Revex: Package Insert and Label Information (Page 2 of 3)

INDICATIONS AND USAGE

REVEX is indicated for the complete or partial reversal of opioid drug effects, including respiratory depression, induced by either natural or synthetic opioids.

REVEX is indicated in the management of known or suspected opioid overdose.

CONTRAINDICATIONS

REVEX is contraindicated in patients with a known hypersensitivity to the product.

WARNINGS

Use of REVEX in Emergencies

REVEX, like all drugs in this class, is not the primary treatment for ventilatory failure. In most emergency settings, treatment with REVEX should follow, not precede, the establishment of a patent airway, ventilatory assistance, administration of oxygen, and establishment of circulatory access.

Risk of Recurrent Respiratory Depression

Accidental overdose with long acting opioids [such as methadone and levo-alpha-acetylmethadol (LAAM)] may result in prolonged respiratory depression. Respiratory depression in both the postoperative and overdose setting may be complex and involve the effects of anesthetic agents, neuromuscular blockers, and other drugs. While REVEX has a longer duration of action than naloxone in fully reversing doses, the physician should be aware that a recurrence of respiratory depression is possible, even after an apparently adequate initial response to REVEX treatment.

Patients treated with REVEX should be observed until, in the opinion of the physician, there is no reasonable risk of recurrent respiratory depression.

PRECAUTIONS

General

Cardiovascular Risks with Narcotic Antagonists

Pulmonary edema, cardiovascular instability, hypotension, hypertension, ventricular tachycardia, and ventricular fibrillation have been reported in connection with opioid reversal in both postoperative and emergency department settings. In many cases, these effects appear to be the result of abrupt reversal of opioid effects.

Although REVEX has been used safely in patients with pre-existing cardiac disease, all drugs of this class should be used with caution in patients at high cardiovascular risk or who have received potentially cardiotoxic drugs. (See DOSAGE AND ADMINISTRATION.)

Risk of Precipitated Withdrawal

REVEX, like other opioid antagonists, is known to produce acute withdrawal symptoms and, therefore, should be used with extreme caution in patients with known physical dependence on opioids or following surgery involving high doses of opioids. Imprudent use or excessive doses of opioid antagonists in the postoperative setting has been associated with hypertension, tachycardia, and excessive mortality in patients at high risk for cardiovascular complications. (See PRECAUTIONS.)

Incomplete Reversal of Buprenorphine

Preclinical studies have shown that nalmefene at doses up to 10 mg/kg (437 times the maximum recommended human dose) produced incomplete reversal of buprenorphine-induced analgesia in animal models. This appears to be a consequence of a high affinity and slow displacement of buprenorphine from the opioid receptors. Hence, REVEX may not completely reverse buprenorphine-induced respiratory depression.

Drug Interactions

REVEX has been administered after benzodiazepines, inhalational anesthetics, muscle relaxants, and muscle relaxant antagonists administered in conjunction with general anesthesia. It also has been administered in outpatient settings, both in trials in conscious sedation and in the emergency management of overdose following a wide variety of agents. No deleterious interactions have been observed.

Preclinical studies have shown that both flumazenil and nalmefene can induce seizures in animals. The coadministration of both flumazenil and nalmefene produced fewer seizures than expected in a study in rodents, based on the expected effects of each drug alone. Based on these data, an adverse interaction from the coadministration of the two drugs is not expected, but physicians should remain aware of the potential risk of seizures from agents in these classes.

Carcinogenesis and Mutagenesis and Impairment of Fertility

Nalmefene did not have mutagenic activity in the Ames test with five bacterial strains or the mouse lymphoma assay. Clastogenic activity was not observed in the mouse micronucleus test or in the cytogenic bone marrow assay in rats. However, nalmefene did exhibit a weak but significant clastogenic activity in the human lymphocyte metaphase assay in the absence but not in the presence of exogenous metabolic activation. Oral administration of nalmefene up to 1200 mg/m 2 /day did not affect fertility, reproductive performance, and offspring survival in rats.

Use in Pregnancy

Pregnancy Category B

Reproduction studies have been performed in rats (up to 1200 mg/m 2 /day) and rabbits (up to 2400 mg/m2 /day) by oral administration of nalmefene and in rabbits by intravenous administration up to 96 mg/m2 /day (114 times the human dose). There was no evidence of impaired fertility or harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Nalmefene and its metabolites were secreted into rat milk, reaching concentrations approximately three times those in plasma at one hour and decreasing to about half the corresponding plasma concentrations by 24 hours following bolus administration. As no clinical information is available, caution should be exercised when REVEX is administered to a nursing woman.

Use in Pediatric Patients

Safety and effectiveness of REVEX in pediatric patients have not been established.

Use in Neonates

The safety and effectiveness of REVEX in neonates have not been established in clinical studies. In a preclinical study, nalmefene was administered by subcutaneous injection to rat pups at doses up to 205 mg/m 2 /day throughout maternal lactation without producing adverse effects. A preclinical study evaluating the irritancy of the dosage form following arterial and venous administration in animals showed no vascular irritancy.

REVEX (nalmefene hydrochloride injection) should only be used in the resuscitation of the newborn when, in the opinion of the treating physician, the expected benefits outweigh the risks.

Geriatric Use

Clinical studies of REVEX (nalmefene hydrochloride injection) did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

Adverse event information was obtained following administration of REVEX to 152 normal volunteers and in controlled clinical trials to 1127 patients for the treatment of opioid overdose or for postoperative opioid reversal.

Nalmefene was well tolerated and showed no serious toxicity during experimental administration to healthy individuals, even when given at 15 times the highest recommended dose. In a small number of subjects, at doses exceeding the recommended REVEX dose, nalmefene produced symptoms suggestive of reversal of endogenous opioids, such as have been reported for other narcotic antagonist drugs. These symptoms (nausea, chills, myalgia, dysphoria, abdominal cramps, and joint pain) were usually transient and occurred at very low frequency.

Such symptoms of precipitated opioid withdrawal at the recommended clinical doses were seen in both postoperative and overdose patients who were later found to have had histories of covert opioid use. Symptoms of precipitated withdrawal were similar to those seen with other opioid antagonists, were transient following the lower doses used in the postoperative setting, and more prolonged following the administration of the larger doses used in the treatment of overdose.

Tachycardia and nausea following the use of nalmefene in the postoperative setting were reported at the same frequencies as for naloxone at equivalent doses. The risk of both these adverse events was low at doses giving partial opioid reversal and increased with increases in dose. Thus, total doses larger than 1.0 µg/kg in the postoperative setting and 1.5 mg/70 kg in the treatment of overdose are not recommended.

Relative Frequencies of Common Adverse Reactions With an Incidence Greater than 1%
(all patients, all clinical settings)
Adverse Event Nalmefene Naloxone Placebo
N=1127 N=369 N=77
Nausea 18% 18% 6%
Vomiting 9% 7% 4%
Tachycardia 5% 8%
Hypertension 5% 7%
Postoperative pain 4% 4% N/A
Fever 3% 4%
Dizziness 3% 4% 1%
Headache 1% 1% 4%
Chills 1% 1%
Hypotension 1% 1%
Vasodilatation 1% 1%

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