AirDuo RespiClick

You should not use this medicine if you are allergic to fluticasone or salmeterol (Serevent), or:

• if you have a severe allergy to milk proteins; or

• if you are having an asthma attack or severe COPD symptoms.

Salmeterol may increase the risk of death in people with asthma, but the risk in people with COPD is not known. Talk with your doctor about your individual risks and benefits of using this medicine.

To make sure this medicine is safe for you, tell your doctor if you have:

• a food or drug allergy;

• heart disease or high blood pressure;

• epilepsy or other seizure disorder;

• any type of infection;

• a weak immune system;

• diabetes;

• glaucoma;

• tuberculosis;

• osteoporosis;

• a thyroid disorder; or

• liver disease.

Long-term use of steroids may lead to bone loss (osteoporosis), especially if you smoke, if you do not exercise, if you do not get enough vitamin D or calcium in your diet, or if you have a family history of osteoporosis.

It is not known whether fluticasone and salmeterol is harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether this medicine passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Fluticasone can affect growth in children. Talk with your doctor if you think your child is not growing at a normal rate while using this medication.

This medicine is not approved for use by anyone younger than 4 years old.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended. Using too much of this medicine can cause life-threatening side effects.

Fluticasone and salmeterol is not a rescue medicine. It will not work fast enough to treat an asthma attack. Use only a fast-acting inhalation medicine for an asthma attack.

Seek medical attention if you think your medications are not working as well.

Advair Diskus is a powder form of fluticasone and salmeterol that comes with a special inhaler device pre-loaded with blister packs containing measured doses of the medicine. The device opens and loads a blister each time you use the inhaler.

Advair HFA and AirDuo Respiclick each come in a canister that is used with an actuator inhaler device.

Use only the inhaler device provided with your medication.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Shake the Advair HFA inhaler for at least 5 seconds before each spray.

Rinse your mouth with water after each use of your inhaler.

Your dose needs may change if you have surgery, are ill, are under stress, or have recently had an asthma attack. Do not change your medication dose or schedule without your doctor's advice.

If you also use an oral steroid medication, you should not stop using it suddenly. Follow your doctor's instructions about tapering your dose.

While using fluticasone and salmeterol, your vision and your bone mineral density may need to be checked often.

Seek medical attention if your breathing problems do not improve, or if your symptoms get worse quickly. If you use a peak flow meter at home, call your doctor if your numbers are lower than normal.

Store your medicine at room temperature away from moisture, light, and heat (especially high heat, such as open flame or in a car on a hot day).

Throw the inhaler device away 1 month after you took it out of the foil pouch, or if the dose indicator shows a zero (even if it feels like there is still medicine inside).

Once your asthma is under control, your doctor may want you to stop using this medicine. Keep all follow-up appointments and do not stop using the medicine unless your doctor tells you to.

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of Advair® Diskus® to treat asthma in children older than 4 years of age. Safety and efficacy have not been established in children younger than 4 years of age.

Appropriate studies have not been performed on the relationship of age to the effects of Advair® HFA oral inhalation or Airduo™ Respiclick® in children younger than 12 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of fluticasone and salmeterol combination in the elderly. However, elderly people with heart and blood vessel problems may require special caution when receiving fluticasone and salmeterol combination.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Desmopressin
• Fluconazole
• Posaconazole

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfuzosin
• Amiodarone
• Amprenavir
• Apomorphine
• Arsenic Trioxide
• Asenapine
• Astemizole
• Atazanavir
• Azithromycin
• Bemiparin
• Boceprevir
• Bupropion
• Ceritinib
• Chloroquine
• Chlorpromazine
• Ciprofloxacin
• Citalopram
• Clarithromycin
• Clozapine
• Cobicistat
• Conivaptan
• Darunavir
• Dasabuvir
• Dasatinib
• Disopyramide
• Dofetilide
• Dolasetron
• Domperidone
• Droperidol
• Fingolimod
• Flecainide
• Fosamprenavir
• Gatifloxacin
• Gemifloxacin
• Granisetron
• Halofantrine
• Haloperidol
• Ibutilide
• Idelalisib
• Iloperidone
• Indinavir
• Itraconazole
• Ketoconazole
• Lapatinib
• Lopinavir
• Lumacaftor
• Lumefantrine
• Mefloquine
• Mifepristone
• Nadroparin
• Nefazodone
• Nelfinavir
• Netupitant
• Nilotinib
• Norfloxacin
• Octreotide
• Ofloxacin
• Ombitasvir
• Ondansetron
• Paliperidone
• Paritaprevir
• Pixantrone
• Posaconazole
• Procainamide
• Prochlorperazine
• Promethazine
• Propafenone
• Quinidine
• Quinine
• Ranolazine
• Ritonavir
• Saquinavir
• Sodium Phosphate
• Sodium Phosphate, Dibasic
• Sodium Phosphate, Monobasic
• Solifenacin
• Sorafenib
• Sunitinib
• Telaprevir
• Telavancin
• Telithromycin
• Tetrabenazine
• Tipranavir
• Toremifene
• Trazodone
• Trifluoperazine
• Vardenafil
• Voriconazole

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Erythromycin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Asthma attack, acute or
• Bronchospasm (difficulty with breathing), acute or
• COPD flare-up or
• Milk protein allergy, severe—Should not be used in patients with these conditions.

