PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Package/Label Display Panel

PC5726 AirDuo Digi 232_14 mcg Sample outer carton

PC5726 AirDuo Digi Sample 232_14 mcg inner carton

NDC 59310-530-08

Rx Only

AirDuo****®****

Digihaler****®****** 232/14**

**(fluticasone propionate 232 mcg****and salmeterol 14 mcg)**Inhalation Powder

SAMPLE NOT FOR SALE

232 mcg/14 mcg

With Dose Counter

FOR ORAL INHALATION ONLY

60 METERED INHALATIONS

0.45 g NET CONTENTS

Refer to enclosed Patient Leaflet and Instructions for Use for detailed information on product use and handling.

For more information visit www.AirDuoDigihaler.com or call 1-888-603-0788

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DESCRIPTION SECTION

11 DESCRIPTION

AirDuo Digihaler 55/14 mcg, AirDuo Digihaler 113/14 mcg and AirDuo Digihaler 232/14 mcg are combinations of fluticasone propionate and salmeterol.

Fluticasone Propionate

One active component of AirDuo Digihaler 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 C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

Salmeterol Xinafoate

The other active component of AirDuo Digihaler is salmeterol xinafoate, a beta2–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 C25H37NO4•C11H8O3. It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water.

AirDuo Digihaler

AirDuo Digihaler is a multidose dry powder inhaler (MDPI) with an electronic module, 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 AirDuo Digihaler inhaler 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 18 to 45 years) with asthma, mean peak inspiratory flow (PIF) through the MDPI was 108.28 L/min (range: 70.37 to 129.24 L/min). In adolescent subjects (N=50, aged 12 to 17 years) with asthma, mean peak inspiratory flow (PIF) through the MDPI was 106.72 L/min (range: 73.64 to 125.51 L/min).

AirDuo Digihaler includes a QR code (on the top of the inhaler), and contains a built-in electronic module which automatically detects, records and stores data on inhaler events, including peak inspiratory flow rate (L/min). AirDuo Digihaler may pair with and transmit data to the mobile App where inhaler events are categorized.

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INDICATIONS & USAGE SECTION

Highlight: AirDuo Digihaler is a combination of fluticasone propionate, a corticosteroid, and salmeterol, a long-acting beta2-adrenergic agonist (LABA), indicated for treatment of asthma in patients aged 12 years and older. AirDuo Digihaler 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 beta2-adrenergic agonist (LABA). (1)

Limitations of Use: Not indicated for the relief of acute bronchospasm. (1)

1 INDICATIONS AND USAGE

AirDuo® Digihaler® is indicated for the treatment of asthma in adult and pediatric patients aged 12 years and older. AirDuo Digihaler 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 beta2-adrenergic agonist (LABA).

Limitations of Use:

AirDuo Digihaler is not indicated for the relief of acute bronchospasm.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Inhalation powder 55 mcg/14 mcg, 113 mcg/14 mcg, or 232 mcg/14 mcg of fluticasone propionate/salmeterol in each actuation. (3)

AirDuo Digihaler contains a built-in electronic module. (3)

3 DOSAGE FORMS AND STRENGTHS

Inhalation powder: an inhalation-driven, multidose dry powder inhaler (MDPI) with an electronic module, for oral inhalation that meters 55 mcg, 113 mcg, or 232 mcg of fluticasone propionate with 14 mcg of salmeterol from the device reservoir and delivers 49 mcg, 100 mcg, or 202 mcg of fluticasone propionate with 12.75 mcg of salmeterol, respectively, from the mouthpiece per actuation. The AirDuo Digihaler is a white inhaler with a yellow cap, and is provided in a sealed foil pouch with desiccant. AirDuo Digihaler contains a built-in electronic module [see How Supplied/Storage and Handling (16)].

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CONTRAINDICATIONS SECTION

Highlight: * Primary treatment of status asthmaticus or acute episodes of asthma requiring intensive measures. (4)

• Severe hypersensitivity to milk proteins or any ingredients of AirDuo Digihaler. (4)

4 CONTRAINDICATIONS

AirDuo Digihaler is contraindicated in:

• the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required [see Warnings and Precautions (5.2)].

• patients with known severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to fluticasone propionate or any of the excipients [see Warnings and Precautions (5.10) and Description (11)].

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DRUG INTERACTIONS SECTION

Highlight: * Avoid strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): 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 DRUG INTERACTIONS

Fluticasone propionate/salmeterol MDPI has been used concomitantly with other drugs, including short‑acting beta2‑agonists, and intranasal corticosteroids, commonly used in patients with asthma without adverse drug reactions [see Clinical Pharmacology (12.2)]. No formal drug interaction trials have been performed with AirDuo Digihaler.

7.1 Inhibitors of Cytochrome P450 3A4

Fluticasone propionate and salmeterol, the individual components of AirDuo Digihaler, are substrates of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with AirDuo Digihaler 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 Cmax increased 1.4‑fold). Three (3) subjects were withdrawn due to beta2‑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 [see Clinical Pharmacology (12.3)].

7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

AirDuo Digihaler 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 AirDuo Digihaler, 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 AirDuo Digihaler, but may also produce severe bronchospasm in patients with asthma. Therefore, patients with asthma 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 AirDuo Digihaler, 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 AirDuo Digihaler with non–potassium‑sparing diuretics.

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: Hepatic impairment: Monitor for systemic corticosteroid effects. (8.6)****

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no randomized clinical studies of AirDuo Digihaler or individual monoproducts, fluticasone propionate and salmeterol, in pregnant women. There are clinical considerations with the use of AirDuo Digihaler in pregnant women [see Clinical Considerations]. 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/m2 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/m2 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 700 times the MRHDID on a mcg/m2 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 [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 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/m2 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/m2 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/m2 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/m2 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/m2 basis at a maternal subcutaneous dose of 150 mcg/kg/day) and salmeterol at a dose approximately 1470 times the MRHDID (on a mcg/m2 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/m2 basis at a maternal subcutaneous dose of 40 mcg/kg) and doses of salmeterol up to approximately 420 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 1400 mcg/kg).

Fluticasone Propionate: 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/m2 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/m2 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/m2 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/m2 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/m2 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 0.1 times the MRHDID (on a mcg/m2 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/m2 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/m2 basis with a maternal subcutaneous dose of 4 mcg/kg/day). The NOAEL was observed in rabbit fetuses with a dose approximately 0.004 times the MRHDID (on a mcg/m2 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 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 approximate equivalence to the MRHDID (on a mcg/m2 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.

Salmeterol: In three embryo/fetal 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 700 times the MRHDID (on a mcg/m2 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/m2 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 7,000 times the MRHDID (on a mcg/m2 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 100 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/m2 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/m2 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.

8.2 Lactation

Risk Summary

There are no available data on the presence of fluticasone propionate or salmeterol in human milk, the effects on the breastfed child, or the effects on milk production. Other corticosteroids have been detected in human milk. However, fluticasone propionate and salmeterol concentrations in plasma after inhaled therapeutic doses are low and therefore concentrations in human breast milk are likely to be correspondingly low [see Clinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AirDuo Digihaler and any potential adverse effects on the breastfed child from AirDuo Digihaler or from the underlying maternal condition.

Data

Animal Data

Subcutaneous administration of tritiated fluticasone propionate at a dose in lactating rats approximately 0.2 times the MRHDID for adults (on a mcg/m2 basis) resulted in measurable levels in milk. Oral administration of salmeterol at a dose in lactating rats approximately 2900 times the MRHDID for adults (on a mcg/m2 basis) resulted in measurable levels in milk.

8.4 Pediatric Use

The safety and effectiveness of AirDuo Digihaler have been established for the treatment of asthma in pediatric patients aged 12 years and older whose asthma (1) is inadequately controlled on a long term asthma control medication or (2) warrants initiation of treatment with both an ICS and a LABA.

Use of AirDuo Digihaler in pediatric patients aged 12 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 1 and 2) [see Clinical Studies (14)]. In these trials, 58 adolescents received fluticasone propionate/salmeterol MDPI one inhalation twice daily.

The safety and effectiveness of AirDuo Digihaler 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 4 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.

Effect on Growth

Inhaled corticosteroids, including fluticasone propionate, a component of AirDuo Digihaler, may cause a reduction in growth velocity in adolescents [see Warning and Precautions (5.13)]. The growth of pediatric patients receiving ICS, including AirDuo Digihaler, 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 AirDuo Digihaler, each patient should be titrated to the lowest strength that effectively controls his/her asthma [see Dosage and Administration (2)].

8.5 Geriatric Use

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 2 and 3 asthma studies.

8.6 Hepatic Impairment

Formal pharmacokinetic studies using AirDuo Digihaler have not been conducted in patients with hepatic impairment. However, since both fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism [see Clinical Pharmacology (12.3)], impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic impairment should be closely monitored.

8.7 Renal Impairment

Formal pharmacokinetic studies using AirDuo Digihaler have not been conducted in patients with renal impairment.

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ADVERSE REACTIONS SECTION

Highlight: Most common adverse reactions (greater than or equal to 3%): nasopharyngitis, oral candidiasis, headache, cough and back pain. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 orwww.fda.gov/medwatch.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Serious asthma-related events – hospitalizations, intubations, death [see Warnings and Precautions (5.1)]

• Oropharyngeal candidiasis [see Warnings and Precautions (5.4)]

• Immunosuppression and risk of infections [see Warnings and Precautions (5.5)]

• Hypercorticism and adrenal suppression [see Warnings and Precautions (5.7)]

• Cardiovascular and central nervous system effects [see Warnings and Precautions (5.11)]

• Reduction in bone mineral density [see Warnings and Precautions (5.12)]

• Growth effects in pediatrics [see Warnings and Precautions (5.13)]

• Glaucoma and cataracts [see Warnings and Precautions (5.14)]

6.1 Clinical Trials Experience in Asthma

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of AirDuo Digihaler has been established from adequate and well- controlled studies of fluticasone propionate and salmeterol MDPI.

In two placebo-controlled, 12-week, clinical studies (Trials 1 and 2) [see Clinical Studies (14)], a total of 1,364 adolescent and adult patients with persistent symptomatic asthma despite ICS or ICS/LABA therapy were treated twice daily with either placebo; fluticasone propionate MDPI 55 mcg, 113 mcg, or 232 mcg (ARMONAIR RESPICLICK, hereafter referred to as fluticasone propionate MDPI); or fluticasone propionate/salmeterol MDPI 55/14 mcg, 113/14 mcg, or 232/14 mcg. Sixty percent of patients were female and 80% of patients were white. The average duration of exposure was 82 to 84 days in the fluticasone propionate MDPI and fluticasone propionate/salmeterol MDPI treatment groups compared with 75 days in the placebo group. Table 2 displays the incidence of most common adverse reactions in pooled Trials 1 and 2.

Table 2: Adverse Reactions with ≥3% Incidence with Fluticasone Propionate/Salmeterol MDPI, and More Common than Placebo in Subjects with Asthma (Trials 1 and 2)

*Oral candidiasis includes oropharyngeal candidiasis, oral fungal infection, and oropharyngitis fungal

Other adverse reactions not previously listed (and occurring in <3% of patients and in three or more patients on fluticasone propionate/salmeterol MDPI) that were reported more frequently by patients with asthma treated with fluticasone propionate/salmeterol MDPI compared with patients treated with placebo include the following:

Sinusitis, oropharyngeal pain, pharyngitis, dizziness, influenza, rhinitis allergic, respiratory tract infection, rhinitis, nasal congestion, abdominal pain upper, myalgia, pain in extremity, dyspepsia, laceration, dermatitis contact, and palpitations.

Long Term Safety Study: This was a 26-week, open labeled study of 674 patients previously treated with ICS who were treated twice daily with fluticasone propionate MDPI 113 mcg or 232 mcg; fluticasone propionate/salmeterol MDPI 113/14 mcg or 232/14 mcg; fluticasone propionate inhalation aerosol 110 mcg or 220 mcg; fluticasone propionate and salmeterol inhalation powder (250/50 mcg), or fluticasone propionate and salmeterol inhalation powder (500/50 mcg). The types of adverse reactions were similar to those reported above in placebo- controlled studies.

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during post approval use of fluticasone propionate and/or salmeterol regardless of indication. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone propionate and/or salmeterol or a combination of these factors.

Cardiac Disorders: Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), ventricular tachycardia.

Endocrine Disorders: Cushing’s syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism.

Eye Disorders: Glaucoma, blurred vision and central serous chorioretinopathy.

Gastrointestinal Disorders: Abdominal pain, dyspepsia, xerostomia.

Immune System Disorders: Immediate and delayed hypersensitivity reaction (including very rare anaphylactic reaction). Very rare anaphylactic reaction in patients with severe milk protein allergy.

Infections and Infestations: Esophageal candidiasis.

Metabolic and Nutrition Disorders: Hyperglycemia, weight gain.

Musculoskeletal, Connective Tissue, and Bone Disorders: Arthralgia, cramps, myositis, osteoporosis.

Nervous System Disorders: Paresthesia, restlessness.

Psychiatric Disorders: Agitation, aggression, depression. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children.

Reproductive System and Breast Disorders: Dysmenorrhea.

Respiratory, Thoracic, and Mediastinal Disorders: Chest congestion; chest tightness, dyspnea; facial and oropharyngeal edema, immediate bronchospasm; paradoxical bronchospasm; tracheitis; wheezing; reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.

Skin and Subcutaneous Tissue Disorders: Ecchymoses, photodermatitis.

Vascular Disorders: Pallor.

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OVERDOSAGE SECTION

10 OVERDOSAGE

AirDuo Digihaler contains both fluticasone propionate and salmeterol; therefore, the risks associated with overdosage for the individual components described below apply to AirDuo Digihaler. Treatment of overdosage consists of discontinuation of AirDuo Digihaler 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 [see Warnings and Precautions (5.7)].

Salmeterol

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.

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SPL PATIENT PACKAGE INSERT SECTION

PATIENT INFORMATION

This Patient Information leaflet has been approved by the U.S. Food and Drug Administration.

AIRDDHPL-002

Revised: July 2021

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

AirDuo Digihaler inhalation powder:

• a multidose dry-powder inhaler (MDPI) with an electronic module
• 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
• available in 3 strengths

Each AirDuo Digihaler inhaler has a dose counter attached to the actuator. Patients should never try to alter the numbers for the dose counter. Discard the inhaler when the counter displays 0, 30 days after opening the foil pouch or after the expiration date on the product, whichever comes first. The labeled amount of medication in each actuation cannot be assured after the counter displays 0, even though the inhaler is not completely empty and will continue to operate [see Patient Counseling Information (17)].

Storage and Handling

Store at room temperature (between 15ºC and 25ºC; 59ºF and 77ºF) in a dry place; excursions permitted from 59ºF to 86ºF (15ºC to 30ºC). Avoid exposure to extreme heat, cold, or humidity.

Store AirDuo Digihaler inside the unopened moisture‑protective foil pouch until initial use. Discard AirDuo Digihaler 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.

AirDuo Digihaler includes a QR code, and contains a built-in electronic module which automatically detects, records, and stores data on inhaler events, including peak inspiratory flow rate (L/min). AirDuo Digihaler may pair with and transmit data to the mobile App via Bluetooth® wireless technology where inhaler events are categorized.

AirDuo Digihaler contains a lithium-manganese dioxide battery and should be disposed of in accordance with state and local regulations.

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INSTRUCTIONS FOR USE SECTION

Instructions for Use

AirDuo® Digihaler® (ayr´due oh di´ji haye´´ler)

(fluticasone propionate and salmeterol) inhalation powder 55 mcg/14 mcg

AirDuo® Digihaler® (ayr´due oh di´ji haye´´ler)

(fluticasone propionate and salmeterol) inhalation powder 113 mcg/14 mcg

AirDuo® Digihaler® (ayr´due oh di´ji haye´´ler)

(fluticasone propionate and salmeterol) inhalation powder 232 mcg/14 mcg

for oral inhalation use

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Your AirDuo Digihaler Inhaler

When you are ready to use AirDuo Digihaler for the first time, remove the AirDuo Digihaler inhaler from the foil pouch.

There are 3 main parts of your AirDuo Digihaler inhaler including the:

• white inhaler with the mouthpiece.See Figure A.
• yellow cap that covers the mouthpiece of the inhaler.See Figure A.
• electronic module.See Figure A.

There is an electronic module built into the top of the inhaler that records and stores information about inhaler events. The electronic module sends information through Bluetooth**®** wireless technology to a mobile application (App). The electronic module does not control or interfere with delivery of the medicine through the inhaler.

There is a dose counter in the back of the inhaler with a viewing window that shows you how many doses of medicine you have left.See Figure A.

Figure A

• Your AirDuo Digihaler inhaler contains 60 doses (inhalations).See Figure B.
• The dose counter shows the number of doses left in your inhaler.
• When there are 20 doses left, the color of the numbers on the dose counter will change to red and you should refill your prescription or ask your healthcare provider for another prescription.
• When the dose counter displays ‘0’ your inhaler is empty and you should stop using the inhaler and throw it away.See Figure B.

Figure B

Important**:**

*Always close the cap after each inhalation so your inhaler will be ready for you to take your next dose. Do not open the cap unless you are ready for your next dose.

• You will hear a “click” sound when the cap is opened all the way. If you do not hear the “click” sound the inhaler may not be activated to give you a dose of medicine. ***AirDuo Digihaler does not have an activation button or medicine canister.**When you open the cap, a dose of AirDuo Digihaler will be activated for delivery of the medicine. *AirDuo Digihaler does not need to be wirelessly connected to the mobile application (App) in order for it to work and for you to take your medicine.
• Do not use a spacer or volume holding chamber with AirDuo Digihaler. AirDuo Digihaler does not need priming.

Using your AirDuo Digihaler inhaler:

Important: Make sure the cap is closed before you start using your inhaler.

Step 1. Open

• Hold the inhaler upright and open the yellow cap all the way until it “clicks”.See Figure C.
• Each time you open the yellow cap and it “clicks”, 1 dose of AirDuo Digihaler is ready to be inhaled.

Figure C

Remember:

• For the correct use of AirDuo Digihaler,** hold the inhaler upright as you open the yellow cap.See Figure D. *******Do nothold the inhaler in any other way as you open the yellow cap. *Do notopen the yellow cap until you are ready to take a dose of AirDuo Digihaler.

Figure D

Step 2. Inhale

• Before you inhale, breathe out (exhale) through your mouth and push as much air from your lungs as you can.S****ee Figure E. *Do notexhale into the inhaler mouthpiece.

Figure E

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• Put the mouthpiece in your mouth and close your lips tightly around it.See Figure F.

Figure F

*Do not block the vent above the mouthpiece with your lips or fingers.See Figure G.

Figure G

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*Breathe in quickly and deeply through your mouth to deliver the dose of medicine to your lungs.

• Remove the inhaler from your mouth. *Hold your breath for about 10 seconds or for as long as you comfortably can.
• Your AirDuo Digihaler inhaler delivers your dose of medicine as a very fine powder that you may or may not taste or feel.Do nottake an extra dose from the inhaler even if you do not taste or feel the medicine.

Step 3. Close

Figure H

• Close the yellow cap firmly over the mouthpiece**. See Figure H.**
• Make sure you close the yellow cap after each inhalation so that the inhaler will be ready for your next dose.
• Rinse your mouth with water** without swallowing**after each inhalation.

How should I store AirDuo Digihaler?

• Store AirDuo Digihaler at room temperature between 59ºF and 77ºF (15ºC and 25ºC).
• Avoid exposure to extreme heat, cold, or humidity.
• Store AirDuo Digihaler in the unopened foil pouch and only open when ready for use.
• Keep the yellow cap on the inhaler closed during storage.
• Keep your AirDuo Digihaler inhaler dry and clean at all times. Keep your**AirDuo Digihaler*** inhaler and all medicines out of the reach of children.**

Cleaning your AirDuo Digihaler inhaler

Do not wash or put any part of your**AirDuo Digihaler*** inhaler in water.**Replace your inhaler if washed or placed in water.

• AirDuo Digihaler contains a powder and must be kept clean and dry at all times.
• You can clean the mouthpiece if needed using a dry cloth or tissue. Routine cleaning is not required.

Replacing your AirDuo Digihaler inhaler

*Immediately replace your inhaler if the mouthpiece cover is damaged or broken. Never take the inhaler apart.

• The dose counter on the back of your inhaler shows how many doses you have left.
• When there are 20 doses left, the color of the numbers on the dose counter will change to red and you should refill your prescription or ask your healthcare provider for another prescription.
• When the counter displays ‘0’ your AirDuo Digihaler inhaler is empty and you should stop using the inhaler and throw it away.
• Throw away AirDuo Digihaler 30 days after opening the foil pouch, when the dose counter displays ‘0’, or after the expiration date on the product, whichever comes first.
• AirDuo Digihaler contains a lithium – manganese dioxide battery and should be thrown away (disposed of) in accordance with state and local regulations.

Important information

• Do not open the yellow cap unless you are taking a dose. Repeatedly opening and closing the cap without inhaling a dose will waste the medicine and may damage your inhaler.
• Your AirDuo Digihaler inhaler contains dry powder so it is important that you do not blow or breathe into it.

Support

• For instructions on setting up the App, go to www.AirDuoDigihaler.com or call Teva at 1-888-603-0788.
• If you have any questions about AirDuo Digihaler or how to use your inhaler, go to www.AirDuoDigihaler.com or call 1-888-603-0788.

This device complies with part 15 of the FCC Rules. Operation is subject to the following two conditions: (1) This device may not cause harmful interference, and (2) this device must accept any interference received, including interference that may cause undesired operation. Changes or modifications not expressly approved by Teva could void the user’s authority to operate the equipment.

These Instructions for Use have been approved by the U.S. Food and Drug Administration.

The Bluetooth® word mark and logos are registered trademarks owned by the Bluetooth SIG, Inc. and any use of such marks by Teva Respiratory, LLC is under license.

Distributed by:

Teva Pharmaceuticals USA, Inc.

Parsippany, NJ 07054

©2021, Teva Respiratory, LLC. All rights reserved.

AIRDDHIFU-002

Revised: July 2021

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