DRUG INTERACTIONS

1. Anticholinergics-                                                                                                        There is potential for an additive interaction with concomitantly used anticholinergic medicines. Therefore, avoid coadministration of YUPELRI with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

2. Transporter-related drug interactions-                                                                  OATP1B1 and OATP1B3 inhibitors (e.g. rifampicin, cyclosporine, etc.) could lead to an increase in systemic exposure of the active metabolite. Therefore, coadministration with YUPELRI is not recommended 

BRIEF SUMMARY

REVEFENACIN- (Nov 2018)

Indn-      To treat patients with chronic pulmonary disease (COPD)               

Comp-     Inhalation solution in a unit-dose vial for nebulization. Each vial contains 175 mcg/3 mL solution.    For oral inhalation use only.         Do not swallow .                              • One 175 mcg vial (3 mL) once daily. 

ADR-   ­ Most common adverse reactions (incidence greater than or equal to 2% and more common than placebo) include cough, nasopharyngitis, upper respiratory tract infection, headache, and back pain. 

CI- I is contraindicated in patients with hypersensitivity to revefenacin or any component of this product. 

WARNINGS-

•  Do not initiate in acutely deteriorating COPD or to treat acute symptoms.

•  If paradoxical bronchospasm occurs, discontinue and institute alternative therapy

Pat infrm-                                                                                                                        Not for Acute Symptoms Inform patients thatI is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose.

Advise patients to treat acute symptoms with an inhaled, short-acting beta-2 agonist such as albuterol

==============================================================

U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  49

ADVERSE REACTIONS

­ Most common adverse reactions (incidence greater than or equal to 2% and more common than placebo) include cough, nasopharyngitis, upper respiratory tract infection, headache, and back pain. 

WARNINGS AND PRECAUTIONS

• Do not initiate YUPELRI in acutely deteriorating COPD or to treat acute symptoms.

• If paradoxical bronchospasm occurs, discontinue YUPELRI and institute alternative therapy. 

• Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to contact a healthcare provider immediately if symptoms occur.

• Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to contact a healthcare provider immediately if symptoms occur. 

• Immediate hypersensitivity reactions may occur. If such a reaction occurs, therapy with YUPELRI should be stopped at once and alternative treatments should be considered. 

. -----------------------DRUG INTERACTIONS------------------------­ • Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of YUPELRI with other anticholinergic-containing drugs. (7.1) • Transporter-related drug interactions: Coadministration of YUPELRI with OATP1B1 and OATP1B3 inhibitors (e.g. rifampicin, cyclosporine, etc.) may lead to an increase in exposure of the active metabolite. Therefore, coadministration with YUPELRI is not recommended. (7.2.,

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) with each new prescription and refill.

Not for Acute Symptoms Inform patients that YUPELRI is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose.

Advise patients to treat acute symptoms with an inhaled, short-acting beta-2 agonist such as albuterol.

Provide patients with such medicine and instruct them in how it should be used.

Instruct patients to seek medical attention immediately if they experience any of the following:                                                                                                                               • Decreasing effectiveness of inhaled, short-acting beta-2 agonists                                   • Need for more inhalations than usual of inhaled, short-acting beta-2 agonists                  • Significant decrease in lung function as outlined by the physician

Tell patients they should not stop therapy with YUPELRI without healthcare provider guidance since symptoms may recur after discontinuation.

Paradoxical Bronchospasm-                                                                                           As with other inhaled medicines, YUPELRI can cause paradoxical bronchospasm.If paradoxical bronchospasm occurs, instruct patients to discontinue YUPELRI. 

Worsening of Narrow-Angle Glaucoma-                                                                Instruct patients to 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 develops.

Worsening of Urinary Retention-                                                                           Instruct patients to be alert for signs and symptoms of urinary retention (e.g. difficulty passing urine, painful urination).Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develops.

 Instructions for Administering YUPELRI                                                                          It is important for patients to understand how to correctly administer YUPELRI using a standard jet nebulizer

Instruct patients that YUPELRI should only be administered via a standard jet nebulizer. Patients should be instructed not to inject or swallow the YUPELRI solution.

Patients should be instructed not to mix other medications with YUPELRI.             Patients should not inhale more than one dose at any one time. The daily dosage of YUPELRI should not exceed one unit-dose vial.

Inform patients to use the contents of one vial of YUPELRI inhaled orally daily at the same time every day.

Patients should throw the plastic dispensing vials away immediately after use.

Due to their small size, the vials pose a danger of choking to young children.

The brands listed are trademarks of their respective owners. Licensed from: Manufactured for: Theravance Biopharma

The brands listed are trademarks of their respective owners. Licensed from: Manufactured for: Theravance Biopharma Ireland Limited Mylan Specialty L.P. Morgantown, WV 26505 USA

Millan Pharmaceuticals

. CLINICAL PHARMACOLOGY

1. Mechanism of Action

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 receptor at the smooth muscle leading to bronchodilation. 

2. Pharmacodynamics                                                                                           Cardiac Electrophysiology                                                                                                QTc interval prolongation was studied in a randomized, double-blind, placebo- and positive-controlled, single dose, crossover trial in 48 healthy subjects. Following a single dose of revefenacin 700 mcg (4 times the recommended dosage), no effects on prolongation of QTc interval were observed.

3. Pharmacokinetics                                                                                            Revefenacin pharmacokinetic parameters are presented as the mean [standard deviation (SD)] unless otherwise specified. Following repeat dosing of inhaled YUPELRI, steady state was achieved within 7 days with <1.6-fold accumulation.

Revefenacin exposure (Cmax and AUC) in COPD patients is approximately 60% lower as compared to healthy subjects. Exposure (Cmax and AUC) of the active metabolite in COPD patients is approximately 2-fold higher as compared to healthy subjects.

Revefenacin Cmax was 0.16 ng/mL (0.11) and AUC was 0.22 ng·hr/mL (0.20) at steady-state after inhaled YUPELRI 175 mcg dose in COPD patients. Cmax of the active metabolite was 0.20 ng/mL (0.13) and AUC was 0.69 ng·hr/mL (0.53) at steady-state after inhaled YUPELRI 175 mcg dose in COPD patients.

Revefenacin and its active metabolite exposure increased in a slightly greater than dose proportional manner with increasing revefenacin dose. After single or multiple once-daily dosing  of YUPELRI, both AUC and Cmax of revefenacin and its active metabolite increased by approximately 11-fold over the 88 to 700 mcg (8-fold) dose range.

Absorption                                                                                                                   Following inhaled administration of YUPELRI in healthy subjects or COPD patients, Cmax of revefenacin and its active metabolite occurred at the first postdose sampling time which ranged from 14 to 41 minutes after start of nebulization. The absolute bioavailability following an oral dose of revefenacin is low (<3%).

Distribution                                                                                                             Following intravenous administration to healthy subjects, the mean steady-state volume of distribution of revefenacin was 218 L suggesting extensive distribution to tissues. In vitro protein binding of revefenacin and its active metabolite in human plasma was on average 71% and 42%, respectively.

Elimination                                                                                                                     The terminal half-life of revefenacin and its active metabolite after once-daily dosing of YUPELRI in COPD patients is 22 to 70 hours.

Metabolism                                                                                                                          In vitro and in vivo data showed that revefenacin is primarily metabolized via hydrolysis of the primary amide to a carboxylic acid forming its major active metabolite.

Following inhaled administration of YUPELRI in COPD patients, conversion to its active metabolite occurred rapidly, and plasma exposures of the active metabolite exceeded those of revefenacin by approximately 4- to 6-fold (based on AUC).

The active metabolite is formed by hepatic metabolism and possesses activity at target muscarinic receptors that is lower (approximately one-third to one-tenth) than that of revefenacin. It could potentially contribute to systemic antimuscarinic effects at therapeutic doses.

Excretion                                                                                                                 Following administration of a single intravenous dose of radiolabeled revefenacin to healthy male subjects, approximately 54% of total radioactivity was recovered in the feces and 27% was excreted in the urine.

Approximately 19% of the administered radioactive dose was recovered in the feces as the active metabolite. Following administration of a single radiolabeled oral dose of revefenacin, 88% of total radioactivity was recovered in the feces and < 5% was present in urine, suggesting low oral absorption.

