Consumer medicine information

REVIA

Naltrexone hydrochloride

BRAND INFORMATION

Brand name

ReVia Tablet

Active ingredient

Naltrexone hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using REVIA.

What is in this leaflet

This leaflet answers some common questions about REVIA®. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking REVIA against the benefits that are expected. This leaflet does not contain everything about REVIA. Your doctor has been provided with full information and can answer any questions you may have. Follow your doctor's advice even if it differs from what is in this leaflet.

Please read this leaflet carefully and keep it in a safe place so you may refer to it later.

What REVIA is used for

REVIA is used to help opiate drug addicts discontinue their habit. It is also used to help alcoholics dry out and remain abstinent. Your doctor may have prescribed REVIA for another use. Ask your doctor if you have any questions about why REVIA was prescribed for you.

REVIA is not addictive. This medicine is available only with a doctor's prescription.

How REVIA works

REVIA tablets contain the active ingredient, naltrexone hydrochloride. It is an opiate antagonist. This means it fights the effects of opiate drugs (such as heroin) on the body, and blocks euphoria (or "high") due to these opiates.

The use of REVIA to treat your condition can lead to side-effects, which are discussed below.

Before you take REVIA

REVIA is not suitable for everyone.

When you must not take REVIA:

  • You must not take REVIA if you have a history of severe allergic reactions to REVIA or to any of the ingredients listed at the end of this leaflet.
  • Do not take REVIA if you are still using heroin or drugs like it.
    If you take REVIA right after taking an opiate you will suffer withdrawal symptoms (cold turkey) (such as nausea, vomiting, shakiness, sweating and anxiety) which may be severe.
  • Do not take REVIA if you are experiencing withdrawal symptoms.
  • Do not take REVIA if you are on certain pain killers. Ask your doctor or pharmacist.
  • Do not take REVIA if you have hepatitis or liver failure. Hepatitis is liver disease with nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark coloured urine.
  • Do not take REVIA after the expiry date printed on the pack. If you take this medicine after the expiry date has passed, it may not work as well.
  • Do not take REVIA if the packaging is torn or shows signs of tampering.

Before you take REVIA

Tell your doctor if you have allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • Tell your doctor if you are pregnant or intend to become pregnant.
  • Tell your doctor if you are breastfeeding or intend to breastfeed.
  • Tell your doctor if you have or have had any liver disease.
  • Tell your doctor if you have or have had any kidney disease.
  • Tell your doctor if you are under 18 years of age.

Taking other medicines

It is especially important to tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop. These medicines may be affected by REVIA or they may affect how well REVIA works.

  • Tell your doctor if you are taking thioridizine or disulfiram.
  • REVIA may reduce or stop the effect of some cough and cold medicines, some medicines that treat loose bowel motions and some pain killers. If this happens, do not take larger doses of these other medicines. If you do, you may become very sick. Talk to your doctor and your doctor will advise you.

Know the medicines you take. Keep a list of your medicines with you to show your doctor or pharmacist.

If you have not told your doctor about any of the above, tell them before you take REVIA.

While you are taking REVIA

Things you must do:

  • You must tell your doctor immediately if you become pregnant while taking REVIA.
  • Tell all of the doctors, dentists and pharmacists who are treating you that you are taking REVIA.
  • If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking REVIA.

Things you must not do:

  • Do not use any other medicines while using REVIA unless you have discussed this with your doctor or pharmacist. This includes medicines you can buy without a prescription from a pharmacy, supermarket or health food shop or street drugs. REVIA may not protect you if you take large amounts of an opiate in an attempt to overcome the blocking effects of REVIA. Large doses of opiate can lead to difficulty in breathing and even to death from opiate overdose.
  • Do not use REVIA to treat any other complaints unless your doctor tells you to.
  • Do not stop taking REVIA, or lower the dosage, without checking with your doctor.
  • Do not stop taking REVIA tablets because you are feeling better unless advised to do so by your doctor.
  • REVIA should only be used by the person for whom it was prescribed. Do not give REVIA to someone else even if the symptoms are the same. It may not be safe for another person to use REVIA.
    Do not give your tablets to people who are known to be dependent on opiate drugs because a withdrawal syndrome "cold turkey" may be precipitated. Signs and symptoms (such as nausea, vomiting, shakiness, sweating and anxiety) which may be severe, may develop within five minutes. If this happens, call a doctor.

