Romazicon

Flumazenil reverses the effects of benzodiazepine (BENZ-oh-dye-AYZ-e-peen) sedatives such as Valium, Versed, Xanax, Tranxene, and others. Benzodiazepines are sometimes used as sedatives before surgery or other medical procedures.

Flumazenil is used to reverse benzodiazepine sedation to help you wake up after your medical procedure. Flumazenil is also used to treat benzodiazepine overdose in adults.

Flumazenil may also be used for purposes not listed in this medication guide.

Flumazenil may cause seizures (convulsions), especially in people who have sedative-addiction withdrawal symptoms or recent antidepressant overdose, people who have recently received injectable benzodiazepines, or people who had symptoms of a seizure just before receiving flumazenil. Talk to your doctor if you have concerns about the risk of seizure.

Flumazenil may cause seizures (convulsions), especially:

• in people withdrawing from sedative addiction;
• in people who have recently taken an antidepressant overdose;
• in people who have recently received injectable benzodiazepines; or
• in people who had seizure-like symptoms just before receiving flumazenil.

Talk to your doctor if you have concerns about the risk of seizure.

You should not receive this medication if you are allergic to flumazenil or any type of benzodiazepine sedative, or if you have taken an overdose of certain antidepressant medication.

To make sure flumazenil is safe for you, tell your doctor if you have:

• epilepsy or other seizure disorder (especially if you take a benzodiazepine to treat seizures);
• a history of head injury;
• any type of breathing problem or lung disease;
• liver disease;
• panic or anxiety disorder;
• a history of alcoholism or drug addiction; or
• if you have been using benzodiazepine long-term.

FDA pregnancy category C. It is not known whether flumazenil will harm an unborn baby. Tell your doctor if you are pregnant.

It is not known whether flumazenil passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

5 mL multiple-use vials containing 0.1 mg/ mL flumazenil - boxes of 10

10 mL multiple-use vials containing 0.1 mg/mL flumazenil - boxes of 10

Storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

Manufactured by: Hikma Farmacêutica (Portugal), S.A.., Estrada do Rio da Mó, n° 8, 8A e 8B - Fervença, 2705 – 906 Terrugem SNT Portugal. Distributed by: West-Ward Pharmaceutical Corp., Eatontown NJ 07724 USA. Revised: Aug 2010

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Romazicon crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the medication. Your doctor and you will decide if the benefits outweigh the risk of using Romazicon.

Flumazenil reverses the effects of benzodiazepine (BENZ-oh-dye-AYZ-e-peen) sedatives such as Valium, Versed, Xanax, Tranxene, and others. Benzodiazepines are sometimes used as sedatives before surgery or other medical procedures.

Flumazenil is used to reverse benzodiazepine sedation to help you wake up after your medical procedure. Flumazenil is also used to treat benzodiazepine overdose in adults.

Flumazenil may also be used for purposes not listed in this medication guide.

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

• Antagonizes CNS effects (e.g., sedation, impaired recall, psychomotor impairment, respiratory depression) of benzodiazepines by competitively inhibiting the activity of the drugs at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex.1

• Does not antagonize the CNS effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (e.g., barbiturates, alcohol, general anesthetics) and does not reverse the effects of opioids.1

Romazicon® (flumazenil) is a benzodiazepine receptor antagonist. Chemically, flumazenil is ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a](1,4) benzodiazepine-3-carboxylate. Flumazenil has an imidazobenzodiazepine structure, a calculated molecular weight of 303.3, and the following structural formula:

Flumazenil is a white to off-white crystalline compound with an octanol:buffer partition coefficient of 14 to 1 at pH 7.4. It is insoluble in water but slightly soluble in acidic aqueous solutions. Romazicon is available as a sterile parenteral dosage form for intravenous administration. Each mL contains 0.1 mg of flumazenil compounded with 1.8 mg of methylparaben, 0.2 mg of propylparaben, 0.9% sodium chloride, 0.01% edetate disodium, and 0.01% acetic acid; the pH is adjusted to approximately 4 with hydrochloric acid and/or, if necessary, sodium hydroxide.

General Principles

The serious adverse effects of Romazicon are related to the reversal of benzodiazepine effects. Using more than the minimally effective dose of Romazicon is tolerated by most patients but may complicate the management of patients who are physically dependent on benzodiazepines or patients who are depending on benzodiazepines for therapeutic effect (such as suppression of seizures in cyclic antidepressant overdose).

In high-risk patients, it is important to administer the smallest amount of Romazicon that is effective. The 1-minute wait between individual doses in the dose-titration recommended for general clinical populations may be too short for high-risk patients. This is because it takes 6 to 10 minutes for any single dose of flumazenil to reach full effects. Practitioners should slow the rate of administration of Romazicon administered to high-risk patients as recommended below.

Anesthesia and Conscious Sedation in Adult Patients

Romazicon is well tolerated at the recommended doses in individuals who have no tolerance to (or dependence on) benzodiazepines. The recommended doses and titration rates in anesthesia and conscious sedation (0.2 mg to 1 mg given at 0.2 mg/min) are well tolerated in patients receiving the drug for reversal of a single benzodiazepine exposure in most clinical settings (see ADVERSE REACTIONS). The major risk will be resedation because the duration of effect of a long-acting (or large dose of a short-acting) benzodiazepine may exceed that of Romazicon. Resedation may be treated by giving a repeat dose at no less than 20-minute intervals. For repeat treatment, no more than 1 mg (at 0.2 mg/min doses) should be given at any one time and no more than 3 mg should be given in any one hour.

