2.1 Recommended Dose

The recommended dose of SEIZALAM is 10 mg, administered by intramuscular injection.

2.2 Important Administration Instructions

SEIZALAM should be administered by a healthcare professional who has had adequate training in the recognition and treatment of status epilepticus.

SEIZALAM is for intramuscular use only. Inject in the mid-outer thigh (vastus lateralis muscle).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit [see Dosage Forms and Strengths (3)].

2.3 Monitoring

After administration of SEIZALAM, continuous monitoring of respiratory and cardiac function is recommended until the patient is stabilized. Serious and life-threatening cardiorespiratory adverse reactions, such as hypoventilation, airway obstruction, apnea, and hypotension have been reported with the use of midazolam. Patients should be monitored in a setting that allows for immediate access to resuscitative drugs. Appropriate resuscitation equipment and personnel trained in their use and skilled in airway management should be available [see Warnings and Precautions (5.4), Adverse Reactions (6.1)].

Observation for signs of cardiorespiratory depression is particularly important in patients with chronic obstructive pulmonary disease (COPD), patients 60 or more years of age, and patients who have received concomitant narcotics or other central nervous system (CNS) depressants.

5.1 Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including SEIZALAM, and opioids may result in profound sedation, respiratory depression, coma, and death. If a decision is made to use midazolam concomitantly with opioids, monitor patients closely for respiratory depression and sedation [see Drug Interactions (7.1)].

Practitioners administering SEIZALAM must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management.

5.2 Abuse, Misuse, and Addiction

The use of benzodiazepines, including SEIZALAM, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see Drug Abuse and Dependence (9.2)].

Before prescribing SEIZALAM and throughout treatment, assess each patient's risk for abuse, misuse, and addiction. Use of SEIZALAM, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of SEIZALAM along with monitoring for signs and symptoms of abuse, misuse, and addiction. Do not exceed the recommended dosing frequency; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

5.3 Dependence and Withdrawal Reactions After Use of SEIZALAM More Frequently Than Recommended

For patients using SEIZALAM more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue SEIZALAM (a patient-specific plan should be used to taper the dose).

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

5.4 Risks of Cardiorespiratory Adverse Reactions

Serious cardiorespiratory adverse reactions have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations, particularly in patients with hemodynamic instability. Hypotension occurs more frequently in patients premedicated with a narcotic. The danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve [see Use in Specific Populations (8.5, 8.7)]; patients with COPD are highly sensitive to the respiratory depressant effect of midazolam. SEIZALAM should be administered with caution to patients in shock or coma with depression of vital signs.

Practitioners administering SEIZALAM must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management.

5.5 Other Adverse Reactions

Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity, and combativeness have been reported with midazolam when used for sedation. These reactions may be caused by inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Agitation also occurred in the randomized controlled clinical study of SEIZALAM in patients with status epilepticus [see Adverse Reactions (6.1)].

5.6 Risks from Concomitant Use of Central Nervous System Depressants

Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect. SEIZALAM should be administered with caution to patients in acute alcohol intoxication with depression of vital signs. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical status of the individual patient, and the use of concomitant medications capable of depressing the central nervous system (CNS). Anticipated effects range from mild sedation to deep levels of sedation virtually equivalent to a state of general anesthesia where the patient may require external support of vital functions. Practitioners administering SEIZALAM must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management. For information regarding withdrawal, see Drug Abuse and Dependence (9.3).

5.7 Impaired Cognitive Function

Midazolam is associated with a high incidence of partial or complete impairment of recall for several hours following an administered dose. Gross tests of recovery from the effects of midazolam cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided, and as their medical condition permits.

5.8 Glaucoma

Benzodiazepines, including SEIZALAM, can increase intraocular pressure in patients with glaucoma. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam; patients with glaucoma have not been studied. Patients with open-angle glaucoma may need to have their ophthalmologic status evaluated following treatment with SEIZALAM. SEIZALAM is not recommended in patients with narrow-angle glaucoma.

5.9 Neonatal Sedation and Withdrawal Syndrome

Use of SEIZALAM late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate [see Use in Specific Populations (8.1)]. Monitor neonates exposed to SEIZALAM during pregnancy or labor for signs of sedation and monitor neonates exposed to SEIZALAM during pregnancy for signs of withdrawal; manage these neonates accordingly.

5.10 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative

SEIZALAM is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including SEIZALAM. The “gasping syndrome” is characterized by CNS depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (SEIZALAM contains 10 mg of benzyl alcohol per mL) [see Use in Specific Populations (8.4)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

7.1 Effect of Concomitant Use of Benzodiazepines and Opioids

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids. Monitor patients closely for respiratory depression and sedation.

7.2 Other CNS Depressants and Alcohol

The sedative effect of SEIZALAM is accentuated by concomitantly administered medication that depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), secobarbital, and droperidol, and also by alcohol [see Warnings and Precautions (5.1, 5.4, 5.6)].

7.3 Cytochrome P450-3A4 Inhibitors

Caution is advised when SEIZALAM is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system (e.g., cimetidine, erythromycin, diltiazem, verapamil, ketoconazole, and itraconazole). These drug interactions may result in prolonged sedation caused by a decrease in plasma clearance of midazolam [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Benzodiazepines are not recognized as a treatment for status epilepticus in neonates and should not be used in this population.

SEIZALAM is not approved for use in neonates or infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low-birth-weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth-weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (SEIZALAM contains 10 mg of benzyl alcohol per mL) [see Warnings and Precautions (5.10)].

8.5 Geriatric Use

Of the total number of patients from the intent-to-treat (ITT) population in the clinical trial of SEIZALAM, 14.9 percent were 65 years of age and over, while 8.3 percent were 75 years of age and over.

Geriatric patients may have altered drug distribution; diminished hepatic and/or renal function; longer elimination half-lives for midazolam and its metabolites, and subjects over 70 years of age may be particularly sensitive [see Clinical Pharmacology (12.3)]. Administration of IM midazolam to elderly patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression [see Warnings and Precautions (5.4)]. In most of these cases, the patients also received other CNS depressants capable of depressing respiration, especially narcotics [see Warnings and Precautions (5.1, 5.6)]. Close monitoring of geriatric patients is recommended.

8.6 Renal Impairment

Patients with renal impairment may have a slower elimination of midazolam and its metabolites, which may result in prolonged drug exposure [see Clinical Pharmacology (12.3)].

8.7 Congestive Heart Failure

Patients with congestive heart failure eliminate midazolam more slowly, which may result in prolonged drug exposure [see Clinical Pharmacology (12.3)].

9.1 Controlled Substance

SEIZALAM contains midazolam hydrochloride, a Schedule IV controlled substance.

9.2 Abuse

SEIZALAM is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.

Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)].

The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

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.

9.3 Dependence

12.1 Mechanism of Action

The exact mechanism of action for midazolam in the treatment of status epilepticus is not fully understood, but is thought to involve potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABAA receptor.

12.2 Pharmacodynamics

The effects of midazolam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications.

12.3 Pharmacokinetics

The pharmacokinetics of midazolam were evaluated in a single dose-escalation trial in healthy subjects; following IM injection of midazolam at doses ranging from fixed total amounts of 5 mg to 30 mg (one half to three times the recommended dose) or body weight based dose of 0.10 mg/kg to 0.49 mg/kg, the overall median time to maximum plasma concentration (Tmax) was observed at approximately 0.5 hours after administration. The rate and extent of systemic exposure, as assessed by maximum plasma concentration (Cmax) and area under the plasma drug concentration-time curve from time 0 to infinity (AUC0-∞), tended to increase proportionally with increasing dose from 5 mg to 30 mg.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

SEIZALAM (midazolam injection) is a clear, colorless to light yellow sterile solution available in multiple-dose fliptop vials containing 50 mg/10 mL (5 mg/mL).

SEIZALAM is supplied in the following packaging configurations:

• One vial: NDC 11704-650-01
• Carton of 10 vials: NDC 11704-650-10

16.2 Storage and Handling

Store at 20 ºC to 25 ºC (68 ºF to 77 ºF); excursions permitted between 15 ºC and 30 ºC (59 ◦F and 86 ◦F) [See USP Controlled Room Temperature].

Risks from Concomitant Use with Opioids

Inform patients and caregivers that potentially fatal additive effects may occur if SEIZALAM is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.1), Drug Interactions (7.1)].

Abuse, Misuse, and Addiction

Inform patients that the use of SEIZALAM more frequently than recommended, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2) and Drug Abuse and Dependence (9.2)].

Withdrawal Reactions

Inform patients that use of SEIZALAM more frequently than recommended may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of SEIZALAM may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.3)].

Concomitant Medications

Advise patients to inform their physician about any alcohol consumption and medicine they are now taking, especially blood pressure medication and antibiotics, including drugs they buy without a prescription. Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment [see Warnings and Precautions (5.6), Drug Interactions (7)].

Impaired Cognitive Function

Advise patients not to operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided [see Warnings and Precautions (5.7)].

Pregnancy

Advise pregnant females that the use of SEIZALAM late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)]. Instruct patients to inform their healthcare provider if they are pregnant. Encourage patients to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Counsel patients that midazolam, the active ingredient in SEIZALAM, is excreted in breast milk. Instruct patients to inform their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients who have been administered SEIZALAM to monitor infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs [see Use in Specific Populations (8.2)].

Manufactured by:
Hospira, Inc.
Lake Forest, IL 60045
A Pfizer Company

Distributed by:
Meridian Medical Technologies®, LLC
St. Louis, MO 63146
0002218