Review form Health Canada of nepafenac (Nevanac) , a non-steroidal anti-inflammatory drug (NSAID) for the management of pain and inflammation associated with cataract surgery
On April 17, 2008, Health Canada issued a Notice of Compliance to Alcon Canada Inc. for the drug product, NevanacTM (nepafenac) Ophthalmic Suspension.
NevanacTM contains the medicinal ingredient nepafenac which is a nonsteroidal
anti-inflammatory drug (NSAID).
NevanacTM is indicated for the management of pain and inflammation associated with cataract surgery. After topical ocular dosing, nepafenac penetrates the cornea and is converted by ocular tissue hydrolases to amfenac. Amfenac inhibits the action of prostaglandin H synthase (cyclooxygenase), an enzyme required to produce prostaglandin which causes pain and swelling in the eye.
The market authorization was based on the review of quality, non-clinical, and clinical information submitted. Four pivotal studies were conducted for the evaluation of the efficacy and safety of NevanacTM (nepafenac) ophthalmic suspension. In two double-masked, randomized clinical studies in which patients were dosed three-times-daily (one day prior to cataract surgery, continued on the day of surgery, and for the first two weeks of the postoperative period), NevanacTM demonstrated clinical efficacy compared to placebo in treating postoperative inflammation and ocular pain, from postoperative Day 3 through Day 14. In the two comparative-controlled studies, NevanacTM demonstrated non-inferiority to the comparator drug, ketorolac. The safety and effectiveness of NevanacTM have not been established in pediatric patients.
NevanacTM (0.1% w/v, nepafenac) is presented as a suspension. One drop of NevanacTM should be applied to the affected eye(s) three-times-daily: beginning one day prior to cataract surgery, and continued on the day of surgery, and through the first two weeks of the postoperative period. Dosing guidelines are also available in the Product Monograph.
NevanacTM is contraindicated for patients who are hypersensitive to nepafenac, to any ingredient in the formulation or component of the container or to other NSAIDs. NevanacTM should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of NevanacTM are also described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, it is considered that the benefit/risk profile of NevanacTM is favourable for the management of pain and inflammation associated with cataract surgery.
An excerpt of the Summary Basis of Decision, detailing clinical pharmadynamic and pharmacokinetic aspects of nepafenac (Nevanac), along with recommendations from Health Canada:
3.3 Clinical Basis for Decision
In eleven clinical studies, NevanacTM Ophthalmic Suspension 0.1% was administered to 811 patients at a dose of one drop one, two, three or four times daily. The most frequent adverse drug reactions (>0.1%) in patients with exposure to NevanacTM Ophthalmic Suspension 0.1% were eyelid margin crusting (0.6%), eye pain (0.5%), foreign body sensation (0.4%), and vision blurred (0.5%). No treatment-related adverse drug reactions were reported at a frequency of ≥ 1% in patients with exposure to NevanacTM Ophthalmic Suspension 0.1%.
Nepafenac is an amide pro-drug of amfenac, a potent NSAID. Following topical ocular administration, nepafenac undergoes amide hydrolysis by intraocular hydrolases to form the pharmacologically active amfenac. Amfenac inhibits both cyclooxygenase COX-1 and COX-2 activity.
Comparing aqueous humor levels at the time of maximum observed mean concentrations relative to COX-1 and COX-2 IC50 values, amfenac had higher mean ratios for both COX-1 and COX-2 than those for ketorolac and nepafenac. The concentration to COX-1 and COX-2 IC50 ratios for amfenac (0.649 and 1.07) were approximately 200% and 900% higher, respectively, than those for ketorolac (0.302 and 0.116). The ratio for nepafenac to COX-1 IC50 was much lower (>50 fold) than that for amfenac. These findings suggest superior anti-inflammatory activity with NevanacTM Ophthalmic Suspension compared with Ketorolac Tromethamine Ophthalmic Solution, 0.4%.
Following bilateral topical ocular three-times-daily dosing of NevanacTM Ophthalmic Suspension 0.1%, low but quantifiable plasma drug concentrations of nepafenac and amfenac were observed in the majority of subjects at two hours (nepafenac) and 5 hours (amfenac) post-dose. The mean steady-state plasma maximum concentration (Cmax) for nepafenac and amfenac were 0.310 ng/mL and 0.422 ng/mL, respectively, following ocular administration. The mean steady-state Cmax for amfenac following ocular administration is approximately 1659 times lower than the mean Cmax (0.7 µg/mL observed in subjects who received multiple 50 mg oral doses of amfenac.
In humans dosed three times per day for 14 days by the topical ocular route with nepafenac 0.1% ophthalmic suspension, the maximal level of 5-hydroxy amfenac amide is estimated to be about 0.07 ng/mL. These estimated levels indicate safety margins in humans to be about 450 fold compared to rats and 110-fold compared to monkeys based on the NOAEL doses.
Amfenac has high affinity toward serum albumin proteins. In vitro, the percent bound to human albumin and human serum was 95.4% and 99.1%, respectively. Studies in rats have shown that radioactive drug-related materials distribute widely in the body following single and multiple oral doses of 14C-nepafenac.
Nepafenac undergoes relatively rapid bioactivation to amfenac via intraocular hydrolases. Subsequently, amfenac undergoes extensive metabolism to more polar metabolites involving hydroxylation of the aromatic ring leading to glucuronide conjugate formation. Radiochromatographic analyses before and after β-glucuronidase hydrolysis indicated that all metabolites were in the form of glucuronide conjugates, with the exception of amfenac. Amfenac was the major metabolite in plasma, representing approximately 13% of total plasma radioactivity. The second most abundant plasma metabolite was identified as 5-hydroxy nepafenac, representing approximately 9% of total radioactivity at Cmax.
After oral administration of 14C-nepafenac to healthy volunteers, urinary excretion was found to be the major route of radioactivity elimination, accounting for approximately 85% of the dose, while fecal excretion represented approximately 6% of the dose. Nepafenac and amfenac were not quantifiable in the urine.
Neither nepafenac nor amfenac inhibits any of the major human cytochrome P450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) metabolic activities in vitro at concentrations up to 300 ng/mL. Therefore, drug-drug interactions involving CYP-mediated metabolism of concomitantly administered drugs are unlikely. Drug-drug interactions mediated by protein binding are also unlikely.
Concomitant use of topical NSAIDs and steroids may increase the potential for slower or reduced healing but there is no evidence the drugs act synergistically. Additionally, topical ocular NSAIDs should be used with caution in patients with known bleeding tendencies or who are receiving medications which may prolong bleeding time.
No clinical studies have been conducted in pediatric patients for the use of NevanacTM Ophthalmic Suspension. NevanacTM Ophthalmic Suspension 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.
3.3.3 Clinical Efficacy
Six clinical studies were conducted to evaluate the efficacy of NevanacTM Ophthalmic Suspension. In each of the six efficacy studies (C-95-93, C-97-30, C-02-53, C-03-32, C-04-65 and C-04-41), aqueous cells and flare, which are the hallmark of ocular inflammation, served as the basis for evaluating the efficacy of the drug product. As is the standard in ophthalmic practice, aqueous cells and flare were evaluated using slit-lamp biomicroscopy. In the two dose-response studies (C-95-93 and C-97-30), aqueous cells and flare scores served as the primary efficacy endpoints. In C-02-53, the primary efficacy endpoint was treatment failure which was based on aqueous cells and flare scores (i.e., a treatment failure was defined as cells score ≥ 3 or flare score 3) and ocular pain scores (i.e., treatment failure was also defined as a Grade 4 or greater pain score). In C-03-32 and C 04 65, the primary efficacy endpoint was percent cures, wherein cures were defined as the absence of inflammation (i.e., cells + flare = 0). In C-04-41, the primary efficacy endpoint was clinical success, wherein clinical success was defined as aqueous cells score ≤ 1 unit (less than or equal to 5 cells) and flare = 0.
Two active-controlled Phase III efficacy studies were performed (C-04-65 and C-04-41), comparing the efficacy of NevanacTM Ophthalmic Suspension 0.1% dosed TID to that of Ketorolac 0.5% dosed TID and Ketorolac 0.4% dosed QID, respectively. In C-04-41, NevanacTM Ophthalmic Suspension, 0.1% dosed three times daily was equal to Ketorolac Ophthalmic Solution, 0.4% dosed four times daily for the prevention and treatment of ocular pain and inflammation associated with cataract surgery based upon clinical assessments of aqueous cells, flare, and ocular pain. The results also indicated that NevanacTM Ophthalmic Suspension, 0.1% exhibited better results than Ketorolac Ophthalmic Solution, 0.4% for patient comfort upon instillation on the day prior to surgery and Day 7 post-operatively.
In conclusion, the most efficacious dosing regimen for NevanacTM Ophthalmic Suspension, 0.1% in preventing and treating ocular pain and inflammation associated with cataract surgery is three times daily. NevanacTM Ophthalmic Suspension, 0.1% dosed three times daily beginning one day prior to surgery, continuing the day of surgery and up to two weeks of the postoperative period is effective in the prevention and treatment of ocular pain. The submission does not support the proposed treatment indication of NevanacTM Ophthalmic Suspension beyond 14 days. NevanacTM Ophthalmic Suspension, 0.1% dosed three times daily beginning one day prior to surgery, continuing the day of surgery and for up to two weeks of the postoperative period is at least as efficacious as Ketorolac Ophthalmic Solution, 0.4% dosed four times daily or Ketorolac Ophthalmic Solution, 0.5% dosed three times daily for the prevention and treatment of pain and inflammation associated with cataract surgery. NevanacTM Ophthalmic Suspension, 0.1% dosed three times daily may be better tolerated than Ketorolac Ophthalmic Solution, 0.5% dosed three times daily or Ketorolac Ophthalmic Solution, 0.4% dosed four times daily.
All patients who received study medication, completed surgery, returned for at least one scheduled postoperative visit, met study inclusion/exclusion criteria, and adhered to protocol guidelines were considered evaluable for the per protocol analysis. In the intent-to-treat data set, last-observation-carried-forward was used to replace missing values due to patient discontinuations or missed visits.
3.3.4 Clinical Safety
The clinical development of NevanacTM Ophthalmic Suspension consisted of 16 topical ocular clinical studies with an overall total of 1938 adult and elderly patients and one open-label excretion study with eight patients who received a single administration of an oral formulation. A total of 1157 patients were exposed to NevanacTM Ophthalmic Suspension with concentrations ranging from 0.003% to 0.3% and dosing regimens ranging from once-daily (QD) to four-times-daily (QID).
A total of 832 patients were exposed to NevanacTM Ophthalmic Suspension, 0.1%. Overall, 1678 patients participated in six post-cataract inflammation studies, including 728 patients (87.5%) who received NevanacTM Ophthalmic Suspension, 0.1%.
No safety issues were noted based upon a review of adverse events which included an assessment of incidence, seriousness (serious/non-serious), treatment-relatedness, rate of discontinuation, and individual adverse event characteristics (e.g., severity, onset, duration). A review of the characteristics of each of the treatment-related ocular and non-ocular adverse events revealed no safety issues across treatment groups for the overall safety population. The most frequently reported treatment-related adverse events in the population of patients participating in the post-cataract studies with exposure to NevanacTM Ophthalmic Suspension, 0.1% (N=728) were eyelid margin crusting (0.5%), eye pain (0.3%), and foreign body sensation (0.3%). No serious adverse events related to NevanacTM Ophthalmic Suspension, 0.1% were reported in clinical trials. Twelve patients discontinued study participation due to non-fatal treatment-related adverse events which included four patients (0.5%) with exposure to NevanacTM Ophthalmic Suspension, 0.1%, one patient (1.4%) with exposure to Ketorolac Tromethamine Ophthalmic Solution, 0.5%, and seven patients (1.3%) with exposure to nepafenac vehicle (placebo).
Single treatment-related occurrences of iritis, conjunctival hyperemia, lacrimation increased, eye discharge, nausea, hypersensitivity, and cutis laxa also were observed.
In addition, no safety issues in any treatment group were identified based upon an analysis of ocular parameters (visual acuity, ocular signs, intraocular pressure, dilated fundus parameters, endothelial cell density, corneal thickness, and pupil diameter/response) in the overall safety population, adult population, and elderly population. An analysis of non-ocular parameters (general physical examination, cardiovascular, and laboratory) also revealed no safety issues for the overall safety population, adult population, and elderly population receiving NevanacTM Ophthalmic Suspension.
In conclusion, NevanacTM Ophthalmic Suspension, 0.1% administered TID is indicated for management of pain and inflammation associated with cataract surgery and is considered safe and well-tolerated.
3.4. Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
NevanacTM Ophthalmic Suspension, 0.1% has demonstrated a favorable safety profile. No safety issues were noted based upon a review of adverse events which included an assessment of incidence, seriousness (serious/non-serious), treatment-relatedness, rate of discontinuation due to adverse events, and individual adverse event characteristics (e.g., severity, onset, duration). A review of the characteristics of each of the treatment-related ocular and non-ocular adverse events revealed no safety concerns across treatment groups for the overall safety population.
No safety concerns were identified based upon a review of ocular and non-ocular adverse events by age, gender, race, iris color, concomitant diseases, concomitant medications, or time of adverse event onset. There were no adequate and well-controlled studies of NevanacTM Ophthalmic Suspension, 0.1% in pregnant women. Nepafenac has been shown to cross the placental barrier in rats and because animal reproduction studies are not always predictive of human response, NevanacTM Ophthalmic Suspension, 0.1% should be used during pregnancy only if clearly needed. Caution should be exercised when NevanacTM Ophthalmic Suspension, 0.1% is administered to a nursing woman. The safety and effectiveness of NevanacTM Ophthalmic Suspension, 0.1% in pediatric patients have not been established.
NevanacTM Ophthalmic Suspension, 0.1% has been safely administered in conjunction with other ophthalmic medications such as antibiotics, anesthetics, beta-blockers, carbonic anhydrase inhibitors, alpha-agonists, cycloplegics, and mydriatics. Within the clinical studies of NevanacTM Ophthalmic Suspension, 0.1%, no adverse events (related and not related combined) were noted which would suggest that therapy would result in an inability to drive or operate machinery or result in an impairment of mental ability.
Overall, the benefits outweigh the risks for the use of NevanacTM Ophthalmic Suspension for the management of pain and inflammation associated with cataract surgery.
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of NevanacTM Ophthalmic Suspension is favourable for the management of pain and inflammation associated with cataract surgery.
The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.