Drug Intercation

Hydrochlorothiazide 50 MG / Triamterene 75 MG Oral Tablet

WARNINGS

: Hyperkalemia: Abnormal elevation of serum potassium levels (greater than or equal to 5.5 mEq/liter) can occur with all potassium-conserving diuretic combinations, including triamterene and hydrochlorothiazide.

Hyperkalemia is more likely to occur in patients with renal impairment, diabetes (even without evidence of renal impairment), or elderly or severely ill patients.

Since uncorrected hyperkalemia may be fatal, serum potassium levels must be monitored at frequent intervals especially in patients first receiving triamterene and hydrochlorothiazide, when dosages are changed or with any illness that may influence renal function.

If hyperkalemia is suspected (warning signs include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia and shock), an electrocardiogram (ECG) should be obtained.

However, it is important to monitor serum potassium levels because mild hyperkalemia may not be associated with ECG changes.

If hyperkalemia is present, triamterene and hydrochlorothiazide should be discontinued immediately and a thiazide alone should be substituted.

If the serum potassium exceeds 6.5 mEq/liter, more vigorous therapy is required.

The clinical situation dictates the procedures to be employed.

These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation.

Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered.

Persistent hyperkalemia may require dialysis.

The development of hyperkalemia associated with potassium-sparing diuretics is accentuated in the presence of renal impairment (see CONTRAINDICATIONS ).

Patients with mild renal functional impairment should not receive this drug without frequent and continuing monitoring of serum electrolytes.

Cumulative drug effects may be observed in patients with impaired renal function.

The renal clearances of hydrochlorothiazide and the pharmacologically active metabolite of triamterene, the sulfate ester of hydroxytriamterene, have been shown to be reduced and the plasma levels increased following triamterene and hydrochlorothiazide administration to elderly patients and patients with impaired renal function.

Hyperkalemia has been reported in diabetic patients with the use of potassium-conserving agents even in the absence of apparent renal impairment.

Accordingly, triamterene and hydrochlorothiazide should be avoided in diabetic patients.

If it is employed, serum electrolytes must be frequently monitored.

Because of the potassium-sparing properties of angiotensin-converting enzyme (ACE) inhibitors, triamterene and hydrochlorothiazide should be used cautiously, if at all, with these agents (see PRECAUTIONS : Drug Interactions ).

Metabolic or Respiratory Acidosis: Potassium-conserving therapy should also be avoided in severely ill patients in whom respiratory or metabolic acidosis may occur.

Acidosis may be associated with rapid elevations in serum potassium levels.

If triamterene and hydrochlorothiazide is employed, frequent evaluations of acid/base balance and serum electrolytes are necessary.

Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma.

Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation.

Untreated acute angle-closure glaucoma can lead to permanent vision loss.

The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible.

Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled.

Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

DRUG INTERACTIONS

Drug Interactions: Thiazides may add to or potentiate the action of other antihypertensive drugs.

The thiazides may decrease arterial responsiveness to norepinephrine.

This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.

Thiazides have also been shown to increase the responsiveness to tubocurarine.

Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity.

Refer to the package insert on lithium before use of such concomitant therapy.

Acute renal failure has been reported in a few patients receiving indomethacin and formulations containing triamterene and hydrochlorothiazide.

Caution is therefore advised when administering non-steroidal anti-inflammatory agents with triamterene and hydrochlorothiazide.

Potassium-sparing agents should be used very cautiously, if at all, in conjunction with angiotensin-converting enzyme (ACE) inhibitors due to a greatly increased risk of hyperkalemia.

Serum potassium should be monitored frequently.

OVERDOSAGE

: No specific data are available regarding triamterene and hydrochlorothiazide overdosage in humans and no specific antidote is available.

Fluid and electrolyte imbalances are the most important concern.

Excessive doses of the triamterene component may elicit hyperkalemia, dehydration, nausea, vomiting and weakness and possibly hypotension.

Overdosing with hydrochlorothiazide has been associated with hypokalemia, hypochloremia, hyponatremia, dehydration, lethargy (may progress to coma) and gastrointestinal irritation.

Treatment is symptomatic and supportive.

Therapy with triamterene and hydrochlorothiazide should be discontinued.

Induce emesis or institute gastric lavage.

Monitor serum electrolyte levels and fluid balance.

Institute supportive measures as required to maintain hydration, electrolyte balance, respiratory, cardiovascular, and renal function.

DESCRIPTION

: Triamterene and hydrochlorothiazide tablets USP, combines triamterene, a potassium-conserving diuretic, with the natriuretic agent, hydrochlorothiazide.

Triamterene and hydrochlorothiazide tablets are available in two strengths.

Each triamterene and hydrochlorothiazide tablet, 75 mg/50 mg, contains triamterene USP, 75 mg and hydrochlorothiazide USP, 50 mg.

Each triamterene and hydrochlorothazide tablet, 37.5 mg/25 mg, contains triamterene USP, 37.5 mg and hydrochlorothiazide USP, 25 mg.

Both strengths of triamterene and hydrochlorothiazide tablets for oral administration contain the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, polacrilin potassium, polyethylene glycol 8000, povidone, and magnesium stearate.

Triamterene and hydrochlorothiazide tablets, 37.5 mg/25 mg also contain FD&C Blue #2.

Triamterene is 2, 4, 7-triamino-6-phenylpteridine.

Triamterene is practically insoluble in water, benzene, chloroform, ether and dilute alkali hydroxides.

It is soluble in formic acid and sparingly soluble in methoxyethanol.

Triamterene is very slightly soluble in acetic acid, alcohol and dilute mineral acids.

Its molecular weight is 253.27.

Its structural formula is: Hydrochlorothiazide is 6-chloro-3, 4-dihydro-2 H -1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide.

Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution, n-butylamine and dimethylformamide.

It is sparingly soluble in methanol and insoluble in ether, chloroform and dilute mineral acids.

Its molecular weight is 297.73.

Its structural formula is: Triamterene Chemical Structure Hydrochlorothiazide Chemical Structure

HOW SUPPLIED

: Triamterene and Hydrochlorothiazide Tablets USP, 75 mg/50 mg, are yellow, round, scored tablets, debossed with Watson 348 and are available in bottles of 50.

Store at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature].

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Distributed by: Watson Pharma, Inc.

Parsippany, NJ 07054 USA Revised: April 2012 Repackaged by: KAISER FOUNDATION HOSPITALS Livermore, CA 94551

INDICATIONS AND USAGE

: This fixed combination drug is not indicated for the initial therapy of edema or hypertension except in individuals in whom the development of hypokalemia cannot be risked.

Triamterene and hydrochlorothiazide tablets are indicated for the treatment of hypertension or edema in patients who develop hypokalemia on hydrochlorothiazide alone.

Triamterene and hydrochlorothiazide is also indicated for those patients who require a thiazide diuretic and in whom the development of hypokalemia cannot be risked (e.g., patients on concomitant digitalis preparations, or with a history of cardiac arrhythmias, etc.).

Triamterene and hydrochlorothiazide may be used alone or in combination with other antihypertensive drugs such as beta-blockers.

Since triamterene and hydrochlorothiazide may enhance the actions of these drugs, dosage adjustments may be necessary.

Usage in Pregnancy: The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard.

Diuretics do not prevent development of toxemia in pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia.

Edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy.

Thiazides are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy.

Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary.

There is hypervolemia during normal pregnancy which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women.

If this edema produces discomfort, increased recumbency will often provide relief.

In rare instances, this edema may cause extreme discomfort which is not relieved by rest.

In these cases, a short course of diuretics may provide relief and may be appropriate.

PEDIATRIC USE

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

PREGNANCY

Pregnancy: Teratogenic Effects: Category C: Animal reproduction studies to determine the potential for fetal harm by triamterene and hydrochlorothiazide tablets have not been conducted.

Nevertheless, a One Generation Study in the rat approximated triamterene and hydrochlorothiazide’s composition by using a 1:1 ratio of triamterene to hydrochlorothiazide (30:30 mg/kg/day).

There was no evidence of teratogenicity at those doses that were, on a body-weight basis, 15 and 30 times, respectively, the MRHD, and, on the basis of body-surface area, 3.1 and 6.2 times, respectively, the MRHD.

The safe use of triamterene and hydrochlorothiazide tablets in pregnancy has not been established since there are no adequate and well-controlled studies with triamterene and hydrochlorothiazide tablets in pregnant women.

Triamterene and hydrochlorothiazide tablets should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

Triamterene: Reproduction studies have been performed in rats at doses as high as 20 times the Maximum Recommended Human Dose (MRHD) on the basis of body-weight, and 6 times the MRHD on the basis of body-surface area without evidence of harm to the fetus due to triamterene.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Hydrochlorothiazide: Hydrochlorothiazide was orally administered to pregnant mice and rats during respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively.

At these doses, which are multiples of the MRHD equal to 3000 for mice and 1000 for rats, based on body-weight, and equal to 282 for mice and 206 for rats, based on body-surface area, there was no evidence of harm to the fetus.

There are, however, no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nonteratogenic Effects: Thiazides and triamterene have been shown to cross the placental barrier and appear in cord blood.

The use of thiazides and triamterene in pregnant women requires that the anticipated benefits be weighed against possible hazards to the fetus.

These hazards include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.

NUSRING MOTHERS

Nursing Mothers: Thiazides and triamterene in combination have not been studied in nursing mothers.

Triamterene appears in animal milk and this may occur in humans.

Thiazides are excreted in human breast milk.

If use of the combination drug product is deemed essential, the patient should stop nursing.

DOSAGE AND ADMINISTRATION

: Note: 37.5 mg/25 mg= 37.5 mg triamterene and 25 mg hydrochlorothiazide 75 mg/50 mg= 75 mg triamterene and 50 mg hydrochlorothiazide The usual dosage of triamterene and hydrochlorothiazide as a tablet is 37.5 mg/25 mg or 75 mg/50 mg daily, given as a single dose, with appropriate monitoring of serum potassium (see WARNINGS ).

There is no experience with the use of more than 75 mg/50 mg daily of triamterene and hydrochlorothiazide.

Clinical experience with the administration of 37.5 mg/25 mg of triamterene and hydrochlorothiazide twice daily in divided doses (rather than as a single dose) suggests an increased risk of electrolyte imbalance and renal dysfunction.

Patients receiving 50 mg of hydrochlorothiazide who become hypokalemic may be transferred to this 75 mg/50 mg product directly.

Patients receiving 25 mg hydrochlorothiazide who become hypokalemic may be transferred to a 37.5 mg/25 mg product directly.

In patients requiring hydrochlorothiazide therapy and in whom hypokalemia cannot be risked, therapy may be initiated with 37.5 mg/25 mg of triamterene and hydrochlorothiazide.

If an optimal blood pressure response is not obtained with 37.5 mg/25 mg triamterene and hydrochlorothiazide, the dose should be increased to 75 mg/50 mg daily as a single dose.

If blood pressure still is not controlled, another antihypertensive agent may be added (see PRECAUTIONS : Drug Interactions ).

Clinical studies have shown that patients taking less bioavailable formulations of triamterene and hydrochlorothiazide in daily doses of 25 mg to 50 mg hydrochlorothiazide and 50 mg to 100 mg of triamterene may be safely changed to 37.5 mg/25 mg of triamterene and hydrochlorothiazide daily.

All patients changed from less bioavailable formulations to triamterene and hydrochlorothiazide tablets should be monitored clinically and for serum potassium after the transfer.

digoxin 500 MCG per 2 ML Injection

Generic Name: DIGOXIN

Brand Name: Digoxin

Substance Name(s):
DIGOXIN

DRUG INTERACTIONS

Digoxin has a narrow therapeutic index, increased monitoring of serum digoxin concentrations and for potential signs and symptoms of clinical toxicity is necessary when initiating, adjusting, or discontinuing drugs that may interact with digoxin.

Prescribers should consult the prescribing information of any drug which is co-prescribed with digoxin for potential drug interaction information.

7.1 P-Glycoprotein (PGP) Inducers/Inhibitors Digoxin is a substrate of P-glycoprotein, at the level of intestinal absorption, renal tubular section and biliary-intestinal secretion.

Therefore, drugs that induce/inhibit P-glycoprotein have the potential to alter digoxin pharmacokinetics.

7.2 Pharmacokinetic Drug Interactions Pharmacokinetic interactions have been observed and reported primarily when digoxin is co-administered by oral route.

There are very few studies that have evaluated the drug interaction when digoxin is administered via IV route.

The magnitude of digoxin exposure change through IV route is generally lower than that through oral route.

Table below provides available interaction data using digoxin IV formulation (NA means not available).

7.3 Potentially Significant Pharmacodynamic Drug Interactions Because of considerable variability of pharmacodynamic interactions, the dosage of digoxin should be individualized when patients receive these medications concurrently.

7.4 Drug/Laboratory Test Interactions Endogenous substances of unknown composition (digoxin-like immunoreactive substances [DLIS]) can interfere with standard radioimmunoassays for digoxin.

The interference most often causes results to be falsely positive or falsely elevated, but sometimes it causes results to be falsely reduced.

Some assays are more subject to these failings than others.

Several LC/MS/MS methods are available that may provide less susceptibility to DLIS interference.

DLIS are present in up to half of all neonates and in varying percentages of pregnant women, patients with hypertrophic cardiomyopathy, patients with renal or hepatic dysfunction, and other patients who are volume-expanded for any reason.

The measured levels of DLIS (as digoxin equivalents) are usually low (0.2-0.4 ng/mL), but sometimes they reach levels that would be considered therapeutic or even toxic.

In some assays, spironolactone, canrenone, and potassium canrenoate may be falsely detected as digoxin, at levels up to 0.5 ng/mL.

Some traditional Chinese and Ayurvedic medicine substances like Chan Su, Siberian Ginseng, Asian Ginseng, Ashwagandha, or Dashen can cause similar interference.

Spironolactone and DLIS are much more extensively protein-bound than digoxin.

As a result, assays of free digoxin levels in protein-free ultrafiltrate (which tend to be about 25% less than total levels, consistent with the usual extent of protein binding) are less affected by spironolactone or DLIS.

It should be noted that ultrafiltration does not solve all interference problems with alternative medicines.

The use of an LC/MS/MS method may be the better option according to the good results it provides, especially in terms of specificity and limit of quantization.

Image5.jpg Image6.jpg

OVERDOSAGE

10.1 Signs and Symptoms in Adults The signs and symptoms of toxicity are generally similar to those previously described [see Adverse Reactions (6.1)] but may be more frequent and can be more severe.

Signs and symptoms of digoxin toxicity become more frequent with levels above 2 ng/mL.

However, in deciding whether a patient’s symptoms are due to digoxin, the clinical state together with serum electrolyte levels and thyroid function are important factors [see Dosage and Administration (2)].

Adults: The most common signs and symptoms of digoxin toxicity are nausea, vomiting, anorexia, and fatigue that occur in 30-70% of patients who are overdosed.

Extremely high serum concentrations produce hyperkalemia especially in patients with impaired renal function.

Almost every type of cardiac arrhythmia has been associated with digoxin overdose and multiple rhythm disturbances in the same patient are common.

Peak cardiac effects occur 3-6 hours following ingestion and may persist for 24 hours or longer.

Arrhythmias that are considered more characteristic of digoxin toxicity are new-onset Mobitz type 1 A-V block, accelerated junctional rhythms, non-paroxysmal atrial tachycardia with A-V block, and bi-directional ventricular tachycardia.

Cardiac arrest from asystole or ventricular fibrillation is usually fatal.

Digoxin toxicity is related to serum concentration.

As digoxin serum levels increase above 1.2 ng/mL, there is a potential for increase in adverse reactions.

Furthermore, lower potassium levels increases the risk for adverse reactions.

In adults with heart disease, clinical observations suggest that an overdose of digoxin of 10-15 mg results in death of half of patients.

A dose above 25 mg ingested by an adult without heart disease appeared to be uniformly fatal if no Digoxin Immune Fab (DIGIBIND®, DIGIFAB®) was administered.

Among the extra-cardiac manifestations, gastrointestinal symptoms (e.g., nausea, vomiting, anorexia) are very common (up to 80% incidence) and precede cardiac manifestations in approximately half of the patients in most literature reports.

Neurologic manifestations (e.g., dizziness, various CNS disturbances), fatigue, and malaise are very common.

Visual manifestations may also occur with aberration in color vision (predominance of yellow green) the most frequent.

Neurological and visual symptoms may persist after other signs of toxicity have resolved.

In chronic toxicity, nonspecific extra-cardiac symptoms, such as malaise and weakness, may predominate.

10.2 Treatment Chronic Overdose If there is suspicion of toxicity, discontinue digoxin and place the patient on a cardiac monitor.

Correct factors such as electrolyte abnormalities, thyroid dysfunction, and concomitant medications [see Dosage and Administration ( 2.4 ].

Correct hypokalemia by administering potassium so that serum potassium is maintained between 4.0 and 5.5 mmol/L.

Potassium is usually administered orally, but when correction of the arrhythmia is urgent and serum potassium concentration is low, potassium may be administered by the intravenous route.

Monitor electrocardiogram for any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the arrhythmia.

Avoid potassium salts in patients with bradycardia or heart block.

Symptomatic arrhythmias may be treated with Digoxin Immune Fab.

Acute Overdose Patients who have intentionally or accidently ingested massive doses of digoxin should receive activated charcoal orally or by nasogastric tube regardless of the time since ingestion since digoxin recirculates to the intestine by enterohepatic circulation.

In addition to cardiac monitoring, temporarily discontinue digoxin until the adverse reaction resolves.

Correct factors that may be contributing to the adverse reactions [see Warnings and Precautions ( 5 )].

In particular, correct hypokalemia and hypomagnesemia.

Digoxin is not effectively removed from the body by dialysis because of its large extravascular volume of distribution.

Life threatening arrhythmias (ventricular tachycardia, ventricular fibrillation, high degree A-V block, bradyarrhythma, sinus arrest) or hyperkalemia requires administration of Digoxin Immune Fab.

Digoxin Immune Fab has been shown to be 80-90% effective in reversing signs and symptoms of digoxin toxicity.

Bradycardia and heart block caused by digoxin are parasympathetically mediated and respond to atropine.

A temporary cardiac pacemaker may also be used.

Ventricular arrhythmias may respond to lidocaine or phenytoin.

When a large amount of digoxin has been ingested, especially in patients with impaired renal function, hyperkalemia may be present due to release of potassium from skeletal muscle.

In this case, treatment with Digoxin Immune Fab is indicated; an initial treatment with glucose and insulin may be needed if the hyperkalemia is life-threatening.

Once the adverse reaction has resolved, therapy with digoxin may be reinstituted following a careful reassessment of dose.

DESCRIPTION

Digoxin is one of the cardiac (or digitalis) glycosides, a closely related group of drugs having in common specific effects on the myocardium.

These drugs are found in a number of plants.

Digoxin is extracted from the leaves of Digitalis lanata.

The term “digitalis” is used to designate the whole group of glycosides.

The glycosides are composed of two portions: a sugar and a cardenolide (hence “glycosides”).

Digoxin has the chemical name: 3β-[(O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-2,6-dideoxy-β-D-ribo-hexopyranosyl)oxy]-12β,14-dihydroxy-5β-card-20(22)-enolide, and the following structural formula: Digoxin exists as odorless white crystals that melt with decomposition above 230°C.

The drug is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine.

Digoxin Injection is a sterile solution for slow intravenous or deep intramuscular injection.

Each mL contains digoxin 250 mcg (0.25 mg), alcohol 0.1 mL, propylene glycol 0.4 mL, dibasic sodium phosphate, anhydrous 3 mg and citric acid, anhydrous 0.8 mg in Water for Injection.

pH 6.7-7.3; citric acid and/or sodium phosphate added, if necessary, for pH adjustment.

Dilution is not required.

Formula1.jpg

CLINICAL STUDIES

14.1 Chronic Heart Failure Two 12-week, double-blind, placebo-controlled studies enrolled 178 (RADIANCE trial) and 88 (PROVED trial) adult patients with NYHA Class II or III heart failure previously treated with oral digoxin, a diuretic, and an ACE inhibitor (RADIANCE only) and randomized them to placebo or treatment with Digoxin Tablets.

Both trials demonstrated better preservation of exercise capacity in patients randomized to digoxin.

Continued treatment with digoxin reduced the risk of developing worsening heart failure, as evidenced by heart failure-related hospitalizations and emergency care and the need for concomitant heart failure therapy.

DIG Trial of Digoxin in Patients with Heart Failure The Digitalis Investigation Group (DIG) main trial was a 37-week, multicenter, randomized, double-blind mortality study comparing digoxin to placebo in 6800 adult patients with heart failure and left ventricular ejection fraction less than or equal to 0.45.

At randomization, 67% were NYHA class I or II, 71% had heart failure of ischemic etiology, 44% had been receiving digoxin, and most were receiving a concomitant ACE inhibitor (94%) and diuretics (82%).

As in the smaller trials described above, patients who had been receiving open-label digoxin were withdrawn from this treatment before randomization.

Randomization to digoxin was again associated with a significant reduction in the incidence of hospitalization, whether scored as number of hospitalizations for heart failure (relative risk 75%), risk of having at least one such hospitalization during the trial (RR 72%), or number of hospitalizations for any cause (RR 94%).

On the other hand, randomization to digoxin had no apparent effect on mortality (RR 99%, with confidence limits of 91-107%).

14.2 Chronic Atrial Fibrillation Digoxin has also been studied as a means of controlling the ventricular response to chronic atrial fibrillation in adults.

Digoxin reduced the resting heart rate, but not the heart rate during exercise.

In 3 different randomized, double-blind trials that included a total of 315 adult patients, digoxin was compared to placebo for the conversion of recent-onset atrial fibrillation to sinus rhythm.

Conversion was equally likely, and equally rapid, in the digoxin and placebo groups.

In a randomized 120-patient trial comparing digoxin, sotalol, and amiodarone, patients randomized to digoxin had the lowest incidence of conversion to sinus rhythm, and the least satisfactory rate control when conversion did not occur.

In at least one study, digoxin was studied as a means of delaying reversion to atrial fibrillation in adult patients with frequent recurrence of this arrhythmia.

This was a randomized, double-blind, 43-patient crossover study.

Digoxin increased the mean time between symptomatic recurrent episodes by 54%, but had no effect on the frequency of fibrillatory episodes seen during continuous electrocardiographic monitoring.

HOW SUPPLIED

/STORAGE AND HANDLING Digoxin Injection, USP is available as: 500 mcg/2 mL (250 mcg/mL) ampuls packaged in 25s (NDC 0641-1410-35) Store at 20˚-25˚C (68˚-77˚F), excursions permitted to 15˚-30˚C (59˚-86˚F) [see USP Controlled Room Temperature].

Protect from light.

DOSAGE FORMS AND STRENGTHS

Digoxin Injection: Ampuls of 500 mcg (0.5 mg) in 2 mL (250 mcg [0.25] per 1 mL).

Digoxin Injection: Ampuls containing 500 mcg (0.5 mg) in 2 mL.

(3)

INDICATIONS AND USAGE

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use digoxin safely and effectively.

See full prescribing information for digoxin.

Digoxin Injection, for intravenous or intramuscular use Initial U.S.

Approval: 1954 1.1 Heart Failure in Adults Digoxin is indicated for the treatment of mild to moderate heart failure in adults.

Digoxin increases left ventricular ejection fraction and imporves heart failure symptoms, as evidenced by improves heart failure symptoms, as evidenced by improved exercise capacity and decreased heart failure-related hospitalizations and emergency care, while having no effect on mortality.

Where possible, digoxin should be used in combination with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor.

1.2 Atrial Fibrillation in Adults Digoxin is indicated for the control of ventricular response rate in adult patients with chronic atrial fibrillation.

Digoxin is a cardiac glycoside indicated for: Treatment of mild to moderate heart failure in adults.

(1.1) Control of resting ventricular rate in adults with chronic artial fibrillation.

(1.2)

WARNING AND CAUTIONS

WARNINGS AND PRECAUTIONS 5.1 Ventricular Fibrillation in Patients With Accessory AV Pathway (Wolff-Parkinson-White Syndrome) Patients with Wolff-Parkinson-White syndrome who develop atrial fibrillation are at high risk of ventricular fibrillation.

Treatment of these patients with digoxin leads to greater slowing of conduction in the atrioventricular node than in accessory pathways, and the risks of rapid ventricular response leading to ventricular fibrillation are thereby increased.

5.2 Sinus Bradycardia and Sino-atrial Block Digoxin may cause severe sinus bradycardia or sino-atrial block particularly in patients with pre-existing sinus node disease and may cause advanced or complete heart block in patients with pre-existing incomplete AV block.

Consider insertion of a pacemake before treatment with digoxin.

5.3 Digoxin Toxicity Signs and symptoms of digoxin toxicity include anorexia, nausea, vomiting, visual changes and cardiac arrhythmias [first-degree, second-degree (Wenckebach), or third-degree heart block (including asystole); atrial tachycardia with block; av dissociation; accelerated junctional (nodal) rhythm; unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy); ventricular tachycardia; and ventricular fibrillation].

Toxicity is usuallyassociated with digoxin levels greater than 2 ng/mL although symptoms may also occur at lower levels.

Low body weight, advanced age or impaired renal function, hypomagnesemia may predispose to digoxin toxicity.

Obtain serum digoxin levels in patients with signs or symptoms of digoxin therapy and interrupt or adjust dose if necessary [ see Adverse Reactions (6) and Overdosage (10) ].

Assess serum electrolytes and renal function periodically.

The earliest and most frequent manifestation of digoxin toxicity in infants and children is the appearance of cardiac arrhythmias, including sinus bradycardia.

In children, the use of digoxin may product any arrhythmia.

The most common are conduction disturbances or supraventricular tacharrhythmias, such as atrial tachycardia (with or without block) and junctional (nodal) tachycardia.

Ventricular arrhythmias are less common.

Sinus bradycardia may be a sign of impending digoxin intoxication, especially in infants, even in the absence of first-degree heart block.

Any arrhythmias or alteration in cardiac conduction that develops in a child taking digoxin should initially be assumed to be a consequence of digoxin intoxication.

Given that adult patients with heart failure have some sympotoms in common with digoxin toxicity, it may be difficult to distinguish digoxin toxicity from heart failure.

Misidentification of their etiology might lead the clinician to continue or increase digoxin dosing, when dosing should actually be suspended.

When the itiology of these signs and symptoms is not clear, measure serum digoxin levels.

5.4 Risk of Ventricular Arrhythmias During Electrical Cardioversion It may be desirable to reduce the dose of or discontinue digoxin for 1-2 days prior to electrical cardioversion of atrial fibrillation to avoid the induction of ventricular arrhythmias, but physicians must consider the consequenc3es of increasing the ventricular response if digoxin is decreased or withdrawn.

If digitalis toxicity is suspected, elective cardioversion should be delayed.

If it is not prudent to delay cardioversion, the lowest possible energy level should be selected to avoid provoking ventricular arrhythmias.

5.5 Risk of Ischemia in Patients With Acute Myocardial Infarction Digoxin is not recommended in patients with acute myocardial infarction because digoxin may increase myocardial oxygen demand and lead to ischemia.

5.6 Vasoconstriction in Patients With Myocarditis Digoxin can precipitate vasoconstriction and may promote production of pro-inflammatory cytokines; therefore, avoid use in patients with myocarditis.

5.7 Decreased Cardiac Output in Patients With Preserved Left Ventricular Systolic Function Patients with heart failure associated with preserved left ventricular ejection fraction may experience decreased cardiac output with use of digoxin.

Such disorders include restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, and acute cor pulmonate.

Patients with idiopathic hypertrophic subaortic stenosis may have worsening of the outflow obstruction due to the inotropic effects of digoxin.

Patients with amyloid heart disease may be ore susceptible to digoxin toxicity effects of digoxin.

Patients with amyloid heart disease may be more susceptible to digoxin toxicity at therapeutic levels because of an increased binding of digoxin to extracellular amyloid fibrils.

Digoxin should generally be avoided in these patients, although it has been used for ventricular rate control in the subgroup of patients with atrial fibrillation.

5.8 Reduced Efficacy in Patients With Hypocalcemia Hypocalcemia can nullify the effects of digoxin in humans; thus, digoxin may be ineffective until serum calcium is restored to normal.

These interactions are related to the fact that digoxin affects contractility and excitability of the heart in a manner similar to that of calcium.

5.9 Altered Response in Thyroid Disorders and Hypermetabolic States Hypothyroidism may reduce the requirements for digoxin.

Heart failure and/or atrial arrhythmias resulting from hypermetabolic or hyperdynamic states (e.g., hyperthyroidism, hyposia, or arteriovenous shunt) are best treated by addressing the underlying condition.

Atrial arrhythmias associated with hypermetabollic states are particularly resistant to digoxin treatment.

Patients with beri beri heart disease may fail to respond adequately to digoxin if the underlying thiamine deficiency is not treated concomitantly.

Risk of rapid ventricular response leading to ventricular fibrillation in patients with AV accessory pathway.

(5.1) Risk of advanced or complete heart block in patients with sinus node disease and AV block.

(5.2) Digoxin toxicity: Indicated by nausea, vomiting, visual disturbances, and cardiac arrhythmias.

Advanced age, low body weight, impaired renal function and electrolyte abnormalities predispose to toxicity.

(5.3) Risk of ventricular arrhythmias during electrical cardioversion.

(5.4) Not recommended in patients with acute myocardial infarction.

(5.5) Avoid digoxin in patients with myocarditis.

(5.6)

DOSAGE AND ADMINISTRATION

2.1 Important Dosing and Administration Information In selecting a digoxin dosing regimen, it is important to consider factors that affect digoxin blood levels (e.g., body weight, age, renal function, concomitant drugs) since toxic levels of digoxin are only slightlyhigher than therapeutic levels.

Dosing can be either initiated with a loading dose followed by maintenance dosing if rapid titration is desired or initiated with maintenance dosing without a loading dose.

Parenteral administration of digoxin should be used only when the need for rapid digitalization is urgent or when the drug cannot be taken orallly.

Intramuscular injection can lead to severe pain at the injection site, thus intravenous administration is preferred.

If the drug must be administered by the intramuscular route, it should be injected deep into the muscle followed by massage.

For adults, no more than 500 mcg of Digoxin Injection should be injected into a single site.

For pediatric patients, see the full prescribing information for pediatric digoxin injection (not available from West-Ward) for specific recommendations.

Administer the dose over a period of 5 minutes or longer and avoid bolus administration to prevent systemic and coronary vasoconstriction.

Mixing of Digoxin Injection with other drugs in the same container or simultaneous administration in the same intravenous line is not recommended.

Digoxin Injection can be administered undiluted or diluted with a 4-fold or greater volume of Sterile Water for Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection.

The use of less than a 4 fold-volume of diluent could lead to precipitation of the digoxin.

Immediate use of the diluted product is recommended.

If tuberculin syringes are used to measure very small doses do not flush with the parenteral solution after its contents are expelled into an indwelling vascular catheter to avoid over administration of digoxin.

Consider interruption or reduction in digoxin dose prior to electriclal cardioversion [see Warnings and Precautions (5.4)].

2.2 Loading Dosing Regimen in Adult Patients 2.3 Maintenance Dosing in Adult Patients The maintenance dose is based on lead body weight, renal function, age, and concomitant products [ see Clinical Pharmacology (12.3)].

The recommended starting maintenance dose in adult patients with normal renal function is given in Table 2.

Doses may be increased every 2 weeks according to clinical response, serum drug levels and toxicity.

Table 3 provides the recommended (once daily) maintenance dose for adult patients according to lean body weight and renal function.

The doses are based on studies in adult patients with heart failure.

Alternatively, the maintenance dose may be estimated by the following formula (peak body stores lost each day through elimination): Total Maintenance Dose = Loading Dose (i.e., Peak Body Stores) x % Daily Loss/100 (%Daily Loss = 14 + Creatinine clearance/5) Reduce the dose of digoxin in patients whose lean weight is an abnormally small fraction of their total body mass because of obesity or edema.

2.4 Monitoring to Assess Safety, Efficacy, and Therapeutic Blood Levels Monitor for signs and symptoms of digoxin toxicity and clinical response.

Adjust dose based on toxicity, efficacy, and blood vessels.

Serum digoxin levels less than 0.5 ng/nL have been associated with diminished efficacy, while levels above 2 ng/mL have been associated with increased toxicity without increased benefit.

Interpret the serum digoxin concentration in the overall clinical context, and do not use an isolated measurement of serum digoxin concentration as the basis for increasing or decreasing the digoxin dose.

Serum digoxin concentrations may be falsely elevated by endogenous digoxin-like substances [ see Drug Interactions (7.4)].

If the assay is sensitive to these substances, consider obtaining a baseline digoxin level before starting digoxin and correct post-treatment values by the reported baseline level.

Obtain serum digoxin concentrations just before the next scheduled digoxin dose or at least 6 hours after the last dose.

The digoxin concentration is likely to be 10-25% lower when sampled right before the next dose (24 hours after dosing) compared to sampling 8 hours after dosing (using once-daily dosing).

However, there will be only minor differences in digoxin concentrations using twice daily dosing whether sampling is done at 8 or 12 hours after a dose.

2.5 Switching from Intravenous Digoxin to Oral Digoxin When switching from intravenous to oral digoxin formulations, make allowances for differences in bioavailability when calculating maintenance dosages (see Table 4).

Digoxin dose is based on patient-specific factors (age, lean body weight, renal function, etc.).

See full prescribing information.

Monitor for toxicity and therapeutic effect.

(2) Intravenous administration is preferable to intramuscular.

Avoid bolus administration.

(2) Image1.jpg Image2.jpg Image3.jpg Image4.jpg

dextromethorphan HBr 10 MG / guaifenesin 100 MG / phenylephrine HCl 5 MG per 5 ML Oral Solution

Generic Name: DEXTROMETHORPHAN HYDROBROMIDE, GUAIFENESIN, PHENYLEPHRINE HYDROCHLORIDE

Brand Name: equaline tussin multi symptom

Substance Name(s):
DEXTROMETHORPHAN HYDROBROMIDE
GUAIFENESIN
PHENYLEPHRINE HYDROCHLORIDE

WARNINGS

Warnings Do not use if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug.

If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.

Ask a doctor before use if you have • heart disease • high blood pressure • thyroid disease • diabetes • trouble urinating due to an enlarged prostate gland • cough that occurs with too much phlegm (mucus) • cough that lasts or is chronic such as occurs with smoking, asthma, chronic bronchitis or emphysema When using this product do not use more than directed Stop use and ask a doctor if • you get nervous, dizzy, or sleepless • symptoms do not get better within 7 days or are accompanied by fever • cough lasts more than 7 days, comes back, or is accompanied by fever, rash, or persistent headache.

A persistent cough may be a sign of a serious condition.

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222).

INDICATIONS AND USAGE

Uses • helps loosen phlegm (mucus) and thin bronchial secretions to drain bronchial tubes • temporarily relieves these symptoms occurring with a cold: • nasal congestion • cough due to minor throat and bronchial irritation

INACTIVE INGREDIENTS

Inactive ingredients anhydrous citric acid, edetate disodium, FD&C red no.

40, flavor, glycerin, propylene glycol, purified water, sodium benzoate, sodium citrate, sorbitol solution, sucralose

PURPOSE

Purposes Cough suppressant Expectorant Nasal decongestant

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222).

ASK DOCTOR

DOSAGE AND ADMINISTRATION

Directions • do not take more than 6 doses in any 24-hour period • measure only with dosing cup provided • keep dosing cup with product • mL = milliliter • this adult product is not intended for use in children under 12 years of age age dose adults and children 12 years and over 10 mL every 4 hours children under 12 years do not use

PREGNANCY AND BREAST FEEDING

If pregnant or breast-feeding, ask a health professional before use.

DO NOT USE

Do not use if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug.

If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.

STOP USE

Stop use and ask a doctor if • you get nervous, dizzy, or sleepless • symptoms do not get better within 7 days or are accompanied by fever • cough lasts more than 7 days, comes back, or is accompanied by fever, rash, or persistent headache.

A persistent cough may be a sign of a serious condition.

ACTIVE INGREDIENTS

Active ingredients (in each 10 mL) Dextromethorphan HBr, USP 20 mg Guaifenesin, USP 200 mg Phenylephrine HCl, USP 10 mg

buspirone hydrochloride 5 MG (equivalent to buspirone 4.6 MG) Oral Tablet

WARNINGS

The administration of buspirone to a patient taking a monoamine oxidase inhibitor (MAOI) may pose a hazard .

There have been reports of the occurrence of elevated blood pressure when buspirone has been added to a regimen including an MAOI.

Therefore, it is recommended that buspirone not be used concomitantly with an MAOI.

Because buspirone has no established antipsychotic activity, it should not be employed in lieu of appropriate antipsychotic treatment.

DRUG INTERACTIONS

Drug Interactions Psychotropic Agents MAO Inhibitors : It is recommended that buspirone hydrochloride not be used concomitantly with MAO inhibitors (see WARNINGS ).

Amitriptyline : After addition of buspirone to the amitriptyline dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (C max , AUC, and Cmin) of amitriptyline or its metabolite nortriptyline were observed.

Diazepam : After addition of buspirone to the diazepam dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (C max , AUC, and Cmin) were observed for diazepam, but increases of about 15% were seen for nordiazepam, and minor adverse clinical effects (dizziness, headache, and nausea) were observed.

Haloperidol : In a study in normal volunteers, concomitant administration of buspirone and haloperidol resulted in increased serum haloperidol concentrations.

The clinical significance of this finding is not clear.

Nefazodone : (See Inhibitors and Inducers of Cytochrome P450 3A4 [CYP3A4] ) Trazodone : There is one report suggesting that the concomitant use of trazodone hydrochloride and buspirone may have caused 3- to 6-fold elevations on SGPT (ALT) in a few patients.

In a similar study attempting to replicate this finding, no interactive effect on hepatic transaminases was identified.

Triazolam/Flurazepam : Coadministration of buspirone with either triazolam or flurazepam did not appear to prolong or intensify the sedative effects of either benzodiazepine.

Other Psychotropics : Because the effects of concomitant administration of buspirone with most other psychotropic drugs have not been studied, the concomitant use of buspirone with other CNS-active drugs should be approached with caution.

Inhibitors and Inducers of Cytochrome P450 3A4 (CYP3A4) Buspirone has been shown in vitro to be metabolized by CYP3A4.

This finding is consistent with the in vivo interactions observed between buspirone and the following: Diltiazem and Verapamil : In a study of nine healthy volunteers, coadministration of buspirone (10 mg as a single dose) with verapamil (80 mg t.i.d.) or diltiazem (60 mg t.i.d.) increased plasma buspirone concentrations (verapamil increased AUC and C max of buspirone 3.4-fold while diltiazem increased AUC and C max 5.4-fold and 4-fold, respectively.) Adverse events attributable to buspirone may be more likely during concomitant administration with either diltiazem or verapamil.

Subsequent dose adjustment may be necessary and should be based on clinical assessment.

Erythromycin : In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with erythromycin (1.5 g/day for 4 days) increased plasma buspirone concentrations (5-fold increase in C max and 6-fold increase in AUC).

These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone.

If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg b.i.d.) is recommended.

Subsequent dose adjustment of either drug should be based on clinical assessment.

Grapefruit Juice : In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with grapefruit juice (200 mL double-strength t.i.d.

for 2 days) increased plasma buspirone concentrations (4.3-fold increase in C max ; 9.2-fold increase in AUC).

Patients receiving buspirone should be advised to avoid drinking such large amounts of grapefruit juice.

Itraconazole : In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with itraconazole (200 mg/day for 4 days) increased plasma buspirone concentrations (13-fold increase in C max and 19-fold increase in AUC).

These pharmacokinetic interactions were accompanied by an increased incidence of side effects attributable to buspirone.

If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg every day) is recommended.

Subsequent dose adjustment of either drug should be based on clinical assessment.

Nefazodone : In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of buspirone (2.5 or 5 mg b.i.d.) with nefazodone (250 mg b.i.d.) resulted in marked increases in plasma buspirone concentrations (increases up to 20-fold in C max and up to 50-fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-PP.

With 5 mg b.i.d.

doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (HO-NEF) (17%) and meta-chlorophenylpiperazine (9%).

Slight increases in C max were observed for nefazodone (8%) and its metabolite HO-NEF (11%).

Subjects receiving buspirone 5 mg b.i.d.

and nefazodone 250 mg b.i.d.

experienced lightheadedness, asthenia, dizziness, and somnolence, adverse events also observed with either drug alone.

If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg every day) is recommended.

Subsequent dose adjustment of either drug should be based on clinical assessment.

Rifampin : In a study in healthy volunteers, coadministration of buspirone (30 mg as a single dose) with rifampin (600 mg/day for 5 days) decreased the plasma concentrations (83.7% decrease in C max ; 89.6% decrease in AUC) and pharmacodynamic effects of buspirone.

If the two drugs are to be used in combination, the dosage of buspirone may need adjusting to maintain anxiolytic effect.

Other Inhibitors and Inducers of CYP3A4 : Substances that inhibit CYP3A4, such as ketoconazole or ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism.

If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone or diminished anxiolytic activity.

Consequently, when administered with a potent inhibitor of CYP3A4, a low dose of buspirone used cautiously is recommended.

When used in combination with a potent inducer of CYP3A4 the dosage of buspirone may need adjusting to maintain anxiolytic effect.

OVERDOSAGE

Signs and Symptoms In clinical pharmacology trials, doses as high as 375 mg/day were administered to healthy male volunteers.

As this dose was approached, the following symptoms were observed: nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress.

A few cases of overdosage have been reported, with complete recovery as the usual outcome.

No deaths have been reported following overdosage with buspirone alone.

Rare cases of intentional overdosage with a fatal outcome were invariably associated with ingestion of multiple drugs and/or alcohol, and a causal relationship to buspirone could not be determined.

Toxicology studies of buspirone yielded the following LD50 values: mice, 655 mg/kg; rats, 196 mg/kg; dogs, 586 mg/kg; and monkeys, 356 mg/kg.

These dosages are 160 to 550 times the recommended human daily dose.

Recommended Overdose Treatment General symptomatic and supportive measures should be used along with immediate gastric lavage.

Respiration, pulse, and blood pressure should be monitored as in all cases of drug overdosage.

No specific antidote is known to buspirone, and dialyzability of buspirone has not been determined.

DESCRIPTION

Buspirone hydrochloride is an antianxiety agent that is not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative/anxiolytic drugs.

Buspirone hydrochloride is a white crystalline, water soluble compound with a molecular weight of 422.0.

Chemically, buspirone hydrochloride is 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl]-8-azaspiro[4.5]decane-7,9- dione monohydrochloride.

The empirical formula C 21 H 31 N 5 O 2 • HCl is represented by the following structural formula: Each tablet for oral administration containing 5 mg, 10 mg, or 15 mg of buspirone hydrochloride USP (equivalent to 4.6 mg, 9.1 mg, and 13.7 mg of buspirone free base respectively).

The 5 mg and 10 mg tablets are scored so they can be bisected.

Thus, the 5 mg tablet can also provide a 2.5 mg dose, and the 10 mg tablet can provide a 5 mg dose.

The 15 mg tablet is provided in a special tablet design.

This tablet is scored so it can be either bisected or trisected.

Thus, a single 15 mg tablet can provide the following doses: 15 mg (entire tablet), 10 mg (two thirds of a tablet), 7.5 mg (one half of a tablet), or 5 mg (one third of a tablet).

In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

Buspirone hydrochloride structural formula

HOW SUPPLIED

Product: 63629-3197 NDC: 63629-3197-1 90 TABLET in a BOTTLE NDC: 63629-3197-2 45 TABLET in a BOTTLE NDC: 63629-3197-3 30 TABLET in a BOTTLE NDC: 63629-3197-4 60 TABLET in a BOTTLE NDC: 63629-3197-5 180 TABLET in a BOTTLE

GERIATRIC USE

Geriatric Use In one study of 6632 patients who received buspirone for the treatment of anxiety, 605 patients were ≥ 65 years old and 41 were ≥ 75 years old; the safety and efficacy profiles for these 605 elderly patients (mean age =70.8 years) were similar to those in the younger population (mean age = 43.3 years).

Review of spontaneously reported adverse clinical events has not identified differences between elderly and younger patients, but greater sensitivity of some older patients cannot be ruled out.

There were no effects of age on the pharmacokinetics of buspirone (see CLINICAL PHARMACOLOGY : Special Populations ).

INDICATIONS AND USAGE

Buspirone hydrochloride tablets are indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety.

Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

The efficacy of buspirone has been demonstrated in controlled clinical trials of outpatients whose diagnosis roughly corresponds to Generalized Anxiety Disorder (GAD).

Many of the patients enrolled in these studies also had coexisting depressive symptoms and buspirone relieved anxiety in the presence of these coexisting depressive symptoms.

The patients evaluated in these studies had experienced symptoms for periods of 1 month to over 1 year prior to the study, with an average symptom duration of 6 months.

Generalized Anxiety Disorder (300.02) is described in the American Psychiatric Association’s Diagnostic and Statistical Manual, lll 1 as follows: Generalized, persistent anxiety (of at least 1 month continual duration), manifested by symptoms from three of the four following categories: Motor tension: shakiness, jitteriness, jumpiness, trembling, tension, muscle aches, fatigability, inability to relax, eyelid twitch, furrowed brow, strained face, fidgeting, restlessness, easy startle.

Autonomic hyperactivity: sweating, heart pounding or racing, cold, clammy hands, dry mouth, dizziness, lightheadedness, paresthesias (tingling in hands or feet), upset stomach, hot or cold spells, frequent urination, diarrhea, discomfort in the pit of the stomach, lump in the throat, flushing, pallor, high resting pulse and respiration rate.

Apprehensive expectation: anxiety, worry, fear, rumination, and anticipation of misfortune to self or others.

Vigilance and scanning: hyperattentiveness resulting in distractibility, difficulty in concentrating, insomnia, feeling “on edge”, irritability, impatience.

The above symptoms would not be due to another mental disorder, such as a depressive disorder or schizophrenia.

However, mild depressive symptoms are common in GAD.

The effectiveness of buspirone in long-term use, that is, for more than 3 to 4 weeks, has not been demonstrated in controlled trials.

There is no body of evidence available that systematically addresses the appropriate duration of treatment for GAD.

However, in a study of long-term use, 264 patients were treated with buspirone for 1 year without ill effect.

Therefore, the physician who elects to use buspirone for extended periods should periodically reassess the usefulness of the drug for the individual patient.

PEDIATRIC USE

Pediatric Use The safety and effectiveness of buspirone were evaluated in two placebo-controlled 6-week trials involving a total of 559 pediatric patients (ranging from 6 to 17 years of age) with GAD.

Doses studied were 7.5 mg to 30 mg b.i.d.

(15-60 mg/day).

There were no significant differences between buspirone and placebo with regard to the symptoms of GAD following doses recommended for the treatment of GAD in adults.

Pharmacokinetic studies have shown that, for identical doses, plasma exposure to buspirone and its active metabolite, 1-PP, are equal to or higher in pediatric patients than adults.

No unexpected safety findings were associated with buspirone in these trials.

There are no long-term safety or efficacy data in this population.

PREGNANCY

Pregnancy: Teratogenic Effects Pregnancy Category B: No fertility impairment or fetal damage was observed in reproduction studies performed in rats and rabbits at buspirone doses of approximately 30 times the maximum recommended human dose.

In humans, however, adequate and well-controlled studies during pregnancy have not been performed.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

NUSRING MOTHERS

Nursing Mothers The extent of the excretion in human milk of buspirone or its metabolites is not known.

In rats, however, buspirone and its metabolites are excreted in milk.

Buspirone administration to nursing women should be avoided if clinically possible.

INFORMATION FOR PATIENTS

Information for Patients To assure safe and effective use of buspirone hydrochloride tablets, the following information and instructions should be given to patients: Inform your physician about any medications, prescription or non-prescription, alcohol, or drugs that you are now taking or plan to take during your treatment with buspirone.

Inform your physician if you are pregnant, or if you are planning to become pregnant, or if you become pregnant while you are taking buspirone.

Inform your physician if you are breast-feeding an infant.

Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery.

You should take buspirone consistently, either always with or always without food.

During your treatment with buspirone, avoid drinking large amounts of grapefruit juice.

DOSAGE AND ADMINISTRATION

The recommended initial dose is 15 mg daily (7.5 mg b.i.d.).

To achieve an optimal therapeutic response, at intervals of 2 to 3 days the dosage may be increased 5 mg per day, as needed.

The maximum daily dosage should not exceed 60 mg per day.

In clinical trials allowing dose titration, divided doses of 20 mg to 30 mg per day were commonly employed.

The bioavailability of buspirone is increased when given with food as compared to the fasted state (see CLINICAL PHARMACOLOGY ).

Consequently, patients should take buspirone in a consistent manner with regard to the timing of dosing; either always with or always without food.

When buspirone is to be given with a potent inhibitor of CYP3A4 the dosage recommendations described in the PRECAUTIONS : Drug Interactions section should be followed.

vancomycin (as vancomycin hydrochloride) 100 MG/ML Injectable Solution

Generic Name: VANCOMYCIN HYDROCHLORIDE

Brand Name: Vancomycin

Substance Name(s):
VANCOMYCIN HYDROCHLORIDE

WARNINGS

Infusion Reactions Rapid bolus administration (e.g., over several minutes) may be associated with exaggerated hypotension, including shock and rarely cardiac arrest.

Vancomycin hydrochloride should be administered in a diluted solution over a period of not less than 60 minutes to avoid rapid-infusion-related reactions.

Stopping the infusion usually results in prompt cessation of these reactions.

Nephrotoxicity Systemic vancomycin exposure may result in acute kidney injury (AKI).

The risk of AKI increases as systemic exposure/serum levels increase.

Monitor renal function in all patients, especially patients with underlying renal impairment, patients with co-morbidities that predispose to renal impairment, and patients receiving concomitant therapy with a drug known to be nephrotoxic.

Ototoxicity Ototoxicity has occurred in patients receiving vancomycin hydrochloride.

It may be transient or permanent.

It has been reported mostly in patients who have been given excessive doses, who have an underlying hearing loss, or who are receiving concomitant therapy with another ototoxic agent, such as an aminoglycoside.

Vancomycin should be used with caution in patients with renal insufficiency because the risk of toxicity is appreciably increased by high, prolonged blood concentrations.

Dosage of vancomycin hydrochloride must be adjusted for patients with renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ).

Severe Dermatologic Reactions Severe dermatologic reactions such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and linear IgA bullous dermatosis (LABD) have been reported in association with the use of vancomycin.

Cutaneous signs or symptoms reported include skin rashes, mucosal lesions, and blisters.

Discontinue vancomycin hydrochloride at the first appearance of signs and symptoms of TEN, SJS, DRESS, AGEP, or LABD.

Clostridium Difficile Associated Diarrhea (CDAD) Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Vancomycin Hydrochloride for Injection, USP, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.

difficile .

difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains of C.

difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.

difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.

difficile , and surgical evaluation should be instituted as clinically indicated.

Hemorrhagic Occlusive Retinal Vasculitis (HORV) Hemorrhagic occlusive retinal vasculitis, including permanent loss of vision, occurred in patients receiving intracameral or intravitreal administration of vancomycin during or after cataract surgery.

The safety and efficacy of vancomycin administered by the intracameral or the intravitreal route have not been established by adequate and well-controlled trials.

Vancomycin is not indicated for the prophylaxis of endophthalmitis.

DRUG INTERACTIONS

Drug Interactions Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing (see Pediatric Use – PRECAUTIONS ) and anaphylactoid reactions (see ADVERSE REACTIONS ).

Monitor renal function in patients receiving vancomycin and concurrent and/or sequential systemic or topical use of other potentially, neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides, bacitracin, polymyxin B, colistin, viomycin, or cisplatin.

OVERDOSAGE

Supportive care is advised, with maintenance of glomerular filtration.

Vancomycin is poorly removed by dialysis.

Hemofiltration and hemoperfusion with polysulfone resin have been reported to result in increased vancomycin clearance.

The median lethal intravenous dose is 319 mg/kg in rats and 400 mg/kg in mice.

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center.

Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR).

In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

DESCRIPTION

Vancomycin Hydrochloride for Injection, USP is an off white to buff-colored lyophilized powder, for preparing intravenous (IV) infusions, in Pharmacy Bulk Package bottles containing the equivalent of 5 grams or 10 grams vancomycin base.

500 mg of the base are equivalent to 0.34 mmol.

When reconstituted with Sterile Water for Injection to a concentration of 50 mg per mL for the 5 gram Pharmacy Bulk Package bottle and 100 mg per mL for the 10 gram Pharmacy Bulk Package bottle, the pH of the solution is between 2.5 and 4.5.

Vancomycin Hydrochloride for Injection, USP should be administered intravenously in diluted solution (see DOSAGE AND ADMINISTRATION ).

Vancomycin Hydrochloride for Injection, USP is a tricyclic glycopeptide antibiotic derived from Amycolatopasis orientalis (formerly Nocardia orientalis ).

The chemical name for vancomycin hydrochloride is ( S a )-( 3S , 6R,7R,22R,23S , 26S , 36R,38aR )-44-[[2- O -(3-Amino- 2,3,6-trideoxy-3- C -methyl-α-L- lyxo -hexopyranosyl)-β-D-glucopyranosyl]oxy]-3-(carbamoylmethyl)-10,19-dichloro-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro- 7,22,28,30,32-pentahydroxy-6-[( 2R )-4-methyl-2-(methylamino)]valeramido]-2,5,24,38,39-pentaoxo- 22H -8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno- 1H , 16H -[1,6,9]oxadiazacyclohexadecino[4,5- m ][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid, monohydrochloride.

The molecular formula is C 66 H 75 Cl 2 N 9 O 24 •HCl and the molecular weight is 1,485.73.

Vancomycin hydrochloride has the following structural formula: A pharmacy bulk package is a container of a sterile preparation for parenteral use that contains many single doses.

The contents of this pharmacy bulk package are intended for use by a pharmacy admixture service for addition to suitable parenteral fluids in the preparation of admixtures for intravenous infusion (see DOSAGE AND ADMINISTRATION, Directions for Proper Use of Pharmacy Bulk Package ).

FURTHER DILUTION IS REQUIRED.

NOT FOR DIRECT INFUSION.

Structural Formula

HOW SUPPLIED

/STORAGE AND HANDLING Vancomycin Hydrochloride for Injection, USP Pharmacy Bulk Package bottle, is supplied as follows: NDC Vancomycin Hydrochloride for Injection, USP Package Factor 25021-157-99 5 gram Pharmacy Bulk Package Bottle 1 bottle per carton (equivalent to 5 grams vancomycin) 25021-158-99 10 gram Pharmacy Bulk Package Bottle 1 bottle per carton (equivalent to 10 grams vancomycin)

GERIATRIC USE

Geriatric Use The natural decrement of glomerular filtration with increasing age may lead to elevated vancomycin serum concentrations if dosage is not adjusted.

Vancomycin dosage schedules should be adjusted in elderly patients (see DOSAGE AND ADMINISTRATION ).

INDICATIONS AND USAGE

Vancomycin Hydrochloride for Injection, USP is indicated for the treatment of serious or severe infections caused by susceptible strains of methicillin-resistant (β-lactam-resistant) staphylococci.

It is indicated for penicillin-allergic patients, for patients who cannot receive or who have failed to respond to other drugs, including the penicillins or cephalosporins, and for infections caused by vancomycin-susceptible organisms that are resistant to other antimicrobial drugs.

Vancomycin Hydrochloride for Injection, USP is indicated for initial therapy when methicillin-resistant staphylococci are suspected, but after susceptibility data are available, therapy should be adjusted accordingly.

Vancomycin Hydrochloride for Injection, USP is effective in the treatment of staphylococcal endocarditis.

Its effectiveness has been documented in other infections due to staphylococci, including septicemia, bone infections, lower respiratory tract infections, skin and skin structure infections.

When staphylococcal infections are localized and purulent, antibiotics are used as adjuncts to appropriate surgical measures.

Vancomycin Hydrochloride for Injection, USP has been reported to be effective alone or in combination with an aminoglycoside for endocarditis caused by S.

viridans or S.

bovis .

For endocarditis caused by enterococci (e.g., E.

faecalis ), Vancomycin Hydrochloride for Injection, USP has been reported to be effective only in combination with an aminoglycoside.

Vancomycin Hydrochloride for Injection, USP has been reported to be effective for the treatment of diphtheroid endocarditis.

Vancomycin Hydrochloride for Injection, USP has been used successfully in combination with either rifampin, an aminoglycoside, or both in early-onset prosthetic valve endocarditis caused by S.

epidermidis or diphtheroids.

Specimens for bacteriologic cultures should be obtained in order to isolate and identify causative organisms and to determine their susceptibilities to vancomycin hydrochloride.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Vancomycin Hydrochloride for Injection, USP and other antibacterial drugs, Vancomycin Hydrochloride for Injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

The parenteral form of Vancomycin Hydrochloride for Injection, USP may be administered orally for treatment of antibiotic-associated pseudomembranous colitis produced by C.

difficile and for staphylococcal enterocolitis.

Parenteral administration of vancomycin hydrochloride alone is of unproven benefit for these indications.

Vancomycin is not effective by the oral route for other types of infections.

PEDIATRIC USE

Pediatric Use In pediatric patients, it may be appropriate to confirm desired vancomycin serum concentrations.

Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing in pediatric patients (see PRECAUTIONS ).

PREGNANCY

Pregnancy Teratogenic Effects Animal reproduction studies have not been conducted with vancomycin.

It is not known whether vancomycin can affect reproduction capacity.

In a controlled clinical study, the potential ototoxic and nephrotoxic effects of vancomycin hydrochloride on infants were evaluated when the drug was administered to pregnant women for serious staphylococcal infections complicating intravenous drug abuse.

Vancomycin hydrochloride was found in cord blood.

No sensorineural hearing loss or nephrotoxicity attributable to vancomycin hydrochloride was noted.

One infant whose mother received vancomycin in the third trimester experienced conductive hearing loss that was not attributed to the administration of vancomycin.

Because the number of patients treated in this study was limited and vancomycin hydrochloride was administered only in the second and third trimesters, it is not known whether vancomycin hydrochloride causes fetal harm.

Vancomycin should be given to a pregnant woman only if clearly needed.

NUSRING MOTHERS

Nursing Mothers Vancomycin hydrochloride is excreted in human milk.

Caution should be exercised when vancomycin hydrochloride is administered to a nursing woman.

Because of the potential for adverse events, 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.

INFORMATION FOR PATIENTS

Information for Patients Severe Dermatologic Reactions Advise patients about the signs and symptoms of serious skin manifestations.

Instruct patients to stop Vancomycin Hydrochloride for Injection, USP immediately and promptly seek medical attention at the first signs or symptoms of skin rash, mucosal lesions and blisters (see WARNINGS ).

Patients should be counseled that antibacterial drugs including Vancomycin Hydrochloride for Injection, USP should only be used to treat bacterial infections.

They do not treat viral infections (e.g., the common cold).

When Vancomycin Hydrochloride for Injection, USP is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Vancomycin Hydrochloride for Injection, USP or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued.

Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic.

If this occurs, patients should contact their physician as soon as possible.

DOSAGE AND ADMINISTRATION

The intent of the pharmacy bulk package for this product is for preparation of solutions for IV infusion only.

Infusion-related events are related to both the concentration and the rate of administration of vancomycin.

Concentrations of no more than 5 mg per mL and rates of no more than 10 mg/min, are recommended in adults (see also age-specific recommendations).

In selected patients in need of fluid restriction, a concentration up to 10 mg per mL may be used; use of such higher concentrations may increase the risk of infusion-related events.

An infusion rate of 10 mg/min or less is associated with fewer infusion-related events (see ADVERSE REACTIONS ).

Infusion-related events may occur, however, at any rate or concentration.

Patients With Normal Renal Function Adults The usual daily intravenous dose is 2 grams divided either as 500 mg every 6 hours or 1 gram every 12 hours.

Each dose should be administered at no more than 10 mg/min or over a period of at least 60 minutes, whichever is longer.

Other patient factors, such as age or obesity, may call for modification of the usual intravenous daily dose.

Pediatric patients The usual intravenous dosage of vancomycin is 10 mg/kg per dose given every 6 hours.

Each dose should be administered over a period of at least 60 minutes.

Close monitoring of serum concentrations of vancomycin may be warranted in these patients.

Neonates In pediatric patients up to the age of 1 month, the total daily intravenous dosage may be lower.

In neonates, an initial dose of 15 mg/kg is suggested, followed by 10 mg/kg every 12 hours for neonates in the 1 st week of life and every 8 hours thereafter up to the age of 1 month.

Each dose should be administered over 60 minutes.

In premature infants, vancomycin clearance decreases as postconceptional age decreases.

Therefore, longer dosing intervals may be necessary in premature infants.

Close monitoring of serum concentrations of vancomycin is recommended in these patients.

Patients With Impaired Renal Function and Elderly Patients Dosage adjustment must be made in patients with impaired renal function.

In premature infants and the elderly, greater dosage reductions than expected may be necessary because of decreased renal function.

Measurement of vancomycin serum concentrations can be helpful in optimizing therapy, especially in seriously ill patients with changing renal function.

Vancomycin serum concentrations can be determined by use of microbiologic assay, radioimmunoassay, fluorescence polarization immunoassay, fluorescence immunoassay, or high-pressure liquid chromatography.

If creatinine clearance can be measured or estimated accurately, the dosage for most patients with renal impairment can be calculated using the following table.

The dosage of vancomycin per day in mg is about 15 times the glomerular filtration rate in mL/min (see following table).

DOSAGE TABLE FOR VANCOMYCIN IN PATIENTS WITH IMPAIRED RENAL FUNCTION (Adapted from Moellering et al.

1 ) Creatinine Clearance mL/min Vancomycin Dose mg/24 hr 100 1,545 90 1,390 80 1,235 70 1,080 60 925 50 770 40 620 30 465 20 310 10 155 The initial dose should be no less than 15 mg/kg, even in patients with mild to moderate renal insufficiency.

The table is not valid for functionally anephric patients.

For such patients, an initial dose of 15 mg/kg of body weight should be given to achieve prompt therapeutic serum concentrations.

The dose required to maintain stable concentrations is 1.9 mg/kg/24 hr.

In patients with marked renal impairment, it may be more convenient to give maintenance doses of 250 to 1,000 mg once every several days rather than administering the drug on a daily basis.

In anuria, a dose of 1,000 mg every 7 to 10 days has been recommended.

When only serum creatinine is known, the following formula (based on sex, weight and age of the patient) may be used to calculate creatinine clearance.

Calculated creatinine clearances (mL/min) are only estimates.

The creatinine clearance should be measured promptly.

The serum creatinine must represent a steady state of renal function.

Otherwise, the estimated value for creatinine clearance is not valid.

Such a calculated clearance is an overestimate of actual clearance in patients with conditions: (1) characterized by decreasing renal function, such as shock, severe heart failure, or oliguria; (2) in which a normal relationship between muscle mass and total body weight is not present, such as in obese patients or those with liver disease, edema, or ascites; and (3) accompanied by debilitation, malnutrition, or inactivity.

The safety and efficacy of vancomycin administration by the intrathecal (intralumbar or intraventricular) routes have not been established.

Intermittent infusion is the recommended method of administration.

Figure Compatibility with Other Drugs and IV Fluids The following diluents are physically and chemically compatible (with 4 g/L vancomycin hydrochloride): 5% Dextrose Injection, USP 5% Dextrose Injection and 0.9% Sodium Chloride Injection, USP Lactated Ringer’s Injection, USP 5% Dextrose and Lactated Ringer’s Injection Normosol ® -M and 5% Dextrose 0.9% Sodium Chloride Injection, USP Isolyte ® E Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible.

Vancomycin solution has a low pH and may cause physical instability of other compounds.

Mixtures of solutions of vancomycin and beta-lactam antibiotics have been shown to be physically incompatible.

The likelihood of precipitation increases with higher concentrations of vancomycin.

It is recommended to adequately flush the intravenous lines between the administration of these antibiotics.

It is also recommended to dilute solutions of vancomycin to 5 mg per mL or less.

Although intravitreal injection is not an approved route of administration for vancomycin, precipitation has been reported after intravitreal injection of vancomycin and ceftazidime for endophthalmitis using different syringes and needles.

The precipitates dissolved gradually, with complete clearing of the vitreous cavity over two months and with improvement of visual acuity.

insulin, human isophane / insulin regular 70/30 Injectable Suspension

WARNINGS

INDICATIONS AND USAGE

Talk to your healthcare provider if you have any questions.

Your healthcare provider should show you how to inject Novolin 70/30 before you start taking it.

Follow your healthcare provider’s instructions to make changes to your insulin dose.

Read the instructions for use that come with your Novolin 70/30 product.

® ® • Take Novolin 70/30 exactly as prescribed.

® The effects of Novolin 70/30 start working ½ hour after injection.

• Novolin 70/30 is an intermediate-acting insulin.

® ® The greatest blood sugar lowering effect is between 2 and 12 hours after the injection.

This blood sugar lowering may last up to 24 hours.

• , any change of insulin should be made cautiously and only under medical supervision.

Doses of oral anti-diabetic medicines may also need to change, if your insulin is changed.

• While using Novolin 70/30 ® with any insulins.

• Do not mix Novolin 70/30 ® Novolin 70/30 may affect your blood sugar levels sooner if you inject it into the skin of your stomach area.

• Inject Novolin 70/30 into the skin of your stomach area, upper arms, buttocks or upper legs.

® ® Never inject Novolin 70/30 into a vein or into a muscle.

® • Change (rotate) your injection site within the chosen area (for example, stomach or upper arm) with each dose.

Do not inject into the same spot for each injection.

You can treat mild low blood sugar (hypoglycemia) by drinking or eating something sugary right away (fruit juice, sugar candies, or glucose tablets).

It is important to treat low blood sugar (hypoglycemia) right away because it could get worse and you could pass out (become unconscious).

If you pass out, you will need help from another person or emergency medical services right away, and will need treatment with a glucagon injection or treatment at a hospital.

See “What are the possible side effects of Novolin 70/30?” for more information on low blood sugar (hypoglycemia).

• If you take too much Novolin 70/30, your blood sugar may fall low (hypoglycemia).

® ® If high blood sugar (hyperglycemia) is not treated it can lead to diabetic ketoacidosis, which can lead to serious problems, like loss of consciousness (passing out), coma or even death.

Follow your healthcare provider’s instructions for treating high blood sugar (hyperglycemia), and talk to your healthcare provider if high blood sugar is a problem for you.

Severe or continuing high blood sugar (hyperglycemia) requires prompt evaluation and treatment by your healthcare provider.

Know your symptoms of high blood sugar (hyperglycemia) and diabetic ketoacidosis which may include: • If you forget to take your dose of Novolin 70/30, your blood sugar may go too high (hyperglycemia).

® increased thirst ∘ frequent urination and dehydration ∘ confusion or drowsiness ∘ loss of appetite ∘ fruity smell on breath ∘ high amounts of sugar and ketones in your urine ∘ nausea, vomiting (throwing up) or stomach pain ∘ a hard time breathing ∘ Ask your healthcare provider how often you should check your blood sugar levels for hypoglycemia (too low blood sugar) and hyperglycemia (too high blood sugar).

Check your blood sugar levels.

Your insulin dosage may need to change because of: illness • stress • other medicines you take • change in diet • change in physical activity or exercise • surgery • See the end of this patient information for instructions about preparing and giving the injection.

What should I avoid while using Novolin 70/30? ® Alcohol, including beer and wine, may affect your blood sugar when you take Novolin 70/30.

• Alcohol.

® .

You may have difficulty concentrating or reacting if you have low blood sugar (hypoglycemia).

Be careful when you drive a car or operate machinery.

Ask your healthcare provider if it is alright to drive if you often have: • Driving and operating machinery low blood sugar ∘ decreased or no warning signs of low blood sugar ∘

INACTIVE INGREDIENTS

Novolin 70/30 ingredients include: ® Zinc chloride • Sodium hydroxide • Phenol • Disodium phosphate dihydrate • Metacresol • Glycerol • Hydrochloric acid • Protamine sulfate • Water for injections • All Novolin 70/30 vials are latex-free.

® Date of issue: March 9, 2013 Version: 6 Novolin and Novo Nordisk are registered trademarks of Novo Nordisk A/S.

800 Scudders Mill Road Plainsboro, New Jersey 08536 Patient Instructions for Use Novolin 70/30 10 mL vial (100 Units/mL, U-100) ® Before starting, gather all of the supplies that you will need to use for preparing and giving your insulin injection.

Never re-use syringes and needles.

How should I use the Novolin 70/30 vial? Check to make sure that you have the correct type of insulin.

Look at the vial and the insulin.

The insulin should be a cloudy or milky suspension.

The tamper-resistant cap should be in place before the first use.

If the cap had been removed before your first use of the vial, or if the precipitate (the white deposit at the bottom of the vial) has become lumpy or granular in appearance or has formed a deposit of solid particles on the wall of the vial, do not use it, and call Novo Nordisk at 1-800-727-6500.

Wash your hands with soap and water.

If you clean your injection site with an alcohol swab, let the injection site dry before you inject.

Talk with your healthcare provider about how to rotate injection sites and how to give an injection.

If you are using a new vial, pull off the tamper-resistant cap.

Wipe the rubber stopper with an alcohol swab.

Roll the vial gently 10 times in your hands to mix it.

This procedure should be carried out with the vial in a horizontal position.

The rolling procedure must be repeated until the suspension appears uniformly white and cloudy.

Shaking right before the dose is drawn into the syringe may cause bubbles or froth, which could cause you to draw up the wrong dose of insulin.

Pull back the plunger on the syringe until the black tip reaches the marking for the number of units you will inject.

Push the needle through the rubber stopper of the vial, and push the plunger all the way in to force air into the vial.

Turn the vial and syringe upside down and slowly pull the plunger back to a few units beyond the correct dose.

If there are any air bubbles, tap the syringe gently with your finger to raise the air bubbles to the top.

Then slowly push the plunger to the marking for your correct dose.

This process should move any air bubbles present in the syringe back into the vial.

Check to make sure you have the right dose of Novolin 70/30 in the syringe.

10.

Pull the syringe with needle out of the vial’s rubber stopper.

11.

Your doctor should tell you if you need to pinch the skin before inserting the needle.

This can vary from patient to patient so it is important to ask your doctor if you did not receive instructions on pinching the skin.

Insert the needle into the skin.

Press the plunger of the syringe to inject the insulin.

When you are finished injecting the insulin, pull the needle out of your skin.

You may see a drop of Novolin 70/30 at the needle tip.

This is normal and has no effect on the dose you just received.

If you see blood after you take the needle out of your skin, press the injection site lightly with a piece of gauze or an alcohol wipe.

12.

Do not rub the area.

After your injection, do not recap the needle.

Place used syringes, needles and used insulin vials in a disposable puncture-resistant sharps container, or some type of hard plastic or metal container with a screw on cap such as a detergent bottle or coffee can.

13.

Ask your healthcare provider about the right way to throw away used syringes and needles.

There may be state or local laws about the right way to throw away used syringes and needles.

Do not throw away used needles and syringes in household trash or recycle.

14.

PURPOSE

Important: Do not change the type of insulin you use unless told to do so by your healthcare provider.

The amount of insulin you take as well as the best time for you to take your insulin may need to change if you take a different type of insulin.

Know your insulin.

Make sure that you know the type and strength of insulin that is prescribed for you.

Read the Patient Information leaflet that comes with Novolin 70/30 before you start taking it and each time you get a refill.

There may be new information.

This leaflet does not take the place of talking with your healthcare provider about your diabetes or your treatment.

Make sure you know how to manage your diabetes.

Ask your healthcare provider if you have any questions about managing your diabetes.

® What is Novolin 70/30? ® Novolin 70/30 is a man-made insulin (recombinant DNA origin) which is a mixture of 70% NPH, Human Insulin Isophane Suspension and 30% Regular, Human Insulin Injection that is structurally identical to the insulin produced by the human pancreas that is used to control high blood sugar in patients with diabetes mellitus.

KEEP OUT OF REACH OF CHILDREN

DOSAGE AND ADMINISTRATION

How should I take Novolin 70/30? ® Only use Novolin 70/30 if it appears cloudy or milky.

There may be air bubbles.

This is normal.

If the precipitate (the white deposit at the bottom of the vial) has become lumpy or granular in appearance or has formed a deposit of solid particles on the wall of the vial, do not use it, and call Novo Nordisk at 1-800-727-6500.

This insulin should not be used if the liquid in the vial remains clear after the vial has been gently rotated.

® Novolin 70/30 comes in: ® 10 mL vials (small bottles) for use with syringe •

DO NOT USE

Who should not use Novolin 70/30? ® Do not take Novolin 70/30 if: ® Your blood sugar is too low (hypoglycemia).

• You are allergic to anything in Novolin 70/30.

See the end of this leaflet for a complete list of ingredients in Novolin 70/30.

Check with your healthcare provider if you are not sure.

• ® ®

ACTIVE INGREDIENTS

Novolin 70/30 ingredients include: ® 70% NPH, Human Insulin Isophane Suspension and 30% Regular, Human Insulin Injection (recombinant DNA origin) •

ASK DOCTOR OR PHARMACIST

ASK YOUR DOCTOR Tell your healthcare provider: Medical conditions can affect your insulin needs and your dose of Novolin 70/30.

• about all of your medical conditions.

® You and your healthcare provider should talk about the best way to manage your diabetes while you are pregnant or breastfeeding.

Novolin 70/30 has not been studied in pregnant or nursing women.

• if you are pregnant or breastfeeding.

® including prescription and non-prescription medicines, vitamins and herbal supplements.

Many medicines can affect your blood sugar levels and your insulin needs.

Your Novolin 70/30 dose may need to change if you take other medicines.

• about all of the medicines you take, ® • if you take any other medicines, especially ones commonly called TZDs (thiazolidinediones).

If you have heart failure, it may get worse while you take TZDs with Novolin 70/30.

• if you have heart failure or other heart problems.

® Keep a list of your medicines with you to show all your healthcare providers when you get a new medicine.

Know the medicines you take.

isosorbide mononitrate 120 MG 24 HR Extended Release Oral Tablet

WARNINGS

Amplification of the vasodilatory effects of isosorbide mononitrate by sildenafil can result in severe hypotension.

The time course and dose dependence of this interaction have not been studied.

Appropriate supportive care has not been studied, but it seems reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central volume expansion.

The benefits of ISMN in patients with acute myocardial infarction or congestive heart failure have not been established; because the effects of isosorbide mononitrate are difficult to terminate rapidly, this drug is not recommended in these settings.

If isosorbide mononitrate is used in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia.

DRUG INTERACTIONS

Drug interactions The vasodilating effects of isosorbide mononitrate may be additive with those of other vasodilators.

Alcohol, in particular, has been found to exhibit additive effects of this variety.

Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination.

Dose adjustments of either class of agents may be necessary.

OVERDOSAGE

Hemodynamic Effects The ill effects of isosorbide mononitrate overdose are generally the result of isosorbide mononitrate’s capacity to induce vasodilatation, venous pooling, reduced cardiac output, and hypotension.

These hemodynamic changes may have protean manifestations, including increased intracranial pressure, with any or all of persistent throbbing headache, confusion, and moderate fever; vertigo, palpitations; visual disturbances; nausea and vomiting (possibly with colic and even bloody diarrhea); syncope (especially in the upright posture); air hunger and dyspnea, later followed by reduced ventilatory effort; diaphoresis, with the skin either flushed or cold and clammy; heart block and bradycardia; paralysis; coma; seizures and death.

Laboratory determinations of serum levels of isosorbide mononitrate and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of isosorbide mononitrate overdose.

There are no data suggesting what dose of isosorbide mononitrate is likely to be life threatening in humans.

In rats and mice, there is significant lethality at doses of 2000 mg/kg and 3000 mg/kg, respectively.

No data are available to suggest physiological maneuvers (eg, maneuvers to change the pH of the urine) that might accelerate elimination of isosorbide mononitrate.

In particular, dialysis is known to be ineffective in removing isosorbide mononitrate from the body.

No specific antagonist to the vasodilator effects of isosorbide mononitrate is known, and no intervention has been subject to controlled study as a therapy of isosorbide mononitrate overdose.

Because the hypotension associated with isosorbide mononitrate overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward an increase in central fluid volume.

Passive elevation of the patient’s legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary.

The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than good.

In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard.

Treatment of isosorbide mononitrate overdose in these patients may be subtle and difficult, and invasive monitoring may be required.

Methemoglobinemia Methemoglobinemia has been reported in patients receiving other organic nitrates, and it probably could also occur as a side effect of isosorbide mononitrate.

Certainly nitrate ions liberated during metabolism of isosorbide mononitrate can oxidize hemoglobin into methemoglobin.

Even in patients totally without cytochrome b 5 reductase activity, however, and even assuming that the nitrate moiety of isosorbide mononitrate is quantitatively applied to oxidation of hemoglobin, about 2 mg/kg of isosorbide mononitrate should be required before any of these patients manifest clinically significant (≥10%) methemoglobinemia.

In patients with normal reductase function, significant production of methemoglobin should require even larger doses of isosorbide mononitrate.

In one study in which 36 patients received 2-4 weeks of continuous nitroglycerin therapy at 3.1 to 4.4 mg/hr (equivalent, in total administered dose of nitrate ions, to 7.8-11.1 mg of isosorbide mononitrate per hour), the average methemoglobin level measured was 0.2%; this was comparable to that observed in parallel patients who received placebo.

Notwithstanding these observations, there are case reports of significant methemoglobinemia in association with moderate overdoses of organic nitrates.

None of the affected patients had been thought to be unusually susceptible.

Methemoglobin levels are available from most clinical laboratories.

The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial pO 2 .

Classically, methemoglobinemic blood is described as chocolate brown without color change on exposure to air.

When methemoglobinemia is diagnosed, the treatment of choice is methylene blue, 1-2 mg/kg intravenously.

DESCRIPTION

Isosorbide mononitrate (ISMN), an organic nitrate and the major biologically active metabolite of isosorbide dinitrate (ISDN), is a vasodilator with effects on both arteries and veins.

Each tablet, for oral administration, contains either 30 mg, 60 mg or 120 mg of isosorbide mononitrate in an extended-release formulation.

In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and talc.

The molecular formula of ISMN is C 6 H 9 NO 6 and the molecular weight is 191.14.

The chemical name for ISMN is 1,4:3,6-dianhydro-,D-glucitol 5-nitrate; the compound has the following structural formula: ISMN is a white, crystalline, odorless compound which is stable in air and in solution, has a melting point of about 90°C, and an optical rotation of +144° (2% in water, 20°C).

Isosorbide mononitrate is freely soluble in water, ethanol, methanol, chloroform, ethyl acetate, and dichloromethane.

Structural Formula

HOW SUPPLIED

Isosorbide Mononitrate Extended-Release Tablets, USP 30 mg are white, capsule-shaped tablets scored on one side and engraved “KU 128” on the unscored side.

They are supplied as follows: Bottles of 30 NDC 54868-4416-0 Bottles of 60 NDC 54868-4416-1 Bottles of 90 NDC 54868-4416-4 Bottles of 100 NDC 54868-4416-3 Isosorbide Mononitrate Extended-Release Tablets, USP 60 mg are white, capsule-shaped tablets scored on one side and engraved “KU 119” on the unscored side.

They are supplied as follows: Bottles of 30 NDC 54868-4417-0 Bottles of 60 NDC 54868-4417-1 Bottles of 100 NDC 54868-4417-2 Store at 20°-30°C (68°-86°F) [See USP].

Distributed by: Kremers Urban Pharmaceuticals Inc.

Princeton, NJ 08540, USA L3958L Rev.

4E 01/2011 Relabeling and Repackaging by: Physicians Total Care, Inc.

Tulsa, Oklahoma 74146

GERIATRIC USE

Geriatric use Clinical studies of isosorbide mononitrate extended-release tablets did not include sufficient information on patients age 65 and over to determine whether they respond differently from younger patients.

Other reported clinical experience for isosorbide mononitrate extended-release tablets has not identified differences in response between elderly and younger patients.

Clinical experience for organic nitrates reported in the literature identified a potential for severe hypotension and increased sensitivity to nitrates in the elderly.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Elderly patients may have reduced baroreceptor function and may develop severe orthostatic hypotension when vasodilators are used.

Isosorbide Mononitrate Extended-Release Tablets should therefore be used with caution in elderly patients who may be volume depleted, on multiple medications or who, for whatever reason, are already hypotensive.

Hypotension induced by isosorbide mononitrate may be accompanied by paradoxical bradycardia and increased angina pectoris.

Elderly patients may be more susceptible to hypotension and may be at a greater risk of falling at therapeutic doses of nitroglycerin.

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy, particularly in the elderly.

INDICATIONS AND USAGE

Isosorbide Mononitrate Extended-Release Tablets are indicated for the prevention of angina pectoris due to coronary artery disease.

The onset of action of oral isosorbide mononitrate is not sufficiently rapid for this product to be useful in aborting an acute anginal episode.

PEDIATRIC USE

Pediatric use The safety and effectiveness of ISMN in pediatric patients have not been established.

PREGNANCY

Pregnancy Teratogenic effects Pregnancy Category B In studies designed to detect effects of isosorbide mononitrate on embryo-fetal development, doses of up to 240 or 248 mg/kg/day, administered to pregnant rats and rabbits, were unassociated with evidence of such effects.

These animal doses are about 100 times the maximum recommended human dose (120 mg in a 50 kg woman) when comparison is based on body weight; when comparison is based on body surface area, the rat dose is about 17 times the human dose and the rabbit dose is about 38 times the human dose.

There are, however, no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, Isosorbide Mononitrate Extended-Release Tablets should be used during pregnancy only if clearly needed.

Nonteratogenic effects Neonatal survival and development and incidence of stillbirths were adversely affected when pregnant rats were administered oral doses of 750 (but not 300) mg isosorbide mononitrate/kg/day during late gestation and lactation.

This dose (about 312 times the human dose when comparison is based on body weight and 54 times the human dose when comparison is based on body surface area) was associated with decreases in maternal weight gain and motor activity and evidence of impaired lactation.

NUSRING MOTHERS

Nursing mothers It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when ISMN is administered to a nursing mother.

INFORMATION FOR PATIENTS

Information for patients Patients should be told that the antianginal efficacy of Isosorbide Mononitrate Extended-Release Tablets can be maintained by carefully following the prescribed schedule of dosing.

For most patients, this can be accomplished by taking the dose on arising.

As with other nitrates, daily headaches sometimes accompany treatment with isosorbide mononitrate.

In patients who get these headaches, the headaches are a marker of the activity of the drug.

Patients should resist the temptation to avoid headaches by altering the schedule of their treatment with isosorbide mononitrate, since loss of headache may be associated with simultaneous loss of antianginal efficacy.

Aspirin or acetaminophen often successfully relieves isosorbide mononitrate-induced headaches with no deleterious effect on isosorbide mononitrate’s antianginal efficacy.

Treatment with isosorbide mononitrate may be associated with light-headedness on standing, especially just after rising from a recumbent or seated position.

This effect may be more frequent in patients who have also consumed alcohol.

DOSAGE AND ADMINISTRATION

The recommended starting dose of Isosorbide Mononitrate Extended-Release Tablets is 30 mg (given as a single 30 mg tablet or as 1/2 of a 60 mg tablet) or 60 mg (given as a single tablet) once daily.

After several days, the dosage may be increased to 120 mg (given as a single 120 mg tablet or as two 60 mg tablets) once daily.

Rarely, 240 mg may be required.

The daily dose of Isosorbide Mononitrate Extended-Release Tablets should be taken in the morning on arising.

Isosorbide Mononitrate Extended-Release Tablets should not be chewed or crushed and should be swallowed together with a half-glassful of fluid.

Do not break the 30 mg tablet.

benazepril HCl 5 MG Oral Tablet

DRUG INTERACTIONS

7 • Diuretics: Excessive drop in blood pressure ( 7.1 ) • Antidiabetics: Increased risk of hypoglycemia ( 7.2 ) • NSAIDS: Increased risk of renal impairment and loss of antihypertensive efficacy ( 7.3 ) • Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension and hyperkalemia ( 7.4 ) • Lithium: Symptoms of lithium toxicity ( 7.6 ) • Neprilysin Inhibitor: Increased risk of angioedema (7.7) • Gold: Nitritoid reactions (7.8) 7.1 Diuretics Hypotension Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with benazepril hydrochloride.

The possibility of hypotensive effects with benazepril hydrochloride can be minimized by either discontinuing or decreasing the dose of diuretic prior to initiation of treatment with benazepril hydrochloride [see Dosage and Administration ( 2.1 )].

Hyperkalemia Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) can increase the risk of hyperkalemia.

Therefore, if concomitant use of such agents is indicated, monitor the patient’s serum potassium frequently.

Benazepril hydrochloride attenuates potassium loss caused by thiazide-type diuretics.

7.2 Antidiabetics Concomitant administration of benazepril hydrochloride and antidiabetic medicines (insulins, oral hypoglycemic agents) may increase the risk of hypoglycemia.

7.3 Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible acute renal failure.

These effects are usually reversible.

Monitor renal function periodically in patients receiving benazepril and NSAID therapy.

The antihypertensive effect of ACE inhibitors, including benazepril, may be attenuated by NSAIDs.

7.4 Dual Blockade of the Renin-Angiotensin System (RAS) Dual Blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.

Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy.

In general, avoid combined use of RAS inhibitors.

Closely monitor blood pressure, renal function and electrolytes in patients on benazepril hydrochloride and other agents that affect the RAS.

Do not coadminister aliskiren with benazepril hydrochloride in patients with diabetes.

Avoid use of aliskiren with benazepril hydrochloride in patients with renal impairment (GFR ˂60 mL/min).

7.5 Mammalian Target of Rapamycin (mTOR) Inhibitors Patients receiving coadministration of ACE inhibitor and mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema.

Monitor for signs of angioedema [see Warnings and Precautions ( 5.2 )].

7.6 Lithium Lithium toxicity has been reported in patients receiving lithium concomitantly with benazepril hydrochloride.

Lithium toxicity was usually reversible upon discontinuation of lithium or benazepril hydrochloride.

Monitor serum lithium levels during concurrent use.

7.7 Neprilysin Inhibitor Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema [see Warnings and Precautions].

7.8 Gold Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy.

OVERDOSAGE

10 Single oral doses of 3 g/kg benazepril were associated with significant lethality in mice.

Rats, however, tolerated single oral doses of up to 6 g/kg.

Reduced activity was seen at 1 g/kg in mice and at 5 g/kg in rats.

Human overdoses of benazepril have not been reported, but the most common manifestation of human benazepril overdosage is likely to be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution.

Hypotension can be associated with electrolyte disturbances and renal failure.

Benazepril is only slightly dialyzable, but consider dialysis to support patients with severely impaired renal function [see Warnings and Precautions ( 5.3 )].

If ingestion is recent, consider activated charcoal.

Consider gastric decontamination (e.g., vomiting, gastric lavage) in the early period after ingestion.

Monitor for blood pressure and clinical symptoms.

Supportive management should be employed to ensure adequate hydration and to maintain systemic blood pressure.

In the case of marked hypotension, infuse physiological saline solution; as needed, consider vasopressors (e.g., catecholamines i.v.).

DESCRIPTION

11 Benazepril hydrochloride, USP is a white to off-white crystalline powder, soluble (>100 mg/mL) in water, in ethanol, and in methanol.

Its chemical name is benazepril 3-[[1-(ethoxy-carbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1 H -1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is: Its molecular formula is C 24 H 28 N 2 O 5 •HCl, and its molecular weight is 460.96.

Benazeprilat, the active metabolite of benazepril, is a non-sulfhydryl angiotensin-converting enzyme inhibitor.

Benazepril hydrochloride tablets, USP contain 5 mg, 10 mg, 20 mg, and 40 mg of benazepril hydrochloride for oral administration.

The inactive ingredients are lactose monohydrate, microcrystalline cellulose, pregelatinized starch (corn), hydrogenated castor oil, crospovidone, colloidal silicon dioxide, zinc stearate, hypromellose, titanium dioxide, polyethylene glycol 400 and polysorbate 80.

The 5 mg and 10 mg tablets also contain D&C yellow No.

10 and FD&C yellow No.

The 20 mg tablets also contain FD&C red No.

40 and FD&C yellow No.

The 40 mg tablets also contain FD&C red No.

40.

Structure

CLINICAL STUDIES

14 Hypertension Adult Patients In single-dose studies, benazepril hydrochloride lowered blood pressure within 1 hour, with peak reductions achieved between 2 and 4 hours after dosing.

The antihypertensive effect of a single dose persisted for 24 hours.

In multiple-dose studies, once-daily doses of between 20 mg and 80 mg decreased seated pressure 24 hours after dosing by about 6 mmHg to 12 mmHg systolic and 4 mmHg to 7 mmHg diastolic.

The trough values represent reductions of about 50% of that seen at peak.

Four dose-response studies using once-daily dosing were conducted in 470 mild-to-moderate hypertensive patients not using diuretics.

The minimal effective once-daily dose of benazepril hydrochloride was 10 mg; but further falls in blood pressure, especially at morning trough, were seen with higher doses in the studied dosing range (10 mg to 80 mg).

In studies comparing the same daily dose of benazepril hydrochloride given as a single morning dose or as a twice-daily dose, blood pressure reductions at the time of morning trough blood levels were greater with the divided regimen.

The antihypertensive effects of benazepril hydrochloride were not appreciably different in patients receiving high-or low-sodium diets.

In normal human volunteers, single doses of benazepril caused an increase in renal blood flow but had no effect on glomerular filtration rate.

Use of benazepril hydrochloride in combination with thiazide diuretics gives a blood-pressure-lowering effect greater than that seen with either agent alone.

By blocking the renin-angiotensin-aldosterone axis, administration of benazepril hydrochloride tends to reduce the potassium loss associated with the diuretic.

Pediatric Patients In a clinical study of 107 pediatric patients, 7 to 16 years of age, with either systolic or diastolic pressure above the 95th percentile, patients were given 0.1 mg/kg or 0.2 mg/kg then titrated up to 0.3 mg/kg or 0.6 mg/kg with a maximum dose of 40 mg once daily.

After four weeks of treatment, the 85 patients whose blood pressure was reduced on therapy were then randomized to either placebo or benazepril and were followed up for an additional two weeks.

At the end of two weeks, blood pressure (both systolic and diastolic) in children withdrawn to placebo rose by 4 mmHg to 6 mmHg more than in children on benazepril.

No dose-response was observed.

HOW SUPPLIED

16 /STORAGE AND HANDLING Benazepril Hydrochloride Tablets, USP, for oral administration, are packaged with a desiccant and available as 5 mg Yellow-orange, round, biconvex, film-coated tablets, debossed “ E ” over “5” on one side and plain on the other side and supplied as: NDC 68788-6361-3 bottles of 30 NDC 68788-6361-6 bottles of 60 NDC 68788-6361-9 bottles of 90 NDC 68788-6361-1 bottles of 100 NDC 68788-6361-8 bottles of 120 Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Protect from moisture.

Dispense contents in a tight, light-resistant container as defined in the USP with a child-resistant closure, as required.

KEEP TIGHTLY CLOSED.

KEEP THIS AND ALL MEDICATION OUT OF THE REACH OF CHILDREN.

GERIATRIC USE

8.4 Geriatric Use Of the total number of patients who received benazepril in U.S.

clinical studies of benazepril hydrochloride, 18% were 65 or older while 2% were 75 or older.

No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Benazepril and benazeprilat are substantially excreted by the kidney.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration ( 2.2 )].

DOSAGE FORMS AND STRENGTHS

3 Tablets: 5 mg, 10 mg, 20 mg, and 40 mg • Each 5 mg tablet is yellow-orange, round, biconvex, film-coated tablets, debossed “E” over “5” on one side and plain on the other.

• Each 10 mg tablet is orange, round, biconvex, film-coated tablets, debossed “E” over “53” on one side and plain on the other.

• Each 20 mg tablet is pink, round, biconvex, film-coated tablets, debossed “E” over “82” on one side and plain on the other.

• Each 40 mg tablet is red, round, biconvex, film-coated tablets, debossed “E” over “48” on one side and plain on the other.

• Tablets: 5 mg, 10 mg, 20 mg, 40 mg

MECHANISM OF ACTION

12.1 Mechanism of Action Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals.

Benazeprilat has much greater ACE inhibitory activity than does benazepril.

ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II.

Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.

Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion.

The latter decrease may result in a small increase of serum potassium.

Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.

In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.

ACE is identical to kininase, an enzyme that degrades bradykinin.

Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of benazepril hydrochloride remains to be elucidated.

While the mechanism through which benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an antihypertensive effect even in patients with low-renin hypertension.

INDICATIONS AND USAGE

1 Benazepril hydrochloride tablets, USP are indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

Many patients will require more than one drug to achieve blood pressure goals.

For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits.

The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.

Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in Black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).

These considerations may guide selection of therapy.

It may be used alone or in combination with thiazide diuretics.

Benazepril hydrochloride is an angiotensin-converting enzyme (ACE) inhibitor indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

( 1 )

PEDIATRIC USE

8.3 Pediatric Use The antihypertensive effects of benazepril hydrochloride have been evaluated in a double-blind study in pediatric patients 7 to 16 years of age [see Clinical Pharmacology ( 12.3 )].

The pharmacokinetics of benazepril hydrochloride has been evaluated in pediatric patients 6 to 16 years of age [see Clinical Pharmacology ( 12.3 )].

Infants below the age of 1 year should not be given benazepril hydrochloride because of the risk of effects on kidney development.

Safety and effectiveness of benazepril hydrochloride have not been established in pediatric patients less than 6 years of age or in children with glomerular filtration rate less than 30 mL/min/1.73m 2 [see Dosage and Administration ( 2.1 ) and Clinical Pharmacology ( 12.3 )].

Neonates with a History of in utero Exposure to Benazepril Hydrochloride If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers with another ACE inhibitor, but experience is limited.

PREGNANCY

8.1 Pregnancy Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue benazepril hydrochloride as soon as possible.

These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy.

Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin angiotensin system from other antihypertensive agents.

Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.

Perform serial ultrasound examinations to assess the intra-amniotic environment.

If oligohydramnios is observed, discontinue benazepril hydrochloride, unless it is considered lifesaving for the mother.

Fetal testing may be appropriate, based on the week of pregnancy.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Closely observe infants with histories of in utero exposure to benazepril hydrochloride for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations ( 8.3 )].

NUSRING MOTHERS

8.2 Nursing Mothers Minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with benazepril.

A newborn child ingesting entirely breast milk would receive less than 0.1% of the mg/kg maternal dose of benazepril and benazeprilat.

BOXED WARNING

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue benazepril hydrochloride tablets as soon as possible.

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions ( 5.1 ) ] .

WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning.

When pregnancy is detected, discontinue benazepril hydrochloride as soon as possible.

( 5.1 ) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

( 5.1 )

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Angioedema: Discontinue benazepril hydrochloride and treat appropriately.

( 5.2 ) • Monitor renal function periodically.

( 5.3 ) • Monitor blood pressure after initiation.

( 5.4 ) • Hyperkalemia: Monitor serum potassium periodically.

( 5.5 ) • Hepatic toxicity: Monitor for jaundice or signs of liver failure.

( 5.6 ) 5.1 Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue benazepril hydrochloride as soon as possible [see Use in Specific Populations ( 8.1 )].

5.2 Angioedema and Anaphylactoid Reactions Angioedema Head and Neck Angioedema Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx including some fatal reactions, have occurred in patients treated with benazepril hydrochloride.

Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery.

Benazepril hydrochloride should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms of angioedema has occurred.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor [see Contraindications ( 4 )] .

ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients.

Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema [see Drug Interactions ( 7.7 )].

Intestinal Angioedema Intestinal angioedema has occurred in patients treated with ACE inhibitors.

These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.

In some cases, the angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor.

Anaphylactoid Reactions Anaphylactoid Reactions During Desensitization Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions.

Anaphylactoid Reactions During Dialysis Sudden and potentially life threatening anaphylactoid reactions have occurred in some patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor.

In such patients, dialysis must be stopped immediately, and aggressive therapy for anaphylactoid reactions must be initiated.

Symptoms have not been relieved by antihistamines in these situations.

In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

5.3 Impaired Renal Function Monitor renal function periodically in patients treated with benazepril hydrochloride.

Changes in renal function, including acute renal failure, can be caused by drugs that inhibit the renin-angiotensin system.

Patients whose renal function may depend on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, post-myocardial infarction, or volume depletion) may be at particular risk of developing acute renal failure on benazepril hydrochloride.

Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on benazepril hydrochloride.

5.4 Hypotension Benazepril hydrochloride can cause symptomatic hypotension, sometimes complicated by oliguria, progressive azotemia acute renal failure or death.

Patients at risk of excessive hypotension include those with the following conditions or characteristics: heart failure with systolic blood pressure below 100 mmHg, ischemic heart disease, cerebrovascular disease, hyponatremia, high dose diuretic therapy, renal dialysis, or severe volume and/or salt depletion of any etiology.

In such patients, follow closely for the first 2 weeks of treatment and whenever the dose of benazepril or diuretic is increased.

Avoid use of benazepril hydrochloride in patients who are hemodynamically unstable after acute MI.

Surgery/Anesthesia In patients undergoing major surgery or during anesthesia with agents that produce hypotension, benazepril hydrochloride may block angiotensin II formation secondary to compensatory renin release.

If hypotension occurs, correct by volume expansion.

5.5 Hyperkalemia Serum potassium should be monitored periodically in patients receiving benazepril hydrochloride.

Drugs that inhibit the renin angiotensin system can cause hyperkalemia.

Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes [see Drug Interactions ( 7.1 )].

5.6 Hepatic Failure ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death.

The mechanism of this syndrome is not understood.

Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Pregnancy Tell female patients of childbearing age about the consequences of exposure to benazepril hydrochloride during pregnancy.

Discuss treatment options with women planning to become pregnant.

Instruct patients to report pregnancies to their physicians as soon as possible.

Angioedema Angioedema, including laryngeal edema, can occur at any time with treatment with ACE inhibitors.

Tell patients to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drugs until they have consulted with the prescribing physician.

Symptomatic Hypotension Tell patients to report light-headedness especially during the first few days of therapy.

If actual syncope occurs, tell the patient to discontinue the drug until they have consulted with the prescribing physician.

Tell patients that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of a reduction in fluid volume.

Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; advise patients accordingly.

Hyperkalemia Tell patients not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.

Hypoglycemia Tell diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor to monitor for hypoglycemia closely, especially during the first month of combined use.

Distributed by Sandoz Inc.

Princeton, NJ 08540 0S8016 Rev.

September 2017 MF0505REV09/17 Repackaged By: Preferred Pharmaceuticals Inc.

DOSAGE AND ADMINISTRATION

2 • Adult Patients: Initiate with 10 mg once daily (or 5 mg if patient is on diuretic).

Titrate to 40 mg daily based on blood pressure response.

( 2.1 ) • Pediatric patients age 6 years and above with glomerular filtration rate (GFR) >30 mL/min/1.73 m 2 : Initiate with 0.2 mg/kg once daily.

Maximum dose is 0.6 mg/kg once daily.

• Renal Impairment: Initiate with 5 mg once daily in patients with GFR ˂30 mL/min/1.73 m 2 (serum creatinine >3 mg/dL) ( 2.2 ) 2.1 Recommended Dosage Adults The recommended initial dose for patients not receiving a diuretic is 10 mg once a day.

The usual maintenance dosage range is 20 mg to 40 mg per day administered as a single dose or in two equally divided doses.

A dose of 80 mg gives an increased response, but experience with this dose is limited.

The divided regimen was more effective in controlling trough (pre-dosing) blood pressure than the same dose given as a once-daily regimen.

Use With Diuretics in Adults The recommended starting dose of benazepril hydrochloride tablets in a patient on a diuretic is 5 mg once daily.

If blood pressure is not controlled with benazepril hydrochloride tablets alone, a low dose of diuretic may be added.

Pediatric Patients 6 Years of Age and Older The recommended starting dose for pediatric patients is 0.2 mg/kg once per day.

Titrate as needed to 0.6 mg/kg once per day.

Doses above 0.6 mg/kg (or in excess of 40 mg daily) have not been studied in pediatric patients.

Benazepril hydrochloride tablets are not recommended in pediatric patients less than 6 years of age or in pediatric patients with GFR less than 30 mL/min/1.73 m 2 [see Use in Specific Populations ( 8.3 )].

2.2 Dosage Adjustment for Renal Impairment For adults with a GFR ˂30 mL/min/1.73 m 2 (serum creatinine >3 mg/dL), the recommended initial dose is 5 mg benazepril hydrochloride tablets once daily.

Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 40 mg.

Benazepril hydrochloride tablets can also worsen renal function [see Warnings and Precautions ( 5.3 )].

2.3 Preparation of Suspension (for 150 mL of a 2 mg/mL Suspension) Add 75 mL of Ora-Plus ®* oral suspending vehicle to an amber polyethylene terephthalate (PET) bottle containing fifteen benazepril hydrochloride tablets, 20 mg tablets, and shake for at least two minutes.

Allow the suspension to stand for a minimum of 1 hour.

After the standing time, shake the suspension for a minimum of one additional minute.

Add 75 mL of Ora-Sweet ®* oral syrup vehicle to the bottle and shake the suspension to disperse the ingredients.

The suspension should be refrigerated at 2° to 8°C (36° to 46°F) and can be stored for up to 30 days in the PET bottle with a child-resistant screw-cap closure.

Shake the suspension before each use.

* Ora-Plus ® and Ora-Sweet ® are registered trademarks of Paddock Laboratories, Inc.

Ora Plus ® contains carrageenan, citric acid, methylparaben, microcrystalline cellulose, carboxymethylcellulose sodium, potassium sorbate, simethicone, sodium phosphate monobasic, xanthan gum, and water.

Ora-Sweet® contains citric acid, berry citrus flavorant, glycerin, methylparaben, potassium sorbate, sodium phosphate monobasic, sorbitol, sucrose, and water.

Advil Cold & Sinus Non-Drowsy 200 MG / 30 MG Oral Capsule

Generic Name: IBUPROFEN, PSEUDOEPHEDRINE HYDROCHLORIDE

Brand Name: ADVIL COLD AND SINUS

Substance Name(s):
IBUPROFEN
PSEUDOEPHEDRINE HYDROCHLORIDE

WARNINGS

Warnings Allergy alert: Ibuprofen may cause a severe allergic reaction, especially in people allergic to aspirin.

Symptoms may include: • hives • facial swelling • asthma (wheezing) • shock • skin reddening • rash • blisters If an allergic reaction occurs, stop use and seek medical help right away.

Stomach bleeding warning: This product contains an NSAID, which may cause severe stomach bleeding.

The chance is higher if you: • are age 60 or older • have had stomach ulcers or bleeding problems • take a blood thinning (anticoagulant) or steroid drug • take other drugs containing prescription or nonprescription NSAIDs [aspirin, ibuprofen, naproxen, or others] • have 3 or more alcoholic drinks every day while using this product • take more or for a longer time than directed Heart attack and stroke warning: NSAIDs, except aspirin, increase the risk of heart attack, heart failure, and stroke.

These can be fatal.

The risk is higher if you use more than directed or for longer than directed.

Do not use • in children under 12 years of age • if you have ever had an allergic reaction to any other pain reliever/fever reducer • right before or after heart surgery • if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug.

If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.

Ask a doctor before use if • stomach bleeding warning applies to you • you have problems or serious side effects from taking pain relievers or fever reducers • you have a history of stomach problems, such as heartburn • you have high blood pressure, heart disease, liver cirrhosis, kidney disease, asthma, thyroid disease, diabetes, have trouble urinating due to an enlarged prostate gland, or had a stroke • you are taking a diuretic Ask a doctor or pharmacist before use if you are • under a doctor’s care for any serious condition • taking any other product that contains pseudoephedrine or any other nasal decongestant • taking aspirin for heart attack or stroke, because ibuprofen may decrease this benefit of aspirin • taking any other drug When using this product • take with food or milk if stomach upset occurs Stop use and ask a doctor if • you experience any of the following signs of stomach bleeding: • feel faint • vomit blood • have bloody or black stools • have stomach pain that does not get better • you have symptoms of heart problems or stroke: • chest pain • trouble breathing • weakness in one part or side of body • slurred speech • leg swelling • fever gets worse or lasts more than 3 days • nasal congestion lasts for more than 7 days • symptoms continue or get worse • redness or swelling is present in the painful area • you get nervous, dizzy, or sleepless • any new symptoms appear If pregnant or breast-feeding, ask a health professional before use.

It is especially important not to use ibuprofen at 20 weeks or later in pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

INDICATIONS AND USAGE

Uses temporarily relieves these symptoms associated with the common cold or flu: • headache • fever • sinus pressure • nasal congestion • minor body aches and pains

INACTIVE INGREDIENTS

Inactive ingredients D&C yellow no.

10, FD&C red no.

40, gelatin, medium-chain triglycerides, pharmaceutical ink, polyethylene glycol, potassium hydroxide, purified water, sorbitol sorbitan solution

PURPOSE

Purposes Pain reliever/fever reducer Nasal decongestant

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

ASK DOCTOR

DOSAGE AND ADMINISTRATION

Directions • do not take more than directed • the smallest effective dose should be used • adults and children 12 years of age and over: • take 1 capsule every 4 to 6 hours while symptoms persist.

If symptoms do not respond to 1 capsule, 2 capsules may be used.

• do not use more than 6 capsules in any 24-hour period unless directed by a doctor • children under 12 years of age: do not use

PREGNANCY AND BREAST FEEDING

If pregnant or breast-feeding, ask a health professional before use.

DO NOT USE

If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.

STOP USE

Stop use and ask a doctor if • you experience any of the following signs of stomach bleeding: • feel faint • vomit blood • have bloody or black stools • have stomach pain that does not get better • you have symptoms of heart problems or stroke: • chest pain • trouble breathing • weakness in one part or side of body • slurred speech • leg swelling • fever gets worse or lasts more than 3 days • nasal congestion lasts for more than 7 days • symptoms continue or get worse • redness or swelling is present in the painful area • you get nervous, dizzy, or sleepless • any new symptoms appear

ACTIVE INGREDIENTS

Active ingredients (in each liquid-filled capsule) Solubilized ibuprofen equal to 200 mg ibuprofen (NSAID)* (present as the free acid and potassium salt) Pseudoephedrine HCl 30 mg *nonsteroidal anti-inflammatory drug

ASK DOCTOR OR PHARMACIST

Ask a doctor or pharmacist before use if you are • under a doctor’s care for any serious condition • taking any other product that contains pseudoephedrine or any other nasal decongestant • taking aspirin for heart attack or stroke, because ibuprofen may decrease this benefit of aspirin • taking any other drug

Advil Cold & Sinus Non-Drowsy 200 MG / 30 MG Oral Capsule

Generic Name: IBUPROFEN, PSEUDOEPHEDRINE HYDROCHLORIDE

Brand Name: ADVIL COLD AND SINUS

Substance Name(s):
IBUPROFEN
PSEUDOEPHEDRINE HYDROCHLORIDE

WARNINGS

Warnings Allergy alert: Ibuprofen may cause a severe allergic reaction, especially in people allergic to aspirin.

Symptoms may include: • hives • facial swelling • asthma (wheezing) • shock • skin reddening • rash • blisters If an allergic reaction occurs, stop use and seek medical help right away.

Stomach bleeding warning: This product contains an NSAID, which may cause severe stomach bleeding.

These can be fatal.

The risk is higher if you use more than directed or for longer than directed.

If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

INDICATIONS AND USAGE

Uses temporarily relieves these symptoms associated with the common cold or flu: • headache • fever • sinus pressure • nasal congestion • minor body aches and pains

INACTIVE INGREDIENTS

Inactive ingredients D&C yellow no.

10, FD&C red no.

40, gelatin, medium-chain triglycerides, pharmaceutical ink, polyethylene glycol, potassium hydroxide, purified water, sorbitol sorbitan solution

PURPOSE

Purposes Pain reliever/fever reducer Nasal decongestant

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

ASK DOCTOR

DOSAGE AND ADMINISTRATION

If symptoms do not respond to 1 capsule, 2 capsules may be used.

• do not use more than 6 capsules in any 24-hour period unless directed by a doctor • children under 12 years of age: do not use

PREGNANCY AND BREAST FEEDING

If pregnant or breast-feeding, ask a health professional before use.

DO NOT USE

If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.