PRODUCT MONOGRAPH
Pr VEXOL®
Rimexolone 1% Ophthalmic Suspension, Alcon std
THERAPEUTIC CLASSIFICATION:
Corticosteroid
Alcon Canada Inc Date of Preparation: 2665 Meadowpine Blvd January 9, 1996 Mississauga, Ontario L5N 8C7 Date of Revision: May 2001
27772, 066995
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PRODUCT MONOGRAPH
Pr VEXOL®
Rimexolone 1% Ophthalmic Suspension, Alcon std
THERAPEUTIC CLASSIFICATION:
Corticosteroid
ACTIONS AND CLINICAL PHARMACOLOGY
Rimexolone is an anti-inflammatory corticosteroid. Corticosteroids suppress the inflammatory response to a variety of inciting agents of a mechanical, chemical, or immunological nature. They inhibit edema, cellular infiltration, capillary dilatation, fibroblastic proliferation, deposition of collagen and late cicatrization. Corticosteroids are capable of producing a rise in intraocular pressure in susceptible individuals.
Placebo-controlled clinical studies demonstrated that VEXOL (Rimexolone 1%) ophthalmic suspension is efficacious for the treatment of anterior chamber inflammation following cataract surgery.
In two controlled clinical trials, VEXOL 1% ophthalmic suspension demonstrated clinical equivalence to 1% prednisolone acetate in reducing uveitic inflammation.
In a controlled six week study of steroid responsive subjects, the time to raise intraocular pressure was similar for
VEXOL 1% ophthalmic suspension and 0.1% fluorometholone given four times daily.
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Pharmacokinetics:
As with other topically administered ophthalmic drugs, VEXOL 1% ophthalmic suspension is absorbed systemically.
Studies in normal volunteers dosed bilaterally once every hour during waking hours for one week have demonstrated
serum concentrations ranging from less than 80 pg/mL to 470 pg/mL. The mean serum concentrations were
approximately 130 pg/mL. Serum concentrations were at or near steady state after 5 to 7 hourly doses.
After decreasing the dosing frequency to once every two hours while awake during the second week of administration,
mean serum concentrations were approximately 100 pg/mL. The serum half-life of rimexolone could not be reliably
estimated due to the large number of samples below the quantitation limit of the assay (80 pg/mL). However, based on
the time required to reach steady state, the half-life appears to be short (1-2 hours).
Based upon in vivo and in vitro preclinical metabolism studies, and on in vitro results with human liver preparations, rimexolone undergoes extensive metabolism.
Following i.v. administration of radio-labelled rimexolone to rats, greater than 80% of the dose is excreted via the feces as rimexolone and metabolites. Metabolites have been shown to be less active than parent drug, or inactive in human glucocorticoid receptor binding assays.
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INDICATIONS AND USAGE
VEXOL™ (Rimexolone 1%) Ophthalmic Suspension is indicated for the treatment of postoperative inflammation
following ocular surgery, and for the treatment of anterior uveitis.
CONTRAINDICATIONS
VEXOL™ (Rimexolone 1%) Ophthalmic Suspension is contraindicated in epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, and most other viral diseases of cornea and conjunctiva; mycobacterial infection of the eye; fungal diseases of the eye; acute purulent untreated infections which, like other diseases caused by microorganisms, may be masked or enhanced by the presence of the steroid; and in those persons with hypersensitivity to any component of the formulation.
WARNINGS
Not for injection. Use in the treatment of herpes simplex infection requires great caution and frequent slit-lamp examinations. Prolonged use may result in ocular hypertension/glaucoma, damage to the optic nerve, defects in visual acuity and visual fields, and posterior subcapsular cataract formation. Prolonged use may also result in secondary ocular infections due to suppression of host response. Acute purulent infections of the eye may be masked or exacerbated by the presence of corticosteroid medication. In those diseases causing thinning of the cornea or sclera, perforation has been known to occur with topical steroids. It is advisable that the intraocular pressure be checked frequently.
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PRECAUTIONS
General: Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been or is in use.
Information for Patients: Do not touch dropper tip to any surface, as this may contaminate the suspension.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Rimexolone has been shown to be non-mutagenic in a battery of in vitro and in vivo mutagenicity assays. Fertility and reproductive capability were not impaired in a study in rats with plasma levels (42 ng/mL) approximately 200 times those obtained in clinical studies after topical administration (<0.2 ng/mL). Long-term studies have not been conducted in animals or humans to evaluate the carcinogenic potential of rimexolone.
