New Medicines Committee Briefing May Nepafenac 1mg/ml eye drops suspension (Nevanac )

Transcription

1 New Medicines Committee Briefing May 2013 Nepafenac 1mg/ml eye drops suspension (Nevanac ) Nevanac is to be reviewed for use within: Primary Care Secondary Care Summary Nevanac is a suspension for ocular use containing the non-steroidal anti-inflammatory drug 1mg/ml of nepafenac. Nevanac is indicated in adults for the prevention and treatment of postoperative pain and inflammation associated with cataract surgery and reduction in the risk of postoperative macular oedema associated with cataract surgery in diabetic patients. Nepafenac is the only ocular NSAID licensed in the UK for reducing the risk of postoperative macular oedema associated with cataract surgery in diabetic patients. SMC has accepted Nevanac for use in NHS Scotland to reduce the risk of postoperative macular oedema associated with cataract surgery in diabetic patients. Evidence from two pivotal clinical trials have found nepafenac to be non-inferior to ketorolac and superior to placebo in the treatment of pain and inflammation and superior to vehicle in the prevention of macular oedema. Nevanac is a black triangle drug ( ) and is monitored intensively by the CHM and MHRA 1

2 Formulary application Consultant submitting application: Dr Anupama Pherwani (Consultant Ophthalmologist) Clinical Director supporting application: Gareth Rowland (Clinical Director) Dr Pherwani has requested that Nevanac be considered for inclusion in the North Staffordshire Joint Formulary for the prevention and treatment of post-operative pain and inflammation associated with cataract surgery. Nepafenac suspension will also be used for reduction of risk of post-operative macular oedema associated with cataract surgery in diabetic patients. It is estimated that patients will be treated per year. Dr Pherwani indicated that Nevanac is the only non-steroidal anti-inflammatory drug (NSAID) ophthalmic suspension licensed in the UK for the reduction of risk of post-operative macular oedema associated with cataract in diabetic patients. It is licensed to be used for up to 60 days. She indicated that this will improve safety, tolerability, enhance convenient administration and will help to prevent post-operative macular oedema, a complication that is associated with treatment costs of up to 470,000. Background Nepafenac is a NSAID and is formulated as a suspension and administered by the topical ocular route. It is licensed for the prevention and treatment of post-operative pain and inflammation associated with cataract surgery for reducing the risk of postoperative macular oedema associated with cataract surgery. Nepafenac is the only ocular NSAID licensed for this route. 1,2 Pain inflammation and macular oedema are complications of cataract surgery. Macular oedema is characterised by swelling within the retina due to the accumulation of excess fluid in the extracellular space of the retina. It has been reported macular oedema occurs in 2% to 20% of patients following cataract surgery although the rate may be higher in diabetic patients, especially those with pre-existing retinopathy. 3 Macular edema is a common cause of poor visual outcome following uneventful cataract surgery. 4 Ocular inflammation, which is common after cataract surgery, may cause patients to have postoperative pain and photophobia and further related complications. Topical steroid therapy is effective in the treatment of ocular inflammation but may inhibit corneal wound healing, increase intraocular pressure, increase the likelihood of infection or worsen an existing one. 5,6 Cataract surgeons have therefore been interested in decreasing dependence on steroid use alone, seeking alternative or complementary treatments for postoperative inflammation that are equally effective but have fewer complications than steroid 2

