Indications & Usage
1 INDICATIONS AND USAGE Fluticasone Propionate/Salmeterol DISKUS is a combination product containing a corticosteroid and a long-acting beta 2 -adrenergic agonist (LABA) indicated for: • Twice-daily treatment of asthma in patients aged 4 years and older. ( 1.1 ) • Maintenance treatment of airflow obstruction and reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD). ( 1.2 ) Important limitation of use: Not indicated for relief of acute bronchospasm. ( 1.1 , 1.2 ) 1.1 Treatment of Asthma Fluticasone Propionate/Salmeterol DISKUS is indicated for the twice-daily treatment of asthma in patients aged 4 years and older. Fluticasone Propionate/Salmeterol DISKUS should be used for patients not adequately controlled on a long-term asthma control medication such as an inhaled corticosteroid (ICS) or whose disease warrants initiation of treatment with both an ICS and long-acting beta 2 -adrenergic agonist (LABA). Important Limitation of Use Fluticasone Propionate/Salmeterol DISKUS is NOT indicated for the relief of acute bronchospasm. 1.2 Maintenance Treatment of Chronic Obstructive Pulmonary Disease Fluticasone Propionate/Salmeterol DISKUS inhalation powder 250/50 mcg is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Fluticasone Propionate/Salmeterol DISKUS inhalation powder 250/50 mcg is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. Fluticasone Propionate/Salmeterol DISKUS inhalation powder 250/50 mcg twice daily is the only approved dosage for the treatment of COPD because an efficacy advantage of the higher strength Fluticasone Propionate/Salmeterol DISKUS inhalation powder 500/50 mcg over Fluticasone Propionate/Salmeterol DISKUS inhalation powder 250/50 mcg has not been demonstrated. Important Limitation of Use Fluticasone Propionate/Salmeterol DISKUS is NOT indicated for the relief of acute bronchospasm.
Contraindications
4 CONTRAINDICATIONS The use of Fluticasone Propionate/Salmeterol DISKUS is contraindicated in the following conditions: • Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required [see Warnings and Precautions ( 5.2 )]. • Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients [see Warnings and Precautions ( 5.11 ), Adverse Reactions ( 6.3 ), Description ( 11 )] . • Primary treatment of status asthmaticus or acute episodes of asthma or COPD requiring intensive measures. ( 4 ) • Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients. ( 4 )
Warnings & Precautions
5 WARNINGS AND PRECAUTIONS • LABA monotherapy increases the risk of serious asthma-related events. ( 5.1 ) • Do not initiate in acutely deteriorating asthma or COPD. Do not use to treat acute symptoms. ( 5.2 ) • Do not use in combination with an additional medicine containing a LABA because of risk of overdose. ( 5.3 ) • 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. ( 5.4 ) • Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. ( 5.5 ) • Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; 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. ( 5.6 ) • Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to Fluticasone Propionate/Salmeterol DISKUS. ( 5.7 ) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue Fluticasone Propionate/Salmeterol DISKUS slowly. ( 5.8 ) • If paradoxical bronchospasm occurs, discontinue Fluticasone Propionate/Salmeterol DISKUS and institute alternative therapy. ( 5.10 ) • Use with caution in patients with cardiovascular or central nervous system disorders because of beta-adrenergic stimulation. ( 5.12 ) • Assess for decrease in bone mineral density initially and periodically thereafter. ( 5.13 ) • Monitor growth of pediatric patients. ( 5.14 ) • Glaucoma and cataracts may occur with long-term use of inhaled corticosteroids. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use Fluticasone Propionate/Salmeterol DISKUS long term. ( 5.15 ) • Be alert to eosinophilic conditions, hypokalemia, and hyperglycemia. ( 5.16 , 5.18 ) • Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.17 ) 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death [see Salmeterol Multicenter Asthma Research Trial (SMART)] . Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. 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 (see Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta 2 -adrenergic Agonists) . Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta 2 -adrenergic Agonists Four (4) large, 26-week, randomized, double-blind, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared with ICS alone in subjects with asthma. Three (3) trials included adult and adolescent subjects aged 12 years and older: 1 trial compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder [see Clinical Studies ( 14.1 )] , 1 trial compared mometasone furoate/formoterol with mometasone furoate, and 1 trial compared budesonide/formoterol with budesonide. The fourth trial included pediatric subjects aged 4 to 11 years and compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder [see Clinical Studies ( 14.1 )] . The primary safety endpoint for all 4 trials was serious asthma-related events (hospitalizations, intubations, death). A blinded adjudication committee determined whether events were asthma related. The 3 adult and adolescent trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk margin of 2.7. Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of the 3 adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone ( Table 1 ). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS. Table 1. Meta-analysis of Serious Asthma-Related Events in Subjects with Asthma Aged 12 Years and Older ICS = Inhaled Corticosteroid, LABA = Long-acting Beta 2 -adrenergic Agonist. a Randomized subjects who had taken at least 1 dose of study drug. Planned treatment used for analysis. b Estimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials. c Number of subjects with event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Subjects can have one or more events, but only the first event was counted for analysis. A single, blinded, independent adjudication committee determined whether events were asthma related. ICS/LABA (n = 17,537) a ICS (n = 17,552) a ICS/LABA vs. ICS Hazard Ratio (95% CI) b Serious asthma-related event c 116 105 1.10 (0.85, 1.44) Asthma-related death 2 0 Asthma-related intubation (endotracheal) 1 2 Asthma-related hospitalization (≥24-hour stay) 115 105 The pediatric safety trial included 6,208 pediatric subjects aged 4 to 11 years who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3,107 (0.9%) subjects randomized to ICS/LABA and 21/3,101 (0.7%) subjects randomized to ICS experienced a serious asthma-related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk of a serious asthma-related event compared with ICS based on the pre-specified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27). Salmeterol Multicenter Asthma Research Trial (SMART) A 28-week, placebo-controlled, U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol versus 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy. 5.2 Deterioration of Disease and Acute Episodes Fluticasone Propionate/Salmeterol DISKUS should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. Fluticasone Propionate/Salmeterol DISKUS has not been studied in subjects with acutely deteriorating asthma or COPD. The initiation of Fluticasone Propionate/Salmeterol DISKUS in this setting is not appropriate. Serious acute respiratory events, including fatalities, have been reported when salmeterol, a component of Fluticasone Propionate/Salmeterol DISKUS, 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 ast
Adverse Reactions
6 ADVERSE REACTIONS Use of LABA may result in the following: • Serious asthma-related events – hospitalizations, intubations, death [see Warnings and Precautions ( 5.1 )] • Cardiovascular and central nervous system effects [see Warnings and Precautions ( 5.12 )] Systemic and local corticosteroid use may result in the following: • Candida albicans infection [see Warnings and Precautions ( 5.4 )] • Pneumonia in patients with COPD [see Warnings and Precautions ( 5.5 )] • Immunosuppression [see Warnings and Precautions ( 5.6 )] • Hypercorticism and adrenal suppression [see Warnings and Precautions ( 5.8 )] • Reduction in bone mineral density [see Warnings and Precautions ( 5.13 )] • Growth effects [see Warnings and Precautions ( 5.14 )] • Glaucoma and cataracts [see Warnings and Precautions ( 5.15 )] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Most common adverse reactions (incidence ≥3%) include: • Asthma: Upper respiratory tract infection or inflammation, pharyngitis, dysphonia, oral candidiasis, bronchitis, cough, headaches, nausea and vomiting. ( 6.1 ) • COPD: Pneumonia, oral candidiasis, throat irritation, dysphonia, viral respiratory infections, headaches, musculoskeletal pain. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience in Asthma Adult and Adolescent Subjects Aged 12 Years and Older The incidence of adverse reactions associated with fluticasone propionate/salmeterol DISKUS in Table 2 is based upon two 12-week, placebo-controlled, U.S. clinical trials (Trials 1 and 2). A total of 705 adult and adolescent subjects (349 females and 356 males) previously treated with salmeterol or ICS were treated twice daily with fluticasone propionate/salmeterol DISKUS (100/50- or 250/50-mcg doses), fluticasone propionate inhalation powder (100- or 250-mcg doses), salmeterol inhalation powder 50 mcg, or placebo. The average duration of exposure was 60 to 79 days in the active treatment groups compared with 42 days in the placebo group. Table 2. Adverse Reactions with Fluticasone Propionate/Salmeterol DISKUS with ≥3% Incidence and More Common than Placebo in Adult and Adolescent Subjects with Asthma Adverse Event Fluticasone Propionate/ Salmeterol DISKUS 100/50 mcg (n = 92) % Fluticasone Propionate/ Salmeterol DISKUS 250/50 mcg (n = 84) % Fluticasone Propionate 100 mcg (n = 90) % Fluticasone Propionate 250 mcg (n = 84) % Salmeterol 50 mcg (n = 180) % Placebo (n = 175) % Ear, nose, and throat Upper respiratory tract infection 27 21 29 25 19 14 Pharyngitis 13 10 7 12 8 6 Upper respiratory inflammation 7 6 7 8 8 5 Sinusitis 4 5 6 1 3 4 Hoarseness/dysphonia 5 2 2 4 <1 <1 Oral candidiasis 1 4 2 2 0 0 Lower respiratory Viral respiratory infections 4 4 4 10 6 3 Bronchitis 2 8 1 2 2 2 Cough 3 6 0 0 3 2 Neurology Headaches 12 13 14 8 10 7 Gastrointestinal Nausea and vomiting 4 6 3 4 1 1 Gastrointestinal discomfort and pain 4 1 0 2 1 1 Diarrhea 4 2 2 2 1 1 Viral gastrointestinal infections 3 0 3 1 2 2 Non-site specific Candidiasis unspecified site 3 0 1 4 0 1 Musculoskeletal Musculoskeletal pain 4 2 1 5 3 3 The types of adverse reactions and events reported in Trial 3, a 28-week, non-U.S. clinical trial in 503 subjects previously treated with ICS who were treated twice daily with fluticasone propionate/salmeterol DISKUS 500/50 mcg, fluticasone propionate inhalation powder 500 mcg and salmeterol inhalation powder 50 mcg used concurrently, or fluticasone propionate inhalation powder 500 mcg, were similar to those reported in Table 2 . Additional Adverse Reactions Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with asthma treated with fluticasone propionate/salmeterol DISKUS compared with subjects treated with placebo include the following: lymphatic signs and symptoms; muscle injuries; fractures; wounds and lacerations; contusions and hematomas; ear signs and symptoms; nasal signs and symptoms; nasal sinus disorders; keratitis and conjunctivitis; dental discomfort and pain; gastrointestinal signs and symptoms; oral ulcerations; oral discomfort and pain; lower respiratory signs and symptoms; pneumonia; muscle stiffness, tightness, and rigidity; bone and cartilage disorders; sleep disorders; compressed nerve syndromes; viral infections; pain; chest symptoms; fluid retention; bacterial infections; unusual taste; viral skin infections; skin flakiness and acquired ichthyosis; disorders of sweat and sebum. Pediatric Subjects Aged 4 to 11 Years The safety data for pediatric subjects aged 4 to 11 years is based upon 1 U.S. trial of 12 weeks’ treatment duration. A total of 203 subjects (74 females and 129 males) who were receiving ICS at trial entry were randomized to either fluticasone propionate/salmeterol DISKUS 100/50 mcg or fluticasone propionate inhalation powder 100 mcg twice daily. Common adverse reactions (≥3% and greater than placebo) seen in the pediatric subjects but not reported in the adult and adolescent clinical trials include: throat irritation and ear, nose, and throat infections. Laboratory Test Abnormalities Elevation of hepatic enzymes was reported in ≥1% of subjects in clinical trials. The elevations were transient and did not lead to discontinuation from the trials. In addition, there were no clinically relevant changes noted in glucose or potassium. 6.2 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease Short-term (6 Months to 1 Year) Trials The short-term safety data are based on exposure to fluticasone propionate/salmeterol DISKUS 250/50 mcg twice daily in one 6-month and two 1-year clinical trials. In the 6-month trial, a total of 723 adult subjects (266 females and 457 males) were treated twice daily with fluticasone propionate/salmeterol DISKUS 250/50 mcg, fluticasone propionate inhalation powder 250 mcg, salmeterol inhalation powder, or placebo. The mean age of the subjects was 64, and the majority (93%) was Caucasian. In this trial, 70% of the subjects treated with fluticasone propionate/salmeterol DISKUS reported an adverse reaction compared with 64% on placebo. The average duration of exposure to fluticasone propionate/salmeterol DISKUS 250/50 mcg was 141.3 days compared with 131.6 days for placebo. The incidence of adverse reactions in the 6-month trial is shown in Table 3 . Table 3. Overall Adverse Reactions with Fluticasone Propionate/Salmeterol DISKUS 250/50 mcg with ≥3% Incidence in Subjects with Chronic Obstructive Pulmonary Disease Associated with Chronic Bronchitis Adverse Event Fluticasone Propionate/ Salmeterol DISKUS 250/50 mcg (n = 178) % Fluticasone Propionate 250 mcg (n = 183) % Salmeterol 50 mcg (n = 177) % Placebo (n = 185) % Ear, nose, and throat Candidiasis mouth/throat 10 6 3 1 Throat irritation 8 5 4 7 Hoarseness/dysphonia 5 3 <1 0 Sinusitis 3 8 5 3 Lower respiratory Viral respiratory infections 6 4 3 3 Neurology Headaches 16 11 10 12 Dizziness 4 <1 3 2 Non-site specific Fever 4 3 0 3 Malaise and fatigue 3 2 2 3 Musculoskeletal Musculoskeletal pain 9 8 12 9 Muscle cramps and spasms 3 3 1 1 In the two 1-year trials, fluticasone propionate/salmeterol DISKUS 250/50 mcg was compared with salmeterol in 1,579 subjects (863 males and 716 females). The mean age of the subjects was 65 years, and the majority (94%) was Caucasian. To be enrolled, all of the subjects had to have had a COPD exacerbation in the previous 12 months. In this trial, 88% of the subjects treated with fluticasone propionate/salmeterol DISKUS and 86% of the subjects treated with salmeterol reported an adverse event. The most common events that occurred with a frequency of >5% and more frequently in the subj
