We would like to bring to your attention important information on the appropriate use of our product VERSED. Data on cases of respiratory and cardiac arrest, reported since VERSED (midazolam HC1/Roche) was marketed in March 1986, indicate the importance of reemphasizing the proper doses and methods for administration of the drug intravenously. The information available about these cases also points out the need for early recognition and treatment of underventilation and apnea, which if not recognized early and counteracted effectively, may lead to hypoxic cardiac arrest. It is especially important to be fully familiar with the appropriate intravenous use of VERSED prior to colonoscopy, gastroscopy and bronchoscopy in elderly or debilitated patients, in patients with various disease states, and in patients receiving other central nervous system depressants (e.g., narcotics, antipsychotics). In some reported cases, particularly colonoscopies, early recognition and effective use of countermeasures may have been more difficult because of patient positioning. In addition, endoscopies are sometimes performed in diminished light which may make visual observation of patients difficult. The extent of preparation needed to administer VERSED properly is stated in the first warning from the package insert (excerpt below): PRIOR TO THE INTRAVENOUS ADMINISTRATION OF MIDAZOLAM IN ANY DOSE -2 FOR THE MAINTENANCE OF A PATENT AIRWAY AND SUPPORT OF VENTILATION SHOULD BE ENSURED. PATIENTS WHO RECEIVE INTRAVENOUS VERSED (MIDAZOLAM) SHOULD BE CONTINUALLY MONITORED FOR EARLY SIGNS OF UNDERVENTILATION OR APNEA, WHICH CAN LEAD TO HYPOXIC CARDIAC ARREST UNLESS EFFECTIVE COUNTERMEASURES ARE TAKEN IMMEDIATELY. Because intravenous midazolam depresses respiration and because opioid agonists and other sedatives can add to this depression, midazolam should be administered as an induction agent only by a person trained in general anesthesia and should be used in conscious sedation only when a person skilled in maintaining a patent airway and supporting ventilation is present. The following highlights, paraphrased from the package insert (copy enclosed), are intended to show how some patients may handle VERSED differently. This will help in selection of candidates to receive VERSED I.V. and in individualization of dose: 1. The intravenous dose requirement of VERSED diminishes with age. The fact that elderly patients may have inefficiency of one or more organ systems should be remembered when selecting drugs and dosage. Elderly and debilitated patients may also take longer to recover completely after administration of VERSED. 2. Concomitant administration of central nervous system depressant drugs may increase the risk of underventilation or apnea and contribute to profound and/or prolonged drug effect. For instance, it is known that narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation. more 3. Patients with chronic obstructive pulmonary disease are susceptible to underventilation (CO2 response) than are patients with healthy lungs. 4. Patients with renal failure or congestive heart failure may have a prolonged elimination half-life and greater volume of distribution. (Remember also that circulation time is prolonged in congestive heart failure, which may delay the effect of any drug.) The enclosed VERSED package insert reflects further recommendations in the administration and dosage of the drug. When used for conscious sedation, VERSED should not be administered by rapid or single bolus intravenous administration. VERSED should be administered immediately prior to the procedure. An initial titration with a small dose, such as 2 to 2.5 mg (0.035 mg/kg), administered over a 2 to 3 minute period, is suggested for an average healthy adult, and approximately 87-445 088 - 5 -3 1 to 1.5 mg for older or chronically ill or debilitated patients. After waiting 1 to 2 minutes, if further sedative effect is necessary, the dosage may then be further titrated, in small increments of the initial dose, to the desired effect, i.e., the initiation of slurred speech. For ease of titration, VERSED may be diluted with 0.9 percent sodium chloride, or 5 percent dextrose in water, to 2 to 5 times the original volume. Generally, a total dose of up to 0.1 to 0.15 mg/kg is adequate in average healthy adults. In rare cases, a total dose of up to 0.2 mg/kg may be necessary, particularly when concomitant narcotics are omitted. Additional maintenance doses may be given in increments of 25 percent of the initial dose to maintain the desired level of sedation. Though narcotic premedication results in less variability in patient response, it is also important to remember that dosage should be lowered by about 25 to 30 percent if narcotics or other CNS depressants have been administered. Dosage should also be reduced as follows: By about 30 percent in patients age 60 or older, or debilitated patients. By a total of 50 percent to 60 percent in patients age 60 or older, or debilitated patients, who have received narcotic or other CNS depressant medication. Peak desired effect, as well as the peak danger of underventilation or apnea, may take longer to appear in elderly patients and those with chronic disease states. Therefore, increments should be smaller and the rate of injection slower. Excess doses or rapid or single bolus administration may result in respiratory depression and/or arrest, especially in these patients. Reactions such as agitation, involuntary movements (including tonic/ clonic movements and muscle tremor), hyperactivity and combativeness have been reported. These reactions may be due to inadequate or excessive dosing or improper administration of VERSED; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Should such reactions occur, caution should be exercised before continuing administration of VERSED. In summary, intravenous VERSED has been found to be an effective drug for conscious sedation prior to endoscopic procedures and, in higher doses, for induction of general anesthesia. Proper and effective use requires careful attention to the warnings, precautions and dosage recommendations contained in the product labeling. Patients must be monitored for early signs of underventilation and early recognition of apnea. -4 The personnel and equipment needed for standard respiratory resuscitation should be immediately available. If the complexities of the procedure prohibit the attending clinician from devoting adequate time to monitoring the clinical status of the patient, an additional person fully trained in monitoring and resuscitation should also be in attendance. Please read the enclosed VERSED package insert completely so that you are fully aware of the important information contained therein. The changes have been highlighted for your convenience. As for all of our products, we ask that adverse experiences associated with VERSED continue to be reported to us. Please call us at (201) 235-3021 or contact one of our area representatives if you have anything to report. We share all adverse experience data with the FDA, as required by law. If you prefer, you can notify the FDA on Form 1639a, available in the periodic FDA Drug Bulletin. We hope this information will be helpful in your use of VERSED. Sincerely, BHM:kke Bruce H. Medd, M.D. Assistant Vice President and Director A.H.FS. Category 28:24.08 VERSED® brand of midazolam HCI/Roche INJECTION DESCRIPTION: VERSED (brand of midazolam hydrochloride Roche) is a water-soluble benzodiazepine available as a stenie parenteral dosage form for intravenous or intramuscular injection Each mi contains midazolam hydrochloride equivalent to 5 mg midazolam compounded with 0.8% sodium chloride and b 01% disodium edetate, with 1% benzyl alcohol as preservative, the pH is adjusted to approximately 3 with hydrochloric acid and, if nec essary, sodium hydroxide. ROCHE CLINICAL PHARMACOLOGY: VERSED is a short-acting benzodiazepine central nervous system depressant. The effects of VERSED on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other premedications Onset time of sedative effects after IM administration was 15 minutes, with peak sedation occurring 30 to 60 minutes folowing injection in one study, when tested the following day. 73% of the patients who received VERSED intramuscularly had no recall of memory cards shown 30 minutes following administration; 40% had no recall of the memory cards shown 60 minutes following drua ministration Sedation after IV injection was achieved within 3 to 5 minutes; the time of onset is affected 3 total dose administered and the concurrent administration of narcotic premedication Seventy-one percent of the patients in the endoscopy studies had no recall of introduction of the endoscope: 82% of the patients had no recall of withdrawal of the endoscope. When VERSED is given intravenously as an anesthetic induction agent, induction of anes thesia occurs in approximately 15 minutes when narcotic premedication has been administered and in 2 to 2.5 minutes without narcotic premedication or with sedative premedication. Some impairment in a test of memory was noted in 90% of the patients studied VERSED, used as directed, does not delay awakening from general anesthesia Gross tests of recovery after awakening (onentation, ability to stand and walk, suitability for discharge from the recovery room, return to baseline Trieger competency) usually indicate recovery within 2 hours but recovery may take up to 6 hours in some cases