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 (estimated glomerular filtration rate (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 3 clinical studies (COUGH-1 and COUGH-2) of 52 week duration which included a total of 1 369 patients with RCC or UCC treated with gefapixant (15 mg or 45 mg twice daily) (see section 5.1). The safety was supported with two 12-week phase 3b clinical studies. These studies included an additional 391 patients with RCC or UCC treated with gefapixant (45 mg twice daily) including 185 female patients with cough induced stress urinary incontinence (C-SUI).

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,

Headache†

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.

†Headache was reported in a phase 3b clinical study in female patients with C-SUI.

‡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 3 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.