Advair Diskus

Name: Advair Diskus

Warnings

Included as part of the PRECAUTIONS section.

Advair Diskus Overview

Advair Diskus is a prescription medication used to treat asthma and COPD. It is a single product containing 2 medications: fluticasone and salmeterol. Fluticasone belongs to a class of medications called steroids. These work by reducing swelling in the airways. Salmeterol belongs to a class of drugs called long-acting beta-agonists (LABAs). These work by relaxing and opening air passages in the lungs, making it easier to breathe.

This medication comes in an inhaler form and is typically used twice a day, in the morning and evening, about 12 hours apart.

Common side effects of Advair Diskus include upper respiratory tract infection, throat irritation, hoarseness and voice changes, and thrush in the mouth or throat.

Advair Diskus can also cause drowsiness. Do not drive or operate heavy machinery until you know how Advair Diskus affects you.

Manufacturer

  • Glaxo SmithKline Pharmaceuticals

Advair Diskus Precautions

Serious side effects have been reported with Advair Diskus including the following:

  • increased risk of death from asthma problems. People with asthma who take long-acting beta2 adrenergic agonist (LABA) medicines, such as salmeterol (one of the medicines in Advair Diskus), have an increased risk of death from asthma problems.
  • pneumonia. People with COPD have a higher chance of getting pneumonia. Advair Diskus may increase the chance of getting pneumonia. Call your healthcare provider if you notice any of the following symptoms: increase in mucus production, change in mucus color, fever, chills, increased cough, and increased breathing problems.
  • immunosuppression. Advair Diskus may increase the chance of getting infections.
  • 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 Advair Diskus). When your body is under stress such as from fever, trauma (such as a car accident), infection, surgery, or worse COPD symptoms, adrenal insufficiency can get worse and may cause death.  Symptoms of adrenal insufficiency include the following: feeling tired, lack of energy, weakness, nausea and vomiting, and low blood pressure.
  • thrush. Advair Diskus can cause a fungal infection in your mouth or throat.  It is important to rinse your mouth with water without swallowing after using Advair Diskus to help reduce your chance of getting thrush.
  • sudden breathing problems immediately after inhaling your medicine. Call your healthcare provider if breathing problems worsen over time while using Advair Diskus.
  • serious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following symptoms of a serious allergic reaction: rash, hives, swelling of your face, mouth, and tongue, and breathing problems.
  • effects on heart. Advair Diskus can cause increased blood pressure, a fast or irregular heartbeat, and chest pain.
  • effects on nervous system. Advair Diskus can cause a tremor and nervousness.
  • osteoporosis. Advair Diskus can cause bone thinning or weakness.
  • slowed growth in children. A child's growth should be checked often.
  • glaucoma and cataracts. Advair Diskus can cause eye problems.  It is important to have regular eye exams while using Advair Diskus.
  • changes in laboratory blood values. Advair Diskus can cause changes in your sugar, potassium, and certain types of white blood cells.

Advair Diskus can cause drowsiness. Do not drive or operate heavy machinery until you know how Advair Diskus affects you.

Do not take Advair Diskus in the following situations:

  • are allergic to Advair Diskus or to any of its ingredients
  • have a severe allergy to milk proteins
  • treatment of a sudden attack of asthma or COPD

Advair Diskus Food Interactions

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Advair Diskus, there are no specific foods that you must exclude from your diet when receiving this medication.

You should not use Advair Diskus if you have a severe allergy to milk proteins. See the "Drug Precautions" section.

What happens if I miss a dose?

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.

How is this medicine (Advair Diskus) best taken?

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • Follow how to use as you have been told by the doctor or read the package insert.
  • To gain the most benefit, do not miss doses.
  • Keep using this medicine (Advair Diskus) as you have been told by your doctor or other health care provider, even if you feel well.
  • Use this medicine at the same time of day.
  • For breathing in only.
  • Do not prepare a dose until you need to take it. If you prepare a dose and close the inhaler without taking a dose, it will waste the drug and may damage the inhaler.
  • Do not breathe out into the puffer (inhaler). Close the inhaler after you use your dose.
  • Do not take the device apart or wash it. Do not use it with a spacer. Do not breathe out into the device.
  • Clean mouthpiece by wiping with a dry tissue or cloth. Do not wash or put in water.
  • This inhaler has a dose counter to keep track of how many doses are left. Throw away the inhaler when you have been told after opening or when the dose counter has a 0 in it, whichever comes first.
  • Have your puffer (inhaler) use checked with your doctor at each visit. Read and follow facts on how to use the puffer. Make sure you use the puffer the right way.
  • Rinse out mouth after each use. Do not swallow the rinse water. Spit it out.
  • If using more than 1 type of puffer (inhaler), ask the doctor which puffer to use first.

What do I do if I miss a dose?

  • Skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.

Indications and Usage for Advair Diskus

Treatment of Asthma

Advair Diskus is indicated for the treatment of asthma in patients aged 4 years and older.

LABA, such as salmeterol, one of the active ingredients in Advair Diskus, increase the risk of asthma-related death. 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)]. Therefore, when treating patients with asthma, physicians should only prescribe Advair Diskus for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Advair Diskus) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Advair Diskus for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

Important Limitation of Use

Advair Diskus is NOT indicated for the relief of acute bronchospasm.

Maintenance Treatment of Chronic Obstructive Pulmonary Disease

Advair Diskus 250/50 is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Advair Diskus 250/50 is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. Advair Diskus 250/50 twice daily is the only approved dosage for the treatment of COPD because an efficacy advantage of the higher strength Advair Diskus 500/50 over Advair Diskus 250/50 has not been demonstrated.

Important Limitation of Use

Advair Diskus is NOT indicated for the relief of acute bronchospasm.

Contraindications

The use of Advair Diskus is contraindicated in the following conditions:

• Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required [see Warnings and Precautions (5.2)]. • Severe hypersensitivity to milk proteins [see Warnings and Precautions (5.11), Adverse Reactions (6.3), Description (11)].

Use in specific populations

Pregnancy

Teratogenic Effects

Pregnancy Category C. There are no adequate and well-controlled trials with Advair Diskus in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal reproduction studies are not always predictive of human response, Advair Diskus should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking Advair Diskus.

Fluticasone Propionate and Salmeterol: In the mouse reproduction assay, fluticasone propionate by the subcutaneous route at a dose approximately 3/5 the maximum recommended human daily inhalation dose (MRHDID) (on a mg/m2 basis at a maternal subcutaneous dose of 150 mcg/kg/day) combined with oral salmeterol at a dose approximately 410 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 10 mg/kg/day) produced cleft palate, fetal death, increased implantation loss, and delayed ossification. These observations are characteristic of glucocorticoids. No developmental toxicity was observed at combination doses of fluticasone propionate subcutaneously up to approximately 1/6 the MRHDID (on a mg/m2 basis at a maternal subcutaneous dose of 40 mcg/kg/day) and doses of salmeterol up to approximately 55 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 1.4 mg/kg/day). In rats, combining fluticasone propionate subcutaneously at a dose equivalent to the MRHDID (on a mg/m2 basis at a maternal subcutaneous dose of 100 mcg/kg/day) and a dose of salmeterol at approximately 810 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 10 mg/kg/day) produced decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone. No such effects were seen when combining fluticasone propionate subcutaneously at a dose less than the MRHDID (on a mg/m2 basis at a maternal subcutaneous dose of 30 mcg/kg/day) and an oral dose of salmeterol at approximately 80 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 1 mg/kg/day).

Fluticasone Propionate: Mice and rats at fluticasone propionate doses less than or equivalent to the MRHDID (on a mg/m2 basis at a maternal subcutaneous dose of 45 and 100 mcg/kg/day, respectively) showed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. No teratogenicity was seen in rats at doses approximately equivalent to the MRHDID (on a mg/m2 basis at maternal inhaled doses up to 68.7 mcg/kg/day).

In rabbits, fetal weight reduction and cleft palate were observed at a fluticasone propionate dose less than the MRHDID (on a mg/m2 basis at a maternal subcutaneous dose of 4 mcg/kg/day). However, no teratogenic effects were reported at fluticasone propionate doses up to approximately 5 times the MRHDID (on a mg/m2 basis at a maternal oral dose up to 300 mcg/kg/day). No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration [see Clinical Pharmacology (12.3)].

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

Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.

Salmeterol: No teratogenic effects occurred in rats at salmeterol doses approximately 160 times the MRHDID (on a mg/m2 basis at maternal oral doses up to 2 mg/kg/day). In pregnant Dutch rabbits administered salmeterol doses approximately 50 times the MRHDID (on an AUC basis at maternal oral doses of 1 mg/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 20 times the MRHDID (on an AUC basis at a maternal oral dose of 0.6 mg/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 1,600 times the MRHDID on a mg/m2 basis at a maternal oral dose of 10 mg/kg/day. Salmeterol xinafoate crossed the placenta following oral administration to mice and rats.

Nonteratogenic Effects

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

Labor and Delivery

There are no well-controlled human trials that have investigated effects of Advair Diskus on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of Advair Diskus during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Nursing Mothers

Plasma levels of salmeterol, a component of Advair Diskus, after inhaled therapeutic doses are very low. In rats, salmeterol xinafoate is excreted in the milk. There are no data from controlled trials on the use of salmeterol by nursing mothers. It is not known whether fluticasone propionate, a component of Advair Diskus, is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of tritiated fluticasone propionate resulted in measurable radioactivity in milk.

Since there are no data from controlled trials on the use of Advair Diskus by nursing mothers, caution should be exercised when Advair Diskus is administered to a nursing woman.

Pediatric Use

Use of Advair Diskus 100/50 in patients aged 4 to 11 years is supported by extrapolation of efficacy data from older subjects and by safety and efficacy data from a trial of Advair Diskus 100/50 in children with asthma aged 4 to 11 years [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1)]. The safety and effectiveness of Advair Diskus in children with asthma younger than 4 years have not been established.

Inhaled corticosteroids, including fluticasone propionate, a component of Advair Diskus, may cause a reduction in growth velocity in children and adolescents [see Warnings and Precautions (5.14)]. The growth of pediatric patients receiving orally inhaled corticosteroids, including Advair Diskus, should be monitored.

A 52-week placebo-controlled trial to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT® ROTADISK®) at 50 and 100 mcg twice daily was conducted in the U.S. in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years. The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (n = 76), 6.07 cm/year in the 50-mcg group (n = 98), and 5.66 cm/year in the 100-mcg group (n = 89). An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data. A separate subset analysis of children who remained prepubertal during the trial revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100-mcg group (n = 79). In children aged 8.5 years, the mean age of children in this trial, the range for expected growth velocity is: boys – 3rd percentile = 3.8 cm/year, 50th percentile = 5.4 cm/year, and 97th percentile = 7.0 cm/year; girls – 3rd percentile = 4.2 cm/year, 50th percentile = 5.7 cm/year, and 97th percentile = 7.3 cm/year. The clinical relevance of these growth data is not certain.

If a child or 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 Advair Diskus, each patient should be titrated to the lowest strength that effectively controls his/her asthma [see Dosage and Administration (2.1)].

Geriatric Use

Clinical trials of Advair Diskus for asthma did not include sufficient numbers of subjects aged 65 years and older to determine whether older subjects with asthma respond differently than younger subjects.

Of the total number of subjects in clinical trials receiving Advair Diskus for COPD, 1,621 were aged 65 years and older and 379 were aged 75 years and older. Subjects with COPD aged 65 years and older had a higher incidence of serious adverse events compared with subjects younger than 65 years. Although the distribution of adverse events was similar in the 2 age-groups, subjects older than 65 years experienced more severe events. In two 1-year trials, the excess risk of pneumonia that was seen in subjects treated with Advair Diskus compared with those treated with salmeterol was greater in subjects older than 65 years than in subjects younger than 65 years [see Adverse Reactions (6.2)]. As with other products containing beta2-agonists, special caution should be observed when using Advair Diskus in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta2-agonists. Based on available data for Advair Diskus or its active components, no adjustment of dosage of Advair Diskus in geriatric patients is warranted.

No relationship between fluticasone propionate systemic exposure and age was observed in 57 subjects with COPD (aged 40 to 82 years) given 250 or 500 mcg twice daily.

Hepatic Impairment

Formal pharmacokinetic studies using Advair Diskus 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 Advair Diskus have not been conducted in patients with renal impairment.

Overdosage

No human overdosage data has been reported for Advair Diskus.

Advair Diskus contains both fluticasone propionate and salmeterol; therefore, the risks associated with overdosage for the individual components described below apply to Advair Diskus. Treatment of overdosage consists of discontinuation of Advair Diskus 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)]. Inhalation by healthy volunteers of a single dose of 4,000 mcg of fluticasone propionate inhalation powder or single doses of 1,760 or 3,520 mcg of fluticasone propionate CFC inhalation aerosol was well tolerated. Fluticasone propionate given by inhalation aerosol at dosages of 1,320 mcg twice daily for 7 to 15 days to healthy human volunteers was also well tolerated. Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in subjects were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups.

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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