Midazolam 1 mg and 5 mg Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Midazolam 1 mg and 5 mg Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: ICU Agitation, Light Anesthesia, Light Sedation
Class: Benzodiazepines
Form: Liquid solution, Intramuscular (IM), Intravenous (IV)
Ingredients: Midazolam

Pharmaceutical Information

Drug Substance

Proper Name: midazolam
Chemical Name: 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine
Structural Formula:
Molecular Formula: C18H13CIFN3
Molecular Weight: 325.78
Description: White to light yellow crystalline solid, insoluble in water. The hydrochloride salt of midazolam, which is formed in situ, is soluble in aqueous solutions. The melting point is 161 - 164°C.
Composition: A sterile parenteral dosage form for intravenous or intramuscular injection. Each mL contains 1 mg or 5 mg midazolam (hydrochloric acid added for solubilization), compounded with 0.1 mg disodium edetate, 10 mg benzyl alcohol, as preservative, 8 mg sodium chloride for isotonicity, and Water for Injection. Hydrochloric acid, and if necessary, sodium hydroxide added to adjust pH.

Stability and Storage Recommendations

The recommended storage temperature for Midazolam Injection is between 15 and 30°C. Protect from light. Discard unused portion 28 days after initial puncture.

Midazolam Injection is compatible and stable for 24 hours when diluted to 0.1 - 0.5 mg/mL with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection.

As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used.

Availability of Dosage Forms

Each mL contains 1 mg or 5 mg midazolam (hydrochloric acid added for solubilization), compounded with 0.1 mg disodium edetate, 10 mg benzyl alcohol, as preservative, 8 mg sodium chloride for isotonicity, and Water for Injection. Hydrochloric acid, and if necessary, sodium hydroxide added to adjust pH.

Midazolam Injection, USP 1 mg/mL contains midazolam hydrochloride equivalent to 1 mg midazolam/mL.

C410102 2 mL multiple-dose vials with flip-top seals in boxes of 10 vials.
C410105 5 mL multiple-dose vials with flip-top seals in boxes of 10 vials.
C410110 10 mL multiple-dose vials with flip-top seals in boxes of 10 vials.

Midazolam Injection, USP 5 mg/mL contains midazolam hydrochloride equivalent to 5 mg midazolam/mL.

C410201 1 mL multiple-dose vials with flip-top seals in boxes of 10 vials.
C410202 2 mL multiple-dose vials with flip-top seals in boxes of 10 vials.
C410210 10 mL multiple-dose vials with flip-top seals in boxes of 10 vials.

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 14C midazolam intravenously, excreted within 24 hours 81% of the radioactivity in the feces 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 sulphate conjugates.

Toxicology

Acute Toxicity

LD50 midazolam hydrochloride
Species Strain Route LD50 mg/kg Observation Period
Mice Charles River i.v. M 47
F 48
14 days
i.m. > 50
Rats Charles River i.v. > 50 14 days
i.m. > 10a

a Highest dose administered

Signs and Symptoms

Decreased motor activity, muscle relaxation, ataxia, loss of righting reflex, hypnosis, respiratory depression.

Long-Term Toxicology

Two-Week IM – Rats

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.

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.

Two-Week IM – Dogs

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.

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Mild focal scarring was seen at the sites of injection in both treated and control dogs.

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 alpha1-globulins and decreased alpha2-globulins were noted in treated animals. Slight and non-significant 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.

Two-week IV – Rabbits

In a two-week toxicity study, a saline solution of midazolam maleate (0.5%) or 'Valium' 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.

One-Year Oral – Dogs

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, 69, 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 eightfold 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 3/4 dogs by the end of the 14-week recovery period.

Mutagenicity

In the Ames test, with and without metabolic activation, using five Salmonellatyphimuriumstrains: TA 1535, TA 1537, TA 1538, TA 100 and TA 98, results were negative at concentrations of 50, 100 and 500 μg of midazolam per plate. A concentration of 750 μg/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 μg/mL. Higher concentrations could not be evaluated because of toxicity to the bacteria.

Carcinogenicity

Twenty-four Month Oral – Mice

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 prominant 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.

Twenty-four Month Oral – Rats

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.

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 tumors (adenomas/carcinomas) was significantly increased. The increase was limited to follicular adenomas; there was no increase observed in the incidence of follicular carcinomas.

Reproduction and Teratology

Fertility and General Reproductive Performance

In a reproduction study, rats were administered midazolam maleate injection at doses of 1.0, 4.0, or 16 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.

Teratology – Rats (IV)

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 days 7 through 15 of gestation. One group of females was not injected and served as a non-treated control. A second control group was injected with the vehicle. Fetuses from 20 rats per group were delivered by Caesarean section. An additional ten rats per group were allowed to deliver for subsequent postnatal evaluation of the pups.

In the Caesarean 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.

Teratology – Rabbits (IV)

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 non-treated 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 does receiving the 2.0 mg/kg/day dose of midazolam. The frequency of external, visceral and skeletal abnormalities was similar in control animals and does treated with the mid- and high-dose of midazolam. However, in one doe receiving 0.2 mg/kg/day of midazolam, 9/10 and 6/10 fetuses had external (open eyelids) and skeletal (cleft palate) abnormalities, respectively.

Perinatal and Postnatal – Rats (IV)

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 non-treated 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.

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.

Dependence Liability

To date only animal data are available.

Physical Dependence

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.

Self-administration

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.

Drug Discrimination

In rats trained to discriminate between saline and diazepam, midazolam, like other benzodiazepines, produced a dose-dependent, diazepam-appropriate response.

Irritation Studies

Venous Irritation – Rabbits

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.

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.

Hemolysis Testing – Dogs

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 posttreatment undiluted plasma sample.

No hemolysis occurred in the animals treated with normal saline at a volume of 0.7 or 0.14 mL/kg.