Product monograph midazolam injection
particularly in elderly or debilitated patients
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particularly in elderly or debilitated patients (see WARNINGS). Clinical experience has
shown midazolam to be more potent than diazepam on a mg per kg basis.
Midazolam injection has been shown to cause dose-related anterograde amnesia, an impairment or a lack of recall of events following administration of the drug.
Midazolam does not protect against the circulatory effects of succinylcholine administration or against the heart rate rise and/or blood pressure rise associated with endotracheal intubation under light general anesthesia.
For intramuscular use, Midazolam Injection should be injected deep in a large muscle mass. Intravenous midazolam should be administered as an induction agent only by a person trained in Midazolam Injection Product Monograph Page 20 of 39
general anesthesia and should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintenance of a patent airway and support of ventilation. The necessary equipment and the appropriate medications must be immediately available to ensure the safety of the procedures involved and the maintenance of respiratory and cardiovascular functions (see WARNINGS).
Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding with the administration of the drug (see WARNINGS).
For induction of general anesthesia in healthy patients, the initial dose should be administered over 20 to 30 seconds for optimal effect. About 2 minutes must pass to see the effect of the dose. Extreme care should be taken to avoid intra-arterial injection or extravasation. Midazolam is compatible with 5% Dextrose Injection and 0.9% Sodium Chloride Injection. Both the 1 mg/mL and 5 mg/mL formulations may be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Usual Recommended Adult Dosage Intramuscular Premedication For preoperative sedation and to impair memory of perioperative events For premedication, the recommended dose of Midazolam Injection is 0.07 to 0.08 mg/kg IM (usual IM dose is about 5 mg for an average adult) administered 30 to 60 minutes preoperatively. Lower doses should be used in elderly or debilitated patients. In a study of patients 60 years or older who did not receive concomitant opioids, 2 to 3 mg of midazolam produced adequate sedation during the preoperative period. Some patients responded to doses as low as 1 mg. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam. Onset of action is within 15 minutes, with peak effect occurring 30 to 60 minutes following injection. Midazolam can be administered concomitantly with atropine sulfate or scopolamine hydrobromide. When administered concomitantly with an opioid, the dose of midazolam should be reduced.
For short endoscopic or short diagnostic procedures and direct current cardioversion: Midazolam Injection 1 mg/mL formulation is recommended for IV sedation to facilitate slow injection.
Midazolam can be used either alone or combined with an opioid immediately before the procedure, with supplemental doses to maintain the desired level of sedation throughout the procedure. For peroral procedures, the use of an appropriate topical anesthetic is recommended. Midazolam Injection Product Monograph Page 21 of 39
During routine diagnostic bronchoscopies, with no compromise of respiratory function, the use of opioid premedication is recommended.
Unpremedicated Patients Premedicated Patients (Opioids or CNS Depressants) Patient Type Initial Dose Total Dose Patients below age 55 No more than 2 to 2.5 mg -Some patients may respond to as little as a total dose of 1 mg. -More than a total dose of 5 mg is not usually necessary. -Do not exceed 0.1 mg/kg Reduce dosage by about 30%
Patients age 55 or older; Debilitated patients; Chronically ill patients; Patients with limited pulmonary reserve No more than 1 to 1.5 mg -Patients may respond to as little as a total dose of 1 mg. -More than a total dose of 3.5 mg is not usually necessary. -Do not exceed 0.07 mg/kg
Reduce dosage by about 30% (i.e. 60% less than for healthy young un- premedicated patients) Method of Administration When used for intravenous sedation, midazolam should not be administered by rapid or single bolus intravenous administration (see WARNINGS). Midazolam should be administered immediately prior to the procedure in small increments and titrated slowly until the desired sedative effect is achieved. An initial titration with a small dose, such as 2 to 2.5 mg (see Table V) administered over a 2 to 3 minute period is suggested for an average healthy adult. After waiting about 2 minutes, the dosage may be further titrated in small
after each increment to fully evaluate the sedative effect. Additional maintenance doses may be given in increments of 25% of the initial dose to maintain the desired level of sedation, only by slow titration. The desired end point can usually be attained within 3 to 6 minutes, depending on the total dose administered and whether or not it is preceded by opioid premedication. Opioid premedication when indicated, results in less variability of patient response.
