Ravoquix 0,5 Mg/1 Mg Film-Coated Tablets

RAVOQUIX is indicated as an aid to smoking cessation in patients committed to stop smoking, in addition to a behaviour modification programme, for 12 weeks.

All smoking cessation therapies are more likely to succeed in patients who are motivated to stop smoking and who are provided with additional advice and continuous support. Patients should be treated with RAVOQUIX for 12 weeks.

Posology

The recommended dose of RAVOQUIX is 1 mg twice daily following a 1-week titration as follows:

• Day 1 -3: 0,5 mg once daily in the evening
• Day 4 -7: 0,5 mg twice daily
• Day 8 -End of treatment: 1 mg twice daily

The patient should set the date to stop smoking. RAVOQUIX dosing should start 1 u2013 2 weeks before this date. Patients who do not succeed in stopping smoking during 12 weeks of initial therapy, or who relapse after treatment, should be encouraged to make another attempt once factors contributing to the failed attempt have been identified and addressed. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks of treatment with RAVOQUIX at 1 mg twice daily may be considered for the maintenance of abstinence. A gradual approach to quitting smoking with RAVOQUIX should be considered for patients who are not able or willing to quit abruptly. Patients should reduce smoking during the first 12 weeks of treatment and quit by the end of that treatment period. Patients should then continue taking RAVOQUIX for an additional 12 weeks for a total of 24 weeks of treatment. Patients who cannot tolerate adverse reactions of RAVOQUIX may have the dose lowered temporarily or permanently. Dose tapering of RAVOQUIX is not required at the end of treatment.

Special populations

Patients with renal insufficiency
No dosage adjustment is necessary for patients with mild (estimated creatinine clearance > 50 mL/min and u2264 80 mL/min) to moderate (estimated creatinine clearance u2265 30 mL/min and u2264 50 mL/min) renal impairment. For patients with severe renal impairment, the recommended dose of RAVOQUIX is 1 mg once daily. Dosing should begin at 0,5 mg once daily for the first 3 days, then increased to 1 mg once daily. There is insufficient clinical experience with RAVOQUIX in patients with end-stage renal disease (see section 5.2).

Patients with hepatic impairment
No dosage adjustment is necessary for patients with hepatic impairment (see section 5.2).

Use in elderly patients
No dosage adjustment is necessary for elderly patients (see section 5.2). Because elderly patients are more likely to have decreased renal function, medical practitioners should consider the renal status of an elderly patient.

Paediatric population
Safety and effectiveness of RAVOQUIX in paediatric patients have not been established; therefore, RAVOQUIX is not recommended for use in patients under 18 years of age (see section 5.2).

Method of administration
For oral use and the tablets should be swallowed whole with water. RAVOQUIX can be taken with or without food.

Hypersensitivity to varenicline or to any of the excipients listed in section 6.1.

Effect of smoking cessation
Physiological changes resulting from smoking cessation, with or without treatment with RAVOQUIX, may alter the pharmacokinetics or pharmacodynamics of some medicines, for which dosage adjustment may be necessary (examples include theophylline, warfarin and insulin). However, in post-marketing data there were cases of increased international normalised ratio (INR). INR should be monitored more frequently, and the warfarin dose adjusted while using RAVOQUIX, and after discontinuation of RAVOQUIX (see section 4.5).

Neuropsychiatric symptoms and suicidality
Serious neuropsychiatric symptoms have been reported in patients being treated with varenicline. These post-marketing reports have included changes in behaviour or thinking, changes in mood (including depression and mania), aggressive behaviour, psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide (see section 4.8 u2013 post-marketing experience). Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking varenicline who continued to smoke. When symptoms were reported, most were during varenicline treatment, but some were following discontinuation of varenicline therapy. These events have occurred in patients with and without pre-existing psychiatric disease; some patients have experienced worsening of their psychiatric illnesses. All patients being treated with RAVOQUIX should be observed for neuropsychiatric symptoms or worsening of pre-existing psychiatric illness. Advise patients and caregivers that the patient should stop taking RAVOQUIX and contact a medical practitioner immediately if agitation, depressed mood, changes in behaviour or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behaviour. In many post-marketing cases, resolution of symptoms after discontinuation of varenicline was reported, although in some cases the symptoms persisted, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve. Medical practitioners should be aware of the possible emergence of serious neuropsychiatric symptoms in patients attempting to quit smoking with or without treatment. If serious neuropsychiatric symptoms occur whilst on RAVOQUIX, patients should discontinue RAVOQUIX immediately and contact a medical practitioner for re-evaluation of treatment.

History of psychiatric disorders
Smoking cessation, with or without pharmacotherapy, has been associated with exacerbation of underlying psychiatric illness (e.g. depression). varenicline smoking cessation studies have provided data in patients with a history of psychiatric disorders (see section 5.1). In a smoking cessation clinical trial, neuropsychiatric adverse events were reported more frequently in patients with a history of psychiatric disorders compared to those without a history of psychiatric disorders, regardless of treatment (see section 5.1). Care should be taken with patients with a history of psychiatric illness and patients should be advised accordingly.

Seizures
In clinical trials and post-marketing experience there have been reports of seizures in patients with or without a history of seizures, treated with varenicline. RAVOQUIX should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

Treatment discontinuation
At the end of treatment, discontinuation of varenicline was associated with an increase in irritability, urge to smoke, depression, and/or insomnia in up to 3 % of patients. The prescriber should inform the patient accordingly and discuss or consider the need for dose tapering.

Angioedema and hypersensitivity reactions
There have been post-marketing reports of hypersensitivity reactions including angioedema in patients treated with varenicline (see section 4.8 u2013post-marketing experience). Clinical signs included swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (throat and larynx). There were reports of life-threatening angioedema requiring urgent medical attention due to respiratory compromise. Patients should be instructed to discontinue RAVOQUIX and immediately seek medical care if they experience these symptoms.

Serious skin reactions
There have been post-marketing reports of serious skin reactions, including Stevens-Johnson Syndrome and Erythema Multiforme in patients using varenicline (see section 4.8 u2013 post-marketing experience). As these skin reactions can be life-threatening, patients should be instructed to stop taking RAVOQUIX and contact their medical practitioner immediately at the first appearance of a skin rash with mucosal lesions or any other signs of seizures or other conditions that potentially lower the seizure threshold.

Cardiovascular effects
In a smoking cessation trial of patients with stable cardiovascular disease, cardiovascular events were reported more frequently in patients treated with varenicline. A meta-analysis of 15 clinical trials, which included the smoking cessation trial of patients with stable cardiovascular disease, had similar results. Cardiovascular events occurred primarily in patients with known cardiovascular disease. Patients should be instructed to notify their medical practitioners of new or worsening cardiovascular symptoms and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction or stroke.

Based on varenicline characteristics and clinical experience to date, RAVOQUIX has no clinically meaningful medicine interactions. No dosage adjustment of RAVOQUIX or co-administered medicine listed below is recommended. In vitro studies demonstrate that varenicline does not inhibit cytochrome P450 enzymes (IC50 > 6 400 ng/mL). The P450 enzymes tested for inhibition were: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. Also, in human hepatocytes in vitro, RAVOQUIX was shown to not induce the activity of cytochrome P450 enzymes 1A2 and 3A4. Therefore, RAVOQUIX is unlikely to alter the pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes. Furthermore, since metabolism of RAVOQUIX represents less than 10 % of its clearance, active substances known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of RAVOQUIX and therefore a dose adjustment of RAVOQUIX would not be required. In vitro studies demonstrate that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, medicines that are cleared by renal secretion (e.g. metformin u2013 see below) are unlikely to be affected by RAVOQUIX. In vitro studies demonstrate that active renal secretion of varenicline is mediated by the human organic cation transporter, OCT2. Co-administration with inhibitors of OCT2 does not require a dose adjustment of RAVOQUIX as the increase in systemic exposure to varenicline is not expected to be clinically meaningful (see cimetidine interaction below). Furthermore, since metabolism of RAVOQUIX represents less than 10 % of its clearance, medicines known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of RAVOQUIX (see section 5.2) and therefore a dose adjustment of RAVOQUIX would not be required.

Metformin
Varenicline (1 mg twice daily) did not affect the pharmacokinetics of metformin (500 mg twice daily), which is a substrate of the organic cation transporter, OCT2. Metformin had no effect on varenicline pharmacokinetics.

Cimetidine
Co-administration of an OCT2 inhibitor, cimetidine (300 mg four times daily), with varenicline (2 mg single dose) increased the systemic exposure of varenicline by 29 % due to a reduction in varenicline renal clearance. No dosage adjustment is recommended based on concomitant cimetidine administration.

Digoxin
Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of digoxin administered as a 0,25 mg daily dose.

Warfarin
Varenicline (1 mg twice daily) did not alter the pharmacokinetics of a single 25 mg dose of (R, S)-warfarin. Prothrombin time (INR) was not affected by varenicline. Smoking cessation itself may result in changes to warfarin pharmacokinetics. However, in post-marketing data there were cases of increased INR. INR should be monitored more frequently, and the warfarin dose adjusted while using RAVOQUIX, and after discontinuation of RAVOQUIX (see section 4.4).

Alcohol
There are limited clinical data on any potential interaction between alcohol and RAVOQUIX. There have been post marketing reports of increased intoxicating effects of alcohol in patients treated with varenicline. A causal relationship between these events and RAVOQUIX use has not been established. Some cases described unusual and sometimes aggressive behaviour and were often accompanied by amnesia for the events. Advise patients to reduce the amount of alcohol they consume while taking RAVOQUIX until they know whether RAVOQUIX affects their tolerance for alcohol.

Use with other therapies for smoking cessation

Bupropion
Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily). However, the incidence of nausea was doubled with co-administration.

Nicotine replacement therapy (NRT)
When varenicline (1 mg twice daily) and NRT (transdermal 21 mg/day) were co-administered to smokers (N=24) for 12 days, there was a statistically significant decrease in average systolic blood pressure (mean 2,6 mmHg) measured on the final day of the study. In this study, the incidence of nausea, headache, vomiting, dizziness, dyspepsia, and fatigue was greater for the combination than for NRT alone. Safety and efficacy of RAVOQUIX in combination with other smoking cessation therapies have not been studied.

Women of childbearing potential
Where therapy is initiated, treatment should be timed such that the course is completed before conception occurs.

Pregnancy
The safety of RAVOQUIX in human pregnancy has not been established. The use of RAVOQUIX in pregnant women is not recommended. Varenicline was not teratogenic in rats and rabbits at oral doses up to 15 and 30 mg/kg/day, respectively (36 and 50-times the maximum recommended human daily exposure based on AUC at 1 mg BD, respectively).

Breastfeeding
The safety of RAVOQUIX during lactation has not been established. Mothers on RAVOQUIX should therefore not breastfeed their infants.

Fertility
There are no clinical data on the effects of varenicline on fertility. Non-clinical data revealed no hazard for humans based on standard male and female fertility studies in the rat (see section 5.3).

RAVOQUIX may have minor or moderate influence on the ability to drive and use machines. RAVOQUIX may cause dizziness, somnolence and transient loss of consciousness, and therefore may influence the ability to drive and use machines. Patients should be advised to use caution driving or operating machinery until they know how quitting smoking and/or RAVOQUIX may affect them.

Summary of the safety profile
Smoking cessation with or without treatment is associated with various symptoms. For example, dysphoric or depressed mood, insomnia, irritability, frustration or anger, anxiety, difficulty concentrating, restlessness, decreased heart rate, increased appetite or weight gain have been reported in patients attempting to stop smoking. No attempt has been made in either the design or the analysis of the RAVOQUIX studies to distinguish between adverse events associated with study drug treatment or those possibly associated with nicotine withdrawal. In patients treated with the recommended dose of 1 mg twice daily following an initial titration period the adverse event most commonly reported was nausea (28,6 %). In the majority of cases nausea occurred early in the treatment period, was mild to moderate in severity.

Tabulated summary of adverse reactions

Post-marketing experience
The following adverse events have been reported during post-approval use of varenicline. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to medicine exposure. There have been reports of depression, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, anxiety, and panic, as well as suicidal ideation, suicide attempt, completed suicide, mood swings, nightmares, insomnia, aggressiveness, suicidal tendency, irritability, abnormal dreaming, abnormal behaviour, psychotic reaction NOS, personality disorder, depressed mood, impaired concentration, agitation, sleepiness, emotional disorder, increased appetite, aggressive reaction, disturbed sleep, reaction, memory loss, forgetfulness, absence of appetite, anger, nervousness, mood disorder, abnormal mental state, drowsiness, confusion, abnormal thinking, sleeplessness, sleep disorder, sleep difficulty, impulsive behaviour, abnormal hunger, emotional lability, disorientation, aggravated depression, depressed state, depressed reaction, completed suicide, acute stress reaction, thoughts of self-harm, irrational thinking, suicide, marked restlessness, nervous tension, narcolepsy, mental impairment, mental disorder, memory impairment, memory disturbance, manic reaction, lethargy, lack of motivation, jitteriness, intentional self-injury, hypersomnia, auditory hallucination, flat effect, feeling strange, feeling high, feeling detached, euphoria, dissociative disorder, delirium, character change, bipolar disorder, loss of appetite, impaired appetite, decreased appetite, apathy, anti-social behaviour and acute stress disorder in patients attempting to quit smoking while taking varenicline (see section 4.4). Smoking cessation with or without treatment is associated with nicotine withdrawal symptoms and the exacerbation of underlying psychiatric illness. Not all patients had known pre-existing psychiatric illness and not all had discontinued smoking. There have been reports of hypersensitivity reactions, including angioedema. Clinical signs included swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (throat and larynx) (see section 4.4). There have also been reports of serious skin reactions, including Stevens Johnson Syndrome and Erythema Multiforme in patients taking varenicline (see section 4.4). There have been reports of seizures, feeling abnormal and crying.

No cases of overdose were reported in pre-marketing clinical trials. In case of overdose, standard supportive measures should be instituted as required. Varenicline has been shown to be dialyzed in patients with end stage renal disease (see section 5.2), however, there is no experience in dialysis following overdose.