Enablex. Prolonged Release Tablets

Transcription

1 Enablex Prolonged Release Tablets Composition The active ingredient is Darifenacin (as hydrobromide). One prolonged release tablet contains 7.5 mg and 15 mg Darifenacin (as hydrobromide) Indications Enablex is indicated for the treatment of overactive bladder whose symptoms includes urgency, urge urinary incontinence, frequency and nocturia Posology and meth of administration Adults The recommended starting dose is 7.5 mg daily. For those patients requiring greater symptom relief, the dose may be increased to 15 mg daily as early as two weeks after starting therapy, based on individual response. Enablex prolonged-release tablets should be taken once daily with liquid. They may be taken with or without fo, and should be swallowed whole and not chewed, divided or crushed. Elderly patients The recommended starting dose for the elderly is 7.5 mg daily. After 2 weeks of starting therapy, patients should be reassessed for efficacy and safety. For those patients who have an acceptable tolerability profile but requiring greater symptoms relief, the dose may be increased to 15 mg daily based on individual response. Use in renal impairment No dose adjustment is required in patients with impaired renal function (see 5.2. Pharmacokinetic properties) Use in hepatic impairment The daily dose of Enablex should not exceed 7.5 mg in patients with merate hepatic impairment (Child Pugh B). Enablex is not recommended for use in patients with severe hepatic impairment (Child Pugh C) Contraindications Hypersensitivity to the active substance or to any of the excipients. Enablex is contraindicated in patients with urinary retention, gastric retention or uncontrolled narrow angle glaucoma, Myasthenia gravis, severe hepatic impairment, severe ulcerative colitis, toxic megacolon, concomitant treatment with potent CYP3A4 inhibitors Special Warnings and Special Precautions for use Enablex should be administered with caution to patients with clinically significant bladder outflow obstruction, risk for urinary retention, severe constipation (defined as two or less bowel movements per week) or gastroinstestinal obstructive disorders, such as pyloric stenosis (see Contraindications)

2 Interaction with aother medicaments and other forms of interaction Effect of other medicinal pructs on darifenacin Darifenacin metabolism is primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4. Therefore, inhibitors of these enzymes may alter darifenacin pharmacokinetics (see also Pharmacokinetic properties) No major safety issues were noted in any of the clinical studies and no treatment related serious adverse events were observed. CYP2D6 inhibitors In patients recieving drugs that are potent CYP2D6 inhibitors (e.g. paroxetine, terbinafine, cimetidine and quinidine), the recommended starting dose should be 7.5 mg daily. The dose may be titrated to 15 mg daily to obtain an improved clinical response provided the dose is well tolerated. Concomitant treatment with potent CYP2D6 inhibitors results in an increase in exposure (e.g. of 30% with paroxetine at the 30 mg dose of darifenacin) CYP3A4 inhibitors Darifenacin should not be used together with potent CYP3A4 inhibitors such as protease inhibitors, ketokonazole and itranazole. Potent P-glycoprotein inhibitors such as cyclosporine and verapamil should also be avoided. Co-administration of darifenacin 7.5 mg with the potent CYP3A4 inhibitor ketoconazole 400 mg resulted in a 5-fold increase in steady state darifenacin AUC. In subjects who are poor metabolisers, darifenacin exposure increased by approximately 10-fold. Due to a greater contribution of CYP3A4 after higher darifenacin doses, the magnitude of the effect is expected to be even more pronounced when combining kotoconazole with darifenacin 15 mg. When co-administered with merate CYP3A4 inhibitors such as erythromycin, clarithromicin, telithromicin, fluconazole and grapefruit juice, the recommended starting dose of darifenacin should be 7.5 mg daily. The dose may be titrated to 15 mg daily to obtain an improved clinical response provided the dose is well tolarated. Darifenacin AUC 24 and C MAX from 30 mg dosing in subjects who are extensive metabolisers were 95% and 128% higher, when erythromycin (merate CYP3A4 inhibitors) was co-administered with darifenacin than when darifenacin was taken alone. Enzyme inducers Drug that are inducers of CYP3A4 such as rifampicin, carbamazepine, barbiturates and St John s wort (Hypericum perforatum) are likely to decrease the plasma concentrations of darifenacin Effects of darifenacin on other medicinal pructs CYP2D6 substrates Darifenacin is a merate inhibitor of the enzyme CYP2D6. Caution should be exercised when darifenacin is used concomitantly with medicinal pructs that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window, such as flecainide, thioridazine, or tricyclic antidepressants such as imipramine. The effects of darifenacin on the metabolism of CYP2D6 substrates are mainly clinically relevant for CYP2D6 substrates which are individually

