L-Arginine HCl Injection

Overview of L-Arginine HCl Injection

Dosage Strength of L-Arginine HCl Injection

200 mg/mL 30 mL Vial

General Information

Arginine hydrochloride is a synthetic derivative of the essential amino acid L-arginine. Arginine hydrochloride may be used as an aid to the detection of growth hormone deficiency in conditions such as panhypopituitarism, pituitary dwarfism, chromophobe adenoma, postsurgical craniopharyngioma, hypophysectomy, pituitary trauma, and in problems with growth and stature. The drug has also been used in the evaluation of pituitary function in gigantism and acromegaly Further, arginine injection is used to treat high ammonia concentrations in patients with urea cycle disorders. Arginine tablets, which are dietary supplements, have been used to improve exercise capacity in patients with stable angina pectoris.1 Arginine injection was originally approved by the FDA in February 1973.

Mechanism of Action

Growth Hormone Deficiency Diagnosis: Arginine stimulates pituitary release of growth hormone in patients with normal pituitary function. Patients with impaired pituitary function who receive arginine will have lower or no increase in plasma concentrations of growth hormone after administration of arginine.2

Urea Cycle Disorders (UCDs): The urea cycle is normally responsible for maintaining low blood concentrations of ammonia and glutamine from protein breakdown. The normal urea cycle requires numerous enzyme-catalyzed steps to form nitrogenous waste such as urea. Hyperammonemia may occur when there is a deficiency in one or more urea cycle enzymes or a cofactor: N-acetylglutamate synthetase (NAGS), carbamyl phosphate synthetase (CPS), argininosuccinate synthetase (ASS), ornithine transcarbamylase (OTC), or argininosuccinate lyase (ASL). Arginine becomes an essential amino acid when any of these enzymes is deficient. If essential amino acids are not available, protein catabolism occurs, which increases ammonia concentrations. Exogenous arginine is administered in patients with UCDs to restore serum levels and prevent the breakdown of endogenous protein. Additionally, arginine administration lowers the blood ammonia level and increases the amount of nitrogen excreted in the urine by stimulating an alternative pathway for waste nitrogen excretion.345

Metabolic Alkalosis: Arginine is a precursor to hydrochloric acid and has a high chloride content and is, therefore, an alternative treatment for severe metabolic alkalosis.6

Cardiovascular disease: Arginine is a precursor of nitric oxide, which is a potent vasodilator with antiplatelet activity. Nitric oxide has been shown to induce vasodilation in patients with atherosclerosis.78

Pharmacokinetics

Arginine is administered orally and via IV administration. Thirty grams of intravenous arginine increased urinary nitrate and cyclic GMP excretion rates by 97 +/- 28 and 66 +/- 20%, respectively. The onset and duration of vasodilator effect on endogenous nitric oxide production paralleled the plasma half-life of arginine.7

Route-Specific Pharmacokinetics:

Intravenous Route: Arginine elimination was biphasic, with concentration dependent renal clearance eliciting a rapid initial decrease in serum concentrations, followed by a slower decrease in serum concentrations due to nonrenal elimination.8 After 30 g IV infusion, about 5 g of arginine was excreted in the urine, with a major portion excreted within 90 minutes after drug administration. Renal clearance in 2 of 12 volunteers within the first 90 minutes after drug administration was 1.16—1.18 mL/kg/minute.8 In a study of 8 healthy males, after receiving 30 g IV of arginine, clearance was 544 +/- 24 mL/min, and after 6 g IV of arginine, clearance was 894 +/-164 mL/min. Elimination half life was dose dependent and was 41.6 min after 30 g IV and 59.6 min after 6 g IV.7

Indications/Dosage

For growth hormone deficiency diagnosis (i.e., evaluation of pituitary growth hormone reserve):

Intravenous dosage: Adults: 30 g IV over 30 minutes.2
Neonates, Infants, Children, and Adolescents: 0.5 g/kg IV, not to exceed 30 g, over 30 minutes. NOTE: Extreme caution must be used when arginine injection is prescribed for children; fatal overdose has occurred.2

For patients with carbamyl phosphate synthetase (CPS) or ornithine transcarbamylase (OTC) deficiency:

Intravenous dosage: Adults, Adolescents, and Children > 20 kg:2 mL/kg (provides 200 mg/kg of arginine) IV loading dose through a central line over 90—120 minutes, then give a maintenance dose of 2 mL/kg (provides 200 mg/kg of arginine) IV through a central line over 24 hours. Administer each dose with 55 mL/m2 of sodium benzoate; sodium phenylacetate (provides 5.5 g/m2of sodium phenylacetate and 5.5 g/m2 of sodium benzoate). Maintenance infusions may be given daily, each over 24 hours, until plasma ammonia concentrations normalize or until the patient can tolerate oral nutrition and medications.43
Neonates, Infants, and Children < 20 kg:2 mL/kg (provides 200 mg/kg of arginine) IV loading dose through a central line over 90—120 minutes, then give a maintenance dose of 2 mL/kg (provides 200 mg/kg of arginine) IV through a central line over 24 hours. Administer each dose with 2.5 mL/kg of sodium benzoate; sodium phenylacetate (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate). Maintenance infusions may be given daily, each over 24 hours, until plasma ammonia concentrations normalize or until the patient can tolerate oral nutrition and medications.43

For patients with argininosuccinate lyase (ASL) or argininosuccinate synthetase (ASS) deficiency:

Intravenous dosage: Adults, Adolescents, and Children > 20 kg:6 mL/kg (provides 600 mg/kg of arginine) IV loading dose through a central line over 90—120 minutes, then give a maintenance dose of 6 mL/kg (provides 600 mg/kg of arginine) IV through a central line over 24 hours. Administer each dose with 55 mL/m2 of sodium benzoate; sodium phenylacetate (provides 5.5 g/m2of sodium phenylacetate and 5.5 g/m2 of sodium benzoate). Maintenance infusions may be given daily, each over 24 hours, until plasma ammonia concentrations normalize or until the patient can tolerate oral nutrition and medications.43
Neonates, Infants, and Children < 20 kg:6 mL/kg (provides 600 mg/kg of arginine) IV loading dose through a central line over 90—120 minutes, then give a maintenance dose of 6 mL/kg (provides 600 mg/kg of arginine) IV through a central line over 24 hours. Administer each dose with 2.5 mL/kg of sodium benzoate; sodium phenylacetate (provides 250 mg/kg of sodium phenylacetate and 250 mg/kg of sodium benzoate). Maintenance infusions may be given daily, each over 24 hours, until plasma ammonia concentrations normalize or until the patient can tolerate oral nutrition and medications.39

Therapeutic Drug Monitoring:

Growth Hormone Reserve Test: In patients with intact pituitary function, the expected peak plasma concentration of human growth hormone in response to arginine is 10—30 ng/ml (control range: 0—6 ng/ml). In patients who have pituitary deficiency, the expected peak plasma concentration of human growth hormone in response to arginine is 0—10 ng/ml (control range: 0—4 ng/ml). The basal and post stimulation levels of growth hormones are elevated in pregnant patients and those taking oral contraceptives.10

Maximum Dosage Limits:

Adults: 30g/dose IV for pituitary growth hormone reserve; doses up to 600 mg/kg/dose for the loading dose and 600 mg/kg/day via continuous IV have been used off-label for urea cycle disorders.

Geriatric: 30g/dose IV for pituitary growth hormone reserve; doses up to 600 mg/kg/dose for the loading dose and 600 mg/kg/day via continuous IV have been used off-label for urea cycle disorders.
Adolescents: >= 60 kg: 30g/dose IV for pituitary growth hormone reserve; doses up to 600 mg/kg/dose for the loading dose and 600 mg/kg/day via continuous IV have been used off-label for urea cycle disorders.< 60 kg: 0.5 mg/kg/dose IV for pituitary growth hormone reserve; doses up to 600 mg/kg/dose for the loading dose and 600 mg/kg/day via continuous IV have been used off-label for urea cycle disorders.

Children: >= 60 kg: 30g/dose IV for pituitary growth hormone reserve; doses up to 600 mg/kg/dose for the loading dose and 600 mg/kg/day via continuous IV have been used off-label for urea cycle disorders.
< 60 kg: 0.5 mg/kg/dose IV for pituitary growth hormone reserve; doses up to 600 mg/kg/dose for the loading dose and 600 mg/kg/day via continuous IV have been used off-label for urea cycle disorders.

Infants: 0.5 mg/kg/dose IV for pituitary growth hormone reserve; doses up to 600 mg/kg/dose for the loading dose and 600 mg/kg/day via continuous IV have been used off-label for urea cycle disorders.

Neonates: 0.5 mg/kg/dose IV for pituitary growth hormone reserve; doses up to 600 mg/kg/dose for the loading dose and 600 mg/kg/day via continuous IV have been used off-label for urea cycle disorders.

Contraindications/Precautions

Arginine injection is contraindicated in patients having know arginine hypersensitivity or a hypersensitivity to any components of the product.

Use arginine injection cautiously in patients with renal impairment, hepatic disease and/or an electrolyte imbalance. Arginine can be metabolized to nitrogen-containing products. Consider the nitrogen or acute amino acid burden on patients with impaired renal function when administering arginine injection. Additionally, arginine injection contains 47.5 mEq chloride/100 mL, which should be considered in patients with an existing electrolyte imbalance.2 In 2 adult patients with severe hepatic disease and moderate renal insufficiency, severe hyperkalemia developed during and after an arginine monohydrochloride infusion. Both patients had received spironolactone prior to the arginine infusion. Arginine shifts intracellular potassium to the extracellular compartment so caution should be used in patients with hepatic and renal failure due to decreased metabolism of arginine and decreased clearance of potassium.11

Use extreme caution when administering arginine injection to neonates, infants, children, and adolescents. Ensure the appropriate dose is being administered. Following high dose arginine hydrochloride administration in pediatric patients, hyperchloremic metabolic acidosis may occur. Chloride and bicarbonate levels should be monitored and bicarbonate should be administered if needed.3 In overdosages in pediatric patients, cerebral edema and death have been reported.25 In a review of adverse events reported to the FDA's Adverse Event Reporting System (AERS), 33 reports were identified and majority of cases involved pediatric patients less than 16 years old.10

Arginine injection is classified as FDA pregnancy category B. Basal and post-stimulation concentrations of growth hormone are elevated in pregnant women. There are no well-controlled studies for the use of arginine injection in pregnant women. Although animal studies have provided no evidence of harm to the fetus, animal reproductive studies are not always predictive of human response; therefore, the manufacturer recommends that arginine injection not be used during pregnancy.2

It is not known if intravenous arginine is secreted in human milk; however, systemically administered amino acids are secreted into breast milk in quantities not likely to be harmful to the infant.2 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Pregnancy

Arginine injection is classified as FDA pregnancy category B. Basal and post-stimulation concentrations of growth hormone are elevated in pregnant women. There are no well-controlled studies for the use of arginine injection in pregnant women. Although animal studies have provided no evidence of harm to the fetus, animal reproductive studies are not always predictive of human response; therefore, the manufacturer recommends that arginine injection not be used during pregnancy.2

Breast-Feeding

It is not known if intravenous arginine is secreted in human milk; however, systemically administered amino acids are secreted into breast milk in quantities not likely to be harmful to the infant.2 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Interactions

Acetaminophen; Aspirin, ASA; Caffeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Aluminum Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.1415

Aluminum Hydroxide; Magnesium Carbonate: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.1415

Aluminum Hydroxide; Magnesium Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.1415

Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.1415

Aluminum Hydroxide; Magnesium Trisilicate: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.1415

Antacids: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.1415

Aspirin, ASA: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Aspirin, ASA; Butalbital; Caffeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Aspirin, ASA; Butalbital; Caffeine; Codeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Aspirin, ASA; Caffeine; Dihydrocodeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Aspirin, ASA; Carisoprodol: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Aspirin, ASA; Carisoprodol; Codeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Aspirin, ASA; Dipyridamole: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Aspirin, ASA; Omeprazole: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Aspirin, ASA; Oxycodone: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Aspirin, ASA; Pravastatin: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Bismuth Subsalicylate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Bismuth Subsalicylate; Metronidazole; Tetracycline: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Calcium Carbonate; Magnesium Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.1213

Choline Salicylate; Magnesium Salicylate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Colchicine: Colchicine is an alkaloid that is inhibited by acidifying agents. The colchicine dose may need adjustment.16

Magnesium Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.1213

Magnesium Salicylate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Methadone: As methadone is a weak base, the renal elimination of methadone is increased by urine acidification. Thus acidifying agents may lower the serum methadone concentration. The limited amounts of circulating methadone that undergo glomerular filtration are partially reabsorbed by the kidney tubules, and this reabsorption is pH-dependent. Several studies have demonstrated that methadone is cleared faster from the body with an acidic urinary pH as compared with a more basic pH.17181920

Salsalate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.1213

Adverse Reactions/Side Effects

During clinical trials of arginine injection (R-Gene 10), one patient developed a maculopapular rash with reddening and swelling of the hands and face. The rash subsided after the infusion was terminated and 50 mg of diphenhydramine was administered. Hypersensitivity reactions, including anaphylactoid reactions, have been reported during post-market surveillance of arginine injection. If serious hypersensitivity or anaphylaxis occurs during arginine therapy, discontinue the infusion and initiate appropriate medical therapy.2

Nausea and vomiting were reported in approximately 3% of patients during clinical trials of arginine injection. Excessive rates of infusion may cause these adverse events; consider decreasing infusion rate if these symptoms develop. When dosing arginine for diagnostic purposes, inadequate dosing or prolongation of the infusion period may diminish the stimulus to the pituitary and nullify the test.2

Flushing and headache were reported in approximately 3% of patients during clinical trials of arginine injection. Excessive rates of infusion may cause flushing; consider decreasing infusion rate if these symptoms develop. When dosing arginine for diagnostic purposes, inadequate dosing or prolongation of the infusion period may diminish the stimulus to the
pituitary and nullify the test.2

During clinical trials of arginine injection, thrombocytopenia was reported in one patient (decrease in platelet count from 150,000 to 60,000).2

Metabolic acidosis and hyperventilation may occur with an overdosage of arginine injection. Ensure the appropriate dose is being administered. In overdosages in pediatric patients, cerebral edema and death have been reported.221 In a review of adverse events reported to the FDA's Adverse Event Reporting System (AERS), 33 reports were identified. most of which were pediatric patients. The acidosis and base deficit will usually self-compensate and return to normal following cessation of the infusion. If the acidosis persists, however, the deficit should be determined and an appropriate dose of an alkalinizing agent, such as bicarbonate, administered.2

Hematuria has been reported in post-marketing reports of arginine injection. Some cases occurred 1—2 days after administration of arginine.2

Extravasation causing a third-degree chemical burn (skin necrosis) requiring surgical intervention was in a 17 year old patient during post-market surveillance of arginine injection.10 An injection site reaction consisting of local venous irritation occurred in 3% of patients in clinical trials. Excessive rates of infusion may cause injection site reaction or skin irritation; consider decreasing infusion rate if local irritation develops. When dosing arginine for diagnostic purposes, inadequate dosing or prolongation of the infusion period may diminish the stimulus to the pituitary and nullify the test.2

Paresthesias were reported in approximately 3% of patients during clinical trials of arginine injection.2 Lethargy has also been reported with arginine administration.10

Arginine is a precursor of nitric oxide and accumulation of large amounts of excess arginine could lead to nitric oxide overproduction and result in vasodilation and hypotension. If hypotension is noted, reduction in arginine administration should be considered.4

Storage

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

  • 1. Ceremuzynski L, Chamiec T, Herbaczynska-Cedro K. Effect of supplemental oral L-arginine on exercise capacity in patients with stable angina pectoris. Am J Card 1997;80:331-333.
  • 2. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. Arginine hydrochloride injection (R-GENE) package insert. Lake Forest, IL: Hospira Inc.; 2010 Jan.
  • 3. a. b. c. d. e. f. Ammonul (sodium phenylacetate and sodium benzoate) injection package insert. Scottsdale, AZ: Ucyclyd Pharma Inc.; 2011 Jul
  • 4. a. b. c. d. e. Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr 2001; 138: S30-S39.
  • 5. a. b. Batshaw, ML, MacArthur RB, Tuchman M. Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr 2001; 138:S46-S55
  • 6. Adrogue HJ, Madias NE: Management of life-threatening acid-base disorders. Second of two parts. N Eng J Med 1998;338:107-11.
  • 7. a. b. c. Bode-Boger SM, Boger RH, Galland A. L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. Br J Clin Pharmacol 1998; 46: 489-497.
  • 8. a. b. c. Tangphao O, Grossmann M, Chalon S, et al. Pharmacokinetics of intravenous and oral L-arginine in normal volunteers. Br J Clin Pharmacol 1999; 47: 261-266.
  • 9. Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr 2001; 138: S30 S39
  • 10. a. b. c. d. FDA: Arginine hydrochloride injection (marketed as R-Gene 10). FDA Drug Safety Newsletter 2009;2(2):16-18.
  • 11. Bushinsky DA, Gennari J. Life-threatening hyperkalemia induced by arginine. Annals of Internal Medicine 1978; 89: 632-634.
  • 12. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. Mudge GH, Weiner IM. Agents affecting volume and composition of body fluids. Gilman AG, Rall TW, Nies AS, Taylor P, (eds.) In: Goodman and Gilman’s Pharmacological Basis of Therapeutics. 8th ed., New York, Pergamon Press. 1990:620, 696—97.
  • 13. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. Hamilton C. Acid-base disorders Gilman AG, Wells BG, Dipiro JT, Schwinghammer TL, et al. (eds.) In: Pharmacotherapy Handbook. 5th ed., New York, Pergamon Press. 1993:753—61.
  • 14. a. b. c. d. e. f. Mudge GH, Weiner IM. Agents affecting volume and composition of body fluids. Gilman AG, Rall TW, Nies AS, Taylor P, (eds.) In: Goodman and Gilman’s Pharmacological Basis of Therapeutics. 8th ed., New York, Pergamon Press. 1990:620, 696-97.
  • 15. a. b. c. d. e. f. Hamilton C. Acid-base disorders Gilman AG, Wells BG, Dipiro JT, Schwinghammer TL, et al. (eds.) In: Pharmacotherapy Handbook. 5th ed., New York, Pergamon Press. 1993:753-61.
  • 16. Colchicine Tablets, USP package insert. Corona, CA: Watson Laboratories, Inc.; 2001 Jun.
  • 17. Bellward GD, Warren PM, Howald W, et al. Methadone maintenance: effect of urinary pH on renal clearance in chronic high and low doses. Clin Pharmacol Ther 1977;22:92—9.
  • 18. Nilsson M-I, Widerlov E, Meresaar U, et al. Effect of urinary pH on the disposition of methadone in man. Eur J Clin Pharmacol 1982;22:337—42.
  • 19. Wolff K, Rostami-Hodjegan A, Hay AW, et al. Population-based pharmacokinetic approach for methadone monitoring of opiate addicts: potential clinical utility. Addiction 2000;95:1771—83.
  • 20. Dolophine® (methadone) package insert. Columbus, OH: Roxane Laboratories, Inc; 2006 Oct.
  • 21. Batshaw, ML, MacArthur RB, Tuchman M. Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr 2001; 138:S46 S55

Related Medications