Timoptic in Ocudose

Generic Name: timolol maleate

Dosage Form: ophthalmic solution
TIMOPTIC®

0.25% AND 0.5%

(TIMOLOL MALEATE

OPHTHALMIC SOLUTION)

in OCUDOSE®

(DISPENSER)

PRESERVATIVE-FREE STERILE OPHTHALMIC SOLUTION

in a Sterile Ophthalmic Unit Dose Dispenser

Timoptic in Ocudose Description

Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. Its chemical name is (-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt). Timolol maleate possesses an asymmetric carbon atom in its structure and is provided as the levo-isomer. The optical rotation of timolol maleate is:

[α]

25° 405 nm

in 1.0N HCl (C = 5%) = –12.2° (–11.7° to –12.5°).

Its molecular formula is C13H24N4O3S•C4H4O4 and its structural formula is:

Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline powder which is soluble in water, methanol, and alcohol. Timolol maleate is stable at room temperature.

Timolol maleate ophthalmic solution is supplied in two formulations: Ophthalmic Solution TIMOPTIC1 (timolol maleate ophthalmic solution), which contains the preservative benzalkonium chloride; and Ophthalmic Solution TIMOPTIC1 (timolol maleate ophthalmic solution), the preservative-free formulation.

Preservative-free Ophthalmic Solution TIMOPTIC is supplied in OCUDOSE1, a unit dose container, as a sterile, isotonic, buffered, aqueous solution of timolol maleate in two dosage strengths: Each mL of Preservative-free Timoptic in Ocudose 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). The pH of the solution is approximately 7.0, and the osmolarity is 252-328 mOsm. Each mL of Preservative-free Timoptic in Ocudose 0.5% contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive ingredients: monobasic and dibasic sodium phosphate, sodium hydroxide to adjust pH, and water for injection.

1

Registered trademark of ATON PHARMA, INC.

COPYRIGHT © 2009 ATON PHARMA, INC.

All rights reserved

Timoptic in Ocudose - Clinical Pharmacology

Mechanism of Action

Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity.

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 parasympathetic activity. Such an effect in patients with asthma or other bronchospastic conditions is potentially dangerous.

TIMOPTIC (timolol maleate ophthalmic solution), when applied topically on the eye, has the action of reducing elevated as well as normal intraocular pressure, whether or not accompanied by glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous visual field loss and optic nerve damage.

The onset of reduction in intraocular pressure following administration of TIMOPTIC (timolol maleate ophthalmic solution) can usually be detected within one-half hour after a single dose. The maximum effect usually occurs in one to two hours and significant lowering of intraocular pressure can be maintained for periods as long as 24 hours with a single dose. Repeated observations over a period of one year indicate that the intraocular pressure-lowering effect of TIMOPTIC (timolol maleate ophthalmic solution) is well maintained.

The precise mechanism of the ocular hypotensive action of TIMOPTIC (timolol maleate ophthalmic solution) is not clearly established at this time. Tonography and fluorophotometry studies in man suggest that its predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed.

Pharmacokinetics

In a study of plasma drug concentration in six subjects, the systemic exposure to timolol was determined following twice daily administration of TIMOPTIC 0.5%. The mean peak plasma concentration following morning dosing was 0.46 ng/mL and following afternoon dosing was 0.35 ng/mL.

Clinical Studies

In controlled multiclinic studies in patients with untreated intraocular pressures of 22 mmHg or greater, TIMOPTIC (timolol maleate ophthalmic solution) 0.25 percent or 0.5 percent administered twice a day produced a greater reduction in intraocular pressure than 1, 2, 3, or 4 percent pilocarpine solution administered four times a day or 0.5, 1, or 2 percent epinephrine hydrochloride solution administered twice a day.

In these studies, TIMOPTIC (timolol maleate ophthalmic solution) was generally well tolerated and produced fewer and less severe side effects than either pilocarpine or epinephrine. A slight reduction of resting heart rate in some patients receiving TIMOPTIC (timolol maleate ophthalmic solution) (mean reduction 2.9 beats/minute standard deviation 10.2) was observed.

Indications and Usage for Timoptic in Ocudose

Preservative-free Timoptic in Ocudose is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Preservative-free Timoptic in Ocudose may be used when a patient is sensitive to the preservative in TIMOPTIC (timolol maleate ophthalmic solution), benzalkonium chloride, or when use of a preservative-free topical medication is advisable.

Contraindications

Preservative-free Timoptic in Ocudose is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma; (3) severe chronic obstructive pulmonary disease (see WARNINGS); (4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac failure (see WARNINGS); (7) cardiogenic shock; or (8) hypersensitivity to any component of this product.

Warnings

As with many topically applied ophthalmic drugs, this drug is absorbed systemically.

The same adverse reactions 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 following systemic or ophthalmic administration of timolol maleate (see CONTRAINDICATIONS).

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.

In 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, Preservative-free Timoptic in Ocudose 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 Timoptic in Ocudose is contraindicated [see CONTRAINDICATIONS]) should, in general, not receive beta-blockers, including Preservative-free Timoptic in Ocudose.

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 experienced protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients undergoing elective surgery, some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents.

If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists.

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 (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents that might precipitate a thyroid storm.

Precautions

General

Because of potential effects of beta-adrenergic blocking agents on 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 Preservative-free Timoptic in Ocudose, alternative therapy should be considered.

Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g. timolol).

Angle-closure glaucoma

In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil. Timolol maleate has little or no effect on the pupil. Timoptic in Ocudose should not be used alone in the treatment of angle-closure glaucoma.

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 accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

Muscle Weakness

Beta-adrenergic blockade has been reported to potentiate 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 myasthenia gravis or myasthenic symptoms.

Information for Patients

Patients should be instructed about the use of Preservative-free Timoptic in Ocudose.

Since sterility cannot be maintained after the individual unit is opened, patients should be instructed to use the product immediately after opening, and to discard the individual unit and any remaining contents immediately after use.

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.)

Drug Interactions

Although TIMOPTIC (timolol maleate ophthalmic solution) used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with TIMOPTIC (timolol maleate ophthalmic solution) and epinephrine has been reported occasionally.

Beta-adrenergic blocking agents

Patients who are receiving a beta-adrenergic blocking agent orally and Preservative-free Timoptic in Ocudose should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not recommended.

Calcium antagonists

Caution should be used in the coadministration of beta-adrenergic blocking agents, such as Preservative-free Timoptic in Ocudose, and oral or intravenous calcium antagonists, because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, coadministration should be avoided.

Catecholamine-depleting drugs

Close observation of the patient 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 result in vertigo, syncope, or postural hypotension.

Digitalis and calcium antagonists

The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.

CYP2D6 inhibitors

Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine, SSRIs) and timolol.

Clonidine

Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate.

Injectable epinephrine

(See PRECAUTIONS, General, Anaphylaxis)

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year oral 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 (approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Similar differences were not observed in rats administered oral doses equivalent to approximately 14,000 times the maximum recommended human ophthalmic dose.

In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas in female mice at 500 mg/kg/day (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000 times, respectively, the systemic exposure following the maximum recommended human ophthalmic dose). In a subsequent study in female mice, in which post-mortem examinations were limited to the uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day.

The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in humans. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin.

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 mcg/mL). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain TA100, 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.

Reproduction and fertility studies in rats demonstrated no adverse effect on male or female fertility at doses up to 21,000 times the systemic exposure following the maximum recommended human ophthalmic dose.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Teratogenicity studies with timolol in mice, rats and rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose) 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 (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose, in this case without apparent maternotoxicity.

There are no adequate and well-controlled studies in pregnant women. Preservative-free Timoptic in Ocudose should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Timolol maleate has been detected in human milk following oral and ophthalmic drug administration. Because of the potential for serious adverse reactions from timolol 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Adverse Reactions

The most frequently reported adverse experiences have been burning and stinging upon instillation (approximately one in eight patients).

The following additional adverse experiences have been reported less frequently with ocular administration of this or other timolol maleate formulations:

BODY AS A WHOLE

Headache, asthenia/fatigue, and chest pain.

CARDIOVASCULAR

Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure, worsening of angina pectoris, palpitation, cardiac arrest, pulmonary edema, edema, claudication, Raynaud's phenomenon, and cold hands and feet.

DIGESTIVE

Nausea, diarrhea, dyspepsia, anorexia, and dry mouth.

IMMUNOLOGIC

Systemic lupus erythematosus.

NERVOUS SYSTEM/PSYCHIATRIC

Dizziness, increase in signs and symptoms of myasthenia gravis, paresthesia, somnolence, insomnia, nightmares, behavioral changes and psychic disturbances including depression, confusion, hallucinations, anxiety, disorientation, nervousness, and memory loss.

SKIN

Alopecia and psoriasiform rash or exacerbation of psoriasis.

HYPERSENSITIVITY

Signs and symptoms of systemic allergic reactions including anaphylaxis, angioedema, urticaria, and localized and generalized rash.

RESPIRATORY

Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnea, nasal congestion, cough and upper respiratory infections.

ENDOCRINE

Masked symptoms of hypoglycemia in diabetic patients (see WARNINGS).

SPECIAL SENSES

Signs and symptoms of ocular irritation including conjunctivitis, blepharitis, keratitis, ocular pain, discharge (e.g., crusting), foreign body sensation, itching and tearing, and dry eyes; ptosis; decreased corneal sensitivity; cystoid macular edema; visual disturbances including refractive changes and diplopia; pseudopemphigoid; choroidal detachment following filtration surgery (see PRECAUTIONS, General); and tinnitus.

UROGENITAL

Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie's disease.

The following additional adverse effects have been reported in clinical experience with ORAL timolol maleate or other ORAL beta blocking agents, and may be considered potential effects of ophthalmic timolol maleate: Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Body as a Whole: Extremity pain, decreased exercise tolerance, weight loss; Cardiovascular: Worsening of arterial insufficiency, vasodilatation; Digestive: Gastrointestinal pain, hepatomegaly, vomiting, mesenteric arterial thrombosis, ischemic colitis; Hematologic: Nonthrombocytopenic purpura; thrombocytopenic purpura; agranulocytosis; Endocrine: Hyperglycemia, hypoglycemia; Skin: Pruritus, skin irritation, increased pigmentation, sweating; Musculoskeletal: Arthralgia; Nervous System/Psychiatric: Vertigo, local weakness, diminished concentration, reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics; Respiratory: Rales, bronchial obstruction; Urogenital: Urination difficulties.

Overdosage

There have been reports of inadvertent overdosage with Ophthalmic Solution TIMOPTIC (timolol maleate ophthalmic solution) 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 REACTIONS).

Overdosage has been reported with Tablets BLOCADREN1 (timolol maleate tablets). A 30 year old female ingested 650 mg of BLOCADREN (maximum recommended oral daily dose is 60 mg) and experienced second and third degree heart block. She recovered without treatment but approximately two months later developed irregular heartbeat, hypertension, dizziness, tinnitus, faintness, increased pulse rate, and borderline first degree heart block.

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.

Timoptic in Ocudose Dosage and Administration

Preservative-free Timoptic in Ocudose is a sterile solution that does not contain a preservative. The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be guaranteed after the individual unit is opened, the remaining contents should be discarded immediately after administration.

Preservative-free Timoptic in Ocudose is available in concentrations of 0.25 and 0.5 percent. The usual starting dose is one drop of 0.25 percent Preservative-free Timoptic in Ocudose in the affected eye(s) administered twice a day. Apply enough gentle pressure on the individual container to obtain a single drop of solution. If the clinical response is not adequate, the dosage may be changed to one drop of 0.5 percent solution in the affected eye(s) administered twice a day.

Since in some patients the pressure-lowering response to Preservative-free Timoptic in Ocudose may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Preservative-free Timoptic in Ocudose.

If the intraocular pressure is maintained at satisfactory levels, the dosage schedule may be changed to one drop once a day in the affected eye(s). Because of diurnal variations in intraocular pressure, satisfactory response to the once-a-day dose is best determined by measuring the intraocular pressure at different times during the day.

Dosages above one drop of 0.5 percent TIMOPTIC (timolol maleate ophthalmic solution) twice a day generally have not been shown to produce further reduction in intraocular pressure. If the patient's intraocular pressure is still not at a satisfactory level on this regimen, concomitant therapy with other agent(s) for lowering intraocular pressure can be instituted taking into consideration that the preparation(s) used concomitantly may contain one or more preservatives. The concomitant use of two topical beta-adrenergic blocking agents is not recommended. (See PRECAUTIONS, Drug Interactions, Beta-adrenergic blocking agents.)

How is Timoptic in Ocudose Supplied

Preservative-free Sterile Ophthalmic Solution Timoptic in Ocudose is a clear, colorless to light yellow solution.

No. 814– Preservative-free TIMOPTIC, 0.25% timolol equivalent, is supplied in OCUDOSE, a clear low density polyethylene unit dose container. Each individual unit contains 0.2 mL of solution, and is available in a foil laminate overwrapped pouch as follows:

NDC 25010-814-66; 60 Individual Unit Doses.

No. 815– Preservative-free TIMOPTIC, 0.5% timolol equivalent, is supplied in OCUDOSE, a clear low density polyethylene unit dose container. Each individual unit contains 0.2 mL of solution, and is available in a foil laminate overwrapped pouch as follows:

NDC 25010-815-66; 60 Individual Unit Doses.

Storage

Store at room temperature, 15-30°C (59-86°F). Protect from freezing. Protect from light.

Because evaporation can occur through the unprotected polyethylene unit dose container and prolonged exposure to direct light can modify the product, the unit dose container should be kept in the protective foil overwrap and used within one month after the foil package has been opened.

Manuf. for:

ATON PHARMA

Lawrenceville

NJ 08648

USA

By: Laboratories Merck Sharp & Dohme-Chibret

      63963 Clermont-Ferrand Cedex 9, France

Issued February 2009

PRINCIPAL DISPLAY PANEL - 0.25% Carton

ATON

PHARMA

60 x 0.2 mL UNIT DOSES

PRESERVATIVE-FREE STERILE

OPHTHALMIC SOLUTION

NDC 25010-814-66

Rx only

TIMOPTIC® in OCUDOSE®

(TIMOLOL MALEATE

OPHTHALMIC SOLUTION)

(DISPENSER)

0.25%

Timolol Equivalent (Timolol Maleate 3.4 mg/mL)

FOR TOPICAL APPLICATION IN THE EYE

Manufactured for:

ATON PHARMA, INC., Lawrenceville, NJ 08648, USA

By: Laboratories Merck Sharp & Dohme-Chibret    63963 Clermont-Ferrand Cedex 9, France    Made in France

PRINCIPAL DISPLAY PANEL - 0.5% Carton

ATON

PHARMA

60 x 0.2 mL UNIT DOSES

PRESERVATIVE-FREE STERILE

OPHTHALMIC SOLUTION

NDC 25010-815-66

Rx only

TIMOPTIC® in OCUDOSE®

(TIMOLOL MALEATE

OPHTHALMIC SOLUTION)

(DISPENSER)

0.5%

Timolol Equivalent (Timolol Maleate 6.8 mg/mL)

FOR TOPICAL APPLICATION IN THE EYE

Manufactured for:

ATON PHARMA, INC., Lawrenceville, NJ 08648, USA

By: Laboratories Merck Sharp & Dohme-Chibret    63963 Clermont-Ferrand Cedex 9, France    Made in France

TIMOPTIC  timolol maleate  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 25010-814 Route of Administration OPHTHALMIC DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Timolol Maleate (Timolol) Timolol Maleate 3.4 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength Sodium Phosphate, Monobasic   Sodium Phosphate, Dibasic   Sodium Hydroxide   Water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 25010-814-66 4 POUCH In 1 CARTON contains a POUCH 1 15 CONTAINER In 1 POUCH This package is contained within the CARTON (25010-814-66) and contains a CONTAINER 1 0.2 mL In 1 CONTAINER This package is contained within a POUCH and a CARTON (25010-814-66)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA019463	11/05/1986

TIMOPTIC  timolol maleate  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 25010-815 Route of Administration OPHTHALMIC DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Timolol Maleate (Timolol) Timolol Maleate 6.8 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength Sodium Phosphate, Monobasic   Sodium Phosphate, Dibasic   Sodium Hydroxide   Water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 25010-815-66 4 POUCH In 1 CARTON contains a POUCH 1 15 CONTAINER In 1 POUCH This package is contained within the CARTON (25010-815-66) and contains a CONTAINER 1 0.2 mL In 1 CONTAINER This package is contained within a POUCH and a CARTON (25010-815-66)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA019463	11/05/1986

Labeler - Aton Pharma, Inc. (795419675)

Establishment
Name	Address	ID/FEI	Operations
Laboratories Merck Sharp & Dohme - Chibret		493743686	MANUFACTURE

Revised: 10/2009Aton Pharma, Inc.

More Timoptic in Ocudose resources

• Timoptic in Ocudose Use in Pregnancy & Breastfeeding
• Timoptic in Ocudose Drug Interactions
• Timoptic in Ocudose Support Group
• 1 Review for Timoptic in Ocudose - Add your own review/rating

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Colestid Orange

Colestid Orange 5.0g

Colestipol hydrochloride

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.



• If you have any further questions, ask your doctor or pharmacist.



• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.



• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What Colestid Orange is and what it is used for



• 2. Before you take Colestid Orange



• 3. How to take Colestid Orange



• 4. Possible side effects



• 5. How to store Colestid Orange



• 6. Further information

What Colestid Orange Is And What It Is Used For

Colestid Orange is a 'lipid lowering agent'. Colestid Orange is one of a group of medicines called bile acid sequestrants. The active ingredient is colestipol hydrochloride.

Colestid Orange is used to help lower the level of cholesterol in your blood. Your doctor will have recommended a special diet to you in order to help you lose weight since this is very important in lowering your cholesterol levels. Your doctor has given you Colestid Orange since the diet on its own is not lowering your cholesterol enough. It is still very important that you follow your special diet even when taking Colestid Orange. You can find out more about cholesterol from The British Heart Foundation whose address is given at the end of this leaflet.

Before You Take Colestid Orange

Do not take Colestid Orange:

• if you are allergic (hypersensitive) to colestipol hydrochloride or any of the other ingredients of Colestid Orange (see section 6 for a list of ingredients).

Take special care with Colestid Orange

Tell your doctor if you have any of these problems:

• an under-active thyroid gland



• nephrotic syndrome (a kidney problem where you get protein in your urine and too much fluid collecting in your body)



• too much or too little protein in your blood



• liver problems e.g. jaundice



• diabetes



• phenylketonuria eg you are on a special diet that is low in phenylalanine

Taking other medicines

There are some medicines that may interact with Colestid Orange and it can affect the way they work. Tell your doctor about other medicines you are taking before you start your Colestid Orange.

It is especially important to tell your doctor if you are taking the following medicines:

• heart drugs e.g. digoxin, digitoxin



• beta-blockers e.g. propranolol - for high blood pressure, angina, migraine or anxiety symptoms



• water tablets ('diuretics') e.g. chlorothiazide or furosemide - usually for heart or kidney problems



• antibiotics e.g. tetracycline hydrochloride and penicillin G



• another cholesterol-lowering medicine called gemfibrozil

Your doctor may need to change your dose of these medicines. If you are taking propranolol, your doctor will need to check your dose when you start taking Colestid Orange and also when you stop.

Please tell your doctor or pharmacist if you are taking or recently have taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

Tell your doctor if you are pregnant, or are planning to become pregnant, or if you are breast-feeding. Your doctor may stop your treatment.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Your ability to drive or operate machinery is not affected by taking Colestid Orange

Important information about some of the ingredients of Colestid Orange

Colestid Orange contains 32.5 mg aspartame which contains (18.2 mg phenylalanine) per sachet. This needs to be taken into consideration in people suffering from a condition known as phenylketonuria, since excessive amounts of aspartame may interfere with the control of this condition. If you suffer from phenylketonuria you should discuss this with your doctor before taking Colestid Orange.

How To Take Colestid Orange

Always take your medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Colestid Orange must not be taken as a dry powder and must be mixed with a drink or taken with liquid food. The Colestid Orange powder should be mixed thoroughly with at least 100 ml of water or another still drink such as orange or skimmed milk. Alternatively, Colestid Orange can be taken with soup or cereal or with pulpy fruit such as grapefruit, provided that there is at least 100 ml or more of liquid.

Colestid Orange has an orange/vanilla smell. It is flavoured with orange and vanilla and contains artificial sweeteners.

Your doctor will advise you on the amount of Colestid Orange you should take, and when.

Most people start by taking one to two sachets of Colestid Orange per day. Your doctor may increase your dose each month until your cholesterol reaches the best level for you. Do not change the number of sachets you take unless your doctor tells you to. Do not take more than 6 sachets (30 grams) a day. If you are prescribed more than two sachets per day, it may be preferable to take Colestid Orange as two separate doses, leaving several hours between e.g. with breakfast and an evening meal.

Taking Colestid with other medicines

If you have other medicines to take, make sure you take them at least one hour before or four hours after your Colestid Orange except if you are taking gemfibrozil, take this at least two hours before or after your Colestid Orange.

You may have to take Colestid Orange every day for a long time. It is important that you stick to your recommended diet as well as taking your Colestid Orange.

Colestid Orange does not actually dissolve and it therefore has a "gritty" texture, especially if it is not well mixed with the liquid you are using. The "grittiness" of Colestid Orange is much more obvious in "dilute" drinks such as water or fruit juice. Some people mix up Colestid Orange the night before to improve results.

Use by Children

Colestid Orange will not normally be given to children. Ask your doctor for more information if they have prescribed Colestid Orange for a child in your care. If children or young adults are given this medicine, your doctor will need to check their growth and development regularly.

If you take more Colestid Orange than you should

Never take more Colestid Orange than your doctor has told you. If you do, tell your doctor because you may get constipation.

If you forget to take Colestid Orange

Don't worry. Take your next sachet (or sachets) at the usual time.

Do not take a double dose to make up for a forgotten dose.

Colestid Orange Side Effects

Like all medicines, Colestid Orange can cause side-effects, although not everyone gets them.

Tell your doctor if you experience any of the following side effects and they do not go away:

• constipation, which is usually mild and does not last for long. Eating more fibre and drinking plenty of fluid usually helps. Sometimes it can be more severe and cause a blockage in your colon. If this happens you might need some treatment like an enema, to relieve the blockage. Tell your doctor if you think you have this problem. Constipation can make piles (haemorrhoids) worse and you may notice blood in your stools. Tell your doctor immediately if this happens.



• stomach discomfort,



• belching,



• wind,



• nausea (feeling sick)



• sickness or diarrhoea.

Other side effects

Rarely, some people have noticed the following side-effects, Tell your doctor immediately if any of these happen.

• stomach ulcers and bleeding stomach ulcers. These will cause severe stomach pains and if these start to bleed you may pass very dark stools or bring up blood if you are sick.



• inflammation of the gall bladder, gallstones or yellowish skin.



• chest pain, angina-like feelings or you may feel your heart beat speeding up.



• allergy effects like a rash, itchy skin or hives..



• aches and pains in your joints and muscles, especially your fingers and toes. You may also feel backache.



• headaches, some of which may feel quite severe (migraine, sinus headache) or feel dizzy and light-headed. You may also have difficulty sleeping,.



• not feel like eating, feeling tired and weak, have a shortness of breath, or swelling of your hands and feet.

Colestid Orange affects the way that your body absorbs fats and some 'fat-soluble' vitamins (A,D,E and K). Your doctor may give you a vitamin supplement if they think this could be happening.

The levels of some fats and enzymes in your blood may rise. This is usually temporary.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

How To Store Colestid Orange

Keep out of the reach and sight of children.

Do not use Colestid Orange after the expiry date which is stated on the label. The expiry date refers to the last day of the month.

Do not store above 25°C.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What Colestid Orange contains

• The active substance is colestipol hydrochloride



• The other ingredients are
  
  • Mannitol E421
  
  
  • Methylcellulose (15CPS) E461
  
  
  • Citric Acid E330
  
  
  • Orange Durarome Wonf
  
  
  • Aspartame Powder E951
  
  
  • Maltol
  
  
  • Ethyl Vanillin
  
  
  • Beta Carotene 1% E160a
  
  
  • Glycerol E422
  
  
  • Purified Water
  
  
  

What Colestid Orange looks like and the contents of the pack

• Colestid Orange is yellow granules for oral suspension with orange particles.



• Colestid Orange comes in boxes of 30 sachets. Each 7.5 g sachet contains 5 g of the active substance, colestipol hydrochloride.

Marketing Authorisation Holder and Manufacturer

Pharmacia Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

Manufacturer

Pfizer Service Company BVBA

10 Hoge Wei

1930 Zaventem

Belgium

More information about cholesterol

If you would like any more information about changing your lifestyle to lower your cholesterol you can contact:

The British Heart Foundation

14 Fitzhardinge Street

London

W1H 4DH

Tel.:020 7935 0185

This leaflet was last approved in 05/2008

Colestid is a registered trademark – Pharmacia Limited.

Ref CL 4_0

Imodium Classic 2 mg Capsules.

1. Name Of The Medicinal Product

Imodium Classic 2 mg Capsules.

2. Qualitative And Quantitative Composition

Each capsule contains 2 mg Loperamide hydrochloride.

Excipient: lactose

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Capsule, hard.

Opaque green cap and grey body, hard gelatin capsule imprinted with 'Imodium' on cap and 'Janssen' on body containing white powder.

4. Clinical Particulars

4.1 Therapeutic Indications

For the symptomatic treatment of acute diarrhoea in adults and children aged 12 years and over.

For the symptomatic treatment of acute episodes of diarrhoea associated with Irritable Bowel Syndrome in adults aged 18 years and over following initial diagnosis by a doctor.

4.2 Posology And Method Of Administration

The capsules should be taken with liquid.

ACUTE DIARRHOEA

Adults and children over 12:

Two capsules (4 mg) initially, followed by one capsule (2 mg) after each loose stool. The usual dose is 3-4 capsules (6 mg – 8 mg) a day. The total daily dose should not exceed 8 capsules (16 mg).

SYMPTOMATIC TREATMENT OF ACUTE EPISODES OF DIARRHOEA ASSOCIATED WITH IRRITABLE BOWEL SYNDROME IN ADULTS AGED 18 YEARS AND OVER

Two capsules (4 mg) to be taken initially. The usual dose is between 2 and 4 capsules (4 mg – 8 mg) per day in divided doses, depending on severity. If required, this dose can be adjusted according to result, up to a maximum of 8 capsules (16 mg) daily.

USE IN ELDERLY

No dose adjustment is required for the elderly.

RENAL IMPAIRMENT

No dose adjustment is required for patients with renal impairment.

HEPATIC IMPAIRMENT

Although no pharmacokinetic data are available in patients with hepatic impairment, Imodium should be used with caution in such patients because of reduced first pass metabolism. (see 4.4 Special warnings and special precautions for use).

Method of administration

Oral use.

4.3 Contraindications

This medicine is contraindicated:

• in patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients.

• in children less than 12 years of age.

• in patients with acute dysentery, which is characterised by blood in stools and high fever.

• in patients with acute ulcerative colitis.

• in patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella and Campylobacter.

• in patients with pseudomembranous colitis associated with the use of broad-spectrum antibiotics.

Imodium must not be used when inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae including ileus, megacolon and toxic megacolon. Imodium must be discontinued promptly when ileus, constipation or abdominal distension develop.

4.4 Special Warnings And Precautions For Use

Treatment of diarrhoea with Imodium is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate. The priority in acute diarrhoea is the prevention or reversal of fluid and electrolyte depletion. This is particularly important in young children and in frail and elderly patients with acute diarrhoea. Use of this medicine does not preclude the administration of appropriate fluid and electrolyte replacement therapy.

Since persistent diarrhoea can be an indicator of potentially more serious conditions, this medicine should not be used for prolonged periods until the underlying cause of the diarrhoea has been investigated.

In acute diarrhoea, if clinical improvement is not observed within 24 hours, the administration of Imodium should be discontinued and patients should be advised to consult their doctor.

Patients with AIDS treated with this medicine for diarrhoea should have therapy stopped at the earliest signs of abdominal distension. There have been isolated reports of obstipation with an increased risk for toxic megacolon in AIDS patients with infectious colitis from both viral and bacterial pathogens treated with loperamide hydrochloride.

Although no pharmacokinetic data are available in patients with hepatic impairment, this medicine should be used with caution in such patients because of reduced first pass metabolism, as it may result in a relative overdose leading to CNS toxicity.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine because it contains lactose

If you are taking this medicine to control episodes of diarrhoea associated with Irritable Bowel Syndrome previously diagnosed by your doctor, you should return to him/her if the pattern of your symptoms changes. You should also return to your doctor if your episodes of diarrhoea continue for more than two weeks or there is a need for continued treatment of more than two weeks.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with quinidine, or ritonavir, which are both P-glycoprotein inhibitors, resulted in a 2 to 3-fold increase in loperamide plasma levels. The clinical relevance of this pharmacokinetic interaction with P-glycoprotein inhibitors, when loperamide is given at recommended dosages, is unknown.

The concomitant administration of loperamide (4 mg single dose) and itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 3 to 4-fold increase in loperamide plasma concentrations. In the same study a CYP2C8 inhibitor, gemfibrozil, increased loperamide by approximately 2-fold. The combination of itraconazole and gemfibrozil resulted in a 4-fold increase in peak plasma levels of loperamide and a 13-fold increase in total plasma exposure. These increases were not associated with central nervous system (CNS) effects as measured by psychomotor tests (i.e., subjective drowsiness and the Digit Symbol Substitution Test).

The concomitant administration of loperamide (16 mg single dose) and ketoconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 5-fold increase in loperamide plasma concentrations. This increase was not associated with increased pharmacodynamic effects as measured by pupillometry.

Concomitant treatment with oral desmopressin resulted in a 3-fold increase of desmopressin plasma concentrations, presumably due to slower gastrointestinal motility.

It is expected that drugs with similar pharmacological properties may potentiate loperamide's effect and that drugs that accelerate gastrointestinal transit may decrease its effect.

4.6 Pregnancy And Lactation

Safety in human pregnancy has not been established, although from animal studies there are no indications that loperamide HCl posseses any teratogenic or embryotoxic properties. As with other drugs, it is not advisable to administer this medicine in pregnancy, especially during the first trimester.

Small amounts of loperamide may appear in human breast milk. Therefore, this medicine is not recommended during breast-feeding.

Women who are pregnant or breast feeding infants should therefore be advised to consult their doctor for appropriate treatment.

4.7 Effects On Ability To Drive And Use Machines

Loss of consciousness, depressed level of consciousness, tiredness, dizziness, or drowsiness may occur when diarrhoea is treated with this medicine. Therefore, it is advisable to use caution when driving a car or operating machinery. See Section 4.8, Undesirable Effects.

4.8 Undesirable Effects

Adults and children aged

The safety of loperamide HCl was evaluated in 2755 adults and children aged

The most commonly reported (i.e.

Table 1 displays ADRs that have been reported with the use of loperamide HCl from either clinical trial (acute diarrhoea) or post-marketing experience.

The frequency categories use the following convention: very common (

Table 1: Adverse Drug Reactions

System Organ Class	Indication
Common	Uncommon	Rare
Immune System Disorders			Hypersensitivity reactiona Anaphylactic reaction (including Anaphylactic shock)a Anaphylactoid reactiona
Nervous System Disorders	Headache	Dizziness Somnolencea	Loss of consciousnessa Stupora Depressed level of consciousnessa Hypertoniaa Coordination abnormalitya
Eye Disorders			Miosisa
Gastrointestinal Disorders	Constipation Nausea Flatulence	Abdominal pain Abdominal discomfort Dry mouth Abdominal pain upper Vomiting Dyspepsiaa	Ileusa (including paralytic ileus) Megacolona (including toxic megacolonb) Abdominal distension
Skin and Subcutaneous Tissue Disorders		Rash	Bullous eruptiona (including Stevens-Johnson syndrome, Toxic epidermal necrolysis and Erythema multiforme) Angioedemaa Urticariaa Pruritusa
Renal and Urinary Disorders			Urinary retentiona
General Disorders and Administration Site Conditions			Fatiguea

a: Inclusion of this term is based on post-marketing reports for loperamide HCl. As the process for determining post marketing ADRs did not differentiate between chronic and acute indications or adults and children, the frequency is estimated from all clinical trials with loperamide HCl (acute and chronic), including trials in children b: See section 4.4 Special Warnings and Special Precautions for use.

4.9 Overdose

Symptoms:

In case of overdose (including relative overdose due to hepatic dysfunction), CNS depression (stupor, coordination abnormality, somnolence, miosis, muscular hypertonia and respiratory depression), constipation, urinary retention and ileus may occur. Children and patients with hepatic dysfunction may be more sensitive to CNS effects.

Treatment:

If symptoms of overdose occur, naloxone can be given as an antidote. Since the duration of action of loperamide is longer than that of naloxone (1 to 3 hours), repeated treatment with naloxone might be indicated. Therefore, the patient should be monitored closely for at least 48 hours in order to detect possible CNS depression.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Antipropulsives; ATC code: A07DA03

Loperamide binds to the opiate receptor in the gut wall, reducing propulsive peristalsis and increasing intestinal transit time. Loperamide increases the tone of the anal sphincter.

In a double blind randomised clinical trial in 56 patients with acute diarrhoea receiving loperamide, onset of anti-diarrhoeal action was observed within one hour following a single 4 mg dose. Clinical comparisons with other antidiarrhoeal drugs confirmed this exceptionally rapid onset of action of loperamide.

5.2 Pharmacokinetic Properties

The half-life of loperamide in man is 10.8 hours with a range of 9-14 hours. Studies on distribution in rats show high affinity for the gut wall with preference for binding to the receptors in the longitudinal muscle layer. Loperamide is well absorbed from the gut, but is almost completely extracted and metabolised by the liver where it is conjugated and excreted via the bile. Due to its high affinity for the gut wall and its high first pass metabolism, very little loperamide reaches the systemic circulation.

5.3 Preclinical Safety Data

No relevant information additional to that contained elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose

Maize starch

Talc

Magnesium stearate (E572)

Capsule cap:

Titanium dioxide (E171)

Yellow ferric oxide (E172)

Indigo carmine (E132)

Gelatin

Capsule body:

Titanium dioxide (E171)

Black ferrous oxide (E172)

Indigo carmine (E132)

Erythrosine (E127)

Gelatin

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Blister packs consisting of aluminium foil, hermetalu and polyvinyl chloride genotherm glass clear.

The blister strips are packed in cardboard cartons to contain 2, 4, 6, 8, 12 or 18 capsules

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire

SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0309

9. Date Of First Authorisation/Renewal Of The Authorisation

15/12/2009

10. Date Of Revision Of The Text

27/07/2011

Quartuss DM

phenylephrine hydrochloride, dextromethorphan hydrobromide and chlorpheniramine maleate

Dosage Form: oral liquid
Quartuss™ DM Drops

Nasal Decongestant/Antitussive/Antihistamine

Quartuss DM Description

Each dropperful (1 mL) contains:

Dextromethorphan HBr.................................................................................................................... 3 mg

Phenylephrine HCl........................................................................................................................ 1.5 mg

Chlorpheniramine Maleate .............................................................................................................. 1 mg

	Dextromethorphan hydrobromide is an antitussive having the chemical name, Morphinan, 3-methoxy-17-methyl-, (9α,13α, 14α)-, hydrobromide, monohydrate with the following structure:		Phenylephrine Hydrochloride is a nasal decongestant having the chemical name, Benzenemethanol, 3-hydroxy-α-[(methylamino)methyl]-, hydrochloride (R)-. (–)-m-Hydroxy-α-[methylamino) methyl]benzyl alcohol hydrochloride, with the following structure:
Molecular formula: C18H25NO•HBr•H2O	M.W.=370.32	Molecular formula: C9H13NO2•HCl	M.W.=203.67
			Chlorpheniramine Maleate is an antihistamine having the chemical name, 2-Pyridinepropanamine, γ-(4-chlorophenyl)-N,N-dimethyl-, (Z)-2-butenedioate (1:1). 2-[p-Chloro-α-[2-(dimethylamino)ethyl]benzyl]pyridine maleate (1:1). with the following structure:
Molecular formula: C16H19ClN2•C4H4O4        M.W.=390.86

INACTIVE INGREDIENTS

Sodium Benzoate, Citric Acid, Sorbitol Solution, Glycerin, FD&C Red No. 40, Bubblegum Flavor, Purified Water.

Quartuss DM - Clinical Pharmacology

Dextromethorphan HBr

Dextromethorphan HBr is a nonopioid antitussive agent. It suppresses the cough reflex by a direct action on the cough center in the medulla of the brain. Dextromethorphan HBr has no significant analgesic or sedative properties. It does not depress respiration or predispose an individual to addiction with usual doses. In therapeutic dosage, Dextromethorphan HBr does not inhibit ciliary activity. The onset of action is typically within 30 minutes and the duration of action can be up to 6 hours. Dextromethorphan HBr is rapidly and extensively metabolized by the liver. It is primarily excreted in the kidneys as unchanged dextromethorphan and demethylated metabolites including dextrorphan, an active metabolite.

Phenylephrine Hydrochloride

Phenylephrine HCl, a nasal decongestant, is a potent postsynaptic alpha-receptor agonist with little effect on the beta receptors of the heart. Phenylephrine HCl has no effect on the beta-adrenergic receptors of the bronchi or peripheral blood vessels. A direct action at receptors accounts for the greater part of its effects, only a small part being due to its ability to release norepinephrine. Therapeutic doses of Phenylephrine HCl may cause vasoconstriction. It increases resistance and, to a lesser extent, decreases capacitance of blood vessels. Total peripheral resistance is increased, resulting in increased systolic and diastolic blood pressure. Pulmonary arterial pressure is usually increased, and renal blood flow is usually decreased. Local vasoconstriction and hemostasis occur following infiltration of Phenylephrine HCl into tissues. The main effect of Phenylephrine HCl on the heart is bradycardia; it produces a positive inotropic effect on the myocardium in doses greater than those usually used therapeutically. Rarely, the drug may increase the irritability of the heart which can cause arrhythmias. Cardiac output is decreased slightly. Phenylephrine HCl increases the work of the heart by increasing peripheral arterial resistance. Phenylephrine HCl has a mild central stimulant effect. Following oral administration of Phenylephrine HCl, constriction of blood vessels in the nasal mucosa relieves nasal congestion associated with allergy or head colds. This may occur within 15 or 20 minutes and may persist for up to 4 hours.

Chlorpheniramine Maleate

Chlorpheniramine Maleate possesses H1 antihistaminic activity and mild anticholinergic and sedative effects.

INDICATIONS

For relief of coughs and upper respiratory symptoms, including nasal congestion, associated with allergy or the common cold.

Contraindications

Quartuss™ DM Drops is contraindicated in patients hypersensitive to any of its ingredients. It is also contraindicated in patients with severe hypertension or severe coronary artery disease, or in those receiving monoamine oxidase (MAO) inhibitors (or for 14 days after stopping MAOI therapy). Antihistamines should not be used to treat lower respiratory tract conditions including asthma.

Warnings

Do not exceed recommended dosage. If nervousness, dizziness, or sleeplessness occur, discontinue use and consult a doctor. If symptoms do not improve within 7 days or are accompanied by a fever, consult a doctor. Sympathomimetic amines should be used with caution in patients with hypertension, ischemic heart disease, diabetes mellitus, increased intraocular pressure, hyperthyroidism, or prostatic hypertrophy. Sympathomimetics may produce central nervous system stimulation with convulsions or cardiovascular collapse with accompanying hypotension. Do no exceed recommended dosage.

Precautions

General

Before prescribing this medication to suppress or modify cough, identify and provide therapy for the underlying cause of the cough. Avoid alcohol and other CNS depressants while taking this product. Patients sensitive to antihistamines may experience moderate to severe drowsiness.

Information For Patients

Patients should be warned about engaging in activities requiring mental alertness, such as driving or operating dangerous machinery.

Drug Interactions

Antihistamines have additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers, antianxiety agents, etc.). MAO inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines. MAO inhibitors may enhance the effect of Phenylephrine HCl. Sympathomimetics may reduce the effects of antihypertensive drugs.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No data is currently available on long term potential for carcinogenesis, mutagenesis, or impairment of fertility in animals or humans.

