Anoro Ellipta

Pregnancy

Risk Summary

There are insufficient data on the use of ANORO ELLIPTA or its individual components, umeclidinium and vilanterol, in pregnant women to inform a drug-associated risk. (See Clinical Considerations.) In animal reproduction studies, umeclidinium administered via inhalation or subcutaneously to pregnant rats and rabbits was not associated with adverse effects on embryofetal development at exposures approximately 50 and 200 times, respectively, the human exposure at the maximum recommended human daily inhaled dose (MRHDID). Vilanterol administered via inhalation to pregnant rats and rabbits produced no fetal structural abnormalities at exposures approximately 70 times the MRHDID. (See Data.)

The estimated risk of major birth defects and miscarriage for the indicated populations 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

Labor or Delivery: ANORO ELLIPTA should be used during late gestation and labor only if the potential benefit justifies the potential for risks related to beta-agonists interfering with uterine contractility.

Data

Animal Data: The combination of umeclidinium and vilanterol has not been studied in pregnant animals. Studies in pregnant animals have been conducted with umeclidinium and vilanterol individually.

Umeclidinium: In separate embryofetal developmental studies, pregnant rats and rabbits received umeclidinium during the period of organogenesis at doses up to approximately 50 and 200 times the MRHDID, respectively (on an AUC basis at maternal inhalation doses up to 278 mcg/kg/day in rats and at maternal subcutaneous doses up to 180 mcg/kg/day in rabbits). No evidence of teratogenic effects was observed in either species.

In a perinatal and postnatal developmental study in rats, dams received umeclidinium during late gestation and lactation periods with no evidence of effects on offspring development at doses up to approximately 26 times the MRHDID (on an AUC basis at maternal subcutaneous doses up to 60 mcg/kg/day).

Vilanterol: In separate embryofetal developmental studies, pregnant rats and rabbits received vilanterol during the period of organogenesis at doses up to approximately 13,000 and 450 times, respectively, the MRHDID (on a mcg/m2 basis at maternal inhalation doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 5,740 mcg/kg/day in rabbits). No evidence of structural abnormalities was observed at any dose in rats or in rabbits up to approximately 70 times the MRHDID (on an AUC basis at maternal doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 450 times the MRHDID (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals.

In a perinatal and postnatal developmental study in rats, dams received vilanterol during late gestation and the lactation periods at doses up to approximately 3,900 times the MRHDID (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day). No evidence of effects in offspring development was observed.

Lactation

Risk Summary

There is no information available on the presence of umeclidinium or vilanterol in human milk, the effects on the breastfed child, or the effects on milk production. Umeclidinium was detected in the plasma of offspring of lactating rats treated with umeclidinium suggesting its presence in maternal milk. (See Data.) The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ANORO ELLIPTA and any potential adverse effects on the breastfed child from umeclidinium or vilanterol or from the underlying maternal condition.

Data

Subcutaneous administration of umeclidinium to lactating rats at greater than or equal to 60 mcg/kg/day resulted in a quantifiable level of umeclidinium in 2 of 54 pups, which may indicate transfer of umeclidinium in rat milk.

Pediatric Use

The safety and effectiveness of ANORO ELLIPTA have not been established in pediatric patients. ANORO ELLIPTA is not indicated for use in pediatric patients.

Geriatric Use

Based on available data, no adjustment of the dosage of ANORO ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.

Clinical trials of ANORO ELLIPTA for COPD included 2,143 subjects aged 65 years and older and 478 subjects aged 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

Hepatic Impairment

Patients with moderate hepatic impairment (Child-Pugh score of 7-9) showed no relevant increases in Cmax or AUC, nor did protein binding differ between subjects with moderate hepatic impairment and their healthy controls. Studies in subjects with severe hepatic impairment have not been performed [see Clinical Pharmacology ].

Renal Impairment

There were no significant increases in either umeclidinium or vilanterol exposure in subjects with severe renal impairment (CrCl <30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology ].

Serious Asthma-Related Events – Hospitalizations, Intubations, Death

The safety and effectiveness of ANORO ELLIPTA in patients with asthma have not been established. ANORO ELLIPTA is not indicated for the treatment of asthma [see Contraindications ].

Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.

Salmeterol Multicenter Asthma Research Trial (SMART)

A 28-week, placebo-controlled, US trial that compared the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs. 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthma-related death is considered a class effect of LABAs, including vilanterol, one of the active ingredients in ANORO ELLIPTA.

No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with ANORO ELLIPTA has been conducted.

Available data do not suggest an increased risk of death with use of LABA in patients with COPD.

Deterioration of Disease and Acute Episodes

ANORO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. ANORO ELLIPTA has not been studied in subjects with acutely deteriorating COPD. The initiation of ANORO ELLIPTA in this setting is not appropriate.

If ANORO ELLIPTA no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting, re-evaluate the patient and the COPD treatment regimen at once. The daily dose of ANORO ELLIPTA should not be increased. Increasing use of inhaled, short-acting beta2-agonists is a signal of deteriorating disease. In this situation, the patient requires immediate re-evaluation with reassessment of the treatment regimen, giving special consideration to the need for additional therapeutic options. Patients should not use more than 1 inhalation of ANORO ELLIPTA once daily.

ANORO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. ANORO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

When beginning treatment with ANORO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing ANORO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used.

Avoid Excessive Use of ANORO ELLIPTA and Avoid Use with Other Long-acting Beta2-agonists

ANORO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other therapies containing LABAs, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ANORO ELLIPTA should not use another therapy containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

Caution should be exercised when considering the coadministration of ANORO ELLIPTA with ketoconazole and other known strong cytochrome P450 3A4 (CYP3A4) inhibitors (including, but not limited to, ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased cardiovascular adverse effects may occur [see Drug Interactions , Clinical Pharmacology ].

Paradoxical Bronchospasm

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

Hypersensitivity Reactions, including Anaphylaxis

Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of ANORO ELLIPTA. Discontinue ANORO 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 ANORO ELLIPTA [see Contraindications , Adverse Reactions (6.2)].

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, ANORO 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 [see Clinical Pharmacology (12.2)]. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

ANORO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

In a 52-week trial of subjects with COPD, the exposure-adjusted rates for any on-treatment major adverse cardiac event, including non-fatal central nervous system hemorrhages and cerebrovascular conditions, non-fatal myocardial infarction, non-fatal acute myocardial infarction, and adjudicated on-treatment death due to cardiovascular events, was 2.2 per 100 patient-years for fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg (n = 4,151), 1.9 per 100 patient-years for fluticasone furoate/vilanterol 100/25 mcg (n = 4,134), and 2.2 per 100 patient-years for ANORO ELLIPTA (n = 2,070). Adjudicated on‑treatment deaths due to cardiovascular events occurred in 20 of 4,151 patients (0.54 per 100 patient-years) receiving fluticasone furoate/umeclidinium/vilanterol, 27 of 4,134 patients (0.78 per 100 patient-years) receiving fluticasone furoate/vilanterol, and 16 of 2,070 patients (0.94 per 100 patient-years) receiving ANORO ELLIPTA.

Coexisting Conditions

ANORO ELLIPTA, like all therapies 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.

Worsening of Narrow-Angle Glaucoma

ANORO ELLIPTA should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should also be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos, or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop.

Worsening of Urinary Retention

ANORO ELLIPTA, like all therapies containing an anticholinergic, should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop.

Hypokalemia and Hyperglycemia

Beta-adrenergic agonist therapies 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. Beta-agonist therapies may produce transient hyperglycemia in some patients. In 4 clinical trials of 6-month duration evaluating ANORO ELLIPTA in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium.