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RAPLONTM (rapacuronium bromide) for Injection
THIS DRUG SHOULD BE ADMINISTERED BY ADEQUATELY TRAINED INDIVIDUALS FAMILIAR WITH ITS ACTIONS, CHARACTERISTICS AND HAZARDS.
RAPLONTM (rapacuronium bromide) for injection is a nondepolarizing neuromuscular blocking agent its chemical name is 1-[(2b , 3a , 5a , 16b , 17b )-3-(Acetyloxy)-17-(1-oxopropoxy)-2-(1-piperidiny)androstan-16-yl]-1-(2-propenyl) piperidinium bromide. The chemical formula of the bromide salt is C37H81BrN2O4 with a molecular weight of 677.78.
RAPLOMTM is a synthetic steroid molecule with a mono-quaternary structure in the form of a bromide salt. This chemical structure has a basic steroid framework similar to other neuromuscular blocking agents like vecuronium, pancuronium, rocuronium, and pipecuronium. Rapacuronium bromide is distinguished as being a propenyl bromide ammonium salt with a 17-hydroxy propionate carboxyester that has the same basic steroid backbone as the rest of the family of steroid neuromuscular blockers.
RAPLON (rapacuronium) Ò is supplied as a sterile, nonpyrogenic lyophilized cake in 5-mL and 10-mL vials. Each 5-mL vial contains 100 mg of rapacuronium bromide base. 35.8 mg citric acid anhydrous. 7.5 mg of sodium phosphate dibasic anhydrous. 137.5 mg of mannitol, and sodium hydroxide and/or phosphoric acid to buffer and adjust the pH. When the 5-mL vial is reconstituted to a volume of 5 mL with sterile water for injection or bacteriostatic water for injection, an isotonic preparation for intravenous injection is obtained at a pH of 4.0 with a concentration of 20 mg of rapacuronium bromide based per mL. Each10-mL vial contains 200 mg of rapacuronium bromide based, 71.5 mg of citric acid an hydroxide and/or phosphoric acide to buffer and adjust the pH. When the 10-mL vial is reconstituted to a volume of 10 mL with sterile water for injection or bacteriostatic water for injection, an isotonic preparation for intravenous injection is obtained at a pH of 4.0 with a concentration of 20 mg of rapacuronium bromide base per mL.
RAPLONTM (rapacuronium bromide) for injection is indicated as an adjunct to general anesthesia to facilitate tracheal intubation, and to provide skeletal muscle relaxation during surgical procedures.
RAPLONTM (rapacuronium bromide) FOR INJECTION IS INTENDED FOR INTRAVENOUS USE ONLY THIS DRUG SHOULD BE ADMINISTERED BY OR UNDER THE SUPERVISION OF EXPERIENCED CLINICIANS FAMILIAR WITH THE USE OF NEUROMUSCULAR BLOCKING AGENTS. THE DOSAGE INFORMATION PROVIDED BELOW IS INTENDED AS A GUIDE ONLY (see CLINICAL PHARMACOLOGY). THE USE OF ADEQUATE NEUROMUSCULAR MONITORING EQUIPMENT SUCH AS A PERIPHERAL NERVE STIMULATOR, WILL PERMIT THE MOST ADVANTAGEOUS USE OF RAPLON (rapacuronium) TM, MINIMIZE THE POSSIBILITY OF OVERDOSAGE OR UNDERDOSAGE, AND ASSIST IN THE EVALUATION OF RECOVERY.
Dose for Tracheal intubation
The recommended initial dose of RAPLON (rapacuronium) TM (rapauronium bromide) for injection in adult and geriatric patients is 1.5 mg/kg for short surgical procedures. In US and European studies, acceptable intubation scores were present in at lease 85% of patients within 60 seconds after administration of 1.5 mg/kg of RAPLON (rapacuronium) TM. Maximum block was achieved in most patients by 90 seconds. This dose had a mean clinical duration of approximately 15 minutes. In patients undergoing Cesarean section, the recommended RAPLON (rapacuronium) TM intubating dose, with thiopental induction, is 2.5 mg/kg.
Repeat Dosing in Adults (Bolus) Following an intubating dose of 1.5 mg/kg. Up to three maintenance doses of 0.50 mg/kg of RAPLON (rapacuronium bromide) for injection, administered at 25% recovery of control T1 provided a mean clinical duration of 12 † 16 minutes under opioid/nitrous oxide/ oxygen anesthesia. The duration of neuromuscular blockade was noted to increase with each additional dose. Repeat dosing should always be guided based on the clinical duration of the previous dose and should not be administered until recovery of neuromuscular function is evident (See PRECAUTIONS, Repeat Dosing).
Use in Pediatrics.
Initial doses of RAPLON (rapacuronium) TM of 2 mg/kg intravenously in pediatric patients (ages 1 month to 12 years) under halothane anesthesia produced acceptable intubating conditions within 60 seconds. Mean maximum block occurred within 90 seconds in most pediatric patients and had a mean clinical duration of approximately 15 minutes. When administration is being considered for patients 13 to 17 years of age, clinicians should consider the physical maturnity, height, and weight of the patient in determining the dose of RAPLON (rapacuronium) TM. The adult (1.5 mg/kg), pediatric (2.0 mg/kg), and Cesarean Section (2.5 mg/kg) dosing recommendations may serve as a general guideline in determining an intubating dose in this age group.
Use in geriatrics
The clinical duration of RAPLONTM (rapacuronium bromide) for injection is not prolonged in geriatric patients at a dose of 1.5 mg/kg. And the median spontaneous recovery time is not different from that in other adults. No dosage adjustment is recommended in elderly patients.
