Neo Cepacol Collutorio

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Neo Cepacol Collutorio uses

Neo Cepacol Collutorio consists of Cetylpyridinium Chloride, Cineole, Cinnamon Oil, Edetate Disodium, Menthol, Methyl Salicylate, Mint Oil, Sodium Diphosphate, Sodium Phosphate.

Cetylpyridinium Chloride:


Drug Facts

Active Ingredient: PEROX-A-MINT: Purpose
Hydrogen Peroxide 1.5% Oral Debriding Agent
Active Ingredient: ANTIPLAQUE*: Purpose
Neo Cepacol Collutorio (Cetylpyridinium Chloride) chloride.05% Antigingivitis/antiplaque

USES

Suction Swab with Perox-A-Mint:

Aids in the removal of secretions and debris.

Suction Toothbrush with Antiplaque Solution:

Aids in the removal and prevention of plaque that leads to gingivitis.

Oropharyngeal Suction Catheter:

Aids in the removal of secretions from the oropharyngeal cavity only.

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WARNINGS

Suction Swab with Perox-A-Mint Solution:

  • Sore mouth symptoms do not improve in 7 days.
  • Swelling, rash or fever develops.
  • Irritation, pain or redness persists or worsens.
Suction Toothbrush with Antiplaque Solution:

  • Gingivitis, bleeding or redness persists for more than 2 weeks.
  • You have painful or swollen gums, pus from the gum line, loose teeth or increasing spacing between the teeth. These may be signs or symptoms of periodontitis, a serious form of gum disease.
Suction Swab with Perox-A-Mint Solution:

Keep out of reach of children.

If more than used for debriding is accidentally swallowed, get medical help or contact a Poison Control Center right away.

Suction Toothbrush with Antiplaque Solution:

Keep out of reach of children under 6 years of age

If more than used for brushing is accidentally swallowed, get medical help or contact a Poison Control Center right away.

DIRECTIONS

Suction Swab with Perox-A-Mint Solution:

  • Before opening, turn package over, burst solution packet with thumbs.
  • Peel lid to open.
  • Remove Mouth Moisturizer and Applicator Swab.
  • Attach Suction Swab to Suction Handle.
  • Clean teeth and oral cavity for approximately one minute.
  • To suction, slide switch to ON. When finished, return switch to OFF.
  • To clear tubing, rinse with sterile saline or appropriate solution.
  • Discard Suction Swab. Reattach Covered Yankauer to Suction Handle.
  • Place Mouth Moisturizer on Applicator Swab.
  • Apply as needed to lips and inside mouth.
  • Use up to 4 times daily or as directed by a dentist or doctor.
  • Children under 12 years of age: supervise use.
  • Children under 3 years of age: consult a dentist or doctor.
  • Use a bite block when performing oral care on patients with altered levels of consciousness or those who cannot comprehend commands.
  • Ensure foam is intact after use. If not, remove any particles from oral cavity.

Suction Toothbrush with Antiplaque Solution:

  • Before opening, turn package over, burst solution packet with thumbs.
  • Peel lid to open.
  • Remove Mouth Moisturizer and Applicator Swab.
  • Attach Toothbrush to Suction Handle.
  • Clean teeth and oral cavity for approximately one minute.
  • To suction, slide switch to ON. When finished, return switch to OFF.
  • To clear tubing, rinse with sterile saline or appropriate solution.
  • Discard Toothbrush. Reattach Covered Yankauer to Suction Handle.
  • Place Mouth Moisturizer on Applicator Swab.
  • Apply as needed to lips and inside mouth.
  • Adults and children 12 years of age and older: use two times daily or as directed by a dentist. Do not swallow the solution.
  • Children ages 6 to 12 years: supervise use.
  • Children under 6 years of age: do not use.
  • Use a bite block when performing oral care on patients with altered levels of consciousness or those who cannot comprehend commands.
  • Ensure foam is intact after use. If not, remove any particles from oral cavity.

Oropharyngeal Suction Catheter:

  • Peel lid to open.
  • Attach Suction Cather to Suction Handle.
  • Suction secretions from the oropharyngeal cavity.
  • To suction, slide switch to ON. When finished, return switch to OFF.
  • To clear tubing, rinse with sterile saline or appropriate solution.
  • Discard Suction Catheter. Reattach Covered Yankauer to Suction Handle.
  • Use a bite block when performing oral care on patients with altered levels of consciousness or those who cannot comprehend commands.

Caution

  • Federal (U.S.A.) law restricts this device to sale by or on the order of a physician or licensed practicioner.
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Inactive Ingredients

Suction Swab with Perox-A-Mint Solution:

Water, menthol flavor, polysorbate 80, phosphoric acid, sodium saccharin, Blue 1 (CI 42090), Yellow 6 (CI 15985)

Suction Toothbrush with Antiplaque Solution:

Water, sorbitol, peppermint flavor, potassium sorbate, polysorbate 80, polysorbate 20, citric acid, Blue 1 (CI42090)

Questions?

Call toll-free 800–323–2220

Manufactured for Sage Products LLC Cary, IL

NOT MADE WITH NATURAL RUBBER LATEX. FOR SINGLE USE ONLY. MADE IN U.S.A.

Neo Cepacol Collutorio

QCare 6804 QCare Film 6804 QCare Drug Facts 6804

QCare Oral Cleansing and Suctioning System, Q8

QCare 6808 QCare film 6808 QCare Drug Facts 6808

Antiplaque Solution, Perox-A-Mint

Antiplaque Solution Perox-A-Mint

Edetate Disodium:


INDICATIONS AND USAGE

Neo Cepacol Collutorio (Edetate Disodium) calcium disodium is indicated for the reduction of blood levels and depot stores of lead in lead poisoning (acute and chronic) and lead encephalopathy, in both pediatric populations and adults.

Chelation therapy should not replace effective measures to eliminate or reduce further exposure to lead.

CONTRAINDICATIONS

Neo Cepacol Collutorio (Edetate Disodium) calcium disodium should not be given during periods of anuria, nor to patients with active renal disease or hepatitis.

WARNINGS

PRECAUTIONS

General Precautions

Neo Cepacol Collutorio calcium disodium may produce the same renal damage as lead poisoning, such as proteinuria and microscopic hematuria. Treatment-induced nephrotoxicity is dose-dependent and may be reduced by assuring adequate diuresis before therapy begins. Urine flow must be monitored throughout therapy which must be stopped if anuria or severe oliguria develop. The proximal tubule hydropic degeneration usually recovers upon cessation of therapy. Neo Cepacol Collutorio (Edetate Disodium) calcium disodium must be used in reduced doses in patients with pre-existing mild renal disease. Patients should be monitored for cardiac rhythm irregularities and other ECG changes during intravenous therapy.

Information for patients

Patients should be instructed to immediately inform their physician if urine output stops for a period of 12 hours.

Laboratory tests

Urinalysis and urine sediment, renal and hepatic function and serum electrolyte levels should be checked before each course of therapy and then be monitored daily during therapy in severe cases, and in less serious cases after the second and fifth day of therapy. Therapy must be discontinued at the first sign of renal toxicity. The presence of large renal epithelial cells or increasing number of red blood cells in urinary sediment or greater proteinuria call for immediate stopping of Neo Cepacol Collutorio calcium disodium administration. Alkaline phosphatase values are frequently depressed (possibly due to decreased serum zinc levels), but return to normal within 48 hours after cessation of therapy. Elevated erythrocyte protoporphyrin levels (> 35 mcg/dl of whole blood) indicate the need to perform a venous blood lead determination. If the whole blood lead concentration is between 25–55 mcg/dl a mobilization test can be considered.7,8 (See Diagnostic Test .) An elevation of urinary coproporphyrin (adults: > 250 mcg/day; pediatric patients under 80 lbs: > 75 mcg/day) and elevation of urinary delta aminolevulinic acid (ALA) (adults: > 4 mg/day; pediatric patients: > 3 mg/m2/day) are associated with blood lead levels > 40 mcg/dl. Urinary coproporphyrin may be falsely negative in terminal patients and in severely iron-depleted pediatric patients who are not regenerating heme.9 In growing pediatric patients long bone x-rays showing lead lines and abdominal x-rays showing radio-opaque material in the abdomen may be of help in estimating the level of exposure to lead.

Drug Interactions

There is no known drug interference with standard clinical laboratory tests. Steroids enhance the renal toxicity of Neo Cepacol Collutorio (Edetate Disodium) calcium disodium in animals.7 Neo Cepacol Collutorio (Edetate Disodium) calcium disodium interferes with the action of zinc insulin preparations by chelating the zinc.7

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term animal studies have not been conducted with Neo Cepacol Collutorio calcium disodium to evaluate its carcinogenic potential, mutagenic potential or its effect on fertility.

Pregnancy

Category B

One reproduction study was performed in rats at doses up to 13 times the human dose and revealed no evidence of impaired fertility or harm to the fetus due to Neo Cepacol Collutorio.10 Another reproduction study performed in rats at doses up to about 25 to 40 times the human dose revealed evidence of fetal malformations due to Neo Cepacol Collutorio (Edetate Disodium), which were prevented by simultaneous supplementation of dietary zinc.11 There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

Neo Cepacol Collutorio (Edetate Disodium) has no recognized use during labor and delivery, and its effects during these processes are unknown.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Neo Cepacol Collutorio is administered to a nursing woman.

Pediatric Use

Since lead poisoning occurs in pediatric populations and adults but is frequently more severe in pediatric patients, Neo Cepacol Collutorio (Edetate Disodium) is used in patients of all ages. The intramuscular route is preferred by some for young pediatric patients. In cases where the intravenous route is necessary, avoid rapid infusion. (See WARNINGS.) Urine flow must be monitored throughout therapy; Neo Cepacol Collutorio (Edetate Disodium) therapy must be stopped if anuria or severe oliguria develops. (See General Precautions .) At no time should the recommended daily dosage be exceeded. (See DOSAGE AND ADMINISTRATION .)

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ADVERSE REACTIONS

The following adverse effects have been associated with the use of Neo Cepacol Collutorio (Edetate Disodium) calcium disodium:

Body as a Whole: pain at intramuscular injection site, fever, chills, malaise, fatigue, myalgia, arthralgia.

Cardiovascular: hypotension, cardiac rhythm irregularities.

Renal: acute necrosis of proximal tubules (which may result in fatal nephrosis), infrequent changes in distal tubules and glomeruli.

Urinary: glycosuria, proteinuria, microscopic hematuria and large epithelial cells in urinary sediment.

Nervous System: tremors, headache, numbness, tingling.

Gastrointestinal: cheilosis, nausea, vomiting, anorexia, excessive thirst.

Hepatic: mild increases in SGOT and SGPT are common, and return to normal within 48 hours after cessation of therapy.

Immunogenic: histamine-like reactions (sneezing, nasal congestion, lacrimation), rash.

Hematopoietic: transient bone marrow depression, anemia.

Metabolic: zinc deficiency, hypercalcemia.

OVERDOSAGE

Symptoms

Inadvertent administration of 5 times the recommended dose, infused intravenously over a 24 hour period, to an asymptomatic 16 month old patient with a blood lead content of 56 mcg/dl did not cause any ill effects. Neo Cepacol Collutorio calcium disodium can aggravate the symptoms of severe lead poisoning, therefore, most toxic effects (cerebral edema, renal tubular necrosis) appear to be associated with lead poisoning. Because of cerebral edema, a therapeutic dose may be lethal to an adult or a pediatric patient with lead encephalopathy. Higher dosage of Neo Cepacol Collutorio (Edetate Disodium) calcium disodium may produce a more severe zinc deficiency.

Treatment

Cerebral edema should be treated with repeated doses of mannitol. Steroids enhance the renal toxicity of Neo Cepacol Collutorio (Edetate Disodium) calcium disodium in animals and, therefore, are no longer recommended.7 Zinc levels must be monitored. Good urinary output must be maintained because diuresis will enhance drug elimination. It is not known if Neo Cepacol Collutorio (Edetate Disodium) calcium disodium is dialyzable.

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DOSAGE AND ADMINISTRATION

When a source for the lead intoxication has been identified, the patient should be removed from the source, if possible. The recommended dose of Neo Cepacol Collutorio for asymptomatic adults and pediatric patients whose blood lead level is < 70 mcg/dl but > 20 mcg/dl (World Health Organization recommended upper allowable level) is 1000 mg/m2/day whether given intravenously or intramuscularly.

For adults with lead nephropathy, the following dosing regimen has been suggested: 500 mg/m2 every 24 hours for 5 days for patients with serum creatinine levels of 2–3 mg/dl, every 48 hours for 3 doses for patients with creatinine levels of 3–4 mg/dl, and once weekly for patients with creatinine levels above 4 mg/dl. These regimens may be repeated at one month intervals.12

Neo Cepacol Collutorio (Edetate Disodium), used alone, may aggravate symptoms in patients with very high blood lead levels. When the blood lead level is > 70 mcg/dl or clinical symptoms consistent with lead poisoning are present, it is recommended that Neo Cepacol Collutorio (Edetate Disodium) be used in conjunction with BAL (dimercaprol). Please consult published protocols and specialized references for dosage recommendations of combination therapy.14–18

Therapy of lead poisoning in adults and pediatric patients with Neo Cepacol Collutorio (Edetate Disodium) is continued over a period of five days. Therapy is then interrupted for 2 to 4 days to allow redistribution of the lead and to prevent severe depletion of zinc and other essential metals. Two courses of treatment are usually employed; however, it depends on severity of the lead toxicity and the patient's tolerance of the drug.

Neo Cepacol Collutorio (Edetate Disodium) is equally effective whether administered intravenously or intramuscularly. The intramuscular route is used for all patients with overt lead encephalopathy and this route is preferred by some for young pediatric patients.

Acutely ill individuals may be dehydrated from vomiting. Since Neo Cepacol Collutorio (Edetate Disodium) calcium disodium is excreted almost exclusively in the urine, it is very important to establish urine flow with intravenous fluid administration before the first dose of the chelating agent is given; however, excessive fluid must be avoided in patients with encephalopathy. Once urine flow is established, further intravenous fluid is restricted to basal water and electrolyte requirements. Administration of Neo Cepacol Collutorio (Edetate Disodium) should be stopped whenever there is cessation of urine flow in order to avoid unduly high tissue levels of the drug. Neo Cepacol Collutorio (Edetate Disodium) calcium disodium must be used in reduced doses in patients with pre-existing mild renal disease.

Intravenous Administration

Add the total daily dose of Neo Cepacol Collutorio (Edetate Disodium) (1000 mg/m2/day) to 250–500 ml of 5% dextrose or 0.9% sodium chloride injection. The total daily dose should be infused over a period of 8–12 hours. Neo Cepacol Collutorio (Edetate Disodium) injection is incompatible with 10% dextrose, 10% invert sugar in 0.9% sodium chloride, lactate Ringer's, Ringer's, one-sixth molar sodium lactate injections, and with injectable amphotericin B and hydralazine hydrochloride.

Intramuscular Administration

The total daily dosage should be divided into equal doses spaced 8–12 hours apart. Lidocaine or procaine should be added to the Neo Cepacol Collutorio (Edetate Disodium) injection to minimize pain at the injection site. The final lidocaine or procaine concentration of 5 mg/ml (0.5%) can be obtained as follows: 0.25 ml of 10% lidocaine solution per 5 ml concentrated Neo Cepacol Collutorio (Edetate Disodium); 1 ml of 1% lidocaine or procaine solution per ml of concentrated Neo Cepacol Collutorio (Edetate Disodium). When used alone, regardless of method of administration, Neo Cepacol Collutorio (Edetate Disodium) should not be given at doses larger than those recommended.

Diagnostic Test

Several methods have been described for lead mobilization tests using Neo Cepacol Collutorio (Edetate Disodium) calcium disodium to assess body stores.7, 9,12,13,18

These procedures have advantages and disadvantages that should be reviewed in current references. Neo Cepacol Collutorio (Edetate Disodium) calcium disodium mobilization tests should not be performed in symptomatic patients and in patients with blood lead levels above 55 mcg/dl for whom appropriate therapy is indicated.

Parenteral drugs should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

SURFACE AREA NOMOGRAM FIGURE

HOW SUPPLIED

Neo Cepacol Collutorio (Edetate Disodium) injection, 5 mL ampul containing 200 mg of Neo Cepacol Collutorio (Edetate Disodium) calcium disodium per ml (1000 mg per ampul), in boxes containing 5 ampuls (NDC 99207-240-05).

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Rx Only

This product is non-returnable.

REFERENCES

  • Thomas DJ, Chisolm JJ. Lead, zinc and copper decorporation during calcium disodium ethylenediamine tetraacetate treatment of lead-poisoned children. J Pharmacol Exp Therapeu 1986; 239: 829–835.
  • The Pharmacological Basis of Therapeutics, 7th edition, Goodman and Gilman, editors. MacMillan Publishing Company, New York, 1985, pp. 1619–1622.
  • Hammond PB, Aronson AL, Olson WC. The mechanism of mobilization of lead by ethylenediaminetetraacetate. J Pharmacol Exp Therapeu 1967; 157: 196–206.
  • Van deVyver FL, D'Haese PC, Visser WJ, et al. Bone lead in dialysis patients. Kidney Intl 1988; 33: 601–607.
  • Cory-Slecta DA, Weiss B, Cox C. Mobilization and redistribution of lead over the course of calcium disodium ethylenediamine tetraacetate chelation therapy. J Pharmacol Exp Therapeu 1987; 243: 804–813.
  • Chisolm JJ. Mobilization of lead by calcium disodium Neo Cepacol Collutorio (Edetate Disodium). Am J Dis Child 1987; 141: 1256–1257.
  • Drug Evaluations, 6th Edition, American Medical Association, Saunders, Philadelphia, 1986, pp. 1637–1639.
  • Centers for Disease Control: Preventing lead poisoning in young children. Atlanta, GA, Department of Health and Human Services, 1985 Jan.
  • Finberg L, Rajagopal V. Diagnosis and treatment of lead poisoning in children. J Family Med 1985 April: 3–12.
  • Schardein JL, Sakowski R, Petrere J, et al. Teratogenesis studies with EDTA and its salts in rats. Toxicol Appl Pharmacol 1981; 61: 423–428.
  • Swenerton H, Hurley LS. Teratogenic effects of a chelating agent and their prevention by zinc. Science 1971; 173: 62–64.
  • American Hospital Formulary Service, Drug Information, 1988, pp. 1695–1698.
  • Markowitz ME, Rosen JF. Assessment of lead stores in children: Validation of an 8-hour CaNa2EDTA (Calcium Disodium Versenate) provocative test. J Pediatrics 1984; 104: 337–341.
  • Piomelli S, Rosen JF, Chisolm JJ, et al. Management of childhood lead poisoning. J Pediatrics 1984; 105: 523–532.
  • Sachs HK, Blanksma LA, Murray EF, et al. Ambulatory treatment of lead poisoning: Report of 1,155 cases. Pediatrics 1970; 46: 389.
  • Chisolm JJ. The use of chelating agents in the treatment of acute and chronic lead intoxication in childhood. J Pediatrics 1968; 73: 1.
  • Coffin R, Phillips JL, Staples WI, et al. Treatment of lead encephalopathy in children. J Pediatrics 1966; 69: 198–206.
  • Chisolm JJ. Increased lead absorption and acute lead poisoning. Current Pediatric Therapy 12, Gillis and Kagan, editors, WB Saunders, Philadelphia, 1986, pp. 667–671.

Manufactured for:

Medicis, The Dermatology Company

Scottsdale, AZ 85256

By: CP Pharmaceuticals, Ltd.

Wrexham LL13 9UF, U.K.

Product of UK

106055/1

Rev. 10/12

MEDICIS Logo

Menthol:


Neo Cepacol Collutorio (Menthol) is a covalent organic compound made synthetically or obtained from peppermint or other mint oils. It is a waxy, crystalline substance, clear or white in color, which is solid at room temperature and melts slightly above. The main form of Neo Cepacol Collutorio (Menthol) occurring in nature is (-)-menthol, which is assigned the (1R,2S,5R) configuration. Neo Cepacol Collutorio (Menthol) has local anesthetic and counterirritant qualities, and it is widely used to relieve minor throat irritation.

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

Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (Menthol) does not cause an actual drop in temperature.

Methyl Salicylate:


INDICATIONS AND USAGE

Neo Cepacol Collutorio (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

Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (Methyl Salicylate) Cream, which includes peanut and almond oil Cream).

This product contains refined peanut oil.

WARNINGS

Neo Cepacol Collutorio (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.

Neo Cepacol Collutorio (Methyl Salicylate) Cream has demonstrated a high rate of contact sensitization (allergenicity). Care should be taken by the physician applying Neo Cepacol Collutorio (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.Neo Cepacol Collutorio (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 Neo Cepacol Collutorio Cream. Thick (hyperkeratotic) actinic keratoses should not be treated with Neo Cepacol Collutorio (Methyl Salicylate) Cream. The safety and efficacy of Neo Cepacol Collutorio (Methyl Salicylate) Cream has not been established in patients with immunosuppression, porphyria or pigmented actinic keratoses.

General

Neo Cepacol Collutorio (Methyl Salicylate) Cream Application

During the time period between the application of Neo Cepacol Collutorio (Methyl Salicylate) (methyl aminolevulinate) Cream and exposure to red light illumination, the treatment site will become photosensitive. After Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (Methyl Salicylate) and PDT light treatment. After illumination of Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (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 Neo Cepacol Collutorio 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 Neo Cepacol Collutorio (Methyl Salicylate) Cream should be avoided.

Coagulation defects

Neo Cepacol Collutorio (Methyl Salicylate) Cream has not been tested on patients with inherited or acquired coagulation defects.

Hypersensitivity

Neo Cepacol Collutorio Cream is formulated with refined peanut and almond oil.

Neo Cepacol Collutorio (Methyl Salicylate) (methyl aminolevulinate) Cream has not been tested in patients who are allergic to peanuts. Neo Cepacol Collutorio (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 Neo Cepacol Collutorio 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 Neo Cepacol Collutorio (Methyl Salicylate) Cream.

Carcinogenesis, Mutagenesis, Impairment to Fertility

Long-term studies to evaluate the carcinogenic potential of Neo Cepacol Collutorio (Methyl Salicylate) Cream have not been performed. 

Neo Cepacol Collutorio (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. Neo Cepacol Collutorio (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 Neo Cepacol Collutorio Cream. It is also not known whether Neo Cepacol Collutorio (Methyl Salicylate) Cream can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

Neo Cepacol Collutorio (Methyl Salicylate) Cream should be given to a pregnant woman only if clearly needed.

Nursing Mothers

The amount of Neo Cepacol Collutorio (Methyl Salicylate) aminolevulinate secreted into human breast milk following topical administration of Neo Cepacol Collutorio (Methyl Salicylate) Cream is not known. Because many drugs are secreted in human milk, caution should be exercised when Neo Cepacol Collutorio (Methyl Salicylate) Cream is administered to a nursing mother. If Neo Cepacol Collutorio (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 Neo Cepacol Collutorio 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 Neo Cepacol Collutorio (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 Neo Cepacol Collutorio Cream is an irritant and sensitizer. A provocative cumulative irritancy and sensitization (allergenicity) study of Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (Methyl Salicylate) Cream, were positive (sensitized). Forty subjects refused challenge with Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (Methyl Salicylate) Cream in all clinical studies of Neo Cepacol Collutorio (Methyl Salicylate) -PDT for actinic keratoses.

EventsMetvixia-PDT

(n=130)

Vehicle PDT*

(n=61)

n (%) of patients with AEsn (%) of patients with AEs
Burning sensation skin65 (50.0%)9 (14.8%)
Erythema60 (46.2%)12 (19.7%)
Skin pain27 (20.8%)6 (9.8%)
Stinging skin25 (19.2%)2 (3.3%)
Crusting 20 (15.4%)6 (9.8%)
Edema skin20 (15.4%)1 (1.6%)
Skin peeling14 (10.8%)2 (3.3%)
Blisters14 (10.8%)2 (3.3%)
Bleeding skin11 (8.5%)2 (3.3%)
Pruritus/Itching17 (13.1%) 2 (3.3%)
Skin ulceration7 (5.4%)0 (0%)
Skin infection3 (2.3%)1 (1.6%)
Skin hyper-pigmentation1 (0.8%)0 (0%)

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 Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (Methyl Salicylate) Cream is unknown. Serious erythema and facial edema have been described in European post-marketing reports.

OVERDOSAGE

Neo Cepacol Collutorio Cream Overdose

Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (Methyl Salicylate) Cream should be applied per treatment session.

One Neo Cepacol Collutorio (Methyl Salicylate) -PDT session consists of: 1) Lesion debriding –

Before applying Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (Methyl Salicylate) Cream

Using a spatula, apply a layer of Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (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. Neo Cepacol Collutorio (Methyl Salicylate) Cream is not intended for use with any device other than the approved lamp: CureLight BroadBand Model CureLight 01. Use of Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (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

Neo Cepacol Collutorio 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

Neo Cepacol Collutorio (Methyl Salicylate) Cream 16.8% (phonetic)

Generic name: Neo Cepacol Collutorio (Methyl Salicylate) aminolevulinate hydrochloride

Read this Patient Information before you get treated with Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (Methyl Salicylate) Cream.

What is the most important thing I need to know about Neo Cepacol Collutorio Cream?

  • Neo Cepacol Collutorio (Methyl Salicylate) Cream with light treatment (Photodynamic therapy or PDT) is only done in medical offices by trained doctors.
  • Neo Cepacol Collutorio (Methyl Salicylate) Cream is not applied by patients. Neo Cepacol Collutorio (Methyl Salicylate) Cream should not be applied by doctors who have not been trained in its use.

What is Neo Cepacol Collutorio Cream?

Neo Cepacol Collutorio (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). Neo Cepacol Collutorio (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. Neo Cepacol Collutorio (Methyl Salicylate) Cream and PDT work together to treat AK skin growths.

Neo Cepacol Collutorio (Methyl Salicylate) Cream has not been studied in children for any condition and should not be used in children.

Who should not use Neo Cepacol Collutorio Cream?

Do not use Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (Methyl Salicylate) Cream. The active ingredient is Neo Cepacol Collutorio (Methyl Salicylate) aminolevulinate hydrochloride. Neo Cepacol Collutorio (Methyl Salicylate) Cream also contains peanut and almond oil. See the end of this leaflet for a complete list of ingredients in Neo Cepacol Collutorio (Methyl Salicylate) Cream.

Before treatment with Neo Cepacol Collutorio Cream, tell your doctor:

  • about your medical conditions, including if you
    • are pregnant or planning to become pregnant. It is not known if Neo Cepacol Collutorio (Methyl Salicylate) Cream can harm your unborn baby.
    • are breastfeeding. It is not known if Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (Methyl Salicylate) Cream and other medicines can affect each other.

How should I use Neo Cepacol Collutorio Cream?

  • Neo Cepacol Collutorio (Methyl Salicylate) Cream and PDT treatment is only done by trained doctors.
  • You will receive 2 treatments with Neo Cepacol Collutorio (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.”)
  • Neo Cepacol Collutorio (Methyl Salicylate) Cream is for skin use only. Do not get Neo Cepacol Collutorio (Methyl Salicylate) Cream in your eyes, mouth, or nose. Tell your doctor right away if this happens.

What should I avoid while using Neo Cepacol Collutorio Cream?

During the 3 hours that Neo Cepacol Collutorio (Methyl Salicylate) Cream is on your skin:

  • Avoid exposure to sunlight or bright indoor light during the 3 hours that Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (Methyl Salicylate) Cream is on your skin. Wear warm clothing and keep your treated skin site covered if you are in cold temperatures.
If for some unavoidable reason you are not treated with the lamp you should
  • 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 Neo Cepacol Collutorio Cream with PDT treatment?

Common side effects of Neo Cepacol Collutorio (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
Tell your doctor if you get any of these side effects. Your healthcare provider should be able to treat these reactions according to standard treatments for such skin reactions. These reactions usually go away within 10 days of treatment. Redness may last for up to 1 month. If any of your skin reactions get worse and last longer than 3 weeks, call your doctor. These are not all the side effects of Neo Cepacol Collutorio (Methyl Salicylate) Cream with PDT. Ask your doctor or pharmacist for more information.

General information about Neo Cepacol Collutorio Cream

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

This leaflet summarizes the most important information about Neo Cepacol Collutorio (Methyl Salicylate) Cream. If you would like more information, talk with your doctor. You can ask your doctor for information about Neo Cepacol Collutorio (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 Neo Cepacol Collutorio Cream?

Active Ingredient: Neo Cepacol Collutorio (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 Neo Cepacol Collutorio Cream and PDT

Figure 1: Lesion debriding

Your doctor will prepare your skin by gently scraping (debriding) your skin growths before treating with Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (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 Neo Cepacol Collutorio (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

Neo Cepacol Collutorio (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 Diphosphate:


1 INDICATIONS AND USAGE

Neo Cepacol Collutorio nitrite is indicated for sequential use with Neo Cepacol Collutorio (Sodium Diphosphate) 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

Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite Injection is indicated for sequential use with Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio 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, Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite Injection and Neo Cepacol Collutorio (Sodium Diphosphate) Thiosulfate Injection should be administered without delay.

Symptoms Signs
  • Headache
  • Confusion
  • Dyspnea
  • Chest Tightness
  • Nausea
  • Altered Mental Status

    (e.g., confusion, disorientation)

  • Seizures or Coma
  • Mydriasis
  • Tachypnea/Hyperpnea (early)
  • Bradypnea/Apnea (late)
  • Hypertension (early)/ Hypotension (late)
  • Cardiovascular Collapse
  • Vomiting
  • Plasma Lactate Concentration ≥ 8 mmol/L

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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate, simultaneously with Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate, with Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Age Intravenous Dose of Neo Cepacol Collutorio Nitrite and Neo Cepacol Collutorio (Sodium Diphosphate) Thiosulfate
Adults
  • Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite -10 mL of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite at the rate of 2.5 to 5 mL/minute
  • Neo Cepacol Collutorio (Sodium Diphosphate) Thiosulfate - 50 mL of Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate immediately following administration of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite.
Children
  • Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Neo Cepacol Collutorio (Sodium Diphosphate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Neo Cepacol Collutorio (Sodium Diphosphate) nitrite and Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite, followed by Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Neo Cepacol Collutorio (Sodium Diphosphate) nitrite and Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate.

Neo Cepacol Collutorio (Sodium Diphosphate) nitrite injection and Neo Cepacol Collutorio (Sodium Diphosphate) 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. Neo Cepacol Collutorio (Sodium Diphosphate) nitrite should be administered first, followed immediately by Neo Cepacol Collutorio (Sodium Diphosphate) 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.

Age Intravenous Dose of Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite and Neo Cepacol Collutorio (Sodium Diphosphate) Thiosulfate
Adults
  • Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite -10 mL of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite at the rate of 2.5 to 5 mL/minute
  • Neo Cepacol Collutorio (Sodium Diphosphate) Thiosulfate - 50 mL of Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate immediately following administration of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite.
Children
  • Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Neo Cepacol Collutorio (Sodium Diphosphate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Neo Cepacol Collutorio (Sodium Diphosphate) nitrite and Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Neo Cepacol Collutorio (Sodium Diphosphate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate and Neo Cepacol Collutorio (Sodium Diphosphate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite Injection consists of:

  • One vial of Neo Cepacol Collutorio (Sodium Diphosphate) 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: Neo Cepacol Collutorio 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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. Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Neo Cepacol Collutorio (Sodium Diphosphate) nitrite whenever possible. When Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite administered to an adult. Neo Cepacol Collutorio (Sodium Diphosphate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Neo Cepacol Collutorio 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite.

5.7 Use with Other Drugs

Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite.

The medical literature has reported the following adverse events in association with Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Neo Cepacol Collutorio 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. Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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, Neo Cepacol Collutorio (Sodium Diphosphate) 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, Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Neo Cepacol Collutorio (Sodium Diphosphate) 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, Neo Cepacol Collutorio 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite is excreted in human milk. Because Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite. In studies conducted with Long-Evans rats, Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio nitrite in conjunction with Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Neo Cepacol Collutorio (Sodium Diphosphate) 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.

Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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

Neo Cepacol Collutorio (Sodium Diphosphate) 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

Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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

Neo Cepacol Collutorio (Sodium Diphosphate) nitrite has the chemical name nitrous acid Neo Cepacol Collutorio (Sodium Diphosphate) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:

Structure of Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite

Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite injection.

Neo Cepacol Collutorio (Sodium Diphosphate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite in 10 mL solution (30 mg/mL). Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio nitrite and Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite

Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite. It has been suggested that Neo Cepacol Collutorio (Sodium Diphosphate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Neo Cepacol Collutorio (Sodium Diphosphate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Neo Cepacol Collutorio (Sodium Diphosphate) 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. Neo Cepacol Collutorio (Sodium Diphosphate) 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

Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite

When 4 mg/kg Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite

Neo Cepacol Collutorio (Sodium Diphosphate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Neo Cepacol Collutorio (Sodium Diphosphate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite and Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Neo Cepacol Collutorio (Sodium Diphosphate) 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. Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Neo Cepacol Collutorio (Sodium Diphosphate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Neo Cepacol Collutorio (Sodium Diphosphate) 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. Neo Cepacol Collutorio (Sodium Diphosphate) 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. Neo Cepacol Collutorio (Sodium Diphosphate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite and Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Neo Cepacol Collutorio (Sodium Diphosphate) nitrite or 1 g/kg Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate alone or in sequence immediately after subcutaneous injection of Neo Cepacol Collutorio (Sodium Diphosphate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Neo Cepacol Collutorio (Sodium Diphosphate) nitrite and/or 0.5 g/kg Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Neo Cepacol Collutorio (Sodium Diphosphate) cyanide required to cause death, and when administered together, Neo Cepacol Collutorio (Sodium Diphosphate) nitrite and Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) nitrite and Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite and Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite, with or without Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) thiosulfate report its use in conjunction with Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) 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 Neo Cepacol Collutorio (Sodium Diphosphate) Nitrite carton (NDC 60267-311-10) consists of the following:

  • One 10 mL glass vial of Neo Cepacol Collutorio (Sodium Diphosphate) nitrite injection 30 mg/mL (containing 300 mg of Neo Cepacol Collutorio (Sodium Diphosphate) 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: Neo Cepacol Collutorio (Sodium Diphosphate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Neo Cepacol Collutorio 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

Neo Cepacol Collutorio (Sodium Diphosphate) 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

Neo Cepacol Collutorio (Sodium Diphosphate) 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

Sodium Phosphate:


1 INDICATIONS AND USAGE

Neo Cepacol Collutorio nitrite is indicated for sequential use with Neo Cepacol Collutorio (Sodium Phosphate) 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

Neo Cepacol Collutorio (Sodium Phosphate) Nitrite Injection is indicated for sequential use with Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio 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, Neo Cepacol Collutorio (Sodium Phosphate) Nitrite Injection and Neo Cepacol Collutorio (Sodium Phosphate) Thiosulfate Injection should be administered without delay.

Symptoms Signs
  • Headache
  • Confusion
  • Dyspnea
  • Chest Tightness
  • Nausea
  • Altered Mental Status

    (e.g., confusion, disorientation)

  • Seizures or Coma
  • Mydriasis
  • Tachypnea/Hyperpnea (early)
  • Bradypnea/Apnea (late)
  • Hypertension (early)/ Hypotension (late)
  • Cardiovascular Collapse
  • Vomiting
  • Plasma Lactate Concentration ≥ 8 mmol/L

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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate, simultaneously with Neo Cepacol Collutorio (Sodium Phosphate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate, with Neo Cepacol Collutorio (Sodium Phosphate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Age Intravenous Dose of Neo Cepacol Collutorio Nitrite and Neo Cepacol Collutorio (Sodium Phosphate) Thiosulfate
Adults
  • Neo Cepacol Collutorio (Sodium Phosphate) Nitrite -10 mL of Neo Cepacol Collutorio (Sodium Phosphate) nitrite at the rate of 2.5 to 5 mL/minute
  • Neo Cepacol Collutorio (Sodium Phosphate) Thiosulfate - 50 mL of Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate immediately following administration of Neo Cepacol Collutorio (Sodium Phosphate) nitrite.
Children
  • Neo Cepacol Collutorio (Sodium Phosphate) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Neo Cepacol Collutorio (Sodium Phosphate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Neo Cepacol Collutorio (Sodium Phosphate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Neo Cepacol Collutorio (Sodium Phosphate) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Neo Cepacol Collutorio (Sodium Phosphate) nitrite and Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite, followed by Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Neo Cepacol Collutorio (Sodium Phosphate) nitrite and Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate.

Neo Cepacol Collutorio (Sodium Phosphate) nitrite injection and Neo Cepacol Collutorio (Sodium Phosphate) 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. Neo Cepacol Collutorio (Sodium Phosphate) nitrite should be administered first, followed immediately by Neo Cepacol Collutorio (Sodium Phosphate) 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.

Age Intravenous Dose of Neo Cepacol Collutorio (Sodium Phosphate) Nitrite and Neo Cepacol Collutorio (Sodium Phosphate) Thiosulfate
Adults
  • Neo Cepacol Collutorio (Sodium Phosphate) Nitrite -10 mL of Neo Cepacol Collutorio (Sodium Phosphate) nitrite at the rate of 2.5 to 5 mL/minute
  • Neo Cepacol Collutorio (Sodium Phosphate) Thiosulfate - 50 mL of Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate immediately following administration of Neo Cepacol Collutorio (Sodium Phosphate) nitrite.
Children
  • Neo Cepacol Collutorio (Sodium Phosphate) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Neo Cepacol Collutorio (Sodium Phosphate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Neo Cepacol Collutorio (Sodium Phosphate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Neo Cepacol Collutorio (Sodium Phosphate) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Neo Cepacol Collutorio (Sodium Phosphate) nitrite and Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Neo Cepacol Collutorio (Sodium Phosphate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Neo Cepacol Collutorio (Sodium Phosphate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate and Neo Cepacol Collutorio (Sodium Phosphate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Neo Cepacol Collutorio (Sodium Phosphate) Nitrite Injection consists of:

  • One vial of Neo Cepacol Collutorio (Sodium Phosphate) 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: Neo Cepacol Collutorio 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 Neo Cepacol Collutorio (Sodium Phosphate) 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. Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Neo Cepacol Collutorio (Sodium Phosphate) nitrite whenever possible. When Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite administered to an adult. Neo Cepacol Collutorio (Sodium Phosphate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Neo Cepacol Collutorio 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite.

5.7 Use with Other Drugs

Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite.

The medical literature has reported the following adverse events in association with Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Neo Cepacol Collutorio 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. Neo Cepacol Collutorio (Sodium Phosphate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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, Neo Cepacol Collutorio (Sodium Phosphate) 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, Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Neo Cepacol Collutorio (Sodium Phosphate) 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, Neo Cepacol Collutorio 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite is excreted in human milk. Because Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Neo Cepacol Collutorio (Sodium Phosphate) nitrite. In studies conducted with Long-Evans rats, Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio nitrite in conjunction with Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Neo Cepacol Collutorio (Sodium Phosphate) 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.

Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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

Neo Cepacol Collutorio (Sodium Phosphate) 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

Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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

Neo Cepacol Collutorio (Sodium Phosphate) nitrite has the chemical name nitrous acid Neo Cepacol Collutorio (Sodium Phosphate) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:

Structure of Neo Cepacol Collutorio (Sodium Phosphate) Nitrite

Neo Cepacol Collutorio (Sodium Phosphate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Neo Cepacol Collutorio (Sodium Phosphate) nitrite injection.

Neo Cepacol Collutorio (Sodium Phosphate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Neo Cepacol Collutorio (Sodium Phosphate) nitrite in 10 mL solution (30 mg/mL). Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio nitrite and Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Neo Cepacol Collutorio (Sodium Phosphate) Nitrite

Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite. It has been suggested that Neo Cepacol Collutorio (Sodium Phosphate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Neo Cepacol Collutorio (Sodium Phosphate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Neo Cepacol Collutorio (Sodium Phosphate) 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. Neo Cepacol Collutorio (Sodium Phosphate) 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

Neo Cepacol Collutorio (Sodium Phosphate) Nitrite

When 4 mg/kg Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Neo Cepacol Collutorio (Sodium Phosphate) Nitrite

Neo Cepacol Collutorio (Sodium Phosphate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Neo Cepacol Collutorio (Sodium Phosphate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite and Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Neo Cepacol Collutorio (Sodium Phosphate) 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. Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Neo Cepacol Collutorio (Sodium Phosphate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Neo Cepacol Collutorio (Sodium Phosphate) 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. Neo Cepacol Collutorio (Sodium Phosphate) 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. Neo Cepacol Collutorio (Sodium Phosphate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Neo Cepacol Collutorio (Sodium Phosphate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite and Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Neo Cepacol Collutorio (Sodium Phosphate) nitrite or 1 g/kg Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate alone or in sequence immediately after subcutaneous injection of Neo Cepacol Collutorio (Sodium Phosphate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Neo Cepacol Collutorio (Sodium Phosphate) nitrite and/or 0.5 g/kg Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Neo Cepacol Collutorio (Sodium Phosphate) cyanide required to cause death, and when administered together, Neo Cepacol Collutorio (Sodium Phosphate) nitrite and Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) nitrite and Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Neo Cepacol Collutorio (Sodium Phosphate) nitrite and Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Neo Cepacol Collutorio (Sodium Phosphate) nitrite, with or without Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) thiosulfate report its use in conjunction with Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) 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 Neo Cepacol Collutorio (Sodium Phosphate) Nitrite carton (NDC 60267-311-10) consists of the following:

  • One 10 mL glass vial of Neo Cepacol Collutorio (Sodium Phosphate) nitrite injection 30 mg/mL (containing 300 mg of Neo Cepacol Collutorio (Sodium Phosphate) 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: Neo Cepacol Collutorio (Sodium Phosphate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Neo Cepacol Collutorio 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

Neo Cepacol Collutorio (Sodium Phosphate) 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

Neo Cepacol Collutorio (Sodium Phosphate) 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

Neo Cepacol Collutorio pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Neo Cepacol Collutorio available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Neo Cepacol Collutorio destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Neo Cepacol Collutorio Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Neo Cepacol Collutorio pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."MYOGESIC-CS (MENTHOL ) SPRAY [VETGENIX]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."IMADA RED FLOWER ANALGESIC (METHYL SALICYLATE) OIL [LUEN WAH HK MEDICINE LTD]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."GENT-L-TIP (SODIUM PHOSPHATE) ENEMA [CHESTER PACKAGING]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Neo Cepacol Collutorio?

Depending on the reaction of the Neo Cepacol Collutorio after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Neo Cepacol Collutorio not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Neo Cepacol Collutorio addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Neo Cepacol Collutorio, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Neo Cepacol Collutorio consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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