Sofracort Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES .......................................................................................... 2

TABLE OF CONTENTS ............................................................................................................ 2

PART I: HEALTH PROFESSIONAL INFORMATION .................................................................... 4

1 INDICATIONS ............................................................................................................. 4

1.1 Pediatrics .................................................................................................................. 4

1.2 Geriatrics .................................................................................................................. 4

2 CONTRAINDICATIONS ................................................................................................ 4

4 DOSAGE AND ADMINISTRATION ................................................................................ 5

4.2 Recommended Dose and Dosage Adjustment ........................................................ 5

4.5 Missed Dose ............................................................................................................. 5

5 OVERDOSAGE ............................................................................................................ 5

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................ 5

7 WARNINGS AND PRECAUTIONS ................................................................................. 5

7.1 Special Populations .................................................................................................. 7

7.1.1 Pregnant Women ............................................................................................... 7

7.1.2 Breast-feeding .................................................................................................... 7

7.1.3 Pediatrics ............................................................................................................ 7

8 ADVERSE REACTIONS................................................................................................. 8

8.2 Clinical Trial Adverse Reactions ............................................................................... 8

8.5 Post-Market Adverse Reactions ............................................................................... 8

9 DRUG INTERACTIONS ................................................................................................ 8

9.4 Drug-Drug Interactions ............................................................................................ 8

9.5 Drug-Food Interactions ............................................................................................ 9

9.6 Drug-Herb Interactions ............................................................................................ 9

9.7 Drug-Laboratory Test Interactions........................................................................... 9

10 CLINICAL PHARMACOLOGY ........................................................................................ 9

11 STORAGE, STABILITY AND DISPOSAL .......................................................................... 9

12 SPECIAL HANDLING INSTRUCTIONS ............................................................................ 9

PART II: SCIENTIFIC INFORMATION ..................................................................................... 10

13 PHARMACEUTICAL INFORMATION .......................................................................... 10

14 CLINICAL TRIALS ...................................................................................................... 13

15 MICROBIOLOGY ...................................................................................................... 13

16 NON-CLINICAL TOXICOLOGY .................................................................................... 13

PATIENT MEDICATION INFORMATION ................................................................................ 14

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

SOFRACORT (framycetin sulfate, dexamethasone and gramicidin ophthalmic/otic solution) is indicated for:

• Eye: Blepharitis and infected eczema of the eyelid; allergic, infective and rosacea conjunctivitis; rosacea keratitis; scleritis and episcleritis; iridocyclitis, and other inflammatory conditions of the anterior segment of the eye.
• Ear: Otitis externa (acute and chronic) and other inflammatory and seborrheic conditions of the external ear.

SOFRACORT contains antibacterial ingredients, framycetin and gramicidin. To reduce the development of drug-resistant bacteria and maintain the effectiveness of framycetin and gramicidin, SOFRACORT should only be used for the authorized indication.

1.1 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use (see 7.1.3 Pediatrics).

1.2 Geriatrics

Geriatrics: No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use.

2 CONTRAINDICATIONS

SOFRACORT is contraindicated in patients with:

• Known hypersensitivity to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

Eye:

• Herpes simplex and other viral diseases of the cornea and conjunctiva; tuberculosis and fungal diseases of the eye; trachoma.
• Acute purulent, untreated infections of the eye, which, like other diseases caused by micro-organisms, may be masked or enhanced by the presence of the steroid.
• Glaucoma.

Ear:

• Viral and fungal infections.
• Acute purulent, untreated infections.
• Perforation of the eardrum because of the risk of ototoxicity.

4 DOSAGE AND ADMINISTRATION

4.2 Recommended Dose and Dosage Adjustment

Eye: In acute conditions, 1 or 2 drops every 1 to 2 hours may be instilled (generally for 2 or 3 days). Subsequently, 1 or 2 drops 3 or 4 times daily. To avoid possibility of reinfection later, do not touch eye with dropper.

Ear: Instill 2 or 3 drops in the ear canal 3 or 4 times daily by tilting head to one side. Squeeze the dropper carefully. To avoid possibility of reinfection later, do not touch ear with dropper. Alternatively, a saturated gauze wick may be inserted by the physician into the external auditory meatus.

Pediatrics (< 18 years of age):

Health Canada has not authorized an indication for pediatric use (see 1.1 Pediatrics).

4.5 Missed Dose

If a dose is missed, it should be administered as soon as possible, and the regular dosage schedule should be resumed. If it is almost time for the next dose, the missed dose should be skipped, and the regular dosing schedule should be resumed. A double dose should not be administered.