Compatibility RAPLONTM (rapacuronium bromide) for injection is compatible in solution with:
| 0.9% NaCi solution | Sterile water for injection |
| 5% dextrose in water | Lactated Ringers |
| 5% dextrose in saline | Bacteriostatic water for injection |
Use within 24 hours of mixing with the above solutions. Prepared solutions may be stored at room temperature.
Studies have shown that RAPLON (rapacuronium) TM is physically compatible when mixed with the following drugs.
| Alfentanil | Lidocaine |
| Aminophylline(compatible if used within 4 hours) | Methohexital |
| Atropine sulfate | Metoclopramide |
| Droperidol | Midazolam |
| Epinephrine | morphine |
| Fentanyl | Potassium chloride |
| Gentamycin | Propranolol |
| Glycopyrrolate | Ranitidine |
| Heparin sulfate | Remifentanil |
| Ketamine | Sufentanil |
| Labetalol | Verapamil |
RAPLON (rapacuronium) TM is physically incompatible when mixed with the following drugs:
cefuroxime
danaparoid sodium
diazeparn
nitroglycerin
thiopental
Parenteral drug products should be inspect visually for particulate matter and clarity prior to administration, whenever solution and container permit. Do not use solution if particulate matter is present.
Safety and Handling
There is no specific work-exposure limit for RAPLONTM (rapacuronium bromide) for injection. In case of eye contact, flush with water for at least 10 minutes.
RAPLONTM (rapacuronium bromide) for Injection is available in the following forms:
5-mL vials containing 100 mg of rapacuronium bromide base and when reconstituted to 5 mL with sterile water for injection or bacteriostatic water for injection providing 20 mg of rapacuronium bromide base per milliliter (20 mg/mL) at a pH of 4.0
Boxes of 10 NDC No. 0052-0490-15
10-mL vials containing 200 mg of rapacuronium bromide base and when reconstituted to 10 mL with sterile water for injection or bacteriostatic water for injection providing 20 mg of rapacuronium bromide base per milliliter (20 mg/mL) at a pH of 4.0
Boxes of 10 NDC No. 0052-0490-16
The packaging of this product contains no natural rubber (latex).
Storage
Storage at 2-25oC (36-77oF).
After reconstitution
When reconstituted with sterile water for injection or other compatible I.V. solutions, keep vial at room temperature or refrigerated 2-25oC (36-77oF) and use within 24 hours. Discard unused portion. Single use only.
When reconstituted with bacteriostatic water for injection, keep vial at room temperature or refrigerated 2-25oC (36-77oF) and use within 24 hours. Bacteriostatic water for injection CONTAINS BENZYL ALCOHOL, WHICH IS NOT INTENDED FOR USE IN NEWBORNS.
Organon Inc., West Orange, NJ 07052
Pre-Marketing Clinical Trial Experience
The safety of RAPLONTM (rapacuronium bromide) Injection was evaluated in 2036 subjects in prospective clinical trails. The majority of use in clinical trials was single bolus intravenous exposure.
Incidence of Adverse Events in Controlled Clinical Trials
The most common adverse event with an incidence of >5% seen with RAPLON (rapacuronium) TM in controlled clinical trials was hypotension (5.2%). Table 18 lists treatment-emergent signs and symptoms that occurred in at least 1% of patients receiving RAPLON (rapacuronium) TM in controlled clinical trials that were numerically more frequent than in the active control.
TABLE 18: Most Frequent Adverse Events Seen with RAPLON (rapacuronium) TM in Controlled Clinical Trials
| Body System Adverse Clinical Experience | RAPLONTM n=1956 | Succinylcholine n=572 |
Other Active Controls n=141 |
|
Cardiovascular | |||
| Hypotension | 5.2% | 6.5% | 4.3% |
| Tachycardia | 3.2% | 0.52% | 1.4% |
| Bradycardia | 1.5% | 1% | 2.1% |
|
Respiratory | |||
| Bronchospasm | 3.2% | 2.1% | 0.71% |
a Active Controls include rocuronium bromide, vecuronium bromide, and mivacurium
Incidence of Other Adverse Events During Premarketing Evaluation of RAPLON (rapacuronium) TM † in all Treated Patients
In the following tabulation, the frequencies represent the proportion of the 1,956 patients exposed to at least one dose of RAPLON (rapacuronium) TM who experienced an event of the type cited on at least one occasion while receiving RAPLON (rapacuronium) TM. All events reported are included except those already listed in the previous table. Although events reported occurred during treatment with RAPLONTM (rapacuronium) , a causal relationship has not necessarily been established.
Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/10000 patients.
Body as a Whole: Infrequent: fever, rigors, back pain, hypothermia, chest pain, peripheral edema, pain; Rare: asthenia, fatigue, non-inflammatory swelling, therapeutic response decrease.
Cardiovascular: Infrequent: hypertension, extrasystoles, abnormal ECG, arrhythmia, cerebrovascular disorder, ventricular fibrillation, atrial fibrillation, ventricular tachycardia; Rare: atria arrhythmia, cardiac failure, right cardiac failurem, cardio-respiratory arrest, cardiac arrest, thrombophlebitis, supraventricular extrasystoles, supraventricular tachycardia, myocardial infarction, left bundle branch block.
Digestive: Frequent: vomiting, nausea; Infrequent: ileus, saliva increased; Rare: abdominal pain, cholelithiasis, nonspecific gastrointestinal disorder, rectal hemorrhage, esophagospasm, oral hemorrhage, tooth disorder.
Hemic and Lymphatic: infrequent thrombosis, post-operative bleeding, Rare: epistaxis, coagulation factor decrease, purpura, anemia, hemoperitoneum.
Metabolic and Nutritional: Rare: acidosis.
Musculoskeletal: Infrequent: myalgia; Rare: muscle weakness, neonatal hypotonia.
Nervous: Infrequent: hyposthesia, hemiparesis, hypertonia, prolonged neuromuscular block, prolonged anesthesia emergence: Rare: headache, cerebral hemomhage, intracranial pressure increased. Migraine, ptosis, tetany, breath holding, confusion, anxiety.
Respiratory: Infrequent: hypoxia, increased airway pressure, hypoventilation, laryngismus, coughing, apnea, respiratory depression, upper airway obstruction, neonatal respiratory distress syndrome, pneumothorax, pulmonary edema, respiratory insufficiency, stridor; Rare: pharyngitis, larynx edema, dyspnea, neonatal respiratory depression, hyperventilation, minitis, sputum increase.
Skin: Frequent: erythematous rash; infrequent; injection site reaction, injection site pain, rash, urticaria, pruritis, sweating increased; Rare; paravenous injection.
Special Senses: Rare: corneal ulceration, meiosis decreased hearing.
Urogenital: Infrequent: Urinary retention, oliguria, Rare: abnormal renal function, urinary tract infection, pelvic inflammation, vaginal bleeding.
Inhalation Anesthetics
Use of inhalation anesthetics (enflurane, isoflurane, halothane, desflurane, sevoflurane) have been shown to enhance the activity of other neuromuscular blocking agents and may enhance the activity of RAPLON (rapacuronium) TM.
Intravenous Anesthetics
In clinical studies, the use of propofol for induction and maintenance of anesthesia did not alter the clinical duration or recovery characteristics of recommended doses of RAPLONTM (rapacuronium bromide) for injection.
Anticonvulsants
As with other nondepolarizing neuromuscular blocking drugs, if RAPLONTM (rapacuronium) is administered to patients chronically receiving anticonvulsant agents such as carbamazepine or phenytoin, shorter durations of neuromuscular block may occur and infusion rates may be higher due to the development of resistance to nondepolarizing muscle relaxants. While the mechanism for development of this resistance is not known, receptor up-regulation may be a contributing factor.
Antibiotics
Certain antibiotics (e.g., aminoglycosides, vancomycin, tetracyclines, bacitracin, polymyxin, and colistin) may enhance the neuromuscular blocking action of nondepolarizing agents such as RAPLON (rapacuronium) TM. If these antibiotics are used in conjunction with RAPLON (rapacuronium) TM, prolongation of neuromuscular block should be considered a possibility.
Other
Magnesium salts, administered for the management of toxemia of pregnancy, may enhance neuromuscular blockade. Experience concerning injection of quinidine during recovery from use of other muscle relaxants suggests that recurrent paralysis may occur. This possibility must also be considered for RAPLON (rapacuronium) TM.
Other drugs that may possibly enhance the neuromuscular blocking action or nondepolarizing muscle relaxants, such as RAPLON (rapacuronium) TM, include lithium, local anesthetics, procainamide, and quindine.
Acid-base and/or serum electrolyte abnormalities may potentiate or antagonize the action of neuromuscular blocking agents.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies in animals to evaluate carcinogenic potential or impairment of fertility with rapacuronium bromide have not been performed. Mutagenicity studies conducted with rapacuronium using the Ames test and the Mouse Lymphoma L5178Y cell assay were negative. An in vivo rat bone marrow micronucleus assay for clastogenic activity was also negative for rapacuronium. Two in vitro human lymphocyte chromosomal aberration assays for clastogenic potential were conducted with rapacuronium. Both assays were negative in the presence of metabolic activation, while in the absence of metabolic activation the first assay was inconclusive and the second assay was positive.
Pregnancy
Pregnancy Category C
Reproduction studies have been performed in pregnant nonventilated New Zealand White rabbits and nonventilated Sprague Dawley rats. Throughout gestation days 6-18, rabbits received 0.75, 1.5, or 3 mg/kg/day of rapacuronium bromide by continuous infusion. Rats, during gestation days 6-17, received intravenous doses of 0.75, 1.5, or 2.25 mg/kg/day of rapacuronium bromide in 3 divided doses at 30 minute intervals on each treatment day. No teratogenic effects were observed in rabbits or rats at the highest doses tested. The high doses of 3 and 2.25 mg/kg are approximately 0.3 and 0.1 times the maximum recommended human intravenous dose for adults on a mg/m2 basis, respectively. Post-implantation losses, as evidenced by increased resorption, were observed in rabbits at and above the lowest dose of 0.75 mg/kg, which is approximately 0.1 times the maximum recommended human intravenous dose for adults on a mg/m2 basis.
Fetotoxicity, as evidenced by increased fetal deaths and subsequent resorption, was observed in rats at the high dose of 2.25 mg/kg. Which is approximately 0.1 times the maximum recommended human intravenous dose for adults on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women.
During pregnancy there is passage of low levels of rapacuronium across the placenta and slow elimination following a single maternal dose (see CLINICAL PHARMACOLOGY, Clinical studies, Cesarean section). The risk to the developing fetus from extended low-dose instruterine exposure to a neuromuscular blocking agent is unknown. Because of these concerns and because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless the potential benefit to the patient outweighs the potential risk to the fetus.
