Listerine Teeth and Gum Defence Antiseptic Mouthwash

Benzoic Acid:

• Precautions
• Instructions for use
• Listerine Teeth and Gum Defence Antiseptic Mouthwash (Benzoic Acid) reviews

Precautions

• Flammable
• Do not expose to temperatures exceeding 50°C
• Do not spray near naked flame
• Keep container tightly closed
• Only use this product in a well ventilated area
• Do not breathe mist or spray
• In case of contact with eyes rinse immediately with plenty of water and seek medical advice
• If swallowed seek medical advice and show this label

• For external use only
• For animal use only

• Keep out of reach of children

Ingredients

E124, E133, Ethanol, Organic Acids (Acetic and Listerine Teeth and Gum Defence Antiseptic Mouthwash (Benzoic Acid)), Polyvinylpyrrolidone, Tea-tree Oil, Triacetin, Water

Instructions for use

• For use in sheep, cattle, horses and goats

• Clean and dry hooves thoroughly before use
• Pare hoof if necessary
• Shake container well and spray liberally
• Allow 1-2 minutes for the Combat film to form, before returning hoof to the ground
• For severe cases in sheep repeat application every 2 days for 1 week
• For severe cases in cattle apply several layers of Combat after each milking for up to 10 days

NB: Always separate sheep with hoof problems from those without

Combat Footspray should be used as part of a routine footcare programme. Ideally use in conjunction with regular footbathing with Provita Hoofsure/Hoofsure Endurance.

Provita

ANIMAL HEALTH NATURALLY

Combat

The Longer Lasting

Foot Spray for

Livestock

A unique film forming spray

containing tea tree oil and

organic acid providing a

persistent longer lasting

antiseptic barrier for hooves

Eucalyptol:

• Listerine Teeth and Gum Defence Antiseptic Mouthwash (Eucalyptol) reviews

ACTIVE INGREDIENTS

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Eucalyptol) 0.091%

THYMOL 0.063%

PURPOSE

ANTISEPTIC

USES

• A MULTIPLE USE ANTISEPTIC
• CONTAINING PREPARATION DESIGNED FOR FREQUENT USE WITHOUT WATER AS AN ANTISEPTIC HANDWASH AND FIRST AID ANTISEPTIC.
• HELPS TO PROTECT AGAINST SKIN INFECTION AND TO HELP PREVENT CROSS CONTAMINATION IN CUTS, SCRAPES, BURNS, AND OR SECONDARY INFECTIONS.

WARNINGS

FOR EXTERNAL USE ONLY.

• DO NOT USE IN EYES OR APPLY OVER LARGE AREAS OF THE BODY.
• IN CASE OF DEEP OR PUNCTURE WOUNDS, ANIMAL BITES, OR SERIOUS BURNS, CONSULT A PHYSICIAN.
• STOP OR CONSULT A PHYSICIAN IF CONDITIONS PERSIST OR GET WORSE.
• DO NOT USE LONGER THAN ONE WEEK UNLESS DIRECTED BY A PHYSICIAN.

• KEEP OUT OF REACH OF CHILDREN.
• IF SWALLOWED GET MEDICAL HELP OR CONTACT A POISON CONTROL CENTER RIGHT AWAY.

DIRECTIONS

• CLEAN THE AFFECTED AREA.
• APPLY A SMALL AMOUNT OF THIS PRODUCT ON THE AREA 1 TO 3 TIMES DAILY.
• BANDAGE LIGHTLY.
• KEEP BANDAGE WET WITH SOLUTION.
• SPRAY A SMALL AMOUNT OF THIS PRODUCT ON THE AREA 1 TO 3 TIMES DAILY.
• MAY BE COVERED WITH STERILE BANDAGE.
• IF BANDAGED, LET DRY FIRST.

OTHER INFORMATION

• SHAKE WELL BEFORE USE.
• STORE AT 1-50°C (33-122°F)

INACTIVE INGREDIENTS

BEESWAX, CASTOR OIL (RICINUS COMMUNIS), CITRUS GRANDIS, EUCALYPTUS RADIATA LEAF OIL, GAULTHERIA PROCUMBENS (WINTERGREEN) LEAF OIL, GLYCERIN, LIMONENE, MELALEUCA ALTERNIFOLIA (TEA TREE) LEAF OIL, MENTHA PIPERITA (PEPPERMINT) OIL, ROSMARINUS OFFICINALIS (ROSEMARY) LEAF EXTRACT, THYMUS VULGARIS (THYME) OIL, TWEEN, WATER (AQUA).

QUESTIONS?

CALL (844) BIOCENCE/ (844) 246-2362 P.S.T. 9AM - 5PM MONDAY-THURSDAY OR VISIT WWW.BIOCENCE.COM

Biocence_1 Biocence_2 Biocence_3

Menthol:

• Listerine Teeth and Gum Defence Antiseptic Mouthwash (Menthol) reviews

Indication: Used to treat occasional minor irritation, pain, sore mouth, and sore throat as well as cough associated with a cold or inhaled irritants.

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Menthol) is a covalent organic compound made synthetically or obtained from peppermint or other mint oils. Menthol's ability to chemically trigger cold-sensitive receptors in the skin is responsible for the well known cooling sensation that it provokes when inhalated, eaten, or applied to the skin. It should be noted that Listerine Teeth and Gum Defence Antiseptic Mouthwash (Menthol) does not cause an actual drop in temperature.

Methyl Salicylate:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) reviews

INDICATIONS AND USAGE

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream in combination with 570 to 670 nm wavelength red light illumination using the CureLight BroadBand Model CureLight 01 lamp is indicated for treatment of non-hyperkeratotic actinic keratoses of the face and scalp in immunocompetent patients when used in conjunction with lesion preparation (debridement using a sharp dermal curette) in the physician’s office when other therapies are unacceptable or considered medically less appropriate.

CONTRAINDICATIONS

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is contraindicated in patients with cutaneous photosensitivity, or known allergies to porphyrins, and in patients with known sensitivities to any of the components of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream, which includes peanut and almond oil Cream).

This product contains refined peanut oil.

WARNINGS

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is intended for topical use in the physician’s office by trained physicians only. Do not apply to the eyes or to mucous membranes.

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream has demonstrated a high rate of contact sensitization (allergenicity). Care should be taken by the physician applying Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream to avoid inadvertent skin contact. Nitrile gloves should be worn when applying and removing the cream. Vinyl and latex gloves do not provide adequate protection when using this product.Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream when used with CureLight BroadBand Model CureLight 01 lamp must be used with appropriate protective sleeves obtained from the product manufacturer to decrease the risk of blood-borne transmitted diseases (hepatitis, HIV, etc.). Change the disposable covers for the device (probe and horseshoe positioning device) between patients. Universal Precautions should be used with this treatment.

PRECAUTIONS

The safety and efficacy have not been established for the treatment of cutaneous malignancies and for skin lesions other than non-hyperkeratotic face and scalp actinic keratoses using PDT with Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream. Thick (hyperkeratotic) actinic keratoses should not be treated with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream. The safety and efficacy of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream has not been established in patients with immunosuppression, porphyria or pigmented actinic keratoses.

General

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream Application

During the time period between the application of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) (methyl aminolevulinate) Cream and exposure to red light illumination, the treatment site will become photosensitive. After Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream application, patients should avoid exposure of the photosensitive treatment sites to sunlight or bright indoor light (e.g., examination lamps, operating room lamps, tanning beds, or lights at close proximity) during the period prior to red light treatment. Exposure to light may result in a stinging and/or burning sensation and may cause erythema and/or edema of the lesions. Before exposure to sunlight, patients should, therefore, protect treated lesions from the sun by wearing a wide-brimmed hat or similar head covering of light-opaque material. Sunscreens will not protect against photosensitivity reactions caused by visible light. The treated site should be protected from extreme cold with adequate clothing or remaining indoors between application of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) and PDT light treatment. After illumination of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream, the area treated should be kept covered and away from light for at least 48 hours. Because of the potential for skin to become photosensitized, the Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream should be used by a trained physician to apply drug only to non-hyperkeratotic actinic keratoses and perilesional skin within 5 mm of the lesion. Redness, swelling, burning, and stinging are expected as a result of therapy; however, if these symptoms increase in severity and persist longer than 3 weeks, the patient should contact their doctor. Metvixia Cream has not been studied for more than two treatment sessions. Information regarding further treatments for residual or new AK lesions performed after 3 months is not available..

Photosensitivity and Device Precautions.

The patient, operator and other persons present should wear protective goggles that sufficiently screen out light with wavelengths from 570 to 670 nm during red light treatment.

If for any reason the patient cannot have the red light treatment after application of Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream, the cream should be rinsed off, and the patient should protect the treated area from sunlight, prolonged or intense light for two days. Prolonged exposure for greater than 4 hours to Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream should be avoided.

