DRUG DESCRIPTION
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.
RAPLONÒ 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.
INDICATIONS
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.
DOSAGE AND ADMINISTRATION
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 RAPLONTM, MINIMIZE THE POSSIBILITY OF OVERDOSAGE OR UNDERDOSAGE, AND ASSIST IN THE EVALUATION OF RECOVERY.
DOSE FOR TRACHEAL INTUBATION
THE RECOMMENDED INITIAL DOSE OF RAPLONTM (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 RAPLONTM. 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 RAPLONTM 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 RAPLONTM 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 RAPLONTM. 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 RAPLONTM 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
RAPLONTM 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.
SIDE EFFECTS
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 RAPLONTM 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 RAPLONTM IN CONTROLLED CLINICAL TRIALS THAT WERE NUMERICALLY MORE FREQUENT THAN IN THE ACTIVE CONTROL.
TABLE 18: MOST FREQUENT ADVERSE EVENTS SEEN WITH RAPLONTM 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 RAPLONTM † 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 RAPLONTM WHO EXPERIENCED AN EVENT OF THE TYPE CITED ON AT LEAST ONE OCCASION WHILE RECEIVING RAPLONTM. ALL EVENTS REPORTED ARE INCLUDED EXCEPT THOSE ALREADY LISTED IN THE PREVIOUS TABLE. ALTHOUGH EVENTS REPORTED OCCURRED DURING TREATMENT WITH RAPLONTM, 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.
DRUG INTERACTIONS
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 RAPLONTM.
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 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 RAPLONTM. IF THESE ANTIBIOTICS ARE USED IN CONJUNCTION WITH RAPLONTM, 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 RAPLONTM.
OTHER DRUGS THAT MAY POSSIBLY ENHANCE THE NEUROMUSCULAR BLOCKING ACTION OR NONDEPOLARIZING MUSCLE RELAXANTS, SUCH AS RAPLONTM, 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 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 RAPLONTM IN THIS POPULATION.
THE INTRAVENOUS ADMINISTRATION OF RAPLONTM 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 RAPLONTM 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. 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.
GERIATRIC USE
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 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.
HEPATIC DISEASE
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 RAPLONTM, 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.
RENAL FAILURE
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.
MALIGNANT HYPERTHERMIA (MH)
RAPLONTM (RAPACURONIUM BROMIDE) FOR INJECTION HAS NOT BEEN STUDIED IN MH-SUSCEPTIBLE PATIENTS. NO SUBJECTS EXPOSED TO RAPLONTM DEVELOPED MH OR ANY OTHER SYNDROME SUGGESTIVE OF MH DURING PREMARKETING CLINICAL STUDIES. IN A STUDY WITH MH-SUSCEPTIBLE SWINE, THE ADMINISTRATION OF RAPLONTM DID NOT TRIGGER MALIGNANT HYPERTHEMIA. SINCE RAPLONTM 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 † TREATED GROUP DEVELOPED AN INCREASE IN INTRACRANIAL PRESSURE FROM 17MMHG TO 34 MMHG TWO MINUTES AFTER RECEIVING 1.5 MG/KG OF RAPLONTM. 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.
WARNINGS
RAPLONTM (RAPACURONIUM BROMIDE) FOR INJECTION SHOULD BE ADMINISTERED IN CAREFULLY ADJUSTED DOSAGE BY OR UNDER THE SUPERVISION OF EXPERIENCED CLINICIANS WHO ARE FAMILIAR WITH THE DRUGS ACTIONS AND THE POSSIBLE COMPLICATIONS OF ITS USE. THE DRUG SHOULD NOT BE ADMINISTERED UNLESS PERSONNEL AND FACILITIES FOR RESUSCITATION AND LIFE SUPPORT (TRACHEAL INTUSATION, ARTIFICIAL VENTILATION, OXYGEN THERAPY). AND AN ANTAGONIST OF RAPLONTM ARE IMMEDIATELY AVAILABLE. IT IS RECOMMENDED THAT ADEQUATE NEUROMUSCULAR MONITORING EQUIPMENT. SUCH AS A PERIPHERAL NERVE STIMULATOR. BE USED TO MEASURE NEUROMUSCULAR FUNCTION DURING THE ADMINISTRATION OF RAPLONTM IN ORDERTO MONITOR DRUG EFFECT. DETERMINE THE NEED FOR ADDITIONAL DOSES. AND CONFIRM RECOVERY FROM NEUROMUSCULAR BLOCK.
RAPLONTM HAS NO KNOWN EFFECT ON CONSCIOUSNESS, PAIN THRESHOLD, OR CEREBRATION, TO AVOID DISTRESS TO THE PATIENT, NEUROMUSCULAR BLOCK SHOULD NOT BE INDUCED BEFORE UNCONSCIOUSNESS. THEREFORE, ADMINISTRATION OF RAPLONTM MUST BE ACCOMPANIED BY ADEQUATE ANESTHESIA OR SEDATING AGENTS.
LONG-TERM USE
RAPLONTM (RAPACURONIUM BROMIDE) FOR INJECTION, SHOULD NOT BE ADMINISTERED BY INFUSION PARTICULARLY IN THE INTENSIVE CARE UNIT (ICU), OR DURING LONG SURGICAL PROCEDURES. IN AN INFUSION STUDY (N=90) WITH RAPLOMTM, ONE PATIENT DISPLAYED A DETERIORATION OF NEUROMUSCULAR FUNCTION AFTER ATTAINING EVIDENCE OF ADEQUATE SPONTANEOUS RECOVERY. SIX MINUTES AFTER SPONTANEOUSLY RECOVERING TO A T0/T2 OF 70%, THE T4/T1 DECREASED TO 64%. THIRTEEN MINUTES LATER T4/T1 RECOVERED TO 80%. THIS PATIENT DID NOT RECEIVE NEOSTIGMINE AND HAD NO RESPIRATORY PROBLEMS THAT REQUIRED REINTUBATION OR MASK ASSISTED BREATHING.
RADIOISOTOPE STUDIES HAVE DEMONSTRATED THAT ONLY 56% OF THE ORIGINAL RAPLON DOSE HAD BEEN EXCRETED TWO WEEKS FOLLOWING A SINGLE IV BOLUS. EXCRETION OF 14C-LABELED RAPACURONIUM CONTINUED FOR AT LEAST SIX WEEKS. ACCUMULATION OF RAPACURONIUM BROMIDE FOLLOWING REPEAT DOSING IS LIKELY TO OCCUR BUT HAS NOT BEEN STUDIED.
ECG ABNORMALITIES HAVE BEEN OBSERVED IN ANIMALS FOLLOWING REPEAT DOSES AND LARGE SINGLE DOSES OF RAPACURONIUM BROMIDE (SEE CLINICAL PHARMACOLOGY, HEMODYNAMICS).
DURING PREGNANCY THERE IS PASSAGE OR LOW LEVELS OR RAPACURONIUM ACROSS THE PLACENTA AND SLOW ELIMINATION FOLLOWING A SINGLE MATERNAL DOSE (SEE CLINICAL PHARMACOLOGY, PHARMACOKINETICS). THE RISK TO THE DEVELOPING FETUS FROM EXTENDED LOW-DOSE INTRAUTERINE 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. THIS WARNING DOES NOT EXTEND TO USE OF RAPLONTM DURING CESAREAN SECTION, BUT APPROPRIATE MONITORING OF THE INFANT IS RECOMMENDED AFTER DELIVERY (SEE CLINICAL PHARMACOLOGY, CLINICAL STUDIES).
