| PROBETA® |
|Levobunolol HCl - Dipivefrin HCl |
|Glaucoma Therapy |
|Action And Clinical Pharmacology: Probeta is a combination of levobunolol (a noncardioselective beta-adrenoceptor blocking agent) and dipivefrin (an adrenergic agonist) which acts to lower elevated intraocular pressure (IOP). Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss. Poor ocular perfusion may also contribute to nerve head damage and visual field loss.
Although the mechanism of action of Probeta has not been studied, it is believed to be a combination of the action of the 2 individual components. Thus, it is expected that Probeta reduces IOP by decreasing aqueous humor production and enhancing the outflow facility.
The onset of action of Probeta has not been directly evaluated, but is expected to reflect that of the 2 individual components. For dipivefrin, onset of action occurs within 30 minutes of instillation while for levobunolol the onset of action occurs approximately 1 hour after instillation, indicating that the onset of effect of Probeta would likely occur between 30 minutes and 1 hour after instillation. A significant effect on IOP occurs within 2 hours of instillation of Probeta, while peak effect, as measured by reduction in IOP, occurs between 4 and 6 hours after instillation.
Probeta, was evaluated in 2 controlled studies of 6 and 3 months duration. Analyses of the proportion of subjects with overall mean decreases in IOP of ³3 mm Hg were performed. The results of the 6 month study showed that approximately 7 hours after the previous dose, 44% of the Probeta group experienced an overall mean IOP decrease of ³3 mm Hg from a levobunolol-only baseline level. Twenty-two percent of the dipivefrin treated group and 24% of the levobunolol treated group experienced this degree of decrease in IOP.
The results of the 3 month study indicated that approximately 7 hours after the previous dose, 31% of the Probeta treated group experienced an overall mean IOP decrease of ³3 mm Hg. Twenty-one percent of the subjects in the dipivefrin treated group and 24% in the levobunolol treated group experienced an overall mean IOP decrease of ³3 mm Hg.
In both of these studies, the overall decrease (average mean decrease over time) in IOP was statistically significantly greater in the Probeta treated group than in the dipivefrin treated group or levobunolol treated group.
In a third clinical study of 6 weeks duration, Probeta provided a significantly better sustained mean diurnal decrease in IOP than that provided by either component alone. Probeta was more effective in lowering IOP than dipivefrin at hours 2, 4 and 6 and than levobunolol at hours 4 and 6.
When a decision to administer both a beta-adrenoceptor blocking and an adrenergic agonist is made, the administration of such drugs in combination has the advantage of greater patient compliance and convenience, with the added assurance that the appropriate dosage of both drugs is administered. When both types of drugs are in the same formulation, compatibility of ingredients is assured and the correct volume of drug is delivered and retained. Combination formulations also allow less preservative to be delivered to the ocular surface as compared to using 2 separate drugs.
Beta-adrenergic receptor blockade reduces cardiac output in both healthy subjects and patients with heart disease. In patients with severe impairment of myocardial function, beta-adrenergic receptor blockade may inhibit the stimulatory effect of the sympathetic nervous system necessary to maintain adequate cardiac function.
Beta-adrenergic receptor blockade in the bronchi and bronchioles results in increased airway resistance from unopposed para-sympathetic activity. Such an effect in patients with asthma or other bronchospastic conditions is potentially dangerous.
Indications And Clinical Uses: For the control of intraocular pressure in chronic open-angle glaucoma or ocular hypertension.
Contra-Indications: Bronchial asthma, or a history of bronchial asthma or severe chronic obstructive pulmonary disease; sinus bradycardia; second or third degree atrioventricular heart block; overt cardiac failure; or cardiogenic shock. Probeta should not be used in patients with narrow angles since any dilation of the pupil may predispose the patient to an attack of angle-closure glaucoma.
Probeta is contraindicated in individuals who are hypersensitive to any components of the medication.
Manufacturers' Warnings In Clinical States: Because the diagnosis of narrow-angle glaucoma is frequently missed during normotensive intervals (between attacks), it is very important that careful slit lamp and gonioscopic study be done before initiating therapy with this drug. Should an elevation of intraocular tension follow the instillation of Probeta, appropriate hypotensive therapy by the treating physician is recommended.