Things to be careful of:

  • Be careful driving or operating machinery until you know how REVIA affects you.

How to take REVIA

The usual adult dose is one tablet every day. You will usually take REVIA for at least 3 months, but it may be much longer. The time depends on how quickly you recover from alcohol or heroin addiction. Your doctor will decide the dose that is most appropriate for you. Please follow your doctor's instructions about how and when to take REVIA.

Your doctor may give you a test called a NARCAN challenge. This is to see if you are still using heroin or drugs like it. If this test result is positive for heroin use, you will not be prescribed REVIA.

How long to take it:

You should not stop taking REVIA, or reduce the dose without first talking to your doctor. Depending on your response and on any side effects that you may experience, your doctor may adjust your dose of REVIA, upward or downward, or may temporarily discontinue your medicine.

If you stop taking REVIA and restart your heroin habit, you are at risk of being more sensitive to opiates. Therefore restarting your heroin habit after stopping REVIA can lead to death from opiate overdose. You should talk to your doctor before you stop taking REVIA and before you start taking heroin again.

If you forget to take it:

If you miss a dose of REVIA, take your next scheduled dose at its regular time. Don't make up for a missed dose by doubling up on your tablets. Call your doctor or pharmacist if you are not sure what to do.

If you take too much (overdose):

Immediately telephone your doctor or Poisons Information Centre (telephone: 13 11 26) or go to the Accident and Emergency Department at your nearest hospital, if you or anyone else may have taken too much REVIA. Do this even if there are no signs of discomfort or poisoning.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking REVIA.

Like all medicines, it is possible that REVIA may have unwanted side effects in some people.

The more common side effects of REVIA are:

  • Nausea, vomiting, diarrhoea, constipation, stomach pain or cramps
  • Headache, dizziness, nervousness
  • Joint and muscle pain
  • Rash
  • Tiredness, feeling anxious or irritable, difficulty sleeping, feeling down, chills, increased energy
  • Thirsty, loss of appetite
  • Delayed ejaculation, decreased potency

Chest pain, euphoria and increased sweating have also been reported since marketing REVIA.

Tell your doctor immediately if you notice any of the following:

  • If you have stomach pain lasting more than a few days, light coloured bowel movements, dark urine, or yellowing of your eyes, you should stop taking REVIA immediately and see your doctor as soon as possible.

These side effects may indicate a serious medical condition and you may need urgent medical attention or hospitalisation.

Tell your doctor immediately, or go to accident and emergency at your nearest hospital if you notice any of the following:

  • swelling to the face, lips, tongue or throat which may cause difficulty in swallowing or breathing
  • wheezing
  • severe and sudden onset of pinkish, itchy swelling of the skin
  • gastrointestinal bleeding (blood in your stool)

REVIA may affect your ability to drive or operate machinery. Be careful driving or operating machinery until you know how REVIA affects you. If you drink alcohol while you are taking REVIA, your blood alcohol level increases in the same way just as it would if you are not taking REVIA. As this level rises, you can become physically and mentally impaired. The use of REVIA will not change this.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

Product Description

REVIA tablets are pale yellow, film-coated and capsule shaped. They are marked with "R11" on one side. The other side is marked with a line and "50".

REVIA tablets are available in packs containing 30 tablets.

Ingredients

Each REVIA tablet contains 50 mg of naltrexone hydrochloride as the active ingredient. It also contains the following inactive ingredients: lactose, microcrystalline cellulose, crospovidone, silicon dioxide, magnesium stearate, and pale yellow Opadry (colouring).

Storage

  • Keep your tablets in the pack until it is time to take them. If you take the tablets out of the bottle or blister pack they may not keep well.
  • Keep the pack in a cool dry place where the temperature stays below 25°C.
  • Do not store REVIA or any other medicine in the bathroom or near a sink.
  • Do not leave it in the car on hot days. Heat and dampness can destroy some medicines.
  • Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

Return any unused medicine to your pharmacist.

Sponsored by

Bristol-Myers Squibb Australia Pty Ltd,
4 Nexus Court, Mulgrave,
Victoria 3170, Australia

Registration Numbers

  • REVIA 50mg tablets, 30 tablets in blister pack
    (AUST R 165096)
  • REVIA 50mg tablets, 30 tablets in plastic bottle
    (AUST R 65400)
    - Not currently available in Australia

Where to get further information

Your doctor is the best person to answer any further questions you may have about REVIA. Anything your doctor tells you about REVIA should be followed even if it is different from what is in this leaflet.

