Drug Intercation

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.

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 another drug therapy.

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.

Fluticasone propionate 250 MCG/INHAL Dry Powder Inhaler, 28 Blisters

Generic Name: FLUTICASONE PROPIONATE

Brand Name: FLOVENT DISKUS

Substance Name(s):
FLUTICASONE PROPIONATE

DRUG INTERACTIONS

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

May increase risk of systemic corticosteroid effects.

( 7.1 ) 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone propionate is a substrate of CYP3A4.

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

Ritonavir A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology (12.3)] .

During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.

Ketoconazole Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.

OVERDOSAGE

10 Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.5)] .

Inhalation by healthy volunteers of a single dose of 4,000 mcg of fluticasone propionate inhalation powder or single doses of 1,760 or 3,520 mcg of fluticasone propionate CFC inhalation aerosol was well tolerated.

Fluticasone propionate given by inhalation aerosol at dosages of 1,320 mcg twice daily for 7 to 15 days to healthy human volunteers was also well tolerated.

Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in subjects were well tolerated.

Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups.

DESCRIPTION

11 FLOVENT DISKUS inhalation powder is a dry powder inhaler for oral inhalation.

The active component of FLOVENT DISKUS 50 mcg, FLOVENT DISKUS 100 mcg, and FLOVENT DISKUS 250 mcg is fluticasone propionate, a corticosteroid having the chemical name S- (fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure: Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C 25 H 31 F 3 O 5 S.

It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

FLOVENT DISKUS is an orange plastic inhaler containing a foil blister strip.

Each blister on the strip contains a white powder mix of micronized fluticasone propionate (50, 100, or 250 mcg) 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, FLOVENT DISKUS delivers 46, 94, and 229 mcg of fluticasone propionate from FLOVENT DISKUS 50 mcg, FLOVENT DISKUS 100 mcg, and FLOVENT DISKUS 250 mcg, respectively, when tested at a flow rate of 60 L/min for 2 seconds.

In children with asthma aged 4 and 8 years, mean PIF through FLOVENT DISKUS was 70 and 104 L/min, respectively (range: 48 to 123 L/min).

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

Chemical structure

CLINICAL STUDIES

14 14.1 Adult and Adolescent Subjects Aged 12 Years and Older Four randomized, double-blind, parallel-group, placebo-controlled, U.S.

clinical trials were conducted in 1,036 adult and adolescent subjects (aged 12 years and older) with asthma to assess the efficacy and safety of FLOVENT DISKUS in the treatment of asthma.

Fixed dosages of 100, 250, and 500 mcg twice daily were compared with placebo to provide information about appropriate dosing to cover a range of asthma severity.

Subjects in these trials included those inadequately controlled with bronchodilators alone and those already maintained on daily ICS.

All doses were delivered by inhalation of the contents of 1 or 2 blisters from FLOVENT DISKUS twice daily.

Figures 1 through 4 display results of pulmonary function tests (mean percent change from baseline in FEV 1 prior to AM dose) for 3 recommended dosages of FLOVENT DISKUS (100, 250, and 500 mcg twice daily) and placebo from the four 12-week trials in adolescents and adults.

These trials used predetermined criteria for lack of efficacy (indicators of worsening asthma), resulting in withdrawal of more patients in the placebo group.

Therefore, pulmonary function results at Endpoint (the last evaluable FEV 1 result, including most patients’ lung function data) are also displayed.

Pulmonary function, as determined by percent change from baseline in FEV 1 at recommended dosages of FLOVENT DISKUS improved significantly compared with placebo by the first week of treatment, and improvement was maintained for up to 1 year or more.

Figure 1.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Bronchodilators Alone Figure 2.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids Figure 3.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 250 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone Figure 4.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 500 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone In all 4 efficacy trials, measures of pulmonary function (FEV 1 ) were statistically significantly improved as compared with placebo at all twice-daily doses.

Subjects on all dosages of FLOVENT DISKUS were also less likely to discontinue study participation due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and subject-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma) compared with placebo.

In a clinical trial of 111 subjects with severe asthma requiring chronic oral prednisone therapy (average baseline daily prednisone dose was 14 mg), fluticasone propionate given by inhalation powder at doses of 500 and 1,000 mcg twice daily was evaluated.

Both doses enabled a statistically significantly larger percentage of subjects to wean from oral prednisone as compared with placebo (75% of the subjects on 500 mcg twice daily and 89% of the subjects on 1,000 mcg twice daily as compared with 9% of subjects on placebo).

Accompanying the reduction in oral corticosteroid use, subjects treated with fluticasone propionate had significantly improved lung function and fewer asthma symptoms as compared with the placebo group.

Figure 1.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Bronchodilators Alone Figure 2.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids Figure 3.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 250 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone Figure 4.

A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 500 mcg Twice Daily in Adults and Adolescents Receiving Inhaled Corticosteroids or Bronchodilators Alone 14.2 Pediatric Subjects Aged 4 to 11 Years A 12-week, placebo-controlled clinical trial was conducted in 437 pediatric subjects (177 received FLOVENT DISKUS), approximately half of whom were receiving ICS at baseline.

In this trial, doses of fluticasone propionate inhalation powder 50 and 100 mcg twice daily significantly improved FEV 1 (15% and 18% change from baseline at Endpoint, respectively) compared with placebo (7% change).

AM PEF was also significantly improved with doses of fluticasone propionate 50 and 100 mcg twice daily (26% and 27% change from baseline at Endpoint, respectively) compared with placebo (14% change).

In this trial, subjects on active treatment were significantly less likely to discontinue treatment due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and subject-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma).

Two other 12-week placebo-controlled clinical trials were conducted in 504 pediatric subjects with asthma, approximately half of whom were receiving ICS at baseline.

In these trials, FLOVENT DISKUS was efficacious at doses of 50 and 100 mcg twice daily when compared with placebo on major endpoints including lung function and symptom scores.

Pulmonary function improved significantly compared with placebo by the first week of treatment, and subjects treated with FLOVENT DISKUS were also less likely to discontinue trial participation due to asthma deterioration.

One hundred ninety-two (192) subjects received FLOVENT DISKUS for up to 1 year during an open-label extension.

Data from this open-label extension suggested that lung function improvements could be maintained up to 1 year.

HOW SUPPLIED

16 /STORAGE AND HANDLING FLOVENT DISKUS 50 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0600-02).

FLOVENT DISKUS 100 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0602-02).

FLOVENT DISKUS 250 mcg is supplied as a disposable orange plastic inhaler containing a foil blister strip with 60 blisters.

The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 0173-0601-02).

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.

FLOVENT DISKUS should be stored inside the unopened moisture-protective foil pouch and only removed from the pouch immediately before initial use.

Discard FLOVENT DISKUS 6 weeks (50-mcg strength) or 2 months (100- and 250-mcg strengths) 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 Safety data have been collected on 280 subjects (FLOVENT DISKUS n = 83, FLOVENT ROTADISK n = 197) aged 65 years and older and 33 subjects (FLOVENT DISKUS n = 14, FLOVENT ROTADISK n = 19) aged 75 years and older who have been treated with fluticasone propionate inhalation powder in U.S.

and non-U.S.

clinical trials.

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

DOSAGE FORMS AND STRENGTHS

3 Inhalation powder: Inhaler containing a foil blister strip of powder formulation for oral inhalation.

The strip contains fluticasone propionate 50, 100, or 250 mcg per blister.

Inhalation powder: Inhaler containing fluticasone propionate (50, 100, or 250 mcg) as a powder formulation for oral inhalation.

( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity.

Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide.

Data from the McKenzie vasoconstrictor assay in man are consistent with these results.

The clinical significance of these findings is unknown.

Inflammation is an important component in the pathogenesis of asthma.

Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation.

These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

Though effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately.

Individual patients will experience a variable time to onset and degree of symptom relief.

Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment.

When corticosteroids are discontinued, asthma stability may persist for several days or longer.

Trials in subjects with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone propionate.

This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (<1%), and the minimal pharmacological activity of the only metabolite detected in man.

INDICATIONS AND USAGE

1 FLOVENT DISKUS is indicated for the maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older.

Important Limitation of Use FLOVENT DISKUS is NOT indicated for the relief of acute bronchospasm.

FLOVENT DISKUS is an inhaled corticosteroid (ICS) indicated for: • Maintenance treatment of asthma as prophylactic therapy in patients aged 4 years and older.