When compared with patients who received thropental, patients who received midazolam generally recovered at a slightly slower rate Reaction time under stress (operating automobiles or other hazardous machinery) has not been studied. (See WARNINGS.) The intravenous administration of VERSED decreases th mum alveolar concentration (MAC) of halothane required for general anesthesia. This ase correlates with the dose of VERSED administered. in nationty three intrarronisl lesinne inserting with VERGEN is seenristed with a map. erate decrease in cerebrospinal fluid pressure (lumbar puncture measurements), similar to that seen following use of thiopental Preliminary data in intracranial surgical patients with normal intracranial pressure but decreased complianc arachnoid screw measurements) show comparable elevations of intracranial presso VERSED and with thiopental during intubation Measurements of intraocular pressure in patients without eye disease show a moderate lowening following induction with VERSED, patients with glaucoma have not been studied Usual intramuscular premedicating doses of VERSED do not depress the ventilatory response to carbon dioxide stimulation to a clinically significant extent Induction doses of VERSED depress the ventilatory response to carbon dioxide stimulation for 15 minutes or more beyond the duration of ventilatory depression following administration of thiopental. Impairment of ventilatory response to carbon dioxide is more marked in patients with chronic obstructive pulmonary disease (COPD) Sedation with intravenous VERSED does not adversely affect the mechanics of respiration (resistance, static recoil, most lung volume measurements), total lung capacity and peak expiratory flow decrease significantly but stat it compliance and maximum expiratory flow at 50% of awake total lung capacity (max) increase in cardiac hemodynamic studies, induction with VERSED was associated with a slight to moderate decrease in mean artenal pressure, cardiac output, stroke volume and systemic vascular resistance Slow heart rates (less than 65/minute), particularly in patients taking propranolol for angina, tended to rise slightly, faster heart rates (p.g.. 85/minute) tended to slow slightly The following preliminary pharmacokinetic data for midazolam have been reported in normai subjects and healthy patients intravenous midazolam exhibited an elimination half-life of 1 2 to 12 3 hours, a large volume of distribution (0.95 to 6.6 L/kg) and a plasma clearance of 0 15 to 0.77 meng. Following intravenous administration, less than 0.03% of the dose is excreted in the urine as intact midazolam Midazolam is rapidly metabolized to 1-hydroxymethyl midazolam, which is conjugated with subsequent excretion in the urine Approximately 45% to 57% of the dose is excreted in the unne as the conjugate of 1-hydroxymethyl midazolam, the major metaboute of midazolam The half-life of elimination of 1-hydroxymethyl midazolam is sim ilar to the parent compound. The concentration of midazolam is 10- to 30-fold greater than that of 1-hydroxymethyl midazolam after single IV administration Clinical effects of VERSED, do not directly correlate with the blood concentrations of midazolam In a small group of patients (n = 11) with congestive heart failure, there appeared to be a 2to 3-fold increase in the elimination half-use and volume of distribution of midazolam, however, the total body clearance of midazolam appeared to remain unchanged at a single 5-mg intravenous dose. There was no apparent change in the pharmacokinetic profile following the intravenous administration of 5 mg of midazolam to a smail group of patients (n=12) with hepatic dysfunction. There was a 15- to 2-fold increase in elimination half-fe, total body clearance and volume of distribution in a small group of patients (n=15) with chronic renal failure in a | small group (n = 12) of surgical patients, aged 49 to 60 years old. given 0 2 mg/kg midazolam intravenously, there appeared to be a small increase in the volume of distribution and elimination half-fe with little change in total body clearance compared to an equal number of younger surgical patients (aged 18 to 30). The mean absolute bioavailability of midazolam following intramuscular administration is greater than 90% The mean time of maximum midazolam plasma concentrations following intramuscular dosing occurs within 45 minutes postadministration Peak concentrations of midazolam as well as 1-hydroxymethyl midazolam arter intramuscular administration are about one-half of those achieved after equivalent intravenous doses The pharmacokinetic profile of elimination after intramuscularly administered midazolam is comparable to that observed following intravenous administration of the drug. Dose-linearity relationships have not been adequately defined Midazolam is approximately 97% plasma protein-bound in normal subjects and patients with renal failure. In animais, midazolam has been shown to cross the blood-brain barrier in anmais and in humans, midazolam has been shown to cross the placenta and enter into fetal circulation it is not known whether midazolam is excreted in human milk INDICATIONS: Injectable VERSED is indicated • intramuscularly for preoperative sedation (induction of sleepiness or drowsiness and relief of apprehension) and to impair memory of perioperative events ⚫ intravenously as an agent for conscious sedation prior to short diagnostic or endoscopic procedures, such as bronchoscopy, gastroscopy cystoscopy, coronary angiography and cardiac catheterization, either alone or with a narcotic • intravenously for induction of general anesthesia, before administration of other anesthetic agents with the use of narcotic premedication, induction of anesthesia can be attained within a relatively narrow dose range and in a short period of time. Intravenous VERSED can also be used as a component of intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia) for short surgical procedures; longer procedures have not been studied When used intravenously, VERSED is associated with a high incidence of partial or complete impairment of recall for the next several hours. (See CLINICAL PHARMACOLOGY) CONTRAINDICATIONS: Injectable VERSED is contraindicated in patients with a known hypersensitivity to the drug. Benzodiazepines are contraindicated in patients with acute narrow angle glaucoma Benzodiazepines may be used in patients with open angle glaucoma only if they are receiving appropriate therapy (See CLINICAL PHARMACOLOGY) WARNINGS: VERSED mest never be used without individualization of desage. Prior to the intravenous administration of VERSED in any does, the immediate availability of esygen and resuscitative equipment for the maintenance of a patent airway sad support of vontilation sho a should be susured. Patients should be continuously monitored for early signs of underventilation or apnon, which can lead to bypoxia cardiac arrest unless effective countermeasures are taken Immediately. Because intravenous VERSED depresses respi ration (see CLINICAL PHARMACOLOGY) and because opioid agonists and other sedatives can add to this depression, VERSED should be administered as an induction agent only by a person trained in general anesthesia and should be used in conscious sedation only when a person silled in maintaining a patent airway and supporting ventilation is present When used for conscious sedation, VERSED should not be administered by rapid or single boles intravenous administration. Serious cardiorespiratory adverse events have occurred. predominantly in older chronically ill patients and/or with concomitant use of other cardiorespiratory depressant agents. These have included respiratory depression, apnes, respiratory arrest and/or cardiac arrest, sometimes resulting in desin. Injectable VERSED should not be administered to patients in shock or coma, or in acute alcohol intoxication with depression of vital signs The hazards of intra-arterial injection of VERSED solutions in humans are unknown; therefore, extreme precautions against unintended intra-arterial injection should be taken. Extravasation should also be avoided. Higher risk surgical patients or debilitated patients require lower dosages for induction of anesthesia, whether premedicated or not Patients with chronic obstructive pulmonary disease are unusually sensitive to the respiratory depressant effect of VERSED. Patients with chronic renal failure have a 15- to 2-fold increase in elimination naif-life, total body clear. ance and volume of distribution of midazolam Patients with congestive heart failure have a 2- to 3-fold increase in the elimination half-life and volume of distribution of midazolam Patients over the age of 55 years require lower dosages for induction of anesthesia, whether premedicated or not Because elderly patients frequently have inefficient function of one or more organ systems, and because dosage requirements have been shown to decrease with age, reduced initial dosage of VERSED is recommended and the possibility of profound and/ or prolonged effect should be considered. Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the nsk of underventilation or apnea and may contribute to profound and/or prolonged drug effect Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation. Hypotension occurred more frequently in the conscious sedation strin patients premedicated with a narcotic TERSED The decision as to when patents who have received injectable VERSED, particularly on an Outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor veftació must be individualized. Gröss tests of recovery from the effects of VERSED (100 CLINICAL PHARMACOLOGY) cannot be relied upon alone to predict reaction time under stress. This drug is never ⚫alone during anesthesia and the contribution of other perioperative drugs and even vary it is recommended that no patient operate hazardous machinery or a motor veer until the effects of the drug, such as drowsiness, have subsided or until the day after anesthesia and surgery. whichever is longer. Usage in Pregnancy. An increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordiazepoxide) has been suggested in several studies. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus. PRECAUTIONS: General Because an increase in cough reflex and laryngospasm may occur with peroral endoscopic procedures, the use of a topical anesthetic agent and the availability of necessary countermeasures are recommended. The use of narcotic premedication is recommended for bronchoscopies Intravenous doses of VERSED should be decreased by 25% to 30% for elderly and debilitated patients (See WARNINGS and DOSAGE AND ADMINISTRATION) These patients will also probably take longer to recover completely after VERSED administration for the induction of anesthesia VERSED does not protect against the increase in intracranial pressure or circulatory effects noted following administration of succinylcholine. VERSED does not protect against the increase in intracranial pressure or against the heart rate rise and/or blood pressure rise associated with endotracheal intubation under light general anesthesia. Information for patients: To assure sale and effective use of benzodiazepines, the following information and instructions should be communicated to the patient when appropriate 1 inform your physician about any alcohol consumption and medicine you are now taking, including drugs you buy without a prescription Alcohol has an increased effect when consumed with benzodiazepines, therefore, caution should be exercised regarding simultaneous ingestion of alcohol duning benzodiazepine treatment. 2. Inform your physician if you are pregnant or are planning to become pregnant, 3 Inform your physician if you are nursing. Drug interactions. The hypnotic effect of intravenous VERSED is accentuated by premedi cation particularly narcotics (eg morphine, meperidine and tentanyl) and also secobar bital and Innover (fentanyl and droperidol) Consequently, the dosage of VERSED should be adjusted according to the type and amount of premedication administered. (See DOSAGE AND ADMINISTRATION) A moderate reduction in induction dosage requirements of thiopental (about 15%) has been noted following use of intramuscular VERSED for premedication. The use of VERSED as an induction agent may result in a reduction of the inhalation anesthetic requirement during maintenance of anesthesia. (See CLINICAL PHARMACOLOGY) Although the possibility of minor interactive effects has not been fully studied. VERSEO and pancuronium have been used together in patients without noting clinically significant changes in dosage, onset or duration VERSED does not protect against the characteristic circulatory changes noted after administration of succinylcholine or pancuromum and does not protect against the increased intracranial pressure noted following administration of succinylcholine VERSED does not cause a clinically significant change in dosage, onset or duration of a single intubating dose of succinylcholine No significant adverse interactions with commonly used premedications or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam hydroxyzine -tubocurarine, succinylcholine and nondepolarizing muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine HCI and Cetacaine) have been observed Drugi laboratory test interactions: Midazolam has not been shown to interfere with results obtained in clinical laboratory tests. Carcinogenesis, mutagenesis, impairment of fertility. Carcinogenesis Midazolam maisate was administered with diet in mice and rats for two years at dosages of 1 9 and 80 mg/kg/day in temale mice in the highest dose group there was a marked increase in the incidence of hepatic tumors in high dose male rats there was a small but statistically significant increase in benign thyroid follicular cell tumors Dosages of 9 mong day of midazolam maleate (25 times a human dose of 0 35 mg/kg) oo not -crease the incidence of tumors. The pathogenesis of induction of these tumors is not known. These tumors were found after chronic administration, whereas human use will ordinarily be of single or several doses. Copyright © 1987 by crimann-La Roche inc. All rights reserved. |