As with other topically applied ophthalmic drugs, Probeta may be absorbed systemically. The same adverse events found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac reactions including death due to bronchospasm in patients with asthma, and, rarely, death in association with cardiac failure, have been reported with topical application of beta-adrenergic blocking agents (see Contraindications and Precautions).
Precautions: General: Probeta should be used with caution in patients with known hypersensitivity to other beta-adrenoceptor blocking agents.
Probeta should be used with caution in patients who are receiving a beta-adrenergic blocking agent orally, because of the potential for additive effects on systemic beta-blockade. Generally, patients should not use more than one topical ophthalmic beta-adrenergic blocking agent simultaneously.
Because of the potential effects of beta-adrenergic blocking agents on blood pressure and pulse rates, this medication must be used cautiously in patients with cerebrovascular insufficiency. Should signs or symptoms develop that suggest reduced cerebral blood flow while using Probeta, alternative therapy should be considered.
Dipivefrin is a prodrug of epinephrine. Macular edema has been known to occur in aphakic patients treated with epinephrine. Discontinuation of epinephrine generally results in reversal of the maculopathy.
Cardiac Failure: Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure.
Patients without a History of Cardiac Failure: Continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure, Probeta should be discontinued.
Obstructive Pulmonary Disease: Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity, bronchospastic disease or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma, in which Probeta is contraindicated, see Contraindications), should in general not receive beta-blockers, including Probeta . However, if Probeta is deemed necessary in such patients, then it should be administered cautiously since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta2-receptors.
Major Surgery: The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures. Some patients receiving beta-adrenergic receptor blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients undergoing elective surgery, gradual withdrawal of beta-adrenergic blocking agents may be appropriate. If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of such agonists as isoproterenol, dopamine, dobutamine or levarterenol (see Overdose: Symptoms and Treatment).
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) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic blocking agents may mask the signs and symptoms of acute hypoglycemia.
Thyrotoxicosis: Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents which might precipitate a thyroid storm.
Muscle Weakness: Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis and generalized weakness).
Pregnancy : No reproduction studies using Probeta were performed. Rat and rabbit reproduction and fertility studies using levobunolol or dipivefrin alone were conducted. Fetotoxicity (as evidenced by a greater number of resorption sites) has been observed in rabbits when doses of levobunolol equivalent to 200 to 700 times the recommended dose for the treatment of glaucoma were given.
No adverse effect on male or female rat fertility was seen at doses up to 1 800 times the human dose for levobunolol. Teratogenic studies with levobunolol in rats at doses up to 25 mg/kg/day (1 800 times the recommended human dose for glaucoma) showed no evidence of fetal malformation, fetotoxicity, and no adverse effects on postnatal development of offspring.
Reproduction studies using dipivefrin have been performed in rats and rabbits at daily oral doses of up to 10 mg/kg body weight and 5 mg/kg in teratogenicity studies. No evidence of impaired fertility or harm to the fetus due to dipivefrin were observed. There are, however, no adequate and well-controlled studies in pregnant women. Probeta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Carcinogenesis, Mutagenesis: In a lifetime oral study of levobunolol in mice, there were statistically significant (p£0.05) increases in the incidence of benign leiomyomas in female mice at 200 mg/kg/day (14 000 times the recommended human dose for glaucoma), but not at 12 or 50 mg/kg/day (850 and 3 500 times the human dose). In a two year oral study of levobunolol in rats, there was a statistically significant (p£0.05) increase in the incidence of benign hepatomas in male rats administered 12 800 times the recommended human dose for glaucoma. Similar differences were not observed in rats administered oral doses equivalent to 350 times to 2 000 times the recommended human dose for glaucoma.
Levobunolol did not show evidence of mutagenic activity in a battery of microbiological and mammalian in vitro and in vivo assays.
Carcinogenicity and mutagenicity studies have not been performed with either dipivefrin or Probeta.
Lactation: It is not known whether or not Probeta is excreted in human milk. Systemic beta-blockers and topical timolol maleate are known to be excreted in human milk. Because of the potential for adverse reactions from Probeta in nursing infants, a decision should be made whether to discontinue this drug, taking into account the importance of the drug to the mother.
Children: The safety and effectiveness of Probeta have not been established in children.
