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OPIOID ANTAGONISTS, LONG ACTING

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) These drugs are long-acting opioid antagonists, with no opioid agonist properties. Opioid antagonists are those drugs that bind but do not activate opioid receptor sites. They are similar in structure to naloxone.

Specific Substances

    A) GENERAL TERMS
    1) Long acting opioid antagonists
    METHYLNALTREXONE (synonym)
    1) N-methylnaltrexone bromide
    NALMEFENE HYDROCHLORIDE (synonym)
    1) JF-1
    2) Nalmetrene
    3) ORF-11676
    4) Molecular Formula C21-H25-N-03
    5) CAS 55096-26-9
    NALMEXONE HYDROCHLORIDE (synonym)
    1) CAS 16676-27-0 (nalmexone hydrochloride)
    2) CAS 16676-26-9 (nalmexone) (synonym)
    NALTREXONE HYDROCHLORIDE (synonym)
    1) Celupan
    2) N-cyclopropylmethyl-14-hydroxydihydromorphinone
    3) Trexan
    4) UM-792
    5) Molecular Formula C20-H23-N-O4
    6) CAS 16590-41-3 (Naltrexone) (synonym)
    7) CAS 16676-29-2 (Naltrexone Hydrochloride)

Available Forms Sources

    A) FORMS
    1) METHYLNALTREXONE
    a) SUBCUTANEOUS INJECTION: Available in single use vial of 12 mg/0.6 mL solution for subcutaneous injection (Prod Info RELISTOR(R) subcutaneous injection, 2010).
    2) NALMEFENE
    a) PARENTERAL: In the United States, nalmefene was available in an ampule containing 1 mL of 100 mcg/mL or a 2 mL ampule containing 1 mg/mL for injection (Prod Info REVEX(R) injection, 2006).
    3) NALTREXONE
    a) ORAL: 50 mg, beige, round biconvex, film-coated, scored tablet (Prod Info naltrexone hydrochloride oral tablets, 2009).
    b) PARENTERAL: Naltrexone for extended-release injectable suspension is supplied in single use cartons. Each carton contains a 380 mg vial, one vial containing 4 mL (to deliver 3.4 mL) (Prod Info VIVITROL(R) extended-release injectable suspension, 2010).
    B) USES
    1) SUMMARY
    a) NALTREXONE: It is used for the treatment of alcohol dependence in patients who are able to abstain from alcohol. Patients should not be actively drinking at the time of drug administration and should be part of a comprehensive alcohol treatment program (Prod Info VIVITROL(R) extended-release injectable suspension, 2010).
    b) NALMEFENE: It is indicated for the complete or partial reversal of opioid drug effects, including respiratory depression caused by natural or synthetic opioids. It is also indicated in the management of known or suspected opioid overdose (Prod Info REVEX(R) injection, 2006).
    c) METHYLNALTREXONE: It is used for the treatment of opioid-induced constipation. It is only indicated for patient's with advanced disease who are receiving palliative care and have failed other laxative therapy; treatment is not indicated beyond 4 months (Prod Info RELISTOR(R) subcutaneous injection, 2010).
    2) ILLICIT MISUSE
    a) NALTREXONE tablets have been sold illicitly on the street with claims of being heroin. Heroin abusers have crushed and intravenously injected these tablets, with resulting opioid withdrawal signs/symptoms (Bristow et al, 2001).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Long acting opioid antagonists (methylnaltrexone, nalmefene, and naltrexone) blunt or reverse the effects of opioid medications. Their indications include reversal of life-threatening respiratory depression secondary to stimulation of opioid receptors (nalmefene), treatment of alcohol dependence (naltrexone), and reversal of opioid-induced constipation (methylnaltrexone). Naltrexone is also used to treat chronic opioid dependence once detoxification is complete. Nalmefene hydrochloride injection was discontinued from the market in 2008.
    B) PHARMACOLOGY: Long acting opioid antagonists compete and displace narcotics at opioid receptor sites.
    C) TOXICOLOGY: Secondary to its antagonists effects at opioid receptors, these drugs may precipitate acute withdrawal symptoms in opioid-dependent patients.
    D) EPIDEMIOLOGY: Naltrexone is used commonly in patients with ethanol or opioid dependence to help prevent relapse. Nalmefene and methylnaltrexone are less widely used for their specific indications. Overdose with these agents is rare.
    E) WITH THERAPEUTIC USE
    1) Adverse reactions to long acting opioid antagonists relate to their antagonistic effects to narcotics and the resulting withdrawal symptoms. They may include pain, hypertension, diaphoresis, and agitation. In neonate, withdrawal symptoms may manifest with crying and poor feeding efforts. Pulmonary edema and dysrhythmias, including ventricular fibrillation, have been reported in association with the use of opioid antagonists to reverse narcotic effects, but it is unclear whether these complications were the result of their use. Other reported adverse effects include dose-related hepatotoxicity, eosinophilic pneumonia, injection site reactions, depression or suicidal ideation, nausea, vomiting, diarrhea, abdominal pain, hypotension, somnolence, headache, dizziness, restlessness, tremor, anxiety, miosis, joint and muscle pain, and rhabdomyolysis.
    F) WITH POISONING/EXPOSURE
    1) Limited data available. High doses have caused tremor, hypotension, tachycardia, dizziness, insomnia, fatigue, and agitation. High doses will precipitate opioid withdrawal in opioid-dependent patients.
    0.2.3) VITAL SIGNS
    A) Fever may occur.
    0.2.20) REPRODUCTIVE
    A) Nalmefene has been classified as FDA pregnancy category B. Methylnaltrexone, naltrexone and morphine/naltrexone have been classified as FDA pregnancy category C. The combination product bupropion hydrochloride/naltrexone hydrochloride has been classified as FDA pregnancy category X. In animal studies, there is evidence of early fetal loss with oral naltrexone exposure. Studies in rats have shown methylnaltrexone and nalmefene (and its metabolites) to be secreted into rat milk. Naltrexone and its metabolite have been shown to be secreted into human breast milk.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturers do not report any carcinogenic potential of methylnaltrexone, nalmefene, or naltrexone in humans.

