Timolol Maleate-Pilocarpine HCl
Elevated Intraocular Pressure Therapy
Action and Clinical Uses:
Timolol is a nonselective beta-adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity. Timolol combines reversibly with a part of the cell membrane, the beta-adrenergic receptor, and thus inhibits the usual biologic response that would occur with stimulation of that receptor. This specific competitive antagonism blocks stimulation of the beta-adrenergic receptors by catecholamines having beta-adrenergic stimulating (agonist) activity, whether these originate from an endogenous or exogenous source. Reversal of this blockade can be accomplished by increasing the concentration of the agonist, which will restore the usual biologic response.
Pharmacokinetics: Timolol maleate (S(-) enantiomer) is significantly metabolized after oral and ophthalmic administration. The drug and the metabolites (hydroxyethylamino, hydroxyethylglycolamino derivatives and a third minor metabolite that results from the hydroxylation of a terminal methyl group on the tertiary butylamino moiety) are excreted primarily via the kidney. Based on correlation with debrisoquine metabolism, timolol metabolism is mediated primarily by cytochrome P450 2D6. Timolol is moderately (<60%) bound to plasma proteins.
In a study of plasma drug concentration in 6 subjects, the systemic exposure to timolol was determined following twice-daily topical administration of timolol maleate ophthalmic solution 0.5% for 8 days. The mean peak plasma concentration following morning dosing was 0.46 ng/mL and following afternoon dosing was 0.35 ng/mL.
By comparison to plasma concentrations (10 to 20 ng/mL) following oral 5 mg dose, it was estimated that timolol was approximately 50% bioavailable systemically following intraocular administration.
Pilocarpine is a parasympathomimetic that directly stimulates cholinergic receptors. It produces contraction of the iris sphincter muscle, resulting in pupillary constriction (miosis); constriction of the ciliary muscle (resulting in increased accommodation) and a reduction in intraocular pressure associated with decreased resistance of aqueous humor outflow. Pilocarpine may also inhibit aqueous humor secretion.
Each of the two components decreases elevated intraocular pressure (IOP) by different but complementary mechanisms. Timolol lowers IOP primarily by reducing aqueous humor production. Pilocarpine lowers IOP primarily by enhancing the outflow of aqueous humor from the anterior chamber of the eye. Although pilocarpine, given alone requires administration 4 times a day, it has been shown that when formulated with timolol in Timpilo, administration twice daily is adequate.
Indications And Clinical Uses :
For the reduction of elevated intraocular pressure in patients whose IOP is not adequately controlled on monotherapy with a beta-adrenergic receptor blocking agent or pilocarpine or when concomitant therapy is appropriate.
In clinical trials, it has been shown to reduce intraocular pressure in patients with ocular hypertension when miosis is not a contraindication and in patients with chronic open-angle glaucoma.
Bronchospasm, including bronchial asthma, or a history of these conditions, or chronic obstructive pulmonary disease.
Sinus bradycardia, second and third degree atrioventricular block, overt congestive cardiac failure, cardiogenic shock.
Conditions in which miosis is undesirable: malignant glaucoma, peripheral anterior synechia, trauma, acute-inflammatory disease of anterior chamber, glaucoma occurring or persisting after extracapsular cataract extraction when posterior synechia may occur, etc.
Hypersensitivity to any component of this product.
Warnings in Clinical States:
As with other topically applied ophthalmic drugs, this drug may be absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration.
Timpilo should be used with caution in patients with diabetes, especially labile diabetes (see Precautions).
Following administration of timolol ophthalmic solution, severe respiratory reactions and cardiac reactions have been reported, including death due to bronchospasm in patients with asthma, and rarely death in association with cardiac failure.
Cardiovascular Function: Cardiac failure should be controlled before beginning therapy with Timpilo. In patients with a history of cardiac disease, signs of cardiac failure should be watched for and pulse rate should be checked.
Because of potential effects of beta-adrenergic blocking agents relative to blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with Timpilo, alternative therapy should be considered.
Eye Accommodation: Miosis usually causes difficulty in dark adaptation. Caution should be exercised in night driving and other hazardous activities in poor illumination.
Choroidal Detachment: Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g., timolol, acetazolamide or combination) after filtration procedures. Management of eyes with chronic or recurrent choroidal detachment should include stopping all forms of aqueous suppressant therapy and treating endogenous inflammation vigorously.
Contact Lenses: Timpilo contains the preservative benzalkonium chloride which may be deposited in soft contact lenses; therefore, Timpilo should not be used while wearing these lenses. The lenses should be removed before application of the drops and not be reinserted earlier than 15 minutes after use.
Risk from Anaphylactic Reaction: While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens, either accidental, diagnostic, or therapeutic. These patients may be more resistant to treatment of anaphylactic reactions with the usual doses of epinephrine since timolol may blunt the beta agonist effect of epinephrine. In such cases, alternatives to epinephrine should be considered.
Major Surgery: The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. 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 norepinephrine.
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 receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.
Thyrotoxicosis: Beta-adrenergic blocking agents may mask certain clinical signs of hyperthyroidism (e.g., tachycardia). 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 blockage has been reported to increase muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis and generalized weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenic symptoms.
Pregnancy: Timpilo has not been studied in human pregnancy. The use of Timpilo in pregnancy requires that the anticipated benefit be weighed against potential hazards.
The use of systemic beta-blockers is not recommended during pregnancy.
Lactation: Timolol is detectable in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Children: Safety and effectiveness in children have not been established.
Drug Interactions :
The use of 2Â topical beta-adrenergic blocking agents is not recommended.
Beta-adrenergic Blockers: Patients already receiving a beta-blocker systemically and who are given Timpilo should be observed for a potential additive effect on the intraocular pressure or on the known systemic effects of beta-blockers (hypotension and/or bradycardia). The concomitant use of 2 topical beta-adrenergic blocking agents is not recommended.
Calcium Channel Blockers or Catecholamine-depleting Drugs: Calcium blockers or catecholamine-depleting drugs, such as reserpine, may produce additive effects, hypotension and/or marked bradycardia, with possible vertigo, syncope or postural hypotension. I.V. calcium blockers should be used with caution in patients receiving beta-blockers.
Quinidine: Potentiated systemic beta-blockage (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via the P450 enzyme, CYP2D6.
Information to Be Provided to the Patient: Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures. Ocular solutions, if handled improperly, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.
Patients should also be advised that if they develop an intercurrent ocular condition (e.g., trauma, ocular surgery or infection), they should immediately seek their physician’s advice concerning the continued use of the present multidose container.
There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithalial surface.
Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second- or third-degree atrioventricular block, or cardiac failure should be advised not to take this product (see Contraindications).
Patients Wearing Contact Lenses: Patients should be instructed to remove their lenses before application of the drops and not to re-insert the lenses earlier than 15 minutes after use.
:Timpilo is generally well tolerated. In clinical studies the adverse experiences reported were mainly well-known pilocarpine side effects: blurring of vision, difficulty with dark adaptation, headache/brow-ache and ocular irritation (see below).
Potential Side Effects: Side effects reported in clinical and post-marketing experience with Timoptic, systemic Blocadren, other timolol maleate formulations and pilocarpine ophthalmic solution may be considered potential side effects of Timpilo Ophthalmic Solution.
Timolol Maleate Ophthalmic Solution: The following adverse reactions have been reported with ocular administration of this or other timolol maleate formulation, either in clinical trials or since the drug has been marketed.
Special Senses: signs and symptoms of ocular irritation, including burning and stinging, conjunctivitis, blepharitis, keratitis, decreased corneal sensitivity and dry eyes.
Visual Disturbances: including diplopia, ptosis, choroidal detachment following filtration surgery (see Precautions).
Cardiovascular: Aggravation or precipitation of certain cardiovascular pulmonary and other disorders presumably related to effects of systemic beta blockade has been reported (see Contraindications and Precautions). These include bradycardia, arrhythmia, hypotension, syncope, heart block, cerebrovascular accident, cerebral ischemia, palpitation, cardiac arrest, edema, claudication, Raynaud’s phenomenon, cold hands and feet. Congestive heart failure and, in insulin-dependent diabetics, masked symptoms of hypoglycemia have been reported rarely. In clinical trials, slight reduction of the resting heart rate in some patients (mean reduction 2.9 beats/minute, standard deviation 10.2) has been observed.
Respiratory: bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnea, cough.
Miscellaneous: headache, asthenia, fatigue, chest pain.
Integumentary: alopecia, psoriasiform rash or exacerbation of psoriasis.
Hypersensitivity: signs and symptoms of allergic reactions including angioedema, urticaria, localized and generalized rash.
Nervous System/Psychiatric: dizziness, depression, increase in signs and symptoms of myasthenia gravis, insomnia, nightmares, memory loss, paresthesia.
Digestive: nausea, diarrhea, dyspepsia, dry mouth.
Urogenital: decreased libido, Peyronie’s disease.
Immunologic: systemic lupus erythematous.
Timolol-Systemic: Side effects reported in clinical experience with systemic timolol maleate may be considered potential side effects of ophthalmic solution Timpilo.
Clinical Laboratory Tests: Clinically important changes in standard laboratory parameters were rarely associated with the administration of systemic timolol maleate. Slight increases in blood urea nitrogen, serum potassium and serum uric acid and triglycerides, and slight decreases in hemoglobin and hematocrit and HDL-cholesterol occurred, but were not progressive or associated with clinical manifestations.
Pilocarpine HCl Ophthalmic Solution: Ocular: ciliary spasm, conjunctival vascular congestion, lacrimation, temporal or supra-orbital headache, induced myopia, reduced visual acuity in poor illumination (especially in the elderly and in patients with lens opacities), retinal detachment (especially in young myopic patients). Lens opacity may occur with prolonged use of pilocarpine.
Systemic: Extremely rare, but have included hypertension, tachycardia, bronchospasm, pulmonary edema, salivation, sweating, nausea, vomiting and diarrhea.
Symptoms And Treatment Of Overdose :
OverdoseThere have been reports of inadvertent overdosage with timolol resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest (see also Adverse Effects).:
The following therapeutic measures should be considered: 1) Gastric lavage: If ingested. 2) Symptomatic bradycardia: Use atropine sulfate i.v. in a dosage of 0.25 to 2 mg to induce vagal blockade. If bradycardia persists, i.v. isoproterenol HCl should be administered cautiously. In refractory cases the use of a transvenous cardiac pacemaker may be considered. 3) Hypotension: Use sympathomimetic pressor drug therapy, such as dopamine, dobutamine or norepinephrine. In refractory cases the use of glucagon HCl has been reported to be useful. 4) Bronchospasm: Use isoproterenol HCl. Additional therapy with aminophylline may be considered. 5) Acute cardiac failure: Conventional therapy with digitalis, diuretics and oxygen should be instituted immediately. In refractory cases the use of i.v. aminophylline is suggested. This may be followed if necessary by glucagon HCl which has been reported to be useful. 6) Heart block (second or third degree): Use isoproterenol HCl or a transvenous cardiac pacemaker.
Pilocarpine: Cholinergic systemic effects are extremely rare with ocular use of pilocarpine (see Adverse Effects). If accidentally swallowed, pilocarpine is readily absorbed from the alimentary tract, and if a large amount is ingested cholinergic symptoms may appear, including salivation, lacrimation, nausea, vomiting, headache, mental confusion, visual disturbances, abdominal colic, diarrhea, bronchospasm and hypotension. Dehydration and shock may develop. Respiratory depression has been reported in severe cases of pilocarpine poisoning.
Treatment is with general measures and atropine.
Dosage And Administration:
Recommended dosing is as follows: Instill 1 drop of Timpilo 2 twice daily in the affected eye. If the clinical response is inadequate the dosage may be increased by using 1 drop of Timpilo 4 twice daily.
When a patient is transferred from prior therapy, the previously-administered agents should be discontinued after proper dosing on one day, and treatment with Timpilo started on the following day.
Availability And Storage:
Timpilo 2: Each mL of sterile, aqueous ophthalmic solution contains: timolol maleate 6.8 mg, equivalent to timolol 5 mg (0.5%) and pilocarpine HCl 20 mg (2.0%). Nonmedicinal ingredients: benzalkonium chloride, sodium phosphate dibasic dodecahydrate, sodium phosphate monobasic dihydrate and water for injection. White, opaque, polyethylene ophthalmic dispensers of 5 mL after reconstitution.
Timpilo 4: Each mL of sterile, aqueous ophthalmic solution contains: timolol maleate 6.8 mg, equivalent to timolol 5 mg (0.5%) and pilocarpine HCl 40 mg (4.0%). Nonmedicinal ingredients: benzalkonium chloride, sodium phosphate dibasic dodecahydrate, sodium phosphate monobasic dihydrate and water for injection. White, opaque, polyethylene ophthalmic dispensers of 5 mL after reconstitution.
Dispensed in a unique, 2-chambered vial system. One chamber contains a concentrated solution of timolol and pilocarpine and the other chamber contains a diluent solution. The two solutions are mixed together prior to use. The resulting solution for administration has a pH of 6.4 to 6.8.
Stability and Storage: Prior to mixing solutions, avoid temperatures above 30°C. After mixing, Timpilo 2 and Timpilo 4 are stable for 28 days when stored at room temperature (15 to 25°C). Protect from light and freezing.
TIMPILO® Merck Frosst Timolol Maleate–Pilocarpine HCl Elevated Intraocular Pressure Therapy