Labor and Delivery
The use of RAPLONTM (rapacuronium bromide) for injection in Cesarean section has been studied in a limited number of patients (see CLINICAL PHARMACOLOGY, Clinical Studies).
Nursing Mothers
It is not known whether this drug is excreted in human milk or what effects it may have after oral administration. Since many drugs are excreted in human milk, caution should be exercised when RAPLONTM (rapacuronium bromide) for injection is administered to nursing mothers.
Pediatric Use
RAPLONTM (rapacuronium bromide) for injection single bolus dose administration has been studied in 397 pediatric patients, the majority of whom were ASA Class I and II.
The use of Raplon (rapacuronium) has not been studied in pediatric and adolescent patients aged 13-17 years.
There are insufficient data to recommended the use of RAPLOMTM in infants 65 years) patients. The ED50 for rapacuronium bromide for pediatric patients (1 to 12 years) is 0.4 mg/kg and for infants (1 month to PRECAUTIONS, Pediatric Use).
Table 3 and 4 present the neuromuscular function parameters following an initial dose of RAPLON (rapacuronium) TM in adult patients (18 to 64 years) and geriatric patients (> 65 years).
TABLE 3: Neuromuscular Function Parameters (Mean SD)) Following and Initial Dose of RAPLON (rapacuronium) TM in Adults (18 to 64 years)
|
Dosage | Time to Maximum Blocka (sec) | Maximum Blockb (%) | Clinical Duration (min)c | 25%-75% T1 Recovery Index (min) | Time to 70% T4/T1 recovered (min) |
|
RAPLON (rapacuronium) Ò 1.5 mg/kg | 88 (47) (n=32) | 99 (2) (n=49) | 15 (5) (n=57) | 9 (5) (n=38) | 34 (15) (n=47) |
a=time from injection to maximum block (peak effect)
b=(100-%T1 control at peak effect)
c=time from injection to return to 25 % of control T1
d=time from injection to recovery of 70% T4/T1
In U.S. clinical trials, in adult patients (18 to 64 years), the mean (SD) time to maximum block
[time from injection to maximum block (peak effect)] following an initial 2.5 mg/kg dose of
RAPLON (rapacuronium) Ò was 72 (24) seconds (n=19). The mean (SD) clinical duration (time from injection to return to 25% of control T,) in adult patients was 24 (8) minutes (n=45) with a mean (SD) 25 %-75%T, recovery index of 13 (7) minutes (n=23) and a mean (SD) time to 70% T,/T,).
TABLE 4: Neuromuscular Function Parameters (Mean (SD) Following an Initial Dose of RAPLON (rapacuronium) Ò in Geriatric Patients (2 65 years)
| Dosage | Time to Maximum Blocka (sec) | Maximum Blockb (%) | Clinical Durationc (min) | 25%-74%T1 Recovery Index (min) | Time to 70%T4/T1 recoveryc (min) |
| RAPLONÒ 1.5 mg/kg | 89 (6) (n=6) | 98 (5) (n=17) | 17 (5) (n=16) | 11 (6) (n=4) | 36 (5) (n=12) |
a=time from injection to maximum block (peat effect)
b= (100.% T1 control at peak effect)
c=time from injection to return to 25% of control T1
d=time from injection to recovery of 70% T4/T1
in U.S. clinical trials, in geriatric patients (≥
65 years), the mean (SD) time to maximum block [[time
from injection to maximum block (peak effect)] following an initial 2.5 mg/kg dose of RAPLON (rapacuronium) Ò was 51 (21) seconds (n=4). The mean (SD) clinical duration (time from injection to return to 25% of control T1) was 43 (37) minutes (n=13) with a mean (SD) 25%-75%T1 recovery index of 17 (16) minutes (n=3) and a mean (SD) time to 70%T4/T1 recovery (n=9) of 76 (20) minutes (time from injection to recovery of 70% T4/T1).
Table 5 presents the neuromuscular function parameters following an initial dose of RAPLON (rapacuronium) Ò in pediatric patients under halothane anesthesia.
TABLE 5" Neuromuscular Function Parameters Following an Initial Dose of RAPLON (rapacuronium) Ò in Pediatric patients (1 month to ≥ 12 years)
| Age Group | Dosage | Time to Maximum Blocka (sec) | Maximum Blockb (%) | Clinical Durationc (min) | 25%-75%T1 Recovery Index (min) | Time to 70%T4/T1 recoveryc (min) |
| Infants (1mo to | RAPLON Ò 1 mg/kg (n=14) | 88 (73) | 96 (12) | 9 (3) (n=13) | 7 (4) (n=9) | 20 (7) (n=12) |
| RAPLONÒ 2 mg/kg (n=16) | 84 (66) | 99 (3) | 16 (7) | 13 (11) (n=8) | 34 (13) | |
| Children (2 to 12yrs) | RAPLONÒ 2 mg/kg (n=23) | 53 (16) | 100 (1) | 14 (7) | 6 (4) (n=19) | 26 (9) (n=21) |
| RAPLONÒ 3 mg/kg (n=21) | 67 (44) | 100 (2) | 18 (3) (n=20) | 11 (6) (n=12) | 37 (9) (n=19) |
a=time from injection to maximum block (peak effect)
b=(100. % T1 control at peak effect)
c= time from injection to return to 25% of control T1
d= time from injection to recovery of 70% T4/T1
Cardiac Patients
Hemodynamic parameters were assessed in patients with coronary artery and valvular disease receiving 1.5 mg/kg of RAPLON (rapacuronium) Ò in one European (n=18) placebo controlled trial. Overall, there were mild to moderate changes in hemodynamic parameters (e.g., mean arterial pressure, heart rate, mean pulmonary artery pressure, pulmonary capilary wedge pressure, central venous pressure, cardiac index , and systemic vascular resistance index) measured invasively, in cardiac patients (valvular disease or coronary artery disease) receiving 1.5 mg/kg RAPLON (rapacuronium) TM
Obese Patients
Obese patients with a body mass index (BMI) >30kg/m2 were compared to normal weight subjects in a European study in which they received 1.5 mg/kg of RAPLON (rapacuronium) TM as part of a rapid sequence induction of anesthesia using either fentanyl/thiopental or alfentanil/propofol. Patients were dosed based on actual body weight. Acceptable (excellent or good) intubating conditions following 1.5 mg/kg of RAPLON (rapacuronium) TM were similar in obese (86% under fentanyl/thiopental, 92% under alfentanil/propofol) and normal weight subjects (87% under fentanyl/thiopental, 91% under alfentanil/propofol) at 60 seconds. The percent of excellent scores under fentanyl/thiopental of alfentanil/propofol were 48% and 65%, respectively in obese patients, and 44% and 52%, respectively, in normal weight patients.