Laboratory Monitoring

    A) No laboratory studies are need unless otherwise clinically indicated.
    B) Serum concentrations of these drugs are not widely available or clinically useful in guiding management.
    C) Patients who receive these agents to reverse opioid toxicity should be monitored for CNS and respiratory depression and evidence of opioid withdrawal.
    D) Monitor vital signs, mental status, CK, and liver enzymes in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) For mild to moderate toxicity, supportive care is the mainstay of treatment. This may include benzodiazepines to treat agitation and antiemetics to treat nausea and vomiting. In addition, medical providers have used clonidine to treat opioid withdrawal symptoms and dicyclomine to treat diarrhea. Manage mild hypotension with IV fluids. If hypertension develops secondary to withdrawal and agitation, benzodiazepines may be useful.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) For severe toxicity, the mainstay of treatment is supportive care. If patients develop pulmonary distress, endotracheal intubation may be required. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension with IV fluids, dopamine, or norepinephrine. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not indicated as toxicity is self-limited.
    2) HOSPITAL: Gastrointestinal decontamination is generally not indicated unless more toxic co-ingestants are involved.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with pulmonary distress.
    E) ANTIDOTE
    1) None.
    F) VENTRICULAR DYSRHYTHMIAS
    1) Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Unstable rhythms require immediate cardioversion.
    G) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is UNLIKELY to be of value because of the large volume of distribution of these agents.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Long acting opioid antagonist exposures in general should be very safe and asymptomatic patients with inadvertent exposure may remain at home. However, if it was used to reverse opioid toxicity, the patient should be brought into a healthcare facility for further evaluation or if the patients are symptomatic.
    2) OBSERVATION CRITERIA: Symptomatic patients, those with deliberate overdose, and patients in whom these drugs were used to reverse opioid toxicity should be referred to a healthcare facility. Criteria for discharge include a patient who is asymptomatic or clearly improving after an observation period of 4 to 6 hours without treatment.
    3) ADMISSION CRITERIA: Patients who have persistent symptoms or any evidence of pulmonary edema should be admitted.
    4) CONSULT CRITERIA: If there are any concerns, a toxicologist or a poison center can be consulted for advice regarding the use of long acting opioid antagonists.
    I) PITFALLS
    1) In using long acting opioid antagonists, one should carefully titrate doses to prevent precipitating acute opioid withdrawal in patients. Naltrexone should not be given to patients until a patient is opioid free for 7 to 10 days, and if there is a high index of suspicion that a patient may not be opioid free, a naloxone challenge test can be used first.
    J) PHARMACOKINETICS
    1) Onset of action depends on the mode of delivery. The quickest onset of action is via intravenous delivery, followed by oral administration, and intramuscular administration. NALTREXONE: Naltrexone's duration of action is dose-dependent. Intramuscular injections may have effect for 4 weeks. Every 50 mg of naltrexone accumulates another 24 hours of duration (eg, 50 mg naltrexone has 24 hours of effect, 100 mg naltrexone has 48 hours of effect). Rapidly absorbed orally, 5% to 40% bioavailable. Vd: 3 L/kg; protein binding: 21%. Extensive hepatic metabolism with renal excretion of metabolites. Half-life 4 hours for naltrexone and 13 hours for 6-B-naltrexol (active metabolite). METHYLNALTREXONE: Rapid absorption after subcutaneous administration. Vd: 1.1 L/kg; protein binding: 10% to 15%. Some hepatic metabolism; 50% renal elimination primarily as unchanged drug. Half-life: 8 hours. Extended release powder for intramuscular injection: Peak plasma concentrations occur after 2 hours, then a second peak occurs 2 to 3 days later. Elimination half life is 5 to 10 days.
    K) PREDISPOSING CONDITIONS
    1) Patients with a history of opioid dependence have a much higher likelihood of experiencing opioid withdrawal symptoms upon receiving opioid antagonists. In heroin-using asthmatic patients, opioid antagonists may lead to worsening asthma symptoms or respiratory failure. Patients with preexisting cardiac disease or who have received cardiotoxic drugs may be at higher risk of complications such as hypotension, hypertension , dysrhythmias, and pulmonary edema. Naltrexone should be used with caution in patients with severe hepatic impairment and it's use is contraindicated in patients with acute hepatitis or hepatic failure.
    L) DIFFERENTIAL DIAGNOSIS
    1) The use of other opioid antagonists such as naloxone would look similar to long acting opioid antagonists use but the duration of effect would be much shorter.
    0.4.6) PARENTERAL EXPOSURE
    A) Refer to ORAL OVERVIEW for specific treatment information.

Range Of Toxicity

    A) TOXICITY: There are no specific known toxic doses associated with long acting opioid antagonists. Adverse effects have been reported following a wide range of doses though large doses (eg, naltrexone 800 mg daily for one week) have been tolerated without ill effects.
    B) THERAPEUTIC EFFECTS: NALTREXONE: IM: 380 mg IM every 4 weeks (or once a month). ORAL: 25 to 50 mg once daily. METHYLNALTREXONE: Weight less than 38 kg (less than 84 pounds): 0.15 mg/kg subQ every other day. Weight 38 to less than 62 kg (84 to less than 136 pounds): 8 mg subQ every other day. Weight 62 to 114 kg (136 to 251 pounds): 12 mg subQ every other day. Weight greater than 114 kg (greater than 251 pounds): 0.15 mg/kg subQ every other day. CHILDREN: The safety and efficacy of methylnaltrexone and naltrexone have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Long acting opioid antagonists (methylnaltrexone, nalmefene, and naltrexone) blunt or reverse the effects of opioid medications. Their indications include reversal of life-threatening respiratory depression secondary to stimulation of opioid receptors (nalmefene), treatment of alcohol dependence (naltrexone), and reversal of opioid-induced constipation (methylnaltrexone). Naltrexone is also used to treat chronic opioid dependence once detoxification is complete. Nalmefene hydrochloride injection was discontinued from the market in 2008.
    B) PHARMACOLOGY: Long acting opioid antagonists compete and displace narcotics at opioid receptor sites.
    C) TOXICOLOGY: Secondary to its antagonists effects at opioid receptors, these drugs may precipitate acute withdrawal symptoms in opioid-dependent patients.
    D) EPIDEMIOLOGY: Naltrexone is used commonly in patients with ethanol or opioid dependence to help prevent relapse. Nalmefene and methylnaltrexone are less widely used for their specific indications. Overdose with these agents is rare.
    E) WITH THERAPEUTIC USE
    1) Adverse reactions to long acting opioid antagonists relate to their antagonistic effects to narcotics and the resulting withdrawal symptoms. They may include pain, hypertension, diaphoresis, and agitation. In neonate, withdrawal symptoms may manifest with crying and poor feeding efforts. Pulmonary edema and dysrhythmias, including ventricular fibrillation, have been reported in association with the use of opioid antagonists to reverse narcotic effects, but it is unclear whether these complications were the result of their use. Other reported adverse effects include dose-related hepatotoxicity, eosinophilic pneumonia, injection site reactions, depression or suicidal ideation, nausea, vomiting, diarrhea, abdominal pain, hypotension, somnolence, headache, dizziness, restlessness, tremor, anxiety, miosis, joint and muscle pain, and rhabdomyolysis.
    F) WITH POISONING/EXPOSURE
    1) Limited data available. High doses have caused tremor, hypotension, tachycardia, dizziness, insomnia, fatigue, and agitation. High doses will precipitate opioid withdrawal in opioid-dependent patients.

