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Pre-Marketing Clinical Trial Experience
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
Other Active Controls n=141
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.
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.
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.
Read the Raplon (rapacuronium) Side Effects Center for a complete guide to possible side effects
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.
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.
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.
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.
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.
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 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).
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.
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 <1 month of age until more is known about the safety of RAPLON (rapacuronium) TM in this population.
The intravenous administration of RAPLON (rapacuronium) TM has been studied in pediatric patients from 1 month up to 12 years of age. (See CLINICAL PHARMACOLOGY, Clinical Studies and DOSAGE AND ADMINISTRATION). Initial doses of 2 mg/kg intravenously in pediatric patients (ages 1 month to 12 years) under halothane anesthesia produce acceptable intubating conditions within 60 seconds. Mean maximum block occurred within 90 seconds in most pediatric patients and had a mean clinical duration of 15 minutes. Intubating doses of 3.0 mg/kg in children (2 to 12 years) provided maximum block within 90 seconds and a mean clinical duration of 18 minutes. Sufficient numbers of pediatric patients 1 month of age and older have received RAPLON (rapacuronium) TM to establish the safety of single-dose administration in this age group.
No long-term follow-up data are available in pediatric patients exposed to Raplon (rapacuronium) . Studies have demonstrated small quantities of residual drug remaining in tissues of animals administered a single bolus injection of rapacuronium one week after injection. This small residual was primarily observed in kidney, heart, lung, and pituitary. Elimination kinetics in pediatric patients have not been studied, although elimination in adult humans is known to be slower than in animal species tested. Measurable concentration in adults were detected over a period of 6 weeks. The effect of sequestered drug in tissues theoretically may affect development, however no studies to date have been conducted to substantiate this possibility.
RAPLONTM (rapacuronium bromide) for injection has been studied in 209 patients ≥ 65 years of age. Advanced age or other conditions associated with slower circulation time, e.g., cardiovascular disease may be associated with a delay in onset time. Nevertheless, the recommended dosage of 1.5 mg/kg should not be increased in these patients to reduce onset time, as higher doses produce a longer duration of action (see CLINICAL PHARMACOLOGY, Pharmacodynamics, Special Populations).
RAPLONTM (rapacuronium) is known to be substantially excreted by the kidney, and the risk of prolonged effect or other toxic reactions to this drug may be greater in patients with impaired renal function. While elderly patients are more likely to have altered renal function, no dosage adjustments are recommended in geriatric patients.
Resistance to neuromuscular blocking agents in patients with hepatic insufficiency has been ascribed to an increase in volume of distribution. RAPLOMTM at a dose of 1.5 mg/kg has been studied in a limited number of patients with cirrhosis (n=6) under isoflurane anesthesia. Following 1.5 mg/kg of RAPLON (rapacuronium) TM, the median (range) of clinical duration and recovery rate in patients with cirrhosis were 14 (8-18) minutes and 14(9-18) minutes, respectively. These times were similar to the median times of 16 minutes clinical duration and recovery rate of 14 minutes in patients with normal hepatic function. The plasma clearance of rapacuronium was faster and the volume of distribution was greater in patients with cirrhosis compared to normal controls.
RAPLONTM (rapacuronium bromide) for injection has been studied at a dose of 1.5 mg/kg in one US study, in patients with end-stage renal disease (n=9) under isoflurane anesthesia. The median (range) onset time in patients with ESRD (83 (38-180) seconds) was slow compared to normal volunteers (median onset time 66 seconds). The median clinical duration of 12 minutes (range 6 to 39 minutes) in patients with ESRD was similar to the median time of 13 minutes in normal volunteera. The recovery time from 25%- 75% T1 ranged from 6 to 68 minutes in patients with ESRD.
RAPLONTM (rapacuronium bromide) for injection has not been studied in MH-susceptible patients. No subjects exposed to RAPLON (rapacuronium) TM developed MH or any other syndrome suggestive of MH during premarketing clinical studies. In a study with MH-susceptible swine, the administration of RAPLON (rapacuronium) TM did not trigger malignant hyperthemia. Since RAPLON (rapacuronium) TM is always used with other agents, and the occurrence of malignant hyperthermia during anesthesia is possible even in the absence of known triggering agents, clinicians should be prepared to diagnose and treat malignant hyperthermia during the administration of any anesthetic.
Use In Patients with Elevated Intracranial Pressure
In a clinical trial enrolling patients with head injury in which intracranial pressure was monitored, the effects of RAPLONTM (rapacuronium bromide) for injection and vecuronium were compared. One patient in the RAPLONTM (rapacuronium) † treated group developed an increase in intracranial pressure from 17mmHg to 34 mmHg two minutes after receiving 1.5 mg/kg of RAPLON (rapacuronium) TM. In the same study, a patient in the vecuronium-treated group developed a rise in intracranial pressure from 26 to 45 mmHg six minutes after receiving vecuronium 0.1 mg/kg. The results of this study were not conclusive.
Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.
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