Midazolam Syrup

• Tell all of your health care providers that you take midazolam syrup. This includes your doctors, nurses, pharmacists, and dentists.
• This medicine may be habit-forming with long-term use.
• Avoid driving and doing other tasks or actions that call for you to be alert for 1 full day after getting this medicine and until the effects of midazolam syrup have worn off.
• Use care moving around after getting this medicine. You may need help with standing and walking until the effects of midazolam syrup have worn off.
• Talk with your doctor before you drink alcohol or use other drugs and natural products that slow your actions.
• Avoid grapefruit and grapefruit juice.
• Use with care in children. Talk with the doctor.
• Studies in young animals and children have shown that frequent or long-term use of anesthesia drugs or drugs used for sleep in children younger than 3 years of age may lead to long-term brain problems. This may also happen in unborn babies if the mother uses this medicine during the third trimester of pregnancy. Talk with the doctor.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant. If you are pregnant or you get pregnant while taking midazolam syrup, call your doctor right away.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.
• Do not take this medicine if you are 65 or older. Talk with your doctor.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

Midazolam is a benzodiazepine available as midazolam HCl syrup for oral administration. Midazolam, a white to light yellow crystalline compound, is insoluble in water, but can be solubilized in aqueous solutions by formation of the hydrochloride salt in situ under acidic conditions. Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine hydrochloride.

Midazolam hydrochloride has the molecular formula C18H13ClFN3·HCl, a calculated molecular weight of 362.25 and the following structural formula:

Each mL of the syrup contains midazolam hydrochloride equivalent to 2 mg midazolam compounded with bitterness modifier, artificial cherry-brandy flavor, citric acid anhydrous, D&C Red #33, edetate disodium, glycerin, sodium benzoate, sodium citrate, sodium saccharin, sorbitol solution, and water; the pH is adjusted to 2.8 to 3.6 with hydrochloric acid.

Under the acidic conditions required to solubilize midazolam in the syrup, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring. The amount of open-ring form is dependent upon the pH of the solution. At the specified pH of the syrup, the solution may contain up to about 40% of the open-ring compound. At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such.

Midazolam Open-ring Form

The following chart below plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions. As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 2.8 to 3.6. Above pH 5, at least 99% of the mixture is present in the closed-ring form.

Midazolam HCl syrup is contraindicated in patients with a known hypersensitivity to the drug or allergies to cherries or formulation excipients. 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. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction of general anesthesia with injectable midazolam; patients with glaucoma have not been studied.

Midazolam HCl syrup is a benzodiazepine and is a Schedule IV controlled substance that can produce drug dependence of the diazepam-type. Therefore, midazolam HCl syrup may be subject to misuse, abuse and addiction. Benzodiazepines can cause physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Withdrawal symptoms (ie, convulsions, hallucinations, tremors, abdominal and muscle cramps, vomiting and sweating), similar in characteristics to those noted with barbiturates and alcohol have occurred following abrupt discontinuation of midazolam following chronic administration. Abdominal distention, nausea, vomiting, and tachycardia are prominent symptoms of withdrawal in infants.

The handling of midazolam HCl syrup should be managed to minimize the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting and as required by law.

1. Remove the cap and push bottle adapter into neck of bottle.

2. Close the bottle tightly with cap. This will assure the proper seating of the bottle adapter in the bottle

The disposal of Schedule IV controlled substances must be consistent with State and Federal Regulations.