IN PATIENTS WITH MYASTHENIA GRAVIS OR MYASTHENIC (EATON-LAMBERT) SYNDROME, SMALL DOSES OF NONDEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS MAY HAVE PROFOUND EFFECTS. IN SUCH PATIENTS, A PERIPHERAL NERVE STIMULATOR AND USE OF A SMALL TEST DOSE MAY BE OF VALUE IN MONITORING THE RESPONSE TO ADMINISTRATION OF MUSCLE RELAXANTS.
RECONSTITUTED RAPLONTM, WHICH HAS AN ACID PH OF 4.0, SHOULD NOT BE MIXED WITH ALKALINE SOLUTIONS (E.G., BARBITURATE SOLUTIONS) IN THE SAME SYRINGE OR ADMINISTERED SIMULTANEOUSLY DURING
INTRAVENOUS INFUSION THROUGH THE SAME NEEDLE.
PRECAUTIONS
REPEAT DOSING
IT IS STRONGLY RECOMMENDED THAT DURING ADMINISTRATION OF RAPLONTM, NEUROMUSCULAR TRANSMISSION AND RECOVERY BE MONITORED CONTINUOUSLY USING A NERVE STIMULATOR. ADDITIONAL DOSES OF RAPLONTM SHOULD NOT BE GIVEN UNTIL THERE IS A DEFINITE RESPONSE (ONE TWITCH OF THE TRAIN-OF-FOUR) TO NERVE STIMULATION.
REPEAT DOSING IN ADULTS AFTER INTUBATING DOSES GREATER THAN 1.5 MG/KG, AND REPEAT DOSING IN PEDIATRIC PATIENTS HAVE NOT BEEN STUDIED, AND ARE, THEREFORE, NOT RECOMMENDED.
THE EXPERIENCE WITH A LIMITED NUMBER OF PATIENTS INDICATES THAT REPEAT BOLUS DOSING OF RAPLONTM MAY HAVE A POTENTIAL FOR PROLONGED BLOCK. THEORETICALLY, INCREASED HISTAMINE EFFECTS MAY RESULT FROM SLOW ELIMINATION OF THE DRUG FROM THE BODY; HOWEVER, NO STUDIES TO DATE HAVE BEEN CONDUCTED TO SUBSTANTIATE THIS POSSIBILITY (SEE CLINICAL PHARMACOLOGY, PHARMACOKINETICS).
IN THREE EUROPEAN STUDIES, ADULT PATIENTS WERE GIVEN AN INTUBATING DOSE OF 1.5 MG/KG OF RAPLONTM (RAPACURONIUM BROMIDE) FOR INJECTION FOLLOWED BY THREE MAINTENANCE DOSES OF RAPLONTM 0.5 MG/KG (N=61) OR 0.55 MG/KG (N=19). IN ONE STUDY, MEDIAN (RANGE) CLINICAL DURATIONS OF THE THREE DOSES OF 0.55 MG/KG WERE 6 (3-12), 8 (5-12), AND 8 (5-13) MINUTES. IN THE SECOND STUDY, THE THREE MAINTENANCE DOSES OF 0.5 MG/KG HAD MEDIAN (RANGE) CLINICAL DURATIONS OF 12 (6-19), 14 (6-22), AND 15 (6-35) MINUTES. NEOSTIGMINE WAS ADMINISTERED TO HALF THE PATIENTS IN THIS STUDY AFTER THE THIRD DOSE WHEN T1 RETURNED TO 25%, AND THE MEDIAN (RANGE) TIME TO RECOVER TO 70% T4/T1 WAS 6 (2-9) MINUTES (N=14). THE REMAINING HALF OF THE PATIENTS HAD SPONTANEOUS RECOVERY AFTER THE THIRD DOSE. THE MEDIAN SPONTANEOUS RECOVERY FROM 25% T1 TO 70% T4/T1 WAS 57 MINUTES AND RANGED FROM 44 TO 80 MINUTES (N=11). IN THE THIRD STUDY, THE MEDIAN (RANGE) CLINICAL DURATIONS OF THE FIRST AND SECOND MAINTENANCE DOSES OF 0.5 MG/KG WERE 13 (7-20) AND 14 (8-29) MINUTES. NEOSTIGMINE (N=12) OR EDROPHONIUM (N=13) WERE ADMINISTERED TWO MINUTES AFTER THE THIRD DOSE OF RAPLON. MEDIAN (RANGE) TIME TO 70% T4/T1 WAS 14 (7-24) MINUTES AFTER NEOSTIGMINE AND 33 (19- 49) MINUTES AFTER EDROPHONIUM (SEE CLINICAL PHARMACOLOGY, REPEAT DOSING IN ADULTS).
IN THE 80 PATIENTS WHO RECEIVED THREE MAINTENANCE DOSES FOLLOWING A BOLUS DOSE OF 1.5 MG/KG OF RAPLONTM, ADVERSE EVENTS REPORTED IN SEPARATE PATIENTS DURING OR FOLLOWING THE MAINTENANCE DOSES CONSISTED OF HYPOTENSION, TACHYCARDIA, RESPIRATORY DEPRESSION, AND BRONCHOSPASM.
OVERDOSE
IN PREMARKETING CLINICAL STUDIES, ONE CASE OF ACCIDENTAL OVERDOSE WITH RAPLONTM (RAPACURONIUM BROMIDE) FOR INJECTION WAS REPORTED. A 22-YEAR-OLD OBSTETRIC PATIENT RECEIVED 5MG/KG OF RAPLONTM DURING RAPID SEQUENCE INDUCTION FOR CESAREAN SECTION. THE PATIENT DID NOT MEET EXTUBATING CRITERIA UNTIL MORE THAN TWO HOURS AFTER ADMINISTRATION OF RAPLONTM. COMPLETE RECOVERY WAS REACHED 19 MINUTES AFTER THE SIXTH DOSE OF 1.0 MG OF NEOSTIGMINE. THERE WAS NO EVIDENCE OF RECURARIZATION OR RESPIRATORY DISTRESS IN THE RECOVERY ROOM. THE PREMATURE NEWBORN DID NOT DEMONSTRATE EVIDENCE OF NEUROMUSCULAR WEAKNESS.
OVERDOSAGE WITH NEUROMUSCULAR BLOCKING AGENTS MAY RESULT IN NEUROMUSCULAR BLOCK EXTENDING BEYOND THE TIME NEEDED FOR SURGERY AND ANESTHESIA. THE PRIMARY TREATMENT IS MAINTENANCE OF A PATENT AIRWAY AND CONTROLLED VENTILATION UNTIL RECOVERY OF NEUROMUSCULAR FUNCTION IS ASSURED.
ANTAGONISM OF NEUROMUSCULAR BLOCKADE
THE USE OF A NERVE STIMULATOR TO DOCUMENT RECOVERY AND ANTAGONISM OF NEUROMUSCULAR BLOCKADE IS RECOMMENDED.
PATIENTS SHOULD BE EVALUATED FOR ADEQUATE CLINICAL EVIDENCE OF ANTAGONISM. E.G., 5 SECOND HEAD LIFT, VENTILATION, AND UPPER AIRWAY MAINTENANCE. VENTILATION MUST BE SUPPORTED UNTIL RECOVERY OF NORMAL RESPIRATION IS ASSURED. A 1.5 MG/KG OR 2.5 MG/KG DOSE OF RAPLONTM (RAPACURONIUM BROMIDE) FOR INJECTION MAY BE REVERSED 2 MINUTES AFTER ADMINISTRATION WITH NEOSTIGMINE 50 MG/KG IN ORDER TO REDUCE THE DURATION BY APPROXIMATELY 50%.
ANTAGONISM MAY BE DELAYED IN THE PRESENCE OF DEBILITATION, CARCINOMATOSIS, AND CONCOMITANT USE OF CERTAIN BROAD-SPECTRUM ANTIBIOTICS, ANESTHETIC AGENTS, AND OTHER DRUGS THAT ENHANCE NEUROMUSCULAR BLOCKADE OR SEPARATELY CAUSE RESPIRATORY DEPRESSION. UNDER SUCH CIRCUMSTANCES, CLINICAL MANAGEMENT IS THE SAME AS THAT FOR PROLONGED NEUROMUSCULAR BLOCKADE.
CONTRAINDICATIONS
RAPLONTM (RAPACURONIUM BROMIDE) OR INJECTION IS CONTRAINDICATED IN PATIENTS KNOWN TO HAVE HYPERSENSITIVITY TO RAPACURONIUM BROMIDE.
CLINICAL PHARMACOLOGY
RAPLONÒ (RAPACURONIUM BROMIDE) FOR INJECTION IS A NONDEPOLARIZING NEUROMUSCULAR BLOCKING AGENT WITH A RAPID ONSET OF ACTION (MEAN ONSET APPROXIMATELY 90 SECONDS; RANGE 35-219 SECONDS) AND A DOSE-DEPENDENT DURATION OF ACTION. THE RECOMMENDED DOSE OF 1.5 MG/KG IN ADULTS HAS A SHORT CLINICAL DURATION OF ACTION (MEAN DURATION APPROXIMATELY 15 MINUTES; RANGE 6-30 MINUTES) (SEE
CLINICAL PHARMACOLOGY
-CLINICAL STUDIES). RAPACURONIUM ACTS BY COMPETING FOR CHOLINERGIC RECEPOTORS AT THE MOTOR END PLATE. PROFOUND NEUROMUSCULAR BLOCKADE INDUCED BY RAPLONÒ CAN BE REVERSED BY NEOSTIGMINE (SEE CLINICAL PHRMACOLOGY-EARLY REVERSAL).
PHARMACODYNAMICS
THE NEUROMUSCULAR BLOCK SEEN AFTER THE INTRAVENOUS ADMINISTRATION OF 1.5 MG/KG RAPLONÒ (RAPRACURONIUM BROMIDE) FOR INJECTION IS PRIMARLY DUE TO RAPACURONIUM. PLASMA LEVELS OF THE MAJOR ACTIVE METABOLITE OF RAPACURONIUM (THE 3-HYDROXY METABOLITE) ARE RELATIVELY LOW COMPARED TO THE PARENT AT A DOSE OF 1.5 MG/KG OF RAPLONÒ . PHARMACOKINETIC AND PHARMACODYNAMIC MODELING STUDIES WERE CONDUCTED AFTER THE SEPARATE ADMINISTRATION OF RAPACURCNIUM BROMIDE AND THE 3-HYDROXY METABOLITE. THESE STUDIES EVALUATED THE EFFECT OF PLASMA DRUG CONCENTRATIONS ON THE NEUROMUSCULAR BLOCK ACHIEVED AS MEASURED BY MECHANOMYOGRAPHY OF THE ADDUCTOR POLLICIES MUSICLE TO INDIRECT SUPRAMAXIMAL TRAIN-OF-FOUR STIMULATION OF THE ULNAR NERVE. THESE RESULTS ARE SHOWN IN TABLES 1 AND 2 COMPARISON OF K° ° (RATE CONSTANT FOR THE EQUILIBRATION BETWEEN EFFECT COMPARTMENT AT 50% DRUG EFFECT) VALUES OF RAPACURONIUM AND THE 3-HYDROXY METABOLITE SHOWS THAT THE METABOLITE HAS SLOWER ONSET AND A HIGHER POTENCY THAN RAPACURONIUM BROMIDE. HOWEVER, WHEN COMPARING THE ED90 (DOSE REQUIRED TO PRODUCE 90% SUPPRESSION OF THE FIRST [T,] MECHANOMYOGRAPHIC [MMG] RESPONSE OF THE ADDUCTOR POLLICIS MUSCLE TO INDIRECT SUPRAMAXIMAL TRAIN-OF-FOUR STIMULATION OF THE ULNAR NERVE) OF RAPACURONIUM (0.3 MG/KG), VECURONIUM (0.05 MG/KG) AND PANCURONIUM (0.06 MG/KG). RAPACURONIUM BROMIDE AND THE3-HYDROXY METABOLITE MAY BE VIEWED AS LOW POTENCY NEUROMUSCULAR BLOCKING DRUGS.
TABLE 1: PHARMACOKINETIC/PHARMACODYNAMIC MODELING PARAMETERS OF RAPACURONIUM BROMIDE AFTER A SLOW OINTRAVENOUS INFUSION OF RAPACURONIUM BROMIDE IN TEN SUBJECTS AT A MEDIAN DOSE OF 0.93 MG/KG OVER A MEDIAN TIME OF FOUR MINUTES AND FORTY SECONDS (MEAN (%CV)).
PARAMETER
K° ° 1/MINUTE
0.44 (41)
Y
2.97 (23)
EC50. MCG/ML
4.44 (33)
ED90. MG/KG
1.03 (33)
TABLE 2: PHARMACOKINETIC/PHARMACODYNAMIC MODELING PARAMETERS OF THE 3-HYDROXY METABOLITE AFTER A SLOW INTAVENOUS INFUSION IN SEVEN SUBJECTS OF A MEDIAN DOSE OF 0.66 MG/KG OVER THREE TO FIVE MINUTES (MEAN (%CV)).
PARAMETER
K° ° . 1/MINUTE
0.10(40)
Y
4.83(44)
EC50. MCG.ML
2.06(55)
ED90, MG/KG
0.46(33)
THE ED50 FOR RAPACURONIUM BROMIDE (DOSE REQUIRED TO PRODUCE 50% SUPPRESSION OF THE FIRST [T1] MECHANOMYOGRAPHIC [MMG] RESPONSE OF THE ADDUCTOR POLLICIS MUSCLE TO INDIRECT SUPRAMAXIMAL TRAIN-OF-FOUR STIMULATION OF THE ULNAR NERVE) DURING OPIOID/NITROUS OXIDE/OXYGEN ANESTHESIA IS APPROXIMATELY 0.3 MG/KG IN ADULT (18 TO 64 YEARS) AND GERIATRIC (> 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 < 1 YEAR) IS 0.3MG/KG (SEE PRECAUTIONS, PEDIATRIC USE).
TABLE 3 AND 4 PRESENT THE NEUROMUSCULAR FUNCTION PARAMETERS FOLLOWING AN INITIAL DOSE OF RAPLONTM IN ADULT PATIENTS (18 TO 64 YEARS) AND GERIATRIC PATIENTS (> 65 YEARS).
TABLE 3: NEUROMUSCULAR FUNCTION PARAMETERS (MEAN SD)) FOLLOWING AND INITIAL DOSE OF RAPLONTM 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)
RAPLONÒ
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
RAPLONÒ 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 RAPLONÒ 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 RAPLONÒ 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 RAPLONÒ IN PEDIATRIC PATIENTS UNDER HALOTHANE ANESTHESIA.
TABLE 5" NEUROMUSCULAR FUNCTION PARAMETERS FOLLOWING AN INITIAL DOSE OF RAPLONÒ 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 < 2YRS)
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 RAPLONÒ 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 RAPLONTM
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 RAPLONTM 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 RAPLONTM 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 RAPLONTM 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 RAPLONTM WAS NOTED WITH SUBSEQUENT MAINTENANCE DOSES (SEE TABLE 6).
TABLE 6: CLINICAL DURATION (25% RECOVERY OF T1) OF MAINTENANCE DOSES OF RAPLON (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 RAPLONTM-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< 0.03 FOR COMPARISONS WITH EACH EARLY REVERSAL WITH NEOSTIGMINE
B=(P=NS)