asthenopia, trichiasis.
Respiratory, thoracic and mediastinal disorders: Uncommon (>1/1000, <1/100): rhinitis.
Skin and subcutaneous tissue disorders: Common: (>1/100, <1/10): blepharal pigmentation.
Uncommon (>1/1000, <1/100): hirsutism.
Additional adverse events that have been seen with one of the components and may potentially occur also with GANFORT.
Bimatoprost: Infections and infestations: infection (primarily colds and upper respiratory symptoms).
Nervous system disorders: dizziness.
Eye disorders: allergic conjuctivitis, cataract, eyelash darkening, increased iris pigmentation, blepharospasm, cystoid macular oedema, eyelid retraction, retinal haemorrhage, uveitis.
Vascular disorders: hypertension.
General disorders and administration site condition: asthenia, peripheral oedema.
Investigations: liver function tests (LFT) abnormal.
Timolol: Psychiatric disorders: insomnia, nightmares, decreased libido.
Nervous system: dizziness, memory loss, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia.
Eye disorders: decreased corneal sensitivity, diplopia, ptosis, choroidal detachment (following filtration surgery), refractive changes (due to withdrawal of miotic therapy in some cases), keratitis.
Ear and labyrinth disorders: tinnitus.
Cardiac disorders: heart block, cardiac arrest, arrhythmia, syncope, bradycardia, cardiac failure, congestive heart failure.
Vascular disorders: hypotension, cerebrovascular accident, claudication, Raynaud's phenomenon, cold hands and feet, palpitation.
Respiratory, thoracic and mediastinal disorders: bronchospasm (predominantly in patients with pre-existing bronchospastic disease) dyspnoea, cough.
Gastrointestinal disorders: nausea, diarrhoea, dyspepsia, dry mouth.
Skin and subcutaneous tissue disorders: alopecia, psoriasis rash or exacerbation of psoriasis.
Musculoskeletal and connective tissue disorders: systemic lupus erythematosus.
Renal and urinary disorders: Peyronie's disease.
General disorders and administration site conditions: oedema, chest pain, fatigue.
Ganfort PF: Clinical Study-Ganfort PF (Single Dose)-Study 192024-050:  Study 192024-050 was a multicenter, double-masked, randomized, parallel study comparing the efficacy and safety of Ganfort PF (single dose) to Ganfort Eye Drops Solution (multidose) in patients with glaucoma or ocular hypertension and treated once daily for 3 months. A total of 278 and 283 patients were randomized to the Ganfort PF (single dose) and Ganfort Eye Drop Solution (multidose) treatment groups, respectively.
Table 1 presents the undesirable effects considered related to treatment that were reported in ≥1% of patients during treatment with Ganfort PF (single dose). Most were ocular, mild and none was serious.

Click on icon to see table/diagram/image

Table 2 presents the adverse reactions with incidence rates <1%.

