Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1119
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Revex (Injection, Solution)
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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��g/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.<br/>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.<br/>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��g/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.<br/>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.<br/>Recommended Doses
for Reversal of Postoperative Opioid Depression: Use 100��g/mL dosage strength (blue label) and see Table 2 for
initial doses. The goal of
treatment with REVEX in the postoperative setting is to achieve
reversal of excessive opioid effects without inducing a complete
reversal and acute pain. This is best accomplished with an
initial dose of 0.25��g/kg followed by 0.25��g/kg incremental doses at 2-5 minute intervals,
stopping as soon as the desired degree of opioid reversal is
obtained. A cumulative total dose above 1.0��g/kg does
not provide additional therapeutic effect. In cases
where the patient is known to be at increased cardiovascular
risk, it may be desirable to dilute REVEX 1:1 with saline or
sterile water and use smaller initial and incremental doses of
0.1��g/kg.<br/>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 respiratoryrate 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.<br/>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.<br/>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.<br/>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.)
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REVEX (nalmefene
hydrochloride injection), an opioid antagonist, is a 6-methylene
analogue of naltrexone. The chemical structure is shown below: Molecular Formula:
CHNO���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 pKof 7.6. REVEX is available
as a sterile solution for intravenous, intramuscular, and subcutaneous
administration in two concentrations, containing 100��g or 1.0
mg of nalmefene free base per mL. The 100��g/mL concentration
contains 110.8��g 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.
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Pharmacodynamics: REVEX
prevents or reverses the effects of opioids, including
respiratory depression, sedation, and hypotension.
Pharmacodynamic studies have shown that REVEX has a longer
duration of action than naloxone at fully reversing doses. REVEX
has no opioid agonist activity. REVEX is
not known to produce respiratory depression, psychotomimetic
effects, or pupillary constriction. No pharmacological activity
was observed when REVEX was administered in the absence of
opioid agonists. REVEX has
not been shown to produce tolerance, physical dependence, or
abuse potential. REVEX can
produce acute withdrawal symptoms in individuals who are opioid dependent.<br/>Pharmacokinetics: Nalmefene
exhibited dose proportional pharmacokinetics following
intravenous administration of 0.5 mg to 2.0 mg. Pharmacokinetic
parameters for nalmefene after a 1 mg intravenous administration
in adult male volunteers are listed in Table 1.<br/>Absorption: Nalmefene was completely bioavailable following
intramuscular or subcutaneous administration in 12 male
volunteers relative to intravenous nalmefene. The
relative bioavailabilities of intramuscular and
subcutaneous routes of administration were 101.5%��8.1% (Mean��SD) and 99.7%��6.9%, respectively. Nalmefene will be
administered primarily as an intravenous bolus, however,
nalmefene can be given intra-muscularly (IM) or
subcutaneously (SC) if venous access cannot be
established. While the time to maximum plasma nalmefene
concentration was 2.3��1.1 hours following
intramuscular and 1.5��1.2 hours following
subcutaneous administrations, therapeutic plasma
concentrations are likely to be reached within 5-15 minutes after a 1 mg dose in an emergency. Because of
the variability in the speed of absorption for IM&SC dosing, and the inability to titrate to
effect, great care should be taken if repeated doses
must be given by these routes.<br/>Distribution: Following a 1 mg parenteral dose, nalmefene was rapidly
distributed. In a study of brain receptor occupancy, a 1
mg dose of nalmefene blocked over 80% of brain opioid
receptors within 5 minutes after administration. The
apparent volumes of distribution centrally (V) and at steady-state (V) are
3.9��1.1 L/kg and 8.6��1.7 L/kg, respectively. Ultrafiltration studies of nalmefene have
demonstrated that 45% (CV 4.1%) is bound to plasma
proteins over a concentration range of 0.1 to 2��g/mL. An in
vitro determination of the distribution of
nalmefene in human blood demonstrated that nalmefene
distributed 67% (CV 8.7%) into red blood cells and 39%
(CV 6.4%) into plasma. The whole blood to plasma ratio
was 1.3 (CV 6.6%) over the nominal concentration range
in whole blood from 0.376 to 30 ng/mL.<br/>Metabolism: Nalmefene is metabolized by the liver, primarily by
glucuronide conjugation, and excreted in the urine.
Nalmefene is also metabolized to trace amounts of an
N-dealkylated metabolite. Nalmefene glucuronide is
inactive and the N-dealkylated metabolite has minimal
pharmacological activity. Less than 5% of nalmefene is
excreted in the urine unchanged. Seventeen percent (17%)
of the nalmefene dose is excreted in the feces. The
plasma concentration-time profile in some subjects
suggests that nalmefene undergoes enterohepatic
recycling.<br/>Elimination: After intravenous administration of 1 mg REVEX to
normal males (ages 19-32), plasma concentrations
declined biexponentially with a redistribution and a
terminal elimination half-life of 41��34
minutes and 10.8��5.2 hours, respectively. The
systemic clearance of nalmefene is 0.8��0.2
L/hr/kg and the renal clearance is 0.08��0.04
L/hr/kg.<br/>Special Populations:<br/>Elderly: Dose proportionality was observed in nalmefene AUCfollowing 0.5 to 2 mg intravenous
administration to elderly male subjects. Following a 1
mg intravenous nalmefene dose, there were no significant
differences between young (19-32 years) and elderly
(62-80 years) adult male subjects with respect to plasma
clearance, steady-state volume of distribution, or
half-life. There was an apparent age-related decrease in
the central volume of distribution (young: 3.9��1.1 L/kg, elderly: 2.8��1.1 L/kg)
that resulted in a greater initial nalmefene
concentration in the elderly group. While initial nalmefene plasma concentrations were transiently higher
in the elderly, it would not be anticipated that this
population would require dosing adjustment. No clinical
adverse events were noted in the elderly following the 1
mg intravenous nalmefene dose.<br/>Patients
with Hepatic Impairment: Subjects with hepatic disease, when compared to matched
normal controls, had a 28.3% decrease in plasma
clearance of nalmefene (0.56��0.21 L/hr/kg
versus 0.78��0.24 L/hr/kg, respectively).
Elimination half-life increased from 10.2��2.2
hours to 11.9��2.0 hours in the hepatically
impaired. No dosage adjustment is recommended since
nalmefene will be administered as an acute course of
therapy.<br/>Patients
with Renal Impairment: There was a statistically significant 27% decrease in plasma clearance of nalmefene in the end-stage renal
disease (ESRD) population during interdialysis (0.57��0.20 L/hr/kg) and a 25% decreased plasma
clearance in the ESRD population during intradialysis
(0.59��0.18 L/hr/kg) compared to normals (0.79��0.24 L/hr/kg). The elimination half-life was
prolonged in ESRD patients from 10.2��2.2
hours in normals to 26.1��9.9 hours.<br/>Gender
Differences: There has not been sufficient pharmacokinetic study to make a definitive statement as to whether the
pharmacokinetics of nalmefene differs between the
genders.
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REVEX is
contraindicated in patients with a known hypersensitivity to the
product.
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REVEX (nalmefene
hydrochloride injection) is available in the following presentations: An ampul containing
1 mL of 100��g/mL nalmefene base (Blue Label) Box of 10 (NDC
10019-315-21) An ampul containing
2 mL of 1 mg/mL nalmefene base (Green Label) Box of 10 (NDC
10019-311-22) Store at controlled room
temperature. REVEX is a
registered trademark of Ivax Laboratories, Inc. Baxter is a
registered trademark of Baxter International Inc. Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015
USA by: Taylor
Pharmaceuticals Decatur, IL 62525 For Product Inquiry
1 800 ANA DRUG (1-800-262-3784) U.S. Patent No.
4,535,157 June
2006
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General:<br/>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.<br/>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.<br/>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.<br/>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.<br/>Carcinogenesis and
Mutagenesis and Impairment of Fertility: Nalmefene
did not have mutagenic activity in the Ames test with five
bacterial strains or the mouse lymphoma assay. Clastogenic
activity was not observed in the mouse micronucleus test or in
the cytogenic bone marrow assay in rats. However, nalmefene did
exhibit a weak but significant clastogenic activity in the human
lymphocyte metaphase assay in the absence but not in the
presence of exogenous metabolic activation. Oral administration
of nalmefene up to 1200 mg/m/day did not affect
fertility, reproductive performance, and offspring survival in
rats.<br/>Use in Pregnancy:<br/>Pregnancy
Category B: Reproduction studies have been performed in rats (up to
1200 mg/m/day) and rabbits (up to 2400
mg/m/day) by oral administration of
nalmefene and in rabbits by intravenous administration
up to 96 mg/m/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.<br/>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.<br/>Use in Pediatric
Patients: Safety and
effectiveness of REVEX in pediatric patients have not been
established.<br/>Use in Neonates: The safety
and effectiveness of REVEX in neonates have not been established
in clinical studies. In a preclinical study, nalmefene was
administered by subcutaneous injection to rat pups at doses up
to 205 mg/m/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.<br/>Geriatric Use: Clinical
studies of REVEX (nalmefene hydrochloride injection) did not
include sufficient number of subjects aged 65 and over to
determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified
differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease
or other drug therapy.
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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 thatrequire 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.
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nalmefene hydrochloride
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Revex (Injection, Solution)
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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��g/kg in the postoperative setting and 1.5
mg/70 kg in the treatment of overdose are not recommended.<br/>Incidence less than
1%: CARDIOVASCULAR: Bradycardia, arrhythmia DIGESTIVE:
Diarrhea, dry mouth NERVOUS
SYSTEM: Somnolence, depression, agitation, nervousness, tremor, confusion, withdrawal syndrome, myoclonus RESPIRATORY: Pharyngitis SKIN:
Pruritus UROGENITAL:
Urinary retention The
incidence of adverse events was highest in patients who received
more than the recommended dose of REVEX.<br/>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.
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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.<br/>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 awarethat 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.
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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.
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Revex
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