Benzodiazepine Overdose in Adult Patients

The risk of confusion, agitation, emotional lability, and perceptual distortion with the doses recommended in patients with benzodiazepine overdose (3 mg to 5 mg administered as 0.5 mg/min) may be greater than that expected with lower doses and slower administration. The recommended doses represent a compromise between a desirable slow awakening and the need for prompt response and a persistent effect in the overdose situation. If circumstances permit, the physician may elect to use the 0.2 mg/minute titration rate to slowly awaken the patient over 5 to 10 minutes, which may help to reduce signs and symptoms on emergence.

Romazicon has no effect in cases where benzodiazepines are not responsible for sedation. Once doses of 3 mg to 5 mg have been reached without clinical response, additional Romazicon is likely to have no effect.

Patients Tolerant to Benzodiazepines

Romazicon may cause benzodiazepine withdrawal symptoms in individuals who have been taking benzodiazepines long enough to have some degree of tolerance. Patients who had been taking benzodiazepines prior to entry into the Romazicon trials, who were given flumazenil in doses over 1 mg, experienced withdrawal-like events 2 to 5 times more frequently than patients who received less than 1 mg.

In patients who may have tolerance to benzodiazepines, as indicated by clinical history or by the need for larger than usual doses of benzodiazepines, slower titration rates of 0.1 mg/min and lower total doses may help reduce the frequency of emergent confusion and agitation. In such cases, special care must be taken to monitor the patients for resedation because of the lower doses of Romazicon used.

Patients Physically Dependent on Benzodiazepines

Romazicon is known to precipitate withdrawal seizures in patients who are physically dependent on benzodiazepines, even if such dependence was established in a relatively few days of high-dose sedation in Intensive Care Unit (ICU) environments. The risk of either seizures or resedation in such cases is high and patients have experienced seizures before regaining consciousness. Romazicon should be used in such settings with extreme caution, since the use of flumazenil in this situation has not been studied and no information as to dose and rate of titration is available. Romazicon should be used in such patients only if the potential benefits of using the drug outweigh the risks of precipitated seizures. Physicians are directed to the scientific literature for the most current information in this area.

Adult Patients

Romazicon is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in cases where general anesthesia has been induced and/or maintained with benzodiazepines, where sedation has been produced with benzodiazepines for diagnostic and therapeutic procedures, and for the management of benzodiazepine overdose.

Pediatric Patients (aged 1 to 17)

Romazicon is indicated for the reversal of conscious sedation induced with benzodiazepines (see PRECAUTIONS: Pediatric Use).

THE USE OF Romazicon HAS BEEN ASSOCIATED WITH THE OCCURRENCE OF SEIZURES.

THESE ARE MOST FREQUENT IN PATIENTS WHO HAVE BEEN ON BENZODIAZEPINES FOR LONG-TERM SEDATION OR IN OVERDOSE CASES WHERE PATIENTS ARE SHOWING SIGNS OF SERIOUS CYCLIC ANTIDEPRESSANT OVERDOSE.

PRACTITIONERS SHOULD INDIVIDUALIZE THE DOSAGE OF Romazicon AND BE PREPARED TO MANAGE SEIZURES.

Risk of Seizures

The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations. Possible risk factors for seizures include: concurrent major sedative-hypnotic drug withdrawal, recent therapy with repeated doses of parenteral benzodiazepines, myoclonic jerking or seizure activity prior to flumazenil administration in overdose cases, or concurrent cyclic antidepressant poisoning.

Romazicon is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases Romazicon should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with Romazicon has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.

Most convulsions associated with flumazenil administration require treatment and have been successfully managed with benzodiazepines, phenytoin or barbiturates. Because of the presence of flumazenil, higher than usual doses of benzodiazepines may be required.

Hypoventilation

Patients who have received Romazicon for the reversal of benzodiazepine effects (after conscious sedation or general anesthesia) should be monitored for resedation, respiratory depression, or other residual benzodiazepine effects for an appropriate period (up to 120 minutes) based on the dose and duration of effect of the benzodiazepine employed.

This is because Romazicon has not been established in patients as an effective treatment for hypoventilation due to benzodiazepine administration. In healthy male volunteers, Romazicon is capable of reversing benzodiazepine-induced depression of the ventilatory responses to hypercapnia and hypoxia after a benzodiazepine alone. However, such depression may recur because the ventilatory effects of typical doses of Romazicon (1 mg or less) may wear off before the effects of many benzodiazepines. The effects of Romazicon on ventilatory response following sedation with a benzodiazepine in combination with an opioid are inconsistent and have not been adequately studied. The availability of flumazenil does not diminish the need for prompt detection of hypoventilation and the ability to effectively intervene by establishing an airway and assisting ventilation.

Overdose cases should always be monitored for resedation until the patients are stable and resedation is unlikely.