• Blood vessel disease (eg, Churg-Strauss syndrome) or
• Bone problems (eg, osteoporosis) or
• Cataracts or
• Diabetes or
• Glaucoma or
• Heart disease or
• Heart rhythm problems (eg, arrhythmia) or
• Hypertension (high blood pressure) or
• Hyperthyroidism (overactive thyroid) or
• Hypokalemia (low potassium in the blood) or
• Ketoacidosis (high ketones in the blood) or
• Seizures, history of—Use with caution. May make these conditions worse.

• Chickenpox (including recent exposure) or
• Herpes simplex (virus) infection of the eye or
• Infections (virus, bacteria, or fungus) or
• Measles or
• Tuberculosis, active or history of—Inhaled fluticasone can reduce the body's ability to fight off these infections.

• Infection or
• Stress or
• Surgery or
• Trauma—Supplementary oral corticosteroids may be needed. Check with your doctor.

• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Black, tarry stools
• blindness
• blurred vision
• burning, tingling, numbness, or pain in the hands, arms, feet, or legs
• chills
• cough
• decreased vision
• difficulty with breathing or swallowing
• eye pain
• fast heartbeat
• fever
• headache
• hives or welts, skin itching, rash, or redness
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• nausea or vomiting
• noisy breathing
• painful or difficult urination
• sensation of pins and needles
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• stabbing pain in the arms or legs
• swelling of the face, throat, or tongue
• swollen glands
• tearing
• unusual bleeding or bruising

Incidence not known

• Abdominal or stomach pain
• backache
• bruising
• darkening of the skin
• decrease in height
• diarrhea
• difficulty with moving
• dizziness
• facial hair growth in females
• fainting
• fast, slow, pounding, or irregular heartbeat or pulse
• flushed, dry skin
• fractures
• fruit-like breath odor
• full or round face, neck, or trunk
• heavy bleeding
• increased hunger
• increased thirst or urination
• irritability
• large, flat, blue, or purplish patches in the skin
• loss of sexual desire or ability
• menstrual irregularities
• mental depression
• muscle pain or stiffness
• muscle wasting
• pain in the back, ribs, arms, or legs
• pain in the joints
• sweating
• troubled breathing
• unexplained weight loss
• unusual tiredness or weakness
• weight gain

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Chest pain or tightness
• confusion
• convulsions (seizures)
• decreased urine output
• dry mouth
• faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• general feeling of discomfort or illness
• high blood pressure
• loss of appetite
• mood changes
• nervousness
• numbness or tingling in the hands, feet, or lips
• sudden sweating
• tremors
• trouble with sleeping

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Body aches or pain
• choking
• congestion
• dryness of the throat
• high-pitched noise when breathing
• hoarseness
• runny nose
• sneezing
• trouble with swallowing
• voice changes

Less common

• Cough-producing mucus
• flu-like symptoms
• irritation or inflammation of the eye
• muscle pain
• pain or tenderness around the eyes and cheekbones
• sleep disorders
• stuffy nose
• white patches in the mouth or throat or on the tongue

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

LABA, such as salmeterol, one of the active ingredients in Airduo Respiclick, increase the risk of asthma‑related death. Data from a large placebo‑controlled US trial that compared the safety of salmeterol or placebo added to usual asthma therapy showed an increase in asthma‑related deaths in subjects receiving salmeterol [see Warnings and Precautions (5.1)]. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long‑term asthma control drugs mitigates the increased risk of asthma‑related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma‑related hospitalization in pediatric and adolescent patients [see Warnings and Precautions (5.1)].

Systemic and local corticosteroid use may result in the following:

• Candida albicans infection [see Warnings and Precautions (5.4)] • Immunosuppression [see Warnings and Precautions (5.5)] • Hypercorticism and adrenal suppression [see Warnings and Precautions (5.7)] • 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)]

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 incidence of adverse reactions associated with Airduo Respiclick in Table 2 is based upon two placebo-controlled, 12-week, clinical studies (Study 1 and 2). A total of 1,364 adolescent and adult patients previously treated with inhaled corticosteroids were treated twice daily ARMONAIR RESPICLICK 55 mcg, 113 mcg, 232 mcg or Airduo Respiclick 55/14 mcg, 113/14 mcg, 232/14 mcg, or placebo. Sixty percent of patients were female and 80% of patients were white. The average duration of exposure was 82 to 84 days in the active treatment groups compared with 75 days in the placebo group.

  Table 2: Adverse Reactions with ≥3% Incidence with Airduo Respiclick, and More Common than Placebo in Subjects with Asthma

Adverse Reaction	ARMONAIR RESPICLICK 55 mcg (n=129) %	ARMONAIR RESPICLICK 113 mcg (n=274) %	ARMONAIR RESPICLICK 232 mcg (n=146) %	Airduo Respiclick 55/14 mcg (n=128) %	Airduo Respiclick 113/14 mcg (n=269) %	Airduo Respiclick 232/14 mcg (n=145) %	Placebo (n=273) %
Infections and infestations
Nasopharyngitis	5.4	5.8	4.8	8.6	4.8	6.9	4.4
Oral candidiasis*	3.1	2.9	4.8	1.6	2.2	3.4	0.7
Musculoskeletal and connective tissue disorders
Back pain	0	1.5	1.4	3.1	0.7	0	1.8
Nervous system disorders
Headache	1.6	7.3	4.8	5.5	4.8	2.8	4.4
Respiratory disorders
Cough	1.6	1.8	3.4	2.3	3.7	0.7	2.6

*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 Airduo Respiclick), whether considered drug-related or not by the investigators, that were reported more frequently by patients with asthma treated with Airduo Respiclick 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 inhaled corticosteroids who were treated twice daily with ARMONAIR RESPICLICK 113 mcg, 232 mcg, Airduo Respiclick 113/14 mcg, 232/14 mcg, fluticasone propionate inhalation aerosol 110 mcg and 220 mcg, and fluticasone propionate 250 mcg and salmeterol 50 mcg inhalation powder, and fluticasone propionate 500 mcg and salmeterol 50 mcg inhalation powder. The types of adverse reactions were similar to those reported above in placebo controlled studies.

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.

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.

Pregnancy

Risk Summary

There are no randomized clinical studies of Airduo Respiclick or individual monoproducts, fluticasone propionate and salmeterol xinafoate, in pregnant women. There are clinical considerations with the use of Airduo Respiclick in pregnant women [see Clinical Considerations]. Animal reproduction studies are available with the combination of fluticasone propionate and salmeterol xinafoate as well as individual monoproducts. 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.

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 Respiclick and any potential adverse effects on the breastfed child from Airduo Respiclick 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.

Pediatric Use

The safety and effectiveness of Airduo Respiclick in pediatric patients below the age of 12 years have not been established.

Inhaled corticosteroids, including fluticasone propionate, a component of Airduo Respiclick, may cause a reduction in growth velocity in adolescents [see Warning and Precautions (5.13)]. The growth of pediatric patients receiving orally inhaled corticosteroids, including Airduo Respiclick, 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. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained. To minimize the systemic effects of orally inhaled corticosteroids, including Airduo Respiclick, each patient should be titrated to the lowest strength that effectively controls his/her asthma [see Dosage and Administration (2)].

Geriatric Use

No overall differences in safety or efficacy were observed in data collected in 54 subjects aged 65 years and older versus younger subjects who were treated with Airduo Respiclick in placebo-controlled Phase 2 and 3 studies.

Hepatic Impairment

Formal pharmacokinetic studies using Airduo Respiclick have not been conducted in patients with hepatic impairment. However, since both fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.

Renal Impairment

Formal pharmacokinetic studies using Airduo Respiclick have not been conducted in patients with renal impairment.

Airduo Respiclick 55/14 mcg, Airduo Respiclick 113/14 mcg and Airduo Respiclick 232/14 mcg are combinations of fluticasone propionate and salmeterol xinafoate.

One active component of Airduo Respiclick 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.

The other active component of Airduo Respiclick 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 Respiclick is a white multidose dry powder inhaler (MDPI) for oral inhalation only. It contains a formulation blend of 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 Respiclick 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 Airduo Respiclick inhaler 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 Airduo Respiclick inhaler was 106.72 L/min (range: 73.64 to 125.51 L/min).

Mechanism of Action

Airduo Respiclick: Airduo Respiclick contains both fluticasone propionate and salmeterol. The mechanisms of action described below for the individual components apply to Airduo Respiclick. These drugs represent 2 different classes of medications (a synthetic corticosteroid and a LABA) that have different effects on clinical, physiologic, and inflammatory indices.

Fluticasone Propionate: Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results. The clinical significance of these findings is unknown.

Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

Salmeterol Xinafoate: Salmeterol is a selective LABA. In vitro studies show salmeterol to be at least 50 times more selective for beta2‑adrenoceptors than albuterol. Although beta2‑adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1‑adrenoceptors are the predominant receptors in the heart, there are also beta2‑adrenoceptors in the human heart comprising 10% to 50% of the total beta‑adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta2‑agonists may have cardiac effects.

The pharmacologic effects of beta2‑adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that salmeterol is a potent and long‑lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D2, from human lung. Salmeterol inhibits histamine‑induced plasma protein extravasation and inhibits platelet‑activating factor‑induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen‑induced bronchial hyperresponsiveness.

Pharmacodynamics

Airduo Respiclick: Healthy Subjects: Cardiovascular Effects:

There were no clinical trials conducted with Airduo Respiclick in healthy subjects.

Other Fluticasone Propionate and Salmeterol Inhalation Powder Products: Healthy Subjects: Cardiovascular Effects:

Since systemic pharmacodynamic effects of salmeterol are not normally seen at the therapeutic dose, higher doses were used to produce measurable effects. Four (4) trials were conducted with healthy adult subjects (1) a single‑dose crossover trial using 2 inhalations of a fluticasone propionate and salmeterol powder product, fluticasone propionate powder 500 mcg and salmeterol powder 50 mcg given concurrently, or fluticasone propionate powder 500 mcg given alone, (2) a cumulative dose trial using 50 to 400 mcg of salmeterol powder given alone or as a fluticasone propionate 500 mcg and salmeterol 50 mcg powder product, (3) a repeat‑dose trial for 11 days using 2 inhalations twice daily of fluticasone propionate 250 mcg and salmeterol 50 mcg powder product, fluticasone propionate powder 250 mcg, or salmeterol powder 50 mcg, and (4) a single-dose trial using 5 inhalations of fluticasone propionate 100 mcg and salmeterol powder 50 mcg product, fluticasone propionate powder 100 mcg alone, or placebo. In these trials, no significant differences were observed in the pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given as fluticasone propionate and salmeterol powder, concurrently with fluticasone propionate from separate inhalers, or as salmeterol alone. The systemic pharmacodynamic effects of salmeterol were not altered by the presence of fluticasone propionate in the fluticasone propionate and salmeterol powder product.

