Fluticasone Furoate and Vilanterol (Page 3 of 11)

5.8 Hypercorticism and Adrenal Suppression

Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic doses of Fluticasone Furoate/Vilanterol ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9), Drug Interactions (7.1)].

Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with Fluticasone Furoate/Vilanterol ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, Fluticasone Furoate/Vilanterol ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD or asthma symptoms should be considered.

5.9 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

Caution should be exercised when considering the coadministration of Fluticasone Furoate/Vilanterol ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

5.10 Paradoxical Bronchospasm

As with other inhaled medicines, Fluticasone Furoate/Vilanterol ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Fluticasone Furoate/Vilanterol ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; Fluticasone Furoate/Vilanterol ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.

5.11 Hypersensitivity Reactions, including Anaphylaxis

Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of Fluticasone Furoate/Vilanterol ELLIPTA. Discontinue Fluticasone Furoate/Vilanterol ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use Fluticasone Furoate/Vilanterol ELLIPTA [see Contraindications (4)].

5.12 Cardiovascular Effects

Vilanterol, like other beta2 -agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, Fluticasone Furoate/Vilanterol ELLIPTA may need to be discontinued. In addition, beta‑agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12- or 10-fold higher systemic exposure than seen in subjects with COPD or asthma, respectively) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, Fluticasone Furoate/Vilanterol ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

In a mortality trial with a median treatment duration of 1.5 years in 16,568 subjects with moderate COPD and cardiovascular disease, the annualized incidence rate of adjudicated cardiovascular events (composite of myocardial infarction, stroke, unstable angina, transient ischemic attack, or on-treatment death due to cardiovascular events) was 2.5 per 100 patient‑years for fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, 2.7 for placebo, 2.4 for fluticasone furoate 100 mcg, and 2.6 for vilanterol 25 mcg. Adjudicated, on-treatment deaths due to cardiovascular events occurred in 82 subjects receiving fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, 86 subjects receiving placebo, 80 subjects receiving fluticasone furoate 100 mcg, and 90 subjects receiving vilanterol 25 mcg (annualized incidence rate ranged from 1.2 to 1.3 per 100 patient-years for the treatment groups).

5.13 Reduction in Bone Mineral Density

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. The clinical significance of small changes in BMD with regard to long‑term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating Fluticasone Furoate/Vilanterol ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and Fluticasone Furoate/Vilanterol ELLIPTA is still considered medically important for that patient’s COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered.

In replicate 12-month trials in 3,255 subjects with moderate to severe COPD, bone fractures were reported by 2% of subjects receiving the fluticasone furoate/vilanterol combination (50/25 mcg: 2% [14 of 820 subjects]; 100/25 mcg: 2% [19 of 806 subjects]; or 200/25 mcg: 2% [14 of 811 subjects]) compared with <1% of subjects receiving vilanterol 25 mcg alone (8 of 818 subjects).

Similar findings were seen in a mortality trial with a median treatment duration of 1.5 years in 16,568 subjects with moderate COPD and cardiovascular disease.

5.14 Glaucoma and Cataracts

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma following the long-term administration of ICS. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use Fluticasone Furoate/Vilanterol ELLIPTA long term.

5.15 Coexisting Conditions

Fluticasone Furoate/Vilanterol ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2 ‑adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.16 Hyperglycemia and Hypokalemia

There have been reports of increases in blood glucose levels with fluticasone furoate/vilanterol ELLIPTA. This should be considered in patients with a history of, or with risk factors for, diabetes mellitus [see Adverse Reactions (6.3)].

Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. In clinical trials evaluating fluticasone furoate/vilanterol ELLIPTA in subjects with COPD or asthma, there was no evidence of a treatment effect on serum potassium.

5.17 Effect on Growth

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents. [See Use in Specific Populations (8.4).]

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