5 OVERDOSAGE

Long-term intensive topical use may lead to systemic effects.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Each milliliter of solution contains: 5 mg framycetin sulfate, 0.5 mg dexamethasone (as dexamethasone sodium metasulfobenzoate), and 0.05 mg gramicidin.

SOFRACORT is available in an amber glass bottle with rubber dropper bulb, containing 8 mL of solution.

7 WARNINGS AND PRECAUTIONS

Driving and Operating Machinery

SOFRACORT may cause transient blurring of vision on instillation. If blurred vision occurs after SOFRACORT administration, the patient must wait until vision clears before driving or operating machinery.

Ear/Nose/Throat

Aminoglycoside antibiotics may cause irreversible, partial or total deafness when applied topically to open wounds or damaged skin. This effect is aggravated by renal or hepatic impairment and by prolonged duration of treatment. The treatment should not be continued after resolution of symptoms.

There have been reported cases of an increased risk of ototoxicity with aminoglycosides administered to patients with mitochondrial mutations, particularly the nucleotide 1555 A to G substitution in the 12S rRNA gene, including cases where the patient's aminoglycoside serum levels were within the recommended range. Some cases were associated with a maternal history of deafness and/or mitochondrial mutation. Mitochondrial mutations are rare, and the penetrance of this observed effect is unknown.

Based on a shared mechanism of action with other aminoglycosides, the risk of ototoxicity with framycetin and other topical aminoglycosides cannot be ruled out.

Endocrine and Metabolism

During therapy with SOFRACORT, a possibly increased need for insulin or antidiabetics should be considered in patients with diabetes (see 8.5 Post-Market Adverse Reactions).

Immune

Discontinue SOFRACORT if there are signs of sensitivity to any of its ingredients. Patients are advised to inform the physicians of the prior use of corticosteroids (see 2 CONTRAINDICATIONS and 8.5 Post-Market Adverse Reactions).

In patients known to be allergic to other aminoglycoside antibiotics (neomycin, kanamycin), cross-sensitization to framycetin may occur, but not invariably so.

Neurologic

Pheochromocytoma crisis, which can be fatal, has been reported after administration of corticosteroids. Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation.

Ophthalmologic

Visual disturbance may be associated with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR). Treatment with corticosteroid preparations should not be repeated or prolonged without regular review to exclude raised intraocular pressure, cataract formation or unsuspected infections. In conditions causing thinning of the cornea, topical steroids may cause perforation. Cataract has occurred after prolonged treatment with topical steroids (see 8.5 Post-Market Adverse Reactions).

Topical corticosteroids should never be given for an undiagnosed red eye as inappropriate use is potentially blinding.

Sensitivity/Resistance

Treatment with corticosteroid/antibiotic combinations should not be continued in the absence of clinical improvement, since prolonged use may lead to occult extension of infections due to the masking effect of the steroid. Prolonged use may also lead to skin sensitization and the emergence of resistant organisms.

Development of Drug Resistant Bacteria:

Prescribing SOFRACORT in the absence of the authorized indications is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.

Potential for Microbial Overgrowth:

The use of SOFRACORT may promote the selection of non-susceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.

7.1 Special Populations

7.1.1 Pregnant Women

There are no available data on SOFRACORT use in pregnant women. The safety of prolonged use of topical steroids during pregnancy has not been substantiated. No conclusions can be drawn regarding whether or not SOFRACORT is safe for use during pregnancy. SOFRACORT should be used during pregnancy only if the potential benefits to the mother outweigh the potential risks, including those to the fetus.

7.1.2 Breast-feeding

There are no available data on the presence of SOFRACORT in human milk, milk production, or the effects on the breast-fed infant. No conclusions can be drawn regarding whether or not SOFRACORT is safe for use during breast-feeding. SOFRACORT should be used during breast-feeding only if the potential benefits to the mother outweigh the potential risks, including those to the breast-fed child.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use (see 1.1 Pediatrics).

There is a risk of adrenal suppression, even without occlusive dressings, after prolonged treatment of infants with topical steroids.

8 ADVERSE REACTIONS

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Eye disorders

Increased intra-ocular pressure; perforation of the cornea; hypersensitivity; burning or stinging of the eye.

8.5 Post-Market Adverse Reactions

Endocrine disorders

Iatrogenic Cushing’s syndrome; adrenal atrophy.

Eye disorders

Blurred vision; chorioretinopathy; increased intra-ocular pressure leading to optic nerve damage, reduced visual acuity and visual field defects; glaucoma; cataracts.