Repeat Dosing in Adults
In three controlled clinical trials, after an initial intubating dose a RAPLON (rapacuronium) TM of 1.5 mg/kg. 3 additional doses of 0.5 to 0.55 mg/kg were administered at 25% recovery of T1 or at the reappearance of T3(n=76). The duration of action of maintenance doses of 0.5 to 0.55 mg/kg ranged from 3 to 35 minutes. A statistically significant increase in the duration of action of RAPLON (rapacuronium) TM was noted with subsequent maintenance doses (See Table 6).
Table 6: Clinical Duration (25% Recovery of T1) of Maintenance Doses of Raplon (rapacuronium) (minutes) following an initial intubating dose of 1.5 mg/kg
| Study 1 Raplon 0.55 mg/kg | Study 2 Raplon 0.5 mg/kg | Study Raplon 0.5 mg/kg | |
|
Dose No.1 | (n=15) | (n=28) | (n=33) |
|
Mean (SD) | 7(3) | 12(3) | 13(3) |
|
Median | 6 | 12 | 13 |
|
Range | 3-12 | 6-19 | 7-20 |
|
Dose No.2 | (n=15) | (n=28) | (n=33) |
|
Mean (SD) | 8(2) | 14(4) | 15(5) |
|
Median | 8 | 14 | 14 |
|
Range | 5-12 | 6-22 | 8-29 |
|
Dose No. 3 | (n=14) | (n-15) | |
|
Mean (SD) | 8(2) | 15(5) | |
|
Median | 8 | 15 | |
|
Rasnge | 5-13 | 6-35 |
Early Reversal
Administration of neostigmine (50 or 70 mcg/kg at 2 or 5 min) at profound neuromuscular block (>90%) following administration of either 1.5 or 2.5 mg/kg of RAPLONTM (rapacuronium bromide) for Injection in adults reduced the recovery time by approximately 50%. After early reversal with neostigmine, a decrease in neuromuscular function did not occur over the clinical trial period.
Table 7 presents the recovery parameters following reversal of profound block from a US study of adult patients. Anesthesia consisted of premedication with midazolam, induction with fentanyl and propofol, and maintenance with N2O supplemented with fentanyl and propofol.
TABLE 7: Recovery Profile Following Neostigmine Reversal at Profound RAPLON (rapacuronium) TM-induced Block (> 90%) in Adults (18 to 64 years)
| RAPLONTM Dose | Neostigmine Dose | Time of Neostigmine Administration | Clinical Duration (min) | 25%-75% T1 Recovery Index (min) | Time to 70% T4/T1 recovery (min) | Time to 80% T4/T1 recovery (min) |
|
1.5 mg/kg | None | N/A (n=11) | 17(5)a | 12(5)a | 38(10)a | 43(12)a |
| 50mcg/kg | 2 min (n=7) | 8(1) | 5(1) | 17(4) | 20(5) | |
| 5 min (n=12) | 9(1) | 5(3) | 17(3) | 19(4) | ||
| 70mcg/kg | 2 min (n=10) | 8(1) | 7(4) | 15(3) | 21(7) | |
| 5 min (n=9) | 9(1) | 6(2) | 19(8) | 24(8) | ||
|
2.5 mg/kg | None | N/A (n=10) | 24(5)a | 15(6)a | 56(13)a | 60(11)a |
| 50 mcg/kg | 2 min(n=12) | 12(2) | 9(4) | 26(7) | 31(8) | |
| 5 min(n=8) | 12(3) | 8(3) | 32(13) | 38(18) | ||
| 70mcg/kg | 2 min (n=9) | 12(2) | 12(5)b | 35(8) | 41(10) | |
| 5 min(n=9) | 12(2) | 8(3) | 28(9) | 36(12) |
a=p
b=(p=NS)
Hemodynamics
After the administration of RAPLONTM (rapacuronium bromide) for Injection, dose-related increase in heart rate were observed, peaking within the first few minutes after RAPLON (rapacuronium) TM administration. These changes in heart rate were generally mild to moderate and were stable or near baseline levels within 5 to 10 minutes of RAPLON (rapacuronium) TM administration. After the administration of RAPLON (rapacuronium) TM, dose-related decreases in mean arterial pressure (MAP) were observed. Decreases in MAP occurred after all doses of RAPLON (rapacuronium) TM. These changes were observed to peak within 5 minutes after the administration of RAPLON (rapacuronium) TM, returning toward baseline by 10 minutes.
Increase in heart rate and decreases in mean blood pressure were also observed in the pediatric population. In neonates, infants, and children treated with RAPLON (rapacuronium) TM, the observed changes of increased heart rate and decreased mean blood pressure were generally small in magnitude (see CLINICAL PHARMAOLOGY, Clinical Studies).
Dose-and duration-related adverse ECG changes were observed in non clinical studies in dogs. These changes included prolongation of the QT interval after dosing 2 times per week over 4 weeks, at a total dosage of 18 mg/kg/day given in 3 divided doses, and prolongation of QT interval, sinus arrhythmia, lengthened PR intervals, P wave widening, and AV dissociation following a bolus dose of 27 mg/kg given at 30 minutes after an uneventful first dose of 13.5 mg/kg. In the cat, night bundle branch block pattern and prolonged PR intervals were observed following a bolus dose of 26 mg/kg given at 30 minutes after an uneventful first dose of 13 mg/kg Therefore, potential adverse ECG effects in humans should be considered when RAPLON (rapacuronium) TM is given in a high bolus dose or following prolonged infusion.
Electrocardiogram parameters (QT, QTC, and RR intervals) were assessed in patients during a 15 minute observation period after receiving 1.5 mg/kg RAPLON (rapacuronium) TM (n=18) and placebo (n=16) in a European study. Mean QT interval decreases up to 0.015 second from baseline were observed in the RAPLON (rapacuronium) TM group while small increases of up to 0.082 second were observed in the placebo group. Mean changes in the QTC interval during the 15-minute period ranged from a decrease of 0.025 second to an increase of 0.052 second from baseline in the RAPLON (rapacuronium) TM group compared to increases of up to 0.04 second in the placebo group. Mean changes in the RR interval ranged from 0.101 to 0.024 second in the RAPLON (rapacuronium) TM group and up to 0.113 second in the placebo group. The clinical significance of these changes is unknown.
Histamine Release
Plasma histamine release was assessed following administration of RAPLONTM (rapacuronium bromide) for Injection (1.0,2.0, and 3.0 mg/kg) in a US study (n=46). Increases in plasma histamine levels peaked at 1 minute following 2.0 and 3.0 mg/kg of RAPLON (rapacuronium) TM. The elevation in histamine levels was dose-related; 1/16, 2/15, and 6/15 subjects in the 1.0 mg/kg. 2.0 mg/kg, and 3.0 mg/kg groups, respectively, demonstrated clinically significant elevations of histamine levels (clinical significance defined as > 1 ng/mL or 100% increase from baseline). Two of six patients in the 3.0 mg/kg group with clinically significant elevations of histamine levels had >30% increase in heart rate and >30% decrease in blood pressure after the administration of RAPLON (rapacuronium) TM.
Events possibly related to histamine release (e.g., erythema, bronchospasm) occurred in 29 (5.1%) of 564 adult patients in US studies and in 43 (6.8%) of 736 adult patients in European studies.
Intraocular Pressure
In a clinical study, intraocular pressure following a single bolus dose of 1.5 mg/kg of RAPLONTM (rapacuronium bromide) for Injection (n=8) decreased by a maximum of 15% at 3 minutes.
Pharmacokinetics
Data from the in vivo pharmacokinetic studies were used to develop population estimates of the parameters for the subpopulations represented (e.g., geriatric, pediatric, renal insufficiency, and hepatic insufficiency). These population-based estimates and a measure of the estimated variability are contained in the following sections.
Following intravenous administration of RAPLONTM (rapacuronium bromide) for Injection, plasma concentration data were best described by a three-compartment model. The pharmacokinetic model was parameterized in clearances and volumes. Estimates of these parameters were used subsequently to calculate volume of distribution at steady state and half-lives. Table 8 presents the results of a population pharmacokinetic analysis from 206 adult patients (18 to 83 years), including patients with end-stage renal disease (n=7) and cirrhosis (n=8). The variability for these parameters is not available from this analysis. See Tables 11 and 12 for variability estimates for these parameters.
TABLE 8: Population Pharmacokinetic Parameter Estimates for RAPLON (rapacuronium) TM a
| PK Parameter | Estimate | CVb |
| Plasma Clearance (mL/kg/min) | 6.56 | 2.5% |
| Volume of Distribution at steady State (mL/kg) | 292 | NDc |
a= Based on basic three compartment model without covariates
b= Coefficient of variation (%)
c= Not determined for derived parameters
Distribution
The mean volume of distribution of RAPLON (rapacuronium) TM at steady state was 292 mL/kg in adult patients. The mean rapid distribution half-life was 4.56 minutes and the mean slow distribution half-life was 27.8 minutes.
Metabolism
Rapacuronium bromide undergoes hydrolysis of the acetyloxy-ester bond at the 3-position to form the 3-hydroxy metabolite, the major and active metabolite of rapacuronium. Relative to its parent, the 3-hydroxy metabolite has greater potency and a slower onset of action. This hydrolysis is non-specific and can occur at physiological temperature and PH. This hydrolysis may also be catalyzed by esterases of unknown identify and at unknown sites. The cytochrome P450 enzyme system does not appear to be involved in the hydrolsis of rapacuronium bromide. A mass balance study suggests that there may be seven additional minor metabolites of unknown identify in addition to the 3-hydroxy metabolite.
Elimination
A mass balance study using 1.5 mg/kg of [14C] rapacuronium bromide demonstrated that urine and feces are the main routes of elimination of [14C] rapacuronium bromide (Table 9). The mean combined excretion in urine and feces at the end of the continuous 13.5-day collection period was approximately 56% (range; 50%-64%), with approximately 28% excreted in urine samples and 28% in feces. Measurable concentrations of radiocarbon were also detected in urine samples collected once a week over four weeks after the end of the continuous 13.5-day collection period.
The estimated radioactivity excreted in expired CO2 over 24 hours was approximately 0.6% of the administered dose. The apparent elimination half-life of radioactivity was estimated to be approximately 22 days, suggesting that complete excretion can take several weeks.
TABLE 9: Recovery of Radioactivity a From Volunteers (n=6) Given [14C] Rapacuronium
| Source | Percentage Recovery mean (SD) | Duration of Sampling |
| Urine | 28.4(4.3) | 13.5 days |
| Stool | 27.7(4.2) | 13.5 days |
| Exhaled Gas b | 0.6(0.07) | 24 hours |
| Total c | 58 (5) (range 50-64%) | 13.5 days |
a= Radioactivity recovery does not distinguish between rapacuronium and the 3-hydroxy metabolite
b= Sampling started 2 hours after anesthesia recovery and a total of 7 samples were collected
c= Excluding exhaled gas
Rapacuronium bromide, in addition to undergoing hydrolysis to its 3-hydroxy metabolite, is also excreted unchanged in urine and feces. The 3-hydroxy metabolite is excreted unchanged in urine and feces without further biotransformation. Approximately 8% of the administered rapacuronium bromide does was recovered from urine up to 48 hours after dosing as unchanged rapacuronium bromide and approximately 5% as the 3-hydroxy metabolite (Table 10).
TABLE 10: Recovery of Rapacuronium Bromide and the 3-hydroxy metabolite From a 48-Hour Urine Collection of Volunteers (n=10) Given Unlabelled Rapacuronium Bromide
| Compound Excreted in Urine mean (SD) | Time After RAPLONTM 1.5mg/kg Bolus | |
| 0-24 hours | 0-48 hours | |
| Rapacuronium Bromide (% excreted) | 7.96 (2) | 8.12(2) |
| 3-hydroxy metabolite (% excreted) | 3.43 (1) | 4.96(1.2) |
The mean plasma clearance of rapacuronium bromide in adult patients was 6.56 mL/kg/min and the mean plasma elimination half-life (T½ ß) was 141 minutes. However, this half-life may not represent the terminal elimination of rapacuronium bromide from the body as characterized in the mass balance study.
Protein Binding
Plasma protein binding of rapacuronium was studied in vitro for human plasma by equilibrium dialysis. The protein binding was variable and ranged between 50% and 88%, which was at least partly due to hydrolysis of rapacuronium bromide to its 3-hydroxy metabolite. The specific plasma protein to which rapacuronium binds is unknown. Plasma protein binding of the 3-hydroxy metabolite was not determined.
Special Populations
Geriatrics
In the pooled population pharmacokinetic analysis based on 206 adult patients ages 18 to 63 years, the analysis of covariates showed that total plasma clearance of rapacuronium bromide decreases with increasing age. However, as these changes were not clinically significant, no dosage adjustment is recommended for geriatric patients.
Pediatrics
Pharmacokinetic parameters in pediatric patients (n=49) ranging in age from 1 month to 12 years (median 3 years) were estimated using population pharmacokinetic (PK) analyses. The plasma concentration data were best described by a three-compartment model in which all PK parameters were proportional to body weight. The mean plasma clearance was 10.6 mL/kg/min. The mean volume of distribution at steady state was 495 mL/kg and the mean elimination half-life was 262 min (see PRECAUTIONS, Pediatric Use).
Gender
In general, studies in normal adult subjects did not reveal any differences in the pharmacokinetics of RAPLON (rapacuronium) TM due to gender.
Race
Race was not examined as a covariate in the pooled population pharmacokinetic analysis of RAPLON (rapacuronium) TM.
Renal Insufficiency
Table 11 summarizes the results of conventional PK analyses from a US study of normal volunteers and patients with end-stage renal disease (ESRD) receiving a single bolus dose of 1.5 mg/kg of RAPLON (rapacuronium) TM. Patients with renal insufficiency had a mean 30% reduction in clearance compared with normal adult patients. The volume of distribution was more variable in patients with renal insufficiency compared to normal volunteers.
Comparison of the concentration of the 3-hydroxy metabolite relative to that of rapacuronium bromide up to eight hours after rapacuronium bromide administration and the plasma concentration versus time profiles between the normal volunteer group and patients with ESRD showed that the pharmacokinetics of the 3-hydroxy metabolite were altered in patients with ESRD. In normal volunteers, the ration of the 3-hydroxy metabolite to rapacuronium increased steadily through the 6-hour period but decreased by the 8-hour time point (from 0.03 at 3 minutes to 4.5 at 8 hours). In patients with ESRD, this ration showed an increasing trend even at the 8-hour time point (from 0.02 at 3 minutes to 7.5 at 8 hours). The decrease in the plasma concentration of the 3-hydroxy metabolite in patents with ESRD was only 35% from peak levels (265 to 171 ng/mL) compared an 87% decrease in the normal volunteer group (381 to 49 ng.mL). No clear elimination phase was observed at the end of 8 hours. Despite the persistence of the 3-hydroxy metabolite, neuromuscular function recovered completely with a mean time course to 70% T4/T1 only slightly longer in patients with ESRD, compared to that in healthy volunteers with normal renal function after a single 1.5 mg/kg bolus. However, it is likely that recovery from supplemental doses of RAPLON (rapacuronium) TM will be prolonged in patients with renal failure.
TABLE 11: Estimates of PK Parameters of RAPLON (rapacuronium) TM in Normal Volunteers and Patients With ESRD
| PK Parameter | Normal Volunteers a | Patients with ESRDa |
| Elimination Half-Life C (t1/2b ,min) | 240(97) | 198(141)b |
| Volume of Distribution at Steady State (mL/kg) | 431.7(78) | 440.3(347) |
| Plasma Clearance (mL/kg/min) | 9.4(2.2) | 6.1(1.7)b |
a= Normal volunteers n=10 patients with ESRD n=9, values are mean (SD)
b= p 65 years).
TABLE 14: Viby-Mogensen Scale
| CLINICALLY ACCEPTABLE | |||
| Excellent | Good= | Poor= | |
| Vocal Cord Position | Abducted | Intermediate | Closed |
| Vocal Cord Movement | None | Moving | Closing |
| Easiness of Laryngoscopy· | Easy | Fair | Difficult |
| Airway Reaction | None | Diaphragm | Sustained > 10 sec |
| Movement of Limbs | None | Slight | Vigorous |
· Easy : Jaw relaxed; no resistance
Fair : Jaw relaxed; slight resistance
= Excellent ; All items excellent
Good: All items excellent or good
Poor: Any item poor
Intubating dosages of 1.5 and 2.5 mg/kg of RAPLON (rapacuronium) TM were evaluated in 784 patients. A population of patients undergoing Cesarean section was also studied (see below).
TABLE 15: Intubation Scores in Adults (16 to 64 years) With Laryngoscopy Initiated at 50 Seconds following Administration of RAPLON (rapacuronium) TM or succinylcholine
| Study | U.S. | France | Germany | |||
|
Drug/Dosage | RAPLONTM | Succinylch-oline | RAPLONTM | Succinylch-oline | RAPLONTM | Succinylch-oline |
| 1.5mg/kg | 1.0mg/kg | 1.5mg/kg | 1.0mg/kg | 1.5mg/kg | 1.0mg/kg | |
| n=124 | n=112 | n=128 | n=128 | n=160 | n=156 | |
| Excellent | 43% | 67% | 30% | 48% | 51% | 73% |
| Good | 44% | 29% | 55% | 41% | 39% | 24% |
| Poor | 13% | 4% | 9% | 9% | 11% | 3% |
| Impossible | 0% | 2% | 5% | 2% | 0% | 0% |
TABLE 16: Intubation Scores in Geriatric Patients (>65 years) With Laryngoscopy Initiated at 50 Seconds after Administration of RAPLON (rapacuronium) TM or succinylcholine
| Study | U.S. | France | ||
| Drug/Dosage | RAPLONTM | Succinylcholine | RAPLONTM | Succinylcholine |
| 1.5 mg/kg | 1.0 mg/kg | 1.5 mg/kg | 1.0 mg/kg | |
| n=26 | n=28 | n=25 | n=36 | |
| Excellent | 50% | 79% | 32% | 62% |
| Good | 46% | 21% | 48% | 35% |
| Poor | 4% | 0% | 4% | 0% |
| Impossible | 0% | 0% | 16% | 4% |
Intubating conditions were also studied in pediatric patients (>1 month to
TABLE 17: Intubation Scores in Pediatric Patients With Laryngoscopy Initiated at 50 Seconds after Administration of RAPLON (rapacuronium) TM
| Infants (1mo to 1 yr) 2.0 mg/kg n=9 | Children (1 to 12 yr) 2.0 mg/kg n=17 | |
| Excellent | 100% | 58% |
| Good | 0% | 41% |
| Poor | 0% | 0% |
| Impossible | 0% | 0% |
Cesarean Section
In a controlled clinical trial, patients undergoing rapid sequence induction of anesthesia for Cesarean section received thiopental 4-6 mg/kg followed by 2.5 mg/kg of RAPLON (rapacuronium) TM or1.5
Mg/kg of succinylcholine. Laryngoscopy was initiated 50 seconds after the muscle relaxant was administered and intubation completed by 60 seconds in all patients. Acceptable (excellent or good) intubating conditions were achieved in 14/15 (93%) patients receiving RAPLON (rapacuronium) TM and in 17/19 (89%) patients receiving succinylcholine. Excellent scores were recorded in 10/15 (67%) RAPLON (rapacuronium) TM patients and 13/19 (68%) succinylcholine patients.
No neonates born of mothers who received RAPLON (rapacuronium) TM during Cesarean section had APGAR scores below 6 at 5 minutes post-delivery or NAC (Neurological and Adaptive Capacity) scores 30 and a group of non-obese patients (body mass index 20-28). When dosed by actual body weight, the obese group had approximately the same percentage of patients with acceptable (excellent or good) intubating conditions as the non-obese group.
Although RAPLON (rapacuronium) TM has not been formally studied in morbidly obese patients (body mass index > 40). Clinical should consider dosing this patient population based on ideal body weight. As with other neuromuscular blocking drugs, RAPLON (rapacuronium) TM may exhibit prolonged duration and delayed spontaneous recovery when the morbidly obese are dosed based on actual body weight.
Burns
Patients with burns are known to develop resistance to nondepolaizing neuromuscular blocking agents, probably due to up-regulation of post-synaptic skeletal muscle cholinergic receptors.
No specific information available. However, please see WARNINGS and PRECAUTIONS.