Vital Signs

    3.3.1) SUMMARY
    A) Fever may occur.
    3.3.3) TEMPERATURE
    A) NALMEFENE: Fever has been reported in 3% of patients given therapeutic doses of nalmefene (Prod Info REVEX(R) injection, 2006).

Heent

    3.4.3) EYES
    A) MIOSIS: Naltrexone has been reported to cause some pupillary constriction at therapeutic doses by an unknown mechanism (Prod Info ReVia(R), naltrexone hydrochloride, 1999; Walsh et al, 1996).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) VENTRICULAR TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Abrupt reversal of opioid effects with the long-acting opiate antagonists may very rarely result in cardiovascular instability, including ventricular tachycardia and ventricular fibrillation (Prod Info Revex(R), nalmefene, 1998).
    b) NALTREXONE: Tachycardia may develop with naltrexone therapy (Prod Info naltrexone hcl oral tablets, 2002).
    c) NALMEFENE: In combined data from clinical trials involving 1127 patients treated for opioid overdose or postoperative respiratory depression with intravenous nalmefene, tachycardia, hypertension, and hypotension were reported in 5%, 5%, and 1%, respectively. Tachycardia appeared more common at higher doses (Prod Info REVEX(R) injection, 2006).
    B) HYPERTENSIVE EPISODE
    1) Hypertension may result from abrupt reversal of opioid effects with the long-acting opiate antagonists (Prod Info REVEX(R) injection, 2006).
    2) NALMEFENE: Data from clinical trials involving 1127 patients treated for opioid overdose or postoperative respiratory depression with IV nalmefene, hypertension was reported in 5% of the patients (Prod Info REVEX(R) injection, 2006).
    3) NALTREXONE: A 32-year-old male diagnosed with post-traumatic stress disorder was administered 50 mg oral naltrexone in a placebo-controlled study. Prior to naltrexone his blood pressure readings averaged 123/73 mm Hg. Following a naltrexone dose, 22.7% of his systolic readings were above 140 mm Hg during the naltrexone 24-hour period, and 18.2% of diastolic readings were over 90 mm Hg (Ibarra et al, 1994).
    4) NALTREXONE: Naltrexone administered at therapeutic doses (50 mg maintenance) alone in a clinical study produced slightly elevated systolic blood pressure (maximum increase of 6 mm Hg) (Walsh et al, 1996).
    C) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Orthostatic hypotension occurred in healthy volunteers following an intravenous methylnaltrexone dose of 0.64 mg/kg (therapeutic dose: 0.15 mg/kg) (Prod Info RELISTOR(R) subcutaneous injection, 2010).
    2) Hypotension may result from abrupt reversal of opioid effects with the long-acting opiate antagonists (Prod Info Revex(R), nalmefene, 1998).
    3) NALMEFENE: Data from clinical trials involving 1127 patients treated for opioid overdose or postoperative respiratory depression with IV nalmefene, hypotension was reported in 1% of the patients (Prod Info REVEX(R) injection, 2006).
    4) Foss et al (1997) report a dose-limiting effect of methylnaltrexone to be orthostatic hypotension in normal subjects which was transient and self-limiting (Foss et al, 1997).
    5) NALTREXONE: Hypovolemic shock secondary to severe dehydration from recurrent vomiting and diarrhea and gastrointestinal bleeding from gastritis and a Mallory-Weiss tear was reported in a patient following rapid opioid detoxification under general anesthesia with placement of a naltrexone subcutaneous pellet (Chanmugam et al, 2000).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) Acute lung injury may result from the use of these agents in connection with opioid reversal in both postoperative and emergency department settings. This effect may be the result of abrupt reversal of opioid effects (Prod Info Revex(R), nalmefene, 1998; Prod Info ReVia(R), naltrexone hydrochloride, 1999).
    2) NALMEFENE: Acute lung injury developed in a 21-year-old patient with no significant past medical history after receiving nalmefene 75 mcg intravenously. Clinical symptoms resolved rapidly, but 36 hours passed before improvement was seen on chest x-ray (Henderson & Reynolds, 1997).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RESPIRATORY FAILURE
    a) Death due to respiratory failure and/or clonic-tonic seizures occurred in mice, rats and dogs administered acute toxic doses of naltrexone (Prod Info ReVia(R), naltrexone hydrochloride, 1999).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) TREMOR
    1) WITH POISONING/EXPOSURE
    a) NALMEFENE: Higher doses of nalmefene have been associated with tremors, dizziness, drowsiness, and fatigue (Dixon et al, 1986).
    B) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) NALMEFENE: Insomnia has been reported with oral nalmefene therapy (Dixon et al, 1987; Stone, 1994; Monroe, 1989) and extended-release injectable naltrexone (Prod Info VIVITROL(R) extended-release injectable suspension, 2009).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) NALTREXONE: Headache was a common adverse event reported with extended-release injectable naltrexone (Prod Info VIVITROL(R) extended-release injectable suspension, 2009).
    b) NALMEFENE: Headache was infrequently reported with therapeutic use of injectable nalmefene (Prod Info REVEX(R) injection, 2006).
    D) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness may develop with the therapeutic use of these agents (Prod Info RELISTOR(R) subcutaneous injection, 2010; Prod Info VIVITROL(R) extended-release injectable suspension, 2009; Prod Info REVEX(R) injection, 2006).
    E) PSYCHOMOTOR AGITATION
    1) NALMEFENE: Panic attacks or agitation have been reported as an adverse effect in some patients treated with nalmefene (Weiss, 1987; Luby & Marrazzi, 1987; Fudala et al, 1991), restlessness and anxiety have also been reported with naltrexone therapy (Prod Info VIVITROL(R) extended-release injectable suspension, 2009; Prod Info naltrexone hcl oral tablets, 2002), which may be related to a hypernoradrenergic state induced by blockade of presynaptic opioid receptors (Luby & Marrazzi, 1987).
    F) DROWSY
    1) NALMEFENE: Tiredness, sleepiness and dizziness were adverse effects reported in a nalmefene study in human volunteers (Fudala et al, 1989).
    2) NALTREXONE: Somnolence has also been reported with naltrexone therapy (Prod Info VIVITROL(R) extended-release injectable suspension, 2009; Prod Info naltrexone hcl oral tablets, 2002)
    G) DELIRIUM
    1) NALTREXONE: Naltrexone-induced opioid withdrawal, without medical supervision, has been associated with delirium. Misuse of naltrexone in these patients has resulted in prolonged withdrawal symptoms accompanied by confusion, disorientation, and delirium (Vassiliadis et al, 1999).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) In animal studies using mice, rats, and dogs that were given toxic doses of naltrexone, death resulted from clonic-tonic seizures and/or respiratory failure (Prod Info ReVia(R), naltrexone hydrochloride, 1999). In rodent studies of nalmefene, acute toxicity resulted in seizures (Prod Info Revex(R), nalmefene, 1998).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are frequent adverse effects of nalmefene and naltrexone (Prod Info VIVITROL(R) extended-release injectable suspension, 2009; Prod Info REVEX(R) injection, 2006) . Diarrhea is also reported with the therapeutic use of these agents (Prod Info RELISTOR(R) subcutaneous injection, 2010; Prod Info naltrexone hcl oral tablets, 2002).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) METHYLNALTREXONE: Abdominal pain is the most common adverse event reported with methylnaltrexone. Other gastrointestinal events include flatulence and nausea (Prod Info RELISTOR(R) subcutaneous injection, 2010).
    b) NALTREXONE: Abdominal pain is also commonly reported with extended-release injectable naltrexone (Prod Info VIVITROL(R) extended-release injectable suspension, 2009).
    C) GASTRITIS
    1) NALTREXONE: Following rapid opioid detoxification under general anesthesia with subcutaneous placement of a naltrexone pellet, a 17-year-old presented to the ED 72 hours later with pain and vomiting. An esophagogastroduodenoscopy revealed a Mallory-Weiss tear in the distal esophagus and ulcerated mucosa consistent with gastritis (Chanmugam et al, 2000).
    D) GASTROINTESTINAL PERFORATION
    1) WITH THERAPEUTIC USE
    a) METHYLNALTREXONE: Rare reports of gastrointestinal perforation have occurred in some patients with advanced cancer being treated with methylnaltrexone (Prod Info RELISTOR(R) subcutaneous injection, 2010).