Coagulation defects

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream has not been tested on patients with inherited or acquired coagulation defects.

Hypersensitivity

Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream is formulated with refined peanut and almond oil.

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) (methyl aminolevulinate) Cream has not been tested in patients who are allergic to peanuts. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) (methyl aminolevulinate) Cream has demonstrated a high rate of contact sensitization (allergenicity). 

Information for Patients

The physician should provide and discuss the attached Patient Package Insert with each patient.

Drug Interactions

There have been no studies of the interaction of Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream with any other drugs, including local anesthetics. It is possible that concomitant use of other known photosensitizing agents might increase the photosensitivity reaction of actinic keratoses treated with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream.

Carcinogenesis, Mutagenesis, Impairment to Fertility

Long-term studies to evaluate the carcinogenic potential of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream have not been performed. 

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) aminolevulinate was negative for genetic toxicity in the Ames assay, and the chromosomal aberration assay in Chinese hamster ovary cells, tested with and without metabolic activation and in the presence and absence of light. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) aminolevulinate was also negative in the in vivo micronucleus assay in the rat. In contrast, at least one report in the literature has noted genotoxic effects in cultured rat hepatocytes after aminolevulinate (ALA) exposure with PpIX formation. Other studies have documented oxidative DNA damage in vivo and in vitro as a result of ALA exposure. No animal fertility studies have been conducted.

Pregnancy

Teratogenic effects

Pregnancy Category C: Animal reproduction studies have not been conducted with Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream. It is also not known whether Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream should be given to a pregnant woman only if clearly needed.

Nursing Mothers

The amount of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) aminolevulinate secreted into human breast milk following topical administration of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is not known. Because many drugs are secreted in human milk, caution should be exercised when Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is administered to a nursing mother. If Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is used in a nursing mother, a decision should be made whether or not to stop nursing.

Pediatric Use

It is not recommended that Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream be used in pediatric patients. Actinic keratosis is rarely found in pediatric patients. 

Geriatric Use

Seventy percent (269 among 383) of the patients treated with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream in all clinical studies of actinic keratosis were 65 years of age or older. No overall differences in safety and efficacy were observed between patients aged 65 years and older and those who were younger.

ADVERSE REACTIONS

Dermal Safety Studies

Provocative studies to evaluate irritancy and sensitization have demonstrated that Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream is an irritant and sensitizer. A provocative cumulative irritancy and sensitization (allergenicity) study of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream with a cross-sensitization challenge with ALA was performed in 156 subjects. Only 98 of the 156 subjects tested entered the challenge phase. Fifty-two percent of the subjects (30/58), who agreed to challenge with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream, were positive (sensitized). Forty subjects refused challenge with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream and 60 withdrew. At least 58 of the 60 subjects who withdrew from the study discontinued due to irritation/sensitization.

Ninety-eight subjects agreed to challenge with ALA. Two percent of the ALA challenged subjects (2/98) were scored as equivocal reactions and 2% in the paraffin vehicle group were scored as positive.

Adverse Events

In vehicle-controlled phase 3 studies of actinic keratosis, 88% of patients treated with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream reported one or more adverse events.

Burning was the most frequent complaint, reported by 50% of patients (ranging from mild, to severe) and 9% of those patients reported severe burning sensation. Pain in the skin was reported by 21% of patients and 7% had severe pain. Local erythema lasting up to two weeks and edema up to one week after treatment were reported by 31% and 6% of patients. Symptoms and signs of local phototoxicity were observed in 88% of patients treated with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream in all clinical studies of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) -PDT for actinic keratoses.

The majority of patients in all the clinical trials had local pain or discomfort upon illumination. There were 4 (1.0%) withdrawals/discontinuations among 383 patients treated with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream in all the clinical trials of actinic keratosis, all of which were due to the adverse event of local pain on illumination.

There have been reported instances of patients treated with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream (2 out of 130) who have developed squamous cell and basal cell carcinoma at the site of treatment. The relationship to treatment with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is unknown. Serious erythema and facial edema have been described in European post-marketing reports.

OVERDOSAGE

Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream Overdose

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream overdose has not been reported. If the patient for any reason cannot have the red light treatment during the prescribed period after application (the 3 hour timespan), the cream should be rinsed off, and the patient should protect the exposed area from sunlight, prolonged or intense light for two days.  

Red Light Overdose

There is no information on overdose of red light following Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream application.

In case of red light overexposure and skin burn occurs, the patient should be treated according to standard of practice guidelines for treatment of cutaneous burns.

DOSAGE AND ADMINISTRATION

Photodynamic therapy for non-hyperkeratotic actinic keratoses with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is a multi-stage process as described below: Two treatment sessions 7 days apart should be conducted. Not more than one gram (half a tube) of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream should be applied per treatment session.

One Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) -PDT session consists of: 1) Lesion debriding –

Before applying Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream, the surface of the lesions should be prepared with a small dermal curette to remove scales and crusts and roughen the surface of the lesion. This is to facilitate access of the cream and light to all parts of the lesion.

Figure 1 A Lesion debriding  Only nitrile gloves should be worn during this and subsequent steps and Universal Precautions should be taken. Vinyl and latex gloves do not provide adequate protection when using this product.

Figure 1B Lesion debriding2) Application of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream –

Using a spatula, apply a layer of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream about 1 mm thick to the lesion and the surrounding 5 mm of normal skin. Do not apply more than one gram of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream for each patient per treatment session.

Figure 2: Cream applicationThe area to which the cream has been applied should then be covered with an occlusive, non-absorbent dressing for 3 hours. Multiple lesions may be treated during the same treatment session. Each treatment field is limited to a diameter of 55 mm. Only nitrile gloves should be worn by the qualified healthcare provider in order to avoid skin contact with the cream. This product is not intended for application by patients or unqualified medical personnel.

Figure 3: Occlusive dressing application3) Wait for 3 hours - (at least 2.5 hours, but no more than 4 hours).

After Cream application, patients should avoid exposure of the photosensitive treatment sites to sunlight or bright indoor light (e.g., examination lamps, operating room lamps, tanning beds, or lights at close proximity) during the period prior to red light treatment. Exposure to light may result in a stinging and/or burning sensation and may cause erythema and/or edema of the lesions. Patients should protect treated areas from the sun by wearing a wide-brimmed hat or similar head covering of light-opaque material. Sunscreens will not protect against photosensitivity reactions caused by visible light. It has not been determined if perspiration can spread the Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream outside the treatment site to the eyes or surrounding skin. The treated site should be protected from extreme cold with adequate clothing or remaining indoors between application of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream and PDT light treatment.4) Removal of Dressing and Rinse Off Excess Cream - Following removal of the occlusive dressing, clean the area with saline and gauze. Nitrile gloves should be worn at this step by the trained physician. 

Figure 4: Cream removal5) Illumination of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Treated Lesion - It is important to ensure that the correct light dose is administered. The light intensity at the lesion surface should not be higher than 200 mW/cm². Patient and operator should adhere to safety instructions and Universal Precautions provided with the lamp. The patient and operator should wear protective goggles during illumination. Patients should be advised that transient stinging and/or burning at the target lesion sites may occur during the period of light exposure.

Figure 5: IlluminationThe CureLight BroadBand Model CureLight 01 lamp is approved for the use in Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) -PDT. The lamp should be carefully calibrated so that dosing is accurate and immediately thereafter the lesion should be exposed to red light with a continuous spectrum of 570 to 670 nm and a total light dose of 75 J/cm². To avoid direct contact between lamp parts and patient skin, always use disposable protective plastic sleeves on the positioning device and on the light measuring probe. Following each patient treatment, the disposable protective plastic sleeves should be removed from the positioning device and from the light measuring probe and discarded. If red light treatment is interrupted or stopped for any reason, it may be restarted. If the patient for any reason cannot have the red light treatment during the prescribed period after application (the 3 hour timespan), the cream should be rinsed off and the patient should protect the exposed area from sunlight, prolonged or intense light for two days. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is not intended for use with any device other than the approved lamp: CureLight BroadBand Model CureLight 01. Use of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream without subsequent red light illumination is not recommended. No more than 1 gram (half a tube) of product should be used for each of the two weekly treatment sessions. Multiple lesions may be treated during the same treatment session using a total of 1 gram of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream. Lesion response should be assessed 3 months after the last treatment session.   This product is not intended for application by patients or unqualified medical personnel, therefore, this product is only dispensed to physicians.

HOW SUPPLIED

Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream, 16.8%, is available as the following:

NDC 63069-401-01, 2 gram aluminum tube, box of 1

Product Package

Keep out of reach of children

For topical use only by physicians in the physician’s office. Rx Only

Storage Conditions

Store refrigerated, 2-8°C.

Use contents within one week after opening.

Should not be used after 24 hours out of refrigerator.

Metvixia Cream is a registered trade name of PhotoCure ASA.

PhotoCure ASA, Hoffsveien 48, N-0377 Oslo, Norway

USA Contact: Cato Research, Westpark Corporate Center, 4364 South Alston Avenue, Durham NC 27713

Revision: September 5, 2007

PATIENT INFORMATION

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate)^™ Cream 16.8% (phonetic)

Generic name: Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) aminolevulinate hydrochloride

Read this Patient Information before you get treated with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream and each time you get a treatment. There may be new information. This leaflet does not take the place of talking with your doctor about your condition or treatment. Ask your healthcare provider about anything you do not understand about Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream.

What is the most important thing I need to know about Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream?

• Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream with light treatment (Photodynamic therapy or PDT) is only done in medical offices by trained doctors.
• Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is not applied by patients. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream should not be applied by doctors who have not been trained in its use.

What is Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream?

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is a prescription cream used with PDT (light treatment) to treat skin growths on the face and scalp called actinic keratosis (AK). Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is only used for AK skin growths that are thin and not dark colored. AK skin growths are not cancer. AK skin growths are caused partly by too much sun exposure. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream and PDT work together to treat AK skin growths.

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream has not been studied in children for any condition and should not be used in children.

Who should not use Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream?

Do not use Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream if:

• your skin over reacts to sun or light (photosensitivity)
• you are allergic to porphyrins or to any of the ingredients in Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream. The active ingredient is Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) aminolevulinate hydrochloride. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream also contains peanut and almond oil. See the end of this leaflet for a complete list of ingredients in Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream.

Before treatment with Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream, tell your doctor:

• about your medical conditions, including if you
  • are pregnant or planning to become pregnant. It is not known if Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream can harm your unborn baby.
  • are breastfeeding. It is not known if Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream passes into your milk and if it can harm your baby. You should decide whether or not to stop breastfeeding while getting treatment with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream. Talk to your doctor for help with this choice.
  • are allergic to nuts or peanuts
  • have or had skin cancer or other skin growths on your body
  • have bleeding problems.
• about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. It is not known if Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream and other medicines can affect each other.

How should I use Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream?

• Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream and PDT treatment is only done by trained doctors.
• You will receive 2 treatments with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream and PDT 7 days (1 week) apart. Your doctor will check you three months after treatment to see if the treatment worked for you. Cream and PDT.”)
• Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is for skin use only. Do not get Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream in your eyes, mouth, or nose. Tell your doctor right away if this happens.

What should I avoid while using Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream?

During the 3 hours that Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is on your skin:

• Avoid exposure to sunlight or bright indoor light during the 3 hours that Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is on your skin. Wear a protective hat and clothing if you need to be outside in the sun.
• Avoid exposure to cold temperatures during the 3 hours that Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is on your skin. Wear warm clothing and keep your treated skin site covered if you are in cold temperatures.

• Carefully rinse off the Cream.
• Avoid exposure to sunlight, prolonged or intense light for two days after treatment.

What are the possible side effects of Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream with PDT treatment?

Common side effects of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream with PDT treatment include the following skin reactions at the treated site:

• burning feeling
• redness
• pain
• stinging
• swelling
• crusting, peeling, blisters, bleeding, itching, ulcers
• infection

General information about Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets.

This leaflet summarizes the most important information about Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream. If you would like more information, talk with your doctor. You can ask your doctor for information about Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream that is written for health professionals. Toll-free number and/or website will be provided when available for the US market.

What are the ingredients in Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream?

Active Ingredient: Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) aminolevulinate hydrochloride

Other Ingredients: Glyceryl monostearate, cetostearyl alcohol, poloxyl stearate, cholesterol, oleyl alcohol glycerin, white petrolatum, isopropyl myristate, refined peanut oil, refined almond oil, edetate disodium, methylparaben and propylparaben. The color of the product is cream to pale yellow.

Treatment with Listerine Teeth and Gum Defence Antiseptic Mouthwash Cream and PDT

Figure 1: Lesion debriding

Your doctor will prepare your skin by gently scraping (debriding) your skin growths before treating with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream and PDT. A small skin scraper is used to remove scales and crusts and to roughen the surface of any skin growths. This is to help Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream and PDT to reach all parts of the skin growths.

Figure 2: Cream application Metvixia Cream is applied to the actinic keratosis skin growths and to a small area of the skin around the growths.

Figure 3: Clear bandage application The treated skin areas will be covered with a special clear bandage for about 3 hours.