Date of Preparation: November 2013

®REVIA is a trademark of Bristol-Myers Squibb Company.

AU_CMI_Revia_V4.0_Nov13.docx

BRAND INFORMATION

Brand name

ReVia Tablet

Active ingredient

Naltrexone hydrochloride

Schedule

S4

 

Name of the medicine

Naltrexone hydrochloride.

Excipients.

Lactose, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, polysorbate 80, yellow iron oxide, red iron oxide.

Description

Chemical name: 17-(cyclopropylmethyl)- 4, 5α-epoxy-3, 14-dihydroxymorphinan- 6-one hydrochloride. CAS: 16676-29-2. Naltrexone hydrochloride is a white, crystalline compound. The hydrochloride salt is soluble in water to the extent of about 100 mg/mL.
Revia (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. Revia is also related to the potent opioid antagonist, naloxone, or n-allylnoroxymorphone.

Pharmacology

Pharmacodynamic properties.

Revia is a pure opioid antagonist. It markedly attenuates or completely blocks, reversibly, the subjective effects of all opioids.
When coadministered with morphine, on a chronic basis, Revia blocks the physical dependence to morphine, heroin and other opioids.
Revia has few, if any, intrinsic actions besides its opioid blocking properties. However, it does produce some pupillary constriction, by an unknown mechanism.
Clinical studies indicate that Revia 50 mg will block the pharmacologic effects of 25 mg of intravenously administered heroin for periods as long as 24 hours. Other data suggest that doubling the dose of Revia provides blockade for 48 hours, and tripling the dose of Revia provides blockade for about 72 hours.
Revia blocks the effects of opioids by competitive binding (i.e. analogous to competitive inhibition of enzymes) at opioid receptors. This makes the blockade produced potentially surmountable, but overcoming full naltrexone blockade by administration of very high doses of opiates has resulted in excessive symptoms of histamine release in experimental subjects.
The mechanism of action of Revia in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Revia, an opioid receptor antagonist, competitively binds to such receptors and may block the effects of endogenous opioids. Opioid antagonists have been shown to reduce alcohol consumption by animals, and Revia has been shown to reduce alcohol consumption in clinical studies.
Revia is not aversive therapy and does not cause a disulfiram-like reaction either as a result of opiate use or ethanol ingestion.

Tolerance and dependence.

The administration of Revia is not associated with the development of tolerance or dependence. In subjects physically dependent on opioids, Revia will precipitate withdrawal symptomatology.

Pharmacokinetics.

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 6-β-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 faecal excretion is a minor elimination pathway. The mean elimination half-life (t1/2) values for naltrexone and 6-β-naltrexol are 4 hours and 13 hours, respectively. The elimination half-life and time to maximum concentration are dose independent. Naltrexone and 6-β-naltrexol are dose proportional in terms AUC and Cmax over the range of 50 to 200 mg and there is no significant accumulation 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. Following the administration of 50 mg tablets to 24 healthy adult male volunteers, the Cmax values for naltrexone and its major metabolite, 6-β-naltrexol, were 8.6 nanogram/mL and 99.3 nanogram/mL respectively.

Distribution.

Steady-state plasma levels of naltrexone and 6-β-naltrexol are achieved rapidly. The volume of distribution for naltrexone following intravenous administration is estimated to be 1350 L. 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% metabolised) 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 30-127 mL/min and suggests that renal elimination is primarily by glomerular filtration. In comparison, the renal clearance for 6-β-naltrexol ranges from 230-369 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.

Hepatic and renal impairment.

Naltrexone appears to have extrahepatic sites of drug metabolism and its major metabolite undergoes active tubular secretion (see Metabolism). Adequate studies of naltrexone in patients with severe hepatic or renal impairment have not been conducted. In a study, increased bioavailability of naltrexone was observed in patients with liver cirrhosis as compared to healthy subjects. (See Precautions, Special risk patients.)

Clinical Trials

Alcohol dependence.