Reproductive

    3.20.1) SUMMARY
    A) Nalmefene has been classified as FDA pregnancy category B. Methylnaltrexone, naltrexone and morphine/naltrexone have been classified as FDA pregnancy category C. The combination product bupropion hydrochloride/naltrexone hydrochloride has been classified as FDA pregnancy category X. In animal studies, there is evidence of early fetal loss with oral naltrexone exposure. Studies in rats have shown methylnaltrexone and nalmefene (and its metabolites) to be secreted into rat milk. Naltrexone and its metabolite have been shown to be secreted into human breast milk.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of nalmefene or naltrexone (Prod Info REVEX(R) injection, 2006; Prod Info VIVITROL(R) IM extended-release injectable suspension, 2007).
    B) ANIMAL STUDIES
    1) NALTREXONE/OXYCODONE
    a) During animal studies, administration of oral oxycodone HCl during the period of organogenesis and at doses up to approximately 3 times the adult human dose showed no evidence of teratogenicity or embryofetal toxicity. Offspring of pregnant animals administered oxycodone during gestation reportedly exhibited neurobehavioral effects, including altered stress responses, increased anxiety-like behavior, and altered learning and memory (Prod Info TROXYCA(R) ER oral extended-release capsules, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of nalmefene or naltrexone use during pregnancy in humans (Prod Info REVEX(R) injection, 2006; Prod Info VIVITROL(R) IM extended-release injectable suspension, 2007).
    B) PREGNANCY CATEGORY
    1) The manufacturers have classified nalmefene as FDA pregnancy category B (Prod Info REVEX(R) injection, 2006). The manufacturers have classified methylnaltrexone, naltrexone and morphine/naltrexone as FDA pregnancy category C (Prod Info RELISTOR(R) subcutaneous injection, 2014; Prod Info EMBEDA(R) oral extended-release capsules, 2009; Prod Info VIVITROL(R) IM extended-release injectable suspension, 2007).
    2) The manufacturer has classified the combination product bupropion hydrochloride/naltrexone hydrochloride as FDA pregnancy category X (Prod Info CONTRAVE(R) oral extended-release tablets, 2014)
    3) NALTREXONE/OXYCODONE: Advise pregnant women of the potential risk to the fetus. Carefully monitor neonates who have been exposed to oxycodone in utero for withdrawal syndrome. Use of naltrexone hydrochloride/oxycodone hydrochloride may also prolong labor and should not be used during or immediately prior to labor (Prod Info TROXYCA(R) ER oral extended-release capsules, 2016).
    C) OPIOID WITHDRAWAL
    1) Methylnaltrexone use during pregnancy may cause opioid withdrawal in a fetus due to an immature fetal blood-brain barrier. Adequate and well-controlled studies with methylnaltrexone bromide in pregnant women have not been conducted. It is recommended that the drug be used during pregnancy only when clearly needed (Prod Info RELISTOR(R) subcutaneous injection, 2014).
    2) NALTREXONE/OXYCODONE: Prolonged use of opioid analgesics during pregnancy may result in neonatal dependence as well as withdrawal shortly following birth. Symptoms of withdrawal include vomiting, diarrhea, failure to gain weight, high-pitched cry, abnormal sleep pattern, irritability, hyperactivity, and tremors. This condition may become life-threatening without early recognition and treatment. Opioids such as oxycodone cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates (Prod Info TROXYCA(R) ER oral extended-release capsules, 2016).
    D) ANIMAL STUDIES
    1) METHYLNALTREXONE: In animal studies, there was no evidence of fetal harm when pregnant rats and rabbits were administered methylnaltrexone during organogenesis IV doses up to 20 times and 26 times the maximum recommended human subcutaneous dose (MRHD), respectively. No adverse effects on pre- or postnatal development were noted in rats exposed to methylnaltrexone doses about 81 times the maximum recommended human dose (Prod Info RELISTOR(R) subcutaneous injection, 2014).
    2) NALMEFENE: There was no evidence of impaired fertility or harm to the fetus in rats and rabbits given oral nalmefene at doses up to 1200 mg/m(2)/day) and up to 2400 mg/m(2)/day), respectively, and in rabbits given IV nalmefene up to 96 mg/m(2)/day (114 times the human dose) (Prod Info REVEX(R) injection, 2006).
    3) NALTREXONE: Early fetal loss was reported in rats and rabbits administered oral naltrexone at doses of 30 mg/kg/day (180 mg/m(2)/day) or greater and 60 mg/kg/day (720 mg/m(2)/day) or greater, respectively (Prod Info VIVITROL(R) IM extended-release injectable suspension, 2007).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of nalmefene use during lactation in humans (Prod Info REVEX(R) injection, 2006).
    B) BREAST MILK
    1) NALTREXONE: Transfer of naltrexone and 6-beta-naltrexol into human milk has been reported with oral naltrexone use (Prod Info VIVITROL(R) IM extended-release injectable suspension, 2007).