During these 3-hours you should avoid exposure of treated area to sunlight or bright indoor light. Exposure to light may make your treated skin area sting or burn. Your treated skin area may turn red or swell (photosensitive reactions). Wear a hat and protective clothes if you are exposed to sunlight during this time. Sunscreens will not help protect your treated skin during this time. In cold weather, your treated skin site should be protected from the cold with warm clothes or you should stay indoors for these 3 hours between the cream and light treatment.

Figure 4: Cream removal The clear bandage will be removed and the area will be rinsed with a saline solution before the PDT (light) treatment.

Figure 5: IlluminationThe skin growth will be treated with PDT. PDT lasts about 10 minutes for each area treated with the lamp. You will wear protective goggles to cover your eyes during this part of the treatment. More than 1 skin growth may be treated at a time. Your treated skin areas may burn, feel painful, sting, or tingle during light treatment. These symptoms may last for a few hours after the treatment. If you cannot have the light treatment 3 hours after Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is applied, rinse the cream off your skin and you must protect your skin from sunlight and bright indoor light for 2 days. This product should only be stored in refrigerators in pharmacies and medical offices. Rx only

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Methyl Salicylate) Cream is a registered trade name of PhotoCure ASA.

Sponsor: PhotoCure ASA, Hoffsveien 48, NO-0377 Oslo, Norway

U.S. Contact: Cato Research, Westpark Corporate Center, 4364 South Alston Avenue, Durham NC 27713

Manufacturer: Penn Pharmaceutical Services Ltd., Tafarnaubach Industrial Estate, Tredegar, Gwent, NP22 3AA, UK.

Sodium Fluoride:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) reviews

1 INDICATIONS AND USAGE

Listerine Teeth and Gum Defence Antiseptic Mouthwash nitrite is indicated for sequential use with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

• Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite Injection is indicated for sequential use with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Listerine Teeth and Gum Defence Antiseptic Mouthwash nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite Injection and Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Thiosulfate Injection should be administered without delay.

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

• Exposure to fire or smoke in an enclosed area
• Presence of soot around the mouth, nose, or oropharynx
• Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate, simultaneously with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate, with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite and Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite, followed by Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite and Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate.

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite injection and Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite should be administered first, followed immediately by Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite and Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite should be reduced proportionately to the hemoglobin concentration.

All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Listerine Teeth and Gum Defence Antiseptic Mouthwash Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO₂ are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate and Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite Injection consists of:

• One vial of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

• Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

• None. (4)

5 WARNINGS AND PRECAUTIONS

• Methemoglobinemia: Listerine Teeth and Gum Defence Antiseptic Mouthwash nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
• Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Listerine Teeth and Gum Defence Antiseptic Mouthwash nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite whenever possible. When Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite administered to an adult. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Listerine Teeth and Gum Defence Antiseptic Mouthwash nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Listerine Teeth and Gum Defence Antiseptic Mouthwash nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite.

5.7 Use with Other Drugs

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite.

The medical literature has reported the following adverse events in association with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

• Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Listerine Teeth and Gum Defence Antiseptic Mouthwash nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Listerine Teeth and Gum Defence Antiseptic Mouthwash nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite is excreted in human milk. Because Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite. In studies conducted with Long-Evans rats, Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of Listerine Teeth and Gum Defence Antiseptic Mouthwash nitrite in conjunction with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Disease

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE

Large doses of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite has the chemical name nitrous acid Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite injection.

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite in 10 mL solution (30 mg/mL). Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of Listerine Teeth and Gum Defence Antiseptic Mouthwash nitrite and Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a₃, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO₂ + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite. It has been suggested that Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN^-), which is relatively nontoxic and readily excreted in the urine. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite

When 4 mg/kg Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite in humans have not been well studied. It has been reported that approximately 40% of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite and Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to Listerine Teeth and Gum Defence Antiseptic Mouthwash nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite and Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite or 1 g/kg Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate alone or in sequence immediately after subcutaneous injection of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite and/or 0.5 g/kg Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) cyanide required to cause death, and when administered together, Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite and Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate resulted in a synergistic effect in raising the lethal dose of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite and Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite and Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite, with or without Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) thiosulfate report its use in conjunction with Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite injection 30 mg/mL (containing 300 mg of Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Listerine Teeth and Gum Defence Antiseptic Mouthwash Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

Listerine Teeth and Gum Defence Antiseptic Mouthwash (Sodium Fluoride) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

Thymol:

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