3 dose titrated. CYP3A4 substrates Darifenacin treatment resulted in a mest increase in the exposure of the CYP3A4 substrate midazolam. The interaction with midazolam lacks clinical relevance but is indicative of a slight CYP3A4 inhibition by darifenacin. Warfarin Standard therapeutic prothrombin time monitoring for warfarin should be continued. The effects of warfarin on prothrombine time was not altered when co-administered with darifenacin. Digoxin Therapeutic drug monitoring for digoxin should be performed when initiating and ending darifenacin treatment as well as changing the darifenacin dose. Darifenacin 30 mg once daily (two times greater than the recommended daily dose) co-administered with digoxin at steady state resulted in a small increase in digoxin exposure (AUC: 16% and C MAX : 20%). The increase in digoxin exposure could be caused by competition between darifenacin and digoxin for P- glycoprotein. Other transposter-related interactions cannot be excluded. Antimuscarinic agents As with any other antimuscarinic agents, the concomitant medication with medicinal pructs that possess antimuscarinic properties, such as oxybutynin, tolterine and flavoxate may result in more pronounced therapeutic and side effects. The potentiation of anticholinergic effects with anti-parkinson agents and tricyclic antidepressants may also occur if antimuscarinic agents are used concurrently with such medicinal pructs. However, no studies involving the interaction with anti-parkinson agents and tricyclic antidepressants have been performed. Pregnancy and laction Use in pregnancy There are no studies of darifenacin in pregnant women. Enablex should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus (see Preclinical safety data). Use in lactation Darifenacin is excreted into the milk of rats. It is not known whether darifenacin is excreted into human milk and therefore caution should be exercised before Enablex is administered to a nursing woman. Effects on ability to drive and use machines No studies of the effects of Enablex on ability to drive and use machines have been performed. Nevertheless, caution should be exercised when driving or using machines. Undesirable effects Consistent with the pharmacological profile, the most common adverse drug reactions (ADRs) were dry mouth and constipation. However, the patient discontinuation rates due to these adverse drug reactions were low (dry mouth: 0% and 0.9% for the 7.5 mg and 15 mg dose,

4 respectively, constipation: 0.6% and 1.2% for the 7.5 mg and 15 mg dose, respectively). In the pivotal clinical trials with doses of 7.5 mg and 15 mg darifenacin, ADRs were reported as presented in the table below. Most were mild or merate and did not result in discontinuation in the majority of the patients. The incidence of serious adverse events with 7.5 mg and 15 mg darifenacin once daily was similar to placebo. Frequency estimate: very common > 10%, common > 1% to < 10%, uncommon > 0.1% to < 1 % By as a whole Common Cardiovascular uncommon Digestive Very common Common Metabolic and nutritional uncommon Nervous Respiratory Skin and appendages uncommon Special senses Common Urogenital Headache, abdominal pain Asthenia, accidental injury, face oedema Hypertension Dry mouth, constipation Dyspepsia, nausea Diarrhoea, flatulence, ulcerative stomatitis SGPT increased, SGOT increased; peripheral oedema, oedema Dizziness, insomnia, somnolence, thinking abnormal Rhinitis, cough increased, dyspnoea Dri skin, rash, pruritus, sweating Dry eyes Abnormal vision, taste perversion Urinary tract disorder, impotence, urinary tract infection, vaginitis, bladder pain Overdose No overdosages were recorded in the darifenacin clinical development programme. However, overdosage with darifenacin can potentially lead to severe anticholinergic effects and should be treated accordingly. Therapy should be aimed at reversing the anticholinergic symptoms under careful medical supervision. The use of agents such as physostigmine can assist in reversing such symptoms. Pharmacological Properties Pharmacynamic properties Pharmacotherapeutic group : Urinary antispasmic, ATC ce: GO4BD10. Darifenacin is a potent muscarinic M3 selective receptor antagonist in vitro. The M3 receptor is

5 the major subtype that controls the detrusor muscle contraction in the bladder. In cystomeric studies performed with darifenacin in patients with involuntary bladder contraction increased bladder capacity as demonstrated by an increased volume threshold for unstable conctractions and diminished frequency of unstable detrusor contractions after darifenacin treatment was shown. These findings are consistent with the clinical observations that darifenacin increases bladder capacity and decreases urinary urgency and the frequency of both incontinence and micturitions. Consistent with its selectivity profile, the incidence of central nervous system adverse events at all doses was similar to placebo. The incidence of cardiovascular adverse events such as tachycardia was less than 1% for all doses and did not increase with dose. As expected from this class of drugs, prolonged colonic transit and reduced salivary flow were observed in a dose dependent manner. The table below shows the primary and secondary pooled efficacy results after 12 weeks for the 7.5 and 15 mg darifenacin once-daily fixed doses. Table 2 N Median baseline Median change for baseline Median difference from placebo 95% Cl P value No of incontinence epises per week Placebo (1002&1041) Darifenacin 7.5 mg * (-3.6, -0.7) Placebo (1002, & 1041) Darifenacin 15 mg * (-4.5, -2.0) <0.001 No of epises of urgency per day Placebo (1002&1041) Darifenacin 7.5 mg * (-1.3, -0.4) <0.001 Placebo (1002, & 1041) Darifenacin 15 mg * (-1.3, -0.5) <0.001 No of micturitions per day Placebo (1002&1041)

6 Darifenacin 7.5 mg * (-1.1, -0.4) <0.001 Placebo (1002, & 1041) Darifenacin 15 mg * (-1.1, -0.4) <0.001 Volume of urine passed per void (ml) Placebo (1002&1041) Darifenacin 7.5 mg * (3, 17) Placebo (1002, & 1041) Darifenacin 15 mg * (14,27) <0.001 No of incontinence epises per week resulting in a change of clothing or pad Placebo (1002&1041) Darifenacin 7.5 mg * (-2.8, -0.9) <0.001 Placebo (1002, & 1041) Darifenacin 15 mg * (-3.0, -1.1) <0.001 Od once daily * The difference between darifenacin and placebo was statistically significant (p<0.05, stratified Wilcoxon test) Effective treatment can be expected within two weeks At two weeks, darifenacin 7.5 mg and 15 mg both pruced statistically significant greater improvements in the number of incontinence epises per week compared to placebo and these were maintained through the course of treatment. In a clinical study of 12 month duration, the improvements from baseline for the number of incontinence epises per week sustained. Improvements from the baseline were also sustained over 12 months for the key secondary efficacy endpoints of the number of micturitions per day, the epises of urgency per day and the average volume of urine passed per void. On quality of life measures darifenacin 7.5 mg and 15 mg were associated with statistically and clinically meaningful improvements over placebo in the incontinence impact, role limitations, social limitations and severity measures domains as defined by the King s Health Questionaire (KHQ). Darifenacin 15 mg was also associated with improvements on the emoticons domain of

7 the KHQ. Pharmacokinetic properties Absorption Darienacin is rapidly and completely (> 98%) absorbed after oral administration, although oral bioavailability is limited by first pass metabolism (see metabolism). Maximum plasma levels are reached approximately 7 hours after administration of the prolonged release tablets and steady state plasma levels are achieved by the sixth day of administration. At steady state, peak-totrough fluctuations in darifenacin concentration are small, thereby maintaining therapeutic plasma levels over the dosing interval. Fo had no effect on darifenacin pharmacokinetics during multiple-dose administration of prolonged release tablets. Distributions Darifenacin is a lipophilic base and is 98% bound to plasma proteins (primarily to alpha-1-acidglycoprotein). The steady state volume of distribution (Vss) is estimated to be 163 litres. Metabolism Darifenacin is extensively metabolized by the liver following oral administration. Metabolism is mediated by cytochrome P450 enzymes CYP2D6 and CYP3A4. The three main metabolic routes are as follows: i Monohydroxylation in the dihydrobenzofuran ring ii Dihydrobenzofuran ring opening iii N-dealkylation of the pyrrolidine nitrogen The initial pructs of the hydroxilation and N-dealkylation pathways are major circulating metabolites but none contributes significanly to the overall clinical effect of darifenacin. The pharmacokinetics of darifenacin at steady state are dose dependent, due to saturation of the CYP2D6 enzyme. Variability in metabolism: A subset of individuals (approximately 7% of the Caucasian population) are devoid of CYP2D6 enzyme activity. Therefore the metabolism of darifenacin in these poor metabolisers will be principally mediated via CYP3A4. Individuals with full CYP2D6 activity are referred to as extensive metabolisers. The estimated mean oral bioavailability of darifenacin in exensive metabolisers at steady state is 15 % and 19 % for 7.5 mg and 15 mg prolonged release tablets, respectively. Population pharmacokinetic analyses of phase 3 data indicated that on average steady state exposure is 66% higher in poor metabolisers than in extensive metabolisers. However, there is a considerable overlap between the ranges of exposures seen in these two populations and clinical experience confirms that there are no special dosing requirements for poor metabolisers. Excretion Following administration of an oral dose of 14 C-darifenacin solution to healthy volunteers, approximately 60% of the radioactivity was recovered in the urine and 40% in the feaces. Only a small percentage of the excreted dose was unchanged darifenacin (3%). Estimated darifenacin clearance is 40 litres/hour for extensive metabolisers and 32 litres/hour for poor metabolisers.

