Lyfnua 45 mg film-coated tablets

Film-coated tablet (tablet) Pink, 10 mm, round and convex tablet debossed with “777” on one side and plain on the other side.

4.1 Therapeutic indications Lyfnua is indicated in adults for the treatment of refractory or unexplained chronic cough.4.2 Posology and method of administration **Posology** The recommended dose of gefapixant is one 45 mg tablet taken orally twice daily with or without food. *Missed dose* Patients should be instructed that if they miss a dose, they should skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed one. **Special populations** *Elderly (≥* *65* *years old)* No dose adjustment is required for elderly patients (see sections 5.1 and 5.2). Gefapixant is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, the risk of adverse reactions to gefapixant may be greater in these patients. Care should be taken with initial dosing frequency. *Renal impairment* Dose adjustment is required in patients with severe renal impairment (eGFR < 30 mL/minute/1.73 m2) not requiring dialysis. The dose should be reduced to one 45 mg tablet taken once daily. No dose adjustment is required in patients with mild or moderate renal impairment (eGFR ≥ 30 mL/minute/1.73 m2). Insufficient data are available in patients with end-stage renal disease requiring dialysis to make dosing recommendations (see section 5.2). *Hepatic impairment* Patients with hepatic impairment have not been studied. However, given that hepatic metabolism is a minor route of elimination of gefapixant, no dose adjustment is recommended (see section 5.2). *Paediatric population* There is no relevant use of Lyfnua in the paediatric population (under 18 years of age) for the indication of refractory or unexplained chronic cough. **Method of administration** Oral use. Tablets should be swallowed whole and may be taken with or without food. Patients should be instructed not to break, crush or chew the tablets.4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.4.4 Special warnings and precautions for use **Obstructive sleep apnoea** In patients with moderate to severe obstructive sleep apnoea (OSA, n=19) who were not using positive airway pressure (PAP), gefapixant 180 mg daily at bedtime was associated with a lower mean SaO2 and a higher mean proportion of time with SaO2 < 90% across all sleep stages compared to placebo. The clinical relevance of these findings for the use of 45 mg gefapixant twice daily in patients with refractory chronic cough (RCC) or unexplained chronic cough (UCC) with comorbid OSA is not known. For patients with OSA, appropriate treatment for OSA should be considered prior to initiating treatment with gefapixant. **Hypersensitivity** Gefapixant contains a sulphonamide moiety but is considered to be a non-sulphonylarylamine. Gefapixant has not been studied in patients with a history of hypersensitivity to sulphonamide, therefore, cross-hypersensitivity with sulphonamide hypersensitivity cannot be excluded. Gefapixant should be used with caution in patients with known hypersensitivity to sulphonamides. **Acute lower respiratory tract infection** Treatment with gefapixant should be evaluated and individualised in patients who develop an acute lower respiratory tract infection (see section 5.1). **Taste-related adverse reactions** Taste-related adverse reactions were very commonly reported in the clinical studies. In most patients, these adverse reactions resolved soon after discontinuation of gefapixant (median time 5 days). In a few patients, these reactions persisted for more than a year after discontinuation (see section 4.8). **Excipients** This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium free'.4.5 Interaction with other medicinal products and other forms of interaction Based on *in vitro* studies (see section 5.2), relevant clinical interaction studies were performed and no clinically meaningful interactions have been identified. **Paediatric population** Interaction studies have only been performed in adults.4.6 Fertility, pregnancy and lactation **Pregnancy** There are no data from the use of gefapixant in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Lyfnua during pregnancy and in women of childbearing potential not using contraception. **Lactation** Available pharmacodynamic/toxicological data in animals have shown excretion of gefapixant in milk (see section 5.3). A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Lyfnua therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. **Fertility** No human data on the effect of gefapixant on fertility are available. In rats, there was no effect on mating or fertility with gefapixant treatment (see section 5.3).4.7 Effects on ability to drive and use machines Gefapixant has no or negligible influence on the ability to drive and use machines. In individual cases, dizziness may occur following administration of gefapixant that may influence the ability to drive and use machines.4.8 Undesirable effects **Summary of the safety profile** The most frequently reported adverse reactions were dysgeusia (41%), ageusia (15%), and hypogeusia (11%). **Tabulated list of adverse reactions** The safety of gefapixant was evaluated in two phase III clinical studies (COUGH-1 and COUGH-2) which included a total of 1,369 patients treated with gefapixant (15 mg or 45 mg twice daily) (see section 5.1). The duration of exposure with gefapixant was 52 weeks. The adverse reactions reported with gefapixant obtained from clinical studies are listed in the table below by MedDRA system organ class and by frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), and very rare (<1/10,000). **Table 1: Adverse reactions** | | | | --- | --- | | **System Organ Class** | **Adverse reactions** | | **Infections and infestations** | | | Common | Upper respiratory tract infection | | **Metabolism and nutrition disorders** | | | Common | Decreased appetite | | **Nervous system disorders** | | | Very Common | Dysgeusia\, Ageusia, Hypogeusia | | Common | Taste disorder, Dizziness | | **Respiratory, thoracic and mediastinal disorders** | | | Common | Cough\\*, Oropharyngeal pain | | **Gastrointestinal disorders** | | | Common | Nausea, Diarrhoea, Dry mouth, Salivary hypersecretion, Abdominal pain upper, Dyspepsia, Hypoaesthesia oral, Paraesthesia oral | | **Psychiatric disorders** | | | Common | Insomnia | | **Renal and urinary disorders** | | | Uncommon | Calculus urinary, Nephrolithiasis, Calculus bladder | \Dysgeusia was commonly reported as taste bitter, taste metallic or taste salty. \\*Cough includes reports of 'worsening', 'exacerbation', 'increase', or 'increased' cough. **Description of selected adverse reactions** *Taste-related adverse reactions* The majority of patients with taste-related adverse reactions (dysgeusia, ageusia, hypogeusia and taste disorder) experienced the onset of the adverse reactions within 9 days of starting gefapixant; the majority were mild (65%) to moderate (32%) in intensity. Resolution of the taste-related adverse reactions occurred in 96% of patients with 25% reporting resolution on or before the last dose of gefapixant. Taste-related adverse reactions persisted for more than a year after discontinuation in 1.6% (7/447) of patients in the gefapixant group and 12.8% (6/47) of patients in the placebo group. Adverse reactions resulting in discontinuation occurred in 22% of patients receiving gefapixant. The most frequently reported adverse reactions leading to discontinuation of treatment were dysgeusia (9%) and ageusia (4%). **Reporting of suspected adverse reactions** Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose In a clinical study with 8 healthy subjects administered gefapixant 1,800 mg twice daily (40 times the recommended human dose) for up to 14 days, crystals composed of gefapixant were detected in the urine of participants. No evidence of renal or urinary system injury was observed. In cases of overdose reported during the Phase III studies, no adverse events were reported. In case of overdose, monitor the patient for adverse reactions and institute appropriate supportive measures. Gefapixant is partially removed by haemodialysis.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other cough suppressants, ATC code: R05DB29 **Mechanism of action** Gefapixant is a selective antagonist of the P2X3 receptor. Gefapixant also has activity against the P2X2/3 receptor subtype. P2X3 receptors are ATP-gated ion channels found on sensory C fibres of the vagus nerve in the airways. C fibres are activated in response to inflammation or chemical irritants. ATP is released from airway mucosal cells under conditions of inflammation. Binding of extracellular ATP to P2X3 receptors is sensed as a damage signal by C fibres. Activation of C fibres, which is sensed by the patient as an urge to cough, initiates a cough reflex. Blockade of ATP signalling through P2X3 receptors reduces excessive sensory-nerve activation and excessive cough induced by extracellular ATP. **Clinical efficacy and safety** The efficacy of Lyfnua for the treatment of refractory or unexplained chronic cough was studied in two 52-week, multicentre, randomised, double-blind, placebo-controlled studies of adults with either refractory or unexplained chronic cough. Refractory chronic cough (RCC) was defined as cough associated with a co-morbid condition (e.g., asthma, gastroesophageal reflux disease, or upper airway cough syndrome) that persisted despite adequate treatment of the co-morbid condition. Unexplained chronic cough (UCC) was defined as cough that was not associated with a co-morbid condition despite a thorough clinical evaluation. The primary objective of both Phase III studies was to assess Lyfnua efficacy in reducing 24-hour cough frequency relative to placebo. Reduction in awake cough frequency and cough-specific quality of life were secondary objectives. In both studies, patients were randomised to twice daily doses of Lyfnua 45 mg, 15 mg, or placebo. The primary efficacy period for COUGH-1 (NCT03449134) was 12 weeks followed by a blinded extension period of 40 weeks. The primary efficacy period for COUGH-2 (NCT03449147) was 24 weeks, followed by a blinded extension period of 28 weeks. Patients enrolled in COUGH-1 and COUGH-2 were current non-smokers, not on angiotensin converting enzyme (ACE) inhibitors, diagnosed with RCC or UCC, and had chronic cough for greater than 1 year. Most patients were female (75%), white (80%), and from Europe (53%) with a mean age of 58 years (range 19 to 89) and 7% of patients were older than 75 years. A total of 61.5% of patients were diagnosed with RCC, 38.5% with UCC, and the mean duration of chronic cough was 11 years. *Cough frequency* In COUGH-1 and COUGH-2, patients treated with Lyfnua 45 mg twice daily demonstrated a significant reduction in 24-hour cough frequency compared with placebo (Table 2). The reduction in the 24-hour cough frequency was observed by Week 4 and persisted throughout the primary efficacy period (12 weeks in COUGH-1 and 24 weeks in COUGH-2; Figure 1). The gefapixant 15 mg twice daily group did not demonstrate a significant reduction in 24-hour cough frequency in either study. **Table 2: 24-hour cough frequency results for Lyfnua 45 mg twice daily (COUGH-1 and COUGH-2)** | | | | | | | --- | --- | --- | --- | --- | | | COUGH-1 | | COUGH-2 | | | Lyfnua | Placebo | Lyfnua | Placebo | | N | 243 | 243 | 439 | 435 | | **Primary Efficacy Endpoint** | | | | | | **24-Hour Cough Frequency (coughs per hour)** | | | | | | Baseline (geometric mean) | 18.24 | 22.83 | 18.55 | 19.48 | | Week 12 (COUGH-1) or Week 24 (COUGH-2) (geometric mean) | 7.05 | 10.33 | 6.83 | 8.34 | | Week 12 (COUGH-1) or Week 24 (COUGH-2) (%-reduction from baseline) | -61.35 | -54.77 | -63.17 | -57.19 | | Reduction Relative to Placebo (%-reduction and 95% CI)† | -18.52 (-32.76, -1.28) | | -13.29 (-24.74, -0.10) | | | p-value | 0.036 | | 0.048 | | | N = Number of participants included in the analysis. CI = Confidence Interval. †Missing baseline values were imputed based on gender and region, followed by multiple imputation of the missing data (m = 50 imputed datasets) for all follow-up visits using treatment, gender, region and the other follow-up visits as covariates. Following imputation, an analysis of covariance (ANCOVA) model was conducted at the time point of interest, adjusting for covariates of treatment, baseline, gender, and region. | | | | | **Figure 1: Analysis of 24-hour cough frequency over time for Lyfnua 45 mg twice daily (COUGH-1 and COUGH-2)** *Cough-specific quality of life* COUGH-2 was specifically designed to assess the impact of Lyfnua on cough-specific quality of life relative to placebo as measured by the Leicester Cough Questionnaire (LCQ) (possible score ranges from 3 to 21, with higher scores indicating a better quality of life). A ≥ 1.3 point increase from baseline in the LCQ total score was defined as clinically meaningful. In COUGH-2, the odds of having a clinically meaningful improvement in cough-specific quality of life were significantly greater in the Lyfnua 45 mg treatment group than in the placebo group as measured at Week 24 (see Table 3). **Table 3: Cough-specific quality of life for Lyfnua 45 mg twice daily (COUGH-2): proportion of patients with ≥ 1.3 point increase from baseline in LCQ total score at Week 24** | | | | | --- | --- | --- | | | Lyfnua | Placebo | | N | 439 | 435 | | Responders\* (%) | 75.7 | 68.1 | | Estimated odds ratio vs. placebo (95% CI)† | 1.46 (1.07, 1.99) | | | Estimated difference† vs. placebo (95% CI)†† | 7.63 (1.34, 13.76) | | | p-value† | 0.016 | | | N = Number of subjects with available data at Week 24. \* Percent responders at Week 24. Number of responders was calculated by averaging over multiple imputations; there were approximately 332 and 296 responders in Lyfnua and placebo arm, respectively. CI = Confidence Interval. LCQ = Leicester Cough Questionnaire. †Missing baseline values were imputed based on gender and region, followed by multiple imputation of the missing data (m = 50 imputed dataset) for all follow-up visits using treatment, gender, region, and the other follow-up visits as covariates. Following imputation, logistic regression was conducted on the dichotomized scores at the time point of interest, adjusting for covariates of treatment, baseline LCQ total (continuous) score, gender, and region. ††Based on the bootstrap method. | | | **Paediatric population** The European Medicines Agency has waived the obligation to submit the results of studies with Lyfnua (gefapixant) in all subsets of the paediatric population in treatment of unexplained or chronic refractory cough (see section 4.2 for information on paediatric use).5.2 Pharmacokinetic properties The pharmacokinetics of gefapixant were studied in healthy adults and in adults with RCC or UCC and were similar between these two populations. The steady-state mean plasma AUC and peak concentration (Cmax) are 4,144 ng∙hr/mL and 531 ng/mL with gefapixant 45 mg twice daily treatment. Steady state is achieved within 2 days, with an accumulation ratio of 1.4- to 1.5-fold. **Absorption** Following oral administration of gefapixant, the time to achieve peak plasma concentrations (Tmax) ranged from 1 to 4 hours. Exposure increases are dose-proportional following multiple doses up to 300 mg twice daily. The fraction absorbed for gefapixant is at least 78%. *Effect of food* Relative to fasting conditions, oral administration of a single dose of gefapixant 50 mg with a standard high fat and high calorie meal had no effect on the AUC or Cmax of gefapixant. **Distribution** Based on population pharmacokinetic analyses, the mean steady-state apparent volume of distribution is estimated to be 138 L following oral administration of a 45 mg dose. *In vitro*, gefapixant exhibits low plasma protein binding (55%) and has a blood-to-plasma ratio of 1.1. Based on preclinical studies, gefapixant has low CNS penetration. **Biotransformation** Hepatic metabolism is a minor route of gefapixant elimination, involving oxidation and glucuronidation. Following oral administration of [14C] gefapixant, 14% of the administered dose was recovered as metabolites in the urine and faeces. Unchanged gefapixant is the major drug-related component in plasma (87%), and each circulating metabolite accounted for less than 10% of the total radioactivity detected. **Elimination** Renal excretion is the major route of elimination of gefapixant and involves both passive renal filtration and active transport mechanisms. Gefapixant is recovered in urine as parent (~64%) or metabolites (~12%), and the remainder is recovered in feces as parent (~20%) or metabolites (~2%). Active renal secretion is estimated to account for ≤ 50% of total elimination. *In vitro,* gefapixant is a substrate of MATE1, MATE2K, P-gp, and BCRP transporters. Gefapixant has a terminal half-life (t½) of 6 – 10 hours. **Special populations** *Renal impairment* Renal excretion is the major route of elimination of gefapixant. Mild or moderate renal impairment (eGFR ≥ 30 mL/minute/1.73 m2) does not have a clinically meaningful effect on the exposure of gefapixant. In a population pharmacokinetic analysis including patients with refractory or unexplained chronic cough, the mean AUC and Cmax of gefapixant were predicted to increase by 89% and 54%, respectively, in patients with severe renal impairment (eGFR < 30 mL/minute/1.73 m2) compared to those with normal renal function. To maintain similar systemic exposures to those with normal renal function, dose adjustment is recommended (see section 4.2). *Hepatic impairment* Hepatic metabolism is a minor route of elimination. Most of an oral dose was recovered as unchanged parent in the urine (64%) or faeces (20%). A dedicated study in subjects with hepatic impairment was not conducted, because hepatic impairment is not likely to have a clinically meaningful effect on exposure (see section 4.2). *Effects of age, body weight, gender, ethnicity, and race* Based on a population pharmacokinetic analysis, age, body weight, gender, ethnicity, and race do not have a clinically meaningful effect on the pharmacokinetics of gefapixant. **Drug Interactions** *Effects of other medicinal products on the pharmacokinetics of gefapixant* Hepatic metabolism is a minor pathway for gefapixant elimination, and the potential for clinically meaningful drug interactions for gefapixant with co-administration of inhibitors or inducers of cytochrome P450 (CYP) or uridine 5'-diphosphoglucuronic acid glucuronosyl transferase (UGT) enzymes is low. Concomitant use of a proton pump inhibitor, omeprazole, did not have a clinically meaningful effect on gefapixant pharmacokinetics. Based on *in vitro* studies, gefapixant is a substrate of efflux transporters multidrug and toxin extrusion 1 (MATE1), MATE2K, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). In a Phase 1 clinical study, a single dose of the MATE1/MATE2K inhibitor pyrimethamine increased gefapixant AUC by 24%, an amount that is not clinically meaningful, and did not affect gefapixant Cmax. *Effects of gefapixant on the pharmacokinetics of other medicinal products* Based on *in vitro* studies, the potential of gefapixant to cause CYP inhibition or induction is low, and therefore it is unlikely that gefapixant would affect the CYP-mediated metabolism of other drugs. Gefapixant is an inhibitor of MATE1, MATE2K, and organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3 *in vitro*. However, the risk of clinically meaningful drug interactions via inhibition of these transporters is low for gefapixant administered at 45 mg twice daily. The clinical relevance of *in vitro* inhibition of organic cation transporter 1 (OCT1) by gefapixant is not established. In a Phase 1 clinical study, multiple doses of gefapixant 45 mg did not affect exposure of the OATP1B substrate pitavastatin.5.3 Preclinical safety data **Repeat dose toxicity** Crystalluria occurred in laboratory animals dosed with gefapixant and the majority of the urinary crystals were confirmed to be composed of gefapixant. In a six month repeat-dose toxicity study in rats, microscopic changes in the kidney (distended tubules due to presence of crystalline material, degeneration of epithelial cells lining tubules and inflammation in the interstitium), ureter (dilatation and inflammation) and bladder (transitional cell hyperplasia) were observed at 9 times the exposure in humans at the maximum recommended human dose (MRHD). In a nine-month repeat-dose oral toxicity study in dogs, crystals were observed in the urine and microscopic observation of focal, minimal tubular degeneration, involving occasional cortical tubules was observed in one male dog at 35 times the exposure in humans at the MRHD. **Carcinogenicity** Carcinogenicity studies in rats (2-years in duration) and rasH2 transgenic mice (6-months in duration) with gefapixant showed no evidence of carcinogenic potential (no treatment related tumours) at exposures up to 9-times (rats) and 4-times (mice) the exposures at the MRHD. **Mutagenesis** Gefapixant was not genotoxic in a battery of *in vitro* or *in vivo* assays including microbial mutagenesis, chromosomal aberration in human peripheral blood lymphocytes and in the *in vivo* rat micronucleus test. **Reproductive toxicity** In animal reproduction studies, oral administration of gefapixant to pregnant rats and rabbits during the period of organogenesis showed no evidence of teratogenicity or embryo-fetal lethality at exposures (AUC) that were 6-times (rats) and 34-times (rabbits) the exposure at the MRHD. A slight reduction in rat fetal weights, which was associated with maternal toxicity, was observed at an exposure approximately 11-times the exposure at the MRHD. Studies in pregnant rats and rabbits showed that gefapixant is transferred to the foetus through the placenta, with foetal plasma concentrations of up to 21% (rats) and 25% (rabbits) that of maternal concentrations observed on gestation day 20. In a lactation study, gefapixant was excreted in milk of lactating rats when administered orally (up to 9-times the exposure at the MRHD) on lactation day 10, with milk concentrations 4 times that of maternal plasma concentrations observed 1-hour post dose on lactation day 10. There were no effects on fertility, mating performance or early embryonic development when gefapixant was administered to female and male rats up to 9-times the exposure at the MRHD.

6.1 List of excipients **Tablet core** Silica, Collodial Anhydrous (E551) Crospovidone (E1202) Hypromellose (E464) Magnesium stearate (E470b) Mannitol (E421) Microcrystalline cellulose (E460) Sodium stearyl fumarate **Film-coating** Hypromellose (E464) Titanium dioxide (E171) Triacetin (E1518) Iron oxide red (E172) Carnauba wax (E903)6.2 Incompatibilities Not applicable.6.3 Shelf life 4 years6.4 Special precautions for storage This medicinal product does not require any special storage conditions.6.5 Nature and contents of container Opaque white PVC/PE/PVdC blisters with push through aluminium lidding foil. Packs of 28, 56 and 98 film-coated tablets in non-perforated blisters (14 tablets per card) and multipacks containing 196 (2 packs of 98) film-coated tablets in non-perforated blisters. Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements.