Euro-Chlorhexidine Product Monograph

SUMMARY PRODUCT INFORMATION

For a complete listing, see Dosage Forms, Composition and Packaging section of the product monograph.

INDICATIONS AND CLINICAL USE

^PrEuro-Chlorhexidine (Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard) is indicated for use as part of a professional program for the treatment of moderate to severe gingivitis, and for management of associated gingival bleeding and inflammation according to the recommended dosage and frequency under supervision of a dentist.

For patients having coexisting gingivitis and periodontitis, see WARNINGS AND PRECAUTIONS.

Pediatrics (< 18 years of age):

No clinical data are available regarding the use of ^PrEuro-Chlorhexidine in children and adolescents younger than 18 years of age (see WARNINGS AND PRECAUTIONS).

Geriatrics (≥ 65 years of age):

Clinical studies of ^PrEuro-Chlorhexidine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. In general, caution should be exercised when administering ^PrEuro-Chlorhexidine in elderly patients, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy (see WARNINGS AND PRECAUTIONS).

CONTRAINDICATIONS

^PrEuro-Chlorhexidine (Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard) should not be used by the persons who are known to be hypersensitive to Chlorhexidine Gluconate, Chlorhexidine compounds or other ingredients.

WARNINGS AND PRECAUTIONS

General

• Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard can cause staining to tooth surfaces, restorations, and the dorsum of the tongue in some patients especially with prolonged use and in patients who have heavier accumulations of plaque. Staining does not affect the health or oral tissues, and can be removed from most tooth surfaces by professional dental prophylaxis. Discretion should be used in prescribing Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard for patients who have exposed root surfaces or anterior facial restorations with rough surfaces or margins, as stains on this area may be difficult to remove and may require restoration replacement in rare instances. If natural stains cannot be removed from these surfaces by a dental prophylaxis, patients should be excluded from treatment if the risk of permanent discolouration is unacceptable.
• Use of a Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard may cause an alteration in taste perception in some patients.

• Parotitis and inflammation of the salivary glands have been reported in some patients using

  Chlorhexidine Gluconate oral rinses (see ADVERSE REACTIONS).

• There is potential for sensitization to the active ingredient Chlorhexidine gluconate.
• For patients having coexisting gingivitis and periodontitis, the absence of gingival inflammation following treatment with ^PrEuro-Chlorhexidine (Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard) may not be indicative of the absence of underlying periodontitis. Appropriate treatment of periodontitis is therefore indicated.
• For maximum effectiveness the patient should avoid rinsing their mouth, eating or drinking for about thirty minutes after using ^PrEuro-Chlorhexidine (Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard).
• If the patient develops allergic symptoms such as skin rash, itch, generalized swelling, breathing difficulties, light headedness, rapid heart rate, upset stomach or diarrhea, they should seek medical attention immediately. ^PrEuro-Chlorhexidine should not be used by persons who have a sensitivity to it or its components.

Special Populations

Pregnant Women: Use in Pregnancy:

No clinical studies with ^PrEuro-Chlorhexidine in pregnant women have been conducted, so the benefits of using ^PrEuro-Chlorhexidine should be weighed against the possible harm to the fetus.

Reproduction and fertility studies with Chlorhexidine gluconate have been conducted. No evidence of impaired fertility was observed in male and female rats at doses up to 100 mg/kg/day. No evidence of

harm to the fetus was observed in rats and rabbits at doses up to 300mg/kg/day and 40 mg/kg/day, respectively. These doses are approximately 100, 300 and 40 times that which would result from a person ingesting 30 ml (2 capfuls) of Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard per day.

Nursing Women:

It is not known whether Chlorhexidine gluconate is excreted in human milk. Cautions should be exercised and the benefits of use weighed against possible risk to the infant being nursed.

In parturition and lactation studies in white rats, no evidence of impaired parturition of toxic effects to suckling pups was observed when Chlorhexidine gluconate was administered at doses over 100 times greater than the recommended daily dose for rinsing.

Pediatrics (< 18 years of age):

The safety and efficacy of ^PrEuro-Chlorhexidine in children and adolescents younger than 18 years of age have not been established.

Geriatrics (≥ 65 years of age):

Clinical studies of ^PrEuro-Chlorhexidine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most common side effects occurring from the use of 0.12% Chlorhexidine Gluconate Oral Rinses are staining of teeth and other oral surfaces, a slight and temporary alteration in taste perception and an increase in supra gingival calculus formation (see WARNINGS AND PRECAUTIONS). Oral irritation and local allergy-type symptoms have been spontaneously reported as side effects associated with the use of chlorhexidine gluconate rinse. The following oral mucosal side effects were reported during placebo-controlled adult clinical trials: aphthous ulcer, grossly obvious gingivitis, trauma, ulceration, erythema, desquamation, coated tongue, keratinisation, geographic tongue, mucocele, and short frenum.

Among post marketing reports, the most frequently reported mucosal symptoms associated with Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard are stomatitis, gingivitis, glossitis, ulcer, dry mouth, hypesthesia, glossal edema, and paresthesia. Minor irritation and superficial desquamation of the oral mucosa have been seen. Parotitis and inflammation of the salivary glands have been reported in some patients using Chlorhexidine gluconate oral rinses.

DRUG INTERACTIONS

Drug-Drug Interactions

Interactions with other drugs have not been established.

DOSAGE AND ADMINISTRATION

Recommended Dosage

Rinse with 15 mL of solution for 30 (thirty) seconds, then expectorate. Use twice daily after breakfast and before bedtime or as prescribed. ^PrEuro-Chlorhexidine is not intended for ingestion and should be

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expectorated after rinsing.

Use of ^PrEuro-Chlorhexidine (Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard) should begin immediately following professional dental prophylaxis. Patients should be re-examined at intervals of not more than six months and given a thorough prophylaxis. Patient referral for periodontal consultation should be done as necessary.

DO NOT SWALLOW.

Note: Wait thirty minutes after brushing with conventional toothpastes before using ^PrEuro-Chlorhexidine. Do not rinse the mouth, eat or drink for thirty minutes after using ^PrEuro-Chlorhexidine.

The suggested initial therapy is three months, at which time patients should be recalled for evaluation. At the time of the recall visit, the dental professional should:

• Evaluate progress, remove any stain, and reinforce proper home care techniques.
• Discontinue use of ^PrEuro-Chlorhexidine if gingival inflammation and bleeding is controlled.
• Recall the patient in three months to assess gingival health.
• Continue use of ^PrEuro-Chlorhexidine for an additional three months if gingival inflammation and bleeding persists. Schedule a three-month recall for evaluation.
• Evaluate for evidence of epithelial irritation, desquamation and parotitis.

The following generally accepted grading scheme may be of use in evaluation the severity of gingivitis.

Loe and Silness GINGIVAL INDEX (GI)

Missed Dose: If a dose of ^PrEuro-Chlorhexidine is missed, take the next dose of ^PrEuro-Chlorhexidine as scheduled. Do not double the next dose.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Ingestion of 30 to 60 ml of ^PrEuro-Chlorhexidine (Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard) by a small child may result in gastric distress including nausea and/or signs of alcohol intoxication. Medical attention should be sought if more than 100 mL is ingested, or if signs of alcohol intoxication develop.

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ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

^PrEuro-Chlorhexidine (Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard) provides antimicrobial activity during oral rinsing which is maintained between rinsing. The mechanism of action is time-dependent and requires a 2 step process. Firstly, the strong cationic CHG molecules attach to the anionic tooth surface and is released over the next 4-12 hours. Next, the cationic molecule attaches to the anionic surface of the bacterial cell. Prolonged contact with the bacteria eventually weakens the cell wall and disrupts its contents. Chlorhexidine is a rapidly acting agent with broad spectrum of activity. Rinsing with Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard inhibits the build-up and maturation of plaque by reducing certain microbes regarded as gingival pathogens, thereby reducing gingivitis. Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard provides antimicrobial activity during rinsing and for several hours thereafter. Microbiologic sampling of plaque has shown a general reduction of both aerobic and anaerobic bacterial counts through six months clinical use of Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard. No significant changes in bacterial sensitivity, overgrowth of potentially opportunistic organisms or other adverse changes in the oral microbial flora were observed following the use of Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard for six months. Three months after discontinued use, the number of bacteria in plaque had returned to pre-treatment levels and sensitivity or plaque bacteria to Chlorhexidine gluconate remained unchanged.

