Acunol®

Dosage Form: Oral 600 mg scored tablet. May be swallowed whole, chewed or dissolved in the mouth and swallowed.

How Supplied: Scored tablets, off white in color with green speckles, with LL imprinted on one side and a score on the other side. In child-resistant and tamper-resistant bottle of 90 tablets.

Dosage & Administration:
Take tablets twice a day (b.i.d.) for best results. Dosage is weight dependent:

Kg	Pounds	Starting Dose	Maximum Daily Dose
23 - 45	51 – 100	½ b.i.d.	1 b.i.d.
46 – 68	101 – 150	1 b.i.d.	2 b.i.d.
69 – 90	151 – 200	1 ½ b.i.d	3 b.i.d.
91 +	201 +	2 b.i.d.	4 b.i.d.

Increase dose only if needed on a monthly basis up to the maximum daily dose. Treatment dose and duration depend on the individual.

Absorption of nickel sulphate is variable among patients. For maximum nickel absorption, tablets should be taken orally upon rising at the beginning of the day and at the end of the day before bed. Patients should take nothing but water for one hour after taking medication to aid nickel absorption.

Acunol® may interfere with the effects of oral antibiotics by reducing their absorption. If a patient is taking Tetracycline Antibiotics, allow at least two (2) hours after taking Acunol® before taking a Tetracycline Antibiotic. If a patient is taking Quinolone Antibiotics, allow at least six (6) hours after taking Acunol® before taking a Quinolone Antibiotic.

In the setting of significant renal impairment: dosage should be adjusted and serum nickel and bromide levels should be followed. Steady state trough nickel level should be drawn prior to ingesting the day’s dose after one week of dosing or at appropriate intervals. Target trough serum nickel level is 10 – 40 mcg/L. (Caution: post dose peak levels are unreliable.) Serum bromide assay by spectrophotometry is the historic standard. Concentrations higher than 50 mg/dl may be compatible with toxicity. No therapeutic target levels exist for bromide.

The active ingredients in Acunol® are simple biochemical compounds. The exact mechanism of action is unknown; however, it is known that bromide enhances phagocytic and bactericidal activity of neutrophils.

POTASSIUM BROMIDE & SODIUM BROMIDE dissolve and dissociate in the digestive tract into their ionic constituents. Each tablet contains approximately 30 mg. of bromide (calculated). Ionic bromide is rapidly and completely absorbed from the intestine and distributed almost exclusively in the extracellular fluids. Bromide is eliminated by the kidneys and the elimination half-life is 11 – 12 days.

ZINC SULPHATE dissolves and dissociates in the digestive tract into its ionic constituents. Each tablet contains approximately 5 mg. of zinc (calculated). Zinc is an essential trace mineral necessary for protein synthesis, enzyme stimulation and alkaline balance. It is primarily absorbed from the duodenum and excreted via feces, urine and sweat.

SULPHUR is a naturally occurring mineral that is an essential part of the human body. It exhibits anti-bacterial, anti-parasitic, fungicidal, and keratolytic properties. Each tablet contains approximately 5 mg. of Sulphur (calculated). Sulphur is highly water soluble and as a result is easily excreted by the body via sweat and urine. Since the Sulphur found in Acunol® is a naturally occurring mineral, it is radically different from sulfa drug (sulfonamide antibiotics). Therefore, patients who are allergic to sulfa drugs CAN safely take Acunol®.

NICKEL SULPHATE dissolves and dissociates in the digestive tract into its ionic constituents. Each tablet contains approximately 0.5 mg of ionic nickel (calculated). According to studies, 15% to 50% of ionic nickel is absorbed on a fasted stomach. Food markedly decreases the rate and extent of nickel absorption. Clinical studies show that serum concentrations of nickel are variable among patients after administration. Nickel is in its highly stable divalent cation state and is therefore not expected to be metabolized to any significant degree in the body. Absorbed nickel is primarily excreted in the urine and elimination half-life is about 21 hours. Renal clearance is rapid and efficient, and nickel does not accumulate in the body.

PRECAUTIONS: Lactose Intolerant Patients: May have gastrointestinal difficulty. This has very rarely been reported at the doses used.

Pediatric Patients: Carefully adjust dosage to weight when treating young children.

Pregnancy: Pregnancy category C. Animal reproduction studies have not been conducted with Acunol®.
Acunol® should not be given to a pregnant woman.

Nursing Mothers: It is not known whether this drug is excreted in human milk. However, since many drugs are excreted in human milk, caution should be exercised when Acunol® is administered to a nursing woman.

General Precautions: Use cautiously in setting of kidney disease. If skin rash appears or if nervous symptoms persist, recur frequently, or are unusual, discontinue patient use.

Caution should be used when administering to patients with a history of contact sensitivity to nickel (common metal exposure) or if there is a history of vesicular hand eczema (dyshidrotic, pomphylox). Nickel allergy may be confirmed by a positive nickel patch test. Most patients with hand eczema, positive nickel allergy history, or a positive nickel patch test do not have any untoward reaction to administration of Acunol®. If there is a history of nickel sensitivity or dyshidrotic hand eczema, begin with a very low dose and slowly increase to a recommended starting dose over a period of 5 weeks as tolerated, thus allowing progressive GI absorption.

If new pruritic rashes occur or persist, discontinue Acunol® and treat appropriately. Do not use if there is a history of extra-cutaneous hypersensitivity to nickel or any ingredient in Acunol®.

DRUG INTERACTIONS: There are no known drug interactions. Since copper deficiency in human nutrition has occasionally been induced by supplemental zinc therapy, copper has been added in order to minimize this rate occurrence. For Tetracycline or Quinolones co-administration with Acunol®, see dosage and administration.

Carcinogenesis, mutagenesis, impairment of fertility: No studies have been done on the carcinogenesis, mutagenesis, or impairment of fertility of Acunol®. No carcinogenesis or mutagenesis has been reported in multiple animal studies for oral administration of soluble nickel and bromide salts (active ingredients) even at very high doses.

Effects of soluble potassium bromide: KBr is not listed as a carcinogen by the NTP, IARC and OSHA.
Effects of sodium bromide: NaBr is not listed as a carcinogen by the IARC, NTP and OSHA.
Effects of zinc sulphate: ZnSO4 is not listed as a carcinogen by the ACGIH, IARC, NTP or CA Prop 65.
Effects of sulphur: Sulphur is not listed as a carcinogen by the ACGIH, IARC, NIOSH, NTP or OSHA.
Effects of soluble nickel sulphate: Studies on experimental animals have never indicated that nickel, at any dose, is a carcinogen when introduced to the body orally. Furthermore, nickel sulphate has never been known to induce carcinogenesis via any route of introduction including: oral, inhalation, cutaneous, IM, or IP. No adverse effects were noted on fertility or reproduction in a 3-generational study of albino wistar rates fed up to 1000 ppm Ni per day, which is equivalent to 50 mg/kg per day Ni.

ADVERSE REACTIONS: Acunol® contains low doses of active ingredients; therefore there are minimal known side effects (see Precautions/Hypersensitivity Information).

OVERDOSAGE: Bromide toxicity: Indications of toxicity due to oral over dosage of bromide may include nausea, vomiting, apathy, and disturbed coordination, loss of memory, drowsiness, and loss of emotional control, agitation, hallucination, tremors, depressed reflexes, stupor and coma. Acute toxic reactions in humans have been reported at doses as low as 1000 mg. This level is 33 times the dose received in one tablet of Acunol®.

Zinc sulphate toxicity: Symptoms of acute toxicity of zinc due to oral over dosage can include dehydration, stomach pain, lethargy, dizziness, muscular incoordination and in severe cases renal failure. Chronic zinc toxicity can occur at levels of 100 – 300 mg/d.

Sulphur toxicity: The oral rat LD50 for sulphur is reported to be greater than 5,000 mg/kg. This is more than 11,000 times the maximum dose recommended for Acunol®. Ingestion of toxic levels of sulphur can cause sore throat, nausea, headache, gastrointestinal irritation and possibly unconsciousness in severe cases.

Sulphur poses such a remote risk that it is placed in the lowest toxic category possible, EP Toxicity Category IV. Nickel sulphate toxicity: The oral rat LD50 for nickel sulphate hexahydrate is 275 mg/kg. Symptoms of toxicity due to oral over dosage of nickel sulphate may include nausea, vomiting, abdominal discomfort, diarrhea, giddiness, lassitude, headaches, cough and shortness of breath. The lowest observed transitory toxic effects from human ingestion of soluble nickel salts are approximately 8 mg. nickel/kg body weight. This is 180 times the maximum dose recommended for Acunol®.