Drug Interactions
7 DRUG INTERACTIONS Fluticasone propionate/salmeterol DISKUS has been used concomitantly with other drugs, including short-acting beta 2 -agonists, methylxanthines, and intranasal corticosteroids, commonly used in patients with asthma or COPD without adverse drug reactions [see Clinical Pharmacology ( 12.2 )] . No formal drug interaction trials have been performed with fluticasone propionate/salmeterol DISKUS. • Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended. May increase risk of systemic corticosteroid and 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 Fluticasone propionate and salmeterol, the individual components of Fluticasone Propionate/Salmeterol DISKUS, are substrates of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with Fluticasone Propionate/Salmeterol DISKUS is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur. Ritonavir Fluticasone Propionate: 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 Fluticasone Propionate: 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. Salmeterol: 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 Fluticasone Propionate/Salmeterol 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, a component of Fluticasone Propionate/Salmeterol DISKUS, 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, a component of Fluticasone Propionate/Salmeterol DISKUS, 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, such as salmeterol, a component of Fluticasone Propionate/Salmeterol DISKUS, 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 Fluticasone Propionate/Salmeterol DISKUS with non–potassium-sparing diuretics.
Use in Pregnancy & Lactation
8.1 Pregnancy Risk Summary There are insufficient data on the use of fluticasone propionate/salmeterol DISKUS or individual monoproducts, fluticasone propionate and salmeterol xinafoate, in pregnant women. There are clinical considerations with the use of fluticasone propionate/salmeterol 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. Oral administration of salmeterol to pregnant rabbits caused teratogenicity characteristic of beta-adrenoceptor stimulation at maternal doses approximately 50 times the 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 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 should be closely monitored and medication adjusted as necessary to maintain optimal control of asthma. Labor and Delivery: There are no human studies evaluating the effects of fluticasone propionate/salmeterol DISKUS during labor and delivery. Because of the potential for beta agonist interference with uterine contractility, use of Fluticasone Propionate/Salmeterol DISKUS during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. Data Human Data: Fluticasone Propionate: Following inhaled administration, fluticasone propionate was detected in the neonatal cord blood after delivery. Animal Data: Fluticasone Propionate and Salmeterol: In an embryofetal development study with pregnant rats that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1,000; 30/0; 10/100; 30/1,000; 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 embryofetal 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 equivalent to the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 100 mcg/kg/day) and salmeterol at a dose approximately 970 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 approximately 0.3 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 30 mcg/kg/day) and salmeterol at a dose approximately 100 times the MRHDID (on a mcg/m 2 basis at a maternal oral dose of 1,000 mcg/kg/day). In an embryofetal development study with pregnant mice that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1,400; 40/0; 10/200; 40/1,400; 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 0.7 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 490 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 0.2 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 70 times the MRHDID (on a mcg/m 2 basis at a maternal oral dose of 1,400 mcg/kg). Fluticasone Propionate: 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 equivalent to 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 0.3 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 0.2 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 0.07 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 0.25 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 0.05 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 0.012 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 0.08 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 0.002 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 by the subcutaneous route 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 0.5 times the MRHDID (on a mcg/m 2 basis with maternal subcutaneous doses up to 50 mcg/kg/day). Salmeterol: In 3 embryofetal devel
Active Ingredients
FLUTICASONE PROPIONATE 0.1MG/INH; SALMETEROL XINAFOATE EQ 0.05MG BASE/INH
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