R-GENE 10

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Administer arginine injection intravenously.
Intravenous Administration
For stimulation of the pituitary gland

Preparation of the IV infusion
Children weighing less than 60 kg:
-The entire 300 mL bottle of R-Gene 10 is NOT intended for use in patients weighing less than 60 kg. Overdosage in pediatric patients has resulted in hyperchloremic metabolic acidosis, cerebral edema, or possibly death.
-To avoid inadvertent administration of the total volume of R-Gene 10, withdraw the appropriate weight-based dose (0.5 g/kg) from an intact bottle of R-Gene 10 and transfer the dose to a separate container, such as an evacuated sterile glass container, polypropylene syringe, or plastic containers made of polyvinyl chloride (PVC) or ethylene vinyl acetate (EVA).
-Solution is stable for 4 hours, including infusion time, at room temperature or for 24 hours refrigerated.

Children and Adolescents weighing 60 kg or more:
-R-Gene 10 is ready to use for patients weighing 60 kg or more; further dilution is not required.

Intermittent IV Infusion
-Arginine injection is hypertonic (950 mOsmol/L) and acidic (average pH of 5.6) and contains 47.5 mEq chloride/100 mL solution. Administration may cause venous irritation and damage to tissues. Ensure administration via a patent catheter with a patent antecubital vein or other suitable vein. In general, administration through a central line is recommended.
-Verify the dose prior to administration.
-If administering in provided glass container, a standard air-inletting, air-filtering intravenous infusion set with a bacterial air filter is required.
-Infuse over 30 minutes.

Test Procedure
-The test should be performed in the morning after a normal night's sleep. An overnight fast should continue through the test period.
-Place patients at bed rest at least 30 minutes prior to start of the infusion. Minimize apprehension and distress, particularly in children.
-Infusion should occur through an indwelling needle or soft catheter placed in a patent antecubital vein or other suitable vein. Blood samples should be taken by venipuncture from the contra-lateral arm.
-Schedule blood samples for -30, 0, 30, 60, 90, 120, and 150 minutes, where "0" indicates initiation of R-Gene 10 infusion.
-Administer R-Gene 10 over 30 minutes.
-Blood samples should be centrifuged promptly and stored at -20 degrees C until assayed by one of the published radioimmunoassay procedures.
-If test results indicate a deficiency of pituitary reserve for HGH, results should be confirmed with either a second test with R-Gene 10 or insulin hypoglycemic test. One day between tests is advised.

For the adjunctive treatment of acute hyperammonemia in urea cycle disorders

Preparation
-Arginine is administered with sodium benzoate and sodium phenylacetate. Prepare the sodium benzoate; sodium phenylacetate dose in 25 to 35 mL/kg of 10% Dextrose Injection. The solution can be prepared in glass or PVC containers.
-Mix the calculated dose of arginine 10% injection in the same container.
-The solution is stable for 24 hours at room temperature.

IV Infusion
-Administer via a central line.
-Loading dose: Infuse IV over 90 to 120 minutes.
-Maintenance dose: Infuse continuously over 24 hours.

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.

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.

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.

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

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. 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.

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

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. 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.

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

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.

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, R-Gene contains 47.5 mEq chloride/100 ml, which should be considered in patients with an existing electrolyte imbalance. 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.

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. In overdosages in pediatric patients, cerebral edema and death have been reported. 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.

Description: 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 and in neonates and children for the treatment of urea cycle disorders. Use caution when administering arginine since several cases of overdosage have been reported in pediatric patients; verify doses for accuracy prior to administration. Arginine is FDA-approved for use in pediatric patients as young as neonates.

For growth hormone deficiency diagnosis (i.e., evaluation of pituitary growth hormone reserve):
Intravenous dosage:
Neonates: 0.5 g/kg IV administered over 30 minutes. NOTE: Extreme caution must be used when arginine injection is prescribed for pediatric patients; fatal overdose has occurred.
Infants, Children, and Adolescents: 0.5 g/kg IV (Max: 30 g) administered over 30 minutes. NOTE: Extreme caution must be used when arginine injection is prescribed for pediatric patients; fatal overdose has occurred.

For the adjunctive treatment of acute hyperammonemia* and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle:
-for patients with carbamyl phosphate synthetase (CPS) or ornithine transcarbamylase (OTC) deficiency:
Intravenous dosage:
Neonates: 2 mL/kg (provides 200 mg/kg of arginine) IV loading dose through a central line over 90 to 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.
Infants and Children weighing less than 20 kg: 2 mL/kg (provides 200 mg/kg of arginine) IV loading dose through a central line over 90 to 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.
Children and Adolescents weighing more than 20 kg: 2 mL/kg (provides 200 mg/kg of arginine) IV loading dose through a central line over 90 to 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/m2 of 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.
-for patients with argininosuccinate lyase (ASL) or argininosuccinate synthetase (ASS) deficiency:
Intravenous dosage:
Neonates: 6 mL/kg (provides 600 mg/kg of arginine) IV loading dose through a central line over 90 to 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.
Infants and Children weighing less than 20 kg: 6 mL/kg (provides 600 mg/kg of arginine) IV loading dose through a central line over 90 to 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.
Children and Adolescents weighing more than 20 kg: 6 mL/kg (provides 600 mg/kg of arginine) IV loading dose through a central line over 90 to 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/m2 of 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.

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.

Urea Cycle Disorders
-In patients on high-flow rate dialysis, hourly ammonia levels should be drawn until the ammonia plasma level has stabilized to < 200-300 micromole/L; then, the frequency can be reduced to once every few hours. Once the patient is receiving a stable drug regimen and not requiring dialysis, the frequency can be reduced to every 12 hours and then once-daily.
-During the acute phase, serum electrolytes and acid-base balance should be monitored every 4 hours.
-Amino acids should be monitored daily to assess nutritional status and the effectiveness of glutamine removal and citrulline/arginine replacement.

Maximum Dosage Limits:
-Neonates
0.5 g/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 g/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
less than 60 kg: 0.5 g/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.
60 kg or more: 30 g/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
less than 60 kg: 0.5 g/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.
60 kg or more: 30 g/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.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

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.

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 1 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 concentrations and prevent the breakdown of endogenous protein. Additionally, arginine administration lowers the blood ammonia concentration and increases the amount of nitrogen excreted in the urine by stimulating an alternative pathway for waste nitrogen excretion. Arginine is a precursor of nitric oxide; excess amounts may cause vasodilation and hypotension.

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.

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.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
In 2 pharmacokinetic studies of healthy volunteers, the oral bioavailability of L-arginine was 68% after 6 g PO (administered as twelve 500 mg capsules) and 21% after 10 g PO (administered as 100 mL of a 10% solution). The Tmax was 90 minutes after 6 g PO and 60 minutes after 10 g PO. After 10 g PO, renal clearance was not found to a significant contributor; nonrenal clearance was 360 mL/minute. In the other study, clearance was 1,018 +/- 230 mL/minute, with a half-life of 79.5 minutes after 6 g PO.

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. 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 to 1.18 mL/kg/minute. In a study of 8 healthy males, after receiving 30 g IV of arginine, clearance was 544 +/- 24 mL/minute, and after 6 g IV of arginine, clearance was 894 +/-164 mL/minute. Elimination half-life was dose-dependent and was 41.6 minutes after 30 g IV and 59.6 minutes after 6 g IV.