The dosage should be lowered in the elderly and debilitated, and in patients with limited pulmonary reserve (see Table V). Because the danger of underventilation or apnea is greatest in these patients and because peak effect may take longer, increments should be smaller and the rate of injections slower.
For induction of general anesthesia before administration of other anesthetic agents: Individual response to midazolam is variable, particularly when an opioid premedicant is not used. The dosage should be titrated according to the patient's age and clinical status. Midazolam Injection Product Monograph Page 22 of 39
Table VI: Dosage Table for Intravenous Induction (see Method of Administration) Patient Type Unpremedicated Patients Premedicated Patients (Opioids or CNS Depressants) Initial Dose Increments Initial Dose Increments Patients below age 55 0.3-0.35 mg/kg If needed to complete induction, increments of approximately 25% of the initial dose may be used. 0.15-0.35 mg/kg
0.25 mg/kg will usually suffice If needed to complete induction, increments of approximately 25% of the initial dose may be used. Patients age 55 or older; (ASA I or II surgical patients) 0.3 mg/kg 0.2 mg/kg Patients with severe systemic disease or other debilitation 0.2-0.25 mg/kg
In some cases as little as 0.15 mg/kg will suffice The need for increment doses to complete induction must be evaluated by the anesthesiologist. 0.15-0,2 mg/kg
In some cases as little as 0.15 mg/kg will suffice The need for increment doses to complete induction must be evaluated by the anesthesiologist.
Doses are administered over 20 to 30 seconds, allowing 2 minutes for effect. ICU Sedation For initiation and maintenance of ICU sedation in intubated, mechanically ventilated patients (see Table VII).
No prior Opioids or CNS Depressants 0.015-0.03 mg/kg 0.01-0.03 mg/kg/hr 0.07-0.15 mg/kg/hr For optimal sedation the maintenance infusion rate may be increased or decreased by increments of 25%-50% of the initial dose at intervals of 30 minutes
Prior/Concomitant Opioids or CNS Depressants 0.015-0.03 mg/kg 0.01-0.03 mg/kg/hr 0.07 mg/kg/hr Dosage and rate of infusion should be individualized to achieve the required level of sedation according to the patient's age and clinical status. In patients who are still sedated and/or who received large doses of opioids, a bolus dose may not be necessary and the initial infusion rate of midazolam should be substantially decreased.
As a group, pediatric patients generally require higher doses of midazolam than do adults and younger children may require higher doses than older children. In obese individuals, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression/airway obstruction is increased. For appropriate patient monitoring, see WARNINGS section. Midazolam should be administered as an induction agent only by a person trained in general anesthesia and should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintenance of a patent airway and support of ventilation (see WARNINGS). Midazolam Injection Product Monograph Page 23 of 39
Patients should be discharged in the care of a responsible individual. Intramuscularly Usual Pediatric Dose For sedation prior to anesthesia or procedures (for longer and/or more stimulating procedures, intramuscular midazolam can be used to facilitate insertion of an intravenous catheter for titration of additional medication.):
Sedation with intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1-0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg may be needed. Midazolam and an opioid should not be mixed as a premedication, however if required then constant monitoring is recommended. Should both be required the initial dose of each must be reduced and the second agent of the two should be administered intravenously on arrival at the procedure area. Intravenously by Intermittent Injection Usual Pediatric Dose For sedation prior to and during procedures or prior to anesthesia:
For all patients titrate slowly to the desired effect. The initial dose should be administered over 2-3 minutes. Wait an additional 2-3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. See Table VIII.
6 months-5 years 0.015-0.1 mg/kg 0.6 mg/kg The initial dose should be administered over 2-3 minutes, wait for an additional 2-3 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments, until the appropriate level of sedation is achieved. 6-12 years 0.025-0.05 mg/kg 0.4 mg/kg 12-17 years Dose as Adults
The dose of Midazolam Injection must be reduced in patients premedicated with opioids or other sedative agents including midazolam.
To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect. Intravenous loading doses
intravenous dose to preterm and term neonates. See below for Preterm and Neonatal Dosing Information). This loading dose may be followed by a continuous intravenous infusion to Midazolam Injection Product Monograph Page 24 of 39
maintain the effect. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of Midazolam Injection should be initiated at a rate of 0.001- 0.002 mg/kg/min (1-2 mcg/kg/min). The rate of infusion can be increased or decreased as required, or supplemental intravenous doses of Midazolam Injection can be administered to increase or maintain the desired effect. Frequent assessment using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P-450IIIa enzyme inhibitors (see DRUG INTERACTIONS) and in patients with liver dysfunction, renal dysfunction, low cardiac output (especially those requiring ionotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when Midazolam Injection is rapidly administered.
When initiating an infusion with Midazolam Injection in hemodynamically compromised patients, the usual loading dose of Midazolam Injection should be titrated in small increments, separated by 2-3 minutes, and the patient monitored for hemodynamic instability, e.g. hypotension, respiratory rate and oxygen saturation.
The dose of Midazolam Injection must be reduced in patients premedicated with opioids or other sedative agents including midazolam. Neonatal Dosage Based on the pharmacokinetic parameters and reported clinical experience in preterm and term neonates, continuous intravenous infusion of Midazolam Injection should be initiated at a rate of 0.0005-0.001 mg/kg/min (0.5-1 mcg/kg/min). Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients in combination with regional anesthesia.
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PHARMACEUTICAL INFORMATION Drug Substance Proper or Common Name: midazolam
8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo [1,5-α][1,4] Benzodiazepine
Molecular Formula: C 18 H 13 C1FN 3
325.8 g/mol
White to yellow crystalline powder. Practically insoluble in water; freely soluble in acetone and in ethanol; soluble in methanol. The hydrochloride salt of midazolam, which is formed in situ, is soluble in aqueous solutions. Melting range: 161-164°C.
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COMPOSITION Each mL of sterile aqueous solution contains: midazolam 1 mg or 5 mg (hydrochloric acid added for solubilization), sodium chloride 8 mg for tonicity, hydrochloric acid and, if necessary, sodium hydroxide to adjust pH and water for injection.
Store between 5°C-25 o C. Protect from light. Protect packaging from any physical damage. Unopened ampoules will be suitable for use for up to 8 months after the foil sachet has been opened, if kept in carton in order to protect from light.
Midazolam Injection is compatible and stable for 24 hours when diluted to 0.03-0.5mg/mL with either 5% dextrose injection, or 0.9% sodium chloride injection.
The 15mg/3mL, 5mg/mL and 5mg/5mL formulations may be diluted to facilitate slow injection. The 50mg/10mL ampoules may be added to the infusion solutions in a mixing ratio of 15mg midazolam per 100-1000mL infusion solution.
The product and its admixtures contain no antimicrobial agent. In order to reduce microbiological hazards, it is recommended that further dilution be effected immediately prior to use and infusion commenced as soon as practicable after the preparation of the admixture.
As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitation, discolouration and leakage prior to administration whenever solution and container permit.
Infusion should be completed within 24 hours of preparation and the residue discarded. However, infusion with calcium chloride intravenous infusion (Ringer’s solution) and compound sodium lactate intravenous infusion (Hartmann’s solution) should be completed within 4 hours as the potency of midazolam is known to decrease. Store diluted solution between 2°C - 8°C for up to 24 hrs. AVAILABILITY OF DOSAGE FORMS Midazolam Injection 5 mg in 1 mL (sterile) Steriluer® Plastic Ampoule (2 x 5 pack) Midazolam Injection 15 mg in 3mL (sterile) Steriluer® Plastic Ampoule (5 pack) Midazolam Injection 5 mg in 5mL (sterile) Steriluer® Plastic Ampoule (2 x 5 pack) Midazolam Injection 50 mg in 10 mL (sterile) Steriluer® Plastic Ampoule (5 pack)
Midazolam Injection Product Monograph Page 27 of 39
DETAILED PHARMACOLOGY Midazolam possesses all the pharmacological effects of the benzodiazepines, namely it is a sedative, hypnotic, anticonvulsant, anxiolytic, muscle relaxant and amnestic agent. In addition, midazolam enhances GABAergic inhibition, decreases the firing rate of single neurons, decreases the cerebral metabolic rate for oxygen, decreases cerebral blood flow, enhances the survival time of mice in a hypoxic milieu and induces amnesia in the passive avoidance paradigm.
Midazolam binds in nanomolar concentrations to the high-affinity, stereospecific benzodiazepine receptor sites in the mammalian brain. These receptor sites are functionally coupled to GABA recognition sites and to sites related to chloride channels. Midazolam decreases the cyclic GMP level in the cerebellum.
The CNS pharmacological effects of midazolam can be reversed with flumazenil (Ro 15-1788), a specific benzodiazepine antagonist.
In most tests, the potency of midazolam is comparable to that of diazepam or somewhat greater. However, in tests predicting sedation, amnesia and attenuation of muscle tone and coordination, midazolam is considerably more potent than diazepam.
The onset of effect of midazolam is rapid and its duration of action short. In conscious normotensive dogs, midazolam causes slight but significant changes in several cardiovascular parameters, namely it decreases mean arterial pressure and systemic vascular resistance and increases heart rate and cardiac output.
Rats given 2.5 mg/kg 14 C midazolam intravenously, excreted within 24 hours 81% of the radioactivity in the fæces and 10% in the urine. During the first day, the highest levels of radioactivity were found in the liver. Four phenolic derivatives of midazolam were identified in the rats' bile. These biliary metabolites were excreted as glucuronide and/or sulfate conjugates.
TOXICOLOGY Acute Toxicity LD 50 Midazolam Hydrochloride Species Strain Route LD 50 (mg/kg) Observation Period
Mice Charles River IV (M) 47
(F) 48
14 days IM >50 Rats
Charles River IV
14 days IM >10 a
Highest dose administered
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Signs and Symptoms Decreased motor activity, muscle relaxation, ataxia, loss of righting reflex, hypnosis, respiratory depression.
Midazolam base (5.0 mg/mL) was administered intramuscularly once a day for two weeks to rats (12/sex/group) at doses of 0 (saline control), 0 (vehicle control), 0.5, 1.6 or 5.0 mg/kg.
The 5.0 mg/kg/day dose produced a significant decrease in food consumption and a slight decrease in body weight gain, in male rats. Transient, dose-related signs of CNS depression were observed in all midazolam-treated groups within five minutes of the injections. The duration of these pharmacological effects was 2.0, 1.0 and 0.5 hr in the high, mid and low-dose groups, respectively. In rats from all midazolam treated groups, multifocal, extensive myositis, myodegeneration and myonecrosis were encountered at the injection sites. The lesions were characterized as chronic active myositis and were moderate to severe in all treatment groups. However, in the low-dose group, the lesions were less extensive with respect to the amount of tissue involved. 2. Five-Week IV-Rats: Midazolam base (5.0 mg/mL) was administered intravenously once a day for five weeks to rats (12/sex/group) at doses of 1.0, 2.5 or 6.0 mg/kg. A control group received 1.2 mL/kg/day of saline. Local tolerance during the first four weeks was good in all treated groups, however, during the last week of treatment intraperitoneal injections were necessary in most members of the high-dose group because of swollen tails. All animals survived the five-week treatment period. Sedation and ataxia were noted in the high-dose group for several minutes after injection. Except for minimal decreases of 6-7% in body weight in males receiving the mid and high doses, no effects on this parameter were observed. The only clinical laboratory finding was a slight reduction in total serum protein in males of the high-dose group.
Midazolam base (5.0 mg/mL) was administered intramuscularly, once a day for two weeks to dogs (three/sex/group) at doses of 0 (saline control), 0 (vehicle control), 0.3, 1.0 or 3.0 mg/kg.
Administration of 3.0 and 1.0 mg/kg/day of midazolam was associated with dose-related and transient behavioural changes and central nervous system effects.
Mean serum total creatine phosphokinase (CPK), alanine aminotransferase (SGPT) and aspartate aminotransferase (SGOT) were significantly elevated in the group treated with 3.0 mg/kg/day compared to the control group. However, the SGOT value was within normal limits.
Mild focal scarring was seen at the sites of injection in both treated and control dogs. Midazolam Injection Product Monograph Page 29 of 39
4. Five-Week IV/IM-Dogs: In a five-week toxicity study, midazolam base (5.0 mg/mL) was administered intravenously once daily for five weeks to dogs (three/sex/group) at doses of 1.0 or 6.0 mg/kg. Two additional groups of dogs (two/sex/group) received 2.5 mg/kg/day intravenously or intramuscularly. The control group received 1.2 mL/kg/day intravenous saline.
All animals survived the five-week treatment period. In the first week, dose-related sedation and ataxia were noted for up to three to five hours after intravenous or intramuscular injection. These effects became considerably less pronounced after one week. Alkaline phosphatase values were slightly increased in treated animals, although no clear dose-relationship was evident. Increased alpha
1 -globulins and decreased alpha 2 -globulins were noted in treated animals. Slight and nonsignificant dose-related increases in absolute pituitary and liver weights were observed, however, relative organ weights did not show similar trends. Postmortem evaluation showed that the frequency and severity of the inflammatory changes at the intravenous injection sites were similar in all groups except at the high dose where both parameters were somewhat greater than in the controls.
In a two-week toxicity study, a saline solution of midazolam maleate (0.5%) or diazepam injectable formulation (0.5%) was administered intravenously into the marginal ear veins of rabbits (four/group) at doses of 1.5 or 5.0 mg/kg/day. A fifth group received a 0.25% solution of midazolam maleate, 1.5 mg/kg/day.
At the 5.0 mg/kg/day dose, two rabbits received midazolam for 14 days and the other two for ten consecutive days.
The diazepam injections could not be continued beyond seven days due to the necrotic condition of the ears. The other irritation parameters, swelling, erythema and hemorrhage, were severe after the injection of diazepam and moderate after midazolam.
At the 1.5 mg/kg/day dose, midazolam was injected for 14 days while diazepam could be administered for 11 to 13 consecutive days. Necrosis was slight in the midazolam-treated rabbits and severe in the diazepam-treated animals. Swelling, erythema and hemorrhage were slight to moderate after midazolam and moderate to severe after diazepam. Rabbits receiving 1.5 mg/kg/day of midazolam in the 0.25% solution showed less irritation than rabbits receiving the same dose of midazolam in the 0.5% solution.
Decreased motor activity, muscle relaxation and hypnosis (in some animals) were noted in the midazolam-treated animals while the diazepam-treated rabbits showed ataxia, decreased motor activity and muscle relaxation.
Serum alkaline phosphatase levels were elevated in a few midazolam-treated rabbits, although this was not a dose-related phenomenon. One high-dose midazolam-treated rabbit exhibited an elevated white blood cell count.
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A one year toxicity study was conducted in beagle dogs (nine/sex/group) with midazolam maleate. The compound was administered orally in gelatin capsules at doses of 0 (control), 1.0, 7.0 or 45 mg/kg/day, seven days per week. The 53-week treatment period was followed by a 14- week recovery period.
Two dogs from the mid-dose group and one dog from the high-dose group died during the study after having received 280, 60 and 212 doses of midazolam, respectively. However, the gross and microscopic findings indicated that the deaths were not treatment related.
Female dogs receiving the high dose and male dogs receiving the mid and high doses of midazolam gained significantly less weight than the controls.
Treatment-related clinical effects included CNS depression and some behavioural changes, both of which declined after a few weeks of treatment. Abnormal stools and salivation, licking and emesis were observed in both treated and control groups, but the incidences were greater in the treated dogs and showed dose-dependency.
Serum alkaline phosphatase levels increased substantially in both male and female dogs in the 45 mg/kg/day groups; the increase was on the average eight-fold over pretreatment levels. The values were somewhat higher in female dogs. The abnormality was reversible and at the end of the 14-week recovery period, serum alkaline phosphatase levels were greatly decreased, although they did not reach pretreatment levels. Serum alkaline phosphatase levels were also increased in the mid-dose midazolam groups, although to a lesser extent and returned to normal during the recovery period.
Gamma glutamyl transpeptidase (GGTP) levels were significantly and dose-dependently elevated in male dogs and significantly elevated at the highest dose in female dogs at week 52. The values were within normal limits. Serum alanine amino-transferase (SGPT) levels were significantly elevated in male dogs in the high dose group, at week 52.
Liver weights were significantly increased, this change was both dose- and time-related. At week 26, the increase was statistically significant in the high dose group, while at week 52, it occurred in both the mid- and high-dose groups. At the end of the 14 week recovery period, the mean liver weights of treated and control dogs were statistically not different.
Microscopic evaluation of the liver revealed the following pathology: parenchymal cell hypertrophy, altered cytoplasmic staining, yellow-brown granules in parenchymal cells and whorls of eosinophilic material. These changes reverted to normal in ¾ dogs by the end of the 14 week recovery period.
In the Ames test, with and without metabolic activation, using five Salmonella typhimurium strains: TA 1535, TA 1537, TA 1538, TA 100 and TA 98, results were negative at concentrations Midazolam Injection Product Monograph Page 31 of 39
of 50, 100 and 500 mcg of midazolam per plate. A concentration of 750 mcg/plate was too toxic to the bacteria and could not be evaluated.
The fluctuation test (without metabolic activation) also revealed no mutagenicity of midazolam for Salmonella typhimurium strains TA 1535, TA 1537, and TA 1538 at concentrations up to 25 mcg/mL. Higher concentrations could not be evaluated because of toxicity of the bacteria.
A twenty-four month oral (dietary admix) carcinogenicity study with midazolam was conducted in mice (80 male and 80 female/group) at doses of 0 (control 1), 0 (control 2), 1, 9 or 80 mg/kg/day.
In male mice in the high-dose group, survival was decreased when compared to controls. Mean body weights were significantly increased in male and female mice in the high-dose group and in female mice in the mid-dose group.
The 24 months administration of midazolam, at the 80 mg/kg/day dose level, led in male mice to decreased white blood cell counts, ulceration/abrasion of the prepuce, inflammatory changes of the urinary tract and distention of the urinary bladder.
Mean absolute and relative liver weights were significantly increased in male and female mice in the high-dose group and in male mice in the mid-dose group.
Hepatocellular hypertrophy was a prominent histological finding in both male and female mice at the 80/mg/kg/day dose and in male mice at the 9 mg/kg/day dose. In female mice, the 80 mg/kg/day dose of midazolam markedly increased the incidence of hepatic neoplasms. The hepatic masses or nodules, seen at autopsy, were found to be primary adenomas and carcinomas upon histologic examination. Hepatic neoplasms were also seen in female mice in the mid and low-dose groups, at a frequency higher than in controls, however, the difference was not statistically significant.
In female mice in the high-dose group, there was an increase in the incidence of follicular hyperplasia, adenoma/carcinoma of the thyroid, and a significant increase in the incidence of adrenal cortical hypertrophy and adrenomedullary hyperplasia.
A twenty-four month oral (dietary admix) carcinogenicity study with midazolam was conducted in rats (90 male and 90 female/group) at doses of 0 (control 1), 0 (control 2), 1, 9 or 80 mg/kg/day.
In female rats, midazolam administration was associated with a decrease of body weight at the high dose and an increase of body weight at the mid dose. In male animals, the 80 mg/kg/day dose caused an increase in body weight during the earlier part of the study.
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The 80 mg/kg/day dose was associated with the following changes in clinical chemical parameters: a decrease of serum glucose in both male and female rats at 26 weeks, an increase of serum urea nitrogen in female rats at 26 weeks and albuminuria in male rats after 26 weeks persisting to 78 weeks. At later times, all parameters were similar to control.
Absolute and relative liver weights were increased in both male and female animals, treated with 80 and 9 mg/kg/day of midazolam. Absolute liver weights were also increased in low-dose treated female rats.
In addition, the following organ weight changes were observed in animals treated with the 80 mg/kg/day dose of midazolam and were considered treatment related: increase in absolute and relative kidney weights in both sexes, increase in absolute and relative thyroid weights in both sexes, increase in absolute and relative adrenal gland weights in male rats, decrease in absolute and relative pituitary gland weights in female rats and decreased weights of the testes.
Dose-related centrilobular hepatocytic hypertrophy and centrilobular fatty changes were observed in the livers of both sexes. In addition, there was a statistically nonsignificant increase in the incidence of hepatocellular adenomas/carcinomas in female rats at all three doses.
In male rats, treated with 80 mg/kg/day of midazolam, the incidence of thyroidal tumours (adenomas/carcinomas) was significantly increased. The increase was limited to follicular adenomas; there was no increase observed in the incidence of follicular carcinomas.
In a reproduction study, rats were administered midazolam maleate injection at doses of 1.0, 4.0, or 16.0 mg/kg/day by oral intubation. The highest dose produced pronounced pharmacological effects, namely sedation and ataxia, which lasted up to 2 hours. Twenty-four male rats were treated for 62 days prior to mating and through the mating period and 24 female rats for 14 days prior to mating and through day 13 of gestation (Group A) or day 21 of lactation (Group B). Control rats received daily intubation of the vehicle. Approximately one-half of the rats were sacrificed on gestation day 13. The remaining dams were allowed to deliver for subsequent perinatal and postnatal evaluations and were sacrificed on lactation day 21.
Gonadal function, mating behaviour, conception rate, early and late stages of gestation, parturition, lactation, neonatal viability, and growth of the pups were not adversely affected when midazolam was administered orally at doses up to 16 mg/kg/day.
A teratology study was performed with groups of 30 rats given midazolam maleate intravenously at doses of 0.2, 1.0 or 4.0 mg/kg/day from day 7 through 15 of gestation. One group of females was not injected and served as a nontreated control. A second control group was injected with the vehicle. Fetuses from 20 rats per group were delivered by Cæsarean section. An additional ten rats per group were allowed to deliver for subsequent postnatal evaluation of the pups.
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In the Cæsarean section group, the average maternal body weight decreased significantly during gestation in dams receiving the 4.0 mg/kg/day dose.
There were no significant differences between control and treated animals in the average litter size, average fetal body weight, distribution of fetuses by sex, the number of fetuses born dead, resorption rate or percent litters showing resorptions. No increase in external soft tissue or skeletal abnormalities was noted and the incidence of skeletal variations was comparable in all groups.
In the 1.0 and 4.0 mg/kg/day group of rats, that were allowed to deliver, a small increase in postimplantation loss was noted. This is considered to be the result of resorbed fetuses and/or pup cannibalism. In the 4.0 mg/kg/day treatment group, two of 133 pups exhibited partial paralysis of fore and hind limbs and poor motor coordination.
A teratology study was conducted in groups of 15 female white rabbits given midazolam maleate intravenously at doses of 0.2, 0.6, or 2.0 mg/kg/day from days 7 through 18 of gestation. A control group of 30 rabbits received injections of the vehicle. A second group of 15 rabbits served as a nontreated control.
Sedation was present in all midazolam-treated rabbits, its severity and duration being dose dependent. Pretreatment parameters (percentage of animals pregnant, average number of corpora lutea and implantation sites) were similar in treated and control groups. Furthermore, there were no significant differences between control and treated animals in the average litter size, the average fetal body weight, average crown-rump length, distribution of fetuses by sex and 24-hr viability index of the kits. The resorption rate and percentage of litters showing resorptions were slightly higher in those receiving the 2.0 mg/kg/day dose of midazolam. The frequency of external, visceral and skeletal abnormalities was similar in control animals and those treated with the mid and high dose of midazolam. However, in one dose receiving 0.2 mg/kg/day of midazolam, 9/10 and 6/10 fetuses had external (open eyelids) and skeletal (cleft palate) abnormalities, respectively.
A perinatal and postnatal study was performed in groups of 20 female rats given midazolam maleate intravenously at doses of 0.2, 1.0 or 4.0 mg/kg/day from day 15 of gestation through day 21 of lactation. A control group of 20 rats received injections of the vehicle. A second control group served as a nontreated control.
Intravenous midazolam induced ataxia in the dams, the severity and duration of which was dose- dependent.
Maternal weight gains were significantly reduced in the 4.0 mg/kg/day dose group on the day of delivery and in the 1.0 and 4.0 mg/kg/day dose groups on lactation day 7. The following slight but significant effects were observed in the 4.0 mg/kg/day dose group: prolonged gestation period, smaller average litter size and increased postimplantation loss.
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Late fetal development, lactation, neonatal viability and growth of the pups were not affected by midazolam treatment. External, visceral and skeletal abnormalities were not seen in any of the treatment groups.
To date only animal data are available.
Physical dependence was studied in several species. In phenobarbital-dependent cynomolgus monkeys, midazolam, in oral doses up to 10 mg/kg, did not suppress the abstinence symptoms which appeared when phenobarbital was withdrawn. A 20 mg/kg dose of midazolam suppressed some of the minor signs (apprehension, hyperirritability, piloerection), but the effect was probably due to general sedation.
Midazolam, when administered at a maximal oral dose of 135 mg/kg/day, for 28 consecutive days, produced only mild symptoms of withdrawal in cynomolgus monkeys. An additional 28 days of drug administration did not intensify the withdrawal symptoms. In contrast, phenobarbital produced withdrawal of intermediate severity, and several benzodiazepines caused intensified withdrawal after the second, as compared to the first, 28-day period.
Signs indicative of withdrawal were not seen in either rats or dogs at the end of the 18 or 12 months toxicity study, respectively.
The intravenous administration of the benzodiazepine antagonist, flumazenil (Ro 15-1788), did not precipitate withdrawal symptoms in monkeys chronically treated with midazolam.
In baboons trained to intravenously self-inject cocaine, both the barbiturates and the benzodiazepines were self-administered, but with different intensities. The barbiturates maintained high levels of self-injection in all the animals and over a wide dose range. Midazolam also produced high rates of self-injection, although not in all of the animals and only in a narrow dose range. Benzodiazepines, with a slow rate of elimination, maintained modest levels of self-administration. The rapid elimination of midazolam might contribute to the effect observed.
In rats trained to discriminate between saline and diazepam, midazolam, like other benzodiazepines, produced a dose-dependent, diazepam-appropriate response.
Midazolam base (2.0 and 5.0 mg/mL), administered intravenously into the ear veins of rabbits at a single dose of 0.7 mg/kg, produced minimal irritation to the ears.
Midazolam Injection Product Monograph Page 35 of 39
II. Muscle Irritation-Rabbits: The intramuscular irritation potential of midazolam base (5.0 mg/mL) and its vehicle was tested in rabbits in volumes of 1.0 and 0.1 mL. Single dose administration of 1.0 mL of midazolam produced moderate hemorrhage and necrosis while the vehicle produced slight hemorrhage and minimal necrosis. At 0.1 mL, midazolam produced very slight hemorrhage and well-defined necrosis; the vehicle also produced very slight hemorrhage but no necrosis. The study indicated that midazolam can cause slight muscle irritation following intramuscular administration.
Intravenous administration of midazolam base (1.0 mg/mL) to dogs did not produce hemolysis after a dose of 0.7 mg/kg (0.7 mL/kg) administered over approximately 30 seconds.
However, intravenous injection of a dose of 0.7 mg/kg (0.14 mL/kg) of the 5.0 mg/mL injectable midazolam base formulation produced a slight hemolysis in one post-treatment undiluted plasma sample.
No hemolysis occurred in the animals treated with normal saline at a volume of 0.7 or 0.14 mL/kg.
Midazolam Injection Product Monograph Page 36 of 39
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1991;49:160. Document Outline
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