Pregnancy: Rimexolone has been shown to be teratogenic and embryotoxic in rabbits following subcutaneous administration at the lowest dose tested (0.5 mg/kg/day, approximately 2 times the recommended human ophthalmic dose). Corticosteroids are recognized to cause fetal resorptions and malformations in animals.
There are no adequate and well-controlled studies in pregnant women. VEXOL™ (Rimexolone 1%) Ophthalmic
Suspension should be used in pregnant women only if the potential benefits to the mother justifies the potential risk to the fetus.
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Nursing Mothers: It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human breast milk. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman; a decision should be made whether to discontinue nursing or discontinue therapy, taking into consideration the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness in children have not been established.
Drug Interactions: No drug interactions or incompatibilities were identified during the clinical development program.
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ADVERSE REACTIONS
Reactions associated with ophthalmic steroids include elevated intraocular pressure which may be associated with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera.
Ocular adverse reactions occurring in 1 - 5% of patients in clinical studies of VEXOL 1% Ophthalmic Suspension included blurred vision (2.9%), discharge (2.4%), discomfort (1.8%), ocular pain (1.4%), increased intraocular pressure (1.1%), and foreign body sensation (1.1%). Other ocular related adverse reactions occurring in less than 1% of patients included hyperemia, ocular pruritus, sticky sensation, increased fibrin, dry eye, conjunctival edema, corneal staining, keratitis, tearing, photophobia, edema, irritation, corneal ulcer, browache, lid margin crusting, corneal edema, infiltrate, and corneal erosion.
Non-ocular adverse reactions were rare and occurred in less than 2% of patients. These included headache, hypotension, rhinitis, pharyngitis, and taste perversion.
SYMPTOMS AND TREATMENT OF OVERDOSE
Discontinue medication when heavy or protracted use is suspected. A topical overdosage may be flushed from the eye(s) with warm tap water.
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DOSAGE AND ADMINISTRATION
Post-operative Inflammation: Apply one - two drops of VEXOL™ (Rimexolone 1%) Ophthalmic Suspension into the conjunctival sac of the affected eye four times daily beginning 24 hours after surgery and continuing throughout the first
2 weeks of the postoperative period.
Uveitis: Apply one - two drops of VEXOL™ 1% Ophthalmic Suspension into the conjunctival sac of the affected eye every hour during waking hours for the first week, one drop every two hours during waking hours of the second week, four times per day during the third week, then three times per day during the first four days of week four and then twice per day during the last three days of week four.
Information for Patients: Shake Well Before Using. Do not touch dropper tip to any surface, as this may contaminate the suspension.
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PHARMACEUTICAL INFORMATION
Drug Substance:
Proper Name: Rimexolone
Chemical Name: 11 -Hydroxy-16 , 17 -dimethyl-17-propionylandrosta-1,4-diene-3-one.
Structural Formula: O
CCH2CH3 CH3 HO CH3 CH3 CH3 H
HH
O rimexolone
Molecular Formula: C24H34O3 Molecular Weight: 370.53
Description: White powder.
Solubility: Soluble in chloroform. Slightly soluble in methanol, acetonitrile, 1-octanol, toluene.
Insoluble in water.
Melting Point: approximately 270C
Composition: VEXOL™ 1% Ophthalmic Suspension is a sterile, multi-dose topical ophthalmic suspension containing the anti-inflammatory corticosteroid, Rimexolone 1%. Preservative: benzalkonium chloride 0.01%. Nonmedicinal ingredients: sodium chloride, carbomer 974P, polysorbate 80, edetate disodium, sodium hydroxide and/or hydrochloric acid (to adjust pH) and purified water.
Stability and Storage Recommendations: Store upright between 2 and 30C.
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AVAILABILITY OF DOSAGE FORMS
Pr VEXOL™ (Rimexolone 1%) Ophthalmic Suspension is available in plastic DROP-TAINER® dispensers containing
5 mL, and 10 mL.
PHARMACOLOGY
Corticosteroids suppress the inflammatory response to a variety of inciting agents of a mechanical, chemical, or immunological nature. They inhibit edema, cellular infiltration, capillary dilatation, fibroblastic proliferation, deposition of collagen and late cicatrization.
Placebo controlled clinical studies demonstrated that VEXOL™ 1% Ophthalmic Suspension is efficacious for the treatment of anterior chamber inflammation following cataract surgery.
In two controlled clinical trials, VEXOL™ 1% Ophthalmic Suspension demonstrated clinical and statistical equivalence to 1% prednisolone acetate in controlling uveitic inflammation.
In a controlled 6 week study of steroid responsive subjects, the time to raise intraocular pressure was similar for VEXOL
1% Ophthalmic Suspension and to 0.1% fluorometholone given four times daily.
As with other topically administered ophthalmic drugs, VEXOL™ 1% Ophthalmic Suspension is absorbed systemically.
Studies in normal volunteers dosed bilaterally once every hour during waking hours for one week have demonstrated maximal serum concentrations ranging from less than 80 pg/mL to 470 pg/mL. The mean maximal serum concentrations were approximately 130 pg/mL. Serum concentrations were at or near steady state after 5 to 7 hourly doses. After decreasing the dosing frequency to once every two hours while awake during the second week of administration, mean serum concentrations were approximately 100 pg/mL. The serum half-life of rimexolone could not
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be reliably estimated due to the large number of samples below the quantitation limit of the assay (80 pg/mL).
However, based on the time required to reach steady-state, the half-life appears to be short (1 - 2 hours).
Based upon in vivo and in vitro preclinical metabolism studies, and on in vitro results with human liver preparations, rimexolone undergoes extensive metabolism. Following i.v. administration of radio-labelled rimexolone to rats, greater than 80% of the dose is excreted via the feces as rimexolone and metabolites. Metabolites have been shown to be less active than parent drug, or inactive in human glucocorticoid receptor binding assays.
TOXICOLOGY
Rimexolone possesses a low order of acute oral and subcutaneous toxicity in animal tests, and does not present a significant acute toxicity hazard in humans when considered on a unit package basis.
Topical ocular administration studies in rabbits with ophthalmic suspensions of Rimexolone at concentrations up to
3.0%, four times a day, elicited no significant ocular effects noted in a one-month study. Systemic effects were consistent with those expected with an anti-inflammatory steroid and were of lesser incidence and severity than those seen with the concurrent 0.1% dexamethasone phosphate comparative controls.
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Systemic toxicity seen in subchronic studies with rats, dogs and rabbits showed effects consistent with high doses of corticosteroids, such as lymphocytic effects in peripheral blood, lymph nodes, thymus and spleen, effects on lipid metabolism reflected in increased serum cholesterol, triglycerides and total lipid, effects on carbohydrate metabolism such as hepatocellular glycogen deposition, and effects on the adrenal-pituitary axis seen in decreased adrenal weights and adrenal cortical atrophy. These effects appear to be less frequent and severe than with dexamethasone.
Mutagenesis: Rimexolone has been shown to be non-mutagenic in a battery of in vitro and in vivo mutagenicity assays.
Carcinogenesis: Long-term studies have not been conducted in animals or humans to evaluate the carcinogenic potential of rimexolone.
Fertility: Fertility and reproductive capability was not impaired in a study in rats with plasma levels (42 ng/mL) approximately 200 times those obtained in clinical studies after topical administration (<0.2 ng/mL).
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BIBLIOGRAPHY
1. Fox PK, Lewis AJ, Rae RM, Sim AW, Woods GF. The biological properties of Org 6216, a new type of steroid with a selective local anti-inflammatory action. Arzneim-Forsch/Drug Res 30:55-59 (1980).
2. Hochhaus H, Moellmann HW. Binding affinities of rimexolone (ORG 6216), flunisolide and their putative metabolites for the glucocorticoid receptor of human synovial tissue. Agents Actions 30: 377-380 (1990).
3. Joosten LAB, Helsen MMA, van den Berg WB. Protective effect of rimexolone on cartilage damage in arthritic mice: A comparative study with triamcinolone hexacetonide. Agents Actions 31: 135-142 (1990).
4. Lewis AJ. The local anti-inflammatory activity of rimexolone (Org 6216) in fibrin-induced monoarticular arthritis and adjuvant-induced arthritis. Agents Actions 10:258-265 (1980).
5. Lewis AJ, Fox PK. ORG 6216: A novel type of anti-inflammatory steroid. J Pharm Pharmacol 28: 82P (1976).
6. Nieuwenhuyse H, Lewis AJ. The persistence and effects of rimexolone in arthritis and normal rabbit knee joints. Arzneim-Forsch/Drug Res 30:1646-1649 (1980).
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