Revex

Contraindications

• Known hypersensitivity to nalmefene or any ingredient in the formulation.a

Warnings/Precautions

Warnings

When used in emergency settings, other resuscitative measures (e.g., maintenance of an adequate airway, artificial respiration, administration of oxygen, vasopressor agents) should be readily available and used first when necessary.a

Risk of recurrent respiratory depression in postoperative and overdose patients after initial response to nalmefene.a

Carefully monitor patients who have responded to nalmefene since the duration of action of some opiates (e.g., methadone and levo-alpha-acetylmethadol [LAAM]) may exceed that of nalmefene; monitor patients until there is no reasonable risk of recurrent respiratory depression.a

General Precautions

Serious adverse cardiovascular effects (e.g., VT and VF, pulmonary edema, hypertension, hypotension, cardiovascular instability) reported in postoperative patients and in emergency department settings following administration of nalmefene; may be associated with excessive doses.a

Use with caution in patients with preexisting cardiovascular disease or in those receiving potentially cardiotoxic drugs.a Reduced dosage recommended in postoperative patients at high risk for cardiovascular complications.a (See Adults under Dosage and Administration.)

Possible precipitation of acute withdrawal symptoms.a Use with extreme caution in patients with known physical dependence on opiates or following surgery involving high doses of opiates.a

Observe patients suspected of opiate dependency for symptoms of withdrawal following initial and subsequent nalmefene injections.a

Incomplete reversal of buprenorphine-induced analgesia reported in animal models; therefore, nalmefene may not completely reverse buprenorphine-induced respiratory depression.a

Possible risk of seizures.a

Specific Populations

Category B.a

Distributed into milk in rats; not known whether distributed into human milk.a Use caution.a

Safety and efficacy not established in children <18 years of age.1 a

Safety and efficacy not established in neonates, however, nalmefene may be used in the resuscitation of neonates when benefits outweigh the risks.a

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.a (See Special Populations under Pharmacokinetics.)

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.a

Decreased clearance; however, dosage adjustments not recommended because nalmefene is administered as an acute course of therapy.a

Decreased clearance; administer dosages slowly to minimize adverse effects.a (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea, vomiting, tachycardia, hypertension.a

Storage

Parenteral

15–30 ºC.a

Revex (nalmefene hydrochloride injection), an opioid antagonist, is a 6-methylene analogue of naltrexone. The chemical structure is shown below:

Molecular Formula: C 21H25NO3•HCl

Molecular Weight: 375.9, CAS # 58895-64-0

Chemical Name: 17-(Cyclopropylmethyl)-4,5α-epoxy-6-methylenemorphinan-3,14-diol, hydrochloride salt.

Nalmefene hydrochloride is a white to off-white crystalline powder which is freely soluble in water up to 130 mg/mL and slightly soluble in chloroform up to 0.13 mg/mL, with a pK a of 7.6.

Revex is available as a sterile solution for intravenous, intramuscular, and subcutaneous administration in two concentrations, containing 100 µg or 1.0 mg of nalmefene free base per mL. The 100 µg/mL concentration contains 110.8 µg of nalmefene hydrochloride and the 1.0 mg/mL concentration contains 1.108 mg of nalmefene hydrochloride per mL. Both concentrations contain 9.0 mg of sodium chloride per mL and the pH is adjusted to 3.9 with hydrochloric acid.

Concentrations and dosages of Revex are expressed as the free base equivalent of nalmefene.

Revex has been administered to reverse the effects of opioids after general anesthesia and in the treatment of overdose. It has also been used to reverse the systemic effects of intrathecal opioids.

Reversal of Postoperative Opioid Depression

Revex (nalmefene hydrochloride injection) (N=326) was studied in 5 controlled trials in patients who had received morphine or fentanyl intraoperatively. The primary efficacy criterion was the reversal of respiratory depression. A positive reversal was defined as both an increase in respiratory rate by 5 breaths per minute and a minimum respiratory rate of 12 breaths per minute. Five minutes after administration, initial single Revex doses of 0.1, 0.25, 0.5, or 1.0 µg/kg had effectively reversed respiratory depression in a dose-dependent manner. Twenty minutes after initial administration, respiratory depression had been effectively reversed in most patients receiving cumulative doses within the recommended range (0.1 to 1.0 µg/kg). Total doses of Revex above 1.0 µg/kg did not increase the therapeutic response. The postoperative administration of Revex at the recommended doses did not prevent the analgesic response to subsequently administered opioids.

Reversal of the Effect of Intrathecally Administered Opioids

Intravenous Revex at doses of 0.5 and 1.0 µg/kg was administered to 47 patients given intrathecal morphine. One to 2 doses of 0.5 and 1.0 µg/kg Revex reversed respiratory depression in most patients. The administration of Revex at the recommended doses did not prevent the analgesic response to subsequently administered opioids.

Management of Known or Suspected Opioid Overdose

Revex (N=284) at doses of 0.5 mg to 2.0 mg was studied in 4 trials of patients who were presumed to have taken an opioid overdose. Revex doses of 0.5 mg to 1.0 mg effectively reversed respiratory depression within 2 to 5 minutes in most patients subsequently confirmed to have opioid overdose. A total dose greater than 1.5 mg did not increase the therapeutic response.

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

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.

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.

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.

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.

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.

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.)