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R-Gene 10 for Intravenous Use (Pharmacia & Upjohn)
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Each 100 mL of R-Gene ® 10 (10% Arginine Hydrochloride Injection, USP) for intravenous use contains 10 g of L-Arginine Hydrochloride, USP in Water for Injection, USP. L-arginine is a naturally occurring amino acid.
R-Gene ® 10 is hypertonic (950 mOsmol/liter) and contains 47.5 mEq of chloride ion per 100 mL of solution. The pH is adjusted to 5.6 (5.0-6.5) with arginine base or hydrochloric acid.
Intravenous infusion of R-Gene ® 10 often induces a pronounced rise in the plasma level of human growth hormone (HGH) in subjects with intact pituitary function. This rise is usually diminished or absent in patients with impairment of this function.
These ranges are based on the mean values of plasma HGH levels calculated from the data of several clinical investigators and reflect their experiences with various methods of radioimmunoassay. Upon gaining experience with this diagnostic test, each clinician will establish his/her own ranges for control and peak levels of HGH.
L-arginine is a normal metabolite in animals and man and has a low order of toxicity.
INDICATIONS AND USAGE
R-Gene ® 10 is indicated as an intravenous stimulant to the pituitary for the release of human growth hormone in patients where the measurement of pituitary reserve for HGH can be of diagnostic usefulness. It can be used as a diagnostic aid in such conditions as panhypopituitarism, pituitary dwarfism, chromophobe adenoma, postsurgical craniopharyngioma, hypophysectomy, pituitary trauma, acromegaly, gigantism and problems of growth and stature.
If the insulin hypoglycemia test has indicated a deficiency of pituitary reserve for HGH, a test with R-Gene ® 10 is advisable to confirm the negative response. This can be done after a waiting period of one day. As patients may not respond to R-Gene ® 10 (10% Arginine Hydrochloride Injection, USP) during the first test, the unresponsive patient should be tested again to confirm the negative result. A second test can be performed after a waiting period of one day. Some patients who respond to R-Gene ® 10 do not respond to insulin and vice versa. The rate of false positive responses for R-Gene ® 10 is approximately 32%, and the rate of false negatives is approximately 27%.
The administration of R-Gene ® 10 is contraindicated in persons having highly allergic tendencies.
There have been two reports of possible overdosage of R-Gene ® 10 in children. EXTREME CAUTION MUST BE EXERCISED WHEN INFUSING R-GENE ® 10 INTO PEDIATRIC PATIENTS. OVERDOSAGE OF R-GENE ® 10 IN PEDIATRIC PATIENTS CAN RESULT IN HYPERCHLOREMIC METABOLIC ACIDOSIS, CEREBRAL EDEMA, OR POSSIBLY DEATH.
R-Gene ® 10 should always be administered by intravenous injection because of its hypertonicity.
A suitable antihistaminic drug should be available in the event that an allergic reaction occurs.
R-Gene ® 10 is a diagnostic aid and is not intended for therapeutic use.
R-Gene ® 10 is a hypertonic (950 mOsmol/liter) and acidic (average pH of 5.6) solution that can irritate tissues. Care should be used to insure administration of R-Gene ® 10 through a patent catheter within a patent vein. Excessive rates of infusion may result in local irritation and in flushing, nausea, or vomiting. Inadequate dosing or prolongation of the infusion period may diminish the stimulus to the pituitary and nullify the test.
The arginine in R-Gene ® 10 can be metabolized resulting in nitrogen-containing products for excretion. The effect of an acute amino acid or nitrogen burden upon patients with impairment of renal function should be considered when R-Gene ® 10 is to be administered.
The chloride content of R-Gene ® 10 is 47.5 mEq per 100 mL of solution, and the effect of infusing this amount of chloride into patients with electrolyte imbalance should be evaluated before the test is undertaken.
It should be noted that the basal and post stimulation levels of growth hormone are elevated in patients who are pregnant or are taking oral contraceptives.
Carcinogenesis, mutagenesis, and impairment of fertility
Long term animal studies have not been performed to evaluate the carcinogenic potential, the mutagenic potential or the effect on fertility of intravenously administered R-Gene ® 10.
Pregnancy Category B
Reproduction studies have been performed in rabbits and mice at doses 12 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to R-Gene ® 10 (10% Arginine Hydrochloride Injection, USP). There have been no adequate or well controlled studies for the use of R-Gene ® 10 in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy.
It is not known whether intravenous administration of R-Gene ® 10 could result in significant quantities of arginine in breast milk. Systemically administered amino acids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when R-Gene ® 10 is to be administered to nursing women.
Clinical studies of arginine did not include a sufficient number 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.
Adverse reactions associated with 1670 infusions in premarketing studies were as follows:
Non-specific side effects consisting of nausea, vomiting, headache, flushing, numbness and local venous irritation were reported in approximately 3% of the patients.
One patient had an allergic reaction which was manifested as a confluent macular rash with reddening and swelling of the hands and face. The rash subsided rapidly after the infusion was terminated and 50 mg of diphenhydramine were administered. One patient had an apparent decrease in platelet count from 150,000 to 60,000. One patient with a history of acrocyanosis had an exacerbation of this condition following infusion of R-Gene ® 10.
An overdosage may cause a transient metabolic acidosis with hyperventilation. The acidosis will be compensated and the base deficit will return to normal following completion of the infusion. If the condition persists, the deficit should be determined and corrected by a calculated dose of an alkalizing agent. See " WARNINGS " for information about overdosage in pediatric patients.
DOSAGE AND ADMINISTRATION
The intravenous dose for adults is 300 mL (30 g arginine hydrochloride) of R-Gene ® 10. The intravenous dose for children is 5 mL (0.5 g arginine hydrochloride) per kilogram of body weight of R-Gene ® 10.
The intravenous infusion of R-Gene ® 10 is a part of the test for measurement of pituitary reserve of human growth hormone and, for successful administration of the test, clinical conditions and procedures should be as follows:
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
R-Gene ® 10 is supplied as a 300 mL fill in 500 mL containers.
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended that the product be stored at room temperature (25°C); however, brief exposure up to 40°C does not adversely affect the product. Solution that has been frozen must not be used.
Pharmacia & Upjohn Company
A subsidiary of Pharmacia Corporation
Kalamazoo, Michigan 49001, USA
Fresenius Kabi Clayton, L.P.
Clayton, NC 27520 USA
R-Gene ® is a registered trademark of Pharmacia AB.
Directions for Use of I.V. Container
The important feature of this container is that it is a closed system. That is, no unfiltered air comes in contact with the solution. The spike is thrust through a solid stopper, the air enters through a bacterial air filter, and only filtered air enters the bottle then or during the infusion. The rubber stopper surface beneath the metal seal is sterile.
A special air-inletting, air-filtering set with a bacterial air filter is required. No airway needle is needed.
CAUTION: While the top of the rubber stopper is sterile, as soon as the seal and disc are removed the stopper is exposed. The longer the time between removal of the seal and disc and the piercing of the stopper, the greater the chance of contamination of the stopper.
NOTE: When medication is to be added to the bottle:
CONTINUED USE OF SOLUTIONS AND SETS
Procedure differs with every hospital for the length of time solutions and administration sets may be used continuously. Some recommend change of both every 8 hours, others recommend change of both every 24 hours, and others recommend change of solutions every 8 hours and change of sets every 24 hours. The shorter the period of use the less the possibility of multiplication of organisms inadvertently introduced.
(Revised August 2003)