Consumer medicine information

APO-Naltrexone Tablets

Naltrexone hydrochloride

BRAND INFORMATION

Brand name

APO-Naltrexone Tablets

Active ingredient

Naltrexone hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Naltrexone Tablets.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about naltrexone. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist. Your doctor has been provided with full information and can answer any questions you may have. Follow your doctor's advice even if it is different from what is in this leaflet.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

The name of your medicine is APO-NALTREXONE Tablets. It contains 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 the euphoria ("high") due to these opiates.

It is used:

  • as part of a treatment programme for alcohol dependence.
  • as adjunctive therapy in the maintenance of formerly opioid-dependent patients who have ceased the use of opioids such as diamorphine (heroin) and morphine
  • Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

How it works

Naltrexone Hydrochloride blocks the effects of opioids by competitive binding (i.e., analogous to competitive inhibition of enzymes) at opioid receptors.

There is no evidence that this medicine is addictive.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You are hypersensitive to, or have had an allergic reaction to, naltrexone or any of the ingredients listed at the end of this leaflet.
  • Do not take this medicine if you are still using heroin or similar drugs
  • If you take this medicine right after taking an opiate you will suffer from withdrawal symptoms (such as nausea, vomiting, shakiness, sweating and anxiety) which may be severe.
  • Do not take this medicine if you are experiencing withdrawal symptoms.
  • Do not take this medicine if you are on certain pain killers. Ask your doctor or pharmacist.
  • Do not take this medicine 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
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • are pregnant or intend to become pregnant.
  • are breastfeeding or intend to breastfeed.
  • have or have had any liver disease.
  • have or have had any kidney disease.
  • are under 18 years of age

Taking other medicines

It is important that you 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.

Some medicines may interact with naltrexone. These include:

  • thioridazine.
  • disulfiram.

If you are taking any of these you may need a different dose or you may need to take different medicines.

This medicine 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

Other medicines not listed above may also interact with naltrexone.

How to take this medicine

The usual adult dose is one tablet every day. You will usually take naltrexone 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 this medicine.

Your doctor may give you a test called a NARCAN (naloxone) 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 naltrexone tablets..

When to take it

Take this medicine at the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

It does not matter if you take it before, with or after food.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

You should not stop taking this medicine, 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 this medicine, upward or downward, or may temporarily discontinue your medicine.

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

Make sure you have enough naltrexone tablets to last over weekends and holidays.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time. Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses.

This may increase the chance of you experiencing side effects.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant
  • you are breastfeeding or are planning to breast-feed
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Use any other medicines while using this medicine unless you have discussed it with your doctor or pharmacist. This includes medicines you can buy without a prescription from your pharmacy, supermarket, health food shop or street drugs. This medicine will not help you if you take large amounts of an opiate to overcome the blocking effects. Large doses of opiate can lead to difficulty breathing or even death.
    Naltrexone tablets should only be used by the person for whom it was prescribed. Do not give this medicine to anyone else, even if their symptoms seem similar to yours. It may not be safe for another person to use.
    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.
  • Take your medicine to treat any other condition unless your doctor tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

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

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking naltrexone or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Some common side effects 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

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 this medicine immediately and see your doctor as soon as possible
  • These may be serious side effects and you may need medical attention

Tell your doctor immediately, or go to the Accident and Emergency department 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)

These are very serious side effects and you may need urgent medical attention or hospitalisation.

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

Other side effects not listed above may occur in some patients.

Tell your doctor if you notice anything else that is making you feel unwell

Allergic reactions

If you think you are having an allergic reaction to naltrexone, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine 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

If your doctor tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-NALTREXONE Tablets looks like

50 mg Tablets are pale yellow film-coated oval biconvex tablets, engraved with "NAL", score & "50" on one side and "APO" on the other.

It is supplied in bottle pack of 30 tablets

Ingredients

Each tablet contains 50 mg of naltrexone as the active ingredient.

It also contains the following inactive ingredients:

  • lactose,
  • hypromellose,
  • colloidal silicon dioxide,
  • magnesium stearate,
  • hydroxypropylcellulose,
  • titanium dioxide,
  • macrogol 8000,
  • iron oxide yellow, and
  • iron oxide red.

This medicine is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

APO-NALTREXONE 50 mg Tablets: AUST R 271013.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO and APOTEX are registered trade marks of Apotex Inc.

This leaflet was last updated in:
January 2017.

BRAND INFORMATION

Brand name

APO-Naltrexone Tablets

Active ingredient

Naltrexone hydrochloride

Schedule

S4

 

1 Name of Medicine

Naltrexone hydrochloride.

2 Qualitative and Quantitative Composition

Naltrexone tablets contain 50 mg of naltrexone hydrochloride.

Excipients with known effect.