The efficacy of Revia as an aid to the treatment of alcoholism was tested in placebo controlled, outpatient, double blind trials. These studies used a dose of Revia 50 mg once daily for 12 weeks as an adjunct to social and psychotherapeutic methods when given under conditions that enhanced patient compliance. Patients with psychosis, dementia and secondary psychiatric diagnoses were excluded from these studies.
In one of these studies, 104 alcohol dependent patients were randomised to receive either Revia 50 mg once daily or placebo. In this study, Revia proved superior to placebo in measures of drinking including abstention rates (51% vs. 23%), number of drinking days, and relapse (31% vs. 60%). In a second study with 82 alcohol dependent patients, the group of patients receiving Revia were shown to have lower relapse rates (21% vs. 41%), less alcohol craving and fewer drinking days compared with patients who received placebo, but these results depended on the specific analysis used. Benefits in preventing relapse were noted in 3 out of 4 trials.
The clinical use of Revia as adjunctive pharmacotherapy for the treatment of alcoholism was also evaluated in a multicentre safety study. This study of 865 individuals with alcoholism included patients with comorbid psychiatric conditions, concomitant medications, polysubstance abuse and HIV disease. Results of this study demonstrated that the side effect profile of Revia appears to be similar in both alcoholic and opioid dependent populations, and that serious side effects are uncommon.
In the clinical studies, treatment with Revia reduced alcohol craving, supported abstinence, prevented relapse and decreased alcohol consumption. In the uncontrolled study, the patterns of abstinence and relapse were similar to those observed in the controlled studies. Revia was not uniformly helpful to all patients, and the expected effect of the drug is a modest improvement in the outcome of conventional treatment.

Opioid dependence.

Revia has been shown to produce complete blockade of the euphoric effects of opioids in both volunteer and addict populations. When administered by means that enforce compliance, it will produce an effective opioid blockade, but has not been shown to affect the use of cocaine or other nonopioid drugs of abuse.
There are no data that demonstrate an unequivocally beneficial effect of Revia on rates of recidivism among detoxified, formerly opioid dependent individuals who self administer the drug. The failure of the drug in this setting appears to be due to poor medication compliance.
The drug is reported to be of greatest use in good prognosis opioid addicts who take the drug as part of a comprehensive occupational rehabilitative programme, behavioural contract or other compliance enhancing protocol. Revia, unlike methadone, does not reinforce medication compliance and is expected to have a therapeutic effect only when given under condition that support continued use of the medication.

Indications

Revia is indicated for use within a comprehensive treatment programme for alcohol dependence.
Revia is also indicated as adjunctive therapy in the maintenance of formerly opioid dependent patients who have ceased the use of opioids such as diamorphine (heroin) and morphine.

Contraindications

Revia is contraindicated in the following.
1. Patients receiving opioid analgesics.
2. Patients currently dependent on opioids since an acute withdrawal syndrome may ensue.
3. Patients in acute opioid withdrawal (see Precautions).
4. Any individual who has failed the Narcan challenge test or who has a positive urine screen for opioids.
5. 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.
6. Any individual with acute hepatitis or liver failure. Revia should not be given to patients with acute hepatitis or liver failure.

Precautions

General.

Hepatotoxicity.

Revia has the capacity to cause hepatocellular injury when given in excessive doses.
Revia 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 Revia and the dose causing hepatic injury appears to be only fivefold or less. Revia 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 Revia and seek medical attention if they experience symptoms of acute hepatitis.
Evidence of the hepatotoxic potential of Revia is derived primarily from a placebo controlled study in which Revia was administered to obese subjects at a dose approximately fivefold that recommended for the blockade of opiate receptors (300 mg per day). In that study, 5 of 26 Revia 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 three to eight 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 Revia is a direct (i.e. not idiosyncratic) hepatotoxin.
This conclusion is also supported by evidence from other placebo controlled studies in which exposure to Revia 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 Revia (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 Revia 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 Revia 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 7-10 days before starting Revia. Since the absence of an opioid drug in the urine is often not sufficient proof that a patient is opioid free, a Narcan challenge should be employed if the prescribing physician feels there is a risk of precipitating a withdrawal reaction following administration of Revia. The Narcan challenge test is described in the Dosage and Administration section.

Attempt to overcome blockade.

While Revia is a potent antagonist with a prolonged pharmacologic effect (24 to 72 hours), the blockade produced by Revia is surmountable. This could be 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.
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.

When reversal of Revia blockade is required.

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 nonopioid analgesics or general anaesthesia.
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 minimises 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, generalised 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.

Accidentally precipitated withdrawal.

Severe opioid withdrawal syndromes precipitated by the accidental ingestion of Revia have been reported in opioid dependent individuals. 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 diarrhoea have required intravenous fluid administration. In all cases patients were closely monitored and therapy with nonopioid medications was tailored to meet individual requirements.
Use of Revia does not eliminate or diminish withdrawal symptoms. If Revia is initiated early in the abstinence process, it will not preclude the patient's experience of the full range of signs and symptoms that would be experienced if Revia had not been started. Numerous adverse events are known to be associated with withdrawal.

Ultrarapid opioid withdrawal.

Safe use of Revia in ultrarapid detoxification programs has not been established (see Adverse Effects).

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.

Cautions should be exercised when naltrexone hydrochloride is administered to patients with liver disease. 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.

Suicide.

The risk of suicide is known to be increased in patients with substance abuse with or without concomitant depression. This risk is not abated by treatment with Revia (see Adverse Effects).

Carcinogenesis, mutagenesis, impairment of fertility.

The following statements are based on the results of experiments in mice and rats, which do not form appreciable quantities of the major human metabolite, 6-β-naltrexol. Thus, the potential carcinogenic, mutagenic and fertility effects of 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 tumours of vascular origin in males and females. The incidence of mesotheliomas in males given naltrexone at a dietary dose of 100 mg/kg/day was 6%, compared with a historical incidence of 4%. The incidences of vascular tumours in males and females given dietary doses of 100 mg/kg/day (16 times the recommended therapeutic dose, based on surface area) 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 2 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 nonspecific 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 a mouse micronucleus assay.
Revia (100 mg/kg PO, 16 times the recommended therapeutic dose, based on 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.

Use in pregnancy.

(Category B3)
The following includes statements based on the results of experiments in rats, which do not form appreciable quantities of the major human metabolite, 6-β-naltrexol. Thus the potential reproductive toxicity of 6-β-naltrexol in rats is not known.
Naltrexone increased the incidence of early foetal loss when administered to rats at oral doses ≥ 30 mg/kg/day (5 times the recommended therapeutic dose, based on surface area) and to rabbits at oral doses ≥ 60 mg/kg/day (18 times the recommended therapeutic dose, based on surface area). There was no evidence of teratogenicity when naltrexone was administered orally to rats and rabbits during the period of organogenesis at doses up to 200 mg/kg/day (respectively 32 and 59 times the recommended therapeutic dose, based on surface area).
There are no adequate and well controlled studies in pregnant women.

Use in lactation.

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.

Use in children.

The safe use of Revia in paediatric patients younger than 18 years old has not been established. Thus, the use of Revia in patients less than 18 years of age is not recommended.

Effects on ability to drive and to use machines.

Dizziness and somnolence may occur.

Interactions

Other opioids.

Naltrexone antagonizes the effects of opioid agonists (see Precautions).
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.

Sedating medications.

Concomitant use with other sedating medications such as opioid containing medications (analgesics, cough medicines, replacement therapies), neuroleptic drugs, barbiturates, benzodiazepines, anxiolytic drugs other than benzodiazepine (e.g. meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, trimipramine), sedating H1-antihistamines, central antihypertensives, baclofen, and thalidomide is not recommended.

Acamprosate.

In an interaction study of naltrexone and acamprosate at therapeutic doses, coadministration of naltrexone with acamprosate significantly increased the rate and extent of absorption of acamprosate, while acamprosate did not affect the pharmacokinetic parameters of naltrexone or 6-β-naltrexol. The exact mechanism of this interaction was unknown.
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. Interaction with other psychotropic drugs has not been studied (e.g. amitriptyline, doxepin, lithium, clozapine, benzodiazepines).
Lethargy and somnolence have been reported following doses of Revia and thioridazine.
Patients receiving therapy with Revia should be advised that they will not benefit from opioid containing medicines, such as cough and cold preparations, antidiarrhoeal preparations, or pain medications and should use alternative therapy if needed. 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).
Revia contains lactose. Patients with rare hereditary galactose intolerance, Lapp lactase or glucose malabsorption should not take Revia.

Laboratory tests.

A high index of suspicion for drug related hepatic injury is critical if the occurrence of liver damage induced by Revia is to be detected at the earliest possible time. Evaluations, using appropriate batteries of tests to detect liver injury are recommended at a frequency appropriate to the clinical situation and the dose of Revia.
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.