( 1 ) Important limitation: • Not indicated for relief of acute bronchospasm.

( 1 )

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of FLOVENT DISKUS in children aged 4 years and older have been established [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)] .

The safety and effectiveness of FLOVENT DISKUS in children younger than 4 years have not been established.

Effects on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients.

A reduction of growth velocity in children or teenagers may occur as a result of poorly controlled asthma or from use of corticosteroids, including ICS.

The effects of long-term treatment of children and adolescents with ICS, including fluticasone propionate, on final adult height are not known.

Controlled clinical trials have shown that ICS may cause a reduction in growth in pediatric patients.

In these trials, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appeared to depend upon dose and duration of exposure.

This effect was observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function.

The long‑term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown.

The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.

The effects on growth velocity of treatment with orally inhaled corticosteroids for over 1 year, including the impact on final adult height, are unknown.

The growth of children and adolescents receiving orally inhaled corticosteroids, including FLOVENT DISKUS, should be monitored routinely (e.g., via stadiometry).

The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies.

To minimize the systemic effects of orally inhaled corticosteroids, including FLOVENT DISKUS, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

A 52-week placebo-controlled trial to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT ROTADISK) at 50 and 100 mcg twice daily was conducted in the U.S.

in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years.

The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (n = 76), 6.07 cm/year in the 50-mcg group (n = 98), and 5.66 cm/year in the 100‑mcg group (n = 89).

An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data.

A separate subset analysis of children who remained prepubertal during the trial revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100‑mcg group (n = 79).

In children aged 8.5 years, the mean age of children in this trial, the range for expected growth velocity is: boys – 3 rd percentile = 3.8 cm/year, 50 th percentile = 5.4 cm/year, and 97 th percentile = 7.0 cm/year; girls – 3 rd percentile = 4.2 cm/year, 50 th percentile = 5.7 cm/year, and 97 th percentile = 7.3 cm/year.

The clinical relevance of these growth data is not certain.

PREGNANCY

8.1 Pregnancy Risk Summary There are insufficient data on the use of FLOVENT DISKUS in pregnant women.

There are clinical considerations with the use of FLOVENT DISKUS in pregnant women.

(See Clinical Considerations.) In animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight, and/or skeletal variations in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the maximum recommended human daily inhaled dose (MRHDID) on a mcg/m 2 basis.

(See Data.) However, fluticasone propionate administered via inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m 2 basis.

(See Data.) Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.

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

In the U.S.

general population, the estimated 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 several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate.

Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.

Data Human Data: Following inhaled administration, fluticasone propionate was detected in the neonatal cord blood after delivery.

Animal Data: In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species.

Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately 0.5 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 100 mcg/kg/day).

The rat no observed adverse effect level (NOAEL) was observed at approximately 0.15 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 30 mcg/kg/day).

Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.1 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 45 mcg/kg/day).

The mouse NOAEL was observed with a dose approximately 0.04 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 15 mcg/kg/day).

In an embryofetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.13 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity.

The NOAEL was observed with a dose approximately 0.03 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 5.5 mcg/kg/day).

In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.006 times the MRHDID and higher (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day).

Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose approximately 0.04 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 4 mcg/kg/day).

The NOAEL was observed in rabbit fetuses with a dose approximately 0.001 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day).

Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.

In a pre- and post-natal development study in pregnant rats dosed from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 0.2 times the MRHDID (on a mcg/m 2 basis with maternal subcutaneous doses up to 50 mcg/kg/day).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Candida albicans infection of the mouth and pharynx may occur.

Monitor patients periodically.

Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk.

( 5.1 ) • Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infection; ocular herpes simplex).

Use with caution in patients with these infections.

More serious or even fatal course of chickenpox or measles can occur in susceptible patients.

( 5.3 ) • Risk of impaired adrenal function when transferring from systemic corticosteroids.

Taper patients slowly from systemic corticosteroids if transferring to FLOVENT DISKUS.

( 5.4 ) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals.

If such changes occur, discontinue FLOVENT DISKUS slowly.

( 5.5 ) • Assess for decrease in bone mineral density initially and periodically thereafter.

( 5.7 ) • Monitor growth of pediatric patients.

( 5.8 ) • Glaucoma and cataracts may occur with long-term use of ICS.

Consider referral to an ophthalmologist in patients who develop ocular symptoms or use FLOVENT DISKUS long term.

( 5.9 ) 5.1 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with FLOVENT DISKUS.

When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with FLOVENT DISKUS continues, but at times therapy with FLOVENT DISKUS may need to be interrupted.

Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

5.2 Acute Asthma Episodes FLOVENT DISKUS is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.

Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with FLOVENT DISKUS.

During such episodes, patients may require therapy with oral corticosteroids.

5.3 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals.

Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids.

In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure.

How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known.

The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.

If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated.

If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated.

(See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

5.4 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available ICS.

After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.

During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss.

Although FLOVENT DISKUS may control asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction.

These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to FLOVENT DISKUS.

Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with FLOVENT DISKUS.

Lung function (mean forced expiratory volume in 1 second [FEV 1 ] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids.

In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to FLOVENT DISKUS may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

5.5 Hypercorticism and Adrenal Suppression Fluticasone propionate will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone.

Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of FLOVENT DISKUS in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose.

A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol.

Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing FLOVENT DISKUS.

Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with FLOVENT DISKUS should be observed carefully for any evidence of systemic corticosteroid effects.

Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects.

If such effects occur, FLOVENT DISKUS should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of asthma symptoms should be considered.

5.6 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of FLOVENT DISKUS.

5.7 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS.

The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown.

Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids), should be monitored and treated with established standards of care.

A 2-year trial in 160 subjects (females aged 18 to 40 years, males 18 to 50) with asthma receiving chlorofluorocarbon (CFC)-propelled fluticasone propionate inhalation aerosol 88 or 440 mcg twice daily demonstrated no statistically significant changes in BMD at any time point (24, 52, 76, and 104 weeks of double-blind treatment) as assessed by dual-energy x-ray absorptiometry at lumbar regions L1 through L4.

5.8 Effect on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients .

Monitor the growth of pediatric patients receiving FLOVENT DISKUS routinely (e.g., via stadiometry).

To minimize the systemic effects of orally inhaled corticosteroids, including FLOVENT DISKUS, titrate each patient’s dosage to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2.2), Use in Specific Populations (8.4)] .

5.9 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of ICS, including fluticasone propionate.

Consider referral to an ophthalmologist in patients who develop ocular symptoms or use FLOVENT DISKUS long term.

5.10 Paradoxical Bronchospasm As with other inhaled medicines, bronchospasm may occur with an immediate increase in wheezing after dosing.

If bronchospasm occurs following dosing with FLOVENT DISKUS, it should be treated immediately with an inhaled, short-acting bronchodilator; FLOVENT DISKUS should be discontinued immediately; and alternative therapy should be instituted.

5.11 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 FLOVENT DISKUS is not recommended because increased systemic corticosteroid adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)] .

5.12 Eosinophilic Conditions and Churg-Strauss Syndrome In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions.

Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy.

These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate.

Cases of serious eosinophilic conditions have also been reported with other ICS in this clinical setting.

Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients.

A causal relationship between fluticasone propionate and these underlying conditions has not been established.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Local Effects Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients.

If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with FLOVENT DISKUS, but at times therapy with FLOVENT DISKUS may need to be temporarily interrupted under close medical supervision.

Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush.

Status Asthmaticus and Acute Asthma Symptoms Inform patients that FLOVENT DISKUS is not a bronchodilator and is not intended for use as rescue medicine for acute asthma exacerbations.

Advise patients to treat acute asthma symptoms with an inhaled, short-acting beta 2 -agonist such as albuterol.

Instruct patients to contact their physicians immediately if there is deterioration of their asthma.

Immunosuppression Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay.

Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Hypercorticism and Adrenal Suppression Advise patients that FLOVENT DISKUS may cause systemic corticosteroid effects of hypercorticism and adrenal suppression.

Additionally, inform patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids.

Patients should taper slowly from systemic corticosteroids if transferring to FLOVENT DISKUS.

Patients should discontinue FLOVENT DISKUS if such reactions occur.

Reduction in Bone Mineral Density Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk.

Reduced Growth Velocity Inform patients that orally inhaled corticosteroids, including FLOVENT DISKUS, may cause a reduction in growth velocity when administered to pediatric patients.

Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route.

Glaucoma and Cataracts Advise patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.

Use Daily for Best Effect Patients should use FLOVENT DISKUS at regular intervals as directed.

Individual patients will experience a variable time to onset and degree of symptom relief and the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks or longer.

Patients should not increase the prescribed dosage but should contact their physicians if symptoms do not improve or if the condition worsens.

Instruct patients not to stop use of FLOVENT DISKUS abruptly.

Patients should contact their physicians immediately if they discontinue use of FLOVENT DISKUS.

Trademarks are owned by or licensed to the GSK group of companies.

FLD:15PI

DOSAGE AND ADMINISTRATION

2 • For oral inhalation only.

( 2.1 ) • Starting dosage is based on prior asthma therapy and disease severity.

( 2.2 ) • Treatment of asthma in patients aged 12 years and older: 100 mcg twice daily up to a maximum recommended dosage of 1,000 mcg twice daily.

( 2.2 ) • Treatment of asthma in patients aged 4 to 11 years: 50 mcg twice daily up to a maximum recommended dosage of 100 mcg twice daily.

( 2.2 ) 2.1 Administration Information FLOVENT DISKUS should be administered by the orally inhaled route in patients aged 4 years and older.

After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.

2.2 Recommended Dosage Adult and Adolescent Patients Aged 12 Years and Older The starting dosage is based on previous asthma therapy and asthma severity, including consideration of patients’ current control of asthma symptoms and risk of future exacerbation.

The recommended starting dosage for patients aged 12 years and older who are not on an inhaled corticosteroid (ICS) is 100 mcg twice daily, approximately 12 hours apart.

For other patients, and for patients who do not respond adequately to the starting dosage after 2 weeks of therapy, higher dosages may provide additional asthma control.

The maximum recommended dosage for patients aged 12 years and older is 1,000 mcg twice daily.

Pediatric Patients Aged 4 to 11 Years The starting dosage is based on previous asthma therapy and asthma severity, including consideration of patients’ current control of asthma symptoms and risk of future exacerbation.

For patients aged 4 to 11 years not on an ICS, the recommended starting dosage is 50 mcg twice daily, approximately 12 hours apart.

For other patients, and for patients who do not respond adequately to the starting dosage after 2 weeks of therapy, increasing the dosage to 100 mcg twice daily may provide additional asthma control.

The maximum recommended dosage for patients aged 4 to 11 years is 100 mcg twice daily.

General Dosing Recommendations If symptoms arise between doses, an inhaled short-acting beta 2 -agonist should be used for immediate relief.

Individual patients will experience a variable time to onset and degree of symptom relief.

Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment.

If a dosage regimen fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, e.g., replacing the current strength with a higher strength, initiating an ICS and long-acting beta2-agonist (LABA) combination product, or initiating oral corticosteroids, should be considered.

After asthma stability has been achieved, titrate to the lowest effective dosage to reduce the possibility of side effects.

vitamin D2 50,000 UNT Oral Capsule

WARNINGS

Hypersensitivity to vitamin D may be one etiologic factor in infants with idiopathic hypercalcemia.

In these cases vitamin D must be strictly restricted.

Keep out of the reach of children.

DRUG INTERACTIONS

Drug Interactions Mineral oil interferes with the absorption of fat-soluble vitamins, including vitamin D preparations.

Administration of thiazide diuretics to hypoparathyroid patients who are concurrently being treated with ergocalciferol may cause hypercalcemia.

OVERDOSAGE

The effects of administered vitamin D can persist for two or more months after cessation of treatment.

Hypervitaminosis D is characterized by: Hypercalcemia with anorexia, nausea, weakness, weight loss, vague aches and stiffness, constipation, mental retardation, anemia, and mild acidosis.

Impairment of renal function with polyuria, nocturia, polydipsia, hypercalciuria, reversible azotemia, hypertension, nephrocalcinosis, generalized vascular calcification, or irreversible renal insufficiency which may result in death.

Widespread calcification of the soft tissues, including the heart, blood vessels, renal tubules, and lungs.

Bone demineralization (osteoporosis) in adults occurs concomitantly.

Decline in the average rate of linear growth and increased mineralization of bones in infants and children (dwarfism).

The treatment of hypervitaminosis D with hypercalcemia consists of immediate withdrawal of the vitamin, a low calcium diet, generous intake of fluids, along with symptomatic and supportive treatment.

Hypercalcemic crisis with dehydration, stupor, coma, and azotemia requires more vigorous treatment.

The first step should be hydration of the patient.

Intravenous saline may quickly and significantly increase urinary calcium excretion.

A loop diuretic (furosemide or ethacrynic acid) may be given with the saline infusion to further increase renal calcium excretion.

Other reported therapeutic measures include dialysis or the administration of citrates, sulfates, phosphates, corticosteroids, EDTA (ethylenediaminetetraacetic acid), and mithramycin via appropriate regimens.

With appropriate therapy, recovery is the usual outcome when no permanent damage has occurred.

Deaths via renal or cardiovascular failure have been reported.

The LD 50 in animals is unknown.

The toxic oral dose of ergocalciferol in the dog is 4 mg/kg.

DESCRIPTION

Ergocalciferol Capsules, USP is a synthetic calcium regulator for oral administration.

Ergocalciferol is a white, colorless crystal, insoluble in water, soluble in organic solvents, and slightly soluble in vegetable oils.

It is affected by air and by light.

Ergosterol or provitamin D 2 is found in plants and yeast and has no antirachitic activity.

There are more than 10 substances belonging to a group of steroid compounds, classified as having vitamin D or antirachitic activity.

One USP Unit of vitamin D 2 is equivalent to one International Unit (IU), and 1 mcg of vitamin D 2 is equal to 40 IU.

Each softgel capsule, for oral administration, contains Ergocalciferol, USP 1.25 mg (equivalent to 50,000 USP units of Vitamin D), in an edible vegetable oil.

Ergocalciferol, also called vitamin D 2 , is 9, 10-secoergosta-5, 7,10(19),22-tetraen-3-ol,(3β,5 Z ,7 E ,22 E )-; (C 28 H 44 O) with a molecular weight of 396.65, and has the following structural formula: Inactive Ingredients : D&C Yellow No.

10, FD&C Blue No.

1, Gelatin, Glycerin, Purified Water, Refined Soybean Oil.

Chemical Structure

HOW SUPPLIED

Each green, oval softgel capsule is imprinted with A3 and contains 1.25 mg (50,000 USP units vitamin D) of ergocalciferol, USP.

Bottles of 12 Softgel Capsules (NDC 60429-245-12) Bottles of 13 Softgel Capsules (NDC 60429-245-13) Bottles of 100 Softgel Capsules (NDC 60429-245-01) Storage and Handling Store at 20°- 25°C (68°-77°F) [See USP Controlled Room Temperature].

Protect from light and moisture.

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

GERIATRIC USE

Geriatric Use Clinical studies of ergocalciferol 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.

A few published reports have suggested that the absorption of orally administered vitamin D may be attenuated in elderly compared to younger individuals.

INDICATIONS AND USAGE

Ergocalciferol Capsules, USP are indicated for use in the treatment of hypoparathyroidism, refractory rickets, also known as vitamin D resistant rickets, and familial hypophosphatemia.

PEDIATRIC USE

Pediatric Use Pediatric doses must be individualized (see DOSAGE AND ADMINISTRATION ).

PREGNANCY

Pregnancy Category C Animal reproduction studies have shown fetal abnormalities in several species associated with hypervitaminosis D.

These are similar to the supravalvular aortic stenosis syndrome described in infants by Black in England (1963).

This syndrome was characterized by supravalvular aortic stenosis, elfin facies, and mental retardation.

For the protection of the fetus, therefore, the use of vitamin D in excess of the recommended dietary allowance during normal pregnancy should be avoided unless, in the judgment of the physician, potential benefits in a specific, unique case outweigh the significant hazards involved.

The safety in excess of 400 USP units of vitamin D daily during pregnancy has not been established.

NUSRING MOTHERS

Nursing Mothers Caution should be exercised when ergocalciferol is administered to a nursing woman.

In a mother given large doses of vitamin D, 25-hydroxycholecalciferol appeared in the milk and caused hypercalcemia in her child.

Monitoring of the infant’s serum calcium concentration is required in that case (Goldberg, 1972).

DOSAGE AND ADMINISTRATION

THE RANGE BETWEEN THERAPEUTIC AND TOXIC DOSES IS NARROW.

Vitamin D Resistant Rickets : 12,000 to 500,000 USP units daily.

Hypoparathyroidism : 50,000 to 200,000 USP units daily concomitantly with calcium lactate 4 g, six times per day.

DOSAGE MUST BE INDIVIDUALIZED UNDER CLOSE MEDICAL SUPERVISION.

Calcium intake should be adequate.

Blood calcium and phosphorus determinations must be made every 2 weeks or more frequently if necessary.

X-rays of the bones should be taken every month until condition is corrected and stabilized.

Generic Name: RIFAMPIN

Brand Name: Rifadin IV

Substance Name(s):
RIFAMPIN

WARNINGS

Hepatotoxicity of hepatocellular, cholestatic, and mixed patterns has been reported in patients treated with rifampin.

Severity ranged from asymptomatic elevations in liver enzymes, isolated jaundice/hyperbilirubinemia, symptomatic self-limited hepatitis to fulminant liver failure and death.

Severe hepatic dysfunction including fatalities were reported in patients with liver disease and in patients taking rifampin with other hepatotoxic agents.

Monitor for symptoms and clinical/laboratory signs of liver injury, especially if treatment is prolonged or given with other hepatotoxic drugs.

Patients with impaired liver function should be given rifampin only in cases of necessity and then under strict medical supervision.

In these patients, careful monitoring of liver function should be done prior to therapy and then every 2 to 4 weeks during therapy.

If signs of hepatic damage occur or worsen, discontinue rifampin.

Rifampin has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase.

Isolated reports have associated porphyria exacerbation with rifampin administration.

The possibility of rapid emergence of resistant meningococci restricts the use of RIFADIN to short-term treatment of the asymptomatic carrier state.

RIFADIN is not to be used for the treatment of meningococcal disease.

Systemic hypersensitivity reactions were reported with RIFADIN administration.

Signs and symptoms of hypersensitivity reactions may include fever, rash, urticaria, angioedema, hypotension, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia, elevated liver transaminases or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, chills, aches, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations).

Manifestations of hypersensitivity, such as fever, lymphadenopathy or laboratory abnormalities (including eosinophilia, liver abnormalities) may be present even though rash is not evident.

Monitor patients receiving RIFADIN for signs and/or symptoms of hypersensitivity reactions.

If these signs or symptoms occur, discontinue RIFADIN and administer supportive measures.

Cases of severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with rifampin.

If symptoms or signs of severe cutaneous adverse reactions develop, discontinue RIFADIN immediately and institute appropriate therapy.

Rifampin may cause vitamin K–dependent coagulation disorders and bleeding (see ADVERSE REACTIONS ).

Monitor coagulation tests during rifampin treatment (prothrombin time and other coagulation tests) in patients at risk of vitamin K deficiency (such as those with chronic liver disease, poor nutritional status, on prolonged antibacterial drugs or anticoagulants).

Consider discontinuation of RIFADIN if abnormal coagulation tests and/or bleeding occur.

Supplemental vitamin K administration should be considered when appropriate.

Pulmonary toxicity manifested as interstitial lung disease (including, but not limited to, pneumonitis, hypersensitivity pneumonitis, eosinophilic pneumonia, pulmonary infiltrates, and organizing pneumonia) has been reported with rifampin treatment.

Pulmonary toxicity could be fatal.

If symptoms or signs of severe pulmonary toxicity (including respiratory failure, pulmonary fibrosis, and acute respiratory distress syndrome) develop, discontinue RIFADIN immediately and initiate appropriate treatment.

Postmarketing reports suggest that concomitant administration of high doses of cefazolin and rifampin may prolong the prothrombin time, leading to severe vitamin K–dependent coagulation disorders that may be life-threatening or fatal.

Avoid concomitant use of cefazolin and rifampin in patients at increased risk for bleeding.

If no alternative treatment options are available, closely monitor prothrombin time and other coagulation tests, and administer vitamin K as indicated.

Postmarketing cases of paradoxical drug reaction (recurrence or appearance of new symptoms, physical and radiological signs in a patient who had previously shown improvement with appropriate antimycobacterial treatment, in the absence of disease relapse, poor treatment compliance, drug resistance, side effects of treatment, or secondary infection/diagnosis) have been reported with RIFADIN (see ADVERSE REACTIONS ).

Paradoxical drug reactions are often transient and should not be misinterpreted as failure to respond to treatment.

If worsening of symptoms or signs occurs during antimycobacterial treatment, consider paradoxical drug reaction in the differential diagnosis, monitor, or treat accordingly.

Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremia syndrome, some fatal, have been reported with rifampin.

Discontinue RIFADIN if clinical symptoms and laboratory findings consistent with TMA occur.

The findings of unexplained thrombocytopenia and anemia should prompt further evaluation and consideration of the diagnosis of TMA.

DRUG INTERACTIONS

Drug Interactions Pharmacodynamic Interactions Healthy subjects who received rifampin 600 mg once daily concomitantly with saquinavir 1000 mg/ritonavir 100 mg twice daily (ritonavir-boosted saquinavir) developed severe hepatocellular toxicity.

Therefore, concomitant use of these medications is contraindicated.

(See CONTRAINDICATIONS .) When rifampin is given concomitantly with other hepatotoxic medications such as halothane or isoniazid, the potential for hepatotoxicity is increased.

The concomitant use of rifampin and halothane should be avoided.

Patients receiving both rifampin and isoniazid should be monitored closely for hepatotoxicity.

Effect of Rifampin on Other Drugs Induction of Drug Metabolizing Enzymes and Transporters Drug metabolizing enzymes and transporters affected by rifampin include cytochromes P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, and 3A4, UDP-glucuronyltransferases (UGT), sulfotransferases, carboxylesterases, and transporters including P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2).

Most drugs are substrates for one or more of these enzyme or transporter pathways and these pathways may be induced by rifampin simultaneously.

Therefore, rifampin may increase the metabolism and decrease the activity of certain coadministered drugs or increase the activity of a coadministered pro-drug (where metabolic activation is required), and has the potential to perpetuate clinically important drug-drug interactions against many drugs and across many drug classes (Table 1).

Table 1 summarizes the effect of rifampin on other drugs or drug classes.

Adjust dosages of concomitant drugs based on approved drug labeling and if applicable, therapeutic drug monitoring, unless otherwise specified.

Table 1: Drug Interactions with Rifampin that Affect Concomitant Drug Concentrations Administered with rifampin 600 mg daily, unless otherwise specified Drug or Drug Class and Prevention or Management Clinical Effect AUC = area under the time-concentration curve Antiretrovirals Prevention or Management: Concomitant use is contraindicated (see CONTRAINDICATIONS ) Atazanavir Decrease AUC by 72% Darunavir Rifampin dosage used concomitantly with the drug(s) is not specified in the proposed package insert.

Substantial decrease in exposure, which may result in loss of therapeutic effect and development of resistance.

Tipranavir Fosamprenavir Administered with rifampin 300 mg daily Decrease AUC by 82% Saquinavir Decrease AUC by 70% Coadministration may result in severe hepatocellular toxicity.

Antiretrovirals Prevention or Management: Avoid concomitant use Zidovudine Decrease AUC by 47% Indinavir Decrease AUC by 92% Efavirenz Decrease AUC by 26% Hepatitis C Antiviral Prevention or Management: Avoid concomitant use Daclatasvir Decrease AUC by 79% Simeprevir Decrease AUC by 48% Sofosbuvir Decrease AUC by 72% Coadministration of sofosbuvir with rifampin may decrease sofosbuvir plasma concentrations, leading to reduced therapeutic effect of sofosbuvir.

Telaprevir Decrease AUC by 92% Systemic Hormonal Contraceptives Prevention or Management: Advise patients to change to non-hormonal methods of birth control during rifampin therapy Estrogens Decrease exposure Progestins Anticonvulsants Phenytoin Administered with rifampin 450 mg daily Decrease exposure Antiarrhythmics Disopyramide Decrease exposure Mexiletine Decrease exposure Quinidine Decrease exposure Propafenone Decrease AUC by 50%–67% Tocainide Decrease exposure Antiestrogens Tamoxifen Decrease AUC by 86% Toremifene Decrease steady state concentrations of toremifene in serum Antithrombotic Agents Clopidogrel Prevention or Management: Concomitant use of clopidogrel and rifampin should be discouraged Increase active metabolite exposure and risk of bleeding Ticagrelor Prevention or Management: Avoid use Decrease exposure Antipsychotics Haloperidol Decrease plasma concentrations by 70% Oral Anticoagulants Prevention or Management: Perform prothrombin time daily or as frequently as necessary to establish and maintain the required dose of anticoagulant Warfarin Decrease exposure Antifungals Fluconazole Decrease AUC by 23% Itraconazole Prevention or Management: Not recommended 2 weeks before and during itraconazole treatment Decrease exposure Ketoconazole Decrease exposure Beta-blockers Metoprolol Decrease exposure Propranolol Decrease exposure Benzodiazepines Diazepam , Administered with rifampin 1200 mg daily Decrease exposure Benzodiazepine-related drugs Zopiclone Decrease AUC by 82% Zolpidem Decrease AUC by 73% Calcium Channel Blockers Diltiazem Decrease exposure Nifedipine Rifampin 1200 mg administered as a single oral dose 8 hours before administering a single oral dose of nifedipine 10 mg Decrease exposure Verapamil Decrease exposure Corticosteroids Numerous cases in the literature describe a decrease in glucocorticoid effect when used concomitantly with rifampin.

The literature contains reports of acute adrenal crisis or adrenal insufficiency induced by the combination of rifampin-isoniazid-ethambutol or rifampin-isoniazid in patients with Addison’s disease.

Prednisolone Decrease exposure Cardiac Glycosides Digoxin Prevention or Management: Measure serum digoxin concentrations before initiating rifampin.

Continue monitoring and increase digoxin dose by approximately 20%–40% as necessary.

Decrease exposure Digitoxin Decrease exposure Fluoroquinolones Pefloxacin Administered with rifampin 900 mg daily Decrease exposure Moxifloxacin , Decrease exposure Oral Hypoglycemic Agents (e.g., sulfonylureas) Glyburide Decrease exposure Rifampin may worsen glucose control of glyburide.

Glipizide Decrease exposure Immunosuppressive Agents Cyclosporine Decrease exposure Tacrolimus Prevention or Management: Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when rifampin and tacrolimus are used concomitantly.

Decrease AUC by 56% Narcotic Analgesics Oxycodone Decrease AUC by 86% Morphine Decrease exposure Selective 5-HT3 Receptor Antagonists Ondansetron Decrease exposure Statins Metabolized by CYP3A4 Simvastatin Decrease exposure Thiazolidinediones Rosiglitazone Decrease AUC by 66% Tricyclic Antidepressants Nortriptyline A tuberculosis treatment regimen including rifampin (600 mg/day), isoniazid (300 mg/day), pyrazinamide (500 mg 3× per day), and pyridoxine (25 mg) was associated with higher than expected doses of nortriptyline were required to obtain a therapeutic drug level.

Following the discontinuation of rifampin, the patient became drowsy and the serum nortriptyline levels rose precipitously (3-fold) into the toxic range.

Decrease exposure Other Drugs Enalapril Decrease active metabolite exposure Chloramphenicol Concomitant use with rifampin in 2 children Decrease exposure Clarithromycin Decrease exposure Dapsone Rifampin has been shown to increase the clearance of dapsone and, accordingly, decrease dapsone exposure.

Rifampin has also been shown to increase the production of the hydroxylamine metabolite of dapsone which could increase the risk of methemoglobinemia.

Doxycycline Administered with rifampin (10 mg/kg daily) Decrease exposure Irinotecan Administered with an antibiotic regimen including rifampin (450 mg/day), isoniazid (300 mg/day), and streptomycin (0.5 g/day) IM Prevention or Management: Avoid the use of rifampin, a strong CYP3A4 inducer, if possible.

Substitute non-enzyme inducing therapies at least 2 weeks prior to initiation of irinotecan therapy Decrease irinotecan and active metabolite exposure Levothyroxine Decrease exposure Losartan Parent Decrease AUC by 30% Active metabolite (E3174) Decrease AUC by 40% Methadone In patients well-stabilized on methadone, concomitant administration of rifampin resulted in a marked reduction in serum methadone levels and a concurrent appearance of withdrawal symptoms.

Praziquantel Prevention or Management: Concomitant use is contraindicated (see CONTRAINDICATIONS ) Decrease plasma praziquantel concentrations to undetectable levels.

Quinine Prevention or Management: Avoid concomitant use Decrease AUC by 75%–85% Telithromycin Decrease AUC by 86% Theophylline Decrease exposure by 20% to 40% Effect of Other Drugs on Rifampin Concomitant antacid administration may reduce the absorption of rifampin.

Daily doses of rifampin should be given at least 1 hour before the ingestion of antacids.

Concomitant use with probenecid and cotrimoxazole increases the concentration of rifampin which may increase the risk of RIFADIN toxicities.

Monitor for adverse reactions associated with RIFADIN during coadministration.

Other Interactions Atovaquone: Concomitant use of rifampin with atovaquone decrease concentrations of atovaquone and increase concentrations of rifampin which may increase the risk of RIFADIN toxicities.

Coadministration of rifampin with atovaquone is not recommended.

OVERDOSAGE

Signs and Symptoms Nausea, vomiting, abdominal pain, pruritus, headache, and increasing lethargy will probably occur within a short time after ingestion; unconsciousness may occur when there is severe hepatic disease.

Transient increases in liver enzymes and/or bilirubin may occur.

Brownish-red or orange discoloration of the skin, urine, sweat, saliva, tears, and feces will occur, and its intensity is proportional to the amount ingested.

Liver enlargement, possibly with tenderness, can develop within a few hours after severe overdosage; bilirubin levels may increase and jaundice may develop rapidly.

Hepatic involvement may be more marked in patients with prior impairment of hepatic function.

Other physical findings remain essentially normal.

A direct effect upon the hematopoietic system, electrolyte levels, or acid-base balance is unlikely.

Facial or periorbital edema has also been reported in pediatric patients.

Hypotension, sinus tachycardia, ventricular arrhythmias, seizures, and cardiac arrest were reported in some fatal cases.

Acute Toxicity The minimum acute lethal or toxic dose is not well established.

However, nonfatal acute overdoses in adults have been reported with doses ranging from 9 to 12 gm rifampin.

Fatal acute overdoses in adults have been reported with doses ranging from 14 to 60 gm.

Alcohol or a history of alcohol abuse was involved in some of the fatal and nonfatal reports.

Nonfatal overdoses in pediatric patients ages 1 to 4 years old of 100 mg/kg for one to two doses has been reported.

Treatment Intensive support measures should be instituted and individual symptoms treated as they arise.

The airway should be secured and adequate respiratory exchange established.

Since nausea and vomiting are likely to be present, gastric lavage within the first 2 to 3 hours after ingestion is probably preferable to induction of emesis.

Following evacuation of the gastric contents, the instillation of activated charcoal slurry into the stomach may help absorb any remaining drug from the gastrointestinal tract.

Antiemetic medication may be required to control severe nausea and vomiting.

Active diuresis (with measured intake and output) will help promote excretion of the drug.

For severe cases, extracorporeal hemodialysis may be required.

If this is not available, peritoneal dialysis can be used along with forced diuresis.

DESCRIPTION

RIFADIN (rifampin capsules USP) for oral administration contains 150 mg or 300 mg rifampin per capsule.

The 150 mg and 300 mg capsules also contain, as inactive ingredients: corn starch, D&C Red No.

28, FD&C Blue No.

1, FD&C Red No.

40, gelatin, magnesium stearate, and titanium dioxide.

RIFADIN IV (rifampin for injection USP) contains rifampin 600 mg, sodium formaldehyde sulfoxylate 10 mg, and sodium hydroxide to adjust pH.

Rifampin is a semisynthetic antibiotic derivative of rifamycin SV.

Rifampin is a red-brown crystalline powder very slightly soluble in water at neutral pH, freely soluble in chloroform, soluble in ethyl acetate and in methanol.

Its molecular weight is 822.95 and its chemical formula is C 43 H 58 N 4 O 12 .

The chemical name for rifampin is either: 3-[[(4-Methyl-1-piperazinyl)imino]methyl]rifamycin or 5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22– heptamethyl-8-[N-(4-methyl-1-piperazinyl)formimidoyl]-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1- b ]furan-1,11(2H)-dione 21-acetate.

Its structural formula is: Chemical Structure

HOW SUPPLIED

RIFADIN IV (rifampin for injection USP) is available in sterile glass vials containing 600 mg rifampin (NDC 0068-0597-01).

Storage: Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

Avoid excessive heat (temperatures above 40°C or 104°F).

Protect from light.

Rx only

GERIATRIC USE

Geriatric Use Clinical studies of RIFADIN 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.

Caution should therefore be observed in using rifampin in elderly patients.

(See WARNINGS .)

MECHANISM OF ACTION

Mechanism of Action Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible Mycobacterium tuberculosis organisms.

Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme.

INDICATIONS AND USAGE

In the treatment of both tuberculosis and the meningococcal carrier state, the small number of resistant cells present within large populations of susceptible cells can rapidly become the predominant type.

Bacteriologic cultures should be obtained before the start of therapy to confirm the susceptibility of the organism to rifampin and they should be repeated throughout therapy to monitor the response to treatment.

Since resistance can emerge rapidly, susceptibility tests should be performed in the event of persistent positive cultures during the course of treatment.

If test results show resistance to rifampin and the patient is not responding to therapy, the drug regimen should be modified.

Tuberculosis Rifampin is indicated in the treatment of all forms of tuberculosis.

A three-drug regimen consisting of rifampin, isoniazid, and pyrazinamide is recommended in the initial phase of short-course therapy which is usually continued for 2 months.

The Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and Centers for Disease Control and Prevention recommend that either streptomycin or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), rifampin, and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH resistance is very low.

The need for a fourth drug should be reassessed when the results of susceptibility testing are known.

If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than four drugs may be considered.

Following the initial phase, treatment should be continued with rifampin and isoniazid for at least 4 months.

Treatment should be continued for longer if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive.

RIFADIN IV is indicated for the initial treatment and retreatment of tuberculosis when the drug cannot be taken by mouth.

Meningococcal Carriers Rifampin is indicated for the treatment of asymptomatic carriers of Neisseria meningitidis to eliminate meningococci from the nasopharynx.

Rifampin is not indicated for the treatment of meningococcal infection because of the possibility of the rapid emergence of resistant organisms.

(See WARNINGS .) Rifampin should not be used indiscriminately, and, therefore, diagnostic laboratory procedures, including serotyping and susceptibility testing, should be performed for establishment of the carrier state and the correct treatment.

So that the usefulness of rifampin in the treatment of asymptomatic meningococcal carriers is preserved, the drug should be used only when the risk of meningococcal disease is high.

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

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

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

PEDIATRIC USE

Pediatric Use See CLINICAL PHARMACOLOGY–Pediatrics; see also DOSAGE AND ADMINISTRATION .

PREGNANCY

Pregnancy–Teratogenic Effects Rifampin has been shown to be teratogenic in rodents.

Congenital malformations, primarily spina bifida, were increased in the offspring of pregnant rats given rifampin during organogenesis at oral doses of 150 to 250 mg/kg/day (about 1 to 2 times the maximum recommended human dose based on body surface area comparisons).

Cleft palate was increased in a dose-dependent fashion in fetuses of pregnant mice treated at oral doses of 50 to 200 mg/kg (about 0.2 to 0.8 times the maximum recommended human dose based on body surface area comparisons).

Imperfect osteogenesis and embryotoxicity were also reported in pregnant rabbits given rifampin at oral doses up to 200 mg/kg/day (about 3 times the maximum recommended human dose based on body surface area comparisons).

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

Rifampin has been reported to cross the placental barrier and appear in cord blood.

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

Pregnancy–Non-Teratogenic Effects When administered during the last few weeks of pregnancy, rifampin can cause postnatal hemorrhages in the mother and infant for which treatment with vitamin K may be indicated.

NUSRING MOTHERS

Nursing Mothers Because of the potential for tumorigenicity shown for rifampin in animal studies, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

INFORMATION FOR PATIENTS

Information for Patients Patients should be counseled that antibacterial drugs including rifampin should only be used to treat bacterial infections.

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

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

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

The patient should be told that rifampin may produce a discoloration (yellow, orange, red, brown) of the teeth, urine, sweat, sputum, and tears, and the patient should be forewarned of this.

Soft contact lenses may be permanently stained.

Rifampin is a well characterized and potent inducer of drug metabolizing enzymes and transporters and might therefore decrease or increase concomitant drug exposure and impact safety and efficacy (see DRUG INTERACTIONS ).

Therefore, patients should be advised not to take any other medication without medical advice.

The patient should be advised that the reliability of oral or other systemic hormonal contraceptives may be affected; consideration should be given to using alternative contraceptive measures.

Patients should be instructed to take rifampin either 1 hour before or 2 hours after a meal with a full glass of water.

Patients should be instructed to notify their physician immediately if they experience any of the following: rash with fever or blisters, with or without peeling skin, itching, or swollen lymph nodes, loss of appetite, malaise, nausea, vomiting, abdominal pain, darkened urine, yellowish discoloration of the skin and eyes, light-colored bowel movements, fever, headache, fatigue, myalgias, cough, shortness of breath, chest pain, wheezing, and pain or swelling of the joints.

Patients should be advised to seek medical advice immediately if their symptoms of mycobacterial disease, including, but not limited to, cough, fever, tiredness, shortness of breath, malaise, headache, pain, night sweats, swollen lymph nodes, loss of appetite, weight loss, weakness, skin ulcers or lesions, worsen (see ADVERSE REACTIONS ).

Advise patients to abstain from alcohol, hepatotoxic medications or herbal products while taking rifampin.

Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed.

DOSAGE AND ADMINISTRATION

Rifampin can be administered by the oral route or by IV infusion (see INDICATIONS AND USAGE ).

IV doses are the same as those for oral.

See CLINICAL PHARMACOLOGY for dosing information in patients with renal failure.

Tuberculosis Adults: 10 mg/kg, in a single daily administration, not to exceed 600 mg/day, oral or IV Pediatric Patients: 10–20 mg/kg, not to exceed 600 mg/day, oral or IV It is recommended that oral rifampin be administered once daily, either 1 hour before or 2 hours after a meal with a full glass of water.

Rifampin is indicated in the treatment of all forms of tuberculosis.

A three-drug regimen consisting of rifampin, isoniazid, and pyrazinamide is recommended in the initial phase of short-course therapy which is usually continued for 2 months.

The Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and the Centers for Disease Control and Prevention recommend that either streptomycin or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), rifampin, and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH resistance is very low.

The need for a fourth drug should be reassessed when the results of susceptibility testing are known.

If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than four drugs may be considered.

Following the initial phase, treatment should be continued with rifampin and isoniazid for at least 4 months.

Treatment should be continued for longer if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive.

Preparation of Solution for IV Infusion Reconstitute the lyophilized powder by transferring 10 mL of sterile water for injection to a vial containing 600 mg of rifampin for injection.

Swirl vial gently to completely dissolve the antibiotic.

The reconstituted solution contains 60 mg rifampin per mL and is stable at room temperature for up to 30 hours.

Prior to administration, withdraw from the reconstituted solution a volume equivalent to the amount of rifampin calculated to be administered and add to 500 mL of infusion medium.

Mix well and infuse at a rate allowing for complete infusion within 3 hours.

Alternatively, the amount of rifampin calculated to be administered may be added to 100 mL of infusion medium and infused in 30 minutes.

Dilutions in dextrose 5% for injection (D5W) are stable at room temperature for up to 8 hours and should be prepared and used within this time.

Precipitation of rifampin from the infusion solution may occur beyond this time.

Dilutions in normal saline are stable at room temperature for up to 6 hours and should be prepared and used within this time.

Other infusion solutions are not recommended.

Incompatibilities Physical incompatibility (precipitate) was observed with undiluted (5 mg/mL) and diluted (1 mg/mL in normal saline) diltiazem hydrochloride and rifampin (6 mg/mL in normal saline) during simulated Y-site administration.

Meningococcal Carriers Adults: For adults, it is recommended that 600 mg rifampin be administered twice daily for two days.

Pediatric Patients: Pediatric patients 1 month of age or older: 10 mg/kg (not to exceed 600 mg per dose) every 12 hours for two days.

Pediatric patients under 1 month of age: 5 mg/kg every 12 hours for two days.

