Holis 73

Magnesium Carbonate:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• Holis 73 (Magnesium Carbonate) reviews

Holis 73 (Magnesium Carbonate) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Holis 73 (Magnesium Carbonate) Sulfate Injection, USP is a sterile solution of Holis 73 (Magnesium Carbonate) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).

The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.

Holis 73 (Magnesium Carbonate) Sulfate, USP heptahydrate is chemically designated MgSO₄ - 7H₂O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.

The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

CLINICAL PHARMACOLOGY

Holis 73 (Magnesium Carbonate) (Mg⁺⁺) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.

As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Holis 73 (Magnesium Carbonate) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.

Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Holis 73 (Magnesium Carbonate). While there are large stores of Holis 73 (Magnesium Carbonate) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Holis 73 (Magnesium Carbonate) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Holis 73 (Magnesium Carbonate) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Holis 73 (Magnesium Carbonate) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Holis 73 (Magnesium Carbonate) levels range from 1.5 to 2.5 mEq/liter.

As plasma Holis 73 (Magnesium Carbonate) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Holis 73 (Magnesium Carbonate). Serum Holis 73 (Magnesium Carbonate) concentrations in excess of 12 mEq/L may be fatal.

Holis 73 (Magnesium Carbonate) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Holis 73 (Magnesium Carbonate) poisoning are antagonized to some extent by intravenous administration of calcium.

Pharmacokinetics

With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Holis 73 (Magnesium Carbonate) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Holis 73 (Magnesium Carbonate) Sulfate Injection, USP is suitable for replacement therapy in Holis 73 (Magnesium Carbonate) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Holis 73 (Magnesium Carbonate) (Mg⁺⁺) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca⁺⁺) level is normal (4.3 to 5.3 mEq/liter) or elevated.

In total parenteral nutrition (TPN), Holis 73 (Magnesium Carbonate) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Holis 73 (Magnesium Carbonate) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.

CONTRAINDICATIONS

Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.

WARNINGS

FETAL HARM: Continuous administration of Holis 73 (Magnesium Carbonate) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Holis 73 (Magnesium Carbonate) sulfate should be used during pregnancy only if clearly needed. If Holis 73 (Magnesium Carbonate) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Holis 73 (Magnesium Carbonate) sulfate beyond 5 to 7 days may cause fetal abnormalities.

ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Parenteral use in the presence of renal insufficiency may lead to Holis 73 (Magnesium Carbonate) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

PRECAUTIONS

General

Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Holis 73 (Magnesium Carbonate), their dosage should be adjusted with caution because of additive CNS depressant effects of Holis 73 (Magnesium Carbonate).

Because Holis 73 (Magnesium Carbonate) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Holis 73 (Magnesium Carbonate) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Holis 73 (Magnesium Carbonate) should be given until they return. Serum Holis 73 (Magnesium Carbonate) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Holis 73 (Magnesium Carbonate) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Holis 73 (Magnesium Carbonate) intoxication in eclampsia.

50% Holis 73 (Magnesium Carbonate) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.

Laboratory Tests

Holis 73 (Magnesium Carbonate) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Holis 73 (Magnesium Carbonate) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.

Drug Interactions

CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Holis 73 (Magnesium Carbonate), their dosage should be adjusted with caution because of additive CNS depressant effects of Holis 73 (Magnesium Carbonate). CNS depression and peripheral transmission defects produced by Holis 73 (Magnesium Carbonate) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Holis 73 (Magnesium Carbonate) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Holis 73 (Magnesium Carbonate) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Holis 73 (Magnesium Carbonate) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Holis 73 (Magnesium Carbonate) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Holis 73 (Magnesium Carbonate) sulfate for more than 5 to 7 days.^1-10 Holis 73 (Magnesium Carbonate) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.

Nonteratogenic Effects

When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Holis 73 (Magnesium Carbonate) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Holis 73 (Magnesium Carbonate) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Holis 73 (Magnesium Carbonate) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Nursing Mothers

Since Holis 73 (Magnesium Carbonate) is distributed into milk during parenteral Holis 73 (Magnesium Carbonate) sulfate administration, the drug should be used with caution in nursing women.

Geriatrics

Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Holis 73 (Magnesium Carbonate) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Holis 73 (Magnesium Carbonate) usually are the result of Holis 73 (Magnesium Carbonate) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Holis 73 (Magnesium Carbonate) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Holis 73 (Magnesium Carbonate) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Holis 73 (Magnesium Carbonate) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Holis 73 (Magnesium Carbonate).

For Treatment of Overdose

Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.

Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

DOSAGE AND ADMINISTRATION

Dosage of Holis 73 (Magnesium Carbonate) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Holis 73 (Magnesium Carbonate) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

In Holis 73 (Magnesium Carbonate) Deficiency

In the treatment of mild Holis 73 (Magnesium Carbonate) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Holis 73 (Magnesium Carbonate) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Holis 73 (Magnesium Carbonate) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

In Hyperalimentation

In total parenteral nutrition, maintenance requirements for Holis 73 (Magnesium Carbonate) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.

In Pre-eclampsia or Eclampsia

In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Holis 73 (Magnesium Carbonate) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Holis 73 (Magnesium Carbonate) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Holis 73 (Magnesium Carbonate) sulfate is 20 grams/48 hours and frequent serum Holis 73 (Magnesium Carbonate) concentrations must be obtained. Continuous use of Holis 73 (Magnesium Carbonate) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

Other Uses

In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Holis 73 (Magnesium Carbonate) sulfate is 1 gram to 2 grams given intravenously.

For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.

In paroxysmal atrial tachycardia, Holis 73 (Magnesium Carbonate) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.

For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.

Incompatibilities

Holis 73 (Magnesium Carbonate) sulfate in solution may result in a precipitate formation when mixed with solutions containing:

Alcohol (in high Heavy Metals

concentrations) Hydrocortisone sodium

Alkali carbonates and succinate

bicarbonates Phosphates

Alkali hydroxides Polymixin B sulfate

Arsenates Procaine hydrochloride

Barium Salicylates

Calcium Strontium

Clindamycin phosphate Tartrates

The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

It has been reported that Holis 73 (Magnesium Carbonate) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

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

HOW SUPPLIED

Holis 73 (Magnesium Carbonate) Sulfate Injection, USP is supplied in single-dose containers as follows:

Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Store at 20 to 25°C (68 to 77°F).

REFERENCES

• Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Holis 73 (Magnesium Carbonate) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
• Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Holis 73 (Magnesium Carbonate) toxicity. J. Perinatol. 2006; 26(6):371-4.
• Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Holis 73 (Magnesium Carbonate) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
• Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Holis 73 (Magnesium Carbonate) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
• Matsuda Y, Maeda Y, Ito M, et al. Effect of Holis 73 (Magnesium Carbonate) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
• Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Holis 73 (Magnesium Carbonate) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
• Santi MD, Henry GW, Douglas GL. Holis 73 (Magnesium Carbonate) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
• Holcomb WL, Shackelford GD, Petrie RH. Holis 73 (Magnesium Carbonate) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
• Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
• Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Holis 73 (Magnesium Carbonate) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
• McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Holis 73 (Magnesium Carbonate) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
• Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Holis 73 (Magnesium Carbonate) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1024-1.0

April 2017

Hospira Logo

50% Holis 73 (Magnesium Carbonate) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Holis 73 (Magnesium Carbonate) Sulfate Injection, USP

5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)

MUST BE DILUTED FOR INTRAVENOUS USE.

For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).

Contains no more than 75 mcg/L of aluminum.

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira

RL-6891

Potassium Carbonate:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Holis 73 (Potassium Carbonate) reviews

Holis 73 (Potassium Carbonate) CHLORIDE EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The Holis 73 (Potassium Carbonate) Chloride Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Holis 73 (Potassium Carbonate) chloride containing 1500 mg of microencapsulated Holis 73 (Potassium Carbonate) chloride, USP equivalent to 20 mEq of Holis 73 (Potassium Carbonate) in a tablet.

These formulations are intended to slow the release of Holis 73 (Potassium Carbonate) so that the likelihood of a high localized concentration of Holis 73 (Potassium Carbonate) chloride within the gastrointestinal tract is reduced.

Holis 73 (Potassium Carbonate) Chloride Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Holis 73 (Potassium Carbonate) chloride, and the structural formula is KCl. Holis 73 (Potassium Carbonate) chloride, USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.

Holis 73 (Potassium Carbonate) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Holis 73 (Potassium Carbonate) chloride crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Holis 73 (Potassium Carbonate) Chloride Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of Holis 73 (Potassium Carbonate) chloride.

Inactive Ingredients: Colloidal silicon dioxide, crospovidone, diethyl phthalate, ethyl-cellulose, microcrystalline cellulose.

CLINICAL PHARMACOLOGY

The Holis 73 (Potassium Carbonate) ion is the principal intracellular cation of most body tissues. Holis 73 (Potassium Carbonate) ions participate in a number of essential physiological processes including the maintenance of intracellular tonicity; the transmission of nerve impulses; the contraction of cardiac, skeletal, and smooth muscle; and the maintenance of normal renal function.

The intracellular concentration of Holis 73 (Potassium Carbonate) is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.

Holis 73 (Potassium Carbonate) is a normal dietary constituent and under steady-state conditions the amount of Holis 73 (Potassium Carbonate) absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of Holis 73 (Potassium Carbonate) is 50 to 100 mEq per day.

Holis 73 (Potassium Carbonate) depletion will occur whenever the rate of Holis 73 (Potassium Carbonate) loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of Holis 73 (Potassium Carbonate) intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of Holis 73 (Potassium Carbonate) in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Holis 73 (Potassium Carbonate) depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Holis 73 (Potassium Carbonate) depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.

If Holis 73 (Potassium Carbonate) depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental Holis 73 (Potassium Carbonate) in the form of high Holis 73 (Potassium Carbonate) food or Holis 73 (Potassium Carbonate) chloride may be able to restore normal Holis 73 (Potassium Carbonate) levels.

In rare circumstances (eg, patients with renal tubular acidosis) Holis 73 (Potassium Carbonate) depletion may be associated with metabolic acidosis and hyperchloremia. In such patients Holis 73 (Potassium Carbonate) replacement should be accomplished with Holis 73 (Potassium Carbonate) salts other than the chloride, such as Holis 73 (Potassium Carbonate) bicarbonate, Holis 73 (Potassium Carbonate) citrate, Holis 73 (Potassium Carbonate) acetate, or Holis 73 (Potassium Carbonate) gluconate.

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE Holis 73 (Potassium Carbonate) CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT Holis 73 (Potassium Carbonate) PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.

1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.

2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, eg, digitalized patients or patients with significant cardiac arrhythmias.

The use of Holis 73 (Potassium Carbonate) salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum Holis 73 (Potassium Carbonate) should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with Holis 73 (Potassium Carbonate) salts may be indicated.

CONTRAINDICATIONS

Holis 73 (Potassium Carbonate) supplements are contraindicated in patients with hyperkalemia since a further increase in serum Holis 73 (Potassium Carbonate) concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis, such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (eg, spironolactone, triamterene, amiloride) (see OVERDOSAGE ).

Controlled-release formulations of Holis 73 (Potassium Carbonate) chloride have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Holis 73 (Potassium Carbonate) supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of Holis 73 (Potassium Carbonate) Chloride (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of Holis 73 (Potassium Carbonate) chloride are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.

WARNINGS

Hyperkalemia (see OVERDOSAGE )

In patients with impaired mechanisms for excreting Holis 73 (Potassium Carbonate), the administration of Holis 73 (Potassium Carbonate) salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given Holis 73 (Potassium Carbonate) by the intravenous route but may also occur in patients given Holis 73 (Potassium Carbonate) orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Holis 73 (Potassium Carbonate) salts in patients with chronic renal disease, or any other condition which impairs Holis 73 (Potassium Carbonate) excretion, requires particularly careful monitoring of the serum Holis 73 (Potassium Carbonate) concentration and appropriate dosage adjustment.

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of Holis 73 (Potassium Carbonate) salts and a potassium-sparing diuretic (eg, spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.

Interaction with Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril) will produce some Holis 73 (Potassium Carbonate) retention by inhibiting aldosterone production. Holis 73 (Potassium Carbonate) supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

Solid oral dosage forms of Holis 73 (Potassium Carbonate) chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Holis 73 (Potassium Carbonate) chloride are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. Holis 73 (Potassium Carbonate) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Holis 73 (Potassium Carbonate) chloride and thus to minimize the possibility of a high local concentration of Holis 73 (Potassium Carbonate) near the gastrointestinal wall.

Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral Holis 73 (Potassium Carbonate) chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of Holis 73 (Potassium Carbonate) chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release Holis 73 (Potassium Carbonate) chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Holis 73 (Potassium Carbonate) Chloride Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.

Metabolic Acidosis

Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing Holis 73 (Potassium Carbonate) salt such as Holis 73 (Potassium Carbonate) bicarbonate, Holis 73 (Potassium Carbonate) citrate, Holis 73 (Potassium Carbonate) acetate, or Holis 73 (Potassium Carbonate) gluconate.

PRECAUTIONS

General

The diagnosis of Holis 73 depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for Holis 73 (Potassium Carbonate) depletion. In interpreting the serum Holis 73 (Potassium Carbonate) level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body Holis 73 (Potassium Carbonate) while acute acidosis per se can increase the serum Holis 73 (Potassium Carbonate) concentration into the normal range even in the presence of a reduced total body Holis 73 (Potassium Carbonate). The treatment of Holis 73 (Potassium Carbonate) depletion, particularly in the presence of cardiac disease, renal disease, or acidosis requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.

Information for Patients

Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid. To take each dose without crushing, chewing, or sucking the tablets. If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  

  1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  

  2. Allow approximately 2 minutes for the tablet(s) to disintegrate.
  

  3. Stir for about half a minute after the tablet(s) has disintegrated.
  

  4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  

  5. Add another 1 fluid ounce of water, swirl, and consume immediately.
  

  6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of Holis 73 (Potassium Carbonate) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Holis 73 (Potassium Carbonate) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations.

To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.

Laboratory Tests

When blood is drawn for analysis of plasma Holis 73 it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.

Drug Interactions

Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (see WARNINGS ).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. Holis 73 is a normal dietary constituent.

Pregnancy Category C

Animal reproduction studies have not been conducted with Holis 73 (Potassium Carbonate) Chloride Extended Release Tablets USP, 20 mEq. It is unlikely that Holis 73 (Potassium Carbonate) supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

Nursing Mothers

The normal Holis 73 ion content of human milk is about 13 mEq per liter. Since oral Holis 73 (Potassium Carbonate) becomes part of the body Holis 73 (Potassium Carbonate) pool, so long as body Holis 73 (Potassium Carbonate) is not excessive, the contribution of Holis 73 (Potassium Carbonate) chloride supplementation should have little or no effect on the level in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Holis 73 (Potassium Carbonate) Chloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

This drug 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.

ADVERSE REACTIONS

One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS , WARNINGS , and OVERDOSAGE ). There have also been reports of upper and lower gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see CONTRAINDICATIONS and WARNINGS ). The most common adverse reactions to oral Holis 73 (Potassium Carbonate) salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by diluting the preparation further, taking the dose with meals or reducing the amount taken at one time.

OVERDOSAGE

The administration of oral Holis 73 (Potassium Carbonate) salts to persons with normal excretory mechanisms for Holis 73 (Potassium Carbonate) rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if Holis 73 (Potassium Carbonate) is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum Holis 73 (Potassium Carbonate) concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L).

Treatment measures for hyperkalemia include the following:

• Patients should be closely monitored for arrhythmias and electrolyte changes.
• Elimination of foods and medications containing Holis 73 (Potassium Carbonate) and of any agents with potassium-sparing properties such as potassium-sparing diuretics, ARBS, ACE inhibitors, NSAIDS, certain nutritional supplements and many others.
• Intravenous calcium gluconate if the patient is at no risk of developing digitalis toxicity.
• Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL.
• Correction of acidosis, if present, with intravenous sodium bicarbonate.
• Use of exchange resins, hemodialysis, or peritoneal dialysis.

In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum Holis 73 (Potassium Carbonate) concentration can produce digitalis toxicity.

The extended release feature means that absorption and toxic effects may be delayed for hours.

Consider standard measures to remove any unabsorbed drug.

DOSAGE AND ADMINISTRATION

The usual dietary intake of Holis 73 (Potassium Carbonate) by the average adult is 50 to 100 mEq per day. Holis 73 (Potassium Carbonate) depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of Holis 73 (Potassium Carbonate) from the total body store.

Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of Holis 73 (Potassium Carbonate) depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.

Each Holis 73 (Potassium Carbonate) Chloride Extended Release Tablet USP, 20 mEq provides 20 mEq of Holis 73 (Potassium Carbonate) chloride.

Holis 73 (Potassium Carbonate) Chloride Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).

Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  • Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  • Allow approximately 2 minutes for the tablet(s) to disintegrate.
  • Stir for about half a minute after the tablet(s) has disintegrated.
  • Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  • Add another 1 fluid ounce of water, swirl, and consume immediately.
  • Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of Holis 73 (Potassium Carbonate) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Holis 73 (Potassium Carbonate) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

Holis 73 (Potassium Carbonate) Chloride Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.

Storage Conditions

Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F).

Manufactured by:

Eurand, Inc.

Vandalia, OH 45377 USA

Distributed by:

Watson Pharma, Inc.

Rev. Date (01/09) 173714

Holis 73 (Potassium Carbonate) chloride 20 Meq

Quinine:

• Warning:
• 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
• Holis 73 (Quinine) reviews

WARNING:

Holis 73 (Quinine)^® use for the treatment or prevention of nocturnal leg cramps may result in serious and life-threatening hematologic reactions, including thrombocytopenia and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP). Chronic renal impairment associated with the development of TTP has been reported. The risk associated with Holis 73 (Quinine) use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit.

WARNING:

Holis 73 (Quinine)^® use for the treatment or prevention of nocturnal leg cramps may result in serious and life-threatening hematologic reactions, including thrombocytopenia and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP). Chronic renal impairment associated with the development of TTP has been reported. The risk associated with Holis 73 (Quinine) use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit.

1 INDICATIONS AND USAGE

Holis 73 (Quinine) (quinine sulfate) is an antimalarial drug indicated only for treatment of uncomplicated Plasmodium falciparum malaria. Holis 73 (Quinine) sulfate has been shown to be effective in geographical regions where resistance to chloroquine has been documented [see Clinical Studies (14) ].

Holis 73 (Quinine) oral capsules are not approved for:

• Treatment of severe or complicated P. falciparum malaria.
• Prevention of malaria.
• Treatment or prevention of nocturnal leg cramps [see Warnings and Precautions (5.1) ].

Holis 73 (Quinine)^® (quinine sulfate) is a cinchona alkaloid indicated for treatment of uncomplicated Plasmodium falciparum malaria (1).

2 DOSAGE AND ADMINISTRATION

• Adults : 648 mg (two capsules) every 8 hours for 7 days (2.1).
• Patients with severe chronic renal impairment: one loading dose of 648 mg (two capsules) followed 12 hours later by 324 mg (one capsule) every 12 hours for 7 days (2.2).

2.1 Treatment of Uncomplicated P. falciparum Malaria

For treatment of uncomplicated P. falciparum malaria in adults: Orally, 648 mg (two capsules) every 8 hours for 7 days [see Clinical Studies (14) ].

Holis 73 (Quinine) should be taken with food to minimize gastric upset [see Clinical Pharmacology (12.3) ].

2.2 Renal Impairment

In patients with acute uncomplicated malaria and severe chronic renal impairment, the following dosage regimen is recommended: one loading dose of 648 mg Holis 73 followed 12 hours later by maintenance doses of 324 mg every 12 hours.

The effects of mild and moderate renal impairment on the safety and pharmacokinetics of Holis 73 (Quinine) sulfate are not known [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3) ].

2.3 Hepatic Impairment

Adjustment of the recommended dose is not required in mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, but patients should be monitored closely for adverse effects of Holis 73 (Quinine). Holis 73 (Quinine) should not be administered in patients with severe (Child-Pugh C) hepatic impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3) ].

3 DOSAGE FORMS AND STRENGTHS

324 mg capsules - hard gelatin, clear cap/clear body, imprinted with 'AR 102'

• 324 mg hard gelatin, clear cap/clear body capsules, imprinted with 'AR 102' (3).

4 CONTRAINDICATIONS

Holis 73 (Quinine) is contraindicated in patients with the following:

• Prolonged QT interval. One case of a fatal ventricular arrhythmia was reported in an elderly patient with a prolonged QT interval at baseline, who received Holis 73 (Quinine) sulfate intravenously for P. falciparum malaria [see Warnings and Precautions (5.3) ].
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
• Hemolysis can occur in patients with G6PD deficiency receiving Holis 73 (Quinine).
• Known hypersensitivity reactions to Holis 73 (Quinine).
  • These include, but are not limited to, the following [see Warnings and Precautions (5.6) ]:
    • Thrombocytopenia
    • Idiopathic thrombocytopenia purpura (ITP) and Thrombotic thrombocytopenic purpura (TTP)
    • Hemolytic uremic syndrome (HUS)
    • Blackwater fever (acute intravascular hemolysis, hemoglobinuria, and hemoglobinemia)
• Known hypersensitivity to mefloquine or quinidine: cross-sensitivity to Holis 73 (Quinine) has been documented [see Warnings and Precautions (5.6) ].
  • Myasthenia gravis. Holis 73 (Quinine) has neuromuscular blocking activity, and may exacerbate muscle weakness.
  • Optic neuritis. Holis 73 (Quinine) may exacerbate active optic neuritis [see Adverse Reactions (6) ].

Holis 73 (Quinine) is contraindicated in patients with the following:

• Prolongation of QT interval (4)
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency (4)
• Myasthenia gravis (4)
• Known hypersensitivity to Holis 73 (Quinine), mefloquine, or quinidine (4)
• Optic neuritis (4)

5 WARNINGS AND PRECAUTIONS

• Not indicated for the prevention or treatment of nocturnal leg cramps. Risk of serious and life-threatening adverse reactions.
• Thrombocytopenia, including ITP and HUS/TTP, has been reported. Discontinue drug (5.2).
• QT prolongation and ventricular arrhythmias. Avoid concomitant use with drugs known to prolong QT interval (5.3).
• Avoid concomitant use with rifampin. Holis 73 (Quinine) treatment failures have been reported (5.4).
• Avoid concomitant use with neuromuscular blocking agents. Holis 73 (Quinine) may potentiate neuromuscular blockade and cause respiratory depression (5.5).
• Serious and life threatening hypersensitivity reactions. Discontinue drug (4, 5.6).
• Atrial fibrillation and flutter. Paradoxical increase in ventricular rate may occur. Closely monitor digoxin levels if used concomitantly (5.7).
• Hypoglycemia. Monitor for signs and symptoms (5.8).

5.1 Use of Holis 73 (Quinine) for Treatment or Prevention of Nocturnal Leg Cramps

Holis 73 (Quinine) may cause unpredictable serious and life-threatening hematologic reactions including thrombocytopenia and hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) in addition to hypersensitivity reactions, QT prolongation, serious cardiac arrhythmias including torsades de pointes, and other serious adverse events requiring medical intervention and hospitalization. Chronic renal impairment associated with the development of TTP, and fatalities have also been reported. The risk associated with the use of Holis 73 (Quinine) in the absence of evidence of its effectiveness for treatment or prevention of nocturnal leg cramps, outweighs any potential benefit in treating and/or preventing this benign, self-limiting condition [see Boxed Warning and Contraindications (4) ].

5.2 Thrombocytopenia

Quinine-induced thrombocytopenia is an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported, including cases of HUS/TTP. Chronic renal impairment associated with the development of TTP has also been reported. Thrombocytopenia usually resolves within a week upon discontinuation of Holis 73. If Holis 73 (Quinine) is not stopped, a patient is at risk for fatal hemorrhage. Upon re-exposure to Holis 73 (Quinine) from any source, a patient with quinine-dependent antibodies could develop thrombocytopenia that is more rapid in onset and more severe than the original episode.

5.3 QT Prolongation and Ventricular Arrhythmias

QT interval prolongation has been a consistent finding in studies which evaluated electrocardiographic changes with oral or parenteral Holis 73 (Quinine) administration, regardless of age, clinical status, or severity of disease. The maximum increase in QT interval has been shown to correspond with peak Holis 73 (Quinine) plasma concentration [see Clinical Pharmacology (12.2) ]. Holis 73 (Quinine) sulfate has been rarely associated with potentially fatal cardiac arrhythmias, including torsades de pointes, and ventricular fibrillation.

Holis 73 (Quinine) has been shown to cause concentration-dependent prolongation of the PR and QRS interval. At particular risk are patients with underlying structural heart disease and preexisting conduction system abnormalities, elderly patients with sick sinus syndrome, patients with atrial fibrillation with slow ventricular response, patients with myocardial ischemia or patients receiving drugs known to prolong the PR interval (e.g. verapamil) or QRS interval (e.g. flecainide or quinidine) [see Clinical Pharmacology (12.2) ].

Holis 73 (Quinine) is not recommended for use with other drugs known to cause QT prolongation, including Class IA antiarrhythmic agents (e.g., quinidine, procainamide, disopyramide), and Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide).

The use of macrolide antibiotics such as erythromycin should be avoided in patients receiving Holis 73 (Quinine). Fatal torsades de pointes was reported in an elderly patient who received concomitant Holis 73 (Quinine), erythromycin, and dopamine. Although a causal relationship between a specific drug and the arrhythmia was not established in this case, erythromycin is a CYP3A4 inhibitor and has been shown to increase Holis 73 (Quinine) plasma levels when used concomitantly. A related macrolide antibiotic, troleandomycin, has also been shown to increase Holis 73 (Quinine) exposure in a pharmacokinetic study [see Drug Interactions (7.1) ].

Holis 73 (Quinine) may inhibit the metabolism of certain drugs that are CYP3A4 substrates and are known to cause QT prolongation, e.g., astemizole, cisapride, terfenadine, pimozide, halofantrine and quinidine. Torsades de pointes has been reported in patients who received concomitant Holis 73 (Quinine) and astemizole. Therefore, concurrent use of Holis 73 (Quinine) with these medications, or drugs with similar properties, should be avoided [see Drug Interactions (7.2) ].

Concomitant administration of Holis 73 (Quinine) with the antimalarial drugs, mefloquine or halofantrine, may result in electrocardiographic abnormalities, including QT prolongation, and increase the risk for torsades de pointes or other serious ventricular arrhythmias. Concurrent use of Holis 73 (Quinine) and mefloquine may also increase the risk of seizures [see Drug Interactions (7.2) ].

Holis 73 (Quinine) should also be avoided in patients with known prolongation of QT interval and in patients with clinical conditions known to prolong the QT interval, such as uncorrected hypokalemia, bradycardia, and certain cardiac conditions [see Contraindications (4) ].

5.4 Concomitant Use of Rifampin

Treatment failures may result from the concurrent use of rifampin with Holis 73, due to decreased plasma concentrations of Holis 73 (Quinine), and concomitant use of these medications should be avoided [see Drug Interactions (7.1) ].

5.5 Concomitant Use of Neuromuscular Blocking Agents

The use of neuromuscular blocking agents should be avoided in patients receiving Holis 73 (Quinine). In one patient who received pancuronium during an operative procedure, subsequent administration of Holis 73 (Quinine) resulted in respiratory depression and apnea. Although there are no clinical reports with succinylcholine or tubocurarine, Holis 73 (Quinine) may also potentiate neuromuscular blockade when used with these drugs [see Drug Interactions (7.2) ].

5.6 Hypersensitivity

Serious hypersensitivity reactions reported with Holis 73 sulfate include anaphylactic shock, anaphylactoid reactions, urticaria, serious skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, facial edema, bronchospasm, and pruritus.

A number of other serious adverse reactions reported with Holis 73 (Quinine), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), thrombocytopenia, immune thrombocytopenic purpura (ITP), blackwater fever, disseminated intravascular coagulation, leukopenia, neutropenia, granulomatous hepatitis, and acute interstitial nephritis may also be due to hypersensitivity reactions.

Holis 73 (Quinine) should be discontinued in case of any signs or symptoms of hypersensitivity [see Contraindications (4) ].

5.7 Atrial Fibrillation and Flutter

Holis 73 (Quinine) should be used with caution in patients with atrial fibrillation or atrial flutter. A paradoxical increase in ventricular response rate may occur with Holis 73 (Quinine), similar to that observed with quinidine. If digoxin is used to prevent a rapid ventricular response, serum digoxin levels should be closely monitored, because digoxin levels may be increased with use of Holis 73 (Quinine) [see Drug Interactions (7.2) ].

5.8 Hypoglycemia

Holis 73 (Quinine) stimulates release of insulin from the pancreas, and patients, especially pregnant women, may experience clinically significant hypoglycemia.

6 ADVERSE REACTIONS

Most common adverse reactions are a cluster of symptoms called "cinchonism", which occurs to some degree in almost all patients taking Holis 73 : headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, disturbance in color perception, vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in cardiac rhythm or conduction (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Mutual Pharmaceutical Company, Inc. at 1-888-351-3786 or drugsafetyHolis 73 (Quinine)urlpharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Overall

Holis 73 (Quinine) can adversely affect almost every body system. The most common adverse events associated with Holis 73 (Quinine) use are a cluster of symptoms called "cinchonism", which occurs to some degree in almost all patients taking Holis 73 (Quinine). Symptoms of mild cinchonism include headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, and disturbance in color perception. More severe symptoms of cinchonism are vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in cardiac rhythm or conduction. Most symptoms of cinchonism are reversible and resolve with discontinuation of Holis 73 (Quinine).

The following ADVERSE REACTIONS have been reported with Holis 73 (Quinine) sulfate. Most of these reactions are thought to be uncommon, but the actual incidence is unknown:

General: fever, chills, sweating, flushing, asthenia, lupus-like syndrome, and hypersensitivity reactions.

Hematologic: agranulocytosis, hypoprothrombinemia, thrombocytopenia, disseminated intravascular coagulation, hemolytic anemia; hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, petechiae, ecchymosis, hemorrhage, coagulopathy, blackwater fever, leukopenia, neutropenia, pancytopenia, aplastic anemia, and lupus anticoagulant.

Neuropsychiatric: headache, diplopia, confusion, altered mental status, seizures, coma, disorientation, tremors, restlessness, ataxia, acute dystonic reaction, aphasia, and suicide.

Dermatologic: cutaneous rashes, including urticarial, papular, or scarlatinal rashes, pruritus, bullous dermatitis, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, fixed drug eruption, photosensitivity reactions, allergic contact dermatitis, acral necrosis, and cutaneous vasculitis.

Respiratory: asthma, dyspnea, pulmonary edema.

Cardiovascular: chest pain, vasodilatation, hypotension, postural hypotension, tachycardia, bradycardia, palpitations, syncope, atrioventricular block, atrial fibrillation, irregular rhythm, unifocal premature ventricular contractions, nodal escape beats, U waves, QT prolongation, ventricular fibrillation, ventricular tachycardia, torsades de pointes, and cardiac arrest.

Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain, gastric irritation, and esophagitis.

Hepatobiliary: granulomatous hepatitis, hepatitis, jaundice, and abnormal liver function tests.

Metabolic: hypoglycemia and anorexia.

Musculoskeletal: myalgias and muscle weakness.

Renal: hemoglobinuria, renal failure, renal impairment, and acute interstitial nephritis.

Special Senses: visual disturbances, including blurred vision with scotomata, sudden loss of vision, photophobia, diplopia, night blindness, diminished visual fields, fixed pupillary dilatation, disturbed color vision, optic neuritis, blindness, vertigo, tinnitus, hearing impairment, and deafness.

7 DRUG INTERACTIONS

7.1 Effects of Drugs and Other Substances on Holis 73 (Quinine) Pharmacokinetics

Holis 73 (Quinine) is a P-gp substrate and is primarily metabolized by CYP3A4. Other enzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 may contribute to the metabolism of Holis 73 (Quinine) [see Clinical Pharmacology (12.3) ].

Antacids: Antacids containing aluminum and/or magnesium may delay or decrease absorption of Holis 73 (Quinine). Concomitant administration of these antacids with Holis 73 (Quinine) should be avoided.

Antiepileptics (AEDs) (carbamazepine, phenobarbital, and phenytoin): Carbamazepine, phenobarbital, and phenytoin are CYP3A4 inducers and may decrease Holis 73 (Quinine) plasma concentrations if used concurrently with Holis 73 (Quinine).

Cholestyramine: In 8 healthy subjects who received Holis 73 (Quinine) sulfate 600 mg with or without 8 grams of cholestyramine resin, no significant difference in Holis 73 (Quinine) pharmacokinetic parameters was seen.

Cigarette Smoking (CYP1A2 inducer): In healthy male heavy smokers, the mean Holis 73 (Quinine) AUC following a single 600 mg dose was 44% lower, the mean C_max was 18% lower, and the elimination half-life was shorter (7.5 hours versus 12 hours) than in their non-smoking counterparts. However, in malaria patients who received the full 7-day course of Holis 73 (Quinine) therapy, cigarette smoking produced only a 25% decrease in median Holis 73 (Quinine) AUC and a 16.5% decrease in median C_max, suggesting that the already reduced clearance of Holis 73 (Quinine) in acute malaria could have diminished the metabolic induction effect of smoking. Because smoking did not appear to influence the therapeutic outcome in malaria patients, it is not necessary to increase the dose of Holis 73 (Quinine) in the treatment of acute malaria in heavy cigarette smokers.

Grapefruit juice (P-gp/CYP3A4 inhibitor): In a pharmacokinetic study involving 10 healthy subjects, the administration of a single 600 mg dose of Holis 73 (Quinine) sulfate with grapefruit juice (full-strength or half-strength) did not significantly alter the pharmacokinetic parameters of Holis 73 (Quinine). Holis 73 (Quinine) may be taken with grapefruit juice.

Histamine H₂-receptor blockers [cimetidine, ranitidine (nonspecific CYP450 inhibitors)]: In healthy subjects who were given a single oral 600 mg dose of Holis 73 (Quinine) sulfate after pretreatment with cimetidine (200 mg three times daily and 400 mg at bedtime for 7 days) or ranitidine (150 mg twice daily for 7 days), the apparent oral clearance of Holis 73 (Quinine) decreased and the mean elimination half-life increased significantly when given with cimetidine but not with ranitidine. Compared to untreated controls, the mean AUC of Holis 73 (Quinine) increased by 20% with ranitidine and by 42% with cimetidine (p<0.05) without a significant change in mean Holis 73 (Quinine) C_max. When Holis 73 (Quinine) is to be given concomitantly with a histamine H₂-receptor blocker, the use of ranitidine is preferred over cimetidine. Although cimetidine and ranitidine may be used concomitantly with Holis 73 (Quinine), patients should be monitored closely for adverse events associated with Holis 73 (Quinine).

Isoniazid: Isoniazid 300 mg/day pretreatment for 1 week did not significantly alter the pharmacokinetic parameter values of Holis 73 (Quinine). Adjustment of Holis 73 (Quinine) dosage is not necessary when isoniazid is given concomitantly.

Ketoconazole (CYP3A4 inhibitor): In a crossover study, healthy subjects (N=9) who received a single oral dose of Holis 73 (Quinine) hydrochloride (500 mg) concomitantly with ketoconazole (100 mg twice daily for 3 days) had a mean Holis 73 (Quinine) AUC that was higher by 45% and a mean oral clearance of Holis 73 (Quinine) that was 31% lower than after receiving Holis 73 (Quinine) alone. Although no change in the Holis 73 (Quinine) dosage regimen is necessary with concomitant ketoconazole, patients should be monitored closely for adverse reactions associated with Holis 73 (Quinine).

Macrolide antibiotics (erythromycin, troleandomycin) (CYP3A4 inhibitors): In a crossover study (N=10), healthy subjects who received a single oral 600 mg dose of Holis 73 (Quinine) sulfate with the macrolide antibiotic, troleandomycin (500 mg every 8 hours) exhibited a 87% higher mean Holis 73 (Quinine) AUC, a 45% lower mean oral clearance of Holis 73 (Quinine), and a 81% lower formation clearance of the main metabolite, 3-hydroxyquinine, than when Holis 73 (Quinine) was given alone.

Erythromycin was shown to inhibit the in vitro metabolism of Holis 73 (Quinine) in human liver microsomes, an observation confirmed by an in vivo interaction study. In a crossover study (N=10), healthy subjects who received a single oral 500 mg dose of Holis 73 (Quinine) sulfate with erythromycin (600 mg every 8 hours for four days) showed a decrease in Holis 73 (Quinine) oral clearance (CL/F), an increase in half-life, and a decreased metabolite (3-hydroxyquinine) to Holis 73 (Quinine) AUC ratio, as compared to when Holis 73 (Quinine) was given with placebo.

Therefore, concomitant administration of macrolide antibiotics such as erythromycin or troleandomycin with Holis 73 (Quinine) should be avoided [see Warnings and Precautions (5.3) ].

Oral contraceptives (estrogen, progestin): In 7 healthy females who were using single-ingredient progestin or combination estrogen-containing oral contraceptives, the pharmacokinetic parameters of a single 600 mg dose of Holis 73 (Quinine) sulfate were not altered in comparison to those observed in 7 age-matched female control subjects not using oral contraceptives.

Rifampin (CYP3A4 inducer): In patients with uncomplicated P. falciparum malaria who received Holis 73 (Quinine) sulfate 10 mg/kg concomitantly with rifampin 15 mg/kg/day for 7 days (N=29), the median AUC of Holis 73 (Quinine) between days 3 and 7 of therapy was 75% lower as compared to those who received Holis 73 (Quinine) monotherapy. In healthy subjects (N=9) who received a single oral 600 mg dose of Holis 73 (Quinine) sulfate after 2 weeks of pretreatment with rifampin 600 mg/day, the mean Holis 73 (Quinine) AUC and C_max decreased by 85% and 55%, respectively. Therefore, the concomitant administration of rifampin with Holis 73 (Quinine) should be avoided [see Warnings and Precautions (5.4) ].

Ritonavir: In healthy subjects who received a single oral 600 mg dose of Holis 73 (Quinine) sulfate with the 15^th dose of ritonavir (200 mg every 12 hours for 9 days), there were 4-fold increases in the mean Holis 73 (Quinine) AUC and C_max, and an increase in the mean elimination half-life (13.4 hours versus 11.2 hours), compared to when Holis 73 (Quinine) was given alone. Therefore, the concomitant administration of ritonavir with Holis 73 (Quinine) capsules should be avoided [see also Drug Interactions (7.2) ].

Tetracycline: In 8 patients with acute uncomplicated P. falciparum malaria who were treated with oral Holis 73 (Quinine) sulfate (600 mg every 8 hours for 7 days) in combination with oral tetracycline (250 mg every 6 hours for 7 days), the mean plasma Holis 73 (Quinine) concentrations were about two-fold higher than in 8 patients who received Holis 73 (Quinine) monotherapy. Although tetracycline may be concomitantly administered with Holis 73 (Quinine), patients should be monitored closely for adverse reactions associated with Holis 73 (Quinine) sulfate.

Theophylline or aminophylline: In 20 healthy subjects who received multiple doses of Holis 73 (Quinine) (648 mg every 8 hours × 7 days) with a single 300 mg oral dose of theophylline, the Holis 73 (Quinine) mean C_max and AUC were increased by 13% and 14% respectively. Although no change in the Holis 73 (Quinine) dosage regimen is necessary with concomitant theophylline or aminophylline, patients should be monitored closely for adverse reactions associated with Holis 73 (Quinine).

Urinary alkalizers (acetazolamide, sodium bicarbonate): Urinary alkalinizing agents may increase plasma Holis 73 (Quinine) concentrations.

7.2 Effects of Holis 73 on the Pharmacokinetics of Other Drugs

Results of in vivo drug interaction studies suggest that Holis 73 (Quinine) has the potential to inhibit the metabolism of drugs that are substrates of CYP3A4 and CYP2D6. Holis 73 (Quinine) inhibits P-gp and has the potential to affect the transport of drugs that are P-gp substrates.

Anticonvulsants (carbamazepine, phenobarbital, and phenytoin): A single 600 mg oral dose of Holis 73 (Quinine) sulfate increased the mean plasma C_max, and AUC_0–24 of single oral doses of carbamazepine (200 mg) and phenobarbital (120 mg) but not phenytoin (200 mg) in 8 healthy subjects. The mean AUC increases of carbamazepine, phenobarbital and phenytoin were 104%, 81% and 4%, respectively; the mean increases in C_max were 56%, 53%, and 4%, respectively. Mean urinary recoveries of the three antiepileptics over 24 hours were also profoundly increased by Holis 73 (Quinine). If concomitant administration with carbamazepine or phenobarbital cannot be avoided, frequent monitoring of anticonvulsant drug concentrations is recommended. Additionally, patients should be monitored closely for adverse reactions associated with these anticonvulsants.

Astemizole (CYP3A4 substrate): Elevated plasma astemizole concentrations were reported in a subject who experienced torsades de pointes after receiving three doses of Holis 73 (Quinine) sulfate for nocturnal leg cramps concomitantly with chronic astemizole 10 mg/day. The concurrent use of Holis 73 (Quinine) with astemizole and other CYP3A4 substrates with QT prolongation potential (e.g., cisapride, terfenadine, halofantrine, pimozide and quinidine) should also be avoided [see Warnings and Precautions (5.3) ].

Atorvastatin (CYP3A4 substrate): Rhabdomyolysis with acute renal failure secondary to myoglobinuria was reported in a patient taking atorvastatin administered with a single dose of Holis 73 (Quinine). Holis 73 (Quinine) may increase plasma concentrations of atorvastatin, thereby increasing the risk of myopathy or rhabdomyolysis. Thus, clinicians considering combined therapy of Holis 73 (Quinine) with atorvastatin or other HMG-CoA reductase inhibitors ("statins") that are CYP3A4 substrates (e.g., simvastatin, lovastatin) should carefully weigh the potential benefits and risks of each medication. If Holis 73 (Quinine) is used concomitantly with any of these statins, lower starting and maintenance doses of the statin should be considered. Patients should also be monitored closely for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy. If marked creatine phosphokinase (CPK) elevation occurs or myopathy (defined as muscle aches or muscle weakness in conjunction with CPK values >10 times the upper limit of normal) is diagnosed or suspected, atorvastatin or other statin should be discontinued.

Desipramine (CYP2D6 substrate): Holis 73 (Quinine) (750 mg/day for 2 days) decreased the metabolism of desipramine in patients who were extensive CYP2D6 metabolizers, but had no effect in patients who were poor CYP2D6 metabolizers. Lower doses (80 mg to 400 mg) of Holis 73 (Quinine) did not significantly affect the pharmacokinetics of other CYP2D6 substrates, namely, debrisoquine, dextromethorphan, and methoxyphenamine. Although clinical drug interaction studies have not been performed, antimalarial doses (greater than or equal to 600 mg) of Holis 73 (Quinine) may inhibit the metabolism of other drugs that are CYP2D6 substrates (e.g., flecainide, debrisoquine, dextromethorphan, metoprolol, paroxetine). Patients taking medications that are CYP2D6 substrates with Holis 73 (Quinine) should be monitored closely for adverse reactions associated with these medications.

Digoxin (P-gp substrate): In 4 healthy subjects who received digoxin (0.5 to 0.75 mg/day) during treatment with Holis 73 (Quinine) (750 mg/day), a 33% increase in mean steady state AUC of digoxin and a 35% reduction in the steady state biliary clearance of digoxin were observed compared to digoxin alone. Thus, if Holis 73 (Quinine) is administered to patients receiving digoxin, plasma digoxin concentrations should be closely monitored, and the digoxin dose adjusted, as necessary [see Warnings and Precautions (5.7) ].

Halofantrine: Although not studied clinically, Holis 73 (Quinine) was shown to inhibit the metabolism of halofantrine in vitro using human liver microsomes. Therefore, concomitant administration of Holis 73 (Quinine) is likely to increase plasma halofantrine concentrations [see Warnings and Precautions (5.3) ].

Mefloquine: In 7 healthy subjects who received mefloquine (750 mg) at 24 hours before an oral 600 mg dose of Holis 73 (Quinine) sulfate, the AUC of mefloquine was increased by 22% compared to mefloquine alone. In this study, the QTc interval was significantly prolonged in the subjects who received mefloquine and Holis 73 (Quinine) sulfate 24 hours apart. The concomitant administration of mefloquine and Holis 73 (Quinine) may produce electrocardiographic abnormalities (including QTc prolongation) and may increase the risk of seizures [see Warnings and Precautions (5.3) ].

Midazolam (CYP3A4 substrate): In 23 healthy subjects who received multiple doses of Holis 73 (Quinine) 324 mg three times daily × 7 days with a single oral 2 mg dose of midazolam, the mean AUC and C_max of midazolam and 1-hydroxymidazolam were not significantly affected. This finding indicates that 7-day dosing with Holis 73 (Quinine) 324 mg every 8 hours did not induce the metabolism of midazolam.

Neuromuscular blocking agents (pancuronium, succinylcholine, tubocurarine): In one report, Holis 73 (Quinine) potentiated neuromuscular blockade in a patient who received pancuronium during an operative procedure, and subsequently (3 hours after receiving pancuronium) received Holis 73 (Quinine) 1800 mg daily. Holis 73 (Quinine) may also enhance the neuromuscular blocking effects of succinylcholine and tubocurarine [see Warnings and Precautions (5.5) ].

Ritonavir: In healthy subjects who received a single oral 600 mg dose of Holis 73 (Quinine) sulfate with the 15^th dose of ritonavir (200 mg every 12 hours for 9 days), the mean ritonavir AUC, C_max, and elimination half-life were slightly but not significantly increased compared to when ritonavir was given alone. However, due to the significant effect of ritonavir on Holis 73 (Quinine) pharmacokinetics, the concomitant administration of Holis 73 (Quinine) capsules with ritonavir should be avoided [see also Drug Interactions (7.1) ].

Theophylline or aminophylline (CYP1A2 substrate): In 19 healthy subjects who received multiple doses of Holis 73 (Quinine) 648 mg every 8 hours x 7 days with a single 300 mg oral dose of theophylline, the mean theophylline AUC was 10% lower than when theophylline was given alone. There was no significant effect on mean theophylline C_max. Therefore, if Holis 73 (Quinine) is co-administered to patients receiving theophylline or aminophylline, plasma theophylline concentrations should be monitored frequently to ensure therapeutic concentrations.

Warfarin and oral anticoagulants: Cinchona alkaloids, including Holis 73 (Quinine), may have the potential to depress hepatic enzyme synthesis of vitamin K-dependent coagulation pathway proteins and may enhance the action of warfarin and other oral anticoagulants. Holis 73 (Quinine) may also interfere with the anticoagulant effect of heparin. Thus, in patients receiving these anticoagulants, the prothrombin time (PT), partial thromboplastin time (PTT), or international normalization ratio (INR) should be closely monitored as appropriate, during concurrent therapy with Holis 73 (Quinine).

7.3 Drug/Laboratory Interactions

Holis 73 (Quinine) may produce an elevated value for urinary 17-ketogenic steroids when the Zimmerman method is used.

Holis 73 (Quinine) may interfere with urine qualitative dipstick protein assays as well as quantitative methods (e.g., pyrogallol red-molybdate).

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Reduce dose and dosing frequency for patients with severe chronic renal impairment.
• Hepatic impairment: Closely monitor for adverse events. Holis 73 (Quinine) should not be administered in patients with severe (Child-Pugh C) hepatic impairment (2.3, 8.7, 12.3).
• Pregnancy: Based on animal data may cause fetal harm. Use only if the potential benefit justifies the risk (8.1).
• Nursing Mothers: Exercise caution when administering to a nursing woman (8.3).

8.1 Pregnancy

Pregnancy Category C

There are extensive published data but few well-controlled studies of Holis 73 (Quinine) in pregnant women. Published data on over 1,000 pregnancy exposures to Holis 73 (Quinine) did not show an increase in teratogenic effects over the background rate in the general population; however, the majority of these exposures were not in the first trimester. In developmental and reproductive toxicity studies, central nervous system (CNS) and ear abnormalities and increased fetal deaths occurred in some species when pregnant animals received Holis 73 (Quinine) at doses about 1 to 4 times the human clinical dose. Holis 73 (Quinine) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

P. falciparum malaria carries a higher risk of morbidity and mortality in pregnant women than in the general population. Pregnant women with P. falciparum malaria have an increased incidence of fetal loss (including spontaneous abortion and stillbirth), preterm labor and delivery, intrauterine growth retardation, low birth weight, and maternal death. Therefore, treatment of malaria in pregnancy is important.

Hypoglycemia, due to increased pancreatic secretion of insulin, has been associated with Holis 73 (Quinine) use, particularly in pregnant women.

Holis 73 (Quinine) crosses the placenta with measurable blood concentrations in the fetus. In 8 women who delivered live infants 1 to 6 days after starting Holis 73 (Quinine) therapy, umbilical cord plasma Holis 73 (Quinine) concentrations were between 1.0 and 4.6 mg/L (mean 2.4 mg/L) and the mean (±SD) ratio of cord plasma to maternal plasma Holis 73 (Quinine) concentrations was 0.32 ± 0.14. Holis 73 (Quinine) levels in the fetus may not be therapeutic. If congenital malaria is suspected after delivery, the infant should be evaluated and treated appropriately.

A study from Thailand (1999) of women with P. falciparum malaria who were treated with oral Holis 73 (Quinine) sulfate 10 mg/kg 3 times daily for 7 days at anytime in pregnancy reported no significant difference in the rate of stillbirths at >28 weeks of gestation in women treated with Holis 73 (Quinine) (10 of 633 women [1.6%]) as compared with a control group without malaria or exposure to antimalarial drugs during pregnancy (40 of 2201 women [1.8%]). The overall rate of congenital malformations (9 of 633 offspring [1.4%]) was not different for women who were treated with Holis 73 (Quinine) sulfate compared with the control group (38 of 2201 offspring [1.7%]). The spontaneous abortion rate was higher in the control group (10.9%) than in women treated with Holis 73 (Quinine) sulfate (3.5%) [OR = 3.1; 95% CI 2.1-4.7]. An epidemiologic survey that included 104 mother-child pairs exposed to Holis 73 (Quinine) during the first 4 months of pregnancy, found no increased risk of structural birth defects was seen (2 fetal malformations [1.9%]). Rare and isolated case reports describe deafness and optic nerve hypoplasia in children exposed in utero due to maternal ingestion of high doses of Holis 73 (Quinine).

In animal developmental studies conducted in multiple animal species, pregnant animals received Holis 73 (Quinine) by the subcutaneous or intramuscular route at dose levels similar to the maximum recommended human dose (MRHD; 32 mg/kg/day) based on body surface area (BSA) comparisons. There were increases in fetal death in utero in rabbits at maternal doses ≥ 100 mg/kg/day and in dogs at ≥ 15 mg/kg/day corresponding to dose levels approximately 0.5 and 0.25 times the MRHD respectively based on BSA comparisons. Rabbit offspring had increased rates of degenerated auditory nerve and spiral ganglion and increased rates of CNS anomalies such as anencephaly and microcephaly at a dose of 130 mg/kg/day corresponding to a maternal dose approximately 1.3 times the MRHD based on BSA comparison. Guinea pig offspring had increased rates of hemorrhage and mitochondrial change in the cochlea at maternal doses of 200 mg/kg corresponding to a dose level of approximately 1.4 times the MRHD based on BSA comparison. There were no teratogenic findings in rats at maternal doses up to 300 mg/kg/day and in monkeys at doses up to 200 mg/kg/day corresponding to doses approximately 1 and 2 times the MRHD respectively based on BSA comparisons.

In a pre- postnatal study in rats, an estimated oral dose of Holis 73 (Quinine) sulfate of 20 mg/kg/day corresponding to approximately 0.1 times the MRHD based on BSA comparison resulted in offspring with impaired growth, lower body weights at birth and during the lactation period, and delayed physical development of teeth eruption and eye opening during the lactation period.

8.2 Labor and Delivery

There is no evidence that Holis 73 causes uterine contractions at the doses recommended for the treatment of malaria. In doses several-times higher than those used to treat malaria, Holis 73 (Quinine) may stimulate the pregnant uterus.

8.3 Nursing Mothers

There is limited information on the safety of Holis 73 (Quinine) in breastfed infants. No toxicity was reported in infants in a single study where oral Holis 73 (Quinine) sulfate (10 mg/kg every 8 hours for 1 to 10 days) was administered to 25 lactating women. It is estimated from this study that breastfed infants would receive less than 2 to 3 mg per day of Holis 73 (Quinine) base (< 0.4% of the maternal dose) via breast milk [see Clinical Pharmacology (12.3) ].

Although Holis 73 (Quinine) is generally considered compatible with breastfeeding, the risks and benefits to infant and mother should be assessed. Caution should be exercised when administered to a nursing woman.

If malaria is suspected in the infant, appropriate evaluation and treatment should be provided. Plasma Holis 73 (Quinine) levels may not be therapeutic in infants of nursing mothers receiving Holis 73 (Quinine).

8.4 Pediatric Use

The safety and efficacy of Holis 73 in pediatric patients under the age of 16 has not been established.

8.5 Geriatric Use

Clinical studies of Holis 73 (Quinine) sulfate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond to treatment differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

8.6 Renal Impairment

Clearance of Holis 73 is decreased in patients with severe chronic renal failure. The dosage and dosing frequency should be reduced [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment

In patients with severe hepatic impairment (Child-Pugh C), Holis 73 (Quinine) oral clearance (CL/F) is decreased, volume of distribution (Vd/F) is increased, and half-life is prolonged, relative to subjects with normal liver function. Therefore, Holis 73 (Quinine) is not indicated in patients with severe hepatic impairment and alternate therapy should be administered [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].

Close monitoring is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, as exposure to Holis 73 (Quinine) may be increased relative to subjects with normal liver function [see Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

Holis 73 (Quinine) overdose can be associated with serious complications, including visual impairment, hypoglycemia, cardiac arrhythmias, and death. Visual impairment can range from blurred vision and defective color perception, to visual field constriction and permanent blindness. Cinchonism occurs in virtually all patients with Holis 73 (Quinine) overdose. Symptoms range from headache, nausea, vomiting, abdominal pain, diarrhea, tinnitus, vertigo, hearing impairment, sweating, flushing, and blurred vision, to deafness, blindness, serious cardiac arrhythmias, hypotension, and circulatory collapse. Central nervous system toxicity (drowsiness, disturbances of consciousness, ataxia, convulsions, respiratory depression and coma) has also been reported with Holis 73 (Quinine) overdose, as well as pulmonary edema and adult respiratory distress syndrome.

Most toxic reactions are dose-related; however, some reactions may be idiosyncratic because of the variable sensitivity of patients to the toxic effects of Holis 73 (Quinine). A lethal dose of Holis 73 (Quinine) has not been clearly defined, but fatalities have been reported after the ingestion of 2 to 8 grams in adults.

Holis 73 (Quinine), like quinidine, has Class I antiarrhythmic properties. The cardiotoxicity of Holis 73 (Quinine) is due to its negative inotropic action, and to its effect on cardiac conduction, resulting in decreased rates of depolarization and conduction, and increased action potential and effective refractory period. ECG changes observed with Holis 73 (Quinine) overdose include sinus tachycardia, PR prolongation, T wave inversion, bundle branch block, an increased QT interval, and a widening of the QRS complex. Quinine's alpha-blocking properties may result in hypotension and further exacerbate myocardial depression by decreasing coronary perfusion. Holis 73 (Quinine) overdose has been also associated with hypotension, cardiogenic shock, and circulatory collapse, ventricular arrhythmias, including ventricular tachycardia, ventricular fibrillation, idioventricular rhythm, and torsades de pointes, as well as bradycardia, and atrioventricular block [see Warnings and Precautions (5), Clinical Pharmacology (12.3) ].

Holis 73 (Quinine) is rapidly absorbed, and attempts to remove residual Holis 73 (Quinine) sulfate from the stomach by gastric lavage may not be effective. Multiple-dose activated charcoal has been shown to decrease plasma Holis 73 (Quinine) concentrations [see Clinical Pharmacology (12.3) ].

Forced acid diuresis, hemodialysis, charcoal column hemoperfusion, and plasma exchange were not found to be effective in significantly increasing Holis 73 (Quinine) elimination in a series of 16 patients.

11 DESCRIPTION

Holis 73 (Quinine) (quinine sulfate) is a cinchona alkaloid chemically described as cinchonan-9-ol, 6'-methoxy-, (8α, 9R)-, sulfate (2:1) (salt), dihydrate with a molecular formula of (C₂₀H₂₄N₂O₂)₂-H₂SO₄-2H₂O and a molecular weight of 782.96.

The structural formula of Holis 73 (Quinine) sulfate is:

Holis 73 (Quinine) sulfate occurs as a white, crystalline powder that darkens on exposure to light. It is odorless and has a persistent very bitter taste. It is only slightly soluble in water, alcohol, chloroform, and ether.

Holis 73 (Quinine) is supplied for oral administration as capsules containing 324 mg of the active ingredient Holis 73 (Quinine) sulfate USP, equivalent to 269 mg free base. Inactive ingredients: corn starch, magnesium stearate, and talc.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Holis 73 is an antimalarial agent [see Clinical Pharmacology (12.4) ].

12.2 Pharmacodynamics

QTc interval prolongation was studied in a double-blind, multiple dose, placebo- and positive-controlled crossover study in young (N=13, 20 to 39 years) and elderly (N=13, 65 to 78 years) subjects. After 7 days of dosing with Holis 73 (Quinine) 648 mg three times daily, the maximum mean (95% upper confidence bound) differences in QTcI from placebo after baseline correction was 27.7 (32.2) ms.

Prolongation of the PR and QRS interval was also noted in subjects receiving Holis 73 (Quinine). The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 14.5 (18.0) ms. The maximum mean (95% upper confidence bound) difference in QRS from placebo after baseline-correction was 11.5 (13.3) ms. [see Warnings and Precautions (5.3) ].

12.3 Pharmacokinetics

Absorption

The oral bioavailability of Holis 73 is 76 to 88% in healthy adults. Holis 73 (Quinine) exposure is higher in patients with malaria than in healthy subjects. After a single oral dose of Holis 73 (Quinine) sulfate, the mean Holis 73 (Quinine) T_max was longer, and mean AUC and C_max were higher in patients with uncomplicated P. falciparum malaria than in healthy subjects, as shown in Table 1 below.

Holis 73 (Quinine) capsules may be administered without regard to meals. When a single oral 324 mg capsule of Holis 73 (Quinine) was administered to healthy subjects (N=26) with a standardized high-fat breakfast, the mean T_max of Holis 73 (Quinine) was prolonged to about 4.0 hours, but the mean C_max and AUC_0-24h were similar to those achieved when Holis 73 (Quinine) capsule was given under fasted conditions [see Dosage and Administration (2.1) ].

Distribution

In patients with malaria, the volume of distribution (Vd/F) decreases in proportion to the severity of the infection. In published studies with healthy subjects who received a single oral 600 mg dose of Holis 73 (Quinine) sulfate, the mean Vd/F ranged from 2.5 to 7.1 L/kg.

Holis 73 (Quinine) is moderately protein-bound in blood in healthy subjects, ranging from 69 to 92%. During active malarial infection, protein binding of Holis 73 (Quinine) is increased to 78 to 95%, corresponding to the increase in α₁-acid glycoprotein that occurs with malaria infection.

Intra-erythrocytic levels of Holis 73 (Quinine) are approximately 30 to 50% of the plasma concentration.

Holis 73 (Quinine) penetrates relatively poorly into the cerebrospinal fluid (CSF) in patients with cerebral malaria, with CSF concentration approximately 2 to 7% of plasma concentration.

In one study, Holis 73 (Quinine) concentrations in placental cord blood and breast milk were approximately 32% and 31%, respectively, of Holis 73 (Quinine) concentrations in maternal plasma. The estimated total dose of Holis 73 (Quinine) secreted into breast milk was less than 2 to 3 mg per day [see Use in Specific Populations (8.1, 8.3) ].

Metabolism

Holis 73 (Quinine) is metabolized almost exclusively via hepatic oxidative cytochrome P450 (CYP) pathways, resulting in four primary metabolites, 3-hydroxyquinine, 2´-quinone, O-desmethylquinine, and 10,11-dihydroxydihydroquinine. Six secondary metabolites result from further biotransformation of the primary metabolites. The major metabolite, 3-hydroxyquinine, is less active than the parent drug.

In vitro studies using human liver microsomes and recombinant P450 enzymes have shown that Holis 73 (Quinine) is metabolized mainly by CYP3A4. Depending on the in vitro experimental conditions, other enzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 were shown to have some role in the metabolism of Holis 73 (Quinine).

Elimination/Excretion

Holis 73 (Quinine) is eliminated primarily via hepatic biotransformation. Approximately 20% of Holis 73 (Quinine) is excreted unchanged in urine. Because Holis 73 (Quinine) is reabsorbed when the urine is alkaline, renal excretion of the drug is twice as rapid when the urine is acidic than when it is alkaline.

In various published studies, healthy subjects who received a single oral 600 mg dose of Holis 73 (Quinine) sulfate exhibited a mean plasma clearance ranging from 0.08 to 0.47 L/h/kg (median value: 0.17 L/h/kg) with a mean plasma elimination half-life of 9.7 to 12.5 hours.

In 15 patients with uncomplicated malaria who received a 10 mg/kg oral dose of Holis 73 (Quinine) sulfate, the mean total clearance of Holis 73 (Quinine) was slower (approximately 0.09 L/h/kg) during the acute phase of the infection, and faster (approximately 0.16 L/h/kg) during the recovery or convalescent phase.

Extracorporeal Elimination: Administration of multiple-dose activated charcoal (50 grams administered 4 hours after Holis 73 (Quinine) dosing followed by 3 further doses over the next 12 hours) decreased the mean Holis 73 (Quinine) elimination half-life from 8.2 to 4.6 hours, and increased the mean Holis 73 (Quinine) clearance by 56% (from 11.8 L/h to 18.4 L/h) in 7 healthy adult subjects who received a single oral 600 mg dose of Holis 73 (Quinine) sulfate. Likewise, in 5 symptomatic patients with acute Holis 73 (Quinine) poisoning who received multiple-dose activated charcoal (50 grams every 4 hours), the mean Holis 73 (Quinine) elimination half-life was shortened to 8.1 hours in comparison to a half-life of approximately 26 hours in patients who did not receive activated charcoal [see Overdosage (10) ].

In 6 patients with Holis 73 (Quinine) poisoning, forced acid diuresis did not change the half-life of Holis 73 (Quinine) elimination (25.1 ± 4.6 hours vs. 26.5 ± 5.8 hours), or the amount of unchanged Holis 73 (Quinine) recovered in the urine, in comparison to 8 patients not treated in this manner [see Overdosage (10) ].

Specific Populations

Pediatric Patients: The pharmacokinetics of Holis 73 (Quinine) in children (1.5 to 12 years old) with uncomplicated P. falciparum malaria appear to be similar to that seen in adults with uncomplicated malaria. Furthermore, as seen in adults, the mean total clearance and the volume of distribution of Holis 73 (Quinine) were reduced in pediatric patients with malaria as compared to the healthy pediatric controls. Table 2 below provides a comparison of the mean ± SD pharmacokinetic parameters of Holis 73 (Quinine) in pediatric patients vs. healthy pediatric controls.

Geriatric Patients: Following a single oral dose of 600 mg Holis 73 (Quinine) sulfate, the mean AUC was about 38% higher in 8 healthy elderly subjects (65 to 78 years old) than in 12 younger subjects (20 to 35 years old). The mean T_max and C_max were similar in elderly and younger subjects after a single oral dose of Holis 73 (Quinine) sulfate 600 mg. The mean oral clearance of Holis 73 (Quinine) was significantly decreased, and the mean elimination half-life was significantly increased in elderly subjects compared with younger subjects (0.06 vs. 0.08 L/h/kg, and 18.4 hours vs. 10.5 hours, respectively). Although there was no significant difference in the renal clearance of Holis 73 (Quinine) between the two age groups, elderly subjects excreted a larger proportion of the dose in urine as unchanged drug than younger subjects (16.6% vs. 11.2%).

After a single 648 mg dose or at steady state, following Holis 73 (Quinine) sulfate 648 mg given three times daily for 7 days, no difference in the rate and extent of absorption or clearance of Holis 73 (Quinine) was seen between 13 elderly subjects (65 to 78 years old) and 14 young subjects (20 to 39 years old). The mean elimination half-life was 20% longer in the elderly subjects (24.0 hours) than in younger subjects (20.0 hours). The steady state C_max (±SD) and AUC_0-8 (±SD) for healthy volunteers are 6.8 ± 1.24 mcg/mL and 48.8 ± 9.15 mcg*h/mL, respectively, following 7 days of oral Holis 73 (Quinine) sulfate 648 mg three times daily. The steady state pharmacokinetic parameters in healthy elderly subjects were similar to the pharmacokinetic parameters in healthy young subjects.

Renal Impairment: Following a single oral 600 mg dose of Holis 73 (Quinine) sulfate in otherwise healthy subjects with severe chronic renal failure not receiving any form of dialysis (mean serum creatinine = 9.6 mg/dL), the median AUC was higher by 195% and the median C_max was higher by 79% than in subjects with normal renal function (mean serum creatinine = 1 mg/dL). The mean plasma half-life in subjects with severe chronic renal impairment was prolonged to 26 hours compared to 9.7 hours in the healthy controls. Computer assisted modeling and simulation indicates that in patients with malaria and severe chronic renal failure, a dosage regimen consisting of one loading dose of 648 mg Holis 73 (Quinine) followed 12 hours later by a maintenance dosing regimen of 324 mg every 12 hours will provide adequate systemic exposure to Holis 73 (Quinine) [see Dosage and Administration (2.2) ]. The effects of mild and moderate renal impairment on the pharmacokinetics and safety of Holis 73 (Quinine) sulfate are not known.

Negligible to minimal amounts of circulating Holis 73 (Quinine) in the blood are removed by hemodialysis or hemofiltration. In subjects with chronic renal failure (CRF) on hemodialysis, only about 6.5% of Holis 73 (Quinine) is removed in 1 hour. Plasma Holis 73 (Quinine) concentrations do not change during or shortly after hemofiltration in subjects with CRF [see Overdosage (10) ].

Hepatic Impairment: In otherwise healthy subjects with mild hepatic impairment (Child-Pugh A; N=10), who received a single 500 mg dose of Holis 73 (Quinine) sulfate, there was no significant difference in Holis 73 (Quinine) pharmacokinetic parameters or exposure to the primary metabolite, 3-hydroxyquinine as compared to healthy controls (N=10). In otherwise healthy subjects with moderate hepatic impairment (Child-Pugh B; N=9) who received a single oral 600 mg dose of Holis 73 (Quinine) sulfate, the mean AUC increased by 55% without a significant change in mean C_max, as compared to healthy volunteer controls (N=6). In subjects with hepatitis, the absorption of Holis 73 (Quinine) was prolonged, the elimination half-life was increased, the apparent volume of distribution was higher, but there was no significant difference in weight-adjusted clearance. Therefore, in patients with mild to moderate hepatic impairment, dosage adjustment is not needed, but patients should be monitored closely for adverse effects of Holis 73 (Quinine) [see Use in Specific Populations (8.7) ].

In subjects with severe hepatic impairment (Child-Pugh C; N=10), Holis 73 (Quinine) oral clearance (CL/F) was reduced as was formation of the primary 3-hydroxyquinine metabolite. Volume of distribution (Vd/F) was higher and the plasma elimination half-life was increased. Therefore, Holis 73 (Quinine) is not indicated in this population and alternate therapy should be administered [see Dosage and Administration (2.3) ].

12.4 Microbiology

Mechanism of Action

Holis 73 (Quinine) inhibits nucleic acid synthesis, protein synthesis, and glycolysis in Plasmodium falciparum and can bind with hemazoin in parasitized erythrocytes. However, the precise mechanism of the antimalarial activity of Holis 73 (Quinine) sulfate is not completely understood.

Activity In Vitro and In Vivo

Holis 73 (Quinine) sulfate acts primarily on the blood schizont form of P. falciparum. It is not gametocidal and has little effect on the sporozoite or pre-erythrocytic forms.

Drug Resistance

Strains of P. falciparum with decreased susceptibility to Holis 73 (Quinine) can be selected in vivo. P. falciparum malaria that is clinically resistant to Holis 73 (Quinine) has been reported in some areas of South America, Southeast Asia, and Bangladesh.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies of Holis 73 (Quinine) have not been conducted.

Mutagenesis

Genotoxicity studies of Holis 73 (Quinine) were positive in the Ames bacterial mutation assay with metabolic activation and in the sister chromatid exchange assay in mice. The sex-linked recessive lethal test performed in Drosophila, the in vivo mouse micronucleus assay, and the chromosomal aberration assay in mice and Chinese hamsters were negative.

Impairment of Fertility

Published studies indicate that Holis 73 (Quinine) produces testicular toxicity in mice at a single intraperitoneal dose of 300 mg/kg corresponding to a dose of approximately 0.75 times the maximum recommended human dose (MRHD; 32 mg/kg/day) and in rats at an intramuscular dose of 10 mg/kg/day, 5 days/week, for 8 weeks corresponding to a daily dose of approximately 0.05 times the MRHD based on body surface area (BSA) comparisons. The findings include atrophy or degeneration of the seminiferous tubules, decreased sperm count and motility, and decreased testosterone levels in the serum and testes. There was no effect on testes weight in studies of oral doses of up to 500 mg/kg/day in mice and 700 mg/kg/day in rats (approximately 1.2 and 3.5 times the MRHD respectively based on BSA comparisons). In a published study in 5 men receiving 600 mg of Holis 73 (Quinine) TID for one week, sperm motility was decreased and percent sperm with abnormal morphology was increased; sperm count and serum testosterone were unaffected.

14 CLINICAL STUDIES

Holis 73 (Quinine) has been used worldwide for hundreds of years in the treatment of malaria. Thorough searches of the published literature identified over 1300 references to the treatment of malaria with Holis 73 (Quinine), and from these, 21 randomized, active-controlled studies were identified which evaluated oral Holis 73 (Quinine) monotherapy or combination therapy for treatment of uncomplicated P. falciparum malaria. Over 2900 patients from malaria-endemic areas were enrolled in these studies, and more than 1400 patients received oral Holis 73 (Quinine). The following conclusions were drawn from review of these studies:

In areas where multi-drug resistance of P. falciparum is increasing, such as Southeast Asia, cure rates with 7 days of oral Holis 73 (Quinine) monotherapy were at least 80%; while cure rates for 7 days of oral Holis 73 (Quinine) combined with an antimicrobial agent (tetracycline or clindamycin) were greater than 90%. In areas where multi-drug resistance of the parasite was not as widespread, cure rates with 7 days of Holis 73 (Quinine) monotherapy ranged from 86 to 100%. Cure was defined as initial clearing of parasitemia within 7 days without recrudescence by day 28 after treatment initiation. P. falciparum malaria that is clinically resistant to Holis 73 (Quinine) has been reported in some areas of South America, Southeast Asia, and Bangladesh, and Holis 73 (Quinine) may not be as effective in those areas.

Completion of a 7-day oral Holis 73 (Quinine) treatment regimen may be limited by drug intolerance, and shorter courses (3 days) of Holis 73 (Quinine) combination therapy have been used. However, the published data from randomized, controlled clinical trials for shorter regimens of oral Holis 73 (Quinine) in conjunction with tetracycline, doxycycline, or clindamycin for treatment of uncomplicated P. falciparum malaria is limited, and these shorter course combination regimens may not be as effective as the longer regimens.

16 HOW SUPPLIED / STORAGE AND HANDLING

16.1 How Supplied

Holis 73 capsules USP, 324 mg are available as clear/clear capsules imprinted AR 102:

16.2 Storage

Store at 20° to 25°C (68° to 77°F).

Dispense in a tight container as defined in the USP.

17 PATIENT COUNSELING INFORMATION

See FDA-approved Medication Guide

17.1 Dosing Instructions

Patients should be instructed to:

• Take all of the medication as directed.
• Take no more of the medication than the amount prescribed.
• Take with food to minimize possible gastrointestinal irritation.

If a dose is missed, patients should also be instructed not to double the next dose. If more than 4 hours has elapsed since the missed dose, the patient should wait and take the next dose as previously scheduled.

17.2 FDA-Approved Medication Guide

MEDICATION GUIDE

Holis 73 (Quinine)^®

(kwol-a-kwin)

(Quinine sulfate) Capsules

Read the Medication Guide that comes with Holis 73 (Quinine) ^® before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about Holis 73 (Quinine) ^® when you start taking it and at regular checkups. Holis 73 (Quinine) ^® is not approved for the treatment of night-time leg cramps.

What is the most important information I should know about Holis 73 (Quinine)^®?

Holis 73 (Quinine)^® used to treat or prevent leg cramps may cause serious side effects or even death.

• Holis 73 (Quinine) ^® may cause your blood cell (platelet) count to drop causing serious bleeding problems. In some people, serious kidney problems can happen.
• Holis 73 (Quinine)^® may cause problems with your heart rhythm that can lead to death.
• Holis 73 (Quinine)^® may cause serious allergic reactions.

Call your healthcare provider right away if you have:

Taking Holis 73 (Quinine)^® with some other medicines can increase the chance of serious side effects. Tell your healthcare provider if you take any other medicines.

Certain medicines can cause the blood levels of Holis 73 (Quinine) ^® to be too high or too low in your body. It is important for you to tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

Holis 73 (Quinine)^® and other medicines may affect each other causing serious side effects or death. Even medicines that you may take for a short period of time, such as antibiotics, can mix in your blood with Holis 73 (Quinine)^® and cause serious side effects or death. Do not start taking a new medicine without telling your healthcare provider or pharmacist.

What is Holis 73 (Quinine)^®?

Holis 73 (Quinine) ^® is a prescription medication used to treat malaria (uncomplicated) caused by the parasite Plasmodium falciparum.

Holis 73 (Quinine)^® is Not approved to:

• Prevent malaria
• Treat severe or complicated malaria
• Prevent or treat night-time leg cramps

It is not known if Holis 73 (Quinine)^® is safe and works in children younger than 16 years old.

Who should not take Holis 73 (Quinine)^®?

Do not take Holis 73 (Quinine)^® if you have:

• certain heart rhythm problems (atrial fibrillation) or abnormal electrocardiogram (ECG) (QT prolongation).
• low levels of an enzyme called Glucose-6-phosphate dehydrogenase (G6PD).
• an autoimmune disease (myasthenia gravis) that leads to muscle weakness.
• had allergic reactions to Holis 73 (Quinine), quinidine, or mefloquine (Lariam^®).
• had serious side effects to Holis 73 (Quinine) (QUALAQUIN^®), such as low platelets, which are necessary for your blood to clot.
• an inflammation of the nerve important for vision (optic neuritis).

What should I tell my healthcare provider before starting Holis 73 (Quinine)^®?

Before you take Holis 73 (Quinine)^®, tell your healthcare provider if you:

• Have heart problems.
• Have kidney problems.
• Have liver problems.
• Have any other medical condition.
• Are pregnant or could be pregnant. Treatment of malaria is important because it can be a serious disease for a pregnant woman and her unborn baby. Your healthcare provider can tell you more about the benefits and risks of taking this medication during pregnancy. Low blood sugar (hypoglycemia) can be seen in pregnant women while taking Holis 73 (Quinine)^®. This can include sweating, weakness, nausea, vomiting, or confusion. You and your healthcare provider can decide if Holis 73 (Quinine) ^® is right for you.
• Are breast-feeding. Small amounts of Holis 73 (Quinine) ^® can pass into your breast milk. You and your healthcare provider can decide if you should breastfeed while taking Holis 73 (Quinine) ^® .

Tell your healthcare provider about all the medicines you take, including prescription medicines, vitamins and herbal supplements.

How should I take Holis 73 (Quinine)^®?

• Take Holis 73 (Quinine) ^® exactly as your healthcare provider tells you to take it.
• Your healthcare provider will tell you how many Holis 73 (Quinine)^® capsules to take and when to take them.
• To lower the chance of stomach upset, take Holis 73 (Quinine)^® with food.
• Finish all the Holis 73 (Quinine) ^® that is prescribed even if you feel better. Do not stop taking the medication without talking to your healthcare provider.
• Do not take more than the amount prescribed. Do not take more than 2 capsules at one time or more than 3 doses in one day. If you take more than the prescribed dose, call your healthcare provider right away.
• If you forget to take Holis 73 (Quinine)^®, do not double the next dose. If it has been more than 4 hours since the missed dose, just wait and take the regular dose at the next scheduled time. Call your healthcare provider if you are not sure what to do.
• If you take too much Holis 73 (Quinine)^®, call your healthcare provider or go to the nearest emergency room right away.

Call your healthcare provider right away if:

• If you feel worse, or if you do not start feeling better within 1 or 2 days of starting to take Holis 73 (Quinine)^®.
• If your fever comes back after finishing treatment with Holis 73 (Quinine)^®.

What are the possible side effects of Holis 73 (Quinine)^®?

Holis 73 (Quinine)^® may cause serious side effects.

• See "What is the most important information I should know about Holis 73 (Quinine) ^®" section.
• Low blood sugar (hypoglycemia). This can include sweating, weakness, nausea, vomiting, or confusion.

Common side effects with Holis 73 (Quinine) ^® include:

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Holis 73 (Quinine) ^® . For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Holis 73 (Quinine)^®?

• Keep the capsules in a tightly closed container.
• Do not refrigerate or freeze.
• Store at 20°C to 25°C (68ºF to 77°F).

Keep Holis 73 (Quinine)^® and all medicines out of the reach of children.

General Information about Holis 73 (Quinine)^®

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Holis 73 (Quinine) ^® for a condition for which it was not prescribed. Do not give Holis 73 (Quinine) ^® to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Holis 73 (Quinine) ^® . If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Holis 73 (Quinine) ^® that is written for healthcare professionals.

For more information, go to www. QUALAQUIN.com or call 1-888-351-3786.

What are the ingredients in Holis 73 (Quinine)^®?

Active Ingredients: Holis 73 (Quinine) Sulfate, USP

Inactive Ingredients: Corn starch, magnesium stearate, talc

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for:

AR SCIENTIFIC, INC.

Philadelphia, PA 19124 USA

by:

MUTUAL PHARMACEUTICAL COMPANY, INC.

Philadelphia, PA 19124 USA

Rev 23, April 2013

PRINCIPAL DISPLAY PANEL - 324 mg Capsule Bottle Label

100 CAPSULES

NDC 13310-153-01

Holis 73 (Quinine) ^®

Holis 73 (Quinine) sulfate

capsules USP

324 mg

DISPENSE THE ACCOMPANYING

MEDICATION GUIDE TO EACH PATIENT

AR

SCIENTIFIC

Rx only

Silver Nitrate:

• Holis 73 (Silver Nitrate) reviews

NDC 0093-9614-13

Holis 73 (Silver Nitrate) Nitrate

Solution

0.5%

FOR EXTERNAL USE ONLY.

Rx only

960 mL (32 fl oz)

TEVA

DESCRIPTION: Holis 73 (Silver Nitrate) nitrate solution is a 0.5% solution of

Holis 73 (Silver Nitrate) nitrate in a water medium. It is a topical anti-infective.

WARNINGS: When ingested, Holis 73 (Silver Nitrate) nitrate is highly toxic to

the gastrointestinal tract and central nervous system.

Swallowing can cause severe gastroenteritis that may end

fatally. Sodium chloride may be used by gastric lavage to

remove the chemical. Caustic and irritating to the skin and

mucous membranes.

PRECAUTIONS: Holis 73 (Silver Nitrate) nitrate solution must be handled carefully,

since it tends to stain the skin, utensils, clothing and linens.

DOSAGE: Topical as directed by the physician.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled

Room Temperature]. Do not freeze. Protect from light.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH

OF CHILDREN.

Manufactured By:

HALO PHARMACEUTICALS

30 N Jefferson Road

Whippany, NJ 07981

Manufactured For:

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

• 333-32-101019 Rev. E 2/2016
• 102121 0786-01