Commercially available ocular hypotensive products: preservative concentration, stability, storage, and in-life utilization.

PURPOSE: With the recent addition of several new ocular hypotensive agents to the pharmacopeia, glaucomatologists have more choices in selection of pharmacotherapy. Several of these new agents have special storage requirements or a limited shelf-life when stored under certain conditions. METHODS: To better inform physicians and patients about pharmaceutical issues relating to the correct usage or storage of ophthalmic products used to manage glaucoma, the authors reviewed the US Food and Drug Administration requirements for sterile ophthalmic preparations, together with the United States Pharmacopeia 24. They also reviewed the Ophthalmic Physicians Desk Reference (2000 edition) for pharmaceutical information regarding branded glaucoma-solution products. RESULTS: The US Food and Drug Administration requires that both analytical tests (e.g., concentration of preservative) and functional tests (e.g., preservative efficacy tests) be undertaken to show the sterility of liquid products. In addition, extensive chemical testing of the potency and stability of the active molecule and other physicochemical properties of the formulation are needed to justify expiration dates and determine the shelf-life of the product. Of the 19 products that met the search criteria, 17 (89%) used benzalkonium chloride as the primary preservative agent, in weight-to-volume ratios ranging from 0.004% (Betagan, Optipranolol) to 0.020% (Xalatan). Five products had a warning against freezing, and 12 required protection from light. Only one product required refrigerated storage before opening, though most products specify an upper range for temperature exposure during storage. CONCLUSIONS: Physicians and their patients need to be aware of the special requirements of each product to assure that they receive the dose of medication as prescribed. The distinction between stability during storage before dispensing (shelf-life) and the acceptable "in-use life" after opening of the dispensed product are essential for the safe and efficacious management of glaucoma.

Ocular safety of INS365 ophthalmic solution: a P2Y(2) agonist in healthy subjects.

The purpose of this study was to evaluate the ocular safety and tolerability of the P2Y(2) receptor agonist, INS365, when applied as eye drops in normal human subjects. This study was a double-masked, placebo-controlled, randomized, within subject paired-comparison, dose-escalation study in five cohorts of ten healthy subjects. The concentrations of INS365 ophthalmic solution were 0.5, 1.0, 2.0, and 5.0% given three times over six hours. Safety was assessed by general and ophthalmic examination and symptomatology. Unanesthetized Schirmer tests were performed in the last cohort of 10 subjects to evaluate the acute effects of INS365 on tear secretion. There were no significant differences in the number of subjects with ocular events reported in placebo-treated eyes compared to INS365-treated eyes. Two adverse events were possibly related to INS365: painless blepharospasm and an increase in lacrimation after 5.0% INS365 instillation. Unanesthetized Schirmer testing showed no acute effects of INS365 on tear secretion, compared to its vehicle, in healthy subjects, in which reflex tearing often produced maximal Schirmer values. INS365 ophthalmic solution was well-tolerated when administered by ocular instillation. Stimulation of ocular surface P2Y(2) receptors was not associated with ocular tolerability issues in healthy subjects.

Update on regulatory review intervals for ophthalmic new drug applications at the United States Food and Drug Administration.

PURPOSE: To update the analysis of the regulatory review interval for ophthalmic new drug applications at the United States Food and Drug Administration for the years 1997 to 1999, based on the previous review by the author of the period 1990 to 1996. METHODS: Publicly available records on ophthalmic drugs approved by the Food and Drug Administration in this time period were reviewed. RESULTS: Of the seven ophthalmic new drug applications approved during the years 1997 to 1999, the range of approval intervals was 5 to 22 months. With only one approval in 1997, the mean was the same as that single product, 22 months. The mean approval time for 1998 was 10.3 months, and for 1999 it was 8.7 months. CONCLUSION: The ophthalmology division continues its rapid rate of New Drug Application review.

Financing new drug development in ophthalmology.

Previously, the author presented an overview of the procedural aspects of ophthalmic drug development. In that article, aspects of drug discovery and development were discussed, including application of the scientific method, compound selection, biological evaluation, pharmaceutical formulation, clinical development, and regulatory approval. An important part of drug discovery and development is funding the work. In this article, the author presents key issues involved in this funding process.

Comparative irritancy study among retinoid creams and gels.

BACKGROUND: Topical retinoids, although very useful in dermatology, may be irritating to some patients. OBJECTIVE: There are a number of topical retinoids available in Canada, and the objective of the present study was to evaluate the irritancy potential in humans of retinoid gels and creams presently available in Canada. METHODS: Thirty healthy adults were administered 10 products (five creams, three gels, petrolatum, and sodium lauryl sulfate (SLS) 0.1% w/v) for up to 21 consecutive days. RESULTS: Early termination of patching due to irritation was required for the tretinoin creams and gels and SLS more frequently and earlier in the study than for adapalene and petrolatum (p =.001). Statistically significant, among-group differences were noted in the severity of irritation at each day and for the cumulative score for both the creams and the gels (p =.0001), in favour of adapalene over the tretinoin products. CONCLUSION: By several measures, adapalene cream and gel were less irritating upon multiple dosing than various tretinoin creams and gels.

A randomized, double-masked, placebo-controlled parallel study of loteprednol etabonate 0.2% in patients with seasonal allergic conjunctivitis.

OBJECTIVE: To evaluate the effects of loteprednol etabonate (LE) 0.2% in reducing the signs and symptoms of seasonal allergic conjunctivitis. DESIGN: Randomized, double-masked, placebo-controlled, parallel group multicenter study of 6 weeks duration. PARTICIPANTS: A total of 135 patients with signs and symptoms of seasonal allergic conjunctivitis participated. INTERVENTION: All patients received either LE 0.2% or placebo (vehicle) four times a day in both eyes for 42 days. MAIN OUTCOME MEASURES: Bulbar conjunctival injection (primary sign) and itching (primary symptom) over the first 2 weeks of treatment was measured. RESULTS: A reduction in severity was seen in both LE and placebo groups for bulbar conjunctival injection (1.5 vs. 1.0 units on a 0-3 scale) and itching (3.4 vs. 3.0 units on a 0-4 scale) over the first 2 weeks. The treatment effect by these measures was -0.5 and -0.4 units in favor of LE (P < or = 0.008). Resolution (i.e., the proportion of patients with signs or symptoms no longer present) at day 14 strongly favored LE-treated patients (36% and 15%; 58% and 38%, for injection and itching, respectively). Both treatments were well tolerated. One patient in each treatment group (1 of 67 and 1 of 68, respectively) had an elevation of intraocular pressure of 10 mmHg or greater during the 6 weeks of treatment. CONCLUSIONS: Loteprednol etabonate 0.2% was more effective than placebo in the treatment of seasonal allergic conjunctivitis. Loteprednol etabonate 0.2% had a safety profile comparable to placebo.

A controlled pharmacokinetic evaluation of tizanidine and baclofen at steady state.

Clinical trials with tizanidine when administered alone have shown that 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiodiazole (tizanidine) is safe and effective for spasticity control. However, given its mechanism of action and requirement for titration, clinical experience suggests that tizanidine is likely to be used in combination with other antispastic agents with different mechanisms of action, such as baclofen. The objective of this study was to examine the pharmacokinetics of both tizanidine and baclofen under steady-state conditions when administered alone or concomitantly. This was a randomized, three-period, multiple-dose, Latin Square design study consisting of tizanidine HCl, 4 mg t.i.d. for seven consecutive doses; baclofen, 10 mg t.i.d. for seven consecutive doses; and both regimens simultaneously for seven consecutive doses. Drug administration was performed every 8 h, three times daily. Fifteen normal men served as study subjects. A priori, a clinically significant difference was set as 30%. Concentrations of tizanidine and baclofen were nearly identical during the single and concomitant dosing periods. All of the calculated steady-state pharmacokinetic parameter changes for baclofen, tizanidine, and its major metabolites were within the 30% criterion. Small differences in renal clearance were observed when the two drugs were coadministered, but these changes are unlikely to be clinically important. Thus, it is unlikely that coadministration of tizanidine and baclofen during dose-titration of the former will result in a pharmacokinetic interaction.

Double-masked, placebo-controlled evaluation of loteprednol etabonate 0.5% for postoperative inflammation. Loteprednol Etabonate Post-operative Inflammation Study Group 1.

PURPOSE: To compare the efficacy and safety of loteprednol etabonate 0.5% with those of a placebo (vehicle) in controlling anterior chamber cell and flare reaction in patients having cataract surgery with intraocular lens (IOL) implantation. METHODS: This randomized, double-masked, placebo-controlled, parallel-group multicenter study comprised patients who exhibited a minimum anterior chamber inflammation (ACI) score (sum of cell and flare reaction) of 3 (0 to 9 scale) on the day after cataract removal with posterior chamber IOL implantation. All 227 patients received loteprednol etabonate 0.5% or the placebo 4 times a day in the operated eye for up to 14 days after surgery. Five patients without valid on-treatment follow-up visits were not evaluated for efficacy. RESULTS: By the final visit, the ACI had resolved in 64% (70/109) of patients in the loteprednol etabonate group and 29% (33/113) of those in the placebo group (P < .001). The resolution rate and mean change from baseline of the individual components of ACI (cell and flare), as well as other signs and symptoms, was better in the loteprednol etabonate group. Both treatments were well tolerated. Among the 53 patients who did not complete the study, 34 (29%) were placebo patients discontinued for inadequate anti-inflammatory effect. The treatment failure rate and the time course of failures were lower in the loteprednol etabonate group; the differences were clinically meaningful and statistically significant (P < .001). Three patients in the loteprednol etabonate group had an intraocular pressure elevation of 10 mm Hg or more over the preoperative screening value. CONCLUSION: Loteprednol etabonate 0.5% led to a clinically meaningful reduction in the signs and symptoms of postoperative ACI and had an acceptable safety profile when compared with a placebo.

A randomized, double-masked, placebo-controlled parallel study of 0.2% loteprednol etabonate in patients with seasonal allergic conjunctivitis.

BACKGROUND: Loteprednol etabonate is a site-active corticosteroid with efficacy and safety in treating ocular inflammation at the 0.5% concentration. Evidence from dose-response studies suggested that the 0.2% concentration might be effective in treating ocular allergy. OBJECTIVES: The objective of this study was to evaluate the effects of 0.2% loteprednol etabonate in reducing the signs and symptoms of seasonal allergic conjunctivitis. METHODS: This was a randomized, double-masked, placebo-controlled, parallel-group multicenter study. Patients with signs and symptoms of environmental seasonal allergic conjunctivitis received either loteprednol etabonate or placebo bilaterally four times daily for 42 days. RESULTS: Enrolled were 133 patients (66 receiving loteprednol etahonate; 67 receiving placebo). A reduction in severity was seen in both loteprednol etabonate and placebo groups for bulbar conjunctival injection (1.3 vs 0.9 units on a 0 to 3 scale) and itching (3.5 vs 3.1 units on a 0 to 4 scale) over the first 2 weeks. The treatment effect was -0.5 and -0.6 units in favor of loteprednol etabonate (P < .001). Resolution (the proportion of patients with the sign or symptom no longer present) at visit 4 (day 14) strongly favored loteprednol etabonate-treated patients over placebo-treated patients (31% and 9%, and 54% and 38%, for injection and itching, respectively). Both treatments were well tolerated. No patients in either treatment group (0 for loteprednol etabonate and 0 for vehicle) had an elevation of intraocular pressure of 10 mm Hg or greater during the 6 weeks of treatment. CONCLUSIONS: Loteprenol etabonate (0.2%) was more effective than placebo in the treatment of seasonal allergic conjunctivitis. Loteprednol etabonate (0.2%) had a safety profile comparable to placebo during this 6-week trial.

Change in intraocular pressure during long-term use of loteprednol etabonate.

PURPOSE: Loteprednol etabonate is a novel site-active corticosteroid synthesized through structural modifications of prednisolone-related compounds so that it will undergo a predictable transformation to an inactive metabolite. In double-masked studies, loteprednol etabonate was effective in the treatment of giant papillary conjunctivitis, seasonal allergic conjunctivitis, postoperative inflammation, and uveitis. The objective of this analysis was to determine the incidence of clinically significant elevations in intraocular pressure (IOP) with long-term use of loteprednol etabonate. PATIENTS AND METHODS: All subjects (healthy volunteers or patients with inflammation or allergy) in all sponsored loteprednol etabonate studies in the United States were evaluated. A clinically significant elevation in IOP was defined as > or = 10 mmHg at any visit, and long-term use was defined as > or = 28 days. Of the 2,210 subjects, 1,648 were treated for 28 days or longer with loteprednol etabonate (0.2% or 0.5%), prednisolone acetate 1%, or vehicle. RESULTS: IOP elevation > or = 10 mmHg occurred in 1.7% (15/901) of patients taking long-term loteprednol etabonate, 0.5% (3/583) of those taking vehicle, and 6.7% (11/164) of those taking prednisolone acetate. Excluding patients who wore contact lenses, the incidence was 0.6% (4/624), 1.0% (3/304), and 6.7% (11/164) for loteprednol etabonate, vehicle, and prednisolone acetate, respectively. The incidence of IOP elevations with 0.2% loteprednol etabonate was 0.8% (1/133), similar to that for vehicle (0.7%, 1/135). CONCLUSION: The results of this analysis in a large population of subjects undergoing long-term therapy and of a previously published controlled, double-masked study in corticosteroid responders suggest that loteprednol etabonate has less propensity to cause clinically significant elevations in IOP than prednisolone acetate.

Regulatory review intervals for ophthalmic new drug applications at the US Food and Drug Administration.

PURPOSE: To evaluate the regulatory review interval for recent ophthalmic new drug applications (NDAs) at the U.S. Food and Drug Administration (FDA). METHODS: Based on publicly available information regarding submission and approval dates, the timing of FDA review of NDAs of first indications for therapeutic ophthalmic drugs in the 1990s was evaluated. RESULTS: The mean (median) interval of the 19 NDAs from submission to approval decreased from 44 (18) months in 1990 to 11 (10.6) months in 1996. At least nine of these agents had their first worldwide ophthalmic approval in the United States. For 10 of the 19 NDAs, the ophthalmic NDA represented the first US approval of this molecule by any route. CONCLUSIONS: Quality filings currently appear to be reviewed and approved in 1 year or less. Because of the confidential nature of corporate development, no analysis can be made regarding changes in the presubmission costs and timing.

A single-blind, crossover comparison of the pharmacokinetics and cognitive effects of a new diazepam rectal gel with intravenous diazepam.

PURPOSE: The objective of this study was to compare the pharmacokinetics and cognitive effects of a new diazepam (DZP) rectal gel (Diastat) with intravenously administered DZP. METHODS: Twenty healthy volunteers were enrolled in a single-blind, randomized, double-dummy, two-period, crossover study. Subjects received either 15 mg of DZP rectal gel or 7.5 mg of DZP by intravenous infusion. Blood samples for DZP and desmethyldiazepam analysis were obtained before the dose and from 3 min to 240 h after the dose. Heart rate and blood pressure were measured over the first 24-h period. Subjects also completed five repetitions of a neuropsychological test battery over the first 8-h period. RESULTS: Diazepam rapidly appeared in plasma after rectal administration, exceeding 200 ng/mL within 15 min and reaching an initial maximum of 373 ng/ml at 45 min and a second maximum of 447 +/- 91.1 ng/ml at approximately 70 min. The absolute bioavailability of DZP rectal gel was 90.4%. Subjects receiving intravenous DZP were less alert and performed less efficiently on the WAIS Digit Symbol test 6 min after the dose. Subjects receiving DZP rectal gel performed less well on the WAIS Digit Span test 1 h after the dose and required more time to complete the Letter Cancellation and Grooved Pegboard tests 1 and 2 h after drug administration. CONCLUSIONS: Diastat displayed rapid, consistent absorption and was well tolerated. Alterations in cognition were mild and dissipated within 4 h of drug administration. This new rectal drug-delivery system offers an easy, safe, and bioavailable method to administer DZP.

Failure to detect systemic levels, and effects of loteprednol etabonate and its metabolite, PJ-91, following chronic ocular administration.

The objective of this study was to determine the systemic exposure to loteprednol etabonate (LE) following its chronic, ocular instillation. This was a randomized, double-masked, placebo controlled, single center trial in 14 normal volunteers. Subjects were randomly assigned to receive either LE (n=10) or placebo (n=4) and instructed to instill one drop into each eye 8 times daily on Days 0 and 1 and four times daily on Days 2 through 42. Blood levels of loteprednol etabonate (LE) and its major metabolite PJ-91 (delta1 cortienic acid etabonate) in plasma, and circulating plasma cortisol levels were measured during the study. Plasma levels of LE or PJ-91 were below the level of quantitation (1 ng/mL) for all subjects in both treatment groups. Plasma cortisol levels were all within the normal range. Chronic exposure to LE at a concentration and frequency equal to or greater than the intended therapeutic dose does not result in detectable systemic levels or hypothalamic pituitary axis suppression.

Ocular toxicology.

This review of recent articles on ocular toxicology concentrates on undesirable effects on the eye induced by systemically used xenobiotics. These include color vision deficiencies or visual field deterioration related to antiepileptic drugs, elevated intraocular pressure associated with inhaled corticosteroids, retinal detachments associated with systemic corticosteroids, rifabutin-induced uveitis, cocaine-related retinal hemorrhagic lesions in utero, deferoxamine-related decreases in vision, ocular allergy to bovine-derived collagen, and a large case study of hydroxychloroquine retinotoxicity. Other publications reviewed include a controlled study showing that glucose levels do not seem to alter color vision, a report that intravenous methotrexate can reach clinically meaningful levels in the aqueous humor, and a study showing the effect of systemic pentoxifylline on ocular blood flow and diabetes. With respect to systemic effects of topical ocular medications, there was a case report of apparent systemic exposure to pilocarpine from an Ocusert (Alza Corp., Palo Alto, CA), generalized urticaria after a single application of 1% cyclopentolate, and asthma induced with topical ketorolac. Readers are reminded that no drug achieves ultimate efficacy or ultimate safety. Thus, the decision to employ a given therapy involves a physician's evaluation of its therapeutic index, that is, the ratio between efficacy and toxicity.

The role of mitomycin treatment duration and previous intraocular surgery on the success of trabeculectomy surgery.

PURPOSE: This study was performed to determine the effect of duration of mitomycin exposure during trabeculectomy surgery on filtration success in eyes that had and had not been subjected to previous surgery. METHODS: On hundred six eyes of 92 patients were retrospectively reviewed. The effect of previous surgery and exposure duration of mitomycin 0.5 mg/ml on outcomes of trabeculectomy surgery were evaluated. RESULTS: The mean duration of mitomycin exposure was 0.7 +/- 0.02 min (mean +/- SEM) in the eyes that had not been subjected to previous surgery and 1.5 +/- 0.11 min in the eyes that had (p < 0.001). The mean follow-up times were 14 months in both groups. The mean decrease in intraocular pressure was 13.6 +/- 1.25 mm Hg in the group that had not been subjected to previous surgery and 13.9 +/- 1.45 mm Hg in the group that had been subjected to previous surgery. Analysis of variance techniques demonstrated no predictive value of demographics, history of previous surgery, or duration of mitomycin exposure with results of trabeculectomy surgery. Hypotony was the most frequent complication in both the no previous surgery and the previous surgery groups. The incidence of complications was numerically greater in the group that had not been subjected to previous surgery. CONCLUSIONS: The duration of mitomycin exposure and the history of previous surgery did not correlate with postoperative intraocular pressure, medications, or incidence of complications. The exposure duration response curve of mitomycin 0.5 mg/ml in these patients appears to be flat through the time evaluated. Lower concentrations of mitomycin and shorter exposure should be used to maintain efficacy with reduced risk of complications.

A placebo-controlled, double-masked evaluation of mitomycin C in combined glaucoma and cataract procedures.

PURPOSE: This study was performed to determine if adjunctive use of mitomycin C (MMC) would increase the success of combined phacoemulsification, intraocular lens implantation, and trabeculectomy surgery with releasable sutures. METHODS: Seventy-two eyes with cataract and glaucoma, requiring surgery for decreased vision, uncontrolled intraocular pressure, or to obtain a better view of the optic nerve, were randomized to receive a 2.5-minute subconjunctival exposure to either MMC (0.5 mg/ml) or placebo balanced salt solution. Postoperative evaluations at 3, 6, and 12 months were performed by a masked observer who recorded visual acuity, intraocular pressure, glaucoma medications, presence of filtering blebs, and complications. Endothelial cell counts were measured before and 3 months after surgery. RESULTS: The MMC group had significantly greater reduction in mean intraocular pressure through the first 12 months of follow-up (7.05-7.65 mmHg versus 2.62-3.84 mmHg; P = 0.001-0.028). In addition, through the first 6 months of follow-up, the MMC group required significantly fewer medications (0.4-0.5 versus 1.1-1.2; P = 0.002-0.004). Requirements for additional glaucoma surgery were less in the MMC group (4/ 36) than in the placebo group (7/35) (P = 0.301). Filtering blebs were significantly larger at 6 and 12 months (P = 0.002 and P = 0.001, respectively), and would leaks were more common (P = 0.101) in the MMC group. The mean decrease in endothelial cell count at month 3 was slightly, although not significantly, greater in the MMC treatment group (206.9 versus 91.3 cells/mm2* P = 0.377). CONCLUSION: The increased success of the glaucoma procedure in the MMC group together with relatively minor toxicity, suggests its use is beneficial in combined glaucoma-cataract surgery.