Revefenacin

Registered South African indications:

• Maintenance treatment of patients with chronic obstructive pulmonary disease (COPD)

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Hepatic impairment

Deterioration of disease and acute episodes

• Revefenacin should not be initiated in patients during acutely deteriorating or potentially life-threatening episodes of COPD
• Revefenacin has not been studied in subjects with acutely deteriorating COPD. The initiation of revefenacin in this setting is not appropriate
• Revefenacin is intended as a once-daily maintenance treatment for COPD and should not be used for relief of acute symptoms (e.g., as rescue therapy for acute episodes of bronchospasm)
• Extra doses should not be used for the relief of acute symptoms
• Acute symptoms should be treated with an inhaled, short-acting beta-agonist
• COPD may deteriorate acutely over hours or chronically over several days or longer
• If revefenacin no longer controls bronchoconstriction symptoms, if the patient's inhaled short-acting beta-agonist becomes less effective, or if the patient needs more inhalations of a short-acting beta-agonist than usual, these may indicate disease deterioration
• In such a setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once
• Increasing the daily dose of revefenacin beyond the recommended dose is not appropriate in this situation

Paradoxical bronchospasm

• Revefenacin can produce paradoxical bronchospasm that may be life-threatening
• If paradoxical bronchospasm occurs following dosing with revefenacin, it should be treated immediately with an inhaled, short-acting bronchodilator
• Revefenacin should be discontinued immediately and alternative therapy should be instituted

Worsening of narrow-angle glaucoma

• Revefenacin should be used with caution in patients with narrow-angle glaucoma
• Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma, such as eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema
• Instruct patients to consult a medical practitioner immediately if any of these signs or symptoms develops

Worsening of urinary retention

• Revefenacin should be used with caution in patients with urinary retention
• Prescribers and patients should be alert for signs and symptoms of urinary retention, such as difficulty passing urine or 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 develops

Immediate hypersensitivity reactions

• Immediate hypersensitivity reactions may occur after administration of revefenacin
• If such a reaction occurs, therapy with revefenacin should be stopped at once and alternative treatments should be considered

Effects on ability to drive and use machines

• Revefenacin has no or negligible influence on the ability to drive or use machines

Forms avail. in SA and covered in this monograph: udv (sol)

South African registered indications and dosages

Maintenance treatment of patients with chronic obstructive pulmonary disease (COPD)

• Inhaled (sol): 175µg, admin. once daily by nebuliser using a mouthpiece

Revefenacin should be administered by the orally inhaled route via a standard jet nebuliser connected to an air compressor

The safety and efficacy of revefenacin have been established in clinical trials when administered using the PARI LC Sprint nebuliser with a mouthpiece and the PARI Trek S compressor. The safety and efficacy of revefenacin delivered from non‑compressor based nebuliser systems have not been established

The revefenacin unit-dose vial should only be removed from the foil pouch and opened IMMEDIATELY BEFORE USE

The vial and any residual content should be discarded after use

The compatibility (physical and chemical), efficacy, and safety of revefenacin when mixed with other medicines in a nebuliser have not been established

Not established for use in children

Pregnancy

South African recommendations

• Caution
• There are no adequate and well-controlled studies with revefenacin in pregnant women
• Women should be advised to contact their medical practitioner if they become pregnant while using revefenacin
• Animal studies showed no evidence of foetal harm at exposures approximately 209 times the maximum recommended human dose
• The estimated background risk of major birth defects and miscarriage for the indicated population is unknown
• In animal studies, placental transfer of revefenacin and its active metabolite was observed in pregnant rabbits
• In pre- and postnatal development studies in rats, revefenacin had no adverse developmental effects on pups at exposures up to 196 times the maximum recommended human dose

Breastfeeding

South African recommendations

• Caution; not recommended
• There is no information regarding the presence of revefenacin in human milk, its effects on the breastfed infant, or its effects on milk production
• Revefenacin was present in the milk of lactating rats following dosing during lactation
• Mothers taking revefenacin are advised not to breastfeed their infants
• The mother’s clinical need for revefenacin and any potential adverse effects on the breastfed infant or from the underlying maternal condition should be considered
• In animal studies, revefenacin and its active metabolite were present in the milk of lactating rats on lactation day 22
• Milk-to-plasma concentration ratios were up to 10 for revefenacin and its active metabolite

Fertility

• No information available

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended
  Monitor for systemic antimuscarinic side effects in COPD patients with severe renal impairment

South African recommendations

• Caution; not recommended
  The systemic exposure of revefenacin is unchanged while that of its active metabolite is increased in subjects with moderate hepatic impairment
  The safety of revefenacin has not been evaluated in COPD patients with mild to severe hepatic impairment
  Revefenacin is not recommended in patients with any degree of hepatic impairment

South African recommendations

• No dose adjustment recommended
  Based on available data, no adjustment of the dosage of revefenacin in elderly patients is necessary
  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 patients, but greater sensitivity of some older individuals cannot be ruled out

Respiratory, Thoracic and Mediastinal Disorders

≥2% incidence and higher than placebo

• Cough

≥1.0% less than 20%, and more common than with placebo

• Oropharyngeal pain
• Bronchitis

Infections and Infestations

≥2% incidence and higher than placebo

• Nasopharyngitis
• Upper respiratory tract infection

Nervous System Disorders

≥2% incidence and higher than placebo

• Headache

Musculoskeletal and Connective Tissue Disorders

≥2% incidence and higher than placebo

• Back pain

Vascular Disorders

≥1.0% less than 20%, and more common than with placebo

• Hypertension
• Dizziness

Serious adverse reactions

• Paradoxical bronchospasm
• Worsening of narrow-angle glaucoma
• Worsening of urinary retention
• Immediate hypersensitivity reactions

• Other anticholinergic-containing medicines
• OATP1B1 and OATP1B3 inhibitors
• Rifampicin
• Ciclosporin

Observations

• Systemic antimuscarinic side effects (in COPD patients with severe renal impairment)

Revefenacin is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo models, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of revefenacin is predominantly a site-specific effect.