8 Gender No special dosage requirements are necessary based on gender. A population pharmacokinetics analysis of patient data indicated that darifenacin exposure was 23% lower in males than females. In clinical studies, the safety and efficacy profiles were not affected by gender. Elderly patients A population pharmacokinetic analysis of patient data indicated a trend for clearance to decrease with age (19% per decade). Pediatric patients The pharmacokinetics of darifenacin have not been studied in the pediatric population. Renal insufficiency There are no special dosage requirements for patients with renal impairment. A study in subjects with varying degrees of renal impairments (creatinine clearance between 10 and 136 ml/min) given darifenacin 15 mg once daily to steady state demonstrated no relationship between renal function and darifenacin clearance. Hepatic insufficiency Darifenacin pharmacokinetics were investigated in subjects with mild (Child Pugh A) or merate (Child Pugh B) impairment of hepatic function given darifenacin 15 mg once daily to steady state. Mild hepatic impairment had no effect on the pharmacokinetics of darifenacin. After adjusting for plasma protein binding, unbound darifenacin exposure was estimated to be 4.7 fold higher in subjects with merate hepatic impairment than subjects with normal hepatic function. Preclinical Safety Data Preclinical data reveal no special hazard for human based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to repruction. Carcinogenicity studies with darifenacin were conducted in mice and rats. No evidence of drug related carconigenicity was revealed in 24 month study in mice at dietary doses up to 100 mg/kg/day or approximately 32 times the estimated human free AUC0-24h reached with 15 mg, the maximum recommended human dose (AUC at MRHD) and in 24 month study in rats at doses up to 15 mg/kg/day or up to approximately 12 times at the AUC at MRHD. Darifenacin was not mutagenic in the bacterial mutation assays (Ames test) and the Chinese hamster ovary assay, and not clastogenic in the human lymphocyte assays, and the in vivo mouse bone marrow cytogenetics assay. There was no evidence for effect on fertility in male or female rats treated at oral doses up to 50 mg/kg/day. Exposures in this study correspond to approximately 78 times the AUC at MRHD. Darifenacin was not teratogenic in rats and rabbits at dosses upt to 50 and 30 mg/kg/day respectively. At the dose of 50 mg/kg in rats, there was a delay in the ossification of the sacral and caudal vertebrae which was not observed at the lower doses of 3 and 10 mg/kg. Exposure in

9 this study at 50 mg/kg corresponds to approximately 59 times the AUC at MRHD. At the dose of 30 mg/kg in rabbits, darifenacin was shown to increase post implantation loss but not at the lower doses tested (3 and 10 mg/kg). Exposure to unbound drug at 30 mg/kg in this study corresponds to approximately 28 times the AUC at MRHD. Pharmaceutical Particulars List of Excipients Core: Calcium hydrogen phospate, anhydrous Hypromellose Magnesium stearate Film coating: Enablex 7.5 mg prolonged release tablets Lactose monohydrate Hypromellose Titanium dioxide (E171) Glycerol triacetate Enablex 7.5 mg prolonged release tablets Lactose monohydrate Hypromellose Titanium dioxide (E171) Glycerol triacetate Sunset yellow FCF lake (E110) Incompatibilities None known Shelf life 3 years Storage Do not store above 25 C. Keep the container in the outer carton in order to protect from light. Keep out of reach and sight of children. Package Enablex Tablet 7.5 mg Boxes of 2 7 tablets Boxes of 4 7 tablets... Enablex Tablet 15 mg Boxes of 2 7 tablets. Boxes of 4 7 tablets Harus Dengan Resep Dokter To be dispensed only on the prescription of a physician

10 Manufactured by Phifer Inc, Brooklyn, NY, USA for Novartis Pharma AG, Basel, Switzerland Imported by PT Novartis Biochemie, Citeureup, Bogor, Indonesia