Drug Intercation

prazosin HCl 1 MG Oral Capsule

WARNINGS

As with all alpha-blockers, prazosin hydrochloride may cause syncope with sudden loss of consciousness.

In most cases, this is believed to be due to an excessive postural hypotensive effect, although occasionally the syncopal episode has been preceded by a bout of severe tachycardia with heart rates of 120 to 160 beats per minute.

Syncopal episodes have usually occurred within 30 to 90 minutes of the initial dose of the drug; occasionally, they have been reported in association with rapid dosage increases or the introduction of another antihypertensive drug into the regimen of a patient taking high doses of prazosin hydrochloride.

The incidence of syncopal episodes is approximately 1% in patients given an initial dose of 2 mg or greater.

Clinical trials conducted during the investigational phase of this drug suggest that syncopal episodes can be minimized by limiting the initial dose of the drug to 1 mg, by subsequently increasing the dosage slowly, and by introducing any additional antihypertensive drugs into the patient’s regimen with caution (see DOSAGE AND ADMINISTRATION).

Hypotension may develop in patients given prazosin hydrochloride who are also receiving a beta-blocker such as propranolol.

If syncope occurs, the patient should be placed in the recumbent position and treated supportively as necessary.

This adverse effect is self-limiting and in most cases does not recur after the initial period of therapy or during subsequent dose titration.

Patients should always be started on the prazosin hydrochloride capsules, 1 mg.

The 2 and 5 mg capsules are not indicated for initial therapy.

More common than loss of consciousness are the symptoms often associated with lowering of the blood pressure, namely, dizziness and lightheadedness.

The patient should be cautioned about these possible adverse effects and advised what measures to take should they develop.

The patient should also be cautioned to avoid situations where injury could result should syncope occur during the initiation of prazosin hydrochloride therapy.

Priapism Prolonged erections and priapism have been reported with alpha-1 blockers including prazosin in postmarketing experience.

In the event of an erection that persists longer than 4 hours, seek immediate medical assistance.

If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.

DRUG INTERACTIONS

Drug Interactions Prazosin hydrochloride has been administered without any adverse drug interaction in limited clinical experience to date with the following: (1) cardiac glycosides – digitalis and digoxin; (2) hypoglycemics – insulin, chlorpropamide, phenformin, tolazamide, and tolbutamide; (3) tranquilizers and sedatives – chlordiazepoxide, diazepam, and phenobarbital; (4) antigout – allopurinol, colchicine, and probenecid; (5) antiarrhythmics – procainamide, propranolol (see however), and quinidine; and (6) analgesics, antipyretics and anti-inflammatories – propoxyphene, aspirin, indomethacin, and phenylbutazone.

WARNINGS Addition of a diuretic or other antihypertensive agent to prazosin hydrochloride has been shown to cause an additive hypotensive effect.

This effect can be minimized by reducing the prazosin hydrochloride dose to 1 to 2 mg three times a day, by introducing additional antihypertensive drugs cautiously, and then by retitrating prazosin hydrochloride based on clinical response.

Concomitant administration of prazosin hydrochloride with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension (see ).

DOSAGE AND ADMINISTRATION

OVERDOSAGE

Accidental ingestion of at least 50 mg of prazosin in a two-year-old child resulted in profound drowsiness and depressed reflexes.

No decrease in blood pressure was noted.

Recovery was uneventful.

Should overdosage lead to hypotension, support of the cardiovascular system is of first importance.

Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position.

If this measure is inadequate, shock should first be treated with volume expanders.

If necessary, vasopressors should then be used.

Renal function should be monitored and supported as needed.

Laboratory data indicate prazosin hydrochloride is not dialyzable because it is protein bound.

DESCRIPTION

Prazosin hydrochloride, USP a quinazoline derivative, is the first of a new chemical class of antihypertensives.

It is the hydrochloride salt of 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furoyl) piperazine and its structural formula is: C H N O •HCl M.W.

419.87 19 21 5 4 It is a white, crystalline substance, slightly soluble in water and isotonic saline.

Each capsule for oral administration, contains prazosin hydrochloride, USP equivalent to 1 mg, 2 mg or 5 mg of prazosin.

Inactive ingredients include: anhydrous lactose, magnesium stearate, and pregelatinized starch.

Additional inactive ingredients for the gelatin capsule include: 1 mg (Ivory): D&C Yellow No.

10 and titanium dioxide; 2 mg (Pink): FD&C Blue No.

1, FD&C Red No.

40, D&C Red No.

28, and titanium dioxide; 5 mg (Light Blue): FD&C Blue No.

1 and titanium dioxide.

prazosin hydrochloride capsules structural formula

HOW SUPPLIED

NDC:54569-2583-1 in a BOTTLE of 30 CAPSULES

INDICATIONS AND USAGE

Prazosin hydrochloride capsules 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 this drug.

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.

Prazosin hydrochloride capsules USP can be used alone or in combination with other antihypertensive drugs such as diuretics or beta-adrenergic blocking agents.

PEDIATRIC USE

Usage in Children Safety and effectiveness in children have not been established.

PREGNANCY

Usage in Pregnancy Teratogenic Effects Pregnancy category C Prazosin hydrochloride has been shown to be associated with decreased litter size at birth, 1, 4, and 21 days of age in rats when given doses more than 225 times the usual maximum recommended human dose.

No evidence of drug-related external, visceral, or skeletal fetal abnormalities were observed.

No drug-related external, visceral, or skeletal abnormalities were observed in fetuses of pregnant rabbits and pregnant monkeys at doses more than 225 times and 12 times the usual maximum recommended human dose, respectively.

The use of prazosin and a beta-blocker for the control of severe hypertension in 44 pregnant women revealed no drug-related fetal abnormalities or adverse effects.

Therapy with prazosin was continued for as long as 14 weeks.

1 Prazosin has also been used alone or in combination with other hypotensive agents in severe hypertension of pregnancy by other investigators.

No fetal or neonatal abnormalities have been reported with the use of prazosin.

2 There are no adequate and well controlled studies which establish the safety of prazosin hydrochloride in pregnant women.

Prazosin hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

NUSRING MOTHERS

Nursing Mothers Prazosin hydrochloride has been shown to be excreted in small amounts in human milk.

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

INFORMATION FOR PATIENTS

Information for Patients Dizziness or drowsiness may occur after the first dose of this medicine.

Avoid driving or performing hazardous tasks for the first 24 hours after taking this medicine or when the dose is increased.

Dizziness, lightheadedness, or fainting may occur, especially when rising from a lying or sitting position.

Getting up slowly may help lessen the problem.

These effects may also occur if you drink alcohol, stand for long periods of time, exercise, or if the weather is hot.

While taking prazosin hydrochloride, be careful in the amount of alcohol you drink.

Also, use extra care during exercise or hot weather, or if standing for long periods.

Check with your physician if you have any questions.

DOSAGE AND ADMINISTRATION

The dose of prazosin hydrochloride capsules USP should be adjusted according to the patient’s individual blood pressure response.

The following is a guide to its administration: Initial Dose 1 mg two or three times a day (see ).

WARNINGS Maintenance Dose Dosage may be slowly increased to a total daily dose of 20 mg given in divided doses.

The therapeutic dosages most commonly employed have ranged from 6 mg to 15 mg daily given in divided doses.

Doses higher than 20 mg usually do not increase efficacy, however a few patients may benefit from further increases up to a daily dose of 40 mg given in divided doses.

After initial titration some patients can be maintained adequately on a twice daily dosage regimen.

Use With Other Drugs When adding a diuretic or other antihypertensive agent, the dose of prazosin hydrochloride capsules USP should be reduced to 1 mg or 2 mg three times a day and retitration then carried out.

Concomitant administration of prazosin hydrochloride capsules USP with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension; therefore, PDE-5 inhibitor therapy should be initiated at the lowest dose in patients taking prazosin hydrochloride capsules USP.

Fosinopril Sodium 20 MG Oral Tablet

WARNINGS

Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including fosinopril sodium) may be subject to a variety of adverse reactions, some of them serious.

Head and Neck Angioedema: Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in patients treated with ACE inhibitors.

If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal.

If laryngeal stridor or angioedema of the face, lips mucous membranes, tongue, glottis or extremities occurs, treatment with fosinopril sodium should be discontinued and appropriate therapy instituted immediately.

Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) should be promptly administered (see PRECAUTIONS: Information for Patients and ADVERSE REACTIONS ).

Intestinal Angioedema: Intestinal angioedema has been reported 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.

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

Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions.

In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor.

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

Hypotension Fosinopril sodium can cause symptomatic hypotension.

Like other ACE inhibitors, fosinopril has been only rarely associated with hypotension in uncomplicated hypertensive patients.

Symptomatic hypotension is most likely to occur in patients who have been volume-and /or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.

Volume and/or salt depletion should be corrected before initiating therapy with fosinopril sodium.

In patients with heart failure, with our without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and rarely, with acute renal failure and death.

In such patients, fosinopril sodium therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of fosinopril or diuretic is increased.

Consideration should be given to reducing the diuretic dose in patients with normal or low blood pressure who have been treated vigorously with diuretics or who are hyponatremic.

If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline.

Fosinopril sodium treatment usually can be continued following restoration of blood pressure and volume.

Neutropenia / Agranulocytosis Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma.

Available data from clinical trials of fosinopril are insufficient to show that fosinopril does not cause agranulocytosis at similar rates.

Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.

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 fosinopril 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 fosinopril, 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 fosinopril for hypotension, oliguria, and hyperkalemia (see Precautions , Pediatric Use ).

No teratogenic effects of fosinopril were seen in studies of pregnant rats and rabbits.

On a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose.

DRUG INTERACTIONS

Drug Interactions 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.

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

Do not co-administer aliskiren with fosinopril in patients with diabetes.

Avoid use of aliskiren with fosinopril in patients with renal impairment (GFR <60 mL/min).

With diuretics: Patients on diuretics, especially those with intravascular volume depletion, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with fosinopril sodium.

The possibility of hypotensive effects with fosinopril sodium can be minimized by either discontinuing the diuretic or increasing salt intake prior to initiation of treatment with fosinopril sodium.

If this is not possible, the starting dose should be reduced and the patient should be observed closely for several hours following an initial dose and until blood pressure has stabilized.

(see DOSAGE AND ADMINISTRATION ).

With potassium supplements and potassium-sparing diuretics: Fosinopril sodium can attenuate potassium loss caused by thiazide diuretics.

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

Therefore, if concomitant use of such agents is indicated, they should be given with caution, and the patient’s serum potassium should be monitored frequently.

With lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium.

These drugs should be co administered with caution, and frequent monitoring of serum lithium levels is recommended.

If a diuretic is also used, the risk of lithium toxicity may be increased.

With antacids: In a clinical pharmacology study, coadministration of an antacid (aluminum hydroxide, magnesium hydroxide, and simethicone) with fosinopril reduced serum levels and urinary excretion of fosinoprilat as compared with fosinopril administrated alone, suggesting that antacids may impair absorption of fosinopril.

Therefore, if concomitant and administration of these agents is indicated, dosing should be separated by 2 hours.

Other: Neither fosinopril sodium nor its metabolites have been found to interact with food.

In separate single or multiple dose pharmacokinetic interaction studies with chlorthalidone, nifedipine, propranolol, hydrochlorothiazide, cimetidine, metoclopramide, propantheline, digoxin, and warfarin, the bioavailability of fosinoprilat was not altered by coadministration of fosinopril with any one of these drugs.

In study with concomitant administration of aspirin and fosinopril sodium.

The bioavailability of unbound fosinoprilat was not altered.

In a pharmacokinetic interaction study with warfarin, bioavailability parameters, the degree of protein binding, and the anticoagulant effect (measured by prothrombin time) of warfarin were not significantly changed.

OVERDOSAGE

Oral doses of fosinopril at 2600 mg/kg in rats were associated with significant lethality.

Human overdoses of fosinopril have not been reported, but the most common manifestation of human fosinopril over dosage is likely to hypotension.

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

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of fosinopril and its metabolites.

Fosinoprilat is poorly removed from the body by both hemodialysis and peritoneal dialysis.

Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of fosinopril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities.

Because the hypotensive effect of fosinopril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat fosinopril overdose by infusion of normal saline solution.

There is published report of a 20 month-old female, weighing 12 kg, who ingested approximately 200 mg MONOPRIL.

After receiving gastric lavage and activated charcoal within one hour of the ingestion, she made an eventful recovery.

Information from clinical studies of fosinopril sodium administered as a single dose greater than the approved dose in the treatment of hypertension in the pediatric patients is available in the approved labeling for Bristol-Myers Squibb Company’s fosinopril sodium drug products.

However, due to Bristol-Myer Squibb’s marketing exclusively rights, this drug product is not labeled for pediatric use.

DESCRIPTION

Fosinopril sodium tablet, USP is the sodium salt of fosinopril USP, the ester prodrug of an angiotensin converting enzyme (ACE) inhibitor, fosinoprilat.

It contains a phosphinate group capable of specific binding to the active site of angiotensin converting enzyme.

Fosinopril sodium, USP is designated chemically as:L-proline,4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy](4- phenylbutyl)phosphinyl]acetyl]-, sodium salt, trans-.

Fosinopril sodium,USP is a white to off-white crystalline powder.

It is soluble in water (100 mg/mL), methanol, and ethanol and slightly soluble in hexane.

Its structural formula is: Its empirical formula is C 30 H 45 NNaO 7 P, and its molecular weight is 585.65.

Fosinopril Sodium, USP is available for oral administrations as 10 mg, 20 mg, and 40 mg tablets.

Inactive ingredients include: crospovidone, lactose, microcrystalline cellulose, magnesium stearate, and povidone.

Chemical Structure

HOW SUPPLIED

Repackaged by Aphena Pharma Solutions – TN.

See Repackaging Information for available configurations.

Fosinopril Sodium Tablets, USP 10 mg tablets: White, round, biconvex partially scored tablets debossed with “IG”on one side and “200” on other side.

They are supplied in bottles of 90 (NDC 76282-200-90) and 1000 (NDC 76282-200-10).

Bottles contain a desiccant canister.

20 mg tablets: White, round, biconvex tablets debossed with “IG” on one side and “201” on other side.

They are supplied in bottles of 90 (NDC 76282-201-90) and 1000 (NDC 76282-201-10).

Bottles contain a desiccant canister.

40 mg tablets: White, round, biconvex tablets debossed with “IG” on one side and “202” on other side.

They are supplied in bottles of 90 (NDC 76282-202-90) and 1000 (NDC 76282-202-10).

Bottles contain a desiccant canister.

STORAGE Store at 20° C to 25° C (68° to 77°F) [see USP Controlled Room Temperature] Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Manufactured by: InvaGen Pharmaceuticals, Inc.

Hauppauge, NY 11788.

Manufactured for: Exelan Pharmaceuticals, Inc.

Lawrenceville, GA 30046.

Rev: 12/13

GERIATRIC USE

Geriatric Use Clinical studies of fosinopril sodium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in response between the elderly and younger patients.

In general, dose selection for and 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.

INDICATIONS AND USAGE

Fosinopril sodium tablets, USP are indicated for the treatment of hypertension.

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

Fosinopril sodium tablets, USP are indicated in the management of heart failure as adjunctive therapy when added to conventional therapy including diuretics with or without digitalis (see DOSAGE AND ADMINISTRATION ).

In using fosinopril sodium, consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease.

Available data are insufficient to show that fosinopril sodium does not have a similar risk (see WARNINGS ).

In considering use of fosinopril sodium, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non- blacks.

In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients (see WARNINGS: Head and Neck Angioedema and Intestinal Angioedema ).

PEDIATRIC USE

Pediatric Use Neonates with a history of in utero exposure to fosinopril sodium tablets: 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.

Removal of fosinopril, which crosses the placenta, from the neonatal circulation is not significantly accelerated by these means.

The antihypertensive effects of fosinopril have been evaluated in a double-blind study in pediatric patients 6 to 16 years of age (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Clinical Effects: Hypertension ).

The pharmacokinetics of fosinopril have been evaluated in pediatric patients 6 to 16 years of age (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism ).

Fosinopril was generally well tolerated and adverse effects were similar to those described in adults (see ADVERSE REACTIONS: Pediatric Patients ).

NUSRING MOTHERS

Nursing Mothers Ingestion of 20 mg daily for three days resulted in detectable levels of fosinoprilat in breast milk.

Fosinopril sodium should not be administered to nursing mothers.

BOXED WARNING

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue fosinopril sodium 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: Fetal Toxicity

INFORMATION FOR PATIENTS

Information for Patients Angioedema: Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose.

Patients should be advised to immediately report to their physician any signs or symptoms suggesting angioedema (e.g., swelling of face, eyes, lips, tongue, larynx, mucous membranes, and extremities; difficulty in swallowing or breathing; hoarseness) and to discontinue therapy.

(See WARNINGS: Head and Neck Angioedema and ADVERSE REACTIONS .) Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported to a physician.

Patients should be told that if syncope occurs, fosinopril sodium should be discontinued until the physician has been consulted.

All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting the physician.

Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.

Pregnancy: Female patients of childbearing age should be told about the consequences of second-and third-trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester.

These patients should be asked to report pregnancies to their physician as soon as possible.

DOSAGE AND ADMINISTRATION

Hypertension Adults The recommended initial dose of fosinopril sodium tablets is 10 mg once a day, both as monotherapy and when the drug is added to a diuretic.

Dosage should then be adjusted according to blood pressure response at peak (2-6 hours) and trough (about 24 hours after dosing) blood levels.

The usual dosage range needed to maintain a response at trough is 20-40 mg but some patients appear to have a further response to 80 mg.

In some patients treated with once daily dosing, the antihypertensive effect may diminish toward the end of the dosing interval.

If trough response is inadequate, dividing the daily dose should be considered.

If blood pressure is not adequately controlled fosinopril sodium alone, a diuretic may be added.

Concomitant administration of fosinopril sodium with potassium supplements, potassium salt substitutes, or potassium sparing diuretics can lead to increases of serum potassium (see PRECAUTIONS ).

In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of fosinopril sodium tablets.

To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with fosinopril sodium tablets (see WARNINGS).

Then, if blood pressure is not controlled with fosinopril sodium tablets alone diuretic therapy should be resumed.

If diuretic therapy cannot be discontinued, an initial dose of 10 mg of fosinopril sodium tablets should be used with careful medical supervision for several hours and until blood pressure has stabilized.

(See WARNINGS ; PRECAUTIONS: Information for Patients and Drug Interactions ).

Since concomitant administration of fosinopril sodium tablets with potassium supplements, or potassium containing salt substitutes or potassium-sparing diuretics may lead to increases in serum potassium, they should be used with caution (see PRECAUTIONS ).

Pediatrics Information related to the dosing of fosinopril sodium in the treatment of hypertension in pediatric patients weighing more than 50 kg is available in the approved labeling for Bristol-Myers Squibb Company’s fosinopril sodium drug product.

However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product is not labeled for pediatric use.

Heart Failure Digitalis is not required for fosinopril sodium tablets to manifest improvements in exercise tolerance and symptoms.

Most placebo-controlled clinical trial experience has been with both digitalis and diuretics presents as background therapy.

The usual starting dose of fosinopril sodium tablets should be 10 mg once daily.

Following the initial dose of fosinopril sodium tablets, the patient should be observed under medical supervision for at least two hours for the presence of hypotension or orthostasis and, if present, until blood pressure stabilizes.

An initial dose of 5 mg is preferred in heart failure patients with moderate to severe renal failure or those who have been vigorously diuresed.

Dosage should be increased, over a several week period, to a dose that is maximal and tolerated but not exceeding 40 mg once daily.

The usual effective dosage range is 20 to 40 mg once daily.

The appearance of hypotension, orthostasis, or azotemia early in dose titration should not preclude further careful dose titration.

Consideration should be given to reducing the dose of concomitant diuretic.

For Hypertensive or Heart Failure Patients with Renal Impairment: In patients with impaired renal function, the total body clearance of fosinoprilat is approximately 50% slower than in patients with normal renal function.

Since hepatobiliary elimination partially compensates for diminished renal elimination, the totally body clearance for fosinoprilat does not differ appreciably with any degree of renal insufficiency (creatinine clearances <80 mL/min/1.73m 2 ), including end stage renal failure (creatinine clearance <10 mL/min/1.73m 2 ) This relative constancy of body clearance of active fosinoprilat, resulting from the dual route of elimination, permits use of the usual dose in patients with any degree of renal impairment.

(See WARNINGS: Anaphylactoid reactions during membrane exposure and PRECAUTIONS: Hemodialysis .)

Nicotine 2 MG Oral Lozenge

Generic Name: NICOTINE POLACRILEX

Brand Name: Topcare Nicotine Polacrilex

Substance Name(s):
NICOTINE

WARNINGS

Warnings If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider.

Smoking can seriously harm your child.

Try to stop smoking without using any nicotine replacement medicine.

This medicine is believed to be safer than smoking.

However, the risks to your child from this medicine are not fully known.

Ask a doctor before use if you have • a sodium-restricted diet • heart disease, recent heart attack, or irregular heartbeat.

Nicotine can increase your heart rate.

• high blood pressure not controlled with medication.

Nicotine can increase your blood pressure.

• stomach ulcer or diabetes • history of seizures Ask a doctor or pharmacist before use if you are • using a non-nicotine stop smoking drug • taking prescription medicine for depression or asthma.

Your prescription dose may need to be adjusted.

Stop use and ask a doctor if • mouth problems occur • persistent indigestion or severe sore throat occurs • irregular heartbeat or palpitations occur • you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness or rapid heartbeat • you have symptoms of an allergic reaction (such as difficulty breathing or rash) Keep out of reach of children and pets.

Nicotine lozenges may have enough nicotine to make children and pets sick.

If you need to remove the lozenge, wrap it in paper and throw away in the trash.

In case of overdose, get medical help or contact a Poison Control Center right away.

(1-800-222-1222)

INDICATIONS AND USAGE

Use • reduces withdrawal symptoms, including nicotine craving, associated with quitting smoking

INACTIVE INGREDIENTS

Inactive ingredients aspartame, magnesium stearate, mannitol, natural peppermint flavor, potassium bicarbonate, sodium alginate, sodium carbonate, xanthan gum

PURPOSE

Purpose Stop smoking aid

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children and pets.

Nicotine lozenges may have enough nicotine to make children and pets sick.

If you need to remove the lozenge, wrap it in paper and throw away in the trash.

In case of overdose, get medical help or contact a Poison Control Center right away.

(1-800-222-1222)

ASK DOCTOR

Ask a doctor before use if you have • a sodium-restricted diet • heart disease, recent heart attack, or irregular heartbeat.

Nicotine can increase your heart rate.

• high blood pressure not controlled with medication.

Nicotine can increase your blood pressure.

• stomach ulcer or diabetes • history of seizures

DOSAGE AND ADMINISTRATION

Directions • if you are under 18 years of age, ask a doctor before use.

No studies have been done to show if this product will work for you.

• before using this product, read the enclosed User’s Guide for complete directions and other important information • begin using the lozenge on your quit day • if you smoke your first cigarette within 30 minutes of waking up, use 4 mg nicotine lozenge • if you smoke your first cigarette more than 30 minutes after waking up, use 2 mg nicotine lozenge according to the following 12 week schedule: Weeks 1 to 6 Weeks 7 to 9 Weeks 10 to 12 1 lozenge every 1 to 2 hours 1 lozenge every 2 to 4 hours 1 lozenge every 4 to 8 hours • nicotine lozenge is a medicine and must be used a certain way to get the best results • place the lozenge in your mouth and allow the lozenge to slowly dissolve (about 20-30 minutes).

Minimize swallowing.

Do not chew or swallow lozenge.

• you may feel a warm or tingling sensation • occasionally move the lozenge from one side of your mouth to the other until completely dissolved (about 20-30 minutes) • do not eat or drink 15 minutes before using or while the lozenge is in your mouth • to improve your chances of quitting, use at least 9 lozenges per day for the first 6 weeks • do not use more than one lozenge at a time or continuously use one lozenge after another since this may cause you hiccups, heartburn, nausea or other side effects • do not use more than 5 lozenges in 6 hours.

Do not use more than 20 lozenges per day.

• it is important to complete treatment.

If you feel you need to use the lozenge for a longer period to keep from smoking, talk to your health care provider.

PREGNANCY AND BREAST FEEDING

If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider.

Smoking can seriously harm your child.

Try to stop smoking without using any nicotine replacement medicine.

This medicine is believed to be safer than smoking.

However, the risks to your child from this medicine are not fully known.

STOP USE

ACTIVE INGREDIENTS

Active ingredient (in each lozenge) Nicotine polacrilex, 2 mg (nicotine)

ASK DOCTOR OR PHARMACIST

Ask a doctor or pharmacist before use if you are • using a non-nicotine stop smoking drug • taking prescription medicine for depression or asthma.

Your prescription dose may need to be adjusted.

nabilone 1 MG Oral Capsule

WARNINGS

• The effects of Cesamet may persist for a variable and unpredictable period of time following its oral administration.

Adverse psychiatric reactions can persist for 48 to 72 hours following cessation of treatment.

• Cesamet has the potential to affect the CNS, which might manifest itself in dizziness, drowsiness, euphoria “high”, ataxia, anxiety, disorientation, depression, hallucinations and psychosis.

• Cesamet can cause tachycardia and orthostatic hypotension.

• Because of individual variation in response and tolerance to the effects of Cesamet, patients should remain under supervision of a responsible adult especially during initial use of Cesamet and during dose adjustments.

• Patients receiving treatment with Cesamet should be specifically warned not to drive, operate machinery, or engage in any hazardous activity while receiving Cesamet.

• Cesamet should not be taken with alcohol, sedatives, hypnotics, or other psychoactive substances because these substances can potentiate the central nervous system effects of nabilone.

DRUG INTERACTIONS

Drug Interactions Potential interactions between Cesamet 2 mg, and diazepam 5 mg; sodium secobarbital 100 mg; alcohol 45 mL (absolute laboratory alcohol); or codeine 65 mg, were evaluated in 15 subjects.

Only a single combination was utilized at any one time.

The subjects were evaluated according to physiologic (i.e., heart rate and blood pressure), psychometric, psychomotor, and subjective parameters.

In this study, as expected, the depressant effects of the combinations were additive.

Psychomotor function was particularly impaired with concurrent use of diazepam.

Caution must thus be used when administering nabilone in combination with any CNS depressant.

Nabilone is purportedly highly bound to plasma proteins, and therefore, might displace other protein-bound drugs.

Therefore, practitioners should monitor patients for a change in dosage requirements when administering nabilone to patients receiving other highly protein-bound drugs.

Published reports of drug-drug interactions involving cannabinoids are summarized in the following table.

CONCOMITANT DRUG CLINICAL EFFECT(S) Amphetamines, cocaine, other sympathomimetic agents Additive hypertension, tachycardia, possibly cardiotoxicity Atropine, scopolamine, antihistamines, other anticholinergic agents Additive or super-additive tachycardia, drowsiness Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants Additive tachycardia, hypertension, drowsiness Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants Additive drowsiness and CNS depression Disulfiram A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge Fluoxetine A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days Antipyrine, barbiturates Decreased clearance of these agents, presumably via competitive inhibition of metabolism Theophylline Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco Opioids Cross-tolerance and mutual potentiation Naltrexone Oral THC effects were enhanced by opioid receptor blockade.

Alcohol Increase in the positive subjective mood effects of smoked marijuana

OVERDOSAGE

Signs and Symptoms Signs and symptoms of overdosage are an extension of the psychotomimetic and physiologic effects of Cesamet.

Treatment 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.

Overdosage may be considered to have occurred, even at prescribed dosages, if disturbing psychiatric symptoms are present.

In these cases, the patient should be observed in a quiet environment and supportive measures, including reassurance, should be used.

Subsequent doses should be withheld until patients have returned to their baseline mental status; routine dosing may then be resumed if clinically indicated.

In such instances, a lower initiating dose is suggested.

In controlled clinical trials, alterations in mental status related to the use of Cesamet resolved within 72 hours without specific medical therapy.

In overdose settings, attention should be paid to vital signs, since both hypertension and hypotension have been known to occur; tachycardia and orthostatic hypotension were most commonly reported.

No cases of overdosage with more than 10 mg/day of nabilone were reported during clinical trials.

Signs and symptoms that would be expected to occur in large overdose situations are psychotic episodes, including hallucinations, anxiety reactions, respiratory depression, and coma.

If psychotic episodes occur, the patient should be managed conservatively, if possible.

For moderate psychotic episodes and anxiety reactions, verbal support and comforting may be sufficient.

In more severe cases, antipsychotic drugs may be useful; however, the utility of antipsychotic drugs in cannabinoid psychosis has not been systematically evaluated.

Support for their use is drawn from limited experience using antipsychotic agents to manage cannabis overdoses.

Because of the potential for drug-drug interactions (e.g., additive CNS depressant effects due to nabilone and chlorpromazine), such patients should be closely monitored.

Protect the patient’s airway and support ventilation and perfusion.

Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, as well as other laboratory values and physical assessments.

Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying.

Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed.

Safeguard the patient’s airway when employing gastric emptying or charcoal.

The use of forced diuresis, peritoneal dialysis, hemodialysis, charcoal hemoperfusion, or cholestyramine has not been reported.

In the presence of normal renal function, most of a dose of nabilone is eliminated through the biliary system.

Treatment for respiratory depression and comatose state consists in symptomatic and supportive therapy.

Particular attention should be paid to the occurrence of hypothermia.

If the patient becomes hypotensive, consider fluids, inotropes, and/or vasopressors.

The estimated oral median lethal dose in female mice is between 1,000 and 2,000 mg/kg; in the female rat, it is greater than 2,000 mg/kg, (See CLINICAL PHARMACOLOGY ).

DESCRIPTION

Cesamet ® (nabilone) is a synthetic cannabinoid for oral administration.

Nabilone as a raw material occurs as a white to off-white polymorphic crystalline powder.

In aqueous media, the solubility of nabilone is less than 0.5 mg/L, with pH values ranging from 1.2 to 7.0.

Chemically, nabilone is similar to the active ingredient found in naturally occurring Cannabis sativa L.

[Marijuana; delta-9-tetrahydrocannabinol (delta-9-THC)].

Nabilone is (±)- trans -3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6-6-dimethyl-9H-dibenzo[b,d]pyran-9-one and has the empirical formula C 24 H 36 O 3 .

It has a molecular weight of 372.55.

The structural formula is as follows: Each 1 mg Cesamet capsule contains 1 mg of nabilone and the following inactive ingredients: povidone and corn starch.

The capsule shells contain the following inactive ingredients: FD&C Blue No.

2 (indigo carmine), red iron oxide, gelatin, and titanium dioxide.

Chemical Structure

CLINICAL STUDIES

Clinical Trials Cesamet was evaluated for its effectiveness and safety in the treatment of nausea and vomiting induced by cancer chemotherapy in patients receiving a wide variety of chemotherapy regimens, including low-dose cisplatin (20 mg/m 2 ) in both placebo-controlled and active controlled (prochlorperazine) trials.

During Cesamet treatment patients reported a higher incidence of adverse effects.

The most frequent were drowsiness, vertigo, dry mouth and euphoria.

However, most of the adverse effects occurring with Cesamet were of mild to moderate severity (See ADVERSE REACTIONS ).

HOW SUPPLIED

Cesamet ® capsules (blue and white): 1 mg (bottles of 50 capsules) NDC 0187-1221-03.

Capsules are imprinted with Valeant on the blue cap and a four-digit code (3101) on the white body.

Store at controlled room temperature, 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

GERIATRIC USE

Geriatric Use Clinical studies of Cesamet did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

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.

Cesamet should be used with caution in elderly patients aged 65 and over because they are generally more sensitive to the psychoactive effects of drugs and Cesamet can elevate supine and standing heart rates and cause postural hypotension.

INDICATIONS AND USAGE

Cesamet capsules are indicated for the treatment of the nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.

This restriction is required because a substantial proportion of any group of patients treated with Cesamet can be expected to experience disturbing psychotomimetic reactions not observed with other antiemetic agents.

Because of its potential to alter the mental state, Cesamet is intended for use under circumstances that permit close supervision of the patient by a responsible individual particularly during initial use of Cesamet and during dose adjustments.

Cesamet contains nabilone, which is controlled in Schedule II of the Controlled Substances Act.

Schedule II substances have a high potential for abuse.

Prescriptions for Cesamet should be limited to the amount necessary for a single cycle of chemotherapy (i.e., a few days).

Cesamet capsules are not intended to be used on as needed basis or as a first antiemetic product prescribed for a patient.

As with all controlled drugs, prescribers should monitor patients receiving nabilone for signs of excessive use, abuse and misuse.

Patients who may be at increased risk for substance abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse) or mental illness.

PEDIATRIC USE

Pediatric Use Safety and effectiveness have not been established in patients younger than 18 years of age.

Caution is recommended in prescribing Cesamet to children because of psychoactive effects.

PREGNANCY

Pregnancy Teratogenic Effects Pregnancy Category C Teratology studies conducted in pregnant rats at doses up to 12 mg/kg/day (about 16 times the human dose on a body surface area basis) and in pregnant rabbits at doses up to 3.3 mg/kg/day (about 9 times the human dose on a body surface area basis) did not disclose any evidence for a teratogenic potential of nabilone.

However, there was dose related developmental toxicity in both species as evidenced by increases in embryo lethality, fetal resorptions, decreased fetal weights and pregnancy disruptions.

In rats, postnatal developmental toxicity was also observed.

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

Because animal studies cannot rule out the possibility of harm, Cesamet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

Nursing Mothers It is not known whether this drug is excreted in breast milk.

Because many drugs including some cannabinoids are excreted in breast milk it is not recommended that Cesamet be given to nursing mothers.

INFORMATION FOR PATIENTS

Information for Patients Persons taking Cesamet should be alerted to the potential for additive central nervous system depression resulting from simultaneous use of Cesamet and alcohol or other central nervous system depressants such as benzodiazepines and barbiturates.

This combination should be avoided.

Patients receiving treatment with Cesamet should be specifically warned not to drive, operate machinery, or engage in any hazardous activity.

Patients using Cesamet should be made aware of possible changes in mood and other adverse behavioral effects of the drug so as to avoid panic in the event of such manifestations.

Patients should remain under supervision of a responsible adult while using Cesamet.

DOSAGE AND ADMINISTRATION

The usual adult dosage is 1 or 2 mg 2 times a day.

On the day of chemotherapy, the initial dose should be given 1 to 3 hours before the chemotherapeutic agent is administered.

To minimize side effects, it is recommended that the lower starting dose be used and that the dose be increased as necessary.

Adose of 1 or 2 mg the night before may be useful.

The maximum recommended daily dose is 6 mg given in divided doses 3 times a day.

Cesamet may be administered 2 or 3 times a day during the entire course of each cycle of chemotherapy and, if needed, for 48 hours after the last dose of each cycle of chemotherapy.

Creon 24 (amylases 120,000 UNT / lipase 24,000 UNT / proteases 76,000 UNT) Delayed Release Oral Capsule

DRUG INTERACTIONS

7 No drug interactions have been identified.

No formal interaction studies have been conducted.

OVERDOSAGE

10 There have been no reports of overdose in clinical trials or postmarketing surveillance with this formulation of CREON.

Chronic high doses of pancreatic enzyme products have been associated with fibrosing colonopathy and colonic strictures .

High doses of pancreatic enzyme products have been associated with hyperuricosuria and hyperuricemia, and should be used with caution in patients with a history of hyperuricemia, gout, or renal impairment .

[see Dosage and Administration ( ) and Warnings and Precautions ( )] 2.2 5.1 [see Warnings and Precautions ( )] 5.3

DESCRIPTION

11 CREON is a pancreatic enzyme preparation consisting of pancrelipase, an extract derived from porcine pancreatic glands.

Pancrelipase contains multiple enzyme classes, including porcine-derived lipases, proteases, and amylases.

Pancrelipase is a beige-white amorphous powder.

It is miscible in water and practically insoluble or insoluble in alcohol and ether.

Each delayed-release capsule for oral administration contains enteric-coated spheres (0.71–1.60 mm in diameter).

The active ingredient evaluated in clinical trials is lipase.

CREON is dosed by lipase units.

Other active ingredients include protease and amylase.

CREON contains the following inactive ingredients: cetyl alcohol, dimethicone, hypromellose phthalate, polyethylene glycol, and triethyl citrate.

9,500 USP units of protease; 15,000 USP units of amylase delayed-release capsules have a white opaque cap with imprint “CREON 1203” and a white opaque body.

The shells contain titanium dioxide and hypromellose.

3,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase delayed-release capsules have a Swedish-orange opaque cap with imprint “CREON 1206” and a blue opaque body.

The shells contain FD&C Blue No.

2, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.

6,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase delayed-release capsules have a brown opaque cap with imprint “CREON 1212” and a colorless transparent body.

The shells contain black iron oxide, gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.

12,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase delayed-release capsules have a Swedish-orange opaque cap with imprint “CREON 1224” and a colorless transparent body.

The shells contain gelatin, red iron oxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.

24,000 USP units of lipase;

CLINICAL STUDIES

14 The short-term efficacy of CREON was evaluated in three studies conducted in 103 patients with exocrine pancreatic insufficiency (EPI).

Two studies were conducted in 49 patients with EPI due to cystic fibrosis (CF); one study was conducted in 54 patients with EPI due to chronic pancreatitis or pancreatectomy.

14.1 Cystic Fibrosis Studies 1 and 2 were randomized, double-blind, placebo-controlled, crossover studies in 49 patients, ages 7 to 43 years, with exocrine pancreatic insufficiency due to cystic fibrosis.

Study 1 included patients aged 12 to 43 years (n = 32).

The final analysis population was limited to 29 patients; 3 patients were excluded due to protocol deviations.

Study 2 included patients aged 7 to 11 years (n = 17).

The final analysis population was limited to 16 patients; 1 patient withdrew consent prior to stool collection during treatment with CREON.

In each study, patients were randomized to receive CREON at a dose of 4,000 lipase units/g fat ingested per day or matching placebo for 5 to 6 days of treatment, followed by crossover to the alternate treatment for an additional 5 to 6 days.

All patients consumed a high-fat diet (greater than or equal to 90 grams of fat per day, 40% of daily calories derived from fat) during the treatment periods.

The coefficient of fat absorption (CFA) was determined by a 72-hour stool collection during both treatments, when both fat excretion and fat ingestion were measured.

Each patient’s CFA during placebo treatment was used as their no-treatment CFA value.

In Study 1, mean CFA was 89% with CREON treatment compared to 49% with placebo treatment.

The mean difference in CFA was 41 percentage points in favor of CREON treatment with 95% CI: (34, 47) and p<0.001.

In Study 2, mean CFA was 83% with CREON treatment compared to 47% with placebo treatment.

The mean difference in CFA was 35 percentage points in favor of CREON treatment with 95% CI: (27, 44) and p<0.001.

Subgroup analyses of the CFA results in Studies 1 and 2 showed that mean change in CFA with CREON treatment was greater in patients with lower no-treatment (placebo) CFA values than in patients with higher no-treatment (placebo) CFA values.

There were no differences in response to CREON by age or gender, with similar responses to CREON observed in male and female patients, and in younger (under 18 years of age) and older patients.

The coefficient of nitrogen absorption (CNA) was determined by a 72-hour stool collection during both treatments, when nitrogen excretion was measured and nitrogen ingestion from a controlled diet was estimated (based on the assumption that proteins contain 16% nitrogen).

Each patient’s CNA during placebo treatment was used as their no-treatment CNA value.

In Study 1, mean CNA was 86% with CREON treatment compared to 49% with placebo treatment.

The mean difference in CNA was 37 percentage points in favor of CREON treatment with 95% CI: (31, 42) and p<0.001.

In Study 2, mean CNA was 80% with CREON treatment compared to 45% with placebo treatment.

The mean difference in CNA was 35 percentage points in favor of CREON treatment with 95% CI: (26, 45) and p<0.001.

14.2 Chronic Pancreatitis or Pancreatectomy A randomized, double-blind, placebo-controlled, parallel group study was conducted in 54 adult patients, ages 32 to 75 years, with EPI due to chronic pancreatitis or pancreatectomy.

The final analysis population was limited to 52 patients; 2 patients were excluded due to protocol violations.

Ten patients had a history of pancreatectomy (7 were treated with CREON).

In this study, patients received placebo for 5 days (run-in period), followed by pancreatic enzyme replacement therapy as directed by the investigator for 16 days; this was followed by randomization to CREON or matching placebo for 7 days of treatment (double-blind period).

Only patients with CFA less than 80% in the run-in period were randomized to the double-blind period.

The dose of CREON during the double-blind period was 72,000 lipase units per main meal (3 main meals) and 36,000 lipase units per snack (2 snacks).

All patients consumed a high-fat diet (greater than or equal to 100 grams of fat per day) during the treatment period.

The CFA was determined by a 72-hour stool collection during the run-in and double-blind treatment periods, when both fat excretion and fat ingestion were measured.

The mean change in CFA from the run-in period to the end of the double-blind period in the CREON and Placebo groups is shown in .

Table 3 Table 3: Change in CFA in the Chronic Pancreatitis and Pancreatectomy Trial (Run-in Period to End of Double-Blind Period) *p<0.0001 CREON n = 24 Placebo n = 28 CFA [%] Run-in Period (Mean, SD) 54 (19) 57 (21) End of Double-Blind Period (Mean, SD) 86 (6) 66 (20) Change in CFA * [%] Run-in Period to End of Double-Blind Period (Mean, SD) 32 (18) 9 (13) Treatment Difference (95% CI) 21 (14, 28) Subgroup analyses of the CFA results showed that mean change in CFA was greater in patients with lower run-in period CFA values than in patients with higher run-in period CFA values.

Only 1 of the patients with a history of total pancreatectomy was treated with CREON in the study.

That patient had a CFA of 26% during the run-in period and a CFA of 73% at the end of the double-blind period.

The remaining 6 patients with a history of partial pancreatectomy treated with CREON on the study had a mean CFA of 42% during the run-in period and a mean CFA of 84% at the end of the double-blind period.

RECENT MAJOR CHANGES

Dosage and Administration, ( ) 6/2011 Infants (up to 12 months) 2.1 Dosage and Administration ( ) 6/2011 2.2 Dosage and Administration, ( ) 6/2011 Infants (up to 12 months) 2.2

GERIATRIC USE

8.5 Geriatric Use Clinical studies of CREON did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

DOSAGE FORMS AND STRENGTHS

3 The active ingredient in CREON evaluated in clinical trials is lipase.

CREON is dosed by lipase units.

Other active ingredients include protease and amylase.

Each CREON delayed-release capsule strength contains the specified amounts of lipase, protease, and amylase as follows: 3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase delayed-release capsules have a white opaque cap with imprint “CREON 1203” and a white opaque body.

6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase delayed-release capsules have an orange opaque cap with imprint “CREON 1206” and a blue opaque body.

12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase delayed-release capsules have a brown opaque cap with imprint “CREON 1212” and a colorless transparent body.

24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase delayed-release capsules have an orange opaque cap with imprint “CREON 1224” and a colorless transparent body.

Delayed-Release Capsules: 3,000 USP units of lipase; 9,500 USP units of protease; 15,000 USP units of amylase ( ) 3 Delayed-Release Capsules: 6,000 USP units of lipase; 19,000 USP units of protease; 30,000 USP units of amylase ( ) 3 Delayed-Release Capsules: 12,000 USP units of lipase; 38,000 USP units of protease; 60,000 USP units of amylase ( ) 3 Delayed-Release Capsules: 24,000 USP units of lipase; 76,000 USP units of protease; 120,000 USP units of amylase ( ) 3

MECHANISM OF ACTION

12.1 Mechanism of Action The pancreatic enzymes in CREON catalyze the hydrolysis of fats to monoglyceride, glycerol and free fatty acids, proteins into peptides and amino acids, and starches into dextrins and short chain sugars such as maltose and maltriose in the duodenum and proximal small intestine, thereby acting like digestive enzymes physiologically secreted by the pancreas.

INDICATIONS AND USAGE

1 CREON (pancrelipase) is indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis, chronic pancreatitis, pancreatectomy, or other conditions.

® CREON is a combination of porcine-derived lipases, proteases, and amylases indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis, chronic pancreatitis, pancreatectomy, or other conditions.

( ) 1

PEDIATRIC USE

8.4 Pediatric Use The short-term safety and effectiveness of CREON were assessed in two randomized, double-blind, placebo-controlled, crossover studies of 49 patients with EPI due to cystic fibrosis, 25 of whom were pediatric patients.

Study 1 included 8 adolescents between 12 and 17 years of age.

Study 2 included 17 children between 7 and 11 years of age.

The safety and efficacy in pediatric patients in these studies were similar to adult patients .

[see Adverse Reactions ( ) and Clinical Studies ( )] 6.1 14 An open-label, single-arm, short-term study of CREON was conducted in 18 infants and children, ages 4 months to six years of age, with EPI due to cystic fibrosis.

Patients received their usual pancreatic enzyme replacement therapy (mean dose of 7,000 lipase units/kg/day for a mean duration of 18.2 days) followed by CREON (mean dose of 7,500 lipase units/kg/day for a mean duration of 12.6 days).

The mean daily fat intake was 48 grams during treatment with usual pancreatic enzyme replacement therapy and 47 grams during treatment with CREON.

When patients were switched from their usual pancreatic enzyme replacement therapy to CREON, they demonstrated similar spot fecal fat testing results; the clinical relevance of spot fecal fat testing has not been demonstrated.

Adverse reactions that occurred in patients during treatment with CREON were vomiting, irritability, and decreased appetite .

[see Adverse Reactions ( )] 6.1 The safety and efficacy of pancreatic enzyme products with different formulations of pancrelipase consisting of the same active ingredient (lipases, proteases, and amylases) for treatment of children with exocrine pancreatic insufficiency due to cystic fibrosis have been described in the medical literature and through clinical experience.

Dosing of pediatric patients should be in accordance with recommended guidance from the Cystic Fibrosis Foundation Consensus Conferences .

Doses of other pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with fibrosing colonopathy and colonic strictures in children less than 12 years of age .

[see Dosage and Administration ( )] 2.1 [see Warnings and Precautions ( )] 5.1

PREGNANCY

8.1 Pregnancy Teratogenic effects Pregnancy Category C: Animal reproduction studies have not been conducted with pancrelipase.

It is also not known whether pancrelipase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

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

The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a pregnant woman with exocrine pancreatic insufficiency.

Adequate caloric intake during pregnancy is important for normal maternal weight gain and fetal growth.

Reduced maternal weight gain and malnutrition can be associated with adverse pregnancy outcomes.

NUSRING MOTHERS

8.3 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 CREON is administered to a nursing woman.

The risk and benefit of pancrelipase should be considered in the context of the need to provide adequate nutritional support to a nursing mother with exocrine pancreatic insufficiency.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Fibrosing colonopathy is associated with high-dose use of pancreatic enzyme replacement in the treatment of cystic fibrosis patients.

Exercise caution when doses of CREON exceed 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day).

( ) 5.1 To avoid irritation of oral mucosa, do not chew CREON or retain in the mouth.

( ) 5.2 Exercise caution when prescribing CREON to patients with gout, renal impairment, or hyperuricemia.

( ) 5.3 There is theoretical risk of viral transmission with all pancreatic enzyme products including CREON.

( ) 5.4 Exercise caution when administering pancrelipase to a patient with a known allergy to proteins of porcine origin.

( ) 5.5 5.1 Fibrosing Colonopathy Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products.

Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic enzyme use, usually over a prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis.

The underlying mechanism of fibrosing colonopathy remains unknown.

Doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture in children less than 12 years of age.

Patients with fibrosing colonopathy should be closely monitored because some patients may be at risk of progressing to stricture formation.

It is uncertain whether regression of fibrosing colonopathy occurs.

It is generally recommended, unless clinically indicated, that enzyme doses should be less than 2,500 lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less than 4,000 lipase units/g fat ingested per day 5, 6 1 1 [see Dosage and Administration ( )].

2.1 Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption.

Patients receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.

5.2 Potential for Irritation to Oral Mucosa Care should be taken to ensure that no drug is retained in the mouth.

CREON should not be crushed or chewed or mixed in foods having a pH greater than 4.5.

These actions can disrupt the protective enteric coating resulting in early release of enzymes, irritation of oral mucosa, and/or loss of enzyme activity .

For patients who are unable to swallow intact capsules, the capsules may be carefully opened and the contents added to a small amount of acidic soft food with a pH of 4.5 or less, such as applesauce, at room temperature.

The CREON-soft food mixture should be swallowed immediately and followed with water or juice to ensure complete ingestion.

[see Dosage and Administration ( ) and Patient Counseling Information ( )] 2.2 17.1 5.3 Potential for Risk of Hyperuricemia Caution should be exercised when prescribing CREON to patients with gout, renal impairment, or hyperuricemia.

Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels.

5.4 Potential Viral Exposure from the Product Source CREON is sourced from pancreatic tissue from swine used for food consumption.

Although the risk that CREON will transmit an infectious agent to humans has been reduced by testing for certain viruses during manufacturing and by inactivating certain viruses during manufacturing, there is a theoretical risk for transmission of viral disease, including diseases caused by novel or unidentified viruses.

Thus, the presence of porcine viruses that might infect humans cannot be definitely excluded.

However, no cases of transmission of an infectious illness associated with the use of porcine pancreatic extracts have been reported.

5.5 Allergic Reactions Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of porcine origin.

Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been reported with other pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase).

The risks and benefits of continued CREON treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) 17.1 Dosing and Administration Instruct patients and caregivers that CREON should only be taken as directed by their healthcare professional.

Patients should be advised that the total daily dose should not exceed 10,000 lipase units/kg body weight/day unless clinically indicated.

This needs to be especially emphasized for patients eating multiple snacks and meals per day.

Patients should be informed that if a dose is missed, the next dose should be taken with the next meal or snack as directed.

Doses should not be doubled .

[see Dosage and Administration ( )] 2 Instruct patients and caregivers that CREON should always be taken with food.

Patients should be advised that CREON delayed-release capsules and the capsule contents must not be crushed or chewed as doing so could cause early release of enzymes and/or loss of enzymatic activity.

Patients should swallow the intact capsules with adequate amounts of liquid at mealtimes.

If necessary, the capsule contents can also be sprinkled on soft acidic foods .

[see Dosage and Administration ( )] 2 17.2 Fibrosing Colonopathy Advise patients and caregivers to follow dosing instructions carefully, as doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic strictures in children below the age of 12 years .

[see Dosage and Administration ( )] 2 17.3 Allergic Reactions Advise patients and caregivers to contact their healthcare professional immediately if allergic reactions to CREON develop .

[see Warnings and Precautions ( )] 5.5 17.4 Pregnancy and Breast Feeding Instruct patients to notify their healthcare professional if they are pregnant or are thinking of becoming pregnant during treatment with CREON .

[see Use in Specific Populations ( )] 8.1 Instruct patients to notify their healthcare professional if they are breast feeding or are thinking of breast feeding during treatment with CREON .

[see Use in Specific Populations ( )] 8.3 Manufactured by: Abbott Products GmbH Hannover, Germany Marketed By: Abbott Laboratories North Chicago, IL 60064, U.S.A.

DOSAGE AND ADMINISTRATION

2 CREON is not interchangeable with other pancrelipase products.

CREON is orally administered.

Therapy should be initiated at the lowest recommended dose and gradually increased.

The dosage of CREON should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet as described in the Limitations on Dosing below .

[see Dosage and Administration ( ) and Warnings and Precautions ( )] 2.2 5.1 CREON is not interchangeable with any other pancrelipase product.

( ) 2.1 Do not crush or chew capsules and capsule contents.

For infants or patients unable to swallow intact capsules, the contents may be sprinkled on soft acidic food, e.g., applesauce.

( ) Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consensus Conferences Guidelines.

( ) 2.1 2.2 Infants (up to 12 months) Prior to each feeding, infants may be given 3,000 lipase units (one capsule) per 120 mL of formula or per breast-feeding.

( ) 2.1 Do not mix CREON capsule contents directly into formula or breast milk prior to administration.

( ) 2.1 Children Older than 12 Months and Younger than 4 Years Begin with 1,000 lipase units/kg of body weight per meal for children less than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

( ) 2.2 Children 4 Years and Older and Adults Begin with 500 lipase units/kg of body weight per meal for those older than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

( ) 2.2 Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatectomy Individualize dosage based on clinical symptoms, the degree of steatorrhea present and the fat content of the diet.

( ) 2.2 2.1 Administration Infants (up to 12 months) CREON should be administered to infants immediately prior to each feeding, using a dosage of lipase units per 120 mL of formula or prior to breast-feeding.

Contents of the capsule may be administered directly to the mouth or with a small amount of applesauce.

Administration should be followed by breast milk or formula.

Contents of the capsule be mixed directly into formula or breast milk as this may diminish efficacy.

Care should be taken to ensure that CREON is not crushed or chewed or retained in the mouth, to avoid irritation of the oral mucosa.

3,000 should not Children and Adults CREON should be taken during meals or snacks, with sufficient fluid.

Capsules should be swallowed whole.

CREON capsules and capsule contents should not be crushed or chewed.

The CREON-soft food mixture should be swallowed immediately without crushing or chewing, and followed with water or juice to ensure complete ingestion.

Care should be taken to ensure that no drug is retained in the mouth.

2.2 Dosage Dosage recommendations for pancreatic enzyme replacement therapy were published following the Cystic Fibrosis Foundation Consensus Conferences.

CREON should be administered in a manner consistent with the recommendations of the Patients may be dosed on a fat ingestion-based or actual body weight-based dosing scheme.

1, 2, 3 Cystic Fibrosis Foundation Consensus Conferences (also known as Conferences) provided in the following paragraphs, except for infants.

Although the Conferences recommend doses of 2,000 to 4,000 lipase units in infants up to 12 months, CREON is available in a 3,000 lipase unit capsule.

Therefore, the recommended dose of CREON in infants up to 12 months is 3,000 lipase units per 120 mL of formula or per breast-feeding.

Additional recommendations for pancreatic enzyme therapy in patients with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy are based on a clinical trial conducted in these populations.

Infants (up to 12 months) CREON is available in the strength of 3,000 USP units of lipase thus infants may be given 3,000 lipase units (one capsule) per 120 mL of formula or per breast-feeding.

Do not mix CREON capsule contents directly into formula or breast milk prior to administration .

[see Administration ( )] 2.1 Children Older than 12 Months and Younger than 4 Years Enzyme dosing should begin with 1,000 lipase units/kg of body weight per meal for children less than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

Children 4 Years and Older and Adults Enzyme dosing should begin with 500 lipase units/kg of body weight per meal for those older than age 4 years to a maximum of 2,500 lipase units/kg of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day), or less than 4,000 lipase units/g fat ingested per day.

Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack.

The total daily dose should reflect approximately three meals plus two or three snacks per day.

Enzyme doses expressed as lipase units/kg of body weight per meal should be decreased in older patients because they weigh more but tend to ingest less fat per kilogram of body weight.

Adults with Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatectomy The initial starting dose and increases in the dose per meal should be individualized based on clinical symptoms, the degree of steatorrhea present, and the fat content of the diet.

In one clinical trial, patients received CREON at a dose of 72,000 lipase units per meal while consuming at least 100 g of fat per day .

Lower starting doses recommended in the literature are consistent with the 500 lipase units/kg of body weight per meal lowest starting dose recommended for adults in the Cystic Fibrosis Foundation Consensus Conferences Guidelines.

Usually, half of the prescribed CREON dose for an individualized full meal should be given with each snack.

[see Clinical Studies ( )] 14.2 1, 2, 3, 4 Limitations on Dosing Dosing should not exceed the recommended maximum dosage set forth by the Cystic Fibrosis Foundation Consensus Conferences Guidelines.

If symptoms and signs of steatorrhea persist, the dosage may be increased by the healthcare professional.

Patients should be instructed not to increase the dosage on their own.

There is great inter-individual variation in response to enzymes; thus, a range of doses is recommended.

Changes in dosage may require an adjustment period of several days.

If doses are to exceed 2,500 lipase units/kg of body weight per meal, further investigation is warranted.

Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption.

Doses greater than 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture, indicative of fibrosing colonopathy, in children less than 12 years of age .

Patients currently receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range.

1, 2, 3 [see Warnings and Precautions ( )] 5.1

Sudafed PE Children’s Cold & Cough 5 MG / 2.5 MG per 5 ML Oral Solution

Generic Name: DEXTROMETHORPHAN HYDROBROMIDE AND PHENYLEPHRINE HYDROCHLORIDE

Brand Name: Childrens SUDAFED PE Cold plus Cough

Substance Name(s):
DEXTROMETHORPHAN HYDROBROMIDE
PHENYLEPHRINE HYDROCHLORIDE

WARNINGS

Warnings Do not use in a child who is 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 child’s prescription drug contains an MAOI, ask a doctor or pharmacist before giving this product.

Ask a doctor before use if the child has heart disease high blood pressure thyroid disease diabetes persistent or chronic cough such as occurs with asthma cough that occurs with too much phlegm (mucus) a sodium-restricted diet When using this product do not exceed recommended dose Stop use and ask a doctor if nervousness, dizziness, or sleeplessness occur symptoms do not improve within 7 days or occur with a fever cough gets worse or lasts for more than 7 days cough tends to come back or occurs with fever, rash or headache that lasts These could be signs of a serious condition.

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 temporarily relieves these symptoms due to the common cold, hay fever, or other upper respiratory allergies: cough nasal congestion sinus congestion and pressure

INACTIVE INGREDIENTS

Inactive ingredients anhydrous citric acid, carboxymethylcellulose sodium, edetate disodium, FD&C blue no.

1, FD&C red no.

40, flavors, glycerin, purified water, sodium benzoate, sodium citrate, sorbitol solution, sucralose

PURPOSE

Active ingredients (in each 5 mL) Purposes Dextromethorphan HBr 5 mg Cough suppressant Phenylephrine HCl 2.5 mg 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 find right dose on chart below mL = milliliters repeat dose every 4 hours do not give more than 6 times in 24 hours Age (yr) Dose (mL) under 4 years do not use 4 to 5 years 5 mL 6 to 11 years 10 mL Attention: use only enclosed dosing cup specifically designed for use with this product.

Do not use any other dosing device.

DO NOT USE

Do not use in a child who is 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 child’s prescription drug contains an MAOI, ask a doctor or pharmacist before giving this product.

STOP USE

Stop use and ask a doctor if nervousness, dizziness, or sleeplessness occur symptoms do not improve within 7 days or occur with a fever cough gets worse or lasts for more than 7 days cough tends to come back or occurs with fever, rash or headache that lasts These could be signs of a serious condition.

ACTIVE INGREDIENTS

Active ingredients (in each 5 mL) Purposes Dextromethorphan HBr 5 mg Cough suppressant Phenylephrine HCl 2.5 mg Nasal decongestant

mercaptopurine 50 MG Oral Tablet

Generic Name: MERCAPTOPURINE

Brand Name: Mercaptopurine

Substance Name(s):
MERCAPTOPURINE

DRUG INTERACTIONS

7 • Allopurinol : Reduce the dose of mercaptopurine tablets when co-administered with allopurinol.

( 2.4 , 7.1 ) • Warfarin : Mercaptopurine tablets may decrease the anticoagulant effect.

( 7.2 ) 7.1 Allopurinol Allopurinol can inhibit the first-pass oxidative metabolism of mercaptopurine by xanthine oxidase, which can lead to an increased risk of mercaptopurine adverse reactions (i.e., myelosuppression, nausea, and vomiting) [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) ] .

Reduce the dose of mercaptopurine tablets when coadministered with allopurinol [see Dosage and Administration (2.4) ] .

7.2 Warfarin The concomitant administration of mercaptopurine tablets and warfarin may decrease the anticoagulant effectiveness of warfarin.

Monitor the international normalized ratio (INR) in patients receiving warfarin and adjust the warfarin dosage as appropriate.

7.3 Myelosuppressive Products Mercaptopurine tablets can cause myelosuppression.

Myelosuppression may be increased when mercaptopurine tablets are coadministered with other products that cause myelosuppression.

Enhanced myelosuppression has been noted in some patients also receiving trimethoprim-sulfamethoxazole.

Monitor the CBC and adjust the dose of mercaptopurine tablets for excessive myelosuppression [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ] .

7.4 Aminosalicylates Aminosalicylates (e.g., mesalamine, olsalazine or sulfasalazine) may inhibit the TPMT enzyme, which may increase the risk of myelosuppression when coadministered with mercaptopurine tablets.

When aminosalicylates and mercaptopurine tablets are coadministered, use the lowest possible doses for each drug and monitor more frequently for myelosuppression [see Warnings and Precautions (5.1) ] .

7.5 Hepatotoxic Products Mercaptopurine tablets can cause hepatotoxicity.

Hepatotoxicity may be increased when mercaptopurine tablets are coadministered with other products that cause hepatotoxicity.

Monitor liver tests more frequently in patients who are receiving mercaptopurine tablets with other hepatotoxic products [see Warnings and Precautions (5.2) ] .

OVERDOSAGE

10 Signs and symptoms of mercaptopurine overdosage may be immediate (anorexia, nausea, vomiting, and diarrhea); or delayed (myelosuppression, liver dysfunction, and gastroenteritis).

Dialysis cannot be expected to clear mercaptopurine.

Hemodialysis is thought to be of marginal use due to the rapid intracellular incorporation of mercaptopurine into active metabolites with long persistence.

Withhold mercaptopurine tablets immediately for severe or life-threatening adverse reactions occur during treatment.

If a patient is seen immediately following an accidental overdosage, it may be useful to induce emesis.

DESCRIPTION

11 Mercaptopurine is a nucleoside metabolic inhibitor, the chemical name is Purine-6-thiol monohydrate.

The molecular formula is C 5 H 4 N 4 S•H 2 O and the molecular weight is 170.20.

Its structural formula is: Mercaptopurine, USP is a yellow, crystalline powder.

Mercaptopurine is practically insoluble in water and in ether.

It has a pKa of 7.8, an average tapped density of 1.0 g/mL and average bulk density of 0.85 g/mL.

It dissolves in solutions of alkali hydroxides.

Mercaptopurine tablets are available for oral use.

Each scored tablet contains 50 mg mercaptopurine and the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, pregelatinized starch (corn) and sodium lauryl sulfate.

Meets USP Dissolution Test 2.

Mercaptopurine Structural Formula

HOW SUPPLIED

16 /STORAGE AND HANDLING Mercaptopurine Tablets, USP are available containing 50 mg of mercaptopurine, USP.

The 50 mg tablets are off-white to light yellow, round, scored tablets debossed with M above the score and 547 below the score on one side of the tablet and blank on the other side.

They are available as follows: NDC 0378-3547-52 bottles of 25 tablets NDC 0378-3547-25 bottles of 250 tablets Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.] Protect from moisture.

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

Mercaptopurine tablets are a cytotoxic drug.

Follow special handling and disposal procedures.

GERIATRIC USE

8.5 Geriatric Use Clinical studies of mercaptopurine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

DOSAGE FORMS AND STRENGTHS

3 Mercaptopurine Tablets, USP are available containing 50 mg of mercaptopurine, USP.

• The 50 mg tablets are off-white to light yellow, round, scored tablets debossed with M above the score and 547 below the score on one side of the tablet and blank on the other side.

Tablets: 50 mg ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Mercaptopurine is a purine analog that undergoes intracellular transport and activation to form metabolites including thioguanine nucleotides (TGNs).

Incorporation of TGNs into DNA or RNA results in cell-cycle arrest and cell death.

TGNs and other mercaptopurine metabolites are also inhibitors of de novo purine synthesis and purine nucleotide interconversions.

Mercaptopurine was cytotoxic to proliferating cancer cells in vitro and had antitumor activity in mouse tumor models.

It is not known which of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death.

INDICATIONS AND USAGE

1 Mercaptopurine tablets are a nucleoside metabolic inhibitor indicated for treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen.

( 1.1 ) 1.1 Acute Lymphoblastic Leukemia Mercaptopurine tablets are indicated for treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen.

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of mercaptopurine tablets have been established in pediatric patients.

Use of mercaptopurine tablets in pediatrics is supported by evidence from the published literature and clinical experience.

Symptomatic hypoglycemia has been reported in pediatric patients with ALL receiving mercaptopurine.

Reported cases were in pediatrics less than 6 years of age or with a low body mass index.

PREGNANCY

8.1 Pregnancy Risk Summary Mercaptopurine tablets can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] .

Pregnant women who receive mercaptopurine have an increased incidence of miscarriage and stillbirth (see Data ) .

Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Human Data Women receiving mercaptopurine in the first trimester of pregnancy have an increased incidence of miscarriage; the risk of malformation in offspring surviving first trimester exposure is not known.

In a series of 28 women receiving mercaptopurine after the first trimester of pregnancy, 3 mothers died prior to delivery, 1 delivered a stillborn child, and 1 aborted; there were no cases of macroscopically abnormal fetuses.

Animal Data Mercaptopurine was embryo-lethal and teratogenic in several animal species (rat, mouse, rabbit, and hamster) at doses less than the recommended human dose.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Myelosuppression : Monitor complete blood count (CBC) and adjust the dose of mercaptopurine tablets for excessive myelosuppression.

Consider testing in patients with severe myelosuppression or repeated episodes of myelosuppression for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency.

Patients with homozygous or homozygous TPMT or NUDT15 deficiency may require a dose reduction.

( 2.2 , 5.1 ) • Hepatotoxicity : Monitor transaminases, alkaline phosphatase and bilirubin.

Withhold mercaptopurine tablets at onset of hepatotoxicity.

( 5.2 ) • Immunosuppression : Response to all vaccines may be diminished and there is a risk of infection with live virus vaccines.

Consult immunization guidelines for immunocompromised patients.

( 5.3 ) • Treatment Related Malignancies : Aggressive and fatal cases of hepatosplenic T-cell lymphoma have occurred.

( 5.4 ) • Macrophage Activation Syndrome : Monitor for and treat promptly; discontinue mercaptopurine tablets.

( 5.5 ) • Embryo-Fetal Toxicity : Can cause fetal harm.

Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception.

( 5.6 , 8.1 , 8.3 ) 5.1 Myelosuppression The most consistent, dose-related adverse reaction is myelosuppression, manifested by anemia, leukopenia, thrombocytopenia, or any combination of these.

Monitor CBC and adjust the dosage of mercaptopurine tablets for excessive myelosuppression [see Dosage and Administration (2.1) ] .

Consider testing for TPMT or NUDT15 deficiency in patients with severe myelosuppression or repeated episodes of myelosuppression.

TPMT genotyping or phenotyping (red blood cell TPMT activity) and NUDT15 genotyping can identify patients who have reduced activity of these enzymes.

Patients with heterozygous or homozygous TPMT or NUDT15 deficiency may require a dose reduction [see Dosage and Administration (2.2), Clinical Pharmacology (12.5) ] .

Myelosuppression can be exacerbated by coadministration with allopurinol, aminosalicylates or other products that cause myelosuppression [see Drug Interactions (7.1 , 7.3 , 7.4) ] .

Reduce the dose of mercaptopurine tablets when coadministered with allopurinol [see Dosage and Administration (2.4) ] .

5.2 Hepatoxicity Mercaptopurine is hepatotoxic.

There are reports of deaths attributed to hepatic necrosis associated with the administration of mercaptopurine.

Hepatic injury can occur with any dosage but seems to occur with greater frequency when the recommended dosage is exceeded.

In some patients, jaundice has cleared following withdrawal of mercaptopurine and reappeared with rechallenge.

Usually, clinically detectable jaundice appears early in the course of treatment (1 to 2 months); however, jaundice has been reported as early as 1 week and as late as 8 years after the starting mercaptopurine.

The hepatotoxicity has been associated in some cases with anorexia, diarrhea, jaundice and ascites.

Hepatic encephalopathy has occurred.

Monitor serum transaminase levels, alkaline phosphatase, and bilirubin levels at weekly intervals when first beginning therapy and at monthly intervals thereafter.

Monitor liver tests more frequently in patients who are receiving mercaptopurine tablets with other hepatotoxic products [see Drug Interactions (7.5) ] or with known pre-existing liver disease.

Withhold mercaptopurine tablets at onset of hepatotoxicity.

5.3 Immunosuppression Mercaptopurine is immunosuppressive and may impair the immune response to infectious agents or vaccines.

Due to the immunosuppression associated with maintenance chemotherapy for ALL, response to all vaccines may be diminished and there is a risk of infection with live virus vaccines.

Consult immunization guidelines for immunocompromised patients.

5.4 Treatment Related Malignancies Hepatosplenic T-cell lymphoma has been reported in patients treated with mercaptopurine for inflammatory bowel disease (IBD), an unapproved use.

Mercaptopurine is mutagenic in animals and humans, carcinogenic in animals, and may increase the risk of secondary malignancies.

Patients receiving immunosuppressive therapy, including mercaptopurine, are at an increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical cancer in situ.

The increased risk appears to be related to the degree and duration of immunosuppression.

It has been reported that discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder.

A treatment regimen containing multiple immunosuppressants (including thiopurines) should therefore be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities.

A combination of multiple immunosuppressants, given concomitantly increases the risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders.

5.5 Macrophage Activation Syndrome Macrophage activation syndrome (MAS) (hemophagocytic lymphohistiocytosis) is a known, life-threatening disorder that may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD), and there could potentially be an increased susceptibility for developing the condition with the use of mercaptopurine (an unapproved use).

If MAS occurs, or is suspected, discontinue mercaptopurine tablets.

Monitor for and promptly treat infections such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.

5.6 Embryo-Fetal Toxicity Mercaptopurine tablets can cause fetal harm when administered to a pregnant woman.

An increased incidence of miscarriage has been reported in women who received mercaptopurine in the first trimester of pregnancy.

Adverse embryo-fetal findings, including miscarriage and stillbirth, have been reported in women who received mercaptopurine after the first trimester of pregnancy.

Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with mercaptopurine tablets and for 6 months after the last dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with mercaptopurine tablets and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Major Adverse Reactions: Advise patients and caregivers that mercaptopurine tablets can cause myelosuppression, hepatotoxicity, and gastrointestinal toxicity.

Advise patients to contact their healthcare provider if they experience fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] .

Embryo-Fetal Toxicity: • Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6) , Use in Specific Populations (8.1) ] .

• Advise females of reproductive potential to use effective contraception during treatment with mercaptopurine tablets and for 6 months after the last dose [see Use in Specific Populations (8.3) ] .

• Advise males with female partners of reproductive potential to use effective contraception during treatment with mercaptopurine tablets and for 3 months after the last dose [see Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ] .

Lactation: Advise women not to breastfeed during treatment with mercaptopurine tablets and for 1 week after the last dose [see Use in Specific Populations (8.2) ] .

Infertility: Advise males and females of reproductive potential that mercaptopurine tablets can impair fertility [see Use in Specific Populations (8.3) ] .

Other Adverse Reactions: Instruct patients to minimize sun exposure due to risk of photosensitivity [see Adverse Reactions (6.1) ] .

Manufactured for: Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Manufactured by: Auro PR Inc.

RD 156 Caguas West Industrial Park, Lot 24 Caguas, PR 00725 U.S.A.

Revised: 3/2022 MCPT:R8

DOSAGE AND ADMINISTRATION

2 • The recommended starting dose of mercaptopurine tablets is 1.5 mg/kg to 2.5 mg/kg orally once daily as part of a combination chemotherapy maintenance regimen.

Adjust dose to maintain desirable absolute neutrophil count and for excessive myelosuppression.

( 2.1 ) • Renal Impairment : Use the lowest recommended starting dose or increase the dosing interval.

( 2.3 , 8.6 ) • Hepatic Impairment : Use the lowest recommended starting dose.

( 2.3 , 8.7 ) 2.1 Recommended Dosage The recommended starting dosage of mercaptopurine tablets is 1.5 mg/kg to 2.5 mg/kg orally once daily as part of combination chemotherapy maintenance regimen.

A recommended dosage for patients less than 17 kg is not achievable, because the only available strength is 50 mg.

Take mercaptopurine tablets either consistently with or without food.

After initiating mercaptopurine tablets, monitor complete blood count (CBC) and adjust the dose to maintain absolute neutrophil count (ANC) at a desirable level and for excessive myelosuppression.

Evaluate the bone marrow in patients with prolonged myelosuppression or repeated episodes of myelosuppression to assess leukemia status and marrow cellularity.

Evaluate thiopurine S-methyltransferase (TPMT) and nucleotide diphosphatase (NUDT15) status in patients with severe myelosuppression or repeated episodes or myelosuppression [see Dosage and Administration (2.2) ] .

Do not administer to patients who are unable to swallow tablets.

If a patient misses a dose, instruct the patient to continue with the next scheduled dose.

Mercaptopurine tablets are a cytotoxic drug.

Follow special handling and disposal procedures.

1 2.2 Dosage Modifications in Patients with TPMT and NUDT15 Deficiency Consider testing for TPMT and NUDT15 deficiency in patients who experience severe myelosuppression or repeated episodes of myelosuppression [see Warnings and Precautions (5.1) , Clinical Pharmacology (12.5) ] .

Homozygous Deficiency in either TPMT or NUDT15 Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage.

Reduce the recommended starting dosage of mercaptopurine tablets in patients who are known to have homozygous TPMT or NUDT15 deficiency.

Heterozygous Deficiency in TPMT and/or NUDT15 Reduce the mercaptopurine tablets dose based on tolerability.

Most patients with heterozygous TPMT or NUDT15 deficiency tolerate the recommended dosage, but some require a dose reduction based on adverse reactions.

Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.

2.3 Dosage Modifications in Renal and Hepatic Impairment Renal Impairment Use the lowest recommended starting dosage for mercaptopurine tablets in patients with renal impairment (CLcr less than 50 mL/min).

Adjust the dosage to maintain absolute neutrophil count (ANC) at a desirable level and for adverse reactions [see Uses in Specific Populations (8.6) ] .

Hepatic Impairment Use the lowest recommended starting dosage for mercaptopurine tablets in patients with hepatic impairment.

Adjust the dosage to maintain absolute neutrophil count (ANC) at a desirable level and for adverse reactions [see Uses in Specific Populations (8.7) ] .

2.4 Dosage Modification with Concomitant Use of Allopurinol Reduce the dose of mercaptopurine tablets to one-third to one-quarter of the current dosage when coadministered with allopurinol [see Drug Interactions (7.1) ] .

Fenofibrate 134 MG Oral Capsule

WARNINGS

Liver Function Fenofibrate at doses equivalent to 134 mg to 200 mg fenofibrate capsules per day has been associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)].

In a pooled analysis of 10 placebo-controlled trials, increases to >3 times the upper limit of normal occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo.

When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed.

The incidence of increases in transaminase related to fenofibrate therapy appear to be dose-related.

In an 8-week dose-ranging study, the incidence of ALT or AST elevations to at least three times the upper limit of normal was 13% in patients receiving dosages equivalent to 134 mg to 200 mg fenofibrate capsules per day and was 0% in those receiving dosages equivalent to 34 mg to 67 mg fenofibrate capsules per day, or placebo.

Hepatocellular, chronic active and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposures of weeks to several years.

In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis.

Regular periodic monitoring of liver function, including serum ALT (SGPT) should be performed for the duration of therapy with fenofibrate capsules, and therapy discontinued if enzyme levels persist above three times the normal limit.

Cholelithiasis Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis.

If cholelithiasis is suspected, gallbladder studies are indicated.

Fenofibrate capsules therapy should be discontinued if gallstones are found.

Concomitant Oral Anticoagulants Caution should be exercised when anticoagulants are given in conjunction with fenofibrate capsules because of the potentiation of coumarin-type anticoagulants in prolonging the prothrombin time/INR.

The dosage of the anticoagulant should be reduced to maintain the prothrombin time/INR at the desired level to prevent bleeding complications.

Frequent prothrombin time/INR determinations are advisable until it has been definitely determined that the prothrombin time/INR has stabilized.

Concomitant HMG-CoA reductase inhibitors The combined use of fenofibrate capsules and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination.

In a single-dose drug interaction study in 23 healthy adults the concomitant administration of fenofibrate capsules and pravastatin resulted in no clinically important difference in the pharmacokinetics of fenofibric acid, pravastatin or its active metabolite 3a-hydroxy iso-pravastatin when compared to either drug given alone.

The combined use of fibric acid derivatives and HMG-CoA reductase inhibitors has been associated, in the absences of a marked pharmacokinetic interaction, in numerous case reports, with rhabdomyolysis, markedly elevated creatine kinase (CK) levels and myoglobinuria, leading in a high proportion of cases to acute renal failure.

The use of fibrates alone, including fenofibrate capsules, may occasionally be associated with myositis, myopathy, or rhabdomyolysis.

Patients receiving fenofibrate capsules and complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myopathy, including serum creatine kinase level determination.

If myopathy/myositis is suspected or diagnosed, fenofibrate capsules therapy should be stopped.

Mortality The effect of fenofibrate capsules on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established.

Other Considerations In the Coronary Drug Project, a large study of post myocardial infarction of patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group.

There was however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs.

1.8%).

Because of chemical, pharmacological, and clinical similarities between fenofibrate capsules, clofibrate, and gemfibrozil, the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to fenofibrate capsules.

In a study conducted by the World Health Organization (WHO), 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one year.

There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs.

3.96%, p=<0.01).

Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis.

This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project.

The Helsinki Heart Study was a large (n=4081) study of middle-aged men without a history of coronary artery disease.

Subjects received either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward.

Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p=0.19, 95% confidence interval for relative risk G:P=0.91-1.64).

Although cancer deaths trended higher in the gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups.

Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from World Health Organization study (RR=1.29).

Similarly, the numerical excess of gallbladder surgeries in the gemfibrozil group did not differ statistically from that observed in the WHO study.

A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease.

Subjects received gemfibrozil or placebo for 5 years.

Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94-5.05).

The rate of gallbladder surgery was not statistically significant between study groups, but did trend higher in the gemfibrozil group, (1.9% vs.

0.3%, p=0.07).

There was a statistically significant difference in the number of appendectomies in the gemfibrozil group (6/311 vs.

0/317, p=0.029).

DRUG INTERACTIONS

Drug Interactions Oral Anticoagulants CAUTION SHOULD BE EXERCISED WHEN COUMARIN ANTICOAGULANTS ARE GIVEN IN CONJUNCTION WITH FENOFIBRATE CAPSULES.

THE DOSAGE OF THE ANTICOAGULANTS SHOULD BE REDUCED TO MAINTAIN THE PROTHROMBIN TIME/INR AT THE DESIRED LEVEL TO PREVENT BLEEDING COMPLICATIONS.

FREQUENT PROTHROMBIN TIME/INR DETERMINATIONS ARE ADVISABLE UNTIL IT HAS BEEN DEFINITELY DETERMINED THAT THE PROTHROMBIN TIME/INR HAS STABILIZED.

HMG-CoA reductase inhibitors The combined use of fenofibrate capsules and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination (see WARNINGS ).

Resins Since bile acid sequestrants may bind other drugs given concurrently, patients should take fenofibrate capsules at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption.

Cyclosporine Because cyclosporine can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of fibrate drugs including fenofibrate capsules, there is a risk that an interaction will lead to deterioration.

The benefits and risks of using fenofibrate capsules with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed.

OVERDOSAGE

There is no specific treatment for overdose with fenofibrate capsules.

General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur.

If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway.

Because fenofibrate is highly bound to plasma proteins, hemodialysis should not be considered.

DESCRIPTION

Fenofibrate Capsules (micronized), is a lipid regulating agent available as capsules for oral administration.

Each capsule contains 67 mg, 134 mg or 200 mg of micronized fenofibrate.

The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester with the following structural formula: The empirical formula is C 20 H 21 O 4 Cl and the molecular weight is 360.83; fenofibrate is insoluble in water.

The melting point is 79-82°C.

Fenofibrate is a white solid which is stable under ordinary conditions.

Inactive Ingredients: Each capsule also contains croscarmellose sodium, NF; hydroxypropyl methylcellulose, USP; magnesium sulfate, NF; microcrystalline cellulose, NF; and sodium lauryl sulfate, NF.

Chemical Structure

CLINICAL STUDIES

Clinical Trials Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb) The effects of fenofibrate at a dose equivalent to 200 mg fenofibrate capsules per day were assessed from four randomized, placebo-controlled, double-blind, parallel-group studies including patients with the following mean baseline lipid values: total-C 306.9 mg/dL; LDL-C 213.8 mg/dL; HDL-C 52.3 mg/dL; and triglycerides 191.0 mg/dL.

Fenofibrate capsules therapy lowered LDL-C, Total-C and the LDL-C/HDL-C ratio.

Fenofibrate capsules therapy also lowered triglycerides and raised HDL-C (see Table 1 ).

Table 1 Mean Percent Change in Lipid Parameters at End of Treatment Duration of study treatment was 3 to 6 months Treatment Group Total-C LDL-C HDL-C TG Pooled Cohort Mean baseline lipid values (n=646) 306.9 mg/dL 213.8 mg/dL 52.3 mg/dL 191.0 mg/dL All FEN (n=361) -18.7% p = <0.05 vs.

Placebo -20.6% +11.0% -28.9% Placebo (n=285) -0.4% -2.2% +0.7% +7.7% Baseline LDL-C > 160 mg/dL and TG 160 mg/dL and TG < 150 mg/dL (Type IIb) Mean baseline lipid values (n=646) 312.8 mg/dL 219.8 mg/dL 46.7 mg/dL 231.9 mg/dL All FEN (n=361) -16.8% -20.1% +14.6% -35.9% Placebo (n=285) -3.0% -6.6% +2.3% +0.9% In a subset of the subjects, measurements of apo B were conducted.

Fenofibrate capsules treatment significantly reduced apo B from baseline to endpoint as compared with placebo (-25.1% vs.

2.4%, p<0.0001, n=213 and 143 respectively).

Hypertriglyceridemia (Fredrickson Type IV and V) The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials 1 of 147 hypertriglyceridemia patients (Fredrickson Types IV and V).

Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline triglyceride (TG) levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 500 mg/dL.

In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia (Type IV/V hyperlipidemia), treatment with fenofibrate at dosages equivalent to 200 mg fenofibrate capsules per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol.

Treatment of patients with Type IV hyperlipoproteinemia and elevated triglycerides often results in an increase of low density lipoprotein (LDL) cholesterol (see Table 2 ).

Table 2 Effects of Fenofibrate Capsules in Patients with Fredrickson Type IV/V Hyperlipidemia Study 1 Placebo Fenofibrate Capsules Baseline TG levels 350 to 499 mg/dL N Baseline (Mean) Endpoint (Mean) % Change (Mean) N Baseline (Mean) Endpoint (Mean) % Change (Mean) Triglycerides 28 449 450 -0.5 27 432 223 -46.2 = p<0.05 vs.

Placebo VLDL Triglycerides 19 367 350 2.7 19 350 178 -44.1 Total Cholesterol 28 255 261 2.8 27 252 227 -9.1 HDL Cholesterol 28 35 36 4 27 34 40 19.6 LDL Cholesterol 28 120 129 12 27 128 137 14.5 VLDL Cholesterol 27 99 99 5.8 27 92 46 -44.7 Study 2 Placebo Fenofibrate Capsules Baseline TG levels 500 to 1500 mg/dL N Baseline (Mean) Endpoint (Mean) % Change (Mean) N Baseline (Mean) Endpoint (Mean) % Change (Mean) Triglycerides 44 710 750 7.2 48 726 308 -54.5 VLDL Triglycerides 29 537 571 187 33 543 205 -50.6 Total Cholesterol 44 272 271 0.4 48 261 223 -13.8 HDL Cholesterol 44 27 28 5.0 48 30 36 22.9 LDL Cholesterol 42 100 90 -4.2 45 103 131 45.0 VLDL Cholesterol 42 137 142 11.0 45 126 54 -49.4 The effect of fenofibrate capsules on cardiovascular morbidity and mortality has not been determined.

HOW SUPPLIED

Fenofibrate Capsules – Each #1 gelatin capsules contains 134 mg of fenofibrate, micronized.

Each capsule is imprinted in black with “G 0522”.

NDC: 60760-0902-30 BOTTLE OF 30 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Protect from moisture.

Dispense in tightly-closed, light-resistant container (USP).

GERIATRIC USE

Geriatric Use Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection.

INDICATIONS AND USAGE

Treatment of Hypercholesterolemia Fenofibrate capsules are indicated as adjunctive therapy to diet for the reduction of LDL-C, Total-C, Triglycerides and apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson Types IIa and IIb).

Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate (see National Cholesterol Education Program [NCEP] Treatment Guidelines , below).

Treatment of Hypertriglyceridemia Fenofibrate capsules are also indicated as adjunctive therapy to diet for treatment of adult patients with hypertriglyceridemia (Fredrickson Types IV and V hyperlipidemia).

Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually reduce fasting triglycerides and eliminate chylomicronemia thereby obviating the need for pharmacologic intervention.

Markedly elevated levels of serum triglycerides (e.g.

> 2,000 mg/dL) may increase the risk of developing pancreatitis.

The effect of fenofibrate capsules therapy on reducing this risk has not been adequately studied.

Drug therapy is not indicated for patients with Type I hyperlipoproteinemia, who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of very low density lipoprotein (VLDL).

Inspection of plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV and V hyperlipoproteinemia 2 .

The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality.

Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy.

Physical exercise can be an important ancillary measure.

Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated.

Estrogen therapy, like thiazide diuretics and beta-blockers, is sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia.

In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia.

The use of drugs should be considered only when reasonable attempts have been made to obtain satisfactory results with non-drug methods.

If the decision is made to use drugs, the patient should be instructed that this does not reduce the importance of adhering to diet (see WARNINGS and PRECAUTIONS ).

Fredrickson Classification of Hyperlipoproteinemias Type Lipoprotein Elevated Lipid Elevation Major Minor C = cholesterol TG = triglycerides LDL = low density lipoprotein VLDL = very low density lipoprotein IDL = intermediate density lipoprotein I (rare) Chylomicrons TG ↑↔C IIa LDL C — IIb LDL, VLDL C TG III (rare) IDL C, TG — IV VLDL TG ↑↔C V (rare) Chylomicrons, VLDL TG ↑↔ The NCEP Treatment Guidelines Definite Athlerosclerotic Disease Coronary heart disease or peripheral vascular disease (including symptomatic carotid artery disease).

Two or More Other Risk Factors Other risk factors for coronary heart disease (CHD) include: age (males: ≥ 45 years; females: ≥ 55 years or premature menopause without estrogen replacement therapy); family history of premature CHD; current cigarette smoking; hypertension; confirmed HDL-C <35 mg/dL (<0.91mmol/L); and diabetes mellitus.

Subtract 1 risk factor if HDL-C is ≥ 60 mg/dL (≥1.6 mmol/L) LDL-Cholesterol mg/dL (mmol/L) Initiation Level Goal No No ≥ 190 (≥ 4.9) < 160 (< 4.1) No Yes ≥ 160 (≥ 4.1) < 130 (< 3.4) Yes Yes or No ≥ 130* In CHD patients with LDL-C levels 100 to 129 mg/dL, the physician should exercise clinical judgment in deciding whether to initiate drug treatment.

(≥ 3.4) < 100 (< 2.6)

PEDIATRIC USE

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

PREGNANCY

Pregnancy Category C Fenofibrate has been shown to be embryocidal and teratogenic in rats when given in doses 7 to 10 times the maximum recommended human dose and embryocidal in rabbits when given at 9 times the maximum recommended human dose (on the basis of mg/meter 2 surface area).

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

Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Administration of 9 times the maximum recommended human dose of fenofibrate to female rats before and throughout gestation caused 100% of dams to delay delivery and resulted in a 60% increase in post-implantation loss, a decrease in litter size, a decrease in birth weight, a 40% survival of pups at birth, a 4% survival of pups as neonates, and a 0% survival of pups to weaning, and an increase in spina bifida.

Administration of 10 times the maximum recommended human dose to female rats on days 6 to 15 of gestation caused an increase in gross, visceral and skeletal findings in fetuses (domed head/hunched shoulders/rounded body/abnormal chest, kyphosis, stunted fetuses, elongated sternal ribs, malformed sternebrae, extra foramen in palatine, misshapen vertebrae, supernumerary ribs).

Administration of 7 times the maximum recommended human dose to female rats from day 15 of gestation through weaning caused a delay in delivery, a 40% decrease in live births, a 75% decrease in neonatal survival, and decreases in pup weight, at birth as well as on days 4 and 21 post-partum.

Administration of 9 and 18 times the maximum recommended human dose to female rabbits caused abortions in 10% of dams at 9 times and 25% of dams at 18 times the maximum recommended human dose and death of 7% of fetuses at 18 times the maximum recommended human dose.

NUSRING MOTHERS

Nursing mothers Fenofibrate should not be used in nursing mothers.

Because of the potential for tumorigenicity seen in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug.

DOSAGE AND ADMINISTRATION

Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate capsules, and should continue this diet during treatment with fenofibrate capsules.

Fenofibrate capsules should be given with meals, thereby optimizing the bioavailability of the medication.

For the treatment of adult patients with primary hypercholesterolemia or mixed hyperlipidemia, the initial dose of fenofibrate capsules is 200 mg per day.

For adult patients with hypertriglyceridemia, the initial dose is 67 to 200 mg per day.

Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals.

The maximum dose is 200 mg per day.

Treatment with fenofibrate capsules should be initiated at a dose of 67 mg/day in patients having impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose.

In the elderly, the initial dose should likewise be limited to 67 mg/day.

Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of fenofibrate capsules if lipid levels fall significantly below the targeted range.

Fleet Phospho-Soda (sodium phosphate, dibasic 2.7 GM / sodium phosphate, monobasic 7.2 GM) per 45 ML Oral Solution

WARNINGS

Warnings Taking more than the recommended dose in 24 hours can be harmful.

Do not use if you have congestive heart failure if you have serious kidney problems in children under 5 years of age

INDICATIONS AND USAGE

Uses relief of occasional constipation to help clean out the bowel before medical procedures

INACTIVE INGREDIENTS

Inactive Ingredients flavor, glycerin, purified water, saccharin sodium, sodium benzoate

PURPOSE

1 tablespoon contains: sodium 1668 mg this product is sugar-free this product usually causes a person to have a bowel movement in 30 minutes to 6 hours chill this product in refrigerator to improve the taste.

Do not freeze

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

Ask a doctor before use if you are under a doctor’s care for any medical condition on a low salt diet Ask a doctor or pharmacist before use if you are taking any other prescription or non-prescription drugs.

Ask a doctor before using any laxative if you have abdominal (belly) pain, nausea, or vomitting a change in your daily bowel movements that lasts more than 2 weeks already used another laxative daily for constipation for more than 1 week

DOSAGE AND ADMINISTRATION

Directions Laxative Dose and Directions Ages (years) Step 1 Step 2 24 Hour Max Dose* 12 years & older Mix 1 tablespoon in a full glass of cold liquid (8 fl oz).

Drink Drink at least 1 extra full glass of liquid (8 fl oz).

3 tablespoons 10 to 11 years Mix 1 tablespoon in a full glass of cold liquid (8 fl oz).

Drink Drink at least 1 extra full glass of liquid (8 fl oz).

1 tablespoon 5 to 9 years Mix 1/2 tablespoon in a full glass of cold liquid (8 fl oz).

Drink Drink at least 1 extra full glass of liquid (8 fl oz).

1/2 tablespoon Under 5 years Do Not Use Do Not Use Do Not Use * Take no more than this amount in a 24 hour period.

Use as a laxative for relieft of occasional constipation.

follow the dose and directions.

do not take more unless directed by a doctor.

See Warnings.

drink as much extra liquids as you can to help replace the fluids you are losing during bowel movements.

STOP USE

Stop use and ask a doctor if you have any rectal bleeding do not have a bowel movement within 6 hours of taking this product have any symptoms that your body is losing more fluids than you are drinking.

This is called dehydration.

Early symptoms of dehydration include – feeling thristy – dizziness – urinating less often than normal – vomiting These symptoms may be signs of serious problems.

ACTIVE INGREDIENTS

Active Ingredient (in each Tablespoon) Monobasic Sodium Phosphate 7.2 g……………..Saline Laxative / Bowel Cleanser Dibasic Sodium Phosphate 2.7 g………………….Saline Laxative / Bowel Cleanser

salmeterol 50 MCG/INHAL Dry Powder Inhaler, 60 Bisters

Generic Name: SALMETEROL XINAFOATE

Brand Name: SEREVENT DISKUS

Substance Name(s):
SALMETEROL XINAFOATE

DRUG INTERACTIONS

7 • Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended.

May increase risk of cardiovascular effects.

( 7.1 ) • Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution.

May potentiate effect of salmeterol on vascular system.

( 7.2 ) • Beta-blockers: Use with caution.

May block bronchodilatory effects of beta-agonists and produce severe bronchospasm.

( 7.3 ) • Diuretics: Use with caution.

Electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists.

( 7.4 ) 7.1 Inhibitors of Cytochrome P450 3A4 Salmeterol is a substrate of CYP3A4.

The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with SEREVENT DISKUS is not recommended because increased cardiovascular adverse effects may occur.

In a drug interaction trial in 20 healthy subjects, coadministration of inhaled salmeterol (50 mcg twice daily) and oral ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16-fold and C max increased 1.4-fold).

Three (3) subjects were withdrawn due to beta 2 -agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia).

Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.

7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants SEREVENT DISKUS should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol on the vascular system may be potentiated by these agents.

7.3 Beta-adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, but may also produce severe bronchospasm in patients with asthma or COPD.

Therefore, patients with asthma or COPD should not normally be treated with beta-blockers.

However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

7.4 Non–Potassium-Sparing Diuretics The ECG changes and/or hypokalemia that may result from the administration of non–potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.

Although the clinical significance of these effects is not known, caution is advised in the coadministration of SEREVENT DISKUS with non–potassium-sparing diuretics.

OVERDOSAGE

10 The expected signs and symptoms with overdosage of SEREVENT DISKUS are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis).

Overdosage with SEREVENT DISKUS can lead to clinically significant prolongation of the QTc interval, which can produce ventricular arrhythmias.

As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of SEREVENT DISKUS.

Treatment consists of discontinuation of SEREVENT DISKUS together with appropriate symptomatic therapy.

The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm.

There is insufficient evidence to determine if dialysis is beneficial for overdosage of SEREVENT DISKUS.

Cardiac monitoring is recommended in cases of overdosage.

DESCRIPTION

11 The active component of SEREVENT DISKUS is salmeterol xinafoate, a beta 2 -adrenergic bronchodilator.

Salmeterol xinafoate is the racemic form of the 1-hydroxy-2-naphthoic acid salt of salmeterol.

It has the chemical name 4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate and the following chemical structure: Salmeterol xinafoate is a white powder with a molecular weight of 603.8, and the empirical formula is C 25 H 37 NO 4 •C 11 H 8 O 3 .

It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water.

SEREVENT DISKUS is a teal green plastic inhaler containing a foil blister strip.

Each blister on the strip contains a white powder mix of micronized salmeterol xinafoate salt (72.5 mcg, equivalent to 50 mcg of salmeterol base) in 12.5 mg of formulation containing lactose monohydrate (which contains milk proteins).

After the inhaler is activated, the powder is dispersed into the airstream created by the patient inhaling through the mouthpiece.

Under standardized in vitro test conditions, SEREVENT DISKUS delivers 47 mcg of salmeterol base per blister when tested at a flow rate of 60 L/min for 2 seconds.

In adult subjects with obstructive lung disease and severely compromised lung function (mean FEV 1 20% to 30% of predicted), mean peak inspiratory flow (PIF) through the DISKUS inhaler was 82.4 L/min (range: 46.1 to 115.3 L/min).

The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.

Salmeterol chemical structure

CLINICAL STUDIES

14 14.1 Asthma The initial trials supporting the approval of SEREVENT DISKUS for the treatment of asthma did not require the regular use of ICS.

However, for the treatment of asthma, SEREVENT DISKUS is currently indicated only as concomitant therapy with an ICS [see Indications and Usage ( 1.1 )] .

Adult and Adolescent Subjects Aged 12 Years and Older In 2 randomized double-blind trials, SEREVENT DISKUS was compared with albuterol inhalation aerosol and placebo in adolescent and adult subjects with mild-to-moderate asthma (protocol defined as 50% to 80% predicted FEV 1 , actual mean of 67.7% at baseline), including subjects who did and who did not receive concurrent ICS.

The efficacy of SEREVENT DISKUS was demonstrated over the 12-week period with no change in effectiveness over this time period (Figure 1).

There were no gender- or age-related differences in safety or efficacy.

No development of tachyphylaxis to the bronchodilator effect was noted in these trials.

FEV 1 measurements (mean change from baseline) from these two 12-week trials are shown in Figure 1 for both the first and last treatment days.

Figure 1.

Serial 12-Hour FEV 1 from Two 12-Week Clinical Trials in Subjects with Asthma First Treatment Day Last Treatment Day (Week 12) Table 4 shows the treatment effects seen during daily treatment with SEREVENT DISKUS for 12 weeks in adolescent and adult subjects with mild-to-moderate asthma.

Table 4.

Daily Efficacy Measurements in Two 12-Week Clinical Trials (Combined Data) a Statistically superior to placebo and albuterol ( P <0.001).

b Statistically superior to placebo ( P <0.001).

Parameter Time SEREVENT DISKUS Albuterol Inhalation Aerosol Placebo No.

of randomized subjects 149 148 152 Mean AM peak expiratory flow (L/min) Baseline 12 weeks 395 394 394 427 a 394 396 Mean % days with no asthma symptoms Baseline 12 weeks 13 12 14 33 21 20 Mean % nights with no awakenings Baseline 12 weeks 63 68 70 85 a 71 73 Rescue medications (mean no.

of inhalations per day) Baseline 12 weeks 4.3 4.3 4.2 1.6 b 2.2 3.3 Asthma exacerbations (%) 15 16 14 Maintenance of efficacy for periods up to 1 year has been documented.

SEREVENT DISKUS and SEREVENT Inhalation Aerosol were compared with placebo in 2 additional randomized double-blind clinical trials in adolescent and adult subjects with mild-to-moderate asthma.

SEREVENT DISKUS 50 mcg and SEREVENT Inhalation Aerosol 42 mcg, both administered twice daily, produced significant improvements in pulmonary function compared with placebo over the 12-week period.

While no statistically significant differences were observed between the active treatments for any of the efficacy assessments or safety evaluations performed, there were some efficacy measures on which the metered-dose inhaler appeared to provide better results.

Similar findings were noted in 2 randomized, single-dose, crossover comparisons of SEREVENT DISKUS and SEREVENT Inhalation Aerosol for the prevention of EIB.

Therefore, while SEREVENT DISKUS was comparable to SEREVENT Inhalation Aerosol in clinical trials in mild-to-moderate subjects with asthma, it should not be assumed that they will produce clinically equivalent outcomes in all subjects.

Subjects on Concomitant Inhaled Corticosteroids: In 4 clinical trials in adult and adolescent subjects with asthma (N = 1,922), the effect of adding SEREVENT Inhalation Aerosol to ICS therapy was evaluated over a 24-week treatment period.

The trials compared the addition of salmeterol therapy to an increase (at least doubling) of the ICS dose.

Two randomized, double-blind, controlled, parallel-group clinical trials (N = 997) enrolled subjects (aged 18 to 82 years) with persistent asthma who were previously maintained but not adequately controlled on ICS therapy.

During the 2-week run-in period, all subjects were switched to beclomethasone dipropionate (BDP) 168 mcg twice daily.

Subjects still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of BDP to 336 mcg twice daily.

As compared with the doubled dose of BDP, the addition of SEREVENT Inhalation Aerosol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reduction in supplemental albuterol use.

The percent of subjects who experienced asthma exacerbations overall was not different between groups (i.e., 16.2% in the group receiving SEREVENT Inhalation Aerosol versus 17.9% in the higher-dose beclomethasone dipropionate group).

Two randomized, double-blind, controlled, parallel-group clinical trials (N = 925) enrolled subjects (aged 12 to 78 years) with persistent asthma who were previously maintained but not adequately controlled on prior asthma therapy.

During the 2- to 4-week run-in period, all subjects were switched to fluticasone propionate 88 mcg twice daily.

Subjects still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of fluticasone propionate to 220 mcg twice daily.

As compared with the increased (2.5 times) dose of fluticasone propionate, the addition of SEREVENT Inhalation Aerosol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reductions in supplemental albuterol use.

Fewer subjects receiving SEREVENT Inhalation Aerosol experienced asthma exacerbations than those receiving the higher dose of fluticasone propionate (8.8% versus 13.8%).

Table 5 shows the treatment effects seen during daily treatment with SEREVENT Inhalation Aerosol for 24 weeks in adolescent and adult subjects with mild-to-moderate asthma.

Onset of Action: During the initial treatment day in several multiple-dose clinical trials with SEREVENT DISKUS in subjects with asthma, the median time to onset of clinically significant bronchodilatation (≥15% improvement in FEV 1 ) ranged from 30 to 48 minutes after a 50-mcg dose.

One hour after a single dose of 50 mcg of SEREVENT DISKUS, the majority of subjects had ≥15% improvement in FEV 1 .

Maximum improvement in FEV 1 generally occurred within 180 minutes, and clinically significant improvement continued for 12 hours in most subjects.

Pediatric Subjects In a randomized, double-blind, controlled trial (N = 449), 50 mcg of SEREVENT DISKUS was administered twice daily to pediatric subjects with asthma who did and who did not receive concurrent ICS.

The efficacy of salmeterol inhalation powder was demonstrated over the 12-week treatment period with respect to periodic serial PEF (36% to 39% postdose increase from baseline) and FEV 1 (32% to 33% postdose increase from baseline).

Salmeterol was effective in demographic subgroup analyses (gender and age) and was effective when coadministered with other inhaled asthma medications such as short-acting bronchodilators and ICS.

A second randomized, double-blind, placebo-controlled trial (N = 207) with 50 mcg of salmeterol inhalation powder via an alternate device supported the findings of the trial with the DISKUS.

Salmeterol Multicenter Asthma Research Trial The SMART trial was a randomized double-blind trial that enrolled LABA-naive subjects with asthma (average age of 39 years; 71% Caucasian, 18% African American, 8% Hispanic) to assess the safety of salmeterol (SEREVENT Inhalation Aerosol) 42 mcg twice daily over 28 weeks compared with placebo when added to usual asthma therapy.

A planned interim analysis was conducted when approximately half of the intended number of subjects had been enrolled (N = 26,355), which led to premature termination of the trial.

The results of the interim analysis showed that subjects receiving salmeterol were at increased risk for fatal asthma events ( Table 5 and Figure 2).

In the total population, a higher rate of asthma-related death occurred in subjects treated with salmeterol than those treated with placebo (0.10% versus 0.02%, relative risk: 4.37 [95% CI: 1.25, 15.34]).

Post hoc subpopulation analyses were performed.

In Caucasians, asthma-related death occurred at a higher rate in subjects treated with salmeterol than in subjects treated with placebo (0.07% versus 0.01%, relative risk: 5.82 [95% CI: 0.70, 48.37]).

In African Americans also, asthma-related death occurred at a higher rate in subjects treated with salmeterol than those treated with placebo (0.31% versus 0.04%, relative risk: 7.26 [95% CI: 0.89, 58.94]).

Although the relative risks of asthma-related death were similar in Caucasians and African Americans, the estimate of excess deaths in subjects treated with salmeterol was greater in African Americans because there was a higher overall rate of asthma-related death in African American subjects ( Table 5 ).

Post hoc analyses in pediatric subjects aged 12 to 18 years were also performed.

Pediatric subjects accounted for approximately 12% of subjects in each treatment arm.

Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% [2/1,653]) and the placebo group (0.12% [2/1,622]; relative risk: 1.0 [95% CI: 0.1, 7.2]).

All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1,653]) versus the placebo group (less than 1% [16/1,622]; relative risk: 2.1 [95% CI: 1.1, 3.7]).

The data from the SMART trial were not adequate to determine whether concurrent use of ICS or other long-term asthma control therapy mitigated the risk of asthma-related death.

Table 5: Asthma-Related Deaths in the 28-Week Salmeterol Multicenter Asthma Research Trial (SMART) a Life-table 28-week estimate, adjusted according to the subjects’ actual lengths of exposure to study treatment to account for early withdrawal of subjects from the study.

b Relative risk is the ratio of the rate of asthma-related death in the salmeterol group and the rate in the placebo group.

The relative risk indicates how many more times likely an asthma-related death occurred in the salmeterol group than in the placebo group in a 28-week treatment period.

c Estimate of the number of additional asthma-related deaths in subjects treated with salmeterol in SMART, assuming 10,000 subjects received salmeterol for a 28-week treatment period.

Estimate calculated as the difference between the salmeterol and placebo groups in the rates of asthma-related death multiplied by 10,000.

d The Total Population includes the following ethnic origins listed on the case report form: Caucasian, African American, Hispanic, Asian, and “Other.” In addition, the Total Population includes those subjects whose ethnic origin was not reported.

The results for Caucasian and African American subpopulations are shown above.

No asthma-related deaths occurred in the Hispanic (salmeterol n = 996, placebo n = 999), Asian (salmeterol n = 173, placebo n = 149), or “Other” (salmeterol n = 230, placebo n = 224) subpopulations.

One asthma-related death occurred in the placebo group in the subpopulation whose ethnic origin was not reported (salmeterol n = 130, placebo n = 127).

Salmeterol n (% a ) Placebo n (% a ) Relative Risk b (95% Confidence Interval) Excess Deaths Expressed per 10,000 Subjects c (95% Confidence Interval) Total Population d Salmeterol: n = 13,176 13 (0.10%) 4.37 (1.25, 15.34) 8 (3, 13) Placebo: n = 13,179 3 (0.02%) Caucasian Salmeterol: n = 9,281 6 (0.07%) 5.82 (0.70, 48.37) 6 (1, 10) Placebo: n = 9,361 1 (0.01%) African American Salmeterol: n = 2,366 7 (0.31%) 7.26 (0.89, 58.94) 27 (8, 46) Placebo: n = 2,319 1 (0.04%) Figure 2.

Cumulative Incidence of Asthma-Related Deaths in the 28-Week Salmeterol Multicenter Asthma Research Trial (SMART), by Duration of Treatment Figure 1 First Treatment Day Figure 1 Week 12 Figure 2.

Cumulative Incidence of Asthma-Related Deaths in the 28-Week Salmeterol Multi-center Asthma Research Trial (SMART), by Duration of Treatment 14.2 Exercise-Induced Bronchospasm In 2 randomized, single-dose, crossover trials in adolescents and adults with EIB (N = 52), 50 mcg of SEREVENT DISKUS prevented EIB when dosed 30 minutes prior to exercise.

For some subjects, this protective effect against EIB was still apparent up to 8.5 hours following a single dose ( Table 6 ).

Table 6.

Results of 2 Exercise-Induced Bronchospasm Trials in Adolescents and Adults SEREVENT DISKUS (N = 52) Placebo (N = 52) n % Total n % Total 0.5-Hour postdose exercise challenge % Fall in FEV 1 <10% 31 60 15 29 ≥10%, <20% 11 21 3 6 ≥20% 10 19 34 65 Mean maximal % fall in FEV 1 (SE) -11% (1.9) -25% (1.8) 8.5-Hour postdose exercise challenge % Fall in FEV 1 <10% 26 50 12 23 ≥10%, <20% 12 23 7 13 ≥20% 14 27 33 63 Mean maximal % fall in FEV 1 (SE) -16% (2.0) -27% (1.5) In 2 randomized trials in children aged 4 to 11 years with asthma and EIB (N = 50), a single 50-mcg dose of SEREVENT DISKUS prevented EIB when dosed 30 minutes prior to exercise, with protection lasting up to 11.5 hours in repeat testing following this single dose in many subjects.

14.3 Chronic Obstructive Pulmonary Disease In 2 clinical trials evaluating twice-daily treatment with SEREVENT DISKUS 50 mcg (n = 336) compared with placebo (n = 366) in subjects with chronic bronchitis with airflow limitation, with or without emphysema, improvements in pulmonary function endpoints were greater with salmeterol 50 mcg than with placebo.

Treatment with SEREVENT DISKUS did not result in significant improvements in secondary endpoints assessing COPD symptoms in either clinical trial.

Both trials were randomized, double-blind, parallel-group trials of 24 weeks’ duration and were identical in design, subject entrance criteria, and overall conduct.

Figure 3 displays the integrated 2-hour postdose FEV 1 results from the 2 clinical trials.

The percent change in FEV 1 refers to the change from baseline, defined as the predose value on Treatment Day 1.

To account for subject withdrawals during the trial, Endpoint (last evaluable FEV 1 ) data are provided.

Subjects receiving SEREVENT DISKUS 50 mcg had significantly greater improvements in 2-hour postdose FEV 1 at Endpoint (216 mL, 20%) compared with placebo (43 mL, 5%).

Improvement was apparent on the first day of treatment and maintained throughout the 24 weeks of treatment.

Figure 3.

Mean Percent Change from Baseline in Postdose FEV 1 Integrated Data from 2 Trials of Subjects with Chronic Bronchitis and Airflow Limitation Onset of Action and Duration of Effect The onset of action and duration of effect of SEREVENT DISKUS were evaluated in a subset of subjects (n = 87) from 1 of the 2 clinical trials discussed above.

Following the first 50-mcg dose, significant improvement in pulmonary function (mean FEV 1 increase of 12% or more and at least 200 mL) occurred at 2 hours.

The mean time to peak bronchodilator effect was 4.75 hours.

As seen in Figure 4, evidence of bronchodilatation was seen throughout the 12-hour period.

Figure 4 also demonstrates that the bronchodilating effect after 12 weeks of treatment was similar to that observed after the first dose.

The mean time to peak bronchodilator effect after 12 weeks of treatment was 3.27 hours.

Figure 4.

Serial 12-Hour FEV 1 on the First Day and at Week 12 of Treatment Figure 3.

Mean Percent Change From Baseline in Postdose FEV1 Integrated Data From 2 Trials of Subjects With Chronic Bronchitis and Airflow Limitation Figure 4.

Serial 12-Hour FEV1 on the First Day and at Week 12 of Treatment

HOW SUPPLIED

16 /STORAGE AND HANDLING SEREVENT DISKUS is supplied as a disposable teal green plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0521-00).

Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature].

Store in a dry place away from direct heat or sunlight.

Keep out of reach of children.

SEREVENT DISKUS should be stored inside the unopened moisture-protective foil pouch and only removed from the pouch immediately before initial use.

Discard SEREVENT DISKUS 6 weeks after opening the foil pouch or when the counter reads “0” (after all blisters have been used), whichever comes first.

The inhaler is not reusable.

Do not attempt to take the inhaler apart.

GERIATRIC USE

8.5 Geriatric Use Of the total number of adult and adolescent subjects with asthma who received SEREVENT DISKUS in chronic dosing clinical trials, 209 were aged 65 years and older.

Of the total number of subjects with COPD who received SEREVENT DISKUS in chronic dosing clinical trials, 167 were aged 65 years and older and 45 were aged 75 years and older.

No apparent differences in the safety of SEREVENT DISKUS were observed when geriatric subjects were compared with younger subjects in clinical trials.

As with other beta 2 -agonists, however, special caution should be observed when using SEREVENT DISKUS in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta-agonists.

Data from the trials in subjects with COPD suggested a greater effect on FEV 1 of SEREVENT DISKUS in subjects younger than 65 years, as compared with subjects aged 65 years and older.

However, based on available data, no adjustment of dosage of SEREVENT DISKUS in geriatric patients is warranted.

DOSAGE FORMS AND STRENGTHS

3 Inhalation powder: Inhaler containing a foil blister strip of powder formulation for oral inhalation.

The strip contains salmeterol 50 mcg per blister.

Inhalation powder: Inhaler containing salmeterol (50 mcg) as a powder formulation for oral inhalation.

( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Salmeterol is a selective LABA.

In vitro studies show salmeterol to be at least 50 times more selective for beta 2 -adrenoceptors than albuterol.

Although beta 2 -adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -adrenoceptors are the predominant receptors in the heart, there are also beta 2 -adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors.

The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta 2 -agonists may have cardiac effects.

The pharmacologic effects of beta 2 -adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP).

Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D 2 , from human lung.

Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet-activating factor–induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route.

In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen-induced bronchial hyper-responsiveness.

INDICATIONS AND USAGE

1 SEREVENT DISKUS is a LABA indicated for: • Treatment of asthma in patients aged 4 years and older with an ICS.

( 1.1 ) • Prevention of exercise-induced bronchospasm (EIB) in patients aged 4 years and older.

( 1.2 ) • Maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD).

( 1.3 ) Important limitation of use: Not indicated for relief of acute bronchospasm.

( 1.1 , 1.3 ) 1.1 Treatment of Asthma SEREVENT DISKUS is indicated for the treatment of asthma and in the prevention of bronchospasm only as concomitant therapy with an ICS in patients aged 4 years and older with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma.

LABA, such as salmeterol, the active ingredient in SEREVENT DISKUS, as monotherapy (without ICS) increase the risk of asthma-related death [see Warnings and Precautions ( 5.1 )] .

Use of SEREVENT DISKUS for the treatment of asthma without concomitant use of an ICS is contraindicated [see Contraindications ( 4 )] .

Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on an ICS.

Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose ICS.

Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA as monotherapy increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

For pediatric and adolescent patients with asthma who require addition of a LABA to an ICS, a fixed-dose combination product containing both an ICS and a LABA should ordinarily be used to ensure adherence with both drugs.

In cases where use of a separate ICS and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components.

If adherence cannot be assured, a fixed-dose combination product containing both an ICS and a LABA is recommended.

Important Limitation of Use SEREVENT DISKUS is NOT indicated for the relief of acute bronchospasm.

1.2 Prevention of Exercise-Induced Bronchospasm SEREVENT DISKUS is also indicated for prevention of exercise-induced bronchospasm (EIB) in patients aged 4 years and older.

Use of SEREVENT DISKUS as a single agent for the prevention of EIB may be clinically indicated in patients who do not have persistent asthma.

In patients with persistent asthma, use of SEREVENT DISKUS for the prevention of EIB may be clinically indicated, but the treatment of asthma should include an ICS.

1.3 Maintenance Treatment of Chronic Obstructive Pulmonary Disease SEREVENT DISKUS is indicated for the long-term twice-daily administration in the maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD) (including emphysema and chronic bronchitis).

Important Limitation of Use SEREVENT DISKUS is NOT indicated for the relief of acute bronchospasm.

PEDIATRIC USE

8.4 Pediatric Use Available data from controlled clinical trials suggest that LABA used as monotherapy increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

The safety and efficacy of SEREVENT DISKUS in adolescents (aged 12 years and older) have been established based on adequate and well-controlled trials conducted in adults and adolescents [see Clinical Studies ( 14.1 )] .

A large 28-week placebo-controlled U.S.

trial comparing salmeterol (SEREVENT Inhalation Aerosol) and placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol [see Clinical Studies ( 14.1 )] .

Post hoc analyses in pediatric subjects aged 12 to 18 years were also performed.

Pediatric subjects accounted for approximately 12% of subjects in each treatment arm.

All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1,653]) versus the placebo group (less than 1% [16/1,622]; relative risk: 2.1 [95% CI: 1.1, 3.7]).

The safety and efficacy of SEREVENT DISKUS have been evaluated in over 2,500 subjects aged 4 to 11 years with asthma, 346 of whom were administered SEREVENT DISKUS for 1 year.

Based on available data, no adjustment of dosage of SEREVENT DISKUS in pediatric patients is warranted for either asthma or EIB.

In 2 randomized, double-blind, controlled clinical trials of 12 weeks’ duration, SEREVENT DISKUS 50 mcg was administered to 211 pediatric subjects with asthma who did and who did not receive concurrent ICS.

The efficacy of SEREVENT DISKUS was demonstrated over the 12-week treatment period with respect to peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV 1 ).

SEREVENT DISKUS was effective in demographic subgroups (gender and age) of the population.

In 2 randomized trials in children aged 4 to 11 years with asthma and EIB, a single 50-mcg dose of SEREVENT DISKUS prevented EIB when dosed 30 minutes prior to exercise, with protection lasting up to 11.5 hours in repeat testing following this single dose in many subjects.

PREGNANCY

8.1 Pregnancy Risk Summary The available data from published epidemiological studies and case reports with use of SEREVENT DISKUS in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) .

Beta‑agonists may interfere with uterine contractility.

There are clinical considerations in pregnant women with asthma (see Clinical Considerations) .

Oral administration of salmeterol to pregnant rabbits caused teratogenicity characteristic of beta‑adrenoceptor stimulation at maternal doses approximately 50 times the maximum recommended human daily inhaled dose (MRHDID) on an AUC basis.

These adverse effects generally occurred at large multiples of the MRHDID when salmeterol was administered by the oral route to achieve high systemic exposures.

No such effects occurred at an oral salmeterol dose approximately 20 times the MRHDID (see Data) .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate.

Severe asthma during pregnancy has been associated with maternal mortality, fetal mortality, or both.

Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.

Labor and Delivery: There are no adequate and well-controlled human studies that have evaluated the effects of SEREVENT DISKUS during labor and delivery.

Because of the potential for beta-agonist interference with uterine contractility, use of SEREVENT DISKUS during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Data Human Data: While available studies cannot definitively establish the absence of risk, published data from epidemiological studies and case reports have not established an association with SEREVENT DISKUS use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes.

The available studies have methodologic limitations, including retrospective data collection and inconsistent comparator groups.

Animal Data: In 3 embryofetal development studies, pregnant rabbits received oral administration of salmeterol at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis.

In pregnant Dutch rabbits administered salmeterol doses approximately 50 times the MRHDID (on an AUC basis at maternal oral doses of 1,000 mcg/kg/day and higher), fetal toxic effects were observed characteristically resulting from beta‑adrenoceptor stimulation.

These included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones.

No such effects occurred at a salmeterol dose approximately 20 times the MRHDID (on an AUC basis at a maternal oral dose of 600 mcg/kg/day).

New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at a salmeterol dose approximately 2,000 times the MRHDID (on a mcg/m 2 basis at a maternal oral dose of 10,000 mcg/kg/day).

In 2 embryofetal development studies, pregnant rats received salmeterol by oral administration at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis.

Salmeterol produced no maternal toxicity or embryofetal effects at doses up to 973 times the MRHDID (on a mcg/m 2 basis at maternal oral doses up to 10,000 mcg/kg/day).

In a peri- and post-natal development study in pregnant rats dosed by the oral route from late gestation through delivery and lactation, salmeterol at a dose 973 times the MRHDID (on a mcg/m 2 basis with a maternal oral dose of 10,000 mcg/kg/day) was fetotoxic and decreased the fertility of survivors.

Salmeterol xinafoate crossed the placenta following oral administration to mice and rats.

BOXED WARNING

WARNING: ASTHMA-RELATED DEATH Long-acting beta 2 -adrenergic agonists (LABA), such as salmeterol, the active ingredient in SEREVENT DISKUS, as monotherapy (without inhaled corticosteroids [ICS]) increase the risk of asthma-related death.

Data from a large placebo-controlled U.S.

trial that compared the safety of salmeterol with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol (13 deaths out of 13,176 subjects treated for 28 weeks on salmeterol versus 3 deaths out of 13,179 subjects on placebo).

Use of background ICS was not required in this study.

When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.

Use of SEREVENT DISKUS for the treatment of asthma as monotherapy without a concomitant ICS is contraindicated.

Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on an ICS.

Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose ICS.

In cases where use of an ICS and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components.

If adherence cannot be assured, a fixed-dose combination product containing both an ICS and a LABA is recommended.

WARNING: ASTHMA-RELATED DEATH See full prescribing information for complete boxed warning.

• Long-acting beta 2 -adrenergic agonists (LABA), such as salmeterol, the active ingredient in SEREVENT DISKUS, as monotherapy (without inhaled corticosteroids [ICS]) increase the risk of asthma – related death.

A U.S.

trial showed an increase in asthma – related deaths in subjects receiving salmeterol (13 deaths out of 13,176 subjects treated for 28 weeks on salmeterol versus 3 out of 13,179 subjects on placebo).

( 5.1 ) • Prescribe SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on an ICS.

Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose ICS.

( 1.1 , 5.1 ) • Available data from controlled clinical trials suggest that LABA as monotherapy increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

( 5.1 )

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • LABA as monotherapy (without ICS) for asthma increase the risk of asthma-related death and asthma-related hospitalizations.

Prescribe for asthma only as concomitant therapy with an inhaled corticosteroid.

( 5.1 ) • Do not initiate in acutely deteriorating asthma or COPD.

Do not use to treat acute symptoms.

( 5.2 ) • Not a substitute for corticosteroids.

Patients with asthma must take a concomitant ICS.

( 5.3 ) • Do not use in combination with an additional medicine containing a LABA because of risk of overdose.

( 5.4 ) • If paradoxical bronchospasm occurs, discontinue SEREVENT DISKUS and institute alternative therapy.

( 5.5 ) • Use with caution in patients with cardiovascular or central nervous system disorders because of beta-adrenergic stimulation.

( 5.6 ) • Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis.

( 5.9 ) • Be alert to hypokalemia and hyperglycemia.

( 5.10 ) 5.1 Asthma-Related Death LABA, such as salmeterol, the active ingredient in SEREVENT DISKUS, as monotherapy (without ICS) increase the risk of asthma-related death.

When LABA are used in fixed – dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.

Use of SEREVENT DISKUS for the treatment of asthma without concomitant use of an ICS is contraindicated.

Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on an ICS.

Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose ICS.

In cases where use of a separate ICS and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components.

If adherence cannot be assured, a fixed-dose combination product containing both an ICS and a LABA is recommended.

The Salmeterol Multicenter Asthma Research Trial (SMART) was a large 28-week placebo-controlled U.S.

trial comparing the safety of salmeterol (SEREVENT Inhalation Aerosol) with placebo, each added to usual asthma therapy, that showed an increase in asthma-related deaths in subjects receiving salmeterol [see Clinical Studies ( 14.1 )] .

Given the similar basic mechanisms of action of beta 2 -agonists, the findings seen in the SMART trial are considered a class effect.

A 16-week clinical trial performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) trial, showed results similar to the SMART trial.

In the SNS trial, the rate of asthma-related death was numerically, though not statistically significantly, greater in subjects with asthma treated with salmeterol (42 mcg twice daily) than those treated with albuterol (180 mcg 4 times daily) added to usual asthma therapy.

The SNS and SMART trials enrolled subjects with asthma.

Available data do not suggest an increased risk of death with use of LABA in patients with COPD.

5.2 Deterioration of Disease and Acute Episodes SEREVENT DISKUS should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD.

SEREVENT DISKUS has not been studied in subjects with acutely deteriorating asthma or COPD.

The initiation of SEREVENT DISKUS in this setting is not appropriate.

Serious acute respiratory events, including fatalities, have been reported when salmeterol has been initiated in patients with significantly worsening or acutely deteriorating asthma.

In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, previous life-threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with significantly increasing symptoms; increasing need for inhaled, short-acting beta 2 -agonists; decreasing response to usual medications; increasing need for systemic corticosteroids; recent emergency room visits; deteriorating lung function).

However, these events have occurred in a few patients with less severe asthma as well.

It was not possible from these reports to determine whether salmeterol contributed to these events.

Increasing use of inhaled, short-acting beta 2 -agonists is a marker of deteriorating asthma.

In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for adding additional ICS or initiating systemic corticosteroids.

Patients should not use more than 1 inhalation twice daily of SEREVENT DISKUS.

SEREVENT DISKUS should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm.

An inhaled, short-acting beta 2 -agonist, not SEREVENT DISKUS, should be used to relieve acute symptoms such as shortness of breath.

When prescribing SEREVENT DISKUS, the healthcare provider should also prescribe an inhaled, short-acting beta 2 -agonist (e.g., albuterol) for treatment of acute symptoms.

When beginning treatment with SEREVENT DISKUS, patients who have been taking oral or inhaled, short-acting beta 2 -agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.

5.3 SEREVENT DISKUS is Not a Substitute for Corticosteroids There are no data demonstrating that SEREVENT DISKUS has a clinical anti-inflammatory effect such as that associated with corticosteroids.

When initiating and throughout treatment with SEREVENT DISKUS in patients receiving oral or ICS for treatment of asthma, patients must continue taking a suitable dosage of corticosteroids to maintain clinical stability even if they feel better as a result of initiating SEREVENT DISKUS.

Any change in corticosteroid dosage should be made ONLY after clinical evaluation.

5.4 Excessive Use of SEREVENT DISKUS and Use with Other Long-acting Beta 2 -agonists SEREVENT DISKUS should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result.

Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Patients using SEREVENT DISKUS should not use another medicine containing a LABA (e.g., formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

5.5 Paradoxical Bronchospasm and Upper Airway Symptoms As with other inhaled medicines, SEREVENT DISKUS can produce paradoxical bronchospasm, which may be life threatening.

If paradoxical bronchospasm occurs following dosing with SEREVENT DISKUS, it should be treated immediately with an inhaled, short-acting bronchodilator; SEREVENT DISKUS should be discontinued immediately; and alternative therapy should be instituted.

Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving SEREVENT DISKUS.

5.6 Cardiovascular and Central Nervous System Effects Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see Overdosage ( 10 )] .

Therefore, SEREVENT DISKUS, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Salmeterol can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms.

Although such effects are uncommon after administration of salmeterol at recommended doses, if they occur, the drug may need to be discontinued.

In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression.

The clinical significance of these findings is unknown.

Large doses of inhaled or oral salmeterol (12 to 20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias.

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

5.7 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of SEREVENT DISKUS.

There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not use SEREVENT DISKUS [see Contraindications ( 4 )] .

5.8 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with SEREVENT DISKUS is not recommended because increased cardiovascular adverse effects may occur [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] .

5.9 Coexisting Conditions SEREVENT DISKUS, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines.

Doses of the related beta 2 -adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.10 Hypokalemia and Hyperglycemia Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology ( 12.2 )] .

The decrease in serum potassium is usually transient, not requiring supplementation.

Clinically significant and dose-related changes in blood glucose and/or serum potassium were seen infrequently during clinical trials with SEREVENT DISKUS at recommended doses.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Asthma-Related Death Inform patients that salmeterol when used alone increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

Inform patients that SEREVENT DISKUS should not be the only therapy for the treatment of asthma and must only be used as additional therapy when ICS do not adequately control asthma symptoms.

Inform patients that when SEREVENT DISKUS is added to their treatment regimen they must continue to use their ICS.

Not for Acute Symptoms Inform patients that SEREVENT DISKUS is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose.

Advise patients to treat acute symptoms with an inhaled, short-acting beta 2 -agonist such as albuterol.

Provide patients with such medication and instruct them in how it should be used.

Instruct patients to seek medical attention immediately if they experience any of the following: • Decreasing effectiveness of inhaled, short-acting beta 2 -agonists • Need for more inhalations than usual of inhaled, short-acting beta 2 -agonists • Significant decrease in lung function as outlined by the physician Tell patients they should not stop therapy with SEREVENT DISKUS without physician/provider guidance since symptoms may recur after discontinuation.

Not a Substitute for Corticosteroids Advise all patients with asthma that they must also continue regular maintenance treatment with an ICS if they are taking SEREVENT DISKUS.

SEREVENT DISKUS should not be used as a substitute for oral or inhaled corticosteroids.

The dosage of these medications should not be changed and they should not be stopped without consulting the physician, even if the patient feels better after initiating treatment with SEREVENT DISKUS.

Do Not Use Additional Long-acting Beta 2 -agonists Instruct patients not to use other LABA.

Immediate Hypersensitivity Reactions Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of SEREVENT DISKUS.

Patients should discontinue SEREVENT DISKUS if such reactions occur.

Risks Associated with Beta-agonist Therapy Inform patients of adverse effects associated with beta 2 -agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

Treatment of Exercise-Induced Bronchospasm Patients using SEREVENT DISKUS for the treatment of EIB should not use additional doses for 12 hours.

Patients who are receiving SEREVENT DISKUS twice daily should not use additional SEREVENT for prevention of EIB.

Trademarks are owned by or licensed to the GSK group of companies.

SRD:16PI

DOSAGE AND ADMINISTRATION

2 SEREVENT DISKUS should be administered by the orally inhaled route only.

More frequent administration or a greater number of inhalations (more than 1 inhalation twice daily) is not recommended as some patients are more likely to experience adverse effects.

Patients using SEREVENT DISKUS should not use additional LABA for any reason.

[See Warnings and Precautions ( 5.4 , 5.6 ).] • For oral inhalation only.

( 2 ) • Treatment of asthma in patients aged 4 years and older: 1 inhalation twice daily in addition to concomitant treatment with an ICS.

( 2.1 ) • EIB: 1 inhalation at least 30 minutes before exercise.

( 2.2 ) • Maintenance treatment of bronchospasm associated with COPD: 1 inhalation twice daily.

( 2.3 ) 2.1 Asthma LABA, such as salmeterol, the active ingredient in SEREVENT DISKUS, as monotherapy (without ICS) increase the risk of asthma-related death [see Warnings and Precautions ( 5.1 )].

Because of this risk, use of SEREVENT DISKUS for the treatment of asthma without concomitant use of an ICS is contraindicated.

Use SEREVENT DISKUS only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on an ICS.

Do not use SEREVENT DISKUS for patients whose asthma is adequately controlled on low- or medium-dose ICS.

For patients with asthma younger than 18 years who require addition of a LABA to an ICS, a fixed-dose combination product containing both an ICS and a LABA should ordinarily be used to ensure adherence with both drugs.

In cases where use of a separate ICS and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components.

If adherence cannot be assured, a fixed-dose combination product containing both an ICS and a LABA is recommended.

For bronchodilatation and prevention of symptoms of asthma, including the symptoms of nocturnal asthma, the usual dosage for adults and children aged 4 years and older is 1 inhalation (50 mcg) twice daily, approximately 12 hours apart.

If a previously effective dosage regimen fails to provide the usual response, medical advice should be sought immediately as this is often a sign of destabilization of asthma.

Under these circumstances, the therapeutic regimen should be reevaluated.

If symptoms arise in the period between doses, an inhaled, short-acting beta 2 -agonist should be taken for immediate relief.

2.2 Exercise-Induced Bronchospasm Use of SEREVENT DISKUS as a single agent for the prevention of EIB may be clinically indicated in patients who do not have persistent asthma.

In patients with persistent asthma, use of SEREVENT DISKUS for the prevention of EIB may be clinically indicated, but the treatment of asthma should include an ICS.

One inhalation of SEREVENT DISKUS at least 30 minutes before exercise has been shown to protect patients against EIB.

When used intermittently as needed for prevention of EIB, this protection may last up to 9 hours in adults and adolescents and up to 12 hours in patients aged 4 to 11 years.

Additional doses of SEREVENT should not be used for 12 hours after the administration of this drug.

Patients who are receiving SEREVENT DISKUS twice daily should not use additional SEREVENT for prevention of EIB.

2.3 Chronic Obstructive Pulmonary Disease For maintenance treatment of bronchospasm associated with COPD (including chronic bronchitis and emphysema), the dosage for adults is 1 inhalation (50 mcg) twice daily, approximately 12 hours apart.