Click on icon to see table/diagram/image

Additional Adverse Reactions: Bimatoprost 0.03% single dose (for ophthalmic use): Eye Disorders: Conjunctival edema, hair growth abnormal, iris hyperpigmentation, vision blurred.
Timolol (ophthalmic use): Eye Disorders: Blepharitis, choroidal detachment following filtration surgery (see Precautions), Cystoid macular edema, decreased corneal sensitivity, diplopia, Eye discharge, pseudopemphigoid, ptosis, refractive changes; signs and symptoms of ocular irritation including conjunctivitis and keratitis.
Cardiac Disorders: Arrhythmia, atrioventricular block, bradycardia (see Contraindications), cardiac arrest, cardiac failure, chest pain, congestive heart failure, edema, heart block, palpitations, pulmonary edema, worsening of angina pectoris.
Ear and Labyrinth Disorders: Tinnitus.
Gastrointestinal Disorders: Abdominal pain, anorexia, diarrhea, dry mouth, dysgeusia, dyspepsia, nausea, vomiting.
General Disorders and Administration Site Conditions: Asthenia/Fatigue.
Immune System Disorders: Systemic allergic reactions including anaphylaxis, angioedema, generalized and localized rash, pruritis, urticaria; Systemic lupus erythematosus.
Metabolism and Nutrition Disorders: Hypoglycemia (in diabetic patients-see Precautions).
Musculoskeletal and Connective Tissue Disorders: Myalgia.
Nervous System Disorders: Cerebral ischemia, cerebrovascular accident, increase in signs and symptoms of myasthenia gravis; paresthesia, syncope
Psychiatric Disorders: Behavioral changes and psychic disturbances including anxiety, confusion, depression, disorientation, hallucinations, insomnia, nervousness, memory loss, somnolence; Nightmares.
Reproductive System and Breast Disorders: Decreased Libido, Peyronie's disease, retroperitoneal fibrosis, sexual dysfunction.
Respiratory, Thoracic and Mediastinal Disorders: Bronchospasm (predominantly in patients with pre-existing bronchospastic disease) (see Precautions), cough, dyspnea, nasal congestion, respiratory failure, upper respiratory infection.
Skin and Subcutaneous Tissue Disorders: Alopecia, exacerbation of psoriasis, psoriasiform rash, skin rash.
Vascular Disorders: Claudication, cold hands and feet, hypotension, Raynaud's phenomenon.
Drug Interactions
No interaction studies have been performed with Ganfort/Ganfort PF.
Ganfort: There is a potential for additive effects resulting in hypotension, and/or marked bradycardia when eye drops containing timolol are administered concomitantly with oral calcium channel blockers, guanethidine, or beta-blocking agents, anti-arrhythmics, digitalis glycosides or parasympathomimetics.
Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia.
The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers.
Ganfort PF: Beta-adrenergic blocking Agents: Patients who are receiving a systemic (e.g., oral orintravenous) beta-adrenergic blocking agent and Ganfort PF should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure.
Anti-hypertensives/Cardiac Glycosides: There is a potential for additive effects resulting in hypotension, and/or marked bradycardia when beta-blocker eye drops are administered concomitantly with oral calcium channel blockers, anti-arrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine and other anti-hypertensives.
Mydriatic Agents: Although timolol has little or no effect on the size of the pupil, mydriasishas occasionally been reported when timolol has been used with mydriatic agents such as adrenaline.
CYP2D6 Inhibitors: Potentiated systemic beta blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors [e.g., quinidine, selective serotonin reuptake inhibitors (SSRIs)] and timolol.
Caution For Usage
Ganfort PF: Instructions for Use, Handling and Disposal: The product should be discarded after the expiration date. Any unused product or waste material should be disposed.
Instructions for use of Ganfort PF: Wash the hands before use. Make sure that the vial is intact before use. The solution should be used immediately after opening. To avoid contamination, do not let the open-end of the vial touch the eye or anything else.
Tear 1 vial from the strip.
Hold the vial upright (with the cap pointing upwards) and twist off the cap.
Gently pull down the lower eyelid to form a pocket. Turn the vial upside down and squeeze it to release 1 drop into the affected eye(s). Blink the eye(s) a few times. Throw away the vial after using it, even if there is some solution left.
Storage
Ganfort: Store below 25°C. On prescription only. Keep out of reach of children. Keep the bottle in the outer carton.
Ganfort PF:
Store below 30°C. Protect from light and moisture. Do not freeze.
Once the pouch is opened, protect from light and moisture, use within 7 days.
ATC Classification
S01ED51 - timolol, combinations ; Belongs to the class of beta blocking agents. Used in the treatment of glaucoma.
Ganfort: E-D; Ganfort PF: S
Presentation/Packing
Ganfort eye drops 3 mL. Ganfort PF eye drops (clear and colorless to slightly yellow, isotonic and sterile) 0.4 mL x 30's.
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