Summary Basis of Decision for Nevanac ™ Ophthalmic Suspension
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
NevanacTM Ophthalmic Suspension
Nepafenac, 0.1% w/v, Suspension, Ophthalmic
ALCON Canada Inc.
Submission control no: 114004
Date issued: 2008-10-29
Health Products and Food Branch
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Health Canada
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrNevanacMC Ophthalmic Suspension, Népafénac, 0.1% w/v, suspension, ALCON Canada Inc., No de contrôle de la présentation 114004
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02308983
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
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.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
NevanacTM Ophthalmic Suspension contains the medicinal ingredient nepafenac which is a nonsteroidal anti-inflammatory drug (NSAID). NevanacTM Ophthalmic Suspension 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.
Manufacturing Process and Process Controls
Nepafenac is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet ICH requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of nepafenac is considered to be adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of nepafenac are considered acceptable.
Stability
Based on the long-term stability data submitted, the proposed shelf-life, for the drug substance is supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
NevanacTM Ophthalmic Suspension, drug product is a homogeneous suspension which is yellow in colour. NevanacTM Ophthalmic Suspension is supplied in an 8 mL round low density polyethylene bottle with a natural low density polyethylene dispensing plug and white polypropylene cap. Net contents are 5 mL supplied in an 8 mL bottle.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of nepafenac with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Several studies which justified the type and proposed concentration of preservative/excipient to be used in the drug product were reviewed and are considered to be acceptable.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
NevanacTM Ophthalmic Suspension is tested to verify its identity, appearance, content uniformity, and the presence of degradation products. The test specifications and analytical methods are considered acceptable; the shelf-life and release limits, for individual and total degradation products, are within acceptable limits.
The test specifications are considered acceptable to control the drug product, and the impurity limits were set according to ICH recommendations.
Stability
Based on the long-term stability data submitted, the proposed 24-month shelf-life at 30°C temperature for NevanacTM Ophthalmic Suspension is considered acceptable.
3.1.3 Facilities and Equipment
All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for NevanacTM Ophthalmic Suspension has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
The topical anti-inflammatory activity of nepafenac was determined in animal models (rabbits, rats, and mice) of ocular inflammation of both the anterior and posterior section of the eye. Nepafenac was found to effectively suppress prostaglandin synthesis and concomitant development of leakage of the blood-aqueous and -retinal barriers, including retinal edema.
In vivo studies demonstrated a fairly uniform inhibition (80-100%) of all prostaglandins formed by the iris/ciliary body of the rabbit following a single topical dose of 0.1% nepafenac. Similar suppression in aqueous humor PGE2 accumulation, concurrent with a 61% reduction in protein extravagation, was evident in a rabbit model of paracentesis following a single prophylactic dose of 0.1% nepafenac. Both in vivo and ex vivo studies showed a long duration of anti-inflammatory action (6-8 hrs) and suppression of PGE2 synthesis in the iris/ciliary body. Paracentesis-induced vascular leakage was noted in the rabbit following a single topical dose of 0.1% nepafenac. In vitro corneal perfusion studies demonstrated a superior corneal permeability of nepafenac with minimal lag time when compared to a standard reference NSAID, diclofenac.
Although there was slow hydrolysis of nepafenac in the cornea, there was rapid bioconversion of nepafenac to amfenac in vitro with tissue slices of the iris/ciliary body and the retina/choroid. Thus, the biodistribution and hydrolytic conversion of nepafenac to amfenac at tissue sites of dominant prostaglandin synthesis is likely associated with nepafenac's long duration of anti-inflammatory action.
The strong cyclooxygenase inhibitory action of the active metabolite also appears to be the likely basis of nepafenac's ability to inhibit retinal neovascularization in a rat model of oxygen-induced retinopathy. It may also be the key contributing factor for the significant reductions observed in retinal vascular leukostasis, PGE2, superoxide anion formation and morphological changes observed in the retina of a rat model of streptozotocin-induced diabetes.
Nepafenac did not show any effect on 21 receptors and ligand binding sites at concentrations up to 100 μM, including neurotransmitters, neuronal regulatory sites, opioids, brain/gut peptides, growth factors, secondary messengers, and steroid receptors, thereby suggesting minimal or no side effect potential following topical ocular dosing.
No deleterious effects of nepafenac were evident in tests of pulmonary (1.0 mg/kg, SC), renal (3.0 mg/kg, SC), cardiovascular (1.0 mg/kg; SC and 1.55 mg/kg, IV), and central nervous system (3.0 mg/kg, SC) function at the highest dose tested. Amfenac at bath concentrations up to 100 ng/mL had no adverse effect on HERG tail current and sodium amfenac at intravenous doses up to 1.08 mg/kg (cumulative dose 1.55 mg/kg) had no effect on blood pressure, heart rate or QTc interval in anesthetized dogs. Nepafenac exhibited no ulcerogenic potential at 3 mg/kg oral administration in rats. In addition, there was no evidence for an effect on ileal smooth muscle responses to various agonists at concentrations as high as 2.5 μg/ml.
Based on the comprehensive pharmacological investigations in various species, it appears that 0.1% NevanacTM Ophthalmic Suspension is unlikely to pose significant side effect risk when administered by the topical ocular route to patients undergoing cataract surgery.
3.2.2 Pharmacokinetics
Absorption
The plasma pharmacokinetics of amfenac amide (nepafenac) were determined in rabbits following a 1 mg/kg intravenous dose of an amfenac amide solution and a bilateral 30 µl topical ocular dose of a 0.3% amfenac amide ophthalmic suspension (equivalent to 0.07 mg/kg). Maximal plasma concentrations of amfenac amide and amfenac following the topical ocular dose were reached after approximately 30 minutes with levels of 45.5 ng/mL and 8.84 ng/mL, respectively.
Distribution
The distribution of radioactivity in ocular tissues of white rabbits and pigmented rabbits was determined following topical ocular doses of a 3 mg/ml 14C-amfenac amide (nepafenac). The maximal rabbit tissue concentrations decreased in the following order: conjunctiva (4.62 µg eq/g), cornea (3.90 µg eq/g), iris-ciliary body (0.639 µg eq/g), aqueous humor (0.577 µg eq/g), choroid (0.115 µg eq/g), retina (0.0508 µg eq/g), lens (0.0429 µg eq/g), and vitreous humor (0.0019 µg eq/g).
The concentrations and half-lives of radioactivity in iris-ciliary body of white rabbits and pigmented rabbits were similar. Choroid and retina concentrations of radioactivity in pigmented rabbits were also similar to those in the associated tissues of white rabbits. These results indicate that 14C-amfenac amide (nepafenac) and its metabolites do not bind to melanin pigmented tissues. Metabolism studies have demonstrated that amfenac amide is metabolized in the eye in vivo to amfenac and at least one unidentified minor metabolite.
The studies conducted have determined the protein binding of amfenac amide in rat and monkey at final concentrations of 10, 30, 100, 300, and 1000 ng/mL. Protein binding was found to be independent of concentration in all three species. The protein binding of amfenac amide was less than that of amfenac. The mean percentages of protein binding in rat and monkey were 72.8% and 79.8 % respectively.
Excretion
Chromatographic profiles of radioactivity in rat plasma and urine were determined following a single 0.5 mg/kg intravenous dose of 14C-amfenac amide to male rats. Plasma samples were collected at 0.25, 4, and 24 hours and urine samples were collected between 0-24 hours from five animals per time point. The percent radioactivity recovered from plasma was 98.8% at 0.25 hours, 84.5% at 4 hours and 41.3% at 24 hours. The percents of radioactivity recovered from plasma after beta-glucuronidase treatment was 97.1% at 0.25 hours, 76.8% at 4 hours, and 46.8% at 24 hours. Radioactivity recoveries from urine were essentially quantitative with 102% recovered before and 97% after beta-glucuronidase treatment.
At least ten different metabolites were observed in urine. The representative radiochromatograms of urine before and after beta-glucuronidase treatment were identified. The percentages of dose excreted during the 24 hour collection period for each metabolite were identified. Comparison of urine radiochromatographic profiles before and after beta-glucuronidase treatment indicated that the majority of metabolites in rat urine were not conjugated. The appearance of Mu-9 and increase in peak height of Mu-10 after glucuronidase treatment suggests they have corresponding beta-glucuronidase hydrolyzable conjugates. However, both are relatively minor metabolites each representing less than 1% of dose excreted.
The excretion of radioactivity in feces indicates biliary excretion is involved in the elimination of amfenac amide-derived radioactive components in rats.
3.2.3 Toxicology
All toxicity studies used acceptable, standard protocols designed according to ICH Guidelines. All of the studies were carried out in accordance with Good Laboratory Practices.
Acute Toxicity
Single dose toxicity studies to approximate the LD50 were conducted in mice and rats by the oral and intraperitoneal (IP) routes. There were no significant clinical signs noted in the mice. The clinical signs noted in rats were swollen abdomen, red exudates on face, small stool quantities, and less active behaviour. None of the mice treated orally with either 1.0 g/kg or 2.0 g/kg of amfenac amide were noted with any significant signs of toxicity during the study. Toxicology concluded that the oral (gavage) LD50 value for amfenac amide in mice was greater than 2.0 g/kg. The intraperitoneal LD50 value for amfenac amide in mice was greater than 1 g/kg. The oral LD50 was greater than 0.1 g/kg in male rats and greater than 0.5 g/kg in female rats. The IP LD50 value for amfenac amide was greater than 0.25 g/kg in male rats and greater than 0.1 g/kg in female rats.
Repeat-Dose Toxicity
Three repeat-dose systemic studies were conducted using rats, where amafenac amide was administered orally by gavage. The clinical signs noted were decreases in red blood cells (RBCs), haemoglobin, and hematocrit in the 25 mg/kg group; renal papillary necrosis in female rats; alopecia of the forelimbs; and discoloration around the nose, eyes, paws and mouth.
There were five topical ocular repeat-dose studies conducted using rabbits and monkeys. The clinical signs noted for the rabbits were minimal conjunctiva congestion. No clinically relevant signs were noted for the monkeys. They did not elicit any signs of ocular or systemic toxicities.
The results demonstrate that the no observed adverse effect level (NOAEL) for oral administration of amfenac amide in rats is 10 mg/kg/day. The NOAEL for daily topical ocular administration is 1.5% and 1% NevanacTM Ophthalmic Suspension in rabbits and monkeys, respectively.
Genotoxicity/Mutagenicity
Studies conducted to evaluate the mutagenic potential of amfenac amide included the Ames assay and the mouse lymphoma forward mutation assay. Amfenac amide was non-mutagenic when tested in the reverse mutation test (Ames assay) and mouse lymphoma forward mutation. In the Ames assay, amfenac amide up to 5 mg/plate was non-mutagenic in all bacterial strains tested in the absence and presence of metabolic activation with S9 mix. The in vitro mouse lymphoma forward mutation assay showed no potential of amfenac amide to induce mutations in mammalian cells at concentrations up to 1 mg/mL in the absence or presence of metabolic activation. Based on the above, amfenac amide and its metabolites are considered negative for mutagenicity.
Carcinogenicity
No long-term carcinogenicity studies were completed for the use of nepafenac. It was determined that carcinogenicity studies were not needed to support the safety of NevanacTM Ophthalmic Suspension based on the chemical class, short duration of therapy, low systemic exposure potential, and nonclinical toxicology study results.
Reproductive and Developmental Toxicity
A series of studies were conducted to assess the effects of amfenac amide on fertility and reproduction, embryo-fetal growth and development, as well as delivery and postnatal development. Effects on fertility and general reproductive performance were evaluated in rats by oral administration. Male rats' sperm motility was significantly lower for the 15 mg/kg/day group compared to the control group. No significant differences between the groups in copulation, fertility indices or in mean precoital intervals were noted. The mean number of viable fetuses was significantly decreased in the 10 mg/kg/day group compared to the control group. Based upon these data, the no observed effect level (NOEL) for reproductive effects was determined to be 3 mg/kg/day of amfenac amide.
Embryo-fetal development was assessed in rats with oral administration amfenac amide during the major period of organogenesis. Maternal toxicity was noted in the 10 and 30 mg/kg/day groups. A statistically significant increase in the total number of litters with external, visceral and/or skeletal malformations were noted in the 30 mg/kg/day group of rabbits and skeletal malformations were observed in the 30 mg/kg/day group of rats. No evidence of significant effects on embryo-fetal growth or development was observed in rabbits or rats at 10 mg/kg/day. The NOEL for developmental toxicity was determined 10 mg/kg/day for both species.
The effects of amfenac amide on peri- and postnatal development were assessed in rats from day 6 of gestation through postnatal day 21. Relative to the control group, F0 females' weight gain and/or food consumption were significantly decreased and gestation length was significantly increased at exposure levels above 10 mg/kg/day. For the 10 and 30 mg/kg/day levels, mean F1 pup mortality was significantly increased and body weight was significantly decreased during lactation. No toxicologically meaningful differences were observed among F1 pups for developmental, functional or reproductive indices. The findings of prolonged gestation, delayed parturition, reduced offspring weight, and reduced offspring survival in rats are consistent with findings elicited by other nonsteroidal anti-inflammatory drugs. Based upon these findings, the NOEL for developmental toxicity in F1 offspring was determined to be 3 mg/kg/day of amfenac amide.
Local Tolerance
Nepafenac suspension is an ophthalmic product that is administered by topical ocular application. The most common clinical sign noted in all animals tested was minimal conjunctival congestion.
3.2.4 Summary and Conclusion
The appropriate non-clinical studies and toxicology studies were performed and are considered adequate. The toxicity findings were consistent with the pharmacological effects of NevanacTM Ophthalmic Suspension. The non-clinical pharmacology and toxicology studies support the use of NevanacTM Ophthalmic Suspension for the proposed indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
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%.
3.3.2 Pharmacokinetics
Absorption
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.
Distribution
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.
Metabolism
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.
Excretion
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.
Drug-Drug Interaction
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.
Special Populations
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.
3.4.2 Recommendation
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.
4 Submission Milestones
Submission Milestones: NevanacTM Ophthalmic Suspension
| Submission Milestone | Date |
|---|---|
| Submission filed | 2007-05-04 |
| Screening | |
| Screening Acceptance Letter issued | 2007-06-22 |
| Review | |
| Quality Evaluation complete | 2008-04-09 |
| Clinical Evaluation complete | 2008-04-15 |
| Labelling Review complete | 2008-04-15 |
| NOC issued by Director General | 2008-04-17 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| NEVANAC | 02308983 | NOVARTIS PHARMACEUTICALS CANADA INC | NEPAFENAC 0.1 % / W/V |