Preparation of Extemporaneous Oral Suspension For pediatric and adult patients in whom capsule swallowing is difficult or where lower doses are needed, a liquid suspension may be prepared as follows: RIFADIN 1% w/v suspension (10 mg/mL) can be compounded using one of four syrups–Simple Syrup (Syrup NF), Simple Syrup (Humco Laboratories), SyrPalta ® Syrup (Emerson Laboratories), or Raspberry Syrup (Humco Laboratories).

Empty the contents of four RIFADIN 300 mg capsules or eight RIFADIN 150 mg capsules onto a piece of weighing paper.

If necessary, gently crush the capsule contents with a spatula to produce a fine powder.

Transfer the rifampin powder blend to a 4-ounce amber glass or plastic (high density polyethylene [HDPE], polypropylene, or polycarbonate) prescription bottle.

Rinse the paper and spatula with 20 mL of one of the above-mentioned syrups and add the rinse to the bottle.

Shake vigorously.

Add 100 mL of syrup to the bottle and shake vigorously.

This compounding procedure results in a 1% w/v suspension containing 10 mg rifampin/mL.

Stability studies indicate that the suspension is stable when stored at room temperature (25±3°C) or in a refrigerator (2–8°C) for four weeks.

This extemporaneously prepared suspension must be shaken well prior to administration.

Generic Name: MIDAZOLAM HYDROCHLORIDE

Brand Name: Midazolam Hydrochloride

Substance Name(s):
MIDAZOLAM HYDROCHLORIDE

WARNINGS

Personnel and Equipment for Monitoring and Resuscitation Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that are equipped to provide continuous monitoring of respiratory and cardiac function.

Midazolam HCl syrup must only be administered to patients if they will be monitored by direct visual observation by a health care professional.

If midazolam HCl syrup will be administered in combination with other anesthetic drugs or drugs which depress the central nervous system, patients must be monitored by persons specifically trained in the use of these drugs and, in particular, in the management of respiratory effects of these drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

For deeply sedated patients, a dedicated individual whose sole responsibility is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Patients should be continuously monitored for early signs of hypoventilation, airway obstruction, or apnea with means for detection readily available (eg, pulse oximetry).

Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately.

The immediate availability of specific reversal agents (flumazenil) is highly recommended.

Vital signs should continue to be monitored during the recovery period.

Because midazolam can depress respiration [see CLINICAL PHARMACOLOGY] , especially when used concomitantly with opioid agonists and other sedatives [see DOSAGE AND ADMINISTRATION] , it should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting ventilation.

Episodes of oxygen desaturation, respiratory depression, apnea, and airway obstruction have been occasionally reported following premedication (sedation prior to induction of anesthesia) with oral midazolam; such events are markedly increased when oral midazolam is combined with other central nervous system depressing agents and in patients with abnormal airway anatomy, patients with cyanotic congenital heart disease, or patients with sepsis or severe pulmonary disease.

Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including midazolam, and opioids may result in profound sedation, respiratory depression, coma and death.

If a decision is made to use midazolam concomitantly with opioids, monitor patients for respiratory depression and sedation [see PRECAUTIONS/Drug Interactions] .

Risk of Respiratory Adverse Events Serious respiratory adverse events have occurred after administration of oral midazolam, most often when midazolam was used in combination with other central nervous system depressants.

These adverse events have included respiratory depression, airway obstruction, oxygen desaturation, apnea, and rarely, respiratory and/or cardiac arrest [see BOX WARNING] .

When oral midazolam is administered as the sole agent at recommended doses respiratory depression, airway obstruction, oxygen desaturation, and apnea occur infrequently [see DOSAGE AND ADMINISTRATION] .

Prior to the administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured.

Individualization of Dosage Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing central nervous system depression.

See DOSAGE AND ADMINISTRATION for complete information.

Other Adverse Events Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients.

Consideration should be given to the possibility of paradoxical reaction.

Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding.

Reversal of such responses with flumazenil has been reported in pediatric and adult patients.

Concomitant Use of Central Nervous System Depressants Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

Drug-Drug Interactions Coadministration of oral midazolam in patients who are taking ketoconazole and intraconazole, and saquinavir has been shown to result in large increases in Cmax and AUC of midazolam due to a decrease in plasma clearance of midazolam [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions and PRECAUTIONS] .

Due to the potential for intense and prolonged sedation and respiratory depression, midazolam syrup should only be coadministered with these medications if absolutely necessary and with appropriate equipment and personnel available to respond to respiratory insufficiency.

Debilitation and Comorbidity Considerations Higher risk pediatric surgical patients may require lower doses, whether or not concomitant sedating medications have been administered.

Pediatric patients with cardiac or respiratory compromise may be unusually sensitive to the respiratory depressant effect of midazolam.

Pediatric patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction.

Patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly [see CLINICAL PHARMACOLOGY] .

Return to Cognitive Function Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours.

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.

Gross tests of recovery from the effects of midazolam HCl syrup [see CLINICAL PHARMACOLOGY] cannot be relied upon to predict reaction time under stress.

It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer.

Particular care should be taken to assure safe ambulation.

Neonatal Sedation and Withdrawal Syndrome Use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate ( see PRECAUTIONS: Pregnancy).

Monitor neonates exposed to midazolam HCl syrup during pregnancy or labor for signs of sedation and monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal; manage these neonates accordingly.

Usage in Preterm Infants and Neonates Midazolam HCl syrup has not been studied in patients less than 6 months of age.

Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.

The clinical significance of these findings is not clear.

However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see PRECAUTIONS; Pregnancy, Pediatric Use and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects.

These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children and pregnant women needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other.

Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

DRUG INTERACTIONS

Drug Interactions Effect of Concomitant Use of Benzodiazepines and Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration.

Benzodiazepines interact at GABA A sites, and opioids interact primarily at mu receptors.

When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.

Monitor patients closely for respiratory depression and sedation.

Other CNS Depressants One case was reported of inadequate sedation with chloral hydrate and later with oral midazolam due to a possible interaction with methylphenidate administered chronically in a 2-year-old boy with a history of Williams syndrome.

The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate.

The sedative effect of midazolam HCl syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol.

Consequently, the dose of midazolam HCl syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response [see DOSAGE AND ADMINISTRATION] .

No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed.

Inhibitors of CYP3A4 Isozymes Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics).

Drugs such as diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, saquinavir, and verapamil were shown to significantly increase the C max and AUC of orally administered midazolam.

These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam.

Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam.

Caution is advised when midazolam HCl syrup is used concomitantly with these drugs.

Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions] .

Inducers of CYP3A4 Isozymes Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and cause a markedly decreased C max and AUC of oral midazolam in adult studies.

Although clinical studies have not been performed, phenobarbital is expected to have the same effect.

Caution is advised when administering midazolam HCl syrup to patients receiving these medications and if necessary dose adjustments should be considered.

OVERDOSAGE

Clinical Presentation Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma.

In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia.

Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur.

In severe overdosage cases, patients may develop respiratory depression and coma.

Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS: Dependence and Withdrawal Reactions).

Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

Management of Overdose In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with longterm benzodiazepine use and physical dependency.

The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy.

Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus).

If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage.

See the flumazenil injection Prescribing Information.

Consider contacting a poison center (1-800-222-1222), poisoncontrol.org, or a medical toxicologist for additional overdosage management recommendations.

DESCRIPTION

Midazolam is a benzodiazepine available as midazolam HCl syrup for oral administration.

Midazolam, a white to light yellow crystalline compound, is insoluble in water, but can be solubilized in aqueous solutions by formation of the hydrochloride salt in situ under acidic conditions.

Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4 H -imidazo[1,5-a][1,4]benzodiazepine hydrochloride.

Midazolam hydrochloride has the molecular formula C 18 H 13 ClFN 3 ·HCl, a calculated molecular weight of 362.25 and the following structural formula: Each mL of the syrup contains midazolam hydrochloride equivalent to 2 mg midazolam compounded with artificial bitterness modifier, citric acid anhydrous, D&C Red #33, edetate disodium, glycerin, mixed fruit flavor, sodium benzoate, sodium citrate, sorbitol, and water; the pH is adjusted to 2.8 to 3.6 with hydrochloric acid.

Under the acidic conditions required to solubilize midazolam in the syrup, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring.

The amount of open-ring form is dependent upon the pH of the solution.

At the specified pH of the syrup, the solution may contain up to about 40% of the open-ring compound.

At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such.

The following chart below plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions.

As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 2.8 to 3.6.