Immune disorders

Hypersensitivity reactions, usually of the delayed type, may occur, leading to irritation, burning, stinging, itching and dermatitis.

Metabolism and nutrition disorders

Diabetes mellitus; decreased glucose tolerance.

9 DRUG INTERACTIONS

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 2 - Established or Potential Drug-Drug Interactions

Legend: T = Theoretical

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

This information is not available for this drug product.

11 STORAGE, STABILITY AND DISPOSAL

Store between 15-25 °C. Do not refrigerate.

Use within four weeks of opening.

12 SPECIAL HANDLING INSTRUCTIONS

This information is not available for this drug product.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Framycetin sulfate or Neomycin B sulfate

Chemical name: Sulfate of 2-deoxy-4-O-(2,6-diamino-2,6-dideoxy-α-D-glucopyranosyl)-5-O-[3-O-(2,6-diamino- 2,6-dideoxy-β-L-idopyranosyl)-β-D-ribofuranosyl]-D-streptamine

Molecular formula: C₂₃H₄₆N₆O₁₃, 3H₂SO₄

Molecular mass: Mr 908.9 (Framycetin sulfate); Mr 614.6 (Framycetin)

Structural formula:

Physicochemical properties: Hygroscopic, white to slightly yellowish powder, not granular to the touch. Framycetin sulfate is highly soluble in water, very slightly soluble in alcohol and practically insoluble in acetone, chloroform and ether. Not more than 80 mcg can be dissolved in 1 mL of cyclohexane.

Drug Substance

Proper name: Dexamethasone sodium metasulfobenzoate or Dexamethasone 21 (sodium metasulfobenzoate)

Chemical name: (11β,16α 9-Fluoro-11, 17-dihydroxy-16-methyl-21-[(3- sulfobenzoyl)oxy]-pregna-1, 4-diene-3, 20-dione Monosodium salt

(9α-Fluoro-11 β, 17 α -dihydroxy-16 α -methyl-3, 20-

dioxopregna-1, 4-dien-21-yl), m-sulfobenzoate, sodium salt

Molecular formula: C₂₉H₃₂FNaO₉S

Molecular mass: Mr = 598.6 (Dexamethasone sodium metasulfobenzoate);

Mr = 392.5 (Dexamethasone)

Structural formula:

Physicochemical properties: White to practically white microcrystalline powder. The polymorphism analyses show the crystalline form I. In addition to an amorphous form, 10 crystalline forms (solvate, hydrate and anhydrous forms) were identified during the polymorph screening. The water content, the TGA and DSC results show that form I is a monohydrate form.

Drug Substance

Proper name: Gramicidin

Chemical name: Gramicidin A1 (Val-Gram A)

Gramicidin A2 (Ile-Gram A)

Gramicidin B1 (Val-Gram B)

Gramicidin C1 (Val-Gram C)

Gramicidin C2 (Ile-Gram C)

Molecular formula: Gramicidin A1: C₉₉H₁₄₀N₂₀O₁₇

Gramicidin A2: C₁₀₀H₁₄₂N₂₀O₁₇

Gramicidin B1: C₉₇H₁₃₉N₁₉O₁₇

Gramicidin C1: C₉₇H₁₃₉N₁₉O₁₈

Gramicidin C2: C₉₈H₁₄₁N₁₉O₁₈

Molecular mass: Gramicidin A1: 1882 g/mol

Gramicidin A2: 1896 g/mol

Gramicidin B1: 1843 g/mol

Gramicidin C1: 1859 g/mol

Gramicidin C2: 1873 g/mol

Structural formula:

The gramicidins constitute a family of end-substituted linear pentadecapeptides where the N-terminal amino group is formylated and the C-terminal carboxylic group is amidated with ethanolamine. Change of the two amino acids elements (first and eleventh) of the polypeptide chain gives the components of the gramicidin family: A1, A2, B1, C1 and C2.

The general structure of the gramicidins is:

The peptide bond is indicated by →.

The amino acid at X and that at Y for each component of the gramicidin family is indicated in the table below:

Physicochemical properties: Gramicidin is a white or almost white, crystalline powder. It is slightly hygroscopic. It is very stable both in the dry form and in solution, also at elevated temperatures. Gramicidin is practically insoluble in water, sparingly soluble in alcohol, and soluble in methanol.

14 CLINICAL TRIALS

This information is not available for this drug product.

15 MICROBIOLOGY

This information is not available for this drug product.

16 NON-CLINICAL TOXICOLOGY

This information is not available for this drug product.