Pharmacodynamics

One short term study and a three month clinical study examining concentration response relationships showed equal efficacy, as measured by plaque reduction, for 0.10 and 0.20% Chlorhexidine Gluconate solutions while a 0.05% solution was less effective. Studies also demonstrated that tooth and tongue discoloration increased with Chlorhexidine gluconate concentration. Also, shorter more frequent rinsing provided higher efficacy as compared to longer less frequent rinsing. A 0.12% Chlorhexidine Gluconate solution was chosen to optimize efficacy while minimizing side effects.

Pharmacokinetics

Oral Retention/De-sorption

Approximately 30% of the Chlorhexidine present in the mouth rinse is retained in the oral cavity after rinsing. The amount retained is directly related to drug concentration (with 6.3 mg of Chlorhexidine being retained orally after a single use of a mouth rinse containing 0.12% Chlorhexidine Gluconate). The rate of release of Chlorhexidine from oral surface is similar for 0.12% and 0.06% Chlorhexidine Gluconate rinses. Based on morning/evening rinses, previous exposure to a Chlorhexidine containing mouth rinse was observed to have little effect on subsequent retention of Chlorhexidine.

Absorption:

Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard is a topical, oral rinse and should not be ingested. In the event of ingestion, studies conducted with human subjects and animals demonstrate that any ingested Chlorhexidine gluconate is poorly absorbed in the gastrointestinal tract.

Distribution:

Approximately 30% of the Chlorhexidine present in the mouth rinse is retained in the oral cavity after rinsing. The amount retained is directly related to drug concentration (with 6.3 mg of Chlorhexidine being

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retained orally after a single use of a mouth rinse containing Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard) .

Excretion:

Excretion of Chlorhexidine Gluconate occurred primarily through the feces (approximately 90%) in 31 to 53 hours. Less than 1% of the Chlorhexidine Gluconate ingested by these subjects was excreted in the urine.

STORAGE AND STABILITY

^PrEuro-Chlorhexidine (Chlorhexidine Gluconate Oral Rinse 0.12% w/v, House Standard) must be stored between 15º and 25ºC. Keep out of reach of children. Protect ^PrEuro-Chlorhexidine from freezing.

SPECIAL HANDLING INSTRUCTIONS

No special handling instructions are available for ^PrEuro-Chlorhexidine.

DOSAGE FORMS, COMPOSITION AND PACKAGING

^PrEuro-Chlorhexidine (Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard) is a near to neutral (pH range: 5 to 7), green coloured, spearmint flavoured liquid.

It contains the following non-medicinal ingredients : 0.12% Chlorhexidine Gluconate in a base consisting of purified water, 10% ethanol, sorbitol solution, glycerin, flavor, polysorbate 60, methyl and propyl parabens, sodium cyclamate, FD&C Blue 1 and FD&C Yellow 5.

^PrEuro-Chlorhexidine is available in 500 mL and 4 L white HDPE containers.

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PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Chlorhexidine Gluconate

Chemical name: 1,1-hexamethylene bis [5-4-chlorphenyle biguanide] digluconate

Molecular formula: C₃₄H₅₄Cl₂N₁₀O₁₄,

Molecular mass: 897.75716 g/mol

Structural formula:

Physiochemical Properties

Description:

Chlorhexidine Gluconate is available as Chlorhexidine Gluconate solution. It is an almost colourless to pale straw-coloured, clear or slightly opalescent liquid, that is odourless or almost odourless. It is miscible with water, with not more than five parts of ethanol (96%) and with not more than three parts of acetone. The pH of a 5% v/v solution is 5.0 to 7.0.

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CLINICAL TRIALS

Human clinical trials:

A number of clinical studies have provided support for the effectiveness of 0.12% Chlorhexidine Gluconate mouth rinses in reducing plaque build-up and rate of occurrence and harshness of gingivitis as well as reducing the number of bleeding sites.

*Results shown are those obtained for the final examination at completion of test product use. The data are expressed a covariance adjusted percent reduction verses placebo; a range is reported when there were duplicate examiners. All reductions were significantly different from placebo (p>0.05; nonparametric Wilcoxon pair test).

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MICROBIOLOGY

In Vitro:

A non-specific mechanism of action of Chlorhexidine Gluconate gives it a wide range of antimicrobial activity against Gram-positive and Gram-negative bacteria. An in-Vitro study of the microbiocidal effect Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard following a thirty-second exposure resulted in a 99.9% reduction in the following micro-organisms: Actinomyces viscosus, Candida albicans, Staphylococcus aureus, mutant Staphylococcus strains, Streptococcus sanguis, Fusobacterium nucleatum, Neisseria sicca, Pseudomonas aeruginosa, Veillonella parvula.

In Vivo:

To determine the efficacy of 0.12% w/v Chlorhexidine gluconate in vivo, various bacteria in the microbial flora of plaque were assayed in subjects who had used either 0.12% w/v Chlorhexidine gluconate or a placebo. During six months’ 0.12% w/v Chlorhexidine gluconate use, subjects showed reductions in total load/tooth, Streptococci and Actinomyces ranging from 54% to 97%. Neisseria and fusobacterial were not detected in over half of the subjects assayed. No changes in numbers of yeast-like organisms and Gram-negative enterics were observed. There were no adverse changes in the oral microbial flora. Three months following cessation of treatment, the reductions observed during mouth rinsing were no longer evident, indicating no “carryover” effect. The results were interpreted as indication that the use of Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard was associated only with a decrease in the number of microbes in plaque and no change in bacterial sensitivity. Another study was conducted to investigate whether changes occurred in resistance to Chlorhexidine which might limit efficacy of the mouth rinse, and if such changes occurred, whether they dissipated or disappeared after cessation of use of the mouth rinse. Minimum Inhibitory Concentrations (MIC’s) for Chlorhexidine were determined on isolates of streptococci and Actinomyces obtained from patients during six months use of the mouth rinse and three months after cessation of use of the mouth rinse. Changes in bacterial sensitivity due to exposure to chlorhexidine were slight, sporadic and had returned to pre-treatment values three months after product usage was discontinued. These results support that Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard usage does not result in significant changes in plaque bacterial resistance and does not cause significant changes in the plaque flora.

TOXICOLOGY

Acute Toxicity Studies:

^PrEuro-Chlorhexidine is not classified as an acute oral toxic substance under GHS 2013 regulations.

Chronic and Sub-chronic Toxicity Studies

The only consistently observed finding in subchronic and chronic toxicity studies was the accumulation of foamy macrophages in the mesenteric lymph nodes of rats. Based on the following facts:

1. 1) the macrophages did not contain bacteria, indicating that a significant change in the intestinal flora has not occurred
2. 2) the reaction is not associated with increased morbidity or mortality
3. 3)

   the reaction does not become progressively more severe with continued exposure to

   Chlorhexidine and

4. 4)

   the reaction is reversible after administration of Chlorhexidine is discontinued, it was concluded that the lesions did not represent a significant toxic effect.

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Reproduction and Teratology:

No adverse reproductive or teratologic effects on rats or rabbits were observed in studies with 0.12% Chlorhexidine Gluconate mouth rinse.

The effect of Chlorhexidine Gluconate on various aspects of reproductive processes has been evaluated using both the rat and rabbit as a model. An apparent embryotoxic effect was observed in rabbits that received a daily 40 mg/kg dose of Chlorhexidine by average and in rats that ingested a 300 mg/kg dose of Chlorhexidine from their diet each day. These doses are about 140 and 1,040 times, respectively, the estimated daily ingestion from Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard with their recommended dose.

Carcinogenicity:

No evidence of carcinogenicity was observed in studies in rats in which Chlorhexidine was administered at levels up to 200 mg/kg/day for two years.

Mutagenicity:

No evidence of mutagenicity was observed when Chlorhexidine Gluconate was evaluated by the dominate lethal assay in mice and micronucleus assay in hamsters. Mutagenicity studies, using bacterial cell system, with or without metabolic activation, produced contradictory results, which are unexpected with drugs having antibacterial activity. While Suessmuth et al. (1979) and Ackerman-Schmidt et al. (1982) obtained positive results, Evans et al. (1978) and Sakagami et al. (1988) found no evidence of genotoxicity for chlorhexidine. The clinical significance of these results is unclear.

Immediate Hypersensitivity:

A variety or regimens were used in an attempt to induct and elicit immediate hypersensitivity to Chlorhexidine Gluconate in guineas pigs, rabbits, rats and man. No evidence of immediate hypersensitivity was observed in any of the tests.

Other Studies:

The emetic dose, irritation potential and sensitization potential have also been determined Chlorhexidine Gluconate Oral Rinse, 0.12% w/v House Standard. The rinse has emetic ED₅₀ of approximately 13.4 ml/kg (tested in dogs using the oral route of administration), is only slightly irritating to the eye (tested in rabbits, and was not irritating to oral mucosa (tested in dogs). In addition, the mouth rinse does not induce delayed contact sensitization.

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REFERENCES

1. 1.

   ORO-CLENSE, DIN 02209055, control number 27154, product monograph (Germiphene Corp.),

   Drug Product Database, Health Canada web site (January 23^rd, 2017)

2. 2.

   Grossman, E.; Reiter, G.; Sturzenberger, O.P.; De la Rosa, M.; Dickinson, T.D.; Ferretti, G.A.;

   Ludlam, G.E.; Meckel, A.H.: Six-month study of the effects of a chlorhexidine mouth rinse on gingivitis in adults. J Periodont Res 1986; 21 (Suppl.16): 33-43.

3. 3.

   Briner W.W.; Grossman, E.; Buckner, R.Y.; Rebitski, G.F.; Sox, T.E.; Setser, R.E.; Ebert, M.L.:

   Effect of chlorhexidine gluconate mouthrinse on plaque bacteria. . J Periodont Res 1986; 21 (Suppl.16); 44-52.

4. 4.

   Briner W.W.; Grossman, E.; Buckner, R.Y.; Rebitski, G.F.; Sox, T.E.; Setser, R.E.; Ebert, M.L.:

   Assessment of susceptibility of plaque bacteria to chlorhexidine after six months’ oral use. J Periodont Res 1986; 21 (Suppl.16): 53-59.

5. 5.

   Loe, H.; Rindom-Schiott, C.; Glavind, L.; Karring, T.: Two years’ oral use of chlorhexidine in man: I.

   General design and clinical effects. J Periodont Res 1976; 11:135-144.

6. 6.

   Rindom-Schiott, C.; Briner, E.W.; Loe, H.: “Two Years of Oral Use of Chlorhexidine in Mann”. II

   The effect of the Salivary Bacterial Flora.” J Periodont Res II: 1976, 145-152.

7. 7.

   Warner, V.D.; Lynch, D.M.; Kim, K.H.; Grunewald, G.L.: “Quantitative Structure-Activity

   Relationships for Biguanides, Carbamimidates and Bisbiguanides as Inhibitors in Streptococcus Mutans,” J Med Chem 22: Issue 4, 1979, 359-366.

8. 8.

   Suessmuth, R.; Lingens, F.; Ackermann, B.: “Mutagenic effect of 1,1’-Hexamethylene-Bis ((5-p-

   Chorophenyl)-Biguanide).” Chem-Biol Interact; 28 (2-3) 1979, 249-258.

9. 9.

   Ackermann-Schmidt, B.; Suessmuth, R.; Lingens, F.: “Effects of 1,1’-Hexamethylene-Bis ((5-p-

   Chorophenyl)-Biguanide) on the genome and on the synthesis of nucleic acid and proteins in the bacterial cells. Chem-Biol Interact; Vol. 40, Iss 1, 1982. 85-96.

10. 10. Evans, R.T.; Baker, P.J.; Coburn R.A.; Genco, R.J.; “Evaluation of chlorhexidine, Tribromsalan and a limited series of alkyl bis biguanides in a in-vitro mutagenicity assay. J Dent Res 1978 57:290