Lactose monohydrate (see Section 4.4 Special Warnings and Precautions for Use).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Naltrexone is presented as pale yellow film-coated oval biconvex tablet, engraved "NAL" score "50" on one side and "APO" on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Naltrexone is indicated for use within a comprehensive treatment programme for alcohol dependence.
Naltrexone 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.

4.2 Dose and Method of Administration

Dosage.

Do not attempt treatment with naltrexone 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 naloxone challenge test and do not initiate naltrexone therapy until the naloxone 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 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 7-10 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.
See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use 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 programme, especially medication compliance.

Treatment of opioid dependence.

Initiate treatment with naltrexone 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 naloxone challenge test (see Naloxone challenge test below). 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.
3. Treatment should be initiated carefully, with an initial dose of 25 mg of naltrexone. 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 hydrochloride.
Observe for 30 seconds for signs or symptoms of withdrawal.
If no evidence of withdrawal, inject 0.6 mg of naloxone hydrochloride.
Observe for an additional 20 minutes.

Subcutaneous.

Administer 0.8 mg naloxone hydrochloride.
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 hydrochloride. In some cases, 0.1 mg IV naloxone hydrochloride 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 naloxone hydrochloride 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, 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 naltrexone 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 Section 4.4 Special Warnings and Precautions for Use).

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

4.3 Contraindications

Naltrexone is contraindicated in:
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 Section 4.4 Special Warnings and Precautions for Use).
4. Any individual who has failed the naloxone challenge test or who has a positive urine screen for opioids.
5. Any individual with a history of sensitivity to naltrexone hydrochloride 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. Naltrexone hydrochloride should not be given to patients with acute hepatitis or liver failure.

4.4 Special Warnings and Precautions for Use

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 hydrochloride 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 hydrochloride 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 hydrochloride 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 naltrexone hydrochloride 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 hydrochloride 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 7-10 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 test 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, see Section 4.2 Dose and Method of Administration.

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 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 naltrexone blockade is required.

In an emergency situation in patients receiving fully blocking doses of naltrexone, a suggested plan of management is regional analgesia, conscious sedation with a benzodiazepine, use of non-opioid 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 naltrexone 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 naltrexone hydrochloride have been reported in opioid-dependent individuals. Symptoms of withdrawal have usually appeared within five minutes of ingestion of naltrexone hydrochloride 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 non-opioid medications was tailored to meet individual requirements.
Use of naltrexone does not eliminate or diminish withdrawal symptoms. If naltrexone 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 naltrexone had not been started. Numerous adverse events are known to be associated with withdrawal.

Ultra rapid opioid withdrawal.

Safe use of naltrexone hydrochloride in ultra-rapid detoxification programs has not been established (see Section 4.8 Adverse Effects (Undesirable Effects)).

Special risk patients.

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 naltrexone (see Section 4.8 Adverse Effects (Undesirable Effects)).

Lactose.

Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose malabsorption should not take naltrexone.

Use in 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 (also see Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity).

Use in renal impairment.

Naltrexone and its primary metabolite are excreted primarily in the urine, and caution is recommended in administering the drug to patients with renal impairment.

Use in the elderly.

No data available.

Paediatric use.

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

Effects on laboratory tests.

A high index of suspicion for drug-related hepatic injury is critical if the occurrence of liver damage induced by naltrexone hydrochloride 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 naltrexone.
Naltrexone 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. Naltrexone 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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Other opioids.

Naltrexone antagonizes the effects of opioid agonists (see Section 4.4 Special Warnings and Precautions for Use).
Studies to evaluate possible interactions between naltrexone and drugs other than opiates have not been performed. Consequently, caution is advised if the concomitant administration of naltrexone and other drugs is required.

Sedating medications.

Concomitant use with sedating medications such as other 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 naltrexone 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 naltrexone and thioridazine.
Patients receiving therapy with naltrexone 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 naltrexone, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on 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.
Naltrexone hydrochloride (100 mg/kg PO, 16 times the recommended therapeutic dose, based on surface area) caused a significant increase in pseudo-pregnancy 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.
(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.
 In animal studies, naltrexone and 6-β-naltrexol were excreted in the milk of lactating rats dosed orally with naltrexone. Whether or not naltrexone is excreted in human milk is unknown. Because many drugs are excreted in human milk, caution should be exercised when naltrexone is administered to a nursing woman.

4.7 Effects on Ability to Drive and Use Machines

Dizziness and somnolence may occur.