Adverse Effects

During two randomised, 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 Interactions with Other Medicines, 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 recognise 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, Precautions and Dosage and Administration).
Adverse events, including withdrawal symptoms and death, have been reported with the use of Revia (naltrexone hydrochloride) in ultrarapid detoxification programmes. No causal relationship between Revia and these deaths has been established. (See Precautions.)

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 7-10 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 (see Dosage and Administration).

Alcohol dependence.

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 (see Table 1).
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 dependence.

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 the following.
Loss of appetite, diarrhoea, 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, rhinorrhoea, sneezing, sore throat, excess mucus or phlegm, sinus trouble, heavy breathing, hoarseness, cough, shortness of breath.

Cardiovascular.

Nose bleeds, phlebitis, oedema, increased blood pressure, nonspecific ECG changes, palpitations, tachycardia.

Gastrointestinal.

Excessive gas, haemorrhoids, diarrhoea, 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, diarrhoea, elevations in liver enzymes or bilirubin, hepatic function abnormalities or hepatitis, palpitations, myalgia, anxiety, confusion, euphoria, hallucinations, insomnia, nervousness, somnolence, abnormal thinking, dyspnoea, rash, increased sweating and vision abnormalities.
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 theorised to contribute to a variety of conditions. 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.

Laboratory tests.

With the exception of liver test abnormalities (see Precautions), results of laboratory tests, like adverse reaction reports, have not shown consistent patterns of abnormalities that can be attributed to treatment with Revia.
Idiopathic thrombocytopenic purpura was reported in one patient who may have been sensitised to Revia in a previous course of treatment with Revia. The condition cleared without sequelae after discontinuation of Revia and corticosteroid treatment.

Dosage and Administration

Do not attempt treatment with Revia unless, in the medical judgement of the prescribing physician, there is no reasonable possibility of opioid use within the past 7-10 days. If there is any question of occult opioid dependence, perform a Narcan challenge test and do not initiate Revia therapy until the Narcan challenge is negative.

Treatment of alcohol dependence.

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.
A patient is a candidate for treatment with Revia if:
the patient is willing to take a medicine to help with alcohol dependence;
the patient is opioid free for 7-10 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 Revia and no other contraindications are present.
See Contraindications and Precautions for additional information.
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 programme, especially medication compliance.

Treatment of opioid dependence.

Initiate treatment with Revia using the following guidelines.

1. Treatment should not be attempted unless the patient has remained opioid free for at least 7-10 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.
2. If there is any question of occult opioid dependence, perform a Narcan challenge test (see Narcan Challenge Test). If signs of opioid withdrawal are still observed following Narcan challenge, treatment with Revia should not be attempted. The Narcan challenge can be repeated in 24 hours.
3. Treatment should be initiated carefully, 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.

Narcan challenge test.

The Narcan 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 Narcan challenge test may be administered by either the intravenous or subcutaneous routes.

Intravenous.

Inject Narcan (naloxone) 0.2 mg.
Observe for 30 seconds for signs or symptoms of withdrawal.
If no evidence of withdrawal, inject Narcan 0.6 mg.
Observe for an additional 20 minutes.

Subcutaneous.

Administer Narcan 0.8 mg.
Observe for 20 minutes for signs or symptoms of withdrawal.

Note.

Individual patients, especially those with opioid dependence, may respond to lower doses of Narcan. In some cases, 0.1 mg IV Narcan 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, rhinorrhoea, 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, back ache, 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 Narcan 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.

Once the patient has been started on Revia, 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). Dosage increase and/or a flexible dosing regimen may be appropriate in some cases. The degree of blockade produced by Revia may be reduced by 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 Precautions).

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 programme, including medication compliance.
As patient motivation and social support are likely to influence treatment outcomes, this makes patient selection an important clinical responsibility.

Overdosage

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 ± 96 mg/kg; 1,450 ± 265 mg/kg; and 1,490 ± 102 mg/kg, respectively. In acute toxicity studies in the mouse, rat and dog, cause of death was 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 the Poisons Information Centre on 131 126 for the most up to date information.

Presentation

Tablet, 50 mg (pale yellow, capsule shaped, film-coated, marked R11, scored and 50 on reverse): 30's (bottle*, blister pack).
*Not currently marketed in Australia.

Storage

Store below 25°C. Do not freeze.

Poison Schedule

S4.