indacaterol, inhaled/glycopyrrolate inhaled (Utibron Neohaler)

Dosing and uses of Utibron Neohaler (indacaterol, inhaled/glycopyrrolate, inhaled)

• Adult
• Pediatric

 

Adult dosage forms and strengths

indacaterol/glycopyrrolate

inhalation powder

• (27.5mcg/15.6mcg)/capsule

 

Chronic Obstructive Pulmonary Disease (COPD)

Combination inhalant containing long-acting muscarinic antagonist (LAMA) plus a long-acting beta2-agonist (LABA) indicated for the long-term, maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema

Orally inhale contents of 1 capsule PO q12hr using the Neohaler device

 

Dosage modifications

No dosage adjustment is required for geriatric patients, patients with mild and moderate hepatic impairment, or patients with mild-to-moderate renal impairment

Severe renal or hepatic impairment: Not studied

 

Dosing Considerations

Limitations of use: Not indicated for the relief of acute bronchospasm or for the treatment of asthma

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Utibron Neohaler (indacaterol, inhaled/glycopyrrolate, inhaled) adverse (side) effects

1-10%

Nasopharyngitis (4.1%)

Hypertension (2%)

Back pain (1.8%)

Oropharyngeal pain (1.6%)

 

Warnings

Black box warnings

Long-acting beta2-adrenergic agonists (LABAs) increase the risk of asthma-related death

Data from a large placebo-controlled US study that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeteroL

This finding with salmeterol is considered a class effect of all LABAs, including indacateroL

Safety and efficacy of indacaterol/glycopyrrolate in patients with asthma have not been established

Not indicated for the treatment of asthma

 

Contraindications

Hypersensitivity

All LABAs are contraindicated in patients with asthma without use of a long-term asthma control medication Indacaterol/glycopyrrolate is not indicated for the treatment of asthma

 

Cautions

Data from a large placebo-controlled US study in asthma patients showed that LABAs may increase the risk of asthma-related death (see Black box warnings)

Should not be initiated in patients with acutely deteriorating or potentially life-threatening episodes of COPD; also do not use for the relief of acute symptoms (ie, as rescue therapy) for treating acute episodes of bronchospasm

Do not use more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABAs, as an overdose may result

Can produce paradoxical bronchospasm that may be life-threatening Immediate hypersensitivity reactions have been reported after administration of indacaterol or glycopyrrolate

LABAs can produce clinically significant cardiovascular effects, including increases in pulse rate or systolic or diastolic blood pressure

Caution with convulsive disorders, thyrotoxicosis, patients who are unusually responsive to sympathomimetic amines, narrow-angle glaucoma (may worsen), or urinary retention (eg, prostatic hyperplasia, bladder-neck obstruction); instruct patients to contact their physician immediately with worsening disease symptoms

Doses of the related beta2-agonist albuterol, when administered IV, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis

LABAs may produce significant hypokalemia, which has the potential to produce adverse cardiovascular effect; in patients with severe COPD, hypokalemia may be potentiated by hypoxia and concomitant treatment, which may increase the susceptibility for cardiac arrhythmias

 

Pregnancy

Pregnancy

There are no adequate and well-controlled studies in humans with Utibron Neohaler or its individual components

Animal studies have not shown teratogenicity

 

Lactation

Unknown if distributed in human breast milk

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Utibron Neohaler (indacaterol, inhaled/glycopyrrolate, inhaled)

Mechanism of action

Glycopyrronium: Long-acting muscarinic antagonist (LAMA); often referred to as an anticholinergic; produces bronchodilation by inhibiting acetylcholine’s effect on muscarinic receptors in the airway smooth muscle

Indacaterol: Long-acting beta2-agonist (LABA); stimulates intracellular adenyl cyclase, causing conversion of ATP to cyclic AMP; increased cyclic AMP levels cause relaxation of bronchial smooth muscle

 

Absorption

Absolute bioavailability: 43-45% (indacaterol)

Peak plasma time: 5 minutes (glycopyrrolate); 15 minutes (indacaterol)

 

Distribution

Protein bound: 38-41% (glycopyrrolate); ~95% (indacaterol)

Vd: 83-376 L (glycopyrrolate); 2361-2557 L (indacaterol)

 

Metabolism

IndacateroL

• Metabolized by UGT1A to the phenolic O-glucuronide
• Also undergoes hydroxylation (predominantly by CYP3A4)

Glycopyrrolate

• Hydroxylation of results in a variety of mono-and bishydroxylated metabolites and direct hydrolysis results in the formation of a carboxylic acid derivative (M9)
• M9 is hydrolyzed by multiple CYP isoenzymes

 

Elimination

Half-life: 40-56 hr (indacaterol oral); 33-53 hr (glycopyrrolate inhaled)

Renal clearance: 0.46-1.2 L/hr (indacaterol)

Systemic clearance: 18.8-23.3 L/hr (indacaterol)

Excretion

• Indacaterol: 54% (unchanged) and 23% (metabolites) in feces
• Glycopyrrolate: 60-70% urine; 30-40% nonrenal (mostly by metabolism; also biliary)

 

Pharmacogenomics

IndacateroL

• The pharmacokinetics of indacaterol were prospectively investigated in subjects with the UGT1A1 (TA)7/(TA)7 genotype (low UGT1A1 expression; also referred to as *28) and the (TA)6, (TA)6 genotype
• Steady-state AUC and Cmax were 1.2-fold higher in the [(TA)7, (TA)7] genotype, suggesting no relevant effect of UGT1A1 genotype of indacaterol exposure

 

Administration

Instructions

For oral inhalation only

Do not swallow the capsules, as the intended effects on the lungs will not be obtained

Capsules should only be used with the Neohaler device

Should be administered at the same time of the day, (1 capsule in the morning and 1 capsule in the evening), every day

More frequent administration or a greater number of inhalations (>1 capsule BID) is not recommended

 

Storage

Store in a dry place at controlled room temperature (77°F [25°C]); excursions permitted to 59-86°F (15-30°C)

Store capsules in the blister package that they are packaged in, and only remove immediately before use with the Neohaler device