SEROFLO

Fluticasone propionate is a synthetic glucocorticoid 9, 10 Label.

These drugs are available as inhalers, nasal, sprays, and topical treatments for various inflammatory indications 9, 10 Label.

Fluticasone propionate was first approved in 1990 7.

Fluticasone propionate is indicated as an inhaler for the treatment and management of asthma by prophylaxis Label as well as inflammatory and pruritic dermatoses 9.

Fluticasone propionate nasal spray is indicated for managing allergic and nonallergic rhinitis 8, 10.

Systemically, fluticasone propionate activates glucocorticoid receptors, and inhibits lung eosinophilia in rats 10 Label.

Fluticasone propionate as a topical formulation is also associated with vasoconstriction in the skin 9, 3.

Intranasal bioavailability of fluticasone propionate is <2%, and oral bioavailability is <1% 10 Label.

Intranasal exposure results in the majority of the dose being swallowed 3.

Topical absorption of fluticasone propionate is very low but can change depending on a number of factors including integrity of the skin and the presence of inflammation or disease 9.

A study of 24 healthy Caucasian males showed an inhaled bioavailability of 9.0% 1.

The volume of distribution of intravenous fluticasone propionate is 4.2 L/kg 10 Label.

A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 577 L following intravenous administration 1.

Fluticasone propionate is cleared from hepatic metabolism by cytochrome P450 3A4 10, 4 Label.

Fluticasone propionate is hydrolysed at the

FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite 9, 3 Label.

Hover over products below to view reaction partners Fluticasone propionate fluticasone 17beta-carboxylic acid.

Fluticasone propionate is mainly eliminated in the feces with <5% eliminated in the urine 10, 5 Label.

hours for intravenous fluticasone propionate 10 Label.

A study of 24 healthy Caucasian males shows a half life of 14.0 hours following intravenous administration and 10.8 hours following inhalation 1.

mL/min for fluticasone propionate 10.

A study of 24 healthy Caucasian males showed a clearance of 63.9 L/h following intravenous administration 1.

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Fluticasone propionate's use in specific populations has not been well studied 10.

Fluticasone propionate is not carcinogenic, mutagenic, or clastogenic, nor did it affect fertility in animal studies 10 Label.

Subcutaneous fluticasone propionate has been shown to produce teratogenic effects in rats though oral administration does not 9 Label.

Generally, there are no reported adverse effects with fluticasone in pregnancy 6.

Fluticasone propionate in human milk may cause growth suppression, effects on endogenous corticosteroid production, or other effects 9, 2.

Pediatric patients treated with fluticasone propionate ointment experienced adrenal suppression 9.

Geriatric patients treated with fluticasone propionate did not show any difference in safety or efficacy compared to other patient groups, though older patients may be more sensitive to adverse effects 9.

There is no difference in the clearance of fluticasone propionate across genders or race Label.

Patients with hepatic impairment should be closely monitored due to the elimination mechanism Label 5.

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.