Naltrexone hydrochloride 50 MG Oral Tablet
Generic Name: NALTREXONE HYDROCHLORIDE
Brand Name: NALTREXONE HYDROCHLORIDE
- Substance Name(s):
- NALTREXONE HYDROCHLORIDE
WARNINGS
Hepatotoxicity Naltrexone has the capacity to cause hepatocellular injury when given in excessive doses.
Naltrexone is contraindicated in acute hepatitis or liver failure, and its use in patients with active liver disease must be carefully considered in light of its hepatotoxic effects.
The margin of separation between the apparently safe dose of naltrexone and the dose causing hepatic injury appears to be only five-fold or less.
Naltrexone does not appear to be a hepatotoxin at the recommended doses.
Patients should be warned of the risk of hepatic injury and advised to stop the use of naltrexone and seek medical attention if they experience symptoms of acute hepatitis.
Evidence of the hepatotoxic potential of naltrexone is derived primarily from a placebo controlled study in which naltrexone hydrochloride was administered to obese subjects at a dose approximately five-fold that recommended for the blockade of opiate receptors (300 mg per day).
In that study, 5 of 26 naltrexone recipients developed elevations of serum transaminases (i.e., peak ALT values ranging from a low of 121 to a high of 532; or 3 to 19 times their baseline values) after 3 to 8 weeks of treatment.
Although 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, the lack of any transaminase elevations of similar magnitude in any of the 24 placebo patients in the same study is persuasive evidence that naltrexone is a direct (i.e., not idiosyncratic) hepatotoxin.
This conclusion is also supported by evidence from other placebo controlled studies in which exposure to naltrexone hydrochloride at doses above the amount recommended for the treatment of alcoholism or opiate blockade (50 mg/day) consistently produced more numerous and more significant elevations of serum transaminases than did placebo.
Transaminase elevations in 3 of 9 patients with Alzheimer’s Disease who received naltrexone hydrochloride (at doses up to 300 mg/day) for 5 to 8 weeks in an open clinical trial have been reported.
Although no cases of hepatic failure due to naltrexone administration have ever been reported, physicians are advised to consider this as a possible risk of treatment and to use the same care in prescribing naltrexone as they would other drugs with the potential for causing hepatic injury.
Unintended Precipitation of Abstinence To prevent occurrence of an acute abstinence syndrome, or exacerbation of a pre-existing subclinical abstinence syndrome, patients must be opioid-free for a minimum of 7 to 10 days before starting naltrexone.
Since the absence of an opioid drug in the urine is often not sufficient proof that a patient is opioid-free, a naloxone challenge should be employed if the prescribing physician feels there is a risk of precipitating a withdrawal reaction following administration of naltrexone.
The naloxone challenge test is described in the DOSAGE AND ADMINISTRATION section.
Attempt to Overcome Blockade While naltrexone is a potent antagonist with a prolonged pharmacologic effect (24 to 72 hours), the blockade produced by naltrexone is surmountable.
This is useful in patients who may require analgesia, but poses a potential risk to individuals who attempt, on their own, to overcome the blockade by administering large amounts of exogenous opioids.
Indeed, any attempt by a patient to overcome the antagonism by taking opioids is very dangerous and may lead to a fatal overdose.
Injury may arise because the plasma concentration of exogenous opioids attained immediately following their acute administration may be sufficient to overcome the competitive receptor blockade.
As a consequence, the patient may be in immediate danger of suffering life endangering opioid intoxication (e.g., respiratory arrest, circulatory collapse).
Patients should be told of the serious consequences of trying to overcome the opiate blockade (see PRECAUTIONS, Information for Patients ).
There is also the possibility that a patient who had been treated with naltrexone will respond to lower doses of opioids than previously used, particularly if taken in such a manner that high plasma concentrations remain in the body beyond the time that naltrexone exerts its therapeutic effects.
This could result in potentially life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.).
Patients should be aware that they may be more sensitive to lower doses of opioids after naltrexone treatment is discontinued.
Ultra Rapid Opioid Withdrawal Safe use of naltrexone in rapid opiate detoxification programs has not been established (see ADVERSE REACTIONS ).
OVERDOSAGE
There is limited clinical experience with naltrexone overdosage in humans.
In one study, subjects who received 800 mg daily naltrexone hydrochloride 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 naltrexone hydrochloride (generally ≥ 1,000 mg/kg) produced salivation, depression/reduced activity, tremors, and convulsions.
Mortalities in animals due to high-dose naltrexone 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 naltrexone hydrochloride 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.
DESCRIPTION
Naltrexone hydrochloride, an opioid antagonist, is a synthetic congener of oxymorphone with no opioid agonist properties.
Naltrexone differs in structure from oxymorphone in that the methyl group on the nitrogen atom is replaced by a cyclopropylmethyl group.
Naltrexone hydrochloride is also related to the potent opioid antagonist, naloxone, or n-allylnoroxymorphone.
Naltrexone hydrochloride has the chemical name of 17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride.
It has the following structural formula: Naltrexone hydrochloride is a white, crystalline compound.
The hydrochloride salt is soluble in water to the extent of about 100 mg/mL.
Naltrexone Hydrochloride Tablets USP for oral administration are available as film coated tablets, containing 50 mg of naltrexone hydrochloride.
In addition, each tablet contains the following inactive ingredients: crospovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, silicon dioxide, titanium dioxide, yellow iron oxide and red iron oxide.
Structural Formula
HOW SUPPLIED
Naltrexone Hydrochloride Tablets USP 50 mg are available as a yellow film coated capsule-shaped tablet with a convex surface, debossed with a number “50” and a full bisect in between the 5 and 0 on one side and “1170” on the other side.
Bottles of 30……………NDC 0406-1170-03 Bottles of 100…………..NDC 0406-1170-01 Storage: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Mallinckrodt, the “M” brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company.
© 2014 Mallinckrodt.
Mallinckrodt Inc.
Hazelwood, MO 63042 USA Rev 11/2014 Mallinckrodt™ Pharmaceuticals
INDICATIONS AND USAGE
Naltrexone hydrochloride tablets are indicated: In the treatment of alcohol dependence and for the blockade of the effects of exogenously administered opioids.
Naltrexone hydrochloride tablets have not been shown to provide any therapeutic benefit except as part of an appropriate plan of management for the addictions.
DOSAGE AND ADMINISTRATION
IF THERE IS ANY QUESTION OF OCCULT OPIOID DEPENDENCE, PERFORM A NALOXONE CHALLENGE TEST AND DO NOT INITIATE NALTREXONE THERAPY UNTIL THE NALOXONE CHALLENGE IS NEGATIVE.
Treatment of Alcoholism A dose of 50 mg once daily is recommended for most patients (see CLINICAL PHARMACOLOGY, Individualization of Dosage ).
The placebo-controlled studies that demonstrated the efficacy of naltrexone hydrochloride as an adjunctive treatment of alcoholism used a dose regimen of naltrexone hydrochloride 50 mg once daily for up to 12 weeks.
Other dose regimens or durations of therapy were not evaluated in these trials.
A patient is a candidate for treatment with naltrexone if: the patient is willing to take a medicine to help with alcohol dependence the patient is opioid free for 7 to 10 days the patient does not have severe or active liver or kidney problems (Typical guidelines suggest liver function tests no greater than 3 times the upper limits of normal, and bilirubin normal.) the patient is not allergic to naltrexone, and no other contraindications are present Refer to CONTRAINDICATIONS , WARNINGS , and PRECAUTIONS sections for additional information.
Naltrexone 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 naltrexone 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 Initiate treatment with naltrexone using the following guidelines – Treatment should not be attempted unless the patient has remained opioid-free for at least 7 to 10 days.
Self-reporting of abstinence from opioids in opioid addicts should be verified by analysis of the patient’s urine for absence of opioids.
The patient should not be manifesting withdrawal signs or reporting withdrawal symptoms.
If there is any question of occult opioid dependence, perform a naloxone challenge test.
If signs of opioid withdrawal are still observed following naloxone challenge, treatment with naltrexone should not be attempted.
The naloxone challenge can be repeated in 24 hours.
Treatment should be initiated carefully, with an initial dose of 25 mg of naltrexone hydrochloride.
If no withdrawal signs occur, the patient may be started on 50 mg a day thereafter.
Naloxone Challenge Test – 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 naltrexone therapy.
Repeat the challenge in 24 hours.
If the test is negative, naltrexone therapy may be started if no other contraindications are present.
If there is any doubt about the result of the test, hold naltrexone and repeat the challenge in 24 hours.
Alternative Dosing Schedules Once the patient has been started on naltrexone hydrochloride, 50 mg every 24 hours will produce adequate clinical blockade of the actions of parenterally administered opioids (i.e., this dose will block the effects of a 25 mg intravenous heroin challenge).
A flexible approach to a dosing regimen may need to be employed in cases of supervised administration.
Thus, patients may receive 50 mg of naltrexone hydrochloride 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 naltrexone 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 and CLINICAL PHARMACOLOGY, Individualization of Dosage ).
Patient Compliance Naltrexone 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.