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名称： 盐酸纳美芬
英文名：Nalmefene
别名：Nalmefene Hydrochloride、Revex
类别：西医药物
药理作用：本品为含亚甲基结构的纳曲酮类似物，是一种长效阿片受体拮抗剂，与阿片受体激动剂竞争中枢神经系统的μ、δ和κ受体的作用点，作用较纳洛酮时间长，纳曲酮作用时间虽然长，但只有口服制剂，本品本身无受体激动作用，在不存在阿片受体激动剂的情况下，无药理活性。动物试验中，本品可改善脑和脊髓局部缺血所致的神经障碍。
动力学：本品静注2分钟即可产生阿片受体拮抗作用，5分钟之内达到高峰。 本品广泛分布于组织中，在肝脏与葡糖苷酸共轭缓慢代谢为非活性物质，然后经尿排泄(约65％)，尿中以原形药物排出量不足5％。 半衰期约11小时，比纳洛酮(1～2小时)长得多，其作用持续时间比多数阿片受体激动剂(除美沙酮、右丙氧芬)长。
适应症：本品可用于手术后逆转阿片药物的作用，包括呼吸抑制、镇静和低血压。在急诊科还用于阿片药物过量或疑有过量的救治。
用法用量：本品通常为静注，亦可肌注或皮下注射，由于后两种用药方式的吸收速度有所不同，多次用药时应加以注意。 (1)纠正术后阿片抑制：其目的是纠正过量阿片药物的作用而并不希望完全逆转或引起剧痛，应使用低浓度(100mcg／ml)的制剂。初始剂量为0.25mcg／kg，以2～5分钟的间隔按0.25mcg/kg逐渐增加剂量，至达到满意的效果即停药，累积总剂量不宜超过1mcg／kg。 (2)治疗阿片药物过量：应使用高浓度(1mg/ml)制剂。对非阿片依赖者，初始剂量为0.5mg／70kg，如需要，2～5分钟后可再次给予1mg／70kg，如果总剂量达1.5mg/70kg仍未见效，再增大剂量也不会有效。 对疑有阿片依赖者，可先给予0.1mg／70kg。并观察2分钟，如无戒断症状发生，则可按上述剂量用药。 如果经初次治疗见效后又复发呼吸抑制，应调整剂量。 对阿片药物具有依赖性或术后使用大剂量阿片类镇痛剂者，在使用本品时，可能出现急性戒断症状，如恶心、寒战、肌痛、发音困难、腹肌紧张、关节疼痛等，需特别注意。 肝、肾功能障碍可显著降低本品的清除率，如果是单次治疗，无需调整剂量。对肾功能障碍者，剂量的增加应缓慢进行，以减少不良反应。
不良反应：本品耐受性好，即使给予最大剂量的15倍，也未见严重不良反应。常见不良反应为恶心(18％)、呕吐(9％)、高血压(5％)、心动过速(5％)。
禁忌：孕妇慎用；儿童用药的有效性和安全性尚未确立。
制剂：注射剂：含本品1mg/ml(1ml安瓿)，1mg／ml(2ml安瓿装)。
Revex
(nalmefene hydrochloride) Injection
DRUG DESCRIPTION
REVEX (nalmefene hydrochloride injection), an opioid antagonist, is a 6-methylene analogue of naltrexone.
Molecular Formula: C21H25NO3· HCl
Molecular Weight: 375.9, CAS # 58895-64-0
Chemical Name: 17-(Cyclopropylmethyl)-4,5 -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 pKa of 7.6.
REVEX is available as a sterile solution for intravenous, intramuscular, and subcutaneous administration in two concentrations, containing 100 mg or 1.0 mg of nalmefene free base per mL. The 100 mg/mL concentration contains 110.8 mg 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.
INDICATIONS
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.
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 mg/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 mg/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.
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 mg/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.
SIDE EFFECTS
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 mg/kg in the postoperative setting and 1.5 mg/70 kg in the treatment of overdose are not recommended.
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.
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.
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.
Carcinogenesis, Mutagenesis, 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/m2/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/m2/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/m2/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 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.
OVERDOSE
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.
CONTRAINDICATIONS
REVEX is contraindicated in patients with a known hypersensitivity to the product. | 