3 therapy such as ocular NSAIDs. Combination therapy of steroids with NSAIDs has been shown to produce a synergistic effect on postoperative inflammation. 7 The royal college of ophthalmologist recommend that, if patients are at increased risk of cystoid macular oedema (CMO) (e.g. diabetes, previous CMO, previous retinal vein occlusion, epi-retinal membrane and prostaglandin use), a topical non-steroidal medication before and following surgery should be considered. 8 As yet an exact regimen has not been specified. Topical NSAIDs reduce inflammation by inhibiting prostaglandin synthesis and have been shown to be clinically effective in controlling inflammation after cataract surgery. 9 Several clinical studies have shown that NSAIDs are as effective as steroids in the treatment of postoperative pain and inflammation. 10,11 NSAID eye drops such as diclofenac, flurbiprofen, ketorolac, bromfenac and nepafenac are used for prophylaxis and treatment of inflammation, pain, and other symptoms associated with ocular surgery or laser treatment of the eye and postoperative inflammation following cataract surgery. 9,12 Nepafenac 0.1% is the only one with a prodrug structure, making it a neutral molecule which allows it to rapidly penetrate the cornea, after which it is converted by intraocular hydrolases to its more active moiety amfenac. 9 Current Formulary Status The North Staffordshire Joint Formulary currently lists the following agents on the formulary: 11.8 MISCELLANEOUS OPHTHALMIC PREPARATIONS Ocular Diagnostic and peri-operative preparations and photodynamic treatment Ocular peri-operative drugs Apraclonidine Ketorolac 3

4 Licensed Indications 1 NEVANAC is indicated in adults for: - Prevention and treatment of postoperative pain and inflammation associated with cataract surgery - Reduction in the risk of postoperative macular oedema associated with cataract surgery in diabetic patients. Dosage and Administration 1 Adults, including the elderly For the prevention and treatment of pain and inflammation, the dose is 1 drop of NEVANAC in the conjunctival sac of the affected eye(s) 3 times daily beginning 1 day prior to cataract surgery, continued on the day of surgery and up to 21 days of the postoperative period, as directed by the clinician. An additional drop should be administered 30 to 120 minutes prior to surgery. For the reduction in the risk of postoperative macular oedema associated with cataract surgery in diabetic patients, the dose is 1 drop of NEVANAC in the conjunctival sac of the affected eye(s) 3 times daily beginning 1 day prior to cataract surgery, continued on the day of surgery and up to 60 days of the postoperative period as directed by the clinician. An additional drop should be administered 30 to 120 minutes prior to surgery. Special populations Patients with renal or hepatic impairment NEVANAC has not been studied in patients with hepatic disease or renal impairment. Nepafenac is eliminated primarily through biotransformation and the systemic exposure is very low following topical ocular administration. No dose adjustment is warranted in these patients. Paediatric population The safety and efficacy of NEVANAC in children and adolescents has not been established. No data are available. Method of administration For ocular use. Patients should be instructed to shake the bottle well before use. If more than one topical ophthalmic medicinal product is being used, the medicinal product must be administered at least 5 minutes apart. 4

5 To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip of the bottle. Patients should be instructed to keep the bottle tightly closed when not in use. Guidance Scottish Medicines Consortium (SMC): 2 SMC accepted Nevanac for use within NHS Scotland for the reduction in the risk of postoperative macular oedema associated with cataract surgery in diabetic patients. This recommendation was based on the results from a pivotal study which included diabetic patients who had undergone cataract surgery in which nepafenac eye drops significantly reduced the incidence of macular oedema compared to vehicle. SMC stated that nepafenac was accepted because the balance of costs and benefits showed that it offered value for money. The holder of the marketing authorisation has not made a submission to SMC regarding the use of nepafenac to reduce pain and inflammation post-surgery therefore SMC could not recommended its use in this indication within NHS Scotland. Efficacy Evaluation of nepafenac in prevention of macular oedema following cataract surgery in patients with diabetic retinopathy 4 Summary: Topical ocular therapy with nepafenac is effective in the prevention of macular oedema and associated loss of visual acuity following cataract surgery. A pivotal, multicentre, randomised, double-masked, vehicle-controlled parallel study was conducted in 263 adult diabetic patients with non-proliferative diabetic retinopathy. The objective of the study was to determine whether treatment with nepafenac up to 90 days prevents macular oedema and the associated loss of visual acuity in diabetic patients post cataract surgery. The primary endpoint of the study was the proportion of patients who developed macular oedema (defined as increase of 30% or more in central subfield macular thickness relative to the pre-operative baseline measurement) within 90 days following cataract surgery. The secondary endpoints included the proportion of patients with a decrease of more than five letters in the best corrected visual acuity (BCVA) from day 7 to 90 (or early exit). 5

6 Subjects were randomised 1:1 to receive either nepafenac eye drops 1mg/ml three times daily or vehicle three times daily starting on the day before surgery and continuing 90 days thereafter. In addition, patients also instilled prednisolone acetate 1mg/ml ophthalmic suspension into the study eye four times daily for 2 weeks post-surgery or longer if considered necessary to treat anterior segment inflammation. The investigators were allowed to discontinue patients from the study and begin rescue therapy if patients developed a 30% increase in central subfield macular thickness, developed cysts, or experienced a decrease in visual acuity associated with macular thickening. The intention-to-treat population comprised 125 patients in the nepafenac group and 126 patients in the vehicle group, and the number of patients who completed the study was 118 vs 102 respectively. Patients were evaluated for safety and efficacy on days 1 (the day following surgery), 7, 14, 30, 60, and 90 (or at the time of early discontinuation from the study). Nepafenac showed superiority over vehicle with regards to the primary efficacy endpoint. A significantly greater percentage of patients in the vehicle group developed macular edema compared with the percentage of patients in the nepafenac group at day 30 (8.7% versus 2.4%, respectively; p = 0.029), day 60 (15.1% versus 2.4%, respectively; p < 0.001), and day 90 (16.7% versus 3.2%, respectively; p < 0.001). Nepafenac also showed superiority over vehicle in terms of the secondary endpoint as the percentages of patients who experienced visual acuity losses of more than five letters from the postsurgical baseline to days 30, 60, and 90 were consistently smaller in the nepafenac group than in the vehicle group (day 30, 2.4% versus 14.8%, respectively; p < 0.001; day 60, 2.4% versus 13.1%; p = 0.002; and day 90, 5.6% versus 11.5%; p = 0.102). However, 4 patients in the nepafenac group had loss of visual acuity that was considered to be unrelated to macular oedema versus no patient in the vehicle group. Removal of these 4 patients from the analysis resulted in a significant difference between nepafenac and vehicle (2.5% versus 11%; p=0.006). Most improvements in BCVA occurred prior to day 7 with small improvements in the mean BCVA for both groups from day 7 to 90 (or exit visit) (2.1 versus 0.9; p=0.226). The proportion of patients with treatment failure (defined as macular oedema and/or cyst and/or changes in BCVA) was significantly lower for nepafenac than for the vehicle group (28% versus 47%; p=0.002). Approximately one third of patients received steroids for more than 2 weeks on investigators advice. A total of 13 patients reported serious adverse events and none were considered to be related to treatment. Three serious adverse events reported in the vehicle group led to patient discontinuation. Separate from the three patients who discontinued due to serious adverse events, four other patients discontinued study participation due to non-serious adverse events. Two reports of punctate keratitis and a single report of corneal epithelium defect were assessed as being related to treatment with nepafenac. A single report of punctate keratitis was assessed as being related to treatment with vehicle. No other ocular or non-ocular adverse events reported in the study were assessed as being related to the study drugs. The authors considered that a review of adverse events revealed no safety issues based upon assessments of incidence, 6

7 seriousness, relationship to the study drug, onset, outcome, duration, severity, and patient discontinuation due to adverse events. 4 The authors concluded that nepafenac is associated with a reduction in risk of macular edema and associated loss of visual acuity in diabetic patients. 4 Analgesic and anti-inflammatory effectiveness of nepafenac.1% for cataract surgery 9 Summary: Nepafenac 0.1% placebo and ketorolac 0.5% were compared for prevention and treatment of pain and inflammation after cataract surgery. In a multi-center, randomized, placebo- and active-controlled, double-blinded clinical trial, 227 patients with cataract were randomized to receive nepafenac 0.1%, ketorolac 0.5%, or placebo TDS beginning 1 day pre-operatively and continuing for 21 days postoperatively. This study was designed to compare the effectiveness of nepafenac 0.1% with placebo and ketorolac 0.5% (a well-studied NSAID) for the prevention and treatment of ocular pain and inflammation following cataract surgery. Subjects were randomised 1:1:1 to receive nepafenac 0.1% (n=76), ketorolac 0.5% (n=73) or placebo (n=76) each to be instilled TDS on the day prior to cataract surgery, on the day of surgery and 21 days thereafter. Additional medication was not dispensed unless the investigator considered a patient to be a treatment failure, at which time the patient was discontinued from the study. Treatment failure was defined as a patient presenting at any postoperative visit with >15 cells, very dense flare, or ocular pain of grade 4 or 5 on a scale of 0 (none) to 5 (severe). Postoperative examinations were conducted on days 1, 3, 7, 14, 21, and 28. Eligible patients were those who were >18 years, in need of cataract extraction by phacoemulsification and implantation of a posterior chamber intraocular lens (IOL). Exclusion criteria included use of topical ocular, inhaled or systemic steroids within 14 days prior to surgery or topical ocular, inhaled or NSAIDs within 7 days of surgery (except for up to 100 mg of aspirin), any cells or flare etc. The primary efficacy variable was the percentages of patients who achieved a cure at day 14 after cataract surgery. Cure was defined as having a sum of aqueous cell and flare ratings of 0 (i.e., absence of cells and flare) at the current and all subsequent study visits. Secondary endpoint was the percentage of patients considered clinical successes which was defined as an aqueous cells rating of 0 (none) or 1 (1 5 cells) and an aqueous flare rating of 0 (none) at the current and all subsequent study visits 14 days after cataract surgery. There were no significant differences in cure rate between nepafenac and ketorolac or between nepafenac and placebo at any time points other than at Day 14. At Day 14 significantly more patients treated with nepafenac were cured compared to those treated with placebo (76.3% vs 59.2%, p=0.0241). Although the nepafenac group had a higher cure rate than the placebo group from Day 3 onward, only the Day 14 visit reached statistical significance (p=0241). There was no significance difference in cure rates between the nepafenac and ketorolac groups at any point. 7

8 Significantly more patients achieved clinical success with nepafenac than with placebo beginning on Day 7 and continuing through to Day 28 (p <0.05). The clinical success rate of nepafenac was superior to that of ketorolac at Day 14 (90.8% vs 78.1%, p=0.0319). At other time points, the clinical successes of nepafenac and ketorolac were not statistically different. The percentage of patients with no ocular pain was significantly higher in the nepafenac group compared to the placebo group starting on Day 3 (p<0.05). More patients treated with nepafenac were pain-free at Day 3 compared with those treated with ketorolac (p=0.0366). At all other times, there was no significant difference. Nepafenac proved more confortable post instillation than ketorolac. Mean ocular discomfort after 7 days was significantly lower for nepafenac group compared to ketorolac group (p=0.0158) but not to placebo. Two serious adverse events were reported (hospitalization due to diabetes mellitus and a branch retinal vein occlusion) both unrelated to study medication. Most frequent treatment related adverse events with nepafenac was eyelid margin crusting (2.6%); ketorolac and placebo treated groups was ocular hyperaemia (2.7% and 5.2% respectively). No safety concerns were identified for intraocular pressure, visual acuity, ocular signs or dilated fundus parameters. The authors concluded that nepafenac 0.1% is superior to placebo for the prevention and treatment of ocular pain and inflammation resulting from cataract surgery and at least equal in efficacy (for both ocular pain and inflammation measures) compared to ketorolac 0.5%. Nepafenac may have the advantage over ketorolac of being more comfortable on instillation. 9 Safety and adverse effects 1 Contraindications: Hypersensitivity to the active substance or to any of the excipients or to other NSAIDs. Patients in whom attacks of asthma, urticaria, or acute rhinitis are precipitated by acetylsalicylic acid or other NSAIDs Adverse effects: Punctate keratitis in diabetic patients (common, i.e. 1/100 to <1/10); less commonly nausea, headache, corneal epithelium defect, iritis etc. Refer to the Summary of Product Characteristics for a full list of adverse effects. Paediatric population The safety and efficacy of NEVANAC in children have not been established. 8

9 Drug Interactions 1 In vitro studies have demonstrated a very low potential for interaction with other medicinal products and protein binding interactions. There are very limited data on the concomitant use of prostaglandin analogues and NEVANAC. Considering their mechanism of action, the concomitant use of these medicinal products is not recommended. Cost Analysis Ms Pherwani estimated that 150 patients will be treated per year. The estimated expenditure per year based on patients treated for 21 days and 60 days will be 2, ,998.00, respectively. Expenditure in Primary and Secondary Care for a 12-month period (January-December 2012): Product Formulary Status UHNS PCT Stokeon-Trent CCG PCT North Staffordshire CCG Ketorolac 0.5% 5 ml Yes Nepafenac 1mg/ml 5 ml No Bromfenac 0.09% 5 ml No Diclofenac 0.1% Single-dose units No

10 Cost Analysis INDICATION Product/Pack size Dose regimen Cost per course Cost per Pack (inc VAT) Prevention of postoperative inflammation Ketorolac 0.5% 5 ml One drop instilled into the eye three times daily starting 24 hours pre-operatively and continuing for up to three weeks post-operatively. Treatment of postoperative inflammation following cataract surgery Reduction of postoperative macular oedema associated with cataract surgery in diabetic patients Nepafenac 1mg/ml 5 ml Bromfenac 0.09% 5 ml Diclofenac 0.1% 5 ml Single-dose units (5) 40 unit dose Ketorolac 0.5% 5 ml Nepafenac 1mg/ml 5 ml Nepafenac 1mg/ml 5 ml One drop three times daily beginning 1 day before surgery and continuing up to 21 days postoperative day One drop twice daily for 2 weeks 1 drop four times daily for up to 28 days. One drop three times daily starting 24 hours pre-operatively and continuing for up to three weeks post-operatively. One drop three times daily beginning 1 day before surgery and continuing up to 21 days postoperative day One drop instilled 3 times daily beginning 1 day prior to cataract surgery, continued on the day of surgery and up to 60 days of the postoperative period 10

11 References Summary of product characteristics Nevanac 1mg/ml eye drops, suspension Alcon SMC Scottish Medicines Consortium nepafenac 1mg/mL eye drops, suspension (Nevanac ) SMC No. (813/12) Alcon Laboratories (UK) Ltd October Accessed via Hayashi K et al. Chages in diabetic macular oedema after phacoemulsification surgery. Eye 2009:23: Singh R, Alpern L, Jaffe G.J et al. Evaluation of nepafenac in prevention of macular oedema following cataract surgery in patients with diabetic retinopathy. Clinical Ophthalmology. 2012; 6: Heier JS et al. Ketorolac versus prednisolone versus combination therapy in treatment of acute pseudophakic cystoid macular edema. Ophthalmology 2000;107: Simone JN, Whitacre MM. Effects of anti-inflammatory drugs following cataract extraction. Curr Opin Ophthalmol 2001;12:63 67 Heier JS et al. Ketorolac versus prednisolone versus combination therapy in treatment of acute pseudophakic cystoid macular edema. Ophthalmology 2000;107: Royal College of Ophthalmologists. Cataract surgery guidelines. September Nardi M et al. Analgesic and anti-inflammatory effectiveness of nepafenac 0.1% for cataract surgery. Clinical ophthalmology 2007;1(4): Brennan KM et al. A comparison of topical non-steroidal anti-inflammatory drugs to steroids for control of post cataract inflammation. Insight J Am Soc Ophthalmic Reg Nurses 1993;18(1);8 9:11 Flach AJ et al. The effect of ketorolac tromethamine solution 0.5% in reducing postoperative inflammation after cataract extraction and intraocular lens implantation. Ophthalmology 1988;95: British National Formulary (BNF) 64 September Produced by Sr Maria Chidiamara Njoku and Athenais Djossou Primary Care/Secondary Care Interface Pharmacist University Hospital of North Staffordshire Telephone: Maria.Njoku@uhns.nhs.uk Produced for use within the NHS. Not to be reproduced for commercial purposes 11