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

Incidence less than 1%

CARDIOVASCULAR: Bradycardia, arrhythmia

DIGESTIVE: Diarrhea, dry mouth

NERVOUS SYSTEM: Somnolence, depression, agitation, nervousness, tremor, confusion, withdrawal syndrome, myoclonus

RESPIRATORY: Pharyngitis

SKIN: Pruritus

UROGENITAL: Urinary retention

The incidence of adverse events was highest in patients who received more than the recommended dose of REVEX.

Laboratory findings

Transient increases in CPK were reported as adverse events in 0.5% of the postoperative patients studied. These increases were believed to be related to surgery and not believed to be related to the administration of REVEX. Increases in AST were reported as adverse events in 0.3% of the patients receiving either nalmefene or naloxone. The clinical significance of this finding is unknown. No cases of hepatitis or hepatic injury due to either nalmefene or naloxone were observed in the clinical trials.

DRUG ABUSE AND DEPENDENCE

REVEX is an opioid antagonist with no agonist activity. It has no demonstrated abuse potential, is not addictive, and is not a controlled substance.

OVERDOSAGE

Intravenous doses of up to 24 mg of nalmefene, administered to healthy volunteers in the absence of opioid agonists, produced no serious adverse reactions, severe signs or symptoms, or clinically significant laboratory abnormalities. As with all opioid antagonists, use in patients physically dependent on opioids can result in precipitated withdrawal reactions that may result in symptoms that require medical attention. Treatment of such cases should be symptomatic and supportive. Administration of large amounts of opioids to patients receiving opioid antagonists in an attempt to overcome a full blockade has resulted in adverse respiratory and circulatory reactions.

DOSAGE AND ADMINISTRATION

Important Information — Dosage Forms

REVEX is supplied in two concentrations that can be identified by their color coded container labels: a concentration suitable for postoperative use (100 µg/mL) in a blue labeled ampul containing ONE (1) mL and a concentration suitable for the management of overdose (1 mg/mL, 10 times as concentrated, 20 times as much drug) in a green labeled ampul containing TWO (2) mL. Proper steps should be taken to prevent use of the incorrect concentration.

General Principles

REVEX should be titrated to reverse the undesired effects of opioids. Once adequate reversal has been established, additional administration is not required and may actually be harmful due to unwanted reversal of analgesia or precipitated withdrawal.

Duration of Action

The duration of action of REVEX is as long as most opioid analgesics. The apparent duration of action of REVEX will vary, however, depending on the half-life and plasma concentration of the narcotic being reversed, the presence or absence of other drugs affecting the brain or muscles of respiration, and the dose of REVEX administered. Partially reversing doses of REVEX (1 µg/kg) lose their effect as the drug is redistributed through the body, and the effects of these low doses may not last more than 30-60 minutes in the presence of persistent opioid effects. Fully reversing doses (1 mg/70 kg) have been shown to last many hours in both experimental and clinical studies, but may complicate the management of patients who are in pain, at high cardiovascular risk, or who are physically dependent on opioids.

The recommended doses represent a compromise between a desirable controlled reversal and the need for prompt response and adequate duration of action. Using higher dosages or shorter intervals between incremental doses is likely to increase the incidence and severity of symptoms related to acute withdrawal such as nausea, vomiting, elevated blood pressure, and anxiety.

Patients Tolerant to or Physically Dependent on Opioids

REVEX may cause acute withdrawal symptoms in individuals who have some degree of tolerance to and dependence on opioids. These patients should be closely observed for symptoms of withdrawal following administration of the initial and subsequent injections of REVEX. Subsequent doses should be administered with intervals of at least 2-5 minutes between doses to allow the full effect of each incremental dose of REVEX to be reached.

Recommended Doses for Reversal of Postoperative Opioid Depression

Use 100µg/mL dosage strength (blue label) and see Table 2 for initial doses.

The goal of treatment with REVEX in the postoperative setting is to achieve reversal of excessive opioid effects without inducing a complete reversal and acute pain. This is best accomplished with an initial dose of 0.25 µg/kg followed by 0.25µg/kg incremental doses at 2-5 minute intervals, stopping as soon as the desired degree of opioid reversal is obtained. A cumulative total dose above 1.0 µg/kg does not provide additional therapeutic effect.

Table 2: Reversal of Postoperative Opioid Depression
Body Weight mL of REVEX 100µg/mL Solution
50 kg 0.125
60 kg 0.150
70 kg 0.175
80 kg 0.200
90 kg 0.225
100 kg 0.250

In cases where the patient is known to be at increased cardiovascular risk, it may be desirable to dilute REVEX 1:1 with saline or sterile water and use smaller initial and incremental doses of 0.1 µg/kg.

Management of Known or Suspected Opioid Overdose

Use 1.0 mg/mL dosage strength (green label).

The recommended initial dose of REVEX for non-opioid dependent patients is 0.5 mg/70 kg. If needed, this may be followed by a second dose of 1.0 mg/70 kg, 2-5 minutes later. If a total dose of 1.5 mg /70 kg has been administered without clinical response, additional REVEX (nalmefene hydrochloride injection) is unlikely to have an effect. Patients should not be given more REVEX than is required to restore the respiratory rate to normal, thus minimizing the likelihood of cardiovascular stress and precipitated withdrawal syndrome.

If there is a reasonable suspicion of opioid dependency, a challenge dose of REVEX 0.1 mg/70 kg should be administered initially. If there is no evidence of withdrawal in 2 minutes, the recommended dosing should be followed.

REVEX had no effect in cases where opioids were not responsible for sedation and hypoventilation. Therefore, patients should only be treated with REVEX when the likelihood of an opioid overdose is high, based on a history of opioid overdose or the clinical presentation of respiratory depression with concurrent pupillary constriction.

Repeated Dosing

REVEX is the longest acting of the currently available parenteral opioid antagonists. If recurrence of respiratory depression does occur, the dose should again be titrated to clinical effect using incremental doses to avoid over-reversal.

Hepatic and Renal Disease

Hepatic disease and renal failure substantially reduce the clearance of nalmefene (see Pharmacokinetics). For single episodes of opioid antagonism, adjustment of REVEX dosage is not required. However, in patients with renal failure, the incremental doses should be delivered slowly (over 60 seconds) to minimize the hypertension and dizziness reported following the abrupt administration of nalmefene to such patients.

Loss of Intravenous Access

Should intravenous access be lost or not readily obtainable, a pharmacokinetic study has shown that a single dose of REVEX should be effective within 5-15 minutes after intramuscular or subcutaneous doses of 1.0 mg. (See Pharmacokinetics.)

SAFETY AND HANDLING

REVEX is distributed in sealed ampuls which represent no known risk to health care workers. As with all parenterals, care should be taken to prevent the generation and inhalation of aerosols during preparation and use. Dermal absorption of spilled REVEX should be prevented by prompt removal of contaminated clothing and rinsing the skin thoroughly with cool water.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

REVEX (nalmefene hydrochloride injection) is available in the following presentations:

An ampul containing 1 mL of 100 µg/mL nalmefene base (Blue Label) Box of 10 (NDC 10019-315-21)

An ampul containing 2 mL of 1 mg/mL nalmefene base (Green Label) Box of 10 (NDC 10019-311-22)

Store at controlled room temperature.

REVEX is a registered trademark of Ivax Laboratories, Inc.

Baxter is a registered trademark of Baxter International Inc.

Manufactured for

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

by: Taylor Pharmaceuticals

Decatur, IL 62525

For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)

U.S. Patent No. 4,535,157

June 2006

REVEX
nalmefene hydrochloride injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:10019-311
Route of Administration INTRAVENOUS, INTRAMUSCULAR, SUBCUTANEOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
nalmefene hydrochloride (nalmefene) nalmefene 1 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
sodium chloride 9 mg in 1 mL
hydrochloric acid
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:10019-311-22 10 AMPULE (10 AMPULE) in 1 BOX contains a AMPULE (10019-311-39)
1 NDC:10019-311-39 2 mL (2 MILLILITER) in 1 AMPULE This package is contained within the BOX (10019-311-22)
REVEX
nalmefene hydrochloride injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:10019-315
Route of Administration INTRAVENOUS, INTRAMUSCULAR, SUBCUTANEOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
nalmefene hydrochloride (nalmefene) nalmefene 100 ug in 1 mL
Inactive Ingredients
Ingredient Name Strength
sodium chloride 9 mg in 1 mL
hydrochloric acid
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:10019-315-21 10 AMPULE (10 AMPULE) in 1 BOX contains a AMPULE (10019-315-39)
1 NDC:10019-315-39 1 mL (1 MILLILITER) in 1 AMPULE This package is contained within the BOX (10019-315-21)
Labeler — Baxter Healthcare Corporation

Revised: 06/2007 Baxter Healthcare Corporation

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