Midolam 1 mg/ml

/ Rafa

Because serious and life-threatening cardiorespiratory adverse events have been breported, provision for monitoring, detection and correction of these reactions must be made for every patient to whom Midolam Injection is administered, regardless of age or health status. Excessive doses or rapid or single bolus intravenous administration may result in respiratory depression and/or arrest.
In addition, reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported. Should such reactions occur, caution should be exercised before continuing administration of Midolam Injection. Midolam Injection should only be administered IM or IV. For IM injections, it is recommended that the medication be injected deep into a large muscle mass. Care should be taken to avoid intra-arterial injection or extravasation. When administered IV, the initial dose and all subsequent doses should never be given as a bolus: administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. Lower doses, smaller increments and slower injection rates are necessary for elderly (over 60 years), debilitated or high-risk surgical patients, and in patients receiving concomitant narcotics or other CNS depressants. When Midolam Injection is given with potent analgesics, the latter should be administered first so that the sedative effects of Midolam Injection can be safely titrated on top of any sedation caused by the analgesic. Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Because serious and life-threatening cardiorespiratory adverse events have been reported, provision for monitoring, detection and correction of these reactions must be made for every patient to whom Midolam Injection is administered, regardless of age or health status. Excessive doses or rapid or single bolus intravenous administration may result in respiratory depression and/or arrest  The following dosing instructions are only intended to serve as general guidelines since the dosage of Midolam must always be individualized, depending on the patient’s age, medical condition and concurrent medication. Continuous monitoring of respiratory and cardiac function is required (i.e., pulse oximetry).
Adults and Pediatrics: Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting. Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam. Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured.
Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.
Usual Adult Dose: Sedation, preoperative and amnesia – IM administration Midazolam should be injected deep in a large muscle mass. The recommended premedication dose of midazolam for good risk (ASA Physical Status I & II) adult patients below the age of 60 years is 0.07 to 0.08 mg/kg (approximately 5 mg IM), approximately 30-60 min before surgery. Lower doses (0.02-0.05 mg/kg) may be sufficient in elderly or debilitated patients. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. Onset is within 15 minutes, peaking at 30 to 60 minutes.
Note: Midazolam may be administered concurrently with atropine or scopolamine hydrochloride and reduced doses of narcotics. Sedation, conscious (endoscopic or cardiovascular procedures) – IV administration
UNPREMEDICATED – Healthy Adults Below the Age of 60:Initially no more than 2.5 mg (1.5 mg in elderly/debilitated/ Chronically III Patients), some patients may respond to as little as 1 mg, administered slowly over a period of at least 2 min, immediately prior to procedure; after an additional 2 or more min to allow for clinical effect, dosage may be further titrated in small increments ( 1 mg) of the initial dose (with intervals of 2 or more min being allowed after each increment) to the desired effect. A total dose of more than 5 mg (3.5 mg in elderly/debilitated) is not usually necessary. Additional maintenance doses may be administered, if necessary, in increments of 25% of the initial dose, but only by slow titration, to maintain the desired level of sedation. When midazolam is administered concomitantly with narcotic analgesics or other CNS depressants, the dosage of midazolam should be reduced by approximately 30% (50% in elderly/debilitated).
Note: The desired endpoint for conscious sedation can usually be attained within 3 to 6 min. The therapeutic dosage range between sedation and unconsciousness or disorientation appears to be narrower than for other benzodiazepines (e.g. diazepam). When midazolam is used for peroral endoscopic procedures, a topical anesthetic agent is recommended; when used for bronchoscopic procedures, a narcotic premedication is recommended.
For full details see prescribing information.

Premedicdbation, induction and maintenance of anesthesia, status epilepticus.

Midolam Injection should not be given to patients who are hypersensitive to benzodiazepines.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.)

Midolam injection has been associated with severe cardiorespiratory adverse events including respiratory depression, apnea, airway obstruction, oxygen desaturation, respiratory arrest, and cardiac arrest, especially when used for conscious sedation and in concomitant use with opioid agonists or other sedatives, or when rapidly administered. In some cases, where this was not recognized promptly and treated effectively, death, permanent neurologic injury or hypoxic ncephalopathy has resulted. Midolam should be used only in hospital or ambulatory care settings, including physicians’ offices, that provide for continuous monitoring of respiratory and cardiac function. Immediate availability of oxygen, resuscitative drugs and equipment and personnel trained in their use
should be assured. Midolam should be administered intravenously as an induction agent only by a person trained in general anesthesia and should be used for conscious sedation only when a person skilled in maintaining a patent airway and supporting ventilation is present, because of possible respiratory depression. During intravenous administration of midazolam, patients should be monitored continuously for early signs of underventilation airway obstruction or apnea, which can lead to hypoxia/cardiac arrest unless effective countermeasures are immediately taken. The immediate availability of specific reversal agents (flumazenil) is highly recommended. Also, monitoring of
vital signs should be continued during the recovery period. After receiving Midolam, patients should not be discharged from hospital or consulting room for at least three hours and then only if accompanied by an attendant.
Particular care is needed when administering Midolam Injection to a patient with myasthenia gravis or other neuromuscular disorders since pre-existing muscle weakness may be exacerbated. In addition, extreme caution should be used in patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances. Caution should be exercised when administering Midolam Injection to higher risk surgical patients including elderly and debilitated patients, who may require lower doses for induction of anesthesia. Patients with obstructive pulmonary disease or acute pulmonary insufficiency may be more sensitive to the respiratory depressant effect of midazolam. Patients with chronic renal failure and congestive heart failure eliminate midazolam more slowly, which may result in slower recovery. The elimination half-life of midazolam may be extended in patients with renal or hepatic impairment, obese patients, or neonates. Patients undergoing procedures involving the upper airway such as upper endoscopy or dental care are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam injection; patients with glaucoma have not been studied. Midazolam 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. It is recommended that patients not operate hazardous machinery or a motor vehicle until the effects of midazolam, such as drowsiness and amnesia, have subsided or until the day after anesthesia and surgery, whichever is longer.

See Warnings concerning serious cardiorespiratory events and paradoxical reactions
Midolam injection is usually well tolerated. The most frequent adverse effects of midazolam during anesthesia and surgery include decreased tidal volume and/or respiratory rate (in 23.3% of patients following intravenous administration and in 10.8% of patients following intramuscular administration) and apnea (in 15.4% of patients following intravenous administration). In addition, slight variations in blood pressure and pulse rate may occur. As a rule, the systolic blood pressure falls by a maximum of 15%, while the pulse rate simultaneously shows a corresponding rise. Significant hypotension is more likely to occur in patients premedicated with a narcotic. The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam is administered with other medications capable of depressing the central nervous system. The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube (e.g., upper endoscopy and dental procedures). Other less serious adverse experiences include headache, hiccups, nausea, vomiting, coughing, “oversedation”, drowsiness ;Local effects at the IM injection site: pain, induration, redness, muscle stiffness ; Local effects at the IV site : pain during injection, tenderness or redness,induration, phlebitis. Other adverse experiences, observed mainly following IV injection as a single sedative/anxiolytic/amnesia agent and occurring at an incidence of <1.0% in adult and pediatric patients, are as follows:
Respiratory: Laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, shallow respirations, airway obstruction, tachypnea.
Cardiovascular: Bigeminy, premature ventricular contractions, vasovagal episode, bradycardia, tachycardia, nodal rhythm.
Gastrointestinal: Acid taste, excessive salivation, retching.
CNS/Neuromuscular: See Warnings concerning serious cardiorespiratory events and paradoxical reactions.5 Retrograde amnesia, euphoria, hallucination, confusion, argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence delirium or agitation, prolonged emergence from anesthesia, dreaming during emergence, sleep disturbance, insomnia, nightmares, athetoid movements, seizure-like activity, ataxia, dizziness, dysphoria, slurred speech, dysphonia, paresthesia. Partial or complete impairment of recall for up to several hours (anterograde amnesia) may occur, particularly after IV administration.
Special Senses: Blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, loss of balance, lightheadedness.
Integumentary: Hive-like elevation at injection site, swelling or feeling of burning, warmth or coldness at injection site.
Hypersensitivity: Allergic reactions including anaphylactoid reactions, hives, rash, pruritus.
Miscellaneous: Yawning, lethargy, chills, weakness, toothache, faint feeling, hematoma. Administration of IM midazolam to elderly and/or higher risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics.
Pediatric Patients: The following adverse events related to the use of IV midazolam in pediatric patients were reported in the medical literature: desaturation, apnea , hypotension, paradoxical reactions, hiccough, seizure-like activity and nystagmus. The majority of airwayrelated events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent.

Midazolam/CNS Depressants or Alcohol: Concurrent use of Midolam with neuroleptics, tranquilizers, opioids, benzodiazepines, barbiturates, hypnotics, antidepressants, analgesics, anesthetics, droperidol or alcohol, may increase the CNS depressant, respiratory depressant,apnea, hypoventilation, airway obstruction, desaturation and hypotensive effects of either midazolam or these medications, and may prolong recovery from anesthesia. Special attention must be paid to the possibility of potentiation in high-risk patients. The dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response.
When midazolam is used as premedication prior to the use of thiopental, a 15% reduction in the thiopental dosage may be required. The IV administration of midazolam decreases the minimum alveolar concentration (MAC) of halothane required for general anesthesia. Patients should be advised not to drink alcoholic beverages for at least 12 hours after Midolam. Narcotic premeditation also depresses the ventilatory response to carbon dioxide stimulation.
Midazolam/Hypotension Producing Agents Concurrent use of Midolam with these medications may potentiate the hypotensive effects. Severe hypotension has been reported when midazolam is used concurrently with fentanyl.
Midazolam/Inhibitors of Cytochrome P450-3A4 Enzyme System Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system such as cimetidine, rythromycin, diltiazem, verapamil, ketoconazole and itraconazole. These drug interactions may result in prolonged sedation caused by a decrease in plasma clearance of midazolam. In a placebo-controlled study, saquinavir administered as a 1200 mg dose, tid, for 5 days (n=12), a 56% reduction in the clearance of midazolam following a single 0.05 mg/kg IV dose was observed. The half-life was approximately doubled.
Benzodiazepines/Neuromuscular Blockers Benzodiazepines, including midazolam, may sometimes unpredictably alter the depth and duration of neuromuscular blockade. Although the possibility of minor interactive effects has not been fully studied, midazolam and pancuronium have been used together in patients without noting clinically significant changes in dosage, onset or duration in adults. Midazolam does not protect against the characteristic circulatory changes noted after administration of succinylcholine or pancuronium and does not protect against the increased intracranial pressure noted following administration of 7 succinylcholine. Midazolam does not cause a clinically significant change in dosage, onset or duration of a single intubating dose of succinylcholine; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults.
Benzodiazepines/Theophyllines Theophyllines, such as aminophylline, may antagonize the sedative effects of benzodiazepines, including midazolam. No significant adverse interactions with commonly used premedications or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, d-tubocurarine, succinylcholine and other nondepolarizing muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine HCl and Cetacaine) have been observed in adults or pediatric patients. In neonates, however, severe hypotension has been reported with concomitant administration of fentanyl. This effect has been observed in neonates on an infusion of midazolam who received a rapid injection of fentanyl and in patients on an infusion of fentanyl who have received a rapid injection of midazolam.

Pregnancy Category D: An increased risk of congenital malformations associated with the use of benzodiazepines (diazepam and chlordiazepoxide) has been suggested in several studies. Midazolam, which crosses the placenta, may be associated with this increased risk also. Risk/benefit should be carefully considered, and the patient should be apprised of the potential hazard to the fetus if used during pregnancy. Midazolam is usually not recommended for obstetric procedures (e.g. prior to Cesarean section), or during labour and delivery since benzodiazepines used during the last few weeks of pregnancy and during labor have caused CNS depressant effects and flaccidity in the neonate. Moreover, high single doses may produce irregularities in the fetal heart rate, hypotonia, poor sucking, and hypothermia in the neonate.
Use in Breastfeeding: Midazolam may pass into breast milk, and caution should be exercised when administering to nursing mothers.

Manifestations: The symptoms of midazolam injection overdose are mainly an intensification of the therapeutic effects (sedation, muscle weakness, profound sleep). In addition, confusion, impaired coordination, paradoxical excitation, or adverse effects on vital signs may be observed. In most cases only observation of vital functions is required. Extreme overdose may lead to impaired reflexes, respiratory depression and apnea, cardiovascular depression, or coma.
Treatment: Respiration, pulse rate and blood pressure should be monitored and supportive measures employed. A patent airway should be maintained and ventilation supported, including administration of oxygen and an IV infusion started. Hypotension should be treated with IV fluid therapy, repositioning, judicious use of vasopressors and other appropriate measures. The value of peritoneal dialysis, forced diuresis or hemodialysis is unknown. Flumazenil (Anexate), a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in cases of overdose. (See the flumazenil monograph for specific dosing guidelines.) Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose.