RESPYTID PLUS

Propionate/Salmeterol MDPI 55 mcg/14 mcg, 113 mcg/14 mcg and 232 mcg/14 mcg are combinations of fluticasone propionate and salmeterol.

One active component of this product is fluticasone propionate, a corticosteroid having the chemical name S -(fluoromethyl) 6α,9-difluoro-11ß,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17ß-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.

The other active component of this product 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 -[[[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.

Propionate/Salmeterol MDPI Fluticasone Propionate/Salmeterol MDPI is a multidose dry powder inhaler (MDPI) for oral inhalation only.

It contains fluticasone propionate, salmeterol xinafoate, and lactose monohydrate (which may contain milk proteins).

The opening of the mouthpiece cover meters 5.5 mg of the formulation from the device reservoir, which contains 55 mcg, 113 mcg, or 232 mcg of fluticasone propionate, and 14 mcg of salmeterol base (equivalent to 20.3 mcg of salmeterol xinafoate).

Patient inhalation through the mouthpiece causes the deagglomeration and aerosolization of the drug particles as the formulation moves through the cyclone component of the device.

This is followed by dispersion into the airstream.

Under standardized in vitro test conditions, the Fluticasone Propionate/Salmeterol MDPI delivers 49 mcg, 100 mcg, or 202 mcg of fluticasone propionate and 12.75 mcg of salmeterol base (equivalent to 18.5 mcg of salmeterol xinafoate), with lactose from the mouthpiece when tested at a flow rate of 85 L/min for 1.4 seconds.

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

In adult subjects (N=50, aged to 45 years) with asthma, mean peak inspiratory flow (PIF) through the Fluticasone Propionate/Salmeterol MDPI was 108.28 L/min (range: 70.37 to 129.24 L/min).

In adolescent subjects (N=50, aged to 17 years) with asthma, mean peak inspiratory flow (PIF) through the Fluticasone Propionate/Salmeterol MDPI was 106.72 L/min (range: 73.64 to 125.51 L/min).

Propionate/Salmeterol Multidose Dry Powder Inhaler (FS MDPI) is indicated for the treatment of asthma in adult and pediatric patients aged 12 years and older.

Propionate/Salmeterol MDPI should be used for patients not adequately controlled on a long term asthma control medication such as an inhaled corticosteroid or whose disease warrants initiation of treatment with both an inhaled corticosteroid and long acting beta 2 -adrenergic agonist (LABA).

Fluticasone Propionate/Salmeterol MDPI is not indicated for the relief of acute bronchospasm.

Propionate/Salmeterol Multi-Dose Dry Powder Inhaler (MDPI) is a combination of fluticasone propionate, a corticosteroid, and salmeterol, a long-acting beta 2 -adrenergic agonist (LABA), indicated for treatment of asthma in adult and pediatric patients aged 12 years and older.

Propionate/Salmeterol inhalation powder should be used for patients not adequately controlled on a long term asthma control medication such as an inhaled corticosteroid or whose disease warrants initiation of treatment with both an inhaled corticosteroid and long acting beta 2 -adrenergic agonist (LABA).

Not indicated for the relief of acute bronchospasm.

Lactation Surrenal dysfunction

Child under 6 years of age Child between and 18 years Pregnancy Nasal infection Nasal surgery, recent history (d) Pulmonary mycosis Newborn exposed in utero to the medicine Nasal obstruction High dose treated patient Corticosteroid treatment in progress Extended treatment Long-term high dose treatment Nasal trauma Pulmonary tuberculosis Nasal partition ulcer.

This product contains both fluticasone propionate and salmeterol.

The mechanisms of action described below for the individual components apply to this.

These drugs represent 2 different classes of medications (a synthetic corticosteroid and a LABA) that have different effects on clinical, physiologic, and inflammatory indices.

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 humans 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, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation.

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

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 hyperresponsiveness. 12.2 Pharmacodynamics Hypothalamic Pituitary Adrenal Axis Effects (HPA) There are no HPA data from controlled trials of the Fluticasone Propionate/Salmeterol MDPI in healthy subjects or subjects with asthma.

Cardiovascular Effects and Effects on Potassium and Glucose Fluticasone Propionate/Salmeterol MDPI in Healthy Subjects There were no clinical trials conducted with Fluticasone Propionate/Salmeterol MDPI that assessed cardiovascular (CV) effects in healthy subjects.

Other Fluticasone Propionate and Salmeterol Dry Powder Inhaler (DPI) Products in Healthy Subjects Since systemic pharmacodynamic effects of salmeterol are not normally seen at the maximum approved salmeterol dosage, higher doses were used to produce measurable effects.

Four trials were conducted with healthy adult subjects to assess CV effects: Single‑dose crossover trial using 2 inhalations of fluticasone propionate and salmeterol DPI (500 mcg/50 mcg) (two times the maximum approved salmeterol dosage for that DPI per dosing interval), fluticasone propionate DPI 500 mcg and salmeterol DPI 50 mcg given concurrently, or fluticasone propionate DPI 500 mcg given alone, Cumulative dose trial using to 400 mcg of salmeterol DPI (1 time to 8 times the maximum approved salmeterol dosage per dosing interval for that DPI, respectively) given alone, or fluticasone propionate and salmeterol DPI (500 mcg/50 mcg), Repeat‑dose trial for 11 days using 2 inhalations twice daily of fluticasone propionate and salmeterol DPI (250 mcg/50 mcg) (two times the maximum approved salmeterol dosage for that DPI per dosing interval), fluticasone propionate DPI 250 mcg, or salmeterol DPI 50 mcg, and Single-dose trial using 5 inhalations of fluticasone propionate and salmeterol DPI (100 mcg/50 mcg) (five times the maximum approved salmeterol dosage for that DPI per dosing interval), fluticasone propionate DPI 100 mcg alone, or placebo.

In these trials, no significant differences were observed in the pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given as fluticasone propionate and salmeterol DPI, concurrently with fluticasone propionate from separate inhalers, or as salmeterol alone.

The systemic pharmacodynamic effects of salmeterol were not altered by the presence of fluticasone propionate in the fluticasone propionate and salmeterol DPI product.

Other Salmeterol Products in Subjects with Asthma: Inhaled salmeterol, like other beta‑adrenergic agonist drugs, can produce dose‑related CV effects and effects on blood glucose and/or serum potassium.

CV effects (heart rate, blood pressure) associated with salmeterol inhalation aerosol occurred with similar frequency, and are of similar type and severity, as those noted following albuterol administration.

The effects of rising inhaled doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in subjects with asthma.

Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of to 16 beats/minute, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/minute).

Adult and adolescent subjects receiving 50 mcg doses of salmeterol MDPI (N=60) underwent continuous electrocardiographic monitoring during two 12‑hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted.

Propionate/Salmeterol MDPI With Other Respiratory Medications: Short-Acting Beta 2 ‑Agonists: In clinical trials in subjects with asthma, the mean daily need for albuterol by 166 adult and adolescent subjects aged 12 years and older using another fluticasone propionate/salmeterol DPI product was approximately 1.3 inhalations/day and ranged from to 9 inhalations/day (0 to about 4.5 times the maximum approved salmeterol dosage for that DPI per dosing interval).

Five percent (5%) of subjects using another fluticasone propionate/salmeterol DPI product in these trials averaged 6 or more inhalations per day (3 times the maximum approved salmeterol dosage for that DPI per dosing interval) over the course of the 12-week trials.

No increase in frequency of

CV adverse events was observed among subjects who averaged 6 or more inhalations per day. Methylxanthines: In clinical trials in subjects with asthma, 39 subjects receiving another fluticasone propionate/salmeterol MDPI product, fluticasone propionate 100 mcg and salmeterol 50 mcg, fluticasone propionate 250 mcg and salmeterol 50 mcg, or fluticasone propionate 500 mcg and salmeterol 50 mcg twice daily concurrently with a theophylline product had adverse event rates similar to those in 304 subjects receiving another fluticasone propionate/salmeterol product without theophylline.

Similar results were observed in subjects receiving salmeterol 50 mcg plus fluticasone propionate 500 mcg twice daily concurrently with a theophylline product (n = 39) or without theophylline (n = 132). 12.3 Pharmacokinetics Absorption Fluticasone Propionate: Fluticasone Propionate/Salmeterol MDPI acts locally in the lung; therefore, plasma levels may not predict therapeutic effect.

Trials using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate was negligible (<1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver.

In contrast, the majority of the fluticasone propionate delivered to the lung was systemically absorbed.

After administration of 232 mcg/14 mcg Fluticasone Propionate/Salmeterol MDPI to patients aged 12 years and older with persistent asthma in a clinical trial, the mean C max value of fluticasone propionate was 66 pg/mL with a median t max value of approximately 2 hours.

After administration of 232 mcg/14 mcg Fluticasone Propionate/Salmeterol MDPI to patients aged 12 years and older with persistent asthma, the mean C max values of salmeterol was 60 pg/mL.

The median t max was 5 minutes.

Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding.

The volume of distribution averaged 4.2 L/kg. The percentage of fluticasone propionate bound to human plasma proteins averages 99%.

Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin.

Volume of distribution data are not available for salmeterol.

The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over the concentration range of to 7,722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol.

Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours.

Terminal half-life estimates of fluticasone propionate following oral inhalation administration of Fluticasone Propionate/Salmeterol MDPI were approximately 10.8 hours.

The total clearance of fluticasone propionate is high (average, 1,093 mL/minute), with renal clearance accounting for less than 0.02% of the total.

The only circulating metabolite detected in humans is the 17β carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway.

This metabolite has less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies.

Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in humans.

Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites.

Terminal half-life estimates for salmeterol for Fluticasone Propionate/Salmeterol MDPI were approximately 12.6 hours.

The xinafoate moiety has no apparent pharmacologic activity.

The xinafoate moiety is highly protein bound (greater than 99%) and has a long elimination half-life of 11 days.

Salmeterol base is extensively metabolized by hydroxylation.

An in vitro study using human liver microsomes showed that salmeterol is extensively metabolized to α hydroxysalmeterol (aliphatic oxidation) by CYP3A4.

Ketoconazole, a strong inhibitor of CYP3A4, essentially completely inhibited the formation of α hydroxysalmeterol in vitro.

In 2 healthy adult subjects who received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in urine and feces, respectively, over a period of 7 days.

Mechanism of action

Fluticasone is a trifluorinated synthetic corticosteroid with a very high affinity for the glucocorticosteroid receptor and has a strong anti-inflammatory activity.

• Application site pain Rash Pruritus Urticaria Systemic effects Surreal impairment
• Hypersensitivity (Rare)
• Anaphylactic reaction Oedema of Quincke Oropharyngeal candidiasis
• Nasal candidiasis Glaucoma (Very rare)
• Cataract (Very rare)
• Eye hypertonia Eye disorder
• Blurty vision Epistaxis (Very common)
• Nasal ulceration (Common)
• Nasal hyposecretion (Common)
• Rhineland (Uncommon)
• Nasal fungus (Uncommon)
• Perforation of nasal septum (Very rare)
• Dry barley Aphonie Anosmia Unusual taste Feeling of nasal burn Dysgueusia Augustusia
• Nasal irritation Dysphony Feeling of unpleasant smell Growth retardation Headache (Common)
• Dyspnoea (Common)
• Bronchospasm.

This product contains both fluticasone propionate and salmeterol; therefore, the risks associated with overdosage for the individual components described below apply to Fluticasone Propionate/Salmeterol MDPI.

Treatment of overdosage consists of discontinuation of Fluticasone Propionate/Salmeterol MDPI together with institution of appropriate symptomatic and/or supportive therapy.

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

Cardiac monitoring is recommended in cases of overdosage.

Fluticasone propionate

Chronic overdosage of fluticasone propionate may result in signs/symptoms of hypercorticism.

The expected signs and symptoms with overdosage of salmeterol 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 salmeterol 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 salmeterol.

Propionate/Salmeterol MDPI is contraindicated in: the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. patients with known severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to fluticasone propionate or any of the excipients.

Primary treatment of status asthmaticus or acute episodes of asthma requiring intensive measures.

Severe hypersensitivity to milk proteins or any ingredients of Fluticasone Propionate/Salmeterol MDPI.

For oral inhalation only.

Starting dosage is based on prior asthma therapy and disease severity. 1 inhalation of Fluticasone Propionate/Salmeterol 55 mcg/14 mcg, 113 mcg/14 mcg, or 232 mcg/14 mcg twice daily.

Do not use with a spacer or volume holding chamber. 2.1 Administration Instructions Fluticasone Propionate/Salmeterol MDPI is for oral inhalation and does not require priming.

Do not use Fluticasone

Propionate/Salmeterol MDPI with a spacer or volume holding chamber.

Do not use more than two times every 24 hours.

More frequent administration or a greater number of daily inhalations (more than one inhalation twice daily) is not recommended as some patients are more likely to experience adverse reactions with higher salmeterol dosages.

Avoid the concomitant use of other long acting beta 2 -adrenergic agonist (LABAs) .

If asthma symptoms arise in the period between doses, an inhaled, short-acting beta 2 -agonist should be taken for immediate relief. 2.2 Recommended Dosage Administer 1 inhalation of Fluticasone Propionate/Salmeterol MDPI twice daily by oral inhalation (approximately 12 hours apart at the same time every day).

Rinse the mouth with water without swallowing after each inhalation.

Dosage Selection The recommended starting dosage for Fluticasone Propionate/Salmeterol MDPI is based on asthma severity and current inhaled corticosteroid use and strength.

Patients not taking inhaled corticosteroids (ICS) (with less severe asthma): 1 inhalation of 55 mcg/14 mcg Fluticasone Propionate/Salmeterol MDPI dose strength (55 mcg of fluticasone propionate and 14 mcg of salmeterol), twice daily by oral inhalation.

Patients with greater asthma severity, use the higher dose strengths: 1 inhalation of 113 mcg/14 mcg Fluticasone Propionate/Salmeterol MDPI (113 mcg of fluticasone propionate and 14 mcg of salmeterol) twice daily; or 1 inhalation of 232 mcg/14 mcg Fluticasone Propionate/Salmeterol MDPI (232 mcg of fluticasone propionate and 14 mcg of salmeterol) twice daily Patients switching to Fluticasone Propionate/Salmeterol MDPI from another inhaled corticosteroid or: 1 inhalation of low (55 mcg/14 mcg), medium (113 mcg/14 mcg) or high (232 mcg/14 mcg) Fluticasone Propionate/Salmeterol MDPI twice daily by oral inhalation based on the strength of the previous inhaled corticosteroid product, or the strength of the inhaled corticosteroid from a, and disease severity.

The maximum recommended dosage of Fluticasone

Propionate/Salmeterol MDPI is 232 mcg/14 mcg twice daily.

General Dosing Information Improvement in asthma control following Fluticasone Propionate/Salmeterol MDPI administration can occur within 15 minutes of beginning treatment; although maximum benefit may not be achieved for 1 week or longer after starting treatment.

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

For patients who do not respond adequately to the starting dose of Fluticasone Propionate/Salmeterol MDPI after 2 weeks of therapy, consider increasing the strength (replace with higher strength) to possibly provide additional improvement in asthma control.

If a previously effective dosage regimen fails to provide adequate improvement in asthma control, re-evaluate the therapeutic regimen, including patient compliance and inhaler technique, and consider additional therapeutic options (e.g., increasing the dose of Fluticasone Propionate/Salmeterol MDPI with a higher strength, adding additional controller therapies).

After asthma stability has been achieved, it is desirable to titrate to the lowest effective dosage to reduce the risk of adverse reactions. 2.3 Storing and Cleaning the Inhaler Keep the inhaler in a cool dry place.

Routine maintenance is not required.

If the mouthpiece needs cleaning, gently wipe the mouthpiece with a dry cloth or tissue as needed.

Never wash or put any part of the inhaler in water. 2.4 Dose Counter The Fluticasone Propionate/Salmeterol MDPI has a dose counter: The number is displayed (prior to use).

The dose counter will count down each time the mouthpiece is opened and closed.

Propionate/Salmeterol MDPI inhalation powder: a multidose, dry-powder inhaler (MDPI) each inhaler is white, has a yellow cap and is packaged individually in a foil pouch with a dessicant, each pouch is packed in a carton each inhaler contains 0.45 grams of the formulation and provides 60 actuations STRENGTH NDC CODE Fluticasone Propionate/Salmeterol 55 mcg/14 mcg (low) 63629-8811-1 Storage and Handling Store at room temperature (between 15ºC and 25ºC; 59ºF and 77ºF) in a dry place; excursions permitted from 59º F to 86º F (15ºC to 30ºC).

Avoid exposure to extreme heat, cold, or humidity.

Propionate/Salmeterol MDPI inside the unopened moisture‑protective foil pouch until initial use.

Discard the product 30 days after opening the foil pouch or when the counter reads 0, whichever comes first.

The inhaler is not reusable.

Do not attempt to take the inhaler apart.

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504.

There are no randomized clinical studies of fluticasone propionate/salmeterol MDPI or individual monoproducts, fluticasone propionate and salmeterol, in pregnant women.

There are clinical considerations with the use of Fluticasone Propionate/Salmeterol MDPI in pregnant women.

Animal reproduction studies are available with the combination of fluticasone propionate and salmeterol as well as individual components.

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.

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.

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

Oral administration of salmeterol to pregnant rabbits caused teratogenicity characteristic of beta-adrenoceptor stimulation at maternal doses approximately 700 times the MRHDID on a mcg/m 2 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 420 times the MRHDID.

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.

Disease‑Associated Maternal and/or Embryo/Fetal Risk In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia 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 Animal Data Fluticasone Propionate and Salmeterol: In an embryo/fetal development study with pregnant rats that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1000, 30/0, 10/100, 30/1000, and 100/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findings were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects.

Omphalocele, increased embryo/fetal deaths, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, when combining fluticasone propionate at a dose approximately 2 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 100 mcg/kg/day) and a dose of salmeterol at approximately 3500 times the MRHDID (on a mcg/m 2 basis at a maternal oral dose of 10,000 mcg/kg/day).

The rat no observed adverse effect level (NOAEL) was observed when combining fluticasone propionate at a dose 0.6 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 30 mcg/kg/day) and a dose of salmeterol at approximately 350 times the MRHDID (on a mcg/m 2 basis at a maternal oral dose of 1000 mcg/kg/day).

In an embryo/fetal development study with pregnant mice that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1400, 40/0, 10/200, 40/1400, or 150/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findings were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects.

Cleft palate, fetal death, increased implantation loss, and delayed ossification were observed in mouse fetuses when combining fluticasone propionate at a dose approximately 1.4 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 150 mcg/kg/day) and salmeterol at a dose approximately 1470 times the MRHDID (on a mcg/m 2 basis at a maternal oral dose of 10,000 mcg/kg/day).

No developmental toxicity was observed at combination doses of fluticasone propionate up to approximately 0.8 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 40 mcg/kg) and doses of salmeterol up to approximately 420 times the MRHDID (on a mcg/m 2 basis at a maternal oral dose of 1400 mcg/kg).

In embryo/fetal 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 2 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 100 mcg/kg/day).

The rat

NOAEL was observed at approximately 0.6 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 0.5 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 0.16 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 15 mcg/kg/day).

In an embryo/fetal 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 0.5 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.

NOAEL was observed with a dose approximately 0.1 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 5.5 mcg/kg/day).

In an embryo/fetal 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 0.02 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 0.2 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 4 mcg/kg/day).

NOAEL was observed in rabbit fetuses with a dose approximately 0.004 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day).

In a pre.

• and post-natal development study in pregnant rats dosed by the subcutaneous route from late gestation through delivery and lactation (Gestation Day 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 approximate equivalence to the MRHDID (on a mcg/m 2 basis with maternal subcutaneous doses up to 50 mcg/kg/day).

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

In three embryo/fetal development studies, pregnant rabbits received oral administration of salmeterol at doses ranging from to 10,000 mcg/kg/day during the period of organogenesis.

In pregnant

Dutch rabbits administered salmeterol doses approximately 700 times the MRHDID (on a mcg/m 2 basis at maternal oral doses of 1000 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 420 times the MRHDID (on a mcg/m 2 basis at a maternal oral dose of 600 mcg/kg/day).

White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at a salmeterol dose approximately 7,000 times the MRHDID (on a mcg/m 2 basis at a maternal oral dose of 10,000 mcg/kg/day).

In two embryo/fetal development studies, pregnant rats received salmeterol by oral administration at doses ranging from to 10,000 mcg/kg/day during the period of organogenesis.

Salmeterol produced no maternal toxicity or embryo/fetal effects at doses up to 3500 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 3500 times the MRHDID (on 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.

The safety and effectiveness of Fluticasone

Propionate/Salmeterol MDPI have been established for the treatment of asthma in pediatric patients aged 12 years and older whose asthma is inadequately controlled on a long term asthma control medication or warrants initiation of treatment with both an ICS and a LABA.

Propionate/Salmeterol MDPI in pediatric patients aged to 17 years for this indication is supported by evidence from two adequate and well-controlled trials in pediatric patients 12 years old and older with persistent symptomatic asthma despite ICS or ICS/LABA therapy (Trials and 2) .

In these trials, 58 adolescents received Fluticasone Propionate/Salmeterol MDPI one inhalation twice daily.

Propionate/Salmeterol MDPI have not been established in pediatric patients younger than 12 years of age for the treatment of asthma.

Effectiveness was not demonstrated in one adequate and well-controlled study conducted in 211 patients aged to 11 years with persistent asthma on a stable asthma regimen who were treated with Fluticasone Propionate/Salmeterol MDPI 55 mcg/14 mcg one inhalation twice daily.

Inhaled corticosteroids, including fluticasone propionate, a component of this product, may cause a reduction in growth velocity in adolescents.

The growth of pediatric patients receiving

ICS, including Fluticasone Propionate/Salmeterol MDPI, should be monitored.

If an adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect of corticosteroids should be considered.

In such patients, the potential growth effects of prolonged ICS treatment should be weighed against the clinical benefits obtained.

To minimize the systemic effects of

ICS, including Fluticasone Propionate/Salmeterol MDPI, each patient should be titrated to the lowest strength that effectively controls his/her asthma.

No overall differences in safety or effectiveness were observed in data collected in 54 subjects aged 65 years and older versus younger subjects who were treated with Fluticasone Propionate/Salmeterol MDPI in placebo-controlled Phase and 3 asthma studies.