ubjects with moderate renal impairment in clinical studies for populationpharmacokinetic analysis. Patients with moderate and severe renal impairment may haveslower elimination of midazolam and its metabolites, which may result in prolonged drugexposure [see Clinical Pharmacology (12.3)].
8.7 Congestive Heart Failure
Patients with congestive heart failure eliminate midazolam more slowly, which may result inprolonged drug exposure [see Clinical Pharmacology (12.3)].
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
NAYZILAM contains the benzodiazepine midazolam, a Schedule IV controlled substanceunder the Controlled Substances Act.
9.2 Abuse
Benzodiazepines, such as midazolam, may be subject to abuse. Abuse is the intentional nontherapeuticuse of a drug, even once, to achieve a desired psychological or physiologicaleffect. Available data concerning the drug abuse and dependence potential of midazolamsuggest that its abuse potential is at least equivalent to that of diazepam.
The pharmacological profile of NAYZILAM is similar to that of other benzodiazepines listedin Schedule IV of the Controlled Substance Act, particularly in its potentiation ofGABAergic transmission through its action on GABAA receptors, which leads to sedationand somnolence.
Midazolam was actively self-administered in primate models used to assess the positivereinforcing effects of psychoactive drugs. Midazolam produced physical dependence of a mild tomoderate intensity in cynomolgus monkeys after 5 to 10 weeks of administration.
Assessment of the abuse-related subjective effects comparing NAYZILAM to oralmidazolam syrup was conducted in adult subjects with a history of benzodiazepine
recreational drug use. No statistically significant or clinically-relevant differences insubjective positive effects (i.e., Drug Liking, Overall Drug Liking, Take Drug Again, andHigh) were observed between NAYZILAM and oral midazolam syrup. However, subjectivepositive effects on all these measures were significantly greater for NAYZILAM than forplacebo confirming that NAYZILAM has abuse potential. Somnolence occurred at a similarrate in both midazolam groups, but euphoric mood occurred at a greater rate in NAYZILAM(4 to 16%) compared to the oral midazolam syrup (4 to 8.5%).
9.3 Dependence
Physical dependence is a state of adaptation that is manifested by a specific withdrawal
syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood
levels of the drug, and/or administration of an antagonist.
Benzodiazepines can cause physical dependence. Physical dependence results in withdrawal
symptoms in patients who abruptly discontinue the drug. Withdrawal symptoms (i.e.,
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.
9.4 Chronic Use
NAYZILAM is not recommended for chronic, daily use as an anticonvulsant because of thepotential for development of tolerance to midazolam. In clinical trials, patients were treatedwith NAYZILAM no more frequently than every 3 days.
Chronic daily use of benzodiazepines may increase the frequency and/or severity of tonicclonicseizures, requiring an increase in the dosage of standard anticonvulsant medication. Insuch cases, abrupt withdrawal of c |