Above pH 5, at least 99% of the mixture is present in the closed-ring form.

chemical-structure-1.jpg chemical-structure-2.jpg midazolam-chart.jpg

HOW SUPPLIED

Midazolam HCl Syrup is supplied as a clear, red to purplish-red, mixed fruit flavored syrup containing midazolam hydrochloride equivalent to 2 mg of midazolam/mL; each amber glass bottle of 118 mL of syrup is supplied with 1 press-in bottle adapter, 4 single-use, graduated, oral dispensers and 4 tip caps; 10 x bottle of 2.5 mL is supplied with 10 single-use, graduated, oral dispensers and 10 tip caps.

NDC 0574-0150-04 Bottle of 118 mL.

NDC 0574-0150-25 10 x Bottle of 2.5 mL.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.]

GERIATRIC USE

Geriatric Use The safety and efficacy of this product have not been fully studied in geriatric patients.

Therefore, there are no available data on a safe dosing regimen.

One study in geriatric subjects, using midazolam 7.5 mg as a premedicant prior to general anesthesia, noted a 60% incidence of hypoxemia (pO 2 <90% for over 30 seconds) at sometime during the operative procedure versus 15% for the nonpremedicated group.

Until further information is available it is recommended that this product should not be used in geriatric patients.

Use in Patients With Heart Disease Following oral administration of 7.5 mg of midazolam to adult patients with congestive heart failure, the half-life of midazolam was 43% higher than in control subjects.

One study suggests that hypercarbia or hypoxia following premedication with oral midazolam might pose a risk to children with congenital heart disease and pulmonary hypertension, although there are no known reports of pulmonary hypertensive crisis that had been triggered by premedication.

In the study, 22 children were premedicated with oral midazolam (0.75 mg/kg) or IM morphine plus scopolamine prior to elective repair of congenital cardiac defects.

Both premedication regimens increased PtcCO 2 and decreased SpO 2 and respiratory rates preferentially in patients with pulmonary hypertension.

INDICATIONS AND USAGE

Midazolam HCl syrup is indicated for use in pediatric patients for sedation, anxiolysis and amnesia prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia.

Midazolam HCl syrup is intended for use in monitored settings only and not for chronic or home use [see WARNINGS] .

PEDIATRIC USE

Pediatric Use Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Midazolam Hydrochloride Syrup 2 mg/mL, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.

Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss.

Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data.

[See WARNINGS; Pediatric Neurotoxicity, PRECAUTIONS; Pregnancy, and Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

PREGNANCY

Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including midazolam HCl syrup, during pregnancy.

Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.

Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and Clinical Considerations ) .

Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data ).

The 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 risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates.

Monitor neonates exposed to midazolam HCl syrup during pregnancy and labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.

Monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal.

Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ) .

Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects.

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted.

In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

All doses produced slight to moderate ataxia.

The high dose produced a 5% decrease in maternal body weight gain compared to control.

Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 to 18).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity.

Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21).

All doses produced ataxia.

The high dose produced a slight decrease in maternal body weight gain compared to control.

There were no clear adverse effects noted in the offspring.

The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits ( see WARNINGS, Pediatric Neurotoxicity, PRECAUTIONS, Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY ).

Nursing Mothers Risk Summary There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for midazolam HCl syrup and any potential adverse effects on the breastfed infant from midazolam HCl syrup or from the underlying maternal condition.

Clinical Considerations Infants exposed to midazolam HCl syrup through breast milk should be monitored for sedation, poor feeding and poor weight gain.

A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least 4 to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant.

BOXED WARNING

WARNINGS Personnel and Equipment for Monitoring and Depression Midazolam HCl syrup has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings.

Midazolam HCl syrup has been associated with reports of respiratory depression, airway obstruction, desaturation, hypoxia, and apnea, most often when used concomitantly with other central nervous system depressants.

Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Risks From Concomitant Use With Opioids Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

Monitor patients for respiratory depression and sedation [see WARNINGS, PRECAUTIONS/Drug Interactions] .

INFORMATION FOR PATIENTS

Information for Patients To assure safe and effective use of midazolam HCl syrup, the following information and instructions should be communicated to the patient when appropriate: 1.

Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication, antibiotics, and protease inhibitors, including drugs you buy without a prescription.

Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment.

Inform your physician if you are pregnant or are planning to become pregnant.

Inform your physician if you are nursing.

Patients should be informed of the pharmacological effects of midazolam HCl syrup, such as sedation and amnesia, which in some patients may be profound.

Midazolam HCl syrup should not be taken in conjunction with grapefruit juice.

For pediatric patients, particular care should be taken to assure safe ambulation.

Effect of Anesthetic and Sedation Drugs on Early Brain Development: Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains.

Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs.

Pregnancy Advise pregnant females that use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy).

Instruct patients to inform their healthcare provider if they are pregnant.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to midazolam HCl syrup during pregnancy (see Precautions, Pregnancy ).

Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed.

Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs.

A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant (see Precautions, Nursing Mothers ).

DOSAGE AND ADMINISTRATION

Midazolam HCl syrup is indicated for use as a single dose (0.25 to 1.0 mg/kg with a maximum dose of 20 mg) for preprocedural sedation and anxiolysis in pediatric patients.

Midazolam HCl syrup is not intended for chronic administration.

Monitoring Midazolam HCl syrup should only be used in hospital or ambulatory care settings, including physicians’ and dentists’ offices that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual whose sole responsibility it is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Continuous monitoring of respiratory and cardiac function is required.

Midazolam HCl syrup must be given only to patients if they will be monitored by direct visual observation by a health care professional.

Midazolam HCl syrup should only be administered by persons specifically trained in the use of anesthetic drugs and the management of respiratory effects of anesthetic drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

Patient response to sedative agents, and resultant respiratory status, is variable.

Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes, particularly when coadministered with anesthetic agents, other CNS depressants, and concomitant medications which may potentially cause a more intense and prolonged sedation [see PRECAUTIONS: Drug Interactions] .

This is especially true in pediatric patients.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities.

Further recommendations include appropriate presedation fasting.

Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing CNS depression.

Younger (<6 years of age) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring.

When midazolam HCl syrup is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased.

For appropriate patient monitoring, see WARNINGS and : Monitoring.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

The recommended dose for pediatric patients is a single dose of 0.25 to 0.5 mg/kg, depending on the status of the patient and desired effect, up to a maximum dose of 20 mg.

In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, concomitant medications, and medical need [see WARNINGS and PRECAUTIONS] .

The younger (6 months to <6 years of age) and less cooperative patients may require a higher than usual dose up to 1.0 mg/kg.

A dose of 0.25 mg/kg may suffice for older (6 to <16 years of age) or cooperative patients, especially if the anticipated intensity and duration of sedation is less critical.

For all pediatric patients, a dose of 0.25 mg/kg should be considered when midazolam HCl syrup is administered to patients with cardiac or respiratory compromise, other higher risk surgical patients, and patients who have received concomitant narcotics or other CNS depressants.

As with any potential respiratory depressant, these patients must be monitored for signs of cardiorespiratory depression after receiving midazolam HCl syrup.

In obese pediatric patients, the dose should be calculated based on ideal body weight.

Midazolam HCl syrup has not been studied, nor is it intended for chronic use.

USE OF ORAL DISPENSERS AND PIBA 1.

Remove the cap.

Before inserting the tip of the oral dispenser into bottle adapter, push the plunger completely down toward the tip of the oral dispenser.

Insert tip firmly into opening of the bottle adapter.

Turn the entire unit (bottle and oral dispenser) upside down.

Pull the plunger out slowly until the desired amount of medication is withdrawn into the oral dispenser.

Turn the entire unit right side up and remove the oral dispenser slowly from the bottle.

The tip of the dispenser may be covered with a tip cap, until time of use.

Close bottle with cap after each use.

Dispense directly into mouth.

Do not mix with any liquid (such as grapefruit juice) prior to dispensing.

INSERTION OF PRESS-IN BOTTLE ADAPTER (PIBA) 1.

Remove the cap and push bottle adapter into neck of bottle.

Close the bottle tightly with cap.

This will assure the proper seating of the bottle adapter in the bottle.

DISPOSAL OF MIDAZOLAM HCl SYRUP The disposal of Schedule IV controlled substances must be consistent with State and Federal Regulations.

plunger.jpg image-1.jpg image-2.jpg image-3.jpg