Airduo Respiclick: Subjects with Asthma: Adults and Adolescents: Hypothalamic‑Pituitary‑Adrenal Axis Effects.

There are no data from controlled trials using the Airduo Respiclick in healthy subjects or subjects with asthma in serum cortisol.

Other Salmeterol Xinafoate Products: Subjects with Asthma: Cardiovascular Effects:

Inhaled salmeterol, like other beta‑adrenergic agonist drugs, can produce dose‑related cardiovascular effects and effects on blood glucose and/or serum potassium [see Warnings and Precautions (5.11, 5.17)]. The cardiovascular effects (heart rate, blood pressure) associated with salmeterol inhalation aerosol occur with similar frequency, and are of similar type and severity, as those noted following albuterol administration.

The effects of rising inhaled doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in subjects with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). Adult and adolescent subjects receiving 50 mcg doses of salmeterol inhalation powder (N=60) underwent continuous electrocardiographic monitoring during two 12‑hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted.

Concomitant Use of Airduo Respiclick With Other Respiratory Medications:
Other Fluticasone Propionate and Salmeterol Inhalation Powder Products:

Short-Acting Beta2‑Agonists: In clinical trials in subjects with asthma, the mean daily need for albuterol by 166 adult and adolescent subjects aged 12 years and older using a fluticasone propionate and salmeterol powder product was approximately 1.3 inhalations/day and ranged from 0 to 9 inhalations/day. Five percent (5%) of subjects using a fluticasone propionate and salmeterol powder product in these trials averaged 6 or more inhalations per day over the course of the 12-week trials. No increase in frequency of cardiovascular adverse events was observed among subjects who averaged 6 or more inhalations per day.

Methylxanthines: In clinical trials in subjects with asthma, 39 subjects receiving fluticasone propionate and salmeterol powder product, fluticasone propionate 100 mcg and salmeterol 50 mcg, fluticasone propionate 250 mcg and salmeterol 50 mcg, or fluticasone propionate 500 mcg and salmeterol 50 mcg twice daily concurrently with a theophylline product had adverse event rates similar to those in 304 subjects receiving fluticasone propionate and salmeterol powder product without theophylline. Similar results were observed in subjects receiving salmeterol 50 mcg plus fluticasone propionate 500 mcg twice daily concurrently with a theophylline product (n = 39) or without theophylline (n = 132).

Pharmacokinetics

Absorption

Fluticasone Propionate:

Airduo Respiclick acts locally in the lung; therefore, plasma levels may not predict therapeutic effect. Trials using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate was negligible (<1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung was systemically absorbed.

After administration of 232/14 mcg Airduo Respiclick to patients aged 12 years and older with persistent asthma in a clinical trial, the mean Cmax value of fluticasone propionate was 66 pg/mL with a median tmax value of approximately 2 hour.

Salmeterol:

After administration of 232/14 mcg Airduo Respiclick to patients aged 12 years and older with persistent asthma, the mean Cmax values of salmeterol was 60 pg/mL. The median tmax was 5 minutes.

Distribution

Fluticasone Propionate:

Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg.

The percentage of fluticasone propionate bound to human plasma proteins averages 99%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin.

Salmeterol:

Volume of distribution data are not available for salmeterol.

The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol.

Elimination

Fluticasone Propionate:

Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Terminal half-life estimates of fluticasone propionate following oral inhalation administration of Airduo Respiclick were approximately 10.8 hours.

  Metabolism

The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway. This metabolite has less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.

  Excretion

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

Salmeterol:

Terminal half-life estimates for salmeterol for Airduo Respiclick were approximately 12.6 hours.

The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highly protein bound (greater than 99%) and has a long elimination half-life of 11 days.

  Metabolism

Salmeterol base is extensively metabolized by hydroxylation.

An in vitro study using human liver microsomes showed that salmeterol is extensively metabolized to α hydroxysalmeterol (aliphatic oxidation) by CYP3A4. Ketoconazole, a strong inhibitor of CYP3A4, essentially completely inhibited the formation of α hydroxysalmeterol in vitro.

  Excretion

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

Special Populations

A population pharmacokinetic analysis was performed for fluticasone propionate and salmeterol utilizing data from 9 controlled clinical trials that included 350 subjects with asthma aged 4 to 77 years who received treatment with a combination dry powder inhaler of fluticasone propionate and salmeterol, the combination of HFA‑propelled fluticasone propionate and salmeterol inhalation aerosol, fluticasone propionate inhalation powder, HFA‑propelled fluticasone propionate inhalation aerosol, or CFC‑propelled fluticasone propionate inhalation aerosol. The population pharmacokinetic analyses for fluticasone propionate and salmeterol showed no clinically relevant effects of age, gender, race, body weight, body mass index, or percent of predicted FEV1 on apparent clearance and apparent volume of distribution.