Drug Interactions: Probeta may have additive effects in patients taking systemic antihypertensive drugs. These possible additive effects may include hypotension, including orthostatic hypotension, bradycardia, dizziness, and/or syncope. Conversely, systemic beta-adrenergic receptor blocking agents may potentiate the ocular hypotensive effect of Probeta.
Close observation is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope or postural hypotension.
Patients receiving beta-adrenergic blocking agents along with either oral or i.v. calcium antagonists should be monitored for possible atrioventricular conduction disturbances, left ventricular failure and hypotension. In patients with impaired cardiac function, simultaneous use should be avoided altogether.
The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects on prolonging atrioventricular conduction time.
Phenothiazine-related compounds and beta-adrenergic blocking agents may have additive hypotensive effects due to the inhibition of each other's metabolism.
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
Adverse Reactions: The ocular events experienced by patients evaluated (n=221) in controlled clinical trials are listed below in decreasing order of frequency: mild, transient burning and stinging (52%); vision problems/blurring (16%); conjunctival erythema (16%); foreign body sensation (10.4%); photophobia (6%); corneal staining (4.5%); itching (4.5%); follicular response (4.0%); eyelid erythema (3.6%); mydriasis (3.1%); eyelid edema (2.2%); tearing (2.2%); corneal endothelial changes (1.8%); conjunctival edema (1.3%); conjunctivitis (0.9%).
Systemic adverse events during clinical trials included headache, dizziness and nervousness. Insignificant increases in heart rate and systolic blood pressure were noted with Probeta.
Although levobunolol has minimal membrane stabilizing activity, there remains a possibility of decreased corneal sensitivity after prolonged use.
The following additional adverse reactions have been reported with levobunolol, dipivefrin, or the ophthalmic use of other beta-adrenergic receptor blocker agents:
Body As A Whole: asthenia, chest pain.
Cardiovascular: bradycardia, arrhythmia, hypotension, syncope, heart block, cerebral vascular accident, cerebral ischemia, congestive heart failure, palpitation, cardiac arrest.
CNS: somnolence, transient ataxia, lethargy.
Digestive: nausea, diarrhea.
Endocrine: masked symptoms of hypoglycemia in insulin-dependent diabetics (see Warnings).
Psychiatric: depression, increase in signs and symptoms of myasthenia gravis, paresthesia.
Respiratory: bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnea and nasal congestion.
Skin: alopecia, Stevens-Johnson syndrome, hypersensitivity, including localized and generalized rash, urticaria and pruritus.
Special Senses: signs and symptoms of keratitis, discharge, and iridocyclitis.
Epinephrine therapy can lead to adrenochrome deposits in the conjunctiva and cornea.
Other reactions associated with the systemic use of non-selective adrenergic receptor blocking agents or epinephrine compounds should be considered potential effects with ophthalmic use of these agents.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: No data are available regarding overdosage in humans. Should accidental ocular overdosage occur, flush eye(s) with clean water or normal saline. If an ingested overdose of Probeta occurs, evacuation of the stomach should be considered during the first few hours after the overdose.
The most common signs and symptoms to be expected with overdosage of systemic beta-adrenergic blocking agents are symptomatic bradycardia, hypotension, bronchospasm and acute cardiac failure. Should these symptoms occur, discontinue Probeta therapy and initiate appropriate supportive therapy.
Dosage And Administration: The recommended dose is 1 drop in the affected eye(s) given every 12 hours. As with any medication, upon initiation of therapy, careful monitoring of patients is advised.
Keep out of reach of children. For external use only. Do not touch the dropper tip to the eye, skin or any surface since this may contaminate the solution. Protect from light and excessive heat. Discard any unused solution at the end of the prescribed treatment period.
Availability And Storage: Each mL of sterile ophthalmic solution contains: levobunolol HCl 5 mg and dipivefrin HCl 1 mg. Nonmedicinal ingredients: benzalkonium chloride 0.005% as preservative, edetate disodium, polyvinyl alcohol, purified water, sodium chloride and hydrochloric acid and/or sodium hydroxide to adjust pH. White opaque plastic dropper bottles with the C Cap Compliance Cap of 5 and 10 mL. Protect from light. Store at 15 to 25°C.