Overdose
There is limited clinical experience with REVIA overdosage
in humans. In one study, subjects who received 800 mg daily REVIA for up to one
week showed no evidence of toxicity.
In the mouse, rat and guinea pig, the oral LD50s were
1,100 to 1,550 mg/kg; 1,450 mg/kg; and 1,490 mg/kg; respectively. High doses of
REVIA (generally ≥ 1,000 mg/kg) produced salivation, depression/reduced
activity, tremors, and convulsions. Mortalities in animals due to high-dose
REVIA administration usually were due to clonic-tonic convulsions and/or
respiratory failure.
Treatment of Overdosage
In view of the lack of actual experience in the treatment
of REVIA overdose, patients should be treated symptomatically in a closely
supervised environment. Physicians should contact a poison control center for
the most up-to-date information.
Contraindications
REVIA is contraindicated in:
- Patients receiving opioid analgesics.
- Patients currently dependent on opioids, including those
currently maintained on opiate agonists (e.g., methadone) or partial agonists
(e.g., buprenorphine).
- Patients in acute opioid withdrawal (see WARNINGS).
- Any individual who has failed the naloxone challenge test
or who has a positive urine screen for opioids.
- Any individual with a history of sensitivity to REVIA or
any other components of this product. It is not known if there is any
cross-sensitivity with naloxone or the phenanthrene containing opioids.
Undesirable effects
During two randomized, double-blind placebo-controlled
12-week trials to evaluate the efficacy of REVIA as an adjunctive treatment of
alcohol dependence, most patients tolerated REVIA well. In these studies, a
total of 93 patients received REVIA at a dose of 50 mg once daily. Five of
these patients discontinued REVIA because of nausea. No serious adverse events
were reported during these two trials.
While extensive clinical studies evaluating the use of
REVIA in detoxified, formerly opioid-dependent individuals failed to identify
any single, serious untoward risk of REVIA use, placebo-controlled studies
employing up to fivefold higher doses of REVIA (up to 300 mg per day) than that
recommended for use in opiate receptor blockade have shown that REVIA causes
hepatocellular injury in a substantial proportion of patients exposed at higher
doses (see WARNINGS and PRECAUTIONS, Laboratory Tests).
Aside from this finding, and the risk of precipitated
opioid withdrawal, available evidence does not incriminate REVIA, used at any
dose, as a cause of any other serious adverse reaction for the patient who is
“opioid-free.” It is critical to recognize that REVIA can precipitate
or exacerbate abstinence signs and symptoms in any individual who is not
completely free of exogenous opioids.
Patients with addictive disorders, especially opioid
addiction, are at risk for multiple numerous adverse events and abnormal
laboratory findings, including liver function abnormalities. Data from both
controlled and observational studies suggest that these abnormalities, other than
the dose-related hepatotoxicity described above, are not related to the use of
REVIA.
Among opioid-free individuals, REVIA administration at
the recommended dose has not been associated with a predictable profile of
serious adverse or untoward events. However, as mentioned above, among
individuals using opioids, REVIA may cause serious withdrawal reactions (see CONTRAINDICATIONS,
WARNINGS, DOSAGE AND ADMINISTRATION).
Reported Adverse Events
REVIA has not been shown to cause significant increases
in complaints in placebo-controlled trials in patients known to be free of
opioids for more than 7 to 10 days. Studies in alcoholic populations and in
volunteers in clinical pharmacology studies have suggested that a small
fraction of patients may experience an opioid withdrawal-like symptom complex
consisting of tearfulness, mild nausea, abdominal cramps, restlessness, bone or
joint pain, myalgia, and nasal symptoms. This may represent the unmasking of
occult opioid use, or it may represent symptoms attributable to naltrexone. A
number of alternative dosing patterns have been recommended to try to reduce
the frequency of these complaints.
Alcoholism
In an open label safety study with approximately 570
individuals with alcoholism receiving REVIA, the following new-onset adverse
reactions occurred in 2% or more of the patients: nausea (10%), headache (7%),
dizziness (4%), nervousness (4%), fatigue (4%), insomnia (3%), vomiting (3%),
anxiety (2%) and somnolence (2%).
Depression, suicidal ideation, and suicidal attempts have
been reported in all groups when comparing naltrexone, placebo, or controls undergoing
treatment for alcoholism.
RATE RANGES OF NEW ONSET EVENTS
| |
Naltrexone |
Placebo |
| Depression |
0 to 15% |
0 to 17% |
| Suicide Attempt/Ideation |
0 to 1% |
0 to 3% |
Although no causal relationship
with REVIA is suspected, physicians should be aware that treatment with REVIA
does not reduce the risk of suicide in these patients (see PRECAUTIONS).
Opioid Addiction
The following adverse reactions
have been reported both at baseline and during the REVIA clinical trials in
opioid addiction at an incidence rate of more than 10%:
Difficulty sleeping, anxiety,
nervousness, abdominal pain/cramps, nausea and/or vomiting, low energy, joint
and muscle pain, and headache.
The incidence was less than 10%
for:
Loss of appetite, diarrhea, constipation, increased
thirst, increased energy, feeling down, irritability, dizziness, skin rash,
delayed ejaculation, decreased potency, and chills.
The following events occurred in less than 1% of
subjects:
Respiratory
Nasal congestion, itching, rhinorrhea, sneezing, sore
throat, excess mucus or phlegm, sinus trouble, heavy breathing, hoarseness,
cough, shortness of breath.
Cardiovascular
Nose bleeds, phlebitis, edema, increased blood pressure,
non-specific ECG changes, palpitations, tachycardia.
Gastrointestinal
Excessive gas, hemorrhoids, diarrhea, ulcer.
Musculoskeletal
Painful shoulders, legs or knees; tremors, twitching.
Genitourinary
Increased frequency of, or discomfort during, urination;
increased or decreased sexual interest.
Dermatologic
Oily skin, pruritus, acne, athlete's foot, cold sores,
alopecia.
Psychiatric
Depression, paranoia, fatigue, restlessness, confusion,
disorientation, hallucinations, nightmares, bad dreams.
Special senses
Eyes–blurred, burning, light sensitive, swollen, aching,
strained; ears–“clogged,” aching, tinnitus.
General
Increased appetite, weight loss, weight gain, yawning,
somnolence, fever, dry mouth, head “pounding,” inguinal pain, swollen
glands, “side” pains, cold feet, “hot spells.”
Postmarketing Experience
Data collected from postmarketing use of REVIA show that
most events usually occur early in the course of drug therapy and are
transient. It is not always possible to distinguish these occurrences from
those signs and symptoms that may result from a withdrawal syndrome. Events
that have been reported include anorexia, asthenia, chest pain, fatigue,
headache, hot flushes, malaise, changes in blood pressure, agitation,
dizziness, hyperkinesia, nausea, vomiting, tremor, abdominal pain, diarrhea,
palpitations, myalgia, anxiety, confusion, euphoria, hallucinations, insomnia,
nervousness, somnolence, abnormal thinking, dyspnea, rash, increased sweating, vision
abnormalities, and idiopathic thrombocytopenic purpura.
In some individuals the use of opioid antagonists has
been associated with a change in baseline levels of some hypothalamic,
pituitary, adrenal, or gonadal hormones. The clinical significance of such
changes is not fully understood.
Adverse events, including withdrawal symptoms and death,
have been reported with the use of REVIA in ultra rapid opiate detoxification
programs. The cause of death in these cases is not known (see WARNINGS).
Laboratory Tests
In a placebo controlled study in which REVIA was
administered to obese subjects at a dose approximately five-fold that
recommended for the blockade of opiate receptors (300 mg per day), 19% (5/26)
of REVIA recipients and 0% (0/24) of placebo-treated patients developed
elevations of serum transaminases (i.e., peak ALT values ranging from 121 to
532; or 3 to 19 times their baseline values) after three to eight weeks of
treatment. The patients involved were generally clinically asymptomatic, and
the transaminase levels of all patients on whom follow-up was obtained returned
to (or toward) baseline values in a matter of weeks.
Transaminase elevations were also observed in other
placebo controlled studies in which exposure to REVIA at doses above the amount
recommended for the treatment of alcoholism or opioid blockade consistently
produced more numerous and more significant elevations of serum transaminases
than did placebo. Transaminase elevations occurred in 3 of 9 patients with
Alzheimer's Disease who received REVIA (at doses up to 300 mg/day) for 5 to 8
weeks in an open clinical trial.
Drug Abuse And Dependence
REVIA is a pure opioid antagonist. It does not lead to
physical or psychological dependence. Tolerance to the opioid antagonist effect
is not known to occur.
Therapeutic indications
REVIA is indicated in the treatment of alcohol dependence
and for the blockade of the effects of exogenously administered opioids.
REVIA has not been shown to provide any therapeutic
benefit except as part of an appropriate plan of management for the addictions.
Pharmacokinetic properties
REVIA is a pure opioid receptor antagonist. Although well
absorbed orally, naltrexone is subject to significant first pass metabolism
with oral bioavailability estimates ranging from 5 to 40%. The activity of
naltrexone is believed to be due to both parent and the 6β-naltrexol
metabolite. Both parent drug and metabolites are excreted primarily by the
kidney (53% to 79% of the dose), however, urinary excretion of unchanged
naltrexone accounts for less than 2% of an oral dose and fecal excretion is a
minor elimination pathway. The mean elimination half-life (T-½) values for
naltrexone and 6-β-naltrexol are 4 hours and 13 hours, respectively. Naltrexone
and 6-β-naltrexol are dose proportional in terms of AUC and Cmax over the range
of 50 to 200 mg and do not accumulate after 100 mg daily doses.
Absorption
Following oral administration, naltrexone undergoes rapid
and nearly complete absorption with approximately 96% of the dose absorbed from
the gastrointestinal tract. Peak plasma levels of both naltrexone and
6-β-naltrexol occur within one hour of dosing.
Distribution
The volume of distribution for naltrexone following
intravenous administration is estimated to be 1350 liters. In vitro tests with
human plasma show naltrexone to be 21% bound to plasma proteins over the therapeutic
dose range.
Metabolism
The systemic clearance (after intravenous administration)
of naltrexone is ~3.5 L/min, which exceeds liver blood flow (~1.2 L/min). This
suggests both that naltrexone is a highly extracted drug ( > 98% metabolized)
and that extrahepatic sites of drug metabolism exist. The major metabolite of
naltrexone is 6-β-naltrexol. Two other minor metabolites are
2-hydroxy-3-methoxy-6-β-naltrexol and 2-hydroxy-3-methyl-naltrexone. Naltrexone
and its metabolites are also conjugated to form additional metabolic products.
Elimination
The renal clearance for naltrexone ranges from 30 to 127
mL/min and suggests that renal elimination is primarily by glomerular
filtration. In comparison, the renal clearance for 6β-naltrexol ranges from 230
to 369 mL/min, suggesting an additional renal tubular secretory mechanism. The
urinary excretion of unchanged naltrexone accounts for less than 2% of an oral
dose; urinary excretion of unchanged and conjugated 6-β-naltrexol accounts for
43% of an oral dose. The pharmacokinetic profile of naltrexone suggests that
naltrexone and its metabolites may undergo enterohepatic recycling.
Date of revision of the text
. 10/2013
Name of the medicinal product
Revia
Fertility, pregnancy and lactation
Teratogenic Effects - Category C
Naltrexone has been shown to increase the incidence of
early fetal loss when given to rats at doses ≥ 30 mg/kg/day (180 mg/m²/day;
5 times the recommended therapeutic dose, based on body surface area) and to
rabbits at oral doses ≥ 60 mg/kg/day (720 mg/m²/day; 18 times
the recommended therapeutic dose, based on body surface area). There was no
evidence of teratogenicity when naltrexone was administered orally to rats and
rabbits during the period of major organogenesis at doses up to 200 mg/kg/day
(32 and 65 times the recommended therapeutic dose, respectively, based on body
surface area).
Rats do not form appreciable quantities of the major
human metabolite, 6-β-naltrexol; therefore, the potential reproductive toxicity
of the metabolite in rats is not known.
There are no adequate and well-controlled studies in
pregnant women. REVIA should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Qualitative and quantitative composition
REVIA® (naltrexone hydrochloride) beige,
round, biconvex, film-coated, scored tablet. Debossed with REVIA on one side
and with a stylized b/275 on the scored side. Available in bottles of:
| 30 Unit-of-use |
NDC 51285-275-01 |
| 100 |
NDC 51285-275-02 |
Store at 20° to 25°C (68° to
77°F).
Dispense in a tight container.
Duramed Pharmaceuticals, Inc. Subsidiary of Barr
Pharmaceuticals, Inc. Pomona, New York 10970. Revised:. 10/2013
Special warnings and precautions for use
WARNINGS
Vulnerability to Opioid Overdose
After opioid detoxification, patients are likely to have
reduced tolerance to opioids. As the blockade of exogenous opioids provided by
REVIA wanes and eventually dissipates completely, patients who have been
treated with REVIA may respond to lower doses of opioids than previously used,
just as they would shortly after completing detoxification.
This could result in potentially life-threatening opioid
intoxication (respiratory compromise or arrest, circulatory collapse, etc.) if
the patient uses previously tolerated doses of opioids. Cases of opioid
overdose with fatal outcomes have been reported in patients after discontinuing
treatment.
Patients should be alerted that they may be more
sensitive to opioids, even at lower doses, after REVIA treatment is
discontinued. It is important that patients inform family members, and the
people closest to the patient of this increased sensitivity to opioids and the
risk of overdose (see PATIENT INFORMATION).
There is also the possibility that a patient who is treated
with REVIA could overcome the opioid blockade effect of REVIA. Although REVIA
is a potent antagonist, the blockade produced by REVIA is surmountable. The
plasma concentration of exogenous opioids attained immediately following their
acute administration may be sufficient to overcome the competitive receptor
blockade. This poses a potential risk to individuals who attempt, on their own,
to overcome the blockade by administering large amounts of exogenous opioids.
Any attempt by a patient to overcome the antagonism by taking opioids is
especially dangerous and may lead to life-threatening opioid intoxication or
fatal overdose. Patients should be told of the serious consequences of trying
to overcome the opioid blockade (see PATIENT INFORMATION).
Precipitated Opioid Withdrawal
The symptoms of spontaneous opioid withdrawal (which are
associated with the discontinuation of opioid in a dependent individual) are
uncomfortable, but they are not generally believed to be severe or necessitate
hospitalization. However, when withdrawal is precipitated abruptly by the
administration of an opioid antagonist to an opioid-dependent patient, the
resulting withdrawal syndrome can be severe enough to require hospitalization.
Symptoms of withdrawal have usually appeared within five minutes of ingestion
of REVIA and have lasted for up to 48 hours. Mental status changes including
confusion, somnolence and visual hallucinations have occurred. Significant
fluid losses from vomiting and diarrhea have required intravenous fluid
administration. Review of postmarketing cases of precipitated opioid withdrawal
in association with naltrexone treatment has identified cases with symptoms of
withdrawal severe enough to require hospital admission, and in some cases, management
in the intensive care unit.
To prevent occurrence of precipitated withdrawal in
patients dependent on opioids, or exacerbation of a pre-existing subclinical
withdrawal syndrome, opioid-dependent patients, including those being treated
for alcohol dependence, should be opioid-free (including tramadol) before
starting REVIA treatment. An opioid-free interval of a minimum of 7 to 10 days
is recommended for patients previously dependent on short-acting opioids.
Patients transitioning from buprenorphine or methadone may be vulnerable to
precipitation of withdrawal symptoms for as long as two weeks.
If a more rapid transition from agonist to antagonist
therapy is deemed necessary and appropriate by the healthcare provider, monitor
the patient closely in an appropriate medical setting where precipitated
withdrawal can be managed.
In every case, healthcare providers should always be
prepared to manage withdrawal symptomatically with non-opioid medications
because there is no completely reliable method for determining whether a
patient has had an adequate opioid-free period. A naloxone challenge test may
be helpful; however, a few case reports have indicated that patients may
experience precipitated withdrawal despite having a negative urine toxicology
screen or tolerating a naloxone challenge test (usually in the setting of
transitioning from buprenorphine treatment). Patients should be made aware of
the risks associated with precipitated withdrawal and encouraged to give an
accurate account of last opioid use. Patients treated for alcohol dependence
with REVIA should also be assessed for underlying opioid dependence and for any
recent use of opioids prior to initiation of treatment with REVIA. Precipitated
opioid withdrawal has been observed in alcohol-dependent patients in
circumstances where the prescriber had been unaware of the additional use of
opioids or co-dependence on opioids.
Hepatotoxicity
Cases of hepatitis and clinically significant liver
dysfunction were observed in association with REVIA exposure during the
clinical development program and in the postmarketing period. Transient,
asymptomatic hepatic transaminase elevations were also observed in the clinical
trials and postmarketing period. When patients presented with elevated
transaminases, there were often other potential causative or contributory
etiologies identified, including pre-existing alcoholic liver disease,
hepatitis B and/or C infection, and concomitant usage of other potentially
hepatotoxic drugs. Although clinically significant liver dysfunction is not
typically recognized as a manifestation of opioid withdrawal, opioid withdrawal
that is precipitated abruptly may lead to systemic sequelae, including acute
liver injury.
Patients should be warned of the risk of hepatic injury
and advised to seek medical attention if they experience symptoms of acute
hepatitis. Use of REVIA should be discontinued in the event of symptoms and/or
signs of acute hepatitis.
Depression and Suicidality
Depression, suicide, attempted suicide and suicidal
ideation have been reported in the postmarketing experience with REVIA
(naltrexone hydrochloride) used in the treatment of opioid dependence. No
causal relationship has been demonstrated. In the literature, endogenous
opioids have been theorized to contribute to a variety of conditions.
Alcohol-and opioid-dependent patients, including those
taking REVIA, should be monitored for the development of depression or suicidal
thinking. Families and caregivers of patients being treated with REVIA should
be alerted to the need to monitor patients for the emergence of symptoms of
depression or suicidality, and to report such symptoms to the patient's
healthcare provider.
Ultra Rapid Opioid Withdrawal
Safe use of REVIA in ultra rapid opiate detoxification
programs has not been established (see ADVERSE REACTIONS).
PRECAUTIONS
General
When Reversal of REVIA Blockade is Required for Pain
Management
In an emergency situation in patients receiving fully
blocking doses of REVIA, a suggested plan of management is regional analgesia,
conscious sedation with a benzodiazepine, use of non-opioid analgesics or
general anesthesia.
In a situation requiring opioid analgesia, the amount of
opioid required may be greater than usual, and the resulting respiratory
depression may be deeper and more prolonged.
A rapidly acting opioid analgesic which minimizes the
duration of respiratory depression is preferred. The amount of analgesic
administered should be titrated to the needs of the patient. Non-receptor
mediated actions may occur and should be expected (e.g., facial swelling,
itching, generalized erythema, or bronchoconstriction) presumably due to
histamine release.
Irrespective of the drug chosen to reverse REVIA
blockade, the patient should be monitored closely by appropriately trained
personnel in a setting equipped and staffed for cardiopulmonary resuscitation.
Special Risk Patients
Renal Impairment
REVIA and its primary metabolite are excreted primarily
in the urine, and caution is recommended in administering the drug to patients
with renal impairment.
Hepatic Impairment
An increase in naltrexone AUC of approximately 5-and
10-fold in patients with compensated and decompensated liver cirrhosis,
respectively, compared with subjects with normal liver function has been
reported. These data also suggest that alterations in naltrexone
bioavailability are related to liver disease severity.
Laboratory Tests
REVIA does not interfere with thin-layer, gas-liquid, and
high pressure liquid chromatographic methods which may be used for the
separation and detection of morphine, methadone or quinine in the urine. REVIA
may or may not interfere with enzymatic methods for the detection of opioids
depending on the specificity of the test. Please consult the test manufacturer
for specific details.
Carcinogenesis, Mutagenesis and Impairment of Fertility
The following statements are based on the results of
experiments in mice and rats. The potential carcinogenic, mutagenic and
fertility effects of the metabolite 6-β-naltrexol are unknown.
In a two-year carcinogenicity study in rats, there were
small increases in the numbers of testicular mesotheliomas in males and tumors
of vascular origin in males and females. The incidence of mesothelioma in males
given naltrexone at a dietary dose of 100 mg/kg/day (600 mg/m²/day;
16 times the recommended therapeutic dose, based on body surface area) was 6%,
compared with a maximum historical incidence of 4%. The incidence of vascular
tumors in males and females given dietary doses of 100 mg/kg/day (600 mg/m²/day)
was 4%, but only the incidence in females was increased compared with a maximum
historical control incidence of 2%. There was no evidence of carcinogenicity in
a two-year dietary study with naltrexone in male and female mice.
There was limited evidence of a weak genotoxic effect of
naltrexone in one gene mutation assay in a mammalian cell line, in the Drosophila
recessive lethal assay, and in non-specific DNA repair tests with E. coli.
However, no evidence of genotoxic potential was observed in a range of other in
vitro tests, including assays for gene mutation in bacteria, yeast, or in a
second mammalian cell line, a chromosomal aberration assay, and an assay for
DNA damage in human cells. Naltrexone did not exhibit clastogenicity in an in
vivo mouse micronucleus assay.
Naltrexone (100 mg/kg/day [600 mg/m²/day] PO;
16 times the recommended therapeutic dose, based on body surface area) caused a
significant increase in pseudopregnancy in the rat. A decrease in the pregnancy
rate of mated female rats also occurred. There was no effect on male fertility
at this dose level. The relevance of these observations to human fertility is
not known.
Pregnancy
Teratogenic Effects - Category C
Naltrexone has been shown to increase the incidence of
early fetal loss when given to rats at doses ≥ 30 mg/kg/day (180 mg/m²/day;
5 times the recommended therapeutic dose, based on body surface area) and to
rabbits at oral doses ≥ 60 mg/kg/day (720 mg/m²/day; 18 times
the recommended therapeutic dose, based on body surface area). There was no
evidence of teratogenicity when naltrexone was administered orally to rats and
rabbits during the period of major organogenesis at doses up to 200 mg/kg/day
(32 and 65 times the recommended therapeutic dose, respectively, based on body
surface area).
Rats do not form appreciable quantities of the major
human metabolite, 6-β-naltrexol; therefore, the potential reproductive toxicity
of the metabolite in rats is not known.
There are no adequate and well-controlled studies in
pregnant women. REVIA should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Labor and Delivery
Whether or not REVIA affects the duration of labor and
delivery is unknown.
Nursing Mothers
In animal studies, naltrexone and 6-β-naltrexol were
excreted in the milk of lactating rats dosed orally with naltrexone. Whether or
not REVIA is excreted in human milk is unknown. Because many drugs are excreted
in human milk, caution should be exercised when REVIA is administered to a
nursing woman.
Pediatric Use
The safe use of REVIA in pediatric patients younger than
18 years old has not been established.
Dosage (Posology) and method of administration
To reduce the risk of precipitated withdrawal in patients
dependent on opioids, or exacerbation of a preexisting subclinical withdrawal
syndrome, opioid-dependent patients, including those being treated for alcohol
dependence, should be opioid-free (including tramadol) before starting REVIA
treatment. An opioid-free interval of a minimum of 7 to 10 days is recommended
for patients previously dependent on short-acting opioids.
Switching from Buprenorphine, Buprenorphine/Naloxone, or
Methadone
There are no systematically collected data that
specifically address the switch from buprenorphine or methadone to REVIA;
however, review of postmarketing case reports have indicated that some patients
may experience severe manifestations of precipitated withdrawal when being
switched from opioid agonist therapy to opioid antagonist therapy (see WARNINGS).
Patients transitioning from buprenorphine or methadone may be vulnerable to
precipitation of withdrawal symptoms for as long as 2 weeks. Healthcare
providers should be prepared to manage withdrawal symptomatically with
non-opioid medications.
Treatment of Alcoholism
A dose of 50 mg once daily is recommended for most
patients. The placebo-controlled studies that demonstrated the efficacy of
REVIA as an adjunctive treatment of alcoholism used a dose regimen of REVIA 50
mg once daily for up to 12 weeks. Other dose regimens or durations of therapy
were not evaluated in these trials.
REVIA should be considered as only one of many factors
determining the success of treatment of alcoholism. Factors associated with a
good outcome in the clinical trials with REVIA were the type, intensity, and
duration of treatment; appropriate management of comorbid conditions; use of
community-based support groups; and good medication compliance. To achieve the
best possible treatment outcome, appropriate compliance-enhancing techniques
should be implemented for all components of the treatment program, especially
medication compliance.
Treatment of Opioid Dependence
Treatment should be initiated with an initial dose of 25
mg of REVIA. If no withdrawal signs occur, the patient may be started on 50 mg
a day thereafter.
A dose of 50 mg once a day will produce adequate clinical
blockade of the actions of parenterally administered opioids. As with many
non-agonist treatments for addiction, REVIA is of proven value only when given
as part of a comprehensive plan of management that includes some measure to
ensure the patient takes the medication.
Naloxone Challenge Test
Clinicians are reminded that there is no completely
reliable method for determining whether a patient has had an adequate opioid-free
period. A naloxone challenge test may be helpful if there is any question of
occult opioid dependence. If signs of opioid withdrawal are still observed
following naloxone challenge, treatment with REVIA should not be attempted. The
naloxone challenge can be repeated in 24 hours.
The naloxone challenge test should not be performed in a
patient showing clinical signs or symptoms of opioid withdrawal, or in a
patient whose urine contains opioids. The naloxone challenge test may be
administered by either the intravenous or subcutaneous routes.
Intravenous
Inject 0.2 mg naloxone.
Observe for 30 seconds for signs or symptoms of
withdrawal.
If no evidence of withdrawal, inject 0.6 mg of naloxone.
Observe for an additional 20 minutes.
Subcutaneous
Administer 0.8 mg naloxone.
Observe for 20 minutes for signs or symptoms of
withdrawal.
Note: Individual patients, especially those with
opioid dependence, may respond to lower doses of naloxone. In some cases, 0.1
mg IV naloxone has produced a diagnostic response.
Interpretation of the Challenge
Monitor vital signs and observe the patient for signs and
symptoms of opioid withdrawal. These may include, but are not limited to:
nausea, vomiting, dysphoria, yawning, sweating, tearing, rhinorrhea, stuffy
nose, craving for opioids, poor appetite, abdominal cramps, sense of fear, skin
erythema, disrupted sleep patterns, fidgeting, uneasiness, poor ability to
focus, mental lapses, muscle aches or cramps, pupillary dilation, piloerection,
fever, changes in blood pressure, pulse or temperature, anxiety, depression,
irritability, backache, bone or joint pains, tremors, sensations of skin
crawling or fasciculations. If signs or symptoms of withdrawal appear, the test
is positive and no additional naloxone should be administered.
Warning: If the test is positive, do NOT initiate
REVIA therapy. Repeat the challenge in 24 hours. If the test is negative,
REVIA therapy may be started if no other contraindications are present. If
there is any doubt about the result of the test, hold REVIA and repeat the
challenge in 24 hours.
Alternative Dosing Schedules
A flexible approach to a dosing regimen may need to be
employed in cases of supervised administration. Thus, patients may receive 50
mg of REVIA every weekday with a 100 mg dose on Saturday, 100 mg every other
day, or 150 mg every third day. The degree of blockade produced by REVIA may be
reduced by these extended dosing intervals.
There may be a higher risk of hepatocellular injury with
single doses above 50 mg, and use of higher doses and extended dosing intervals
should balance the possible risks against the probable benefits (see WARNINGS).
Patient Compliance
REVIA should be considered as only one of many factors
determining the success of treatment. To achieve the best possible treatment
outcome, appropriate compliance-enhancing techniques should be implemented for
all components of the treatment program, including medication compliance.
Interaction with other medicinal products and other forms of interaction
SIDE EFFECTS
During two randomized, double-blind placebo-controlled
12-week trials to evaluate the efficacy of REVIA as an adjunctive treatment of
alcohol dependence, most patients tolerated REVIA well. In these studies, a
total of 93 patients received REVIA at a dose of 50 mg once daily. Five of
these patients discontinued REVIA because of nausea. No serious adverse events
were reported during these two trials.
While extensive clinical studies evaluating the use of
REVIA in detoxified, formerly opioid-dependent individuals failed to identify
any single, serious untoward risk of REVIA use, placebo-controlled studies
employing up to fivefold higher doses of REVIA (up to 300 mg per day) than that
recommended for use in opiate receptor blockade have shown that REVIA causes
hepatocellular injury in a substantial proportion of patients exposed at higher
doses (see WARNINGS and PRECAUTIONS, Laboratory Tests).
Aside from this finding, and the risk of precipitated
opioid withdrawal, available evidence does not incriminate REVIA, used at any
dose, as a cause of any other serious adverse reaction for the patient who is
“opioid-free.” It is critical to recognize that REVIA can precipitate
or exacerbate abstinence signs and symptoms in any individual who is not
completely free of exogenous opioids.
Patients with addictive disorders, especially opioid
addiction, are at risk for multiple numerous adverse events and abnormal
laboratory findings, including liver function abnormalities. Data from both
controlled and observational studies suggest that these abnormalities, other than
the dose-related hepatotoxicity described above, are not related to the use of
REVIA.
Among opioid-free individuals, REVIA administration at
the recommended dose has not been associated with a predictable profile of
serious adverse or untoward events. However, as mentioned above, among
individuals using opioids, REVIA may cause serious withdrawal reactions (see CONTRAINDICATIONS,
WARNINGS, DOSAGE AND ADMINISTRATION).
Reported Adverse Events
REVIA has not been shown to cause significant increases
in complaints in placebo-controlled trials in patients known to be free of
opioids for more than 7 to 10 days. Studies in alcoholic populations and in
volunteers in clinical pharmacology studies have suggested that a small
fraction of patients may experience an opioid withdrawal-like symptom complex
consisting of tearfulness, mild nausea, abdominal cramps, restlessness, bone or
joint pain, myalgia, and nasal symptoms. This may represent the unmasking of
occult opioid use, or it may represent symptoms attributable to naltrexone. A
number of alternative dosing patterns have been recommended to try to reduce
the frequency of these complaints.
Alcoholism
In an open label safety study with approximately 570
individuals with alcoholism receiving REVIA, the following new-onset adverse
reactions occurred in 2% or more of the patients: nausea (10%), headache (7%),
dizziness (4%), nervousness (4%), fatigue (4%), insomnia (3%), vomiting (3%),
anxiety (2%) and somnolence (2%).
Depression, suicidal ideation, and suicidal attempts have
been reported in all groups when comparing naltrexone, placebo, or controls undergoing
treatment for alcoholism.
RATE RANGES OF NEW ONSET EVENTS
| |
Naltrexone |
Placebo |
| Depression |
0 to 15% |
0 to 17% |
| Suicide Attempt/Ideation |
0 to 1% |
0 to 3% |
Although no causal relationship
with REVIA is suspected, physicians should be aware that treatment with REVIA
does not reduce the risk of suicide in these patients (see PRECAUTIONS).
Opioid Addiction
The following adverse reactions
have been reported both at baseline and during the REVIA clinical trials in
opioid addiction at an incidence rate of more than 10%:
Difficulty sleeping, anxiety,
nervousness, abdominal pain/cramps, nausea and/or vomiting, low energy, joint
and muscle pain, and headache.
The incidence was less than 10%
for:
Loss of appetite, diarrhea, constipation, increased
thirst, increased energy, feeling down, irritability, dizziness, skin rash,
delayed ejaculation, decreased potency, and chills.
The following events occurred in less than 1% of
subjects:
Respiratory
Nasal congestion, itching, rhinorrhea, sneezing, sore
throat, excess mucus or phlegm, sinus trouble, heavy breathing, hoarseness,
cough, shortness of breath.
Cardiovascular
Nose bleeds, phlebitis, edema, increased blood pressure,
non-specific ECG changes, palpitations, tachycardia.
Gastrointestinal
Excessive gas, hemorrhoids, diarrhea, ulcer.
Musculoskeletal
Painful shoulders, legs or knees; tremors, twitching.
Genitourinary
Increased frequency of, or discomfort during, urination;
increased or decreased sexual interest.
Dermatologic
Oily skin, pruritus, acne, athlete's foot, cold sores,
alopecia.
Psychiatric
Depression, paranoia, fatigue, restlessness, confusion,
disorientation, hallucinations, nightmares, bad dreams.
Special senses
Eyes–blurred, burning, light sensitive, swollen, aching,
strained; ears–“clogged,” aching, tinnitus.
General
Increased appetite, weight loss, weight gain, yawning,
somnolence, fever, dry mouth, head “pounding,” inguinal pain, swollen
glands, “side” pains, cold feet, “hot spells.”
Postmarketing Experience
Data collected from postmarketing use of REVIA show that
most events usually occur early in the course of drug therapy and are
transient. It is not always possible to distinguish these occurrences from
those signs and symptoms that may result from a withdrawal syndrome. Events
that have been reported include anorexia, asthenia, chest pain, fatigue,
headache, hot flushes, malaise, changes in blood pressure, agitation,
dizziness, hyperkinesia, nausea, vomiting, tremor, abdominal pain, diarrhea,
palpitations, myalgia, anxiety, confusion, euphoria, hallucinations, insomnia,
nervousness, somnolence, abnormal thinking, dyspnea, rash, increased sweating, vision
abnormalities, and idiopathic thrombocytopenic purpura.
In some individuals the use of opioid antagonists has
been associated with a change in baseline levels of some hypothalamic,
pituitary, adrenal, or gonadal hormones. The clinical significance of such
changes is not fully understood.
Adverse events, including withdrawal symptoms and death,
have been reported with the use of REVIA in ultra rapid opiate detoxification
programs. The cause of death in these cases is not known (see WARNINGS).
Laboratory Tests
In a placebo controlled study in which REVIA was
administered to obese subjects at a dose approximately five-fold that
recommended for the blockade of opiate receptors (300 mg per day), 19% (5/26)
of REVIA recipients and 0% (0/24) of placebo-treated patients developed
elevations of serum transaminases (i.e., peak ALT values ranging from 121 to
532; or 3 to 19 times their baseline values) after three to eight weeks of
treatment. The patients involved were generally clinically asymptomatic, and
the transaminase levels of all patients on whom follow-up was obtained returned
to (or toward) baseline values in a matter of weeks.
Transaminase elevations were also observed in other
placebo controlled studies in which exposure to REVIA at doses above the amount
recommended for the treatment of alcoholism or opioid blockade consistently
produced more numerous and more significant elevations of serum transaminases
than did placebo. Transaminase elevations occurred in 3 of 9 patients with
Alzheimer's Disease who received REVIA (at doses up to 300 mg/day) for 5 to 8
weeks in an open clinical trial.
Drug Abuse And Dependence
REVIA is a pure opioid antagonist. It does not lead to
physical or psychological dependence. Tolerance to the opioid antagonist effect
is not known to occur.
DRUG INTERACTIONS
Studies to evaluate possible interactions between REVIA
and drugs other than opiates have not been performed. Consequently, caution is
advised if the concomitant administration of REVIA and other drugs is required.
The safety and efficacy of concomitant use of REVIA and
disulfiram is unknown, and the concomitant use of two potentially hepatotoxic
medications is not ordinarily recommended unless the probable benefits outweigh
the known risks.
Lethargy and somnolence have been reported following
doses of REVIA and thioridazine.
Patients taking REVIA may not benefit from opioid
containing medicines, such as cough and cold preparations, antidiarrheal
preparations, and opioid analgesics. In an emergency situation when opioid
analgesia must be administered to a patient receiving REVIA, the amount of
opioid required may be greater than usual, and the resulting respiratory
depression may be deeper and more prolonged (see PRECAUTIONS).