Age: No pharmacokinetic studies have been performed with Airduo Respiclick in children or geriatric patients. A subgroup analysis was conducted to compare patients aged 12-17 (n=15) and ≥18 (n=23) years following administration of 232/14 mcg Airduo Respiclick. No overall differences in fluticasone propionate and salmeterolpharmacokinetics were observed. .

Sex: A subgroup analysis was conducted to compare male (n=21) and female (n=16) patients following administration of 232/14 mcg Airduo Respiclick. No overall differences in fluticasone propionate and salmeterol pharmacokinetics were observed.

Renal Impairment: The effect of renal impairment of the pharmacokinetics of Airduo Respiclick has not been evaluated.

Hepatic Impairment: Formal pharmacokinetic studies using Airduo Respiclick have not been conducted in patients with hepatic impairment. However, since both fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma.

Drug Interaction Studies: In a single-dose trial, the presence of salmeterol does not alter fluticasone propionate exposure.

No studies have been performed with Airduo Respiclick to investigate the effect of fluticasone propionate on salmeterol pharmacokinetics when given in combination.

Other Fluticasone Propionate and Salmeterol Inhalation Powder Products:

Drug Interactions: The population pharmacokinetic analysis from 9 controlled clinical trials in 350 subjects with asthma showed no significant effects on fluticasone propionate or salmeterol pharmacokinetics following co-administration with beta2-agonists, corticosteroids, antihistamines, or theophyllines.

Inhibitors of Cytochrome P450 3A4: Ritonavir: Fluticasone Propionate: Fluticasone propionate is a substrate of CYP3A4. Coadministration of fluticasone propionate and the strong CYP3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction trial in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (<10 pg/mL) in most subjects, and when concentrations were detectable peak levels (Cmax) averaged 11.9 pg/mL (range: 10.8 to 14.1 pg/mL) and AUC0-τ averaged 8.43 pg•h/mL (range: 4.2 to 18.8 pg•h/mL). Fluticasone propionate Cmax and AUC0-τ increased to 318 pg/mL (range: 110 to 648 pg/mL) and 3,102.6 pg•h/mL (range: 1,207.1 to 5,662.0 pg•h/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in serum cortisol AUC.

Ketoconazole: Fluticasone Propionate: In a placebo-controlled crossover trial in 8 healthy adult volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1,000 mcg) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol.

Salmeterol: In a placebo-controlled, crossover drug interaction trial in 20 healthy male and female subjects, coadministration of salmeterol (50 mcg twice daily) and the strong CYP3A4 inhibitor ketoconazole (400 mg once daily) for 7 days resulted in a significant increase in plasma salmeterol exposure as determined by a 16-fold increase in AUC (ratio with and without ketoconazole 15.76 [90% CI: 10.66, 23.31]) mainly due to increased bioavailability of the swallowed portion of the dose. Peak plasma salmeterol concentrations were increased by 1.4-fold (90% CI: 1.23, 1.68). Three (3) out of 20 subjects (15%) were withdrawn from salmeterol and ketoconazole coadministration due to beta-agonist–mediated systemic effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). Coadministration of salmeterol and ketoconazole did not result in a clinically significant effect on mean heart rate, mean blood potassium, or mean blood glucose. 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.

Erythromycin: Fluticasone Propionate: In a multiple-dose drug interaction trial, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.

Salmeterol: In a repeat-dose trial in 13 healthy subjects, concomitant administration of erythromycin (a moderate CYP3A4 inhibitor) and salmeterol inhalation aerosol resulted in a 40% increase in salmeterol Cmax at steady state (ratio with and without erythromycin 1.4 [90% CI: 0.96, 2.03], P = 0.12), a 3.6-beat/min increase in heart rate ([95% CI: 0.19, 7.03], P<0.04), a 5.8-msec increase in QTc interval ([95% CI: -6.14, 17.77], P = 0.34), and no change in plasma potassium.

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Patients should be given the following information:

Asthma‑Related Death

Inform patients with asthma that salmeterol, one of the active ingredients in Airduo Respiclick, increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Also inform them that currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma‑related death from LABA.

Not for Acute Symptoms

Inform patients that Airduo Respiclick is not meant to relieve acute asthma symptoms and extra doses should not be used for that purpose. Advise patients to treat acute asthma symptoms with an inhaled, short‑acting beta2‑agonist such as albuterol. Provide patients with such medication and instruct them in how it should be used.

Instruct patients to seek medical attention if they experience any of the following:

• Decreasing effectiveness of inhaled, short‑acting beta2‑agonists • Need for more inhalations than usual of inhaled, short‑acting beta2‑agonists • Significant decrease in lung function as outlined by the physician

Tell patients they should not stop therapy with Airduo Respiclick without physician/provider guidance since symptoms may recur after discontinuation.

Do Not Use Additional Long-Acting Beta2‑Agonists

Instruct patients not to use other LABA for asthma.

Local Effects

Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with Airduo Respiclick, but at times therapy with Airduo Respiclick may need to be temporarily interrupted under close medical supervision. Rinsing the mouth with water without swallowing after inhalation is advised to help reduce the risk of thrush.

Immunosuppression

Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Hypercorticism and Adrenal Suppression

Advise patients that Airduo Respiclick may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, inform patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to Airduo Respiclick.

Immediate Hypersensitivity Reactions

Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of Airduo Respiclick. Patients should discontinue Airduo Respiclick if such reactions occur and contact their healthcare provider or get emergency medical help. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not take Airduo Respiclick.

Reduction in Bone Mineral Density

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

Reduced Growth Velocity

Inform patients that orally inhaled corticosteroids, including fluticasone propionate, may cause a reduction in growth velocity when administered to adolescent patients. Physicians should closely follow the growth of adolescents taking corticosteroids by any route.

Ocular Effects

Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.

Risks Associated with Beta‑Agonist Therapy

Inform patients of adverse effects associated with beta2‑agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

Pregnancy

Inform patients who are pregnant or nursing that they should contact their physician about the use of Airduo Respiclick.

Use Daily for Best Effect

Patients should use Airduo Respiclick at regular intervals as directed. The daily dosage of Airduo Respiclick should not exceed 1 inhalation twice a day. Advise patients, if they miss a dose, to take their next dose at the same time they normally do and to not take 2 doses at one time. Individual patients will experience a variable time to onset and degree of symptom relief and full benefit may not be achieved until treatment has been administered for 1 to 2 weeks or longer. Patients should not increase the prescribed dosage but should contact their physicians if symptoms do not improve or if the condition worsens. Instruct patients not to stop use of Airduo Respiclick abruptly. Patients should contact their physicians immediately if they discontinue use of Airduo Respiclick.

Caring for and Storing the Inhaler

Instruct patients to not open their inhaler unless they are taking a dose. Repeated opening and closing the cover without taking medication will waste medication and may damage the inhaler.

Advise patients to keep their inhaler dry and clean at all times. Never wash or put any part of the inhaler in water. Patient should replace inhaler if washed or placed in water. Advise patients to immediately replace inhaler if mouthpiece cover is damaged or broken.

Gently wipe the mouthpiece with a dry cloth or tissue as needed.

Instruct patients to store the inhaler at room temperature and to avoid exposure to extreme heat, cold, or humidity.

Instruct patients to never take the inhaler apart.

Inform patients that Airduo Respiclick has a dose counter. When the patient receives the inhaler, the number 60 will be displayed. The dose counter will count down each time the mouthpiece cap is opened and closed. The dose-counter window displays the number of actuations left in the inhaler in units of two (e.g., 60, 58, 56, etc.). When the counter displays 20, the color of the numbers will change to red to remind the patient to contact their pharmacist for a refill of medication or consult their physician for a prescription refill. When the dose counter reaches 0, the background will change to solid red. Inform patients to discard Airduo Respiclick when the dose counter displays 0, 30 days after opening the foil pouch or after the expiration date on the product, whichever comes first.

Rx only

Marketed by: Teva Respiratory, LLC
Frazer, PA 19355

Manufactured by: Teva Pharmaceutical Industries Ltd.
Jerusalem, Israel

Copyright ©2017 Teva Respiratory, LLC

All rights reserved.

AIRDUO™, ARMONAIR™ and RESPICLICK® are trademarks owned by Teva Respiratory, LLC.

United States Patent Nos. 6446627, 6701917, 6718972, 6748947, 6871646, 7540282, 8006690, 8651103, 8714149, 8978966, 9066957, 9216260, 9415008, 9463288

AIRD-001

MEDICATION GUIDE AIRDUO™ RESPICLICK® (ayr´ due oh  res-pē-klik) (fluticasone propionate and salmeterol) inhalation powder 55 mcg/14 mcg Airduo Respiclick (ayr´ due oh  res-pē-klik) (fluticasone propionate and salmeterol) inhalation powder 113 mcg/14 mcg Airduo Respiclick (ayr´ due oh res-pē-klik) (fluticasone propionate and salmeterol) inhalation powder 232 mcg/14 mcg for oral inhalation use

What is the most important information I should know about Airduo Respiclick? Airduo Respiclick can cause serious side effects, including:   ● People with asthma who take long-acting beta2-adrenergic agonist (LABA) medicines, such as salmeterol (one of the medicines in Airduo Respiclick), have an increased risk of death from asthma problems. It is not known whether fluticasone propionate, the other medicine in Airduo Respiclick, reduces the risk of death from asthma problems seen with LABA medicines.   ● Call your healthcare provider if breathing problems worsen over time while using Airduo Respiclick. You may need different treatment. ● Get emergency medical care if:   ○ your breathing problems worsen quickly.   ○ you use your rescue inhaler, but it does not relieve your breathing problems.   ● Airduo Respiclick should be used only if your healthcare provider decides that your asthma is not well controlled with a long term asthma control medicine, such as an inhaled corticosteroid. When your asthma is well controlled, your healthcare provider may tell you to stop taking Airduo Respiclick. Your healthcare provider will decide if you can stop Airduo Respiclick without loss of asthma control. Your healthcare provider may prescribe a different asthma control medicine for you, such as an inhaled corticosteroid. ● Adolescents who take LABA medicines may have an increased risk of being hospitalized for asthma problems.

What is Airduo Respiclick?   ● Airduo Respiclick combines the inhaled corticosteroid (ICS) medicine fluticasone propionate and the LABA medicine salmeterol.   ● ICS medicines such as fluticasone propionate help to decrease inflammation in the lungs. Inflammation in the lungs can lead to breathing problems.   ● LABA medicines such as salmeterol help the muscles around the airways in your lungs stay relaxed to prevent symptoms, such as wheezing, cough, chest tightness, and shortness of breath. These symptoms can happen when the muscles around the airways tighten. This makes it hard to breathe.   ● Airduo Respiclick is a prescription medicine used to control symptoms of asthma and to prevent symptoms such as wheezing in people 12 years of age and older. Airduo Respiclick contains salmeterol. LABA medicines such as salmeterol increase the risk of death from asthma problems. Airduo Respiclick is not for people 12 years of age and older with asthma who are well controlled with an asthma control medicine, such as a low or medium dose of an inhaled corticosteroid medicine. Airduo Respiclick is not used to relieve sudden breathing problems. It is not known if Airduo Respiclick is safe and effective in children younger than 12 years of age.

Do not use Airduo Respiclick: ● to treat sudden, severe symptoms of asthma. ● if you have a severe allergy to milk proteins. Ask your healthcare provider if you are not sure.   ● if you are allergic to fluticasone propionate or any of the inactive ingredients in Airduo Respiclick. See the end of this leaflet for a complete list of ingredients in Airduo Respiclick.

Tell your healthcare provider about all of your medical conditions, including if you: ● have heart problems. ● have high blood pressure. ● have seizures. ● have thyroid problems. ● have diabetes. ● have liver problems. ● have weak bones (osteoporosis). ● have an immune system problem. ● have eye problems, such as glaucoma or cataracts. ● are allergic to milk proteins. ● have any type of viral, bacterial, fungal, or parasitic infection. ● are exposed to chickenpox or measles. ● are pregnant or plan to become pregnant. It is not known if Airduo Respiclick may harm your unborn baby.   ● are breastfeeding. It is not known if the medicines in Airduo Respiclick pass into your breast milk and if they can harm your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Airduo Respiclick and certain other medicines may interact with each other. This may cause serious side effects. Especially, tell your healthcare provider if you take antifungal or anti-HIV medicines.

How should I use Airduo Respiclick? ● Read the step-by-step instructions for using Airduo Respiclick at the end of this Medication Guide.   ● Airduo Respiclick comes in 3 different strengths. Your healthcare provider prescribed the strength that is best for you.   ● Use Airduo Respiclick exactly as your healthcare provider tells you to use it. Do not use Airduo Respiclick more often than prescribed.   ● Use 1 inhalation of Airduo Respiclick 2 times each day. Use Airduo Respiclick at the same time each day, about 12 hours apart. If you miss a dose of Airduo Respiclick, just skip that dose. Take your next dose at your usual time. Do not take 2 doses at one time.   ● If you take too much Airduo Respiclick, call your healthcare provider or go to the nearest hospital emergency room right away if you have any unusual symptoms, such as worsening shortness of breath, chest pain, increased heart rate, or shakiness.   ● Do not use other medicines that contain a LABA for any reason. Examples of other medicines that contain a LABA include salmeterol, formoterol fumarate, arformoterol tartrate, and indacaterol. Ask your healthcare provider or pharmacist if any of your other medicines are LABA medicines.   ●Do not stop using Airduo Respiclick unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider will change your medicines as needed.   ● Airduo Respiclick does not relieve sudden asthma symptoms. You should not take extra doses of Airduo Respiclick to relieve sudden asthma symptoms. Always have a rescue inhaler with you to treat sudden asthma symptoms. If you do not have a rescue inhaler, call your healthcare provider to have one prescribed for you. ●Call your healthcare provider or get medical care right away if:   ○ your breathing problems get worse.   ○ you need to use your rescue inhaler more often than usual.   ○ your rescue inhaler does not work as well to relieve your symptoms.   ○ your peak flow meter results decrease. Your healthcare provider will tell you the numbers that are right for you.   ○ you have asthma and your symptoms do not improve after using Airduo Respiclick regularly for one week.

What are the possible side effects with Airduo Respiclick? Airduo Respiclick can cause serious side effects, including: ● See “What is the most important information I should know about Airduo Respiclick?”   ● fungal infection in your mouth and throat (thrush). Rinse your mouth with water without swallowing after using Airduo Respiclick to help reduce your chance of getting thrush. ● weakened immune system and increased chance of getting infections (immunosuppression).   ● reduced adrenal function (adrenal insufficiency). Adrenal insufficiency is a condition where the adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines (such as prednisone) and start taking a medicine containing an inhaled steroid (such as Airduo Respiclick). When your body is under stress such as from fever, trauma (such as a car accident), infection, or surgery, adrenal insufficiency can get worse and may cause death.   Symptoms of adrenal insufficiency include: o Feeling tired ο nausea and vomiting o Lack of energy ο low blood pressue o weakness   ● sudden breathing problems immediately after inhaling your medicine. If you have sudden breathing problems immediately after inhaling your medicine, stop using Airduo Respiclick and call your healthcare provider right away.   ● serious allergic reactions. Stop using Airduo Respiclick and call your healthcare provider or get emergency medical help if you get any of the following symptoms of a serious allergic reaction: o rash ο swelling of your face, mouth, and tongue o hives ο breathing problems ● effects on heart. o increased blood pressure ο chest pain o a fast or irregular heartbeat ● effects on nervous system. o tremor ο nervousness ● bone thinning or weakness (osteoporosis). ● slowed growth in children. Thegrowth of a child should be checked often. ● eye problems including glaucoma and cataracts. You should have regular eye exams while using Airduo Respiclick. ● changes in laboratory blood values (sugar, potassium, certain types of white blood cells). Common side effects of Airduo Respiclick include: • infection of nose and throat (nasopharyngitis) • back pain • thrush in your mouth or throat. Rinse your mouth with water without swallowing after use to help prevent this. • Headache • cough These are not all the possible side effects of Airduo Respiclick. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Airduo Respiclick?   ● Store Airduo Respiclick at room temperature between 59ºF and 77ºF (15ºC and 25ºC).   ● Avoid exposure to extreme heat, cold, or humidity. ● Store Airduo Respiclick 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 Respiclick inhaler dry and clean at all times.   ● Throw away AIRDUORESPICLICK 30 days after opening the foil pouch, when the dose counter displays ‘0’, or after the expiration date on the product, whichever comes first.   Keep Airduo Respiclick and all medicines out of the reach of children.

General information about the safe and effective use of Airduo Respiclick. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Airduo Respiclick for a condition for which it was not prescribed. Do not give Airduo Respiclick to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about Airduo Respiclick that is written for health professionals.

What are the ingredients in Airduo Respiclick? Active ingredients: fluticasone propionate, salmeterol xinafoate Inactive ingredient: lactose monohydrate (may contain milk proteins) This Medication Guide has been approved by the U.S. Food and Drug Administration. Marketed by: Teva Respiratory, LLC, Frazer, PA 19355; Manufactured by: Teva Pharmaceutical Industries Ltd., Jerusalem, Israel; Copyright ©2017, Teva Respiratory, LLC; All rights reserved; AIRDUOTM and RESPICLICK® are trademarks owned by Teva Respiratory, LLC.   For more information about Airduo Respiclick, call 1-888-482-9522 or visit our website at www.AIRDUORESPICLICK.com.

AIRDMG-001

Rev. 01/2017

Instructions for Use

AIRDUO™ RESPICLICK® (ayr´due oh res-pē-klik)

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

Airduo Respiclick (ayr´due oh res-pē-klik)

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

Airduo Respiclick (ayr´due oh res-pē-klik)

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

for oral inhalation use

Your Airduo Respiclick Inhaler

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

There are 2 main parts of your Airduo Respiclick inhaler including the:

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

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 Respiclick 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 Respiclick does not have an activation button or medicine canister. When you open the cap, a dose of AIRDUO will be activated for delivery of the medicine. • Do not use a spacer or volume holding chamber with Airduo Respiclick. Airduo Respiclick does not need priming.

Using your Airduo Respiclick inhaler:

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

Step 1. Open

  Figure C
• 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 Respiclick is ready to be inhaled.

Remember:

• For the correct use of Airduo Respiclick, hold the inhaler upright as you open the yellow cap. See Figure D. • Do not hold the inhaler in any other way as you open the yellow cap. • Do not open the yellow cap until you are ready to take a dose of Airduo Respiclick.   Figure D

Step 2. Inhale

Figure E

• Before you inhale, breathe out (exhale) through your mouth and push as much air from your lungs as you can. See Figure E. • Do not exhale into the inhaler mouthpiece.   Figure F
• Put the mouthpiece in your mouth and close your lips tightly around it. See Figure F.

Figure G

• Do not block the vent above the mouthpiece with your lips or fingers. See Figure G. • 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 Respiclick inhaler delivers your dose of medicine as a very fine powder that you may or may not taste or feel. Do not take 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 Respiclick?

• Store Airduo Respiclick at room temperature between 59ºF and 77ºF (15ºC and 25ºC). • Avoid exposure to extreme heat, cold, or humidity. • Store Airduo Respiclick 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 Respiclick inhaler dry and clean at all times. • Keep your Airduo Respiclick inhaler and all medicines out of the reach of children.

Cleaning your Airduo Respiclick inhaler

• Do not wash or put any part of your Airduo Respiclick inhaler in water. Replace your inhaler if washed or placed in water. • Airduo Respiclick 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 Respiclick 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 Respiclick inhaler is empty and you should stop using the inhaler and throw it away. • Throw away Airduo Respiclick 30 days after opening the foil pouch, when the dose counter displays ‘0’, or after the expiration date on the product, whichever comes first.

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 Respiclick inhaler contains dry powder so it is important that you do not blow or breathe into it.

Support

• If you have any questions about Airduo Respiclick or how to   use your inhaler, go to www.AIRDUORESPICLICK.com, or call 1-888-482-9522.

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

Marketed by: Teva Respiratory, LLC, Frazer, PA 19355; Manufactured by: Teva Pharmaceutical Industries, Ltd., Jerusalem, Israel; Copyright ©2017, Teva Respiratory, LLC; All rights reserved; AIRDUOTM and RESPICLICK® are trademarks owned by Teva Respiratory, LLC.

AIRDIFU-001

Rev. 01/2017