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with this product. It is not known whether this product can cause fetal harm when administered to a pregnant woman or affect reproduction capacity. Give to pregnant women only if clearly needed. Administration of Phenylephrine HCl to patients in late pregnancy or labor may cause fetal anoxia or bradycardia by increasing contractility of the uterus and decreasing uterine blood flow.

Nursing Mothers

Some sympathomimetics are excreted in breast milk. Use of this product by nursing mothers is not recommended.

Adverse Reactions

Dextromethorphan HBr

Adverse effects with Dextromethorphan HBr are rare, but nausea and/or other gastrointestinal disturbances, headache, slight dizziness and drowsiness sometimes occur.

Phenylephrine HCl

Hyperreactive individuals may display ephedrine-like reactions such as tachycardia, palpitations, headache, dizziness, or nausea. Sympathomimetics have been associated with certain untoward reactions including fear, anxiety, nervousness, restlessness, tremor, weakness, pallor, respiratory difficulty, dysuria, insomnia, hallucinations, convulsions, CNS depression, arrhythmias, and cardiovascular collapse with hypotension.

Chlorpheniramine Maleate

Antihistamines may cause sedation, dizziness, diplopia, vomiting, diarrhea, dry mouth, headache, nervousness, nausea, anorexia, heartburn, weakness, polyuria and; rarely, excitability in children.

Overdosage

Signs and Symptoms

Overdosage with dextromethorphan HBr may produce CNS excitement and metal confusion. Overdosage with sympathomimetic amines can cause hypertension, headache, convulsions, cerebral hemorrhage and vomiting may occur. Headache may be a symptom of hypertension. Bradycardia may also be seen early in Phenylephrine HCl overdosage through stimulation of baroreceptors. Excessive CNS stimulation may result in excitement, tremor, restlessness, and insomnia. Other effects may include pallor, mydriasis, hyperglycemia, and urinary retention. Severe overdosage may cause tachypnea or hyperpnea, hallucinations, convulsions, or delirium, but in some individuals, there may be CNS depression. Arrhythmias (including ventricular fibrillation) may lead to hypotension and circulatory collapse. Severe hypokalemia can occur, probably due to a compartmental shift rather that a depletion of potassium. Should antihistamine effects predominate, central action constitutes the greatest danger. In the small child, symptoms include excitation, hallucination, ataxia, uncoordination, tremors, flushed face and fever. Convulsions, fixed and dilated pupils, coma and death may occur in severe cases. In the adult, fever and flushing are uncommon, excitement leading to convulsions and postictal depression is often preceded by drowsiness and coma. Respiration is usually not seriously depressed; blood pressure is usually stable.

Treatment

The patient should be induced to vomit, even if emesis has occurred spontaneously. Pharmacologic vomiting by the administration of ipecac syrup is a preferred method, however, vomiting should not be induced in patients with impaired consciousness. Precautions against aspiration must be taken, especially in infants, children and comatose patients. Following emesis, any drug remaining in the stomach may be absorbed by activated charcoal administered as a slurry with water. Treatment of the signs and symptoms of overdosage is symptomatic and supportive.

Quartuss DM Dosage and Administration

Consult physician for dosing. Dosing is based on weight and month of age of child. May be repeated every 4-6 hours if required for relief. Not to exceed 4 doses in 24 hours. In mild cases or in particularly sensitive patients less frequent or reduced doses may be adequate.

How is Quartuss DM Supplied

Quartuss™ DM Drops is supplied as an alcohol free, sugar free, bubblegum flavored liquid, in bottles of 1 fl. oz. (30 mL), NDC 51991-537-03, with a calibrated (1 mL) dropper.

WARNING: KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. IN CASE OF ACCIDENTAL OVERDOSE SEEK PROFESSIONAL ASSISTANCE OR CONTACT A POISON CONTROL CENTER IMMEDIATELY.

Storage

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). See USP Controlled Room Temperature. Protect from freezing.

Pharmacist: Dispense in original container.

All prescription substitutions using this product shall be pursuant to state statues as applicable. This is not an Orange Book product.

Rx ONLY

Distributed by:

Breckenridge Pharmaceutical, Inc.

Boca Raton, FL 33487

Manufactured by:

Tri-Med Laboratories, Inc.

Somerset, NJ 08873

Iss. 6/07

PRINCIPAL DISPLAY PANEL - 30 mL Box

Breckenridge

Pharmaceutical, Inc

NDC 51991-537-03

Quartuss™ DM

Drops

Antitussive/Nasal Decongestant/Antihistamine

•Sugar Free •Alcohol Free

Each 1 mL contains:

Phenylephrine Hydrochloride ...........1.5 mg

Chlorpheniramine Maleate ..................1 mg

Dextromethorphan HBr .......................3 mg

Inactive Ingredients: Sodium Benzoate, Citric Acid,

Sorbitol Solution, Glycerin, FD & C Red No.40, Artificial

Bubblegum Flavor, Purified Water.

Rx ONLY

Net Contents: 1 fl. oz. (30 mL)

With Calibrated Dropper

Quartuss DM  phenylephrine hydrochloride, dextromethorphan hydrobromide and chlorpheniramine maleate  liquid

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 51991-537 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Phenylephrine Hydrochloride (Phenylephrine) Phenylephrine Hydrochloride 1.5 mg  in 1 mL Dextromethorphan Hydrobromide (Dextromethorphan) Dextromethorphan Hydrobromide 3 mg  in 1 mL Chlorpheniramine Maleate (Chlorpheniramine) Chlorpheniramine Maleate 1 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength sodium benzoate   citric acid monohydrate   sorbitol   glycerin   FD&C Red No. 40   water

Product Characteristics Color RED (Clear) Score      Shape Size Flavor BUBBLE GUM Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 51991-537-03 30 mL In 1 BOTTLE, DROPPER None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
Unapproved drug other		10/01/2007	12/31/2011

Labeler - Breckenridge Pharmaceutical, Inc. (150554335)

Establishment
Name	Address	ID/FEI	Operations
Trimed		182050567	MANUFACTURE

Revised: 10/2010Breckenridge Pharmaceutical, Inc.

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