    2) METHYLNALTREXONE: Lactation studies with methylnaltrexone bromide have not been conducted in humans. In animal studies, the drug was excreted in the milk of lactating rats. Because of the potential for opioid withdrawal or other serious adverse reactions in the nursing infant, nursing or methylnaltrexone should be discontinued while considering the importance of the drug to the mother (Prod Info RELISTOR(R) subcutaneous injection, 2014).
    3) NALTREXONE/OXYCODONE
    a) Oxycodone has been detected in human breast milk and plasma naltrexone levels were detectable in some patients administered naltrexone hydrochloride/oxycodone hydrochloride during clinical studies. Excess sedation and respiratory depression may occur in the nursing infant. Withdrawal symptoms may also occur in breastfeeding infants when maternal administration of an opioid analgesic is discontinued or when the mother stops breastfeeding (Prod Info TROXYCA(R) ER oral extended-release capsules, 2016).
    b) Advise nursing mothers not to breastfeed during oxycodone hydrochloride/naltrexone hydrochloride combination therapy. Carefully monitor infants who have been exposed to these drugs during breast milk for excess sedation and respiratory depression. In addition, monitor infants for withdrawal syndrome when maternal administration of an opioid analgesic is discontinued or when the mother stops breastfeeding (Prod Info TROXYCA(R) ER oral extended-release capsules, 2016; Prod Info XTAMPZA(TM) ER oral extended-release capsules, 2016; Prod Info OXYCONTIN(R) oral extended release tablets, 2014).
    C) ANIMAL STUDIES
    1) METHYLNALTREXONE: Methylnaltrexone bromide is excreted in the milk of lactating rats (Prod Info RELISTOR(R) subcutaneous injection, 2014).
    2) NALMEFENE: Studies in rats have shown nalmefene and its metabolites to be secreted into rat milk, with concentrations approximately 3 times those in plasma at 1 hour and decreasing to about half the corresponding plasma concentrations by 24 hours after a bolus dose (Prod Info REVEX(R) injection, 2006).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of nalmefene or naltrexone on human fertility (Prod Info VIVITROL(R) IM extended-release injectable suspension, 2007; Prod Info REVEX(R) injection, 2006).
    2) NALTREXONE/OXYCODONE
    a) Chronic opioid use may adversely affect fertility in males and females of reproductive potential, and it is not known if such effects are reversible (Prod Info TROXYCA(R) ER oral extended-release capsules, 2016).
    B) ANIMAL STUDIES
    1) METHYLNALTREXONE: In studies of male and female rats, the subQ administration of methylnaltrexone bromide at doses approximately 122 times the maximum recommended human dose based on body surface area did not affect fertility or reproductive performance (Prod Info RELISTOR(R) subcutaneous injection, 2014).
    2) NALMEFENE: Fertility, reproductive performance, and offspring survival in rats were not affected at oral nalmefene doses up to 1200 mg/m(2)/day (Prod Info REVEX(R) injection, 2006).
    3) NALTREXONE: There was a significant increase in pseudopregnancy and a decrease in pregnancy rates in rats at oral naltrexone doses of 100 mg/kg/day (600 mg/m(2)/day). There was no effect on male fertility at this dose level (Prod Info VIVITROL(R) IM extended-release injectable suspension, 2007).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturers do not report any carcinogenic potential of methylnaltrexone, nalmefene, or naltrexone in humans.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential of naltrexone in humans (Prod Info VIVITROL(R) extended-release injectable suspension, 2009).
    3.21.4) ANIMAL STUDIES
    A) TESTICULAR MESOTHELIOMA
    1) NALTREXONE: In a 2-year study, an increased incidence of testicular mesothelioma was reported in male rats administered dietary naltrexone doses of 100 mg/kg/day (600 mg/m(2)/day; 16 times the recommended dose based on body surface area) compared with the maximum historical incidence (6% vs 4%) (Prod Info naltrexone hydrochloride oral tablets, 2009).
    B) VASCULAR TUMOR
    1) NALTREXONE: In a 2-year study, an increased incidence of vascular tumors was reported in male and female rats administered dietary naltrexone doses of 100 mg/kg/day (600 mg/m(2)/day; 16 times the recommended dose based on body surface area) compared with the maximum historical incidence (4% vs 2%). Tumor risk only exceeded historical incidence in female rats (Prod Info naltrexone hydrochloride oral tablets, 2009).
    C) LACK OF EFFECT
    1) METHYLNALTREXONE: A 2-year study in mice administered oral methylnaltrexone doses up to 200 mg/kg/day in males and 400 mg/kg/day in females (about 81 and 162 times, respectively, the maximum recommended human dose (MRHD) of 0.2 mg/kg based on body surface area (BSA)) found no evidence of tumors. No tumors were produced in Sprague-Dawley rats administered oral doses up to 300 mg/kg/day (about 243 times the MRHD based on BSA) (Prod Info RELISTOR(R) subcutaneous injection, 2014).
    2) NALTREXONE: A 2-year study found no evidence of carcinogenicity in male or female mice administered naltrexone in the diet (Prod Info naltrexone hydrochloride oral tablets, 2009).

Genotoxicity

    A) METHYLNALTREXONE: No mutagenicity was demonstrated in the following tests: Ames, mouse lymphoma cell forward mutation, chromosome aberration (in Chinese hamster ovary cells and human lymphocytes), and in vivo mouse micronucleus (Prod Info RELISTOR(R) subcutaneous injection, 2014) .
    B) NALMEFENE: No mutagenicity was found in the Ames test with 5 bacterial strains or the mouse lymphoma assay. Clastogenicity was not observed in the mouse micronucleus test or in the cytogenic bone marrow assay in rats. Weak, but significant, clastogenicity was reported in the human lymphocyte metaphase assay in absence (but not presence) of exogenous metabolic activation (Prod Info REVEX(R) injection, 2006).
    C) NALTREXONE: Weak genotoxic effects were reported in one mammalian gene mutation assay, in the Drosophila recessive lethal assay, in nonspecific DNA repair tests with E. coli and WI-38 cells, and urinalysis for methylated histidine residues; however, no genotoxicity was observed in various other in vitro tests. No clastogenicity was observed in an in vivo mouse micronucleus assay (Prod Info naltrexone hydrochloride oral tablets, 2009; Prod Info VIVITROL(R) extended-release injectable suspension, 2009).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) The narcotic antagonist naltrexone may cause dose-related increases in liver enzymes when used chronically, with doses up to 300 mg/day (Mitchell, 1986; Prod Info ReVia(R), naltrexone hydrochloride, 1999). Patients receiving up to 300 mg/day for treatment of obesity have experienced elevations in transaminase levels which returned to normal on discontinuation of naltrexone (Atkinson et al, 1985; Mitchell, 1986).
    2) NALTREXONE: Chronic administration of naltrexone has resulted in initial increases in SGOT and SGPT over 10 to 36 months which subsequently declined to high normal ranges. Doses of 50 mg to 300 mg daily caused no overt hepatotoxicity in 10 patients from this prolonged use (Sax et al, 1994).
    3) LACK OF EFFECT: In one study, no alteration in hepatic enzyme concentrations occurred in 53 male patients treated with naltrexone 350 mg orally weekly for 12 weeks (Brahen et al, 1988).
    4) NALMEFENE: A 38-year-old alcoholic, with normal baseline liver function, was administered nalmefene for treatment of alcoholism. On week 8 of treatment her ALT showed a 7-fold increase and her AST showed a 4-fold increase from baseline. It was decided to continue her treatment based on the patients response of achieving complete abstinence, and the liver function tests gradually returned to normal (Salvato & Mason, 1994).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) NALTREXONE: Acute renal failure secondary to rhabdomyolysis and hypotension has been reported in a 17-year-old male following rapid opioid detoxification under general anesthesia with placement of a subcutaneous naltrexone pellet (Chanmugam et al, 2000).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) Greater than 10% of patients receiving naltrexone have reported joint and muscle pain (Prod Info ReVia(R), naltrexone hydrochloride, 1999) or muscle tension (Fudala et al, 1991).
    B) RHABDOMYOLYSIS
    1) NALTREXONE: Within 72 hours of undergoing rapid opioid detoxification under general anesthesia with subcutaneous naltrexone pellet placement, a 17-year-old male presented to the ED with hypovolemic shock, GI hemorrhage, and rhabdomyolysis (CPK, 1,074 IU/L). Myoglobinuria was noted on a urine screen (Chanmugam et al, 2000). Use of a narcotic antagonist results in displacement of the opioid from the opioid receptors, which may have contributed to the rhabdomyolysis.

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) INCREASED HORMONAL ACTIVITY
    1) Acute dosing with naltrexone has been associated with increased secretion of the gonadotropins (luteinizing hormone, follicle-stimulating hormone), adrenocorticotropin (ACTH), cortisol, and catecholamines. This same effect is not seen with chronic dosing (Atkinson, 1984).
    B) HYPERGLYCEMIA
    1) NALTREXONE: A 29-year-old insulin-dependent type I diabetic taking therapeutic naltrexone for anorexia nervosa reportedly had an increased insulin requirement. The authors suggest an opiate modulation of insulin action (Marrazzi et al, 1994).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No laboratory studies are need unless otherwise clinically indicated.
    B) Serum concentrations of these drugs are not widely available or clinically useful in guiding management.
    C) Patients who receive these agents to reverse opioid toxicity should be monitored for CNS and respiratory depression and evidence of opioid withdrawal.
    D) Monitor vital signs, mental status, CK, and liver enzymes in symptomatic patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD SERUM/CHEMISTRY
    1) These drugs may cause hepatotoxicity. Monitor liver function tests for patients following chronic exposure.
    2) Monitor CK in patients with seizures and in patients who are severely agitated.

Methods

    A) IMMUNOASSAY
    1) Dixon et al (1986) describe a radioimmunoassay (RIA) technique for quantifying concentrations of nalmefene and nalmefene glucuronide in plasma, urine, and dialysate (Dixon et al, 1986a).
    B) CHROMATOGRAPHY
    1) Monti et al (1991) describe a gas chromatography/mass spectrometry electron-capture method for the determination of naltrexone in plasma and urine. The lower limit of sensitivity for the assay is 0.1 ng/ml (Monti et al, 1991).
    2) Chou et al (1993) describe a solid-phase extraction procedure followed by high-performance liquid chromatography (HPLC) analysis for the quantification of nalmefene in human plasma following oral and intravenous doses (Chou et al, 1993).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who have persistent symptoms or any evidence of pulmonary edema should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Long acting opioid antagonist exposures in general should be very safe and asymptomatic patients with inadvertent exposure may remain at home. However, if it was used to reverse opioid toxicity, the patient should be brought into a healthcare facility for further evaluation or if the patients are symptomatic.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) If there are any concerns, a toxicologist or a poison center can be consulted for advice regarding the use of long acting opioid antagonists.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Symptomatic patients, those with deliberate overdose, and patients in whom these drugs were used to reverse opioid toxicity should be referred to a healthcare facility. Criteria for discharge include a patient who is asymptomatic or clearly improving after an observation period of 4 to 6 hours without treatment.
    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients who have persistent symptoms or any evidence of pulmonary edema should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) Long acting opioid antagonist exposures in general should be very safe and asymptomatic patients with inadvertent exposure may remain at home. However, if it was used to reverse opioid toxicity, the patient should be brought into a healthcare facility for further evaluation or if the patients are symptomatic.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) If there are any concerns, a toxicologist or a poison center can be consulted for advice regarding the use of long acting opioid antagonists.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Symptomatic patients, those with deliberate overdose, and patients in whom these drugs were used to reverse opioid toxicity should be referred to a healthcare facility. Criteria for discharge include a patient who is asymptomatic or clearly improving after an observation period of 4 to 6 hours without treatment.

Monitoring

    A) No laboratory studies are need unless otherwise clinically indicated.
    B) Serum concentrations of these drugs are not widely available or clinically useful in guiding management.
    C) Patients who receive these agents to reverse opioid toxicity should be monitored for CNS and respiratory depression and evidence of opioid withdrawal.
    D) Monitor vital signs, mental status, CK, and liver enzymes in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not indicated as toxicity is self-limited.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Gastrointestinal decontamination is generally not indicated unless more toxic co-ingestants are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY: For mild to moderate toxicity, supportive care is the mainstay of treatment. This may include benzodiazepines to treat agitation and antiemetics to treat nausea and vomiting. In addition, medical providers have used clonidine to treat opioid withdrawal symptoms and dicyclomine to treat diarrhea. Manage mild hypotension with IV fluids. If hypertension develops secondary to withdrawal and agitation, benzodiazepines may be useful.
    2) MANAGEMENT OF SEVERE TOXICITY: For severe toxicity, the mainstay of treatment is supportive care. If patients develop pulmonary distress, endotracheal intubation may be required. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension with IV fluids, dopamine, or norepinephrine. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives.
    B) MONITORING OF PATIENT
    1) No laboratory studies are need unless otherwise clinically indicated.
    2) Serum concentrations of these drugs are not widely available or clinically useful in guiding management.
    3) Patients who receive these agents to reverse opioid toxicity should be monitored for CNS and respiratory depression and evidence of opioid withdrawal.
    4) Monitor vital signs, mental status, CK, and liver enzymes in symptomatic patients.
    C) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    E) HYPERTENSIVE EPISODE
    1) If hypertension develops secondary to withdrawal and agitation, benzodiazepines may be useful.
    2) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    3) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    4) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    5) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    6) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    9) PHENTOLAMINE/INDICATIONS
    a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    10) PHENTOLAMINE/ADULT DOSE
    a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    11) PHENTOLAMINE/PEDIATRIC DOSE
    a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    12) PHENTOLAMINE/ADVERSE EFFECTS
    a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    13) CAUTION
    a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    14) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    15) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    16) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    F) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    G) VENTRICULAR ARRHYTHMIA
    1) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    H) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).
    6) Russo et al (1995) described a technique of continuous venovenous hemodiafiltration (CVVH-D) and fasciotomy for patients with severe rhabdomyolysis and compartment syndrome. This aggressive method has been shown to improve renal function in the face of acute kidney failure (Russo et al, 1995).

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis is UNLIKELY to be of value because of the large volume of distribution of these agents.
    B) HEMODIALYSIS
    1) Matzke et al (1996) reported hemodialysis clearance of nalmefene to be approximately 3.3% of total body clearance. The half-life of its glucuronide metabolite was significantly reduced, but a dramatic rebound of nalmefene glucuronide concentrations occurred at the end of the hemodialysis. It is thus concluded that hemodialysis does not result in clinically significant alterations in disposition of nalmefene or its metabolite (Matzke et al, 1996).

Range Of Toxicity

Summary

    A) TOXICITY: There are no specific known toxic doses associated with long acting opioid antagonists. Adverse effects have been reported following a wide range of doses though large doses (eg, naltrexone 800 mg daily for one week) have been tolerated without ill effects.
    B) THERAPEUTIC EFFECTS: NALTREXONE: IM: 380 mg IM every 4 weeks (or once a month). ORAL: 25 to 50 mg once daily. METHYLNALTREXONE: Weight less than 38 kg (less than 84 pounds): 0.15 mg/kg subQ every other day. Weight 38 to less than 62 kg (84 to less than 136 pounds): 8 mg subQ every other day. Weight 62 to 114 kg (136 to 251 pounds): 12 mg subQ every other day. Weight greater than 114 kg (greater than 251 pounds): 0.15 mg/kg subQ every other day. CHILDREN: The safety and efficacy of methylnaltrexone and naltrexone have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) METHYLNALTREXONE BROMIDE
    a) OPIOID-INDUCED CONSTIPATION IN ADULT PATIENTS WITH ADVANCED ILLNESS: Individual doses and injection volumes are based on patient weight. Use of pre-filled syringes is only for patients requiring an 8-mg or 12-mg dose (Prod Info RELISTOR(R) oral tablets, subcutaneous injection, 2016).
    1) Weight less than 38 kg: The recommended dose is 0.15 mg/kg subQ every other day; MAX: 1 dose in a 24-hour period. Injection volume: weight in kg multiplied by 0.0075 and rounded up to the nearest 0.1 mL (Prod Info RELISTOR(R) oral tablets, subcutaneous injection, 2016).
    2) Weight 38 to less than 62 kg: The recommended dose is 8 mg subQ every other day; MAX: 1 dose in a 24-hour period. Injection volume: 0.4 mL (Prod Info RELISTOR(R) oral tablets, subcutaneous injection, 2016).
    3) Weight 62 to 114 kg: The recommended dose is 12 mg subQ every other day; MAX: 1 dose in a 24-hour period. Injection volume: 0.6 mL (Prod Info RELISTOR(R) oral tablets, subcutaneous injection, 2016).
    4) Weight greater than 114 kg: The recommended dose is 0.15 mg/kg subQ every other day; MAX: 1 dose in a 24-hour period. Injection volume: weight in kg multiplied by 0.0075 and rounded up to the nearest 0.1 mL (Prod Info RELISTOR(R) oral tablets, subcutaneous injection, 2016).
    b) OPIOID-INDUCED CONSTIPATION IN PATIENTS WITH CHRONIC NON-CANCER PAIN: 450 mg orally once daily or 12 mg subQ once daily (Prod Info RELISTOR(R) oral tablets, subcutaneous injection, 2016)
    2) NALMEFENE
    a) In the United States, nalmefene was supplied in 2 concentrations: The ampule with the blue label contains 1 mL in a concentration of 100 mcg/mL, suitable for POSTOPERATIVE USE; the ampule with the green label contains 2 mL in a concentration of 1 mg/mL, suitable for the management of OPIOID OVERDOSE (Prod Info REVEX(R) injection, 2006). Nalmefene is no longer available in the United States.
    b) OPIOID OVERDOSE: If opioid dependency is suspected, initiate a challenge dose of 0.1 mg/70 kg. If no evidence of withdrawal after 2 minutes, follow recommended dosing. In non-opioid dependent patients, the recommended initial dose is 0.5 mg/70 kg. A second dose of 1 mg/70 kg may be administered 2 to 5 minutes later if required (Prod Info REVEX(R) injection, 2006).
    c) REVERSAL OF POSTOPERATIVE RESPIRATORY DEPRESSION: The recommended initial dose is 0.25 mcg/kg followed by 0.25-mcg/kg incremental doses at 2- to 5-minute intervals (Prod Info REVEX(R) injection, 2006).
    3) NALTREXONE
    a) INTRAMUSCULAR: The recommended dose is 380 mg every 4 weeks (or once a month) (Prod Info VIVITROL(R) extended-release injectable suspension, 2009).
    b) ORAL: The recommended dose is 25 to 50 mg once daily. Extended dosing intervals are permitted (Prod Info naltrexone hydrochloride oral tablets, 2009).
    4) NALTREXONE/BUPROPION
    a) Contrave(R): The recommended oral dose of naltrexone hydrochloride 8 mg/bupropion 90 mg tablets is as follows (Prod Info CONTRAVE(R) oral extended-release tablets, 2014):
    1) Week one: 1 tablet in the morning
    2) Week two: 1 tablet in the morning and 1 tablet in the evening
    3) Week three: 2 tablets in the morning and 1 tablet in the evening
    4) Week four and onward: 2 tablets in the morning and 2 tablets in the evening (MAXIMUM dose)
    5) NALTREXONE/OXYCODONE
    a) Initial dose is oxycodone 10 mg/naltrexone 1.2 mg orally every 12 hours in opioid-naive and opioid-non-tolerant patients; adjust by oxycodone 20 mg/naltrexone 2.4 mg every 2 to 3 days as needed based on efficacy, safety, and tolerability (Prod Info TROXYCA(R) ER oral extended-release capsules, 2016).
    b) Oxycodone/naltrexone extended-release 60 mg/7.2 mg and 80 mg/9.6 mg capsules, single doses greater than oxycodone 40 mg/naltrexone 4.8 mg, or daily doses greater than 80 mg/9.6 mg should only be used in opioid-tolerant patients; an opioid-tolerant patient is defined as using at least 60 mg of morphine/day, 25 mcg/hr transdermal fentanyl, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oxymorphone/day, 60 mg oral hydrocodone/day or an equianalgesic dose of another opioid for a week or longer (Prod Info TROXYCA(R) ER oral extended-release capsules, 2016).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of methylnaltrexone bromide, nalmefene, naltrexone, naltrexone/bupropion, and naltrexone/oxycodone have not been established in pediatric patients (Prod Info TROXYCA(R) ER oral extended-release capsules, 2016; Prod Info RELISTOR(R) oral tablets, subcutaneous injection, 2016; Prod Info VIVITROL(R) extended-release injectable suspension, 2009; Prod Info naltrexone hydrochloride oral tablets, 2009; Prod Info REVEX(R) injection, 2006; Prod Info CONTRAVE(R) oral extended-release tablets, 2014).
    B) NALMEFENE: In a safety study of nalmefene for the reversal of procedural sedation with an opioid agent in children 6 months to 12 years of age, nalmefene was administered intravenously (infused over 15 seconds) at 0.25-mcg/kg increments (maximum 10 mcg) until sedation was resolved, or to a maximum of 1 mcg/kg (maximum 40 mcg). Study results showed this to be safe and effective (Chumpa et al, 2001). Nalmefene is no longer available in the United States.

Maximum Tolerated Exposure

    A) ADULT
    1) METHYLNALTREXONE: In a study of healthy volunteers (n=41), a single dose of methylnaltrexone 0.5 mg/kg administered as a subcutaneous injection was well tolerated; orthostatic hypotension occurred in healthy volunteers following an intravenous methylnaltrexone dose of 0.64 mg/kg (Prod Info RELISTOR(R) subcutaneous injection, 2010).
    2) NALMEFENE: Healthy volunteers given intravenous doses of up to 24 mg (15 times the recommended dose) experienced no serious adverse reactions, severe signs or symptoms, or clinically significant laboratory abnormalities (Prod Info REVEX(R) injection, 2006).
    3) NALTREXONE: In a clinical study, subjects receiving 800 mg daily for up to one week demonstrated no evidence of toxicity (Prod Info naltrexone hcl oral tablets, 2002). Single doses up to 784 mg of extended-release injectable naltrexone produced no evidence of serious toxicity (Prod Info VIVITROL(R) extended-release injectable suspension, 2009)

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 1100 to 1550 mg/kg
    B) LD50- (ORAL)RAT:
    1) 1450 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) These agents are relatively pure opioid antagonists, similar in structure to naloxone, but with prolonged durations of action. Antagonistic effects occur by competitive displacement of opiate molecules at opiate receptors as well as the blocking of access of narcotics to opiate receptor sites (Greenstein et al, 1992; Anon, 1978) Anon, 1982).
    1) When administered to normal individuals or drug-free addicts, no significant effects are observed. However, these drugs can block the euphoriant effect of opiates (Willette, 1982; Anon, 1978; Schecter, 1980).
    2) Overcoming full opioid antagonist blockade by administration of very high doses of opiates has resulted in excessive symptoms of histamine release (Prod Info ReVia(R), naltrexone hydrochloride, 1999).

References

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    78) Product Information: NITROPRESS(R) injection for IV infusion, Sodium Nitroprusside injection for IV infusion. Hospira, Inc., Lake Forest, IL, 2007.
    79) Product Information: NITROPRESS(R) injection, sodium nitroprusside injection. Hospira,Inc, Lake Forest, IL, 2004.
    80) Product Information: OXYCONTIN(R) oral extended release tablets, oxycodone HCl oral extended release tablets. Purdue Pharma L.P. (per FDA), Stamford, CT, 2014.
    81) Product Information: Phentolamine Mesylate IM, IV injection Sandoz Standard, phentolamine mesylate IM, IV injection Sandoz Standard. Sandoz Canada (per manufacturer), Boucherville, QC, 2005.
    82) Product Information: RELISTOR(R) oral tablets, subcutaneous injection, methylnaltrexone bromide oral tablets, subcutaneous injection. Salix Pharmaceuticals (per FDA), Bridgewater , NJ, 2016.
    83) Product Information: RELISTOR(R) subcutaneous injection, methylnaltrexone bromide subcutaneous injection. Salix Pharmaceuticals, Inc. (per FDA), Raleigh, NC, 2014.
    84) Product Information: RELISTOR(R) subcutaneous injection, methylnaltrexone bromide subcutaneous injection. Wyeth Pharmaceuticals, Inc, Philadelphia, PA, 2010.
    85) Product Information: REVEX(R) injection, nalmefene hcl injection. Baxter Healthcare Corporation, Deerfield, IL, 2006.
    86) Product Information: ReVia(R), naltrexone hydrochloride. Dupont Pharmaceuticals, Wilmington, Delaware, 1999.
    87) Product Information: Revex(R), nalmefene. Ohmeda Pharmaceuticals Products, Liberty Corner, NJ, 1998.
    88) Product Information: TROXYCA(R) ER oral extended-release capsules, oxycodone HCl naltrexone HCl oral extended-release capsules. Pfizer Inc (per FDA), New York, NY, 2016.
    89) Product Information: VIVITROL(R) IM extended-release injectable suspension, naltrexone IM extended-release injectable suspension. Alkermes Inc, Cambridge, MA, 2007.
    90) Product Information: VIVITROL(R) extended-release injectable suspension, naltrexone extended-release injectable suspension. Alkermes, Inc, Cambridge, MA, 2009.
    91) Product Information: VIVITROL(R) extended-release injectable suspension, naltrexone extended-release injectable suspension. Alkermes, Inc, Waltham, MA, 2010.
    92) Product Information: VIVITROL(R) intramuscular injection extended-release suspension, naltrexone intramuscular injection extended-release suspension. Alkermes, Inc. (per Manufacturer), Waltham, MA, 2013.
    93) Product Information: XTAMPZA(TM) ER oral extended-release capsules, oxycodone oral extended-release capsules. Collegium Pharmaceutical Inc (per manufacturer), Canton, MA, 2016.
    94) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    95) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    96) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    97) Product Information: naltrexone hcl oral tablets, naltrexone hcl oral tablets. Eon Labs,Inc, Laurelton, NY, 2002.
    98) Product Information: naltrexone hcl oral tablets, naltrexone hcl oral tablets. Mallinckrodt Inc., St. Loius, MO, 2003.
    99) Product Information: naltrexone hydrochloride oral tablets, naltrexone hydrochloride oral tablets. Mallinckrodt Inc, Hazelwood, MO, 2009.
    100) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
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