There was minimal renal excretion (<1%) of revefenacin and its active metabolite following inhaled administration of YUPELRI in COPD patients.

Specific Populations                                                                                               Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (44 to 79 years), gender (59% male), smoking status (42% current smoker) or weight (46 to 155 kg) on systemic exposure of revefenacin and its active metabolite.

Patients with Hepatic Impairment:                                                                               The pharmacokinetics of YUPELRI was evaluated in subjects with moderate hepatic impairment (Child-Pugh score of 7-9). There was no increase in Cmax of revefenacin and 1.5-fold increase in Cmax of the active metabolite.

There was 1.2-fold increase in AUC of revefenacin and up to 4.7-fold increase in AUC of the active metabolite. YUPELRI has not been evaluated in subjects with severe hepatic impairment.

Patients with Renal Impairment:                                                                                     The pharmacokinetics of YUPELRI was evaluated in subjects with severe renal impairment (CrCl <30 mL/min). There was 1.5-fold increase in Cmax of revefenacin and up to 2-fold increase in Cmax of the active metabolite.

There was up to 2.3-fold increase in AUCinf of revefenacin; the active metabolite exposure (AUCinf) was increased by up to 2.5-fold. YUPELRI has not been evaluated in subjects with end stage renal disease.

Drug Interactions

Revefenacin and Cytochrome P450: Neither revefenacin nor its active metabolite inhibits the following cytochrome P450 isoforms: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. Neither revefenacin nor its active metabolite induces CYP1A2, CYP2B6, and CYP3A4/5.

Revefenacin and Efflux Transporters: Revefenacin is a substrate of P-gp and BCRP. Neither revefenacin nor its active metabolite is an inhibitor of these efflux transporters.

Revefenacin and Uptake Transporters:                                                                         The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3. Neither revefenacin nor its active metabolite is an inhibitor of the uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary                                                                                        There are no adequate and well-controlled studies with YUPELRI in pregnant women. Women should be advised to contact their physician if they become pregnant while taking YUPELRI.

In animal reproduction studies, subcutaneous administration of revefenacin to pregnant rats and rabbits during the period of organogenesis produced no evidence of fetal harm at respective exposures approximately 209 times the exposure at the maximum recommended human dose (MRHD) (on an area under the curve [AUC] basis) (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

2. Lactation Risk Summary                                                                                          There is no information regarding the presence of revefenacin in human milk, the effects on the breastfed infant, or the effects on milk production. However, revefenacin was present in the milk of lactating rats following dosing during pregnancy and lactation

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for YUPELRI and any potential adverse effects on the breastfed infant from YUPELRI or from the underlying maternal condition.

4. Pediatric Use                                                                                                      YUPELRI is not indicated for use in children. The safety and efficacy in pediatric patients have not been established.

5. Geriatric Use                                                                                                            Based on available data, no adjustment of the dosage of YUPELRI in geriatric patients is necessary.

Clinical trials of YUPELRI included 441 subjects aged 65 years and older, and, of those, 101 subjects were 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 patients, but greater sensitivity of some older individuals cannot be ruled out.

6. Hepatic Impairment                                                                                                    The systemic exposure of revefenacin is unchanged while that of its active metabolite is increased in subjects with moderate hepatic impairment.

The safety of YUPELRI has not been evaluated in COPD patients with mild-to-severe hepatic impairment. YUPELRI is not recommended in patients with any degree of hepatic impairment.

7. Renal Impairment-                                                                                                       No dosage adjustment is required in patients with renal impairment. Monitor for systemic antimuscarinic side effects in COPD patients with severe renal impairment. 

 OVERDOSAGE

An overdose of YUPELRI may lead to anticholinergic signs and symptoms such as nausea, vomiting, dizziness, lightheadedness, blurred vision, increased intraocular pressure (causing pain, vision disturbances, or reddening of the eye), obstipation or difficulties in voiding.

In COPD patients, orally inhaled administration of YUPELRI at a once daily dose of up to 700 mcg (4 times the maximum recommended daily dose) for 7 days was well tolerated.

Treatment of overdosage consists of discontinuation of YUPELRI along with institution of appropriate symptomatic and/or supportive therapy.