Side Effects of midazolam

Midazolam injection is a benzodiazepine used before or during surgery for sedation, reducing anxiety, and helping patients forget the surgical experience. It also is given before anesthesia and to maintain anesthesia. 

Patients who are intubated for control of respiration are given midazolam for sedation. Midazolam also is used for treating seizures. It is thought that excessive activity of nerves in the brain may cause anxiety and other psychological disorders.

 Gamma-aminobutyric acid (GABA) is a neurotransmitter, a chemical that nerves in the brain use to send messages to one another. GABA reduces the activity of nerves in the brain. Midazolam and other benzodiazepines may act by enhancing the effects of GABA in the brain. 

Common side effects of midazolam include

• sedation,
• difficulty breathing,
• nausea,
• vomiting, and
• pain at the injection site.

Drug interactions of midazolam include other medications and drugs that slow the brain's processes such as alcohol, barbiturates, narcotics, and tranquilizers.

Boceprevir, itraconazole, nelfinavir, and telaprevir increase blood level of midazolam by reducing its breakdown in the liver and, therefore can increase the side effects of midazolam. 

Midazolam and other benzodiazepines have been associated with fetal damage, including congenital malformations, when taken by pregnant women in their first trimester. Midazolam is best avoided if at all possible in the first trimester and probably throughout pregnancy. 

Midazolam is secreted in breast milk. Consult your doctor before breastfeeding.

The most common side effects associated with midazolam are:

• sedation,
• difficulty breathing,
• nausea,
• vomiting, and
• pain at the injection site.

• See prescribing information concerning serious cardiorespiratory events and possible paradoxical reactions.
• Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease (23.3% of patients following IV and 10.8% of patients following IM administration) and apnea (15.4% of patients following IV administration), as well as variations in blood pressure and pulse rate.
• 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 (eg, upper endoscopy and dental procedures).

Adults

The following additional adverse reactions were reported after intramuscular administration:

headache (1.3%)	Local effects at IM Injection site
	pain (3.7%) induration (0.5%) redness (0.5%) muscle stiffness (0.3%)

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.

The following additional adverse reactions were reported subsequent to intravenous administration as a single sedative/anxiolytic/amnestic agent in adult patients:

hiccoughs (3.9%)	Local effects at the IV site
nausea (2.8%) vomiting (2.6%) coughing (1.3%) "oversedation" (1.6%) headache (1.5%) drowsiness (1.2%)	tenderness (5.6%) pain during injection (5.0%) redness (2.6%) induration (1.7%) phlebitis (0.4%)

Pediatric Patients

The following adverse events related to the use of IV midazolam in pediatric patients were reported in the medical literature:

• desaturation 4.6%, apnea 2.8%,
• hypotension 2.7%,
• paradoxical reactions 2.0%,
• hiccough 1.2%,
• seizure-like activity 1.1% and
• nystagmus 1.1%.

The majority of airway-related events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent.

Neonates

For information concerning hypotensive episodes and seizures following the administration of midazolam to neonates, see the prescribing information.

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: 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.

Special Senses: Blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, loss of balance, light-headedness.

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.

Drug Abuse And Dependence

• Midazolam is subject to Schedule IV control under the Controlled Substances Act of 1970.
• Midazolam was actively self-administered in primate models used to assess the positive reinforcing effects of psychoactive drugs.
• Midazolam produced physical dependence of a mild to moderate intensity in cynomolgus monkeys after 5 to 10 weeks of administration. Available data concerning the drug abuse and dependence potential of midazolam suggest that its abuse potential is at least equivalent to that of diazepam.
• Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (convulsions, hallucinations, tremor, abdominal and muscle cramps, vomiting and sweating), have occurred following abrupt discontinuation of benzodiazepines, including midazolam. Abdominal distention, nausea, vomiting, and tachycardia are prominent symptoms of withdrawal in infants.
• The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms (eg, dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months.
• Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. There is no consensus in the medical literature regarding tapering schedules; therefore, practitioners are advised to individualize therapy to meet patient's needs.
• In some case reports, patients who have had severe withdrawal reactions due to abrupt discontinuation of high-dose long-term midazolam, have been successfully weaned off of midazolam over a period of several days.

• The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication, which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response.
• Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the P450 3A4 enzyme system such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole. These drug interactions may result in prolonged sedation due to a decrease in plasma clearance of midazolam.
• The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine on steady-state concentrations of midazolam was examined in a randomized crossover study (n=8).
• Cimetidine increased the mean midazolam steady-state concentration from 57 to 71 ng/mL. Ranitidine increased the mean steady-state concentration to 62 ng/mL. No change in choice reaction time or sedation index was detected after dosing with the H2 receptor antagonists.
• In a placebo-controlled study, erythromycin administered as a 500 mg dose, tid, for 1 week (n=6), reduced the clearance of midazolam following a single 0.5 mg/kg IV dose. The half-life was approximately doubled.
• The effects of diltiazem (60 mg tid) and verapamil (80 mg tid) on the pharmacokinetics and pharmacodynamics of midazolam were investigated in a three-way cross-over study (n=9). The half-life of midazolam increased from 5 to 7 hours when midazolam was taken in conjunction with verapamil or diltiazem. No interaction was observed in healthy subjects between midazolam and nifedipine.
• A moderate reduction in induction dosage requirements of thiopental (about 15%) has been noted following use of intramuscular midazolam for premedication in adults.
• The intravenous administration of midazolam decreases the minimum alveolar concentration (MAC) of halothane required for general anesthesia. This decrease correlates with the dose of midazolam administered; 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.
• 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 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.
• 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 benzocaine) 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.
• Caution is advised when midazolam is administered to patients receiving erythromycin since this may result in a decrease in the plasma clearance of midazolam.

Drug/Laboratory Test Interactions

• Midazolam has not been shown to interfere with results obtained in clinical laboratory tests.