Pregaine Clear Gel Shampoo

Citric Acid:

• Description
• Action
• Indications
• Contraindications
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Pregaine Clear Gel Shampoo (Citric Acid) reviews

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DESCRIPTION

The product is a clear, colorless solution containing Pregaine Clear Gel Shampoo (Citric Acid) Acid USP 640 mg/5 mL, and Hydrous Sodium Citrate USP 490 mg/5 mL. It also contains Methylparaben NF and Propylparaben NF as preservatives. These concentrations yield 1 mEq of sodium, equivalent to 1 mEq of bicarbonate per mL of solution.

ACTION

Oral citrate solution is used as a systemic and urinary alkalinizer. Less than 5% of the citrate is excreted in the urine unchanged, since citrate oxidation is to a great extent complete.

INDICATIONS

Pregaine Clear Gel Shampoo (Citric Acid)^® is indicated for the treatment of metabolic acidosis. This solution is also useful in conditions where long term maintenance of alkaline urine is needed (e.g. uric acid and cystine calculi of the urinary tract). Pregaine Clear Gel Shampoo (Citric Acid)^® is also effective in treatment for acidosis of certain renal tubular disorders.

CONTRAINDICATIONS

Pregaine Clear Gel Shampoo (Citric Acid)^® is contraindicated in patients with severe renal impairment, oliguria or azotemia, untreated Addison's disease, adynamia episodica hereditaria, acute dehydration, heat cramp, anuria, severe myocardial damage, and hyperkalemia.

PRECAUTIONS

The citrate solution should be used with caution in patients with impaired renal function to avoid hypernatremia or alkalosis in the presence of hypocalcemia. Periodic determinations of serum electrolyte levels (especially bicarbonate levels) should be done in patients with renal disease to avoid cardiac failure, hypertension, peripheral and pulmonary edema, and toxemia of pregnancy. The solution should be diluted with water and preferably taken after meals to avoid saline laxative effects.

ADVERSE REACTIONS

Citrate solution is generally well tolerated when given in recommended doses when the patient has normal renal functions.

DOSAGE AND ADMINISTRATION

The dose of Pregaine Clear Gel Shampoo (Citric Acid)^® is 10 to 30 mL, diluted with water, after meals and at bedtime. The dose should be titrated to achieve desired effects.

HOW SUPPLIED

Pregaine Clear Gel Shampoo ^® is supplied in 500 mL bottles (NDC 46287-014-01), 30 mL unit dose bottles, 10 bottles per carton (NDC 46287-014-30), and 15 mL unit dose bottles, 10 bottles per carton (NDC 46287-014-15).

PHARMACIST

Dispense in well-closed containers.

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F)..

CMP Pharma, Inc.

Post Office Box 147

Farmville, North Carolina 27828

Revised July 2015

Copyright ^© CMP Pharma, Inc. 2015

NDC 46287-014-01

500 mL

Pregaine Clear Gel Shampoo (Citric Acid)^®

ORAL CITRATE (SHOHL'S) SOLUTION

CONTAINS: Hydrous Sodium Citrate USP 490 mg/5 mL;

Pregaine Clear Gel Shampoo (Citric Acid) Acid USP 640 mg/5 mL; Methylparaben NF;

Propylparaben NF; Alcohol USP 0.25%.

USUAL

Dosage: See package insert.

Dispense in a well-closed container.

Store at 20°-25°C (68°-77°F); excursions permitted

to 15°-30°C (59°-86°F). [See USP Controlled Room

Temperature].

Rx Only

LOT:

EXP:

CMP

PHARMA

Farmville, NC 27828

Edetate Disodium:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• Pregaine Clear Gel Shampoo (Edetate Disodium) reviews

INDICATIONS AND USAGE

Pregaine Clear Gel Shampoo (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

Pregaine Clear Gel Shampoo (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

Pregaine Clear Gel Shampoo 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. Pregaine Clear Gel Shampoo (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 Pregaine Clear Gel Shampoo 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 Pregaine Clear Gel Shampoo (Edetate Disodium) calcium disodium in animals.⁷ Pregaine Clear Gel Shampoo (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 Pregaine Clear Gel Shampoo 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 Pregaine Clear Gel Shampoo.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 Pregaine Clear Gel Shampoo (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

Pregaine Clear Gel Shampoo (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 Pregaine Clear Gel Shampoo 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, Pregaine Clear Gel Shampoo (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; Pregaine Clear Gel Shampoo (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 .)

ADVERSE REACTIONS

The following adverse effects have been associated with the use of Pregaine Clear Gel Shampoo (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. Pregaine Clear Gel Shampoo 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 Pregaine Clear Gel Shampoo (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 Pregaine Clear Gel Shampoo (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 Pregaine Clear Gel Shampoo (Edetate Disodium) calcium disodium is dialyzable.

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 Pregaine Clear Gel Shampoo 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

Pregaine Clear Gel Shampoo (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 Pregaine Clear Gel Shampoo (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 Pregaine Clear Gel Shampoo (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.

Pregaine Clear Gel Shampoo (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 Pregaine Clear Gel Shampoo (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 Pregaine Clear Gel Shampoo (Edetate Disodium) should be stopped whenever there is cessation of urine flow in order to avoid unduly high tissue levels of the drug. Pregaine Clear Gel Shampoo (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 Pregaine Clear Gel Shampoo (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. Pregaine Clear Gel Shampoo (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 Pregaine Clear Gel Shampoo (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 Pregaine Clear Gel Shampoo (Edetate Disodium); 1 ml of 1% lidocaine or procaine solution per ml of concentrated Pregaine Clear Gel Shampoo (Edetate Disodium). When used alone, regardless of method of administration, Pregaine Clear Gel Shampoo (Edetate Disodium) should not be given at doses larger than those recommended.

Diagnostic Test

Several methods have been described for lead mobilization tests using Pregaine Clear Gel Shampoo (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. Pregaine Clear Gel Shampoo (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

Pregaine Clear Gel Shampoo (Edetate Disodium) injection, 5 mL ampul containing 200 mg of Pregaine Clear Gel Shampoo (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 Pregaine Clear Gel Shampoo (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

Fragrance:

• Pharmacological action
• Pharmacokinetics
• Why is Pregaine Clear Gel Shampoo prescribed?
• Dosage and administration
• Pregaine Clear Gel Shampoo (Fragrance) side effects, adverse reactions
• Pregaine Clear Gel Shampoo contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Pregaine Clear Gel Shampoo drug interactions
• Pregaine Clear Gel Shampoo (Fragrance) reviews

Pharmacological action

Pregaine Clear Gel Shampoo is an antiseptic. This medication is a quaternary ammonium compound, belongs to the cationic surfactant. Benzalkonium chloride has antimicrobial and antiviral activity against Neisseria gonorrhoeae, Chlamydia spp., Trichomonas vaginalis, Herpes simplex Type 2, Staphylococcus aureus, little active against Gardnerella vaginalis, Candida albicans, Haemophilus ducreyi and Treponema pallidum.

Pregaine Clear Gel Shampoo (Fragrance) is not active against Mycoplasma spp.

This medicine exerts spermicidal action which is due to the ability to damage the sperm membrane; inhibits sperm motility, disrupting electrolyte balance of the aqueous phase of cervical mucus.

Pharmacokinetics

Pregaine Clear Gel Shampoo (Fragrance) for external and local application is practically not absorbed.

Why is Pregaine Clear Gel Shampoo prescribed?

For external use only. Topical solution - a primary and delayed primary wound treatment, prevention of secondary infection of wounds hospital strains of microorganisms (injury of soft and bone tissue, burns), festering wounds, drainage of bone cavities following surgery for osteomyelitis.

Weight thick - superficial thermal burns, trophic ulcers, long-unhealed wounds of soft tissues (including infected), pyo-inflammatory skin diseases and diabetes mellitus; paraproctitis.

Tablets and capsules for intravaginal use, vaginal suppositories, creams, tampons - local contraception for women of reproductive age: for the presence of contraindications to the use of oral contraceptives or intrauterine devices, in the postpartum period, lactation, after the termination of pregnancy in premenopause period at irregular sexual life, omission or delay in receiving consistently used oral contraceptives.

Liquid concentrate - disinfection of facilities and medical products.

Dosage and administration

Topically. The solution was diluted with distilled water to make 1% aqueous solution, impregnated gauze dressings, napkins or tampons and put on the wound daily.

Mass is applied at the rate of 0.2-0.4 g/cm2 of wound surface, pre-clean the wound from the purulent discharge, necrotic tissue, or impose gauze or use turundas impregnated with drugs. The maximum daily dose is 50 g. Ligation is carried out daily, the course of treatment is 14 days.

Intravaginally. Benzalkonium chloride entered deeply into the vagina before coition; in case of repeated sexual intercourse it should be re-imposition of tablets, capsules, suppositories, creams; tampon can be removed not earlier than 3 h after the last sexual intercourse but no later than 24 hours after its installation (with repeated sexual acts for 1 day shift tampon is not required).

Concentrate Liquid. Benzalkonium chloride used for disinfection after prior dilution with water.

Pregaine Clear Gel Shampoo (Fragrance) side effects, adverse reactions

Contact dermatitis, candidiasis, vulvovaginal and allergic reactions.

With prolonged use of Pregaine Clear Gel Shampoo (Fragrance) it is possible a local irritation.

Pregaine Clear Gel Shampoo contraindications

Hypersensitivity to benzalkonium chloride, contact dermatitis, malignant neoplasm of the skin; for intravaginal use - coleitis, ulceration and irritation of the mucous membrane of the vagina and uterus.

Using during pregnancy and breastfeeding

Pregaine Clear Gel Shampoo has no negative impact on pregnancy. This medicine is not excreted in breast milk and it can be used during lactation.

Special instructions

To improve the efficiency it requires careful observance of the application method. Benzalkonium chloride can be used in conjunction with a vaginal diaphragm or intrauterine device. You should avoid bathing or irrigation of the vagina with soapy water for 2 hours before and within 2 hours after sexual intercourse (this medication is destroyed by soap), outdoor toilet is only possible with clean water.

Benzalkonium chloride is incompatible with soaps and other anionic surfactants as well as citrates, iodides, nitrates, permanganates, salicylates, silver salts and tartrates.

Pregaine Clear Gel Shampoo drug interactions

Any substance introduced intravaginally can reduce local spermicidal action (including soaps and solutions containing it). Iodine solutions inactivate Pregaine Clear Gel Shampoo (Fragrance).

Propylene Glycol:

• Pregaine Clear Gel Shampoo (Propylene Glycol) reviews

Sodium Chloride:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Pregaine Clear Gel Shampoo (Sodium Chloride) reviews

1 INDICATIONS AND USAGE

Pregaine Clear Gel Shampoo nitrite is indicated for sequential use with Pregaine Clear Gel Shampoo (Sodium Chloride) 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

Pregaine Clear Gel Shampoo (Sodium Chloride) Nitrite Injection is indicated for sequential use with Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo 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, Pregaine Clear Gel Shampoo (Sodium Chloride) Nitrite Injection and Pregaine Clear Gel Shampoo (Sodium Chloride) Thiosulfate Injection should be administered without delay.

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

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

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) thiosulfate, simultaneously with Pregaine Clear Gel Shampoo (Sodium Chloride) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Pregaine Clear Gel Shampoo (Sodium Chloride) thiosulfate, with Pregaine Clear Gel Shampoo (Sodium Chloride) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

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

Pregaine Clear Gel Shampoo (Sodium Chloride) nitrite injection and Pregaine Clear Gel Shampoo (Sodium Chloride) 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. Pregaine Clear Gel Shampoo (Sodium Chloride) nitrite should be administered first, followed immediately by Pregaine Clear Gel Shampoo (Sodium Chloride) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Pregaine Clear Gel Shampoo (Sodium Chloride) nitrite and Pregaine Clear Gel Shampoo (Sodium Chloride) thiosulfate.

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

3 DOSAGE FORMS AND STRENGTHS

Pregaine Clear Gel Shampoo (Sodium Chloride) Nitrite Injection consists of:

• One vial of Pregaine Clear Gel Shampoo (Sodium Chloride) 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: Pregaine Clear Gel Shampoo 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 Pregaine Clear Gel Shampoo (Sodium Chloride) 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. Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo nitrite.

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

5.3 Anemia

Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Pregaine Clear Gel Shampoo 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 Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo 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 Pregaine Clear Gel Shampoo (Sodium Chloride) nitrite.

5.7 Use with Other Drugs

Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) nitrite.

The medical literature has reported the following adverse events in association with Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Pregaine Clear Gel Shampoo 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. Pregaine Clear Gel Shampoo (Sodium Chloride) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) 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, Pregaine Clear Gel Shampoo (Sodium Chloride) 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, Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

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

Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) 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

Pregaine Clear Gel Shampoo (Sodium Chloride) 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

Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) 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

Pregaine Clear Gel Shampoo (Sodium Chloride) nitrite has the chemical name nitrous acid Pregaine Clear Gel Shampoo (Sodium Chloride) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Pregaine Clear Gel Shampoo (Sodium Chloride) Nitrite

Pregaine Clear Gel Shampoo (Sodium Chloride) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Pregaine Clear Gel Shampoo (Sodium Chloride) nitrite injection.

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

Pregaine Clear Gel Shampoo (Sodium Chloride) Nitrite

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

Pregaine Clear Gel Shampoo (Sodium Chloride) 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. Pregaine Clear Gel Shampoo (Sodium Chloride) 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

Pregaine Clear Gel Shampoo (Sodium Chloride) Nitrite

When 4 mg/kg Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Pregaine Clear Gel Shampoo (Sodium Chloride) Nitrite

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

Mutagenesis

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

While intravenous injection of Pregaine Clear Gel Shampoo (Sodium Chloride) nitrite and Pregaine Clear Gel Shampoo (Sodium Chloride) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Pregaine Clear Gel Shampoo (Sodium Chloride) nitrite, with or without Pregaine Clear Gel Shampoo (Sodium Chloride) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) thiosulfate report its use in conjunction with Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Pregaine Clear Gel Shampoo (Sodium Chloride) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Pregaine Clear Gel Shampoo (Sodium Chloride) nitrite injection 30 mg/mL (containing 300 mg of Pregaine Clear Gel Shampoo (Sodium Chloride) 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: Pregaine Clear Gel Shampoo (Sodium Chloride) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Pregaine Clear Gel Shampoo 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

Pregaine Clear Gel Shampoo (Sodium Chloride) 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

Pregaine Clear Gel Shampoo (Sodium Chloride) 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 Lauryl Sulfate:

• Pregaine Clear Gel Shampoo (Sodium Lauryl Sulfate) reviews

Indication: SLS is used as a surfactant in shampoos and toothpastes. SLS also has microbicidal activities against both enveloped (Herpes simplex viruses, HIV-1, Semliki Forest virus) and nonenveloped (papillomaviruses, reovirus, rotavirus and poliovirus) viruses, although it has not been approved for this use.

SLS is an anionic surfactant. Its amphiphilic properties make it an ideal detergent.

Water:

• Active ingredient
• Purpose
• Uses
• Warnings
• Directions
• Other information
• Inactive ingredients
• Questions?
• Pregaine Clear Gel Shampoo (Water) reviews

Active ingredient

Pregaine Clear Gel Shampoo (Water) 99.8%

Purpose

Emergency eyewash

Uses

• for flushing or irrigating the eye to reduce chances of severe injury caused by acid, alkali, or particulate contamination.

Warnings

For external use only

Do not use

• if solution changes color or gets cloudy
• with contact lenses
• if twist-off top is broken or missing
• in open wounds in or near the eyes
  

When using this product

• avoid contamination, do not touch tip of container to any surface
  

When using this product

• avoid contamination, do not touch tip of container to any surface
  

Stop use and consult a doctor if you have

• changes in vision
• eye pain
• continued redness or irritation of the eye, or if the condition worsens or persists
  

Keep out of reach of children.

If swallowed, get medical help or contact a Poison Control Center right away.

Directions

• remove contacts before using
• twist top to remove
• flush the affected eye as needed, controlling the rate of flow of the solution by pressure on the bottle
  

• if necessary, continue flushing with emergency eyewash or shower
  

• do not reuse
• once opened, discard
  

• obtain medical treatment
  

Other information

• store at room temperature, 15^o to 30^o C (59^o to 86^o F)
• do not freeze
  

Inactive ingredients

Questions?

Sperian Eye and Face Protection, Inc.

(a Honeywell Company)

825 East Highway 151

Platteville, WI 53818 USA