4.8 Adverse Effects (Undesirable Effects)

During two randomised, double-blind placebo-controlled 12 week trials to evaluate the efficacy of naltrexone as an adjunctive treatment of alcohol dependence, most patients tolerated naltrexone hydrochloride well. In these studies, a total of 93 patients received naltrexone hydrochloride at a dose of 50 mg once daily. Five of these patients discontinued naltrexone hydrochloride because of nausea. No serious adverse events were reported during these two trials.
While extensive clinical studies evaluating the use of naltrexone in detoxified, formerly opioid-dependent individuals failed to identify any single, serious untoward risk of naltrexone use, placebo-controlled studies employing up to five-fold higher doses of naltrexone hydrochloride (up to 300 mg per day) than that recommended for use in opiate receptor blockade have shown that naltrexone hydrochloride causes hepatocellular injury in a substantial proportion of patients exposed at higher doses (see Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests).
Aside from this finding, and the risk of precipitated opioid withdrawal, available evidence does not incriminate naltrexone hydrochloride, 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 naltrexone 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 naltrexone.
Among opioid free individuals, naltrexone hydrochloride 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, naltrexone may cause serious withdrawal reactions (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).
Adverse events, including withdrawal symptoms and death, have been reported with the use of naltrexone hydrochloride in ultra rapid detoxification programmes. No causal relationship between naltrexone and these deaths has been established. (See Section 4.4 Special Warnings and Precautions for Use.)

Reported adverse events.

Naltrexone 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 Section 4.2 Dose and Method of Administration).

Alcohol dependence.

In an open label safety study with approximately 570 individuals with alcoholism receiving naltrexone hydrochloride, 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 naltrexone is suspected, physicians should be aware that treatment with naltrexone does not reduce the risk of suicide in these patients (see Section 4.4 Special Warnings and Precautions for Use).

Opioid dependence.

The following adverse reactions have been reported both at baseline and during the naltrexone 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, 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, non-­specific 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."

Post-marketing experience.

Data collected from post-marketing use of naltrexone hydrochloride 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 post-marketing experience with 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 Section 4.4 Special Warnings and Precautions for Use), results of laboratory tests, like adverse reaction reports, have not shown consistent patterns of abnormalities that can be attributed to treatment with naltrexone.
Idiopathic thrombocytopenic purpura was reported in one patient who may have been sensitised to naltrexone in a previous course of treatment with naltrexone. The condition cleared without sequelae after discontinuation of naltrexone and corticosteroid treatment.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

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 ± 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 naltrexone overdose, patients should be treated symptomatically in a closely supervised environment.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Naltrexone is a pure opioid antagonist. It markedly attenuates or completely blocks, reversibly, the subjective effects of all opioids.
When co-administered with morphine, on a chronic basis, naltrexone hydrochloride blocks the physical dependence to morphine, heroin and other opioids.
Naltrexone hydrochloride 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 50 mg of naltrexone hydrochloride 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 naltrexone hydrochloride provides blockade for 48 hours, and tripling the dose of naltrexone hydrochloride provides blockade for about 72 hours.
Naltrexone 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 naltrexone in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Naltrexone, 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 naltrexone has been shown to reduce alcohol consumption in clinical studies.
Naltrexone 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 naltrexone is not associated with the development of tolerance or dependence. In subjects physically dependent on opioids, naltrexone will precipitate withdrawal symptomatology.

Clinical trials.

Alcohol dependence.

The efficacy of naltrexone as an aid to the treatment of alcoholism was tested in placebo-controlled, outpatient, double blind trials. These studies used a dose of naltrexone hydrochloride 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 naltrexone hydrochloride 50 mg once daily or placebo. In this study, naltrexone 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 naltrexone 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 naltrexone 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 naltrexone appears to be similar in both alcoholic and opioid dependent populations, and that serious side effects are uncommon.
In the clinical studies, treatment with naltrexone 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. Naltrexone 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.

Naltrexone 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 non-opioid drugs of abuse.
There are no data that demonstrate an unequivocally beneficial effect of naltrexone 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. Naltrexone, 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.

5.2 Pharmacokinetic Properties

Naltrexone 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 of AUC and Cmax over the range of 50 mg 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 extra-hepatic 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.

Excretion.

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 extra-hepatic sites of drug metabolism and its major metabolite undergoes active tubular secretion (see Metabolism above). 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 Section 4.4 Special Warnings and Precautions for Use, Special risk patients.)

5.3 Preclinical Safety Data

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.

Genotoxicity.

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 NDA 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.

Carcinogenicity.

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, hypromellose, colloidal anhydrous silica, magnesium stearate, hyprolose, titanium dioxide, macrogol 8000, iron oxide yellow, iron oxide red.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

APO-Naltrexone 50 mg tablets.

Bottle (HDPE) of 30 tablets, Aust R 271013.
APO is a registered trade mark of Apotex Inc.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

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 is also related to the potent opioid antagonist, naloxone, or n-allylnoroxymorphone (naloxone hydrochloride).
Naltrexone hydrochloride is a white, crystalline compound. The hydrochloride salt is soluble in water to the extent of about 100 mg/mL.

Chemical structure.


Chemical name.

17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride.

Molecular formula.

C20H23NO4.HCl.

Molecular weight.

377.86.

CAS number.

16676-29-2.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes