Consumer medicine information

Contrave 8/90

Naltrexone hydrochloride; Bupropion hydrochloride

BRAND INFORMATION

Brand name

Contrave 8/90

Active ingredient

Naltrexone hydrochloride; Bupropion hydrochloride

Schedule

What is in this leaflet

This leaflet answers some common questions about CONTRAVE tablets. It does not contain all the available information about CONTRAVE tablets. It does not replace talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking CONTRAVE against the benefits he or she expects it will have.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What CONTRAVE is used for

The name of your medicine is CONTRAVE.

It contains 2 active ingredients - bupropion hydrochloride and naltrexone hydrochloride.

It is used in obese or overweight adults to manage weight together with a reduced calorie diet and physical exercise. This medicine works on areas on the brain involved in the control of food intake and energy use.

Your doctor will review your treatment after 16 weeks, and you should only continue using CONTRAVE if you have lost at least 5% of your initial body weight.

Ask your doctor if you have any questions about why CONTRAVE has been prescribed for you.

If you have any concerns, discuss them with your doctor.

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

Use in Children

CONTRAVE is not recommended for use in children less than 18 years because it has not been adequately studied in these patients.

Before you take CONTRAVE

When you must not take it

Do not take CONTRAVE if you are allergic to bupropion, naltrexone or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

Do not take CONTRAVE if you:

have high blood pressure that is not controlled with medicines
have ever had a seizure
have a brain tumour
are usually a heavy drinker and have just suddenly stopped drinking a lot of alcohol, or are going to stop while you are taking this medicine
have recently stopped taking sedatives (sleeping tablets) or medicines to treat anxiety or epilepsy or you plan to stop them while you are taking this medicine
are taking any other medicines containing bupropion or naltrexone
have an eating disorder or had one in the past, such as bulimia or anorexia nervosa
are regularly using opioids or opiate agonists (for example methadone), or you are going through acute withdrawal (cold turkey)
have or have had a bipolar disorder (extreme mood swings)
are taking medicines called monoamine oxidase inhibitors (MAOIs) or have taken them in the last 14 days
have severe liver disease
have end-stage kidney disease.

Do not take CONTRAVE if you are pregnant or currently planning to become pregnant.

Do not take CONTRAVE after the expiry date (EXP) printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking CONTRAVE, talk to your doctor.

Before you start to take it

Tell your doctor if:

You are allergic to any other medicines or any foods, dyes or preservatives.

You feel depressed, contemplate suicide, have a history of attempting suicide or any other mental health problems.

You are aged 65 years or older. CONTRAVE has not been adequately studied in older people to know if they will respond to CONTRAVE in the same way as younger adults.

You are at risk of having a seizure.

CONTRAVE may cause fits (seizures) in some people. Fits are more likely while taking CONTRAVE if you:

have had a serious head injury, head trauma or stroke
regularly drink a lot of alcohol
regularly use medicines to help you to sleep (sedatives)
are dependent on or addicted to cocaine or other stimulating products
have diabetes for which you use insulin or tablets
have a brain or spinal tumour or infection
have severe liver disease
have low blood sugar or salt levels
have hypoxia, a condition where oxygen levels in your tissues are low
are taking medicines that may increase the chance of having a fit.

Tell your doctor if you have or have had any other medical conditions, including:

high blood pressure
heart disease
liver or kidney problems
mood disorders including depression or mania
galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

CONTRAVE contains lactose.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor will discuss the risks and benefits of taking CONTRAVE if you are pregnant, planning a pregnancy or breastfeeding.

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

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may increase your chance of having a seizure when taking CONTRAVE. These medicines need to be used very carefully. Examples include:

antidepressants
antipyschotics
asthma medicines such as theophylline and systemic corticosteroids
antimalarials
tramadol
sedating antihistamines
quinolone antibiotics
insulin or oral diabetic medicines
sedatives, such as benzodiazepines.

Some medicines may interfere with CONTRAVE. These include:

Medicines for depression known as monoamine oxidase inhibitors, even if you have stopped taking them now, but have taken them within the last 14 days. Your doctor or pharmacist can tell you what to do if you are taking any of these medicines
opioid painkillers e.g. codeine, morphine, methadone
medicines used to treat high blood pressure such as metoprolol
medicines used to treat irregular heart rhythm such as propafenone or flecainide
medicines for Parkinson's disease such as levodopa or amantadine
ticlopidine or clopidogrel, mainly used in the treatment of heart disease or stroke
medicines used in the treatment of HIV infection and AIDS, such as efavirenz and ritonavir
medicines for depression or other mental health conditions that affect serotonin levels, such as amitriptyline, desipramine, venlafaxine, imipramine, paroxetine, fluoxetine, citalopram, escitalopram, risperidone, haloperidol and thioridazine
digoxin, used to treat certain heart problems.

You may need to use different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking CONTRAVE.

Tell your doctor if you are taking CONTRAVE tablets before you undergo any laboratory test. CONTRAVE may interfere with laboratory tests.

How to take CONTRAVE

CONTRAVE will only assist in reducing body weight if it is used in conjunction with a reduction in calorie intake and/or an increase in physical activity.

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how many tablets you need to take each day. This may depend on whether you have any other illnesses and whether or not you are taking any other medicines.

The starting dose is usually one tablet once a day in the morning. The dose will be gradually increased as follows:

Week 1: One tablet once a day in the morning
Week 2: One tablet twice a day, one in the morning and one in the evening
Week 3: Three tablets every day, two in the morning and one in the evening
Week 4 and onward: Two tablets twice a day, two in the morning and two in the evening.

The maximum recommended daily dose of CONTRAVE is two tablets taken twice a day.

Do not change your dose unless your doctor tells you to.

If you have liver or kidney problems you may need a lower dose of CONTRAVE.

How to take it

Swallow the tablet whole with a glass of water.

Take your tablet with food.

Do not cut, chew or crush CONTRAVE tablets.

How long to take it

Continue taking CONTRAVE as long as your doctor recommends it.

Some people do not respond to CONTRAVE. Treatment should not be continued for more than 16 weeks if you have not lost more than 5% of your initial body weight.

If you forget to take it

Skip the missed dose and take your next dose at the next usual time.

Do not take a double dose to make up for the dose that you missed.

Do not try to make up for missed doses by taking more than one dose at a time. This may increase the chance of you getting an unwanted side effect.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (Australia: telephone 13 11 26; New Zealand: 0800 POISON or 0800 764 766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much CONTRAVE. Do this even if there are no signs of discomfort or poisoning.

Also report any other medicine or alcohol which has been taken. You may need urgent medical attention.

If you take too much CONTRAVE you may experience some of the following symptoms: seizure, hallucinations, loss of consciousness, increased heart rate or irregular heartbeat, fever, muscle stiffness and/or pain, low blood pressure and breathing difficulties.

While you are using CONTRAVE

Reduce the energy content of your diet by at least 500 kcal (2092 kJ), a review by a dietician is recommended.

Things you must do

Take CONTRAVE exactly as your doctor has prescribed.

Tell all doctors, dentists and pharmacists who are treating you that you are taking CONTRAVE.

Tell your doctor immediately if you have depression and it gets worse or you any have thoughts about suicide or doing harm to yourself.

All thoughts or talk about suicide are serious, including

thoughts or talk about death or suicide
thoughts or talk about self-harm
an increase in aggressive behaviour, irritability or agitation.

Avoid or minimise drinking alcohol when taking CONTRAVE. If you drink a lot of alcohol or suddenly stop drinking you may increase your chance of having a seizure.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking CONTRAVE.

Always discuss with your doctor any problems or difficulties you have during or after taking CONTRAVE.

Keep enough CONTRAVE to last weekends and holidays.

Things you must not do

Do not take any other medicines while you are taking CONTRAVE without first telling your doctor.

Do not drive or operate machinery until you know how CONTRAVE affects you.

CONTRAVE may cause dizziness in some people and therefore may affect alertness.

Make sure you know how you react to CONTRAVE before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or have blurred vision.

Do not take CONTRAVE for a longer time than your doctor has prescribed.

Do not change your dose without first checking with your doctor.

Do not stop taking CONTRAVE or lower the dose, without first checking with your doctor.

Do not use this medicine to treat any other complaints unless your doctor says to.

Do not give this medicine to anyone else, even if their symptoms or condition seem similar to yours.

Side effects

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

CONTRAVE helps some overweight or obese adults with weight management, but it often causes unwanted side effects. These side effects are most common in the first few weeks of starting treatment.

All medicines have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

If you are over 65 years of age you may have an increased chance of getting side effects.

Ask your doctor or pharmacist any questions you may have.

The most commonly reported side effects are:

nausea or vomiting
dizziness
dry mouth
constipation
headache

Tell your doctor or pharmacist if you notice any of the following side effects and they worry you:

Changes in your behaviour such as:

mood swings
difficulty sleeping or abnormal dreams
feeling spacey or jittery
forgetfulness or difficulty concentrating
weakness or lack of energy
tremor
sexual function problems such as delayed ejaculation or difficulty getting an erection

Stomach or bowel problems such as:

diarrhoea
loss of appetite
stomach pain or cramps
burping
sudden need to urinate

Changes in your senses such as:

taste disorders
ringing in the ears
feeling thirsty
excessive sweating
hot flushes
chills
watery eyes

Other effects such as:

toothache or jaw pain
joint or muscle pain
chest pain
hair loss
irregular menstrual periods
vaginal dryness
tingling or numbness of the hands or feet
fast or irregular heartbeat
feeling faint when standing up from sitting or lying down
muscle stiffness
feeling agitated
lack of coordination
unstable blood pressure

Seizures

If you have a seizure, tell your doctor when you have recovered. Do not take any more CONTRAVE tablets.

Symptoms of a seizure include convulsions and usually loss of consciousness. Someone who has had a seizure may be confused afterwards and may not remember what has happened.

You can reduce the chance of having a seizure by giving your doctor the information they need before taking CONTRAVE and following carefully your doctor's directions on how to take CONTRAVE.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you experience any of the following:

signs of an allergic reaction to CONTRAVE such as:
- wheezing
- swelling of the lips, mouth or eyelids
- difficulty breathing
- hayfever
- hives (itchy skin rash)
seizure
mental disturbances such as:
- suicidal thoughts
- suicide attempts
- feeling hostile
- irritability, anxiety or agitation
bleeding from the rectum
skin or the whites of your eyes turning yellow
severe skin blisters, bleeding in the lips, eyes, mouth, nose and genitals (Stevens Johnson syndrome)

These are all serious side effects of CONTRAVE. You may need urgent medical attention or hospitalisation.

Some side effects can only be detected by your doctor. So it is important to visit your doctor for regular check-ups when CONTRAVE is taken for long periods of time.

Tell your doctor if you notice anything else that is making you feel unwell. Some people may get other side effects while using CONTRAVE.

Check with your doctor as soon as possible if you have any problems while taking CONTRAVE, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

After using CONTRAVE

Storage

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.

Keep CONTRAVE in a cool dry place where the temperature stays below 25°C. Do not freeze.

Do not store it, or any other medicines, in a bathroom or near a sink.

Do not leave it in the car or on windowsills. Heat and dampness can destroy some medicines.

Do not take CONTRAVE if the tablets do not look quite right.

Keep your tablets in the pack they were provided in until it is time to take them.

Disposal

If your doctor tells you to stop taking the tablets or they have passed their expiry date, ask your pharmacist what to do with any left over.

Product description

What it looks like

CONTRAVE is a blue, biconvex, round tablet with "NB-890" on one side. It is available in blisters in pack sizes of 28 (starter pack) and 112 tablets.

Ingredients

Each CONTRAVE tablet contains the following active ingredients: naltrexone hydrochloride 8mg and bupropion hydrochloride 90 mg.

The other ingredients are:

Cysteine hydrochloride monohydrate
Microcrystalline cellulose
Hyprolose
Magnesium stearate
Lactose
Lactose monohydrate
Crospovidone
Indigo carmine aluminium lake
Hypromellose
Disodium edetate
Silicon dioxide
OPADRY II complete film coating system 85F90663 BLUE

CONTRAVE tablets contain sugars as lactose.

Sponsor

Australia:

iNova Pharmaceuticals (Australia) Pty Limited
ABN: 13 617 871 539
Level 10, 12 Help Street
Chatswood, NSW 2067
Telephone: 1800 630 056

Registration Number:
AUST R 288372.

New Zealand:

iNova Pharmaceuticals (New Zealand) Limited
C/- Simpson Grierson,
Private Bag 92518,
88 Shortland Street
AUCKLAND 1141
Telephone: 0508 375 394

® = Registered trademark

This leaflet was prepared on June 2021.

Published by MIMS August 2021

BRAND INFORMATION

Brand name

Contrave 8/90

Active ingredient

Naltrexone hydrochloride; Bupropion hydrochloride

Schedule

1 Name of Medicine

Naltrexone hydrochloride and bupropion hydrochloride.

2 Qualitative and Quantitative Composition

Contrave is a blue film-coated round biconvex tablet formulated as a fixed combination tri-layer tablet for extended-release oral delivery. Each tablet has a tri-layer core composed of two drug layers, containing the drug and excipients, separated by a more rapidly dissolving inert layer.
Each tablet contains 8 mg of naltrexone hydrochloride and 90 mg of bupropion hydrochloride.
For the full list of excipients, see Section 6.1 List of Excipients.

Excipient with known effect.

Contains sugars as lactose.

3 Pharmaceutical Form

Modified release tablet.
Contrave 8/90 (naltrexone HCl 8 mg and bupropion HCl 90 mg) is a blue film-coated, biconvex, round tablet of 12.0-12.2 mm diameter debossed with "NB-890" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Contrave is indicated, as an adjunct to a reduced-calorie diet and increased physical activity, for the management of weight in adult patients (≥ 18 years) with an initial Body Mass Index (BMI) of:
≥ 30 kg/m² (obese); or
≥ 27 kg/m² to < 30 kg/m² (overweight) in the presence of one or more weight-related comorbidities (e.g. type 2 diabetes, dyslipidaemia, or controlled hypertension).
Treatment with Contrave should be discontinued after 16 weeks if patients have not lost at least 5% of their initial body weight (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Contrave tablets should be swallowed whole with some water. The tablets should preferably be taken with food (see Section 5 Pharmacological Properties). The tablets should not be cut, chewed, or crushed.
Upon initiating treatment, the dose should be escalated over a 4-week period as in Table 1.
The maximum recommended daily dose of Contrave is two tablets taken twice daily (32 mg naltrexone hydrochloride and 360 mg bupropion hydrochloride), which is reached at the start of week 4.
If a dose is missed, patients should not take an additional dose, but take the prescribed next dose at the usual time.
Patients may develop elevated blood pressure or heart rate during Contrave treatment. Blood pressure and pulse should be measured prior to starting therapy with Contrave and should be monitored at regular intervals consistent with usual clinical practice (see Section 4.4 Special Warnings and Precautions for Use).
The need for continued treatment should be evaluated after 16 weeks (see Section 4.1 Therapeutic Indications) and re-evaluated annually.

Special populations.

Elderly.

Contrave should be used with caution in patients over 65 years of age and is not recommended in patients over 75 years of age (see Section 4.4 Special Warnings and Precautions for Use).

Renal impairment.

Contrave is contraindicated in patients with end-stage renal failure. In patients with moderate or severe renal impairment, the maximum recommended daily dose for Contrave is two tablets (one tablet in the morning and one tablet in the evening). Dose reduction is not necessary in patients with mild renal impairment. For individuals who are at elevated risk for renal impairment, in particular patients with diabetes or elderly individuals, estimated glomerular filtration rate (eGFR) should be assessed prior to initiating therapy with Contrave (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Special populations).

Hepatic impairment.

Contrave is contraindicated in patients with severe hepatic impairment (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Special populations). Contrave is not recommended in patients with mild or moderate hepatic impairment.

Paediatrics.

Contrave is not recommended in children and adolescents below 18 years of age (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Contrave is contraindicated in:
Hypersensitivity to bupropion, naltrexone or any of the excipients.
Uncontrolled hypertension.
Seizure disorder or a history of seizures.
Patients with a known central nervous system tumour.
Patients undergoing acute alcohol or benzodiazepine withdrawal.
Patients with a history of bipolar disorder.
Use of concomitant treatment containing bupropion or naltrexone.
Current or previous diagnosis of bulimia or anorexia nervosa.
Patients currently dependent on opioids including opioid-containing medication, patients treated with opioid agonists used in opioid dependence (e.g. methadone, buprenorphine), or patients in acute opioid withdrawal (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Concomitant administration of monoamine oxidase inhibitors (MAOI). At least 14 days should elapse between discontinuation of MAOI and initiation of treatment with Contrave. Starting Contrave in a patient treated with reversible MAOIs is also contraindicated.
Pregnancy.
Patients with severe hepatic impairment.
Patients with end-stage renal failure.
See Section 4.4 Special Warnings and Precautions for Use for further details.

4.4 Special Warnings and Precautions for Use

The safety and tolerability of Contrave should be assessed at regular intervals.
The treatment should be discontinued if there are concerns with the safety or tolerability of ongoing treatment; including concerns about increased blood pressure (see Section 4.8 Adverse Effects (Undesirable Effects)).
The safety and efficacy of Contrave for long term use (> 1 year) has not yet been established.

Identified precautions.

Suicide and suicidal behaviour.

Contrave contains bupropion. Bupropion is indicated for the treatment of depression in some countries. A meta-analysis of placebo controlled clinical trials of antidepressants in adult subjects with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in subjects less than 25 years old.
Although in placebo controlled clinical trials with Contrave for the treatment of obesity in adult subjects, no suicides or suicide attempts were reported in studies up to 56 weeks duration with Contrave, suicidality events (including suicidal ideation) have been reported in subjects of all ages treated with Contrave postmarketing.
Close supervision of patients, particularly those at high risk, should accompany therapy with Contrave especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Seizures.

Bupropion is associated with a dose-related risk of seizures. Bupropion sustained release (SR) 300 mg yields an estimated seizure incidence of 0.1%. The incidence of seizure in subjects receiving Contrave in clinical trials was approximately 0.06% (2/3239 subjects) vs. 0.0% (0/1515 subjects) on placebo. This incidence of seizure, along with incidence of seizure in subjects who received Contrave in a large cardiovascular outcomes trial (CVOT), was no higher than the seizure rate with bupropion as a single agent at approved doses.
The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold (see Section 4.3 Contraindications). Consider these risks before initiating treatment with Contrave. Contrave should be discontinued and not restarted in patients who experience a seizure while being treated with the medicinal product.
Caution should be used when prescribing Contrave to patients with predisposing factors that may increase the risk of seizure including:
history of head trauma;
excessive use of alcohol or addiction to cocaine or stimulants;
as treatment with Contrave may result in lowered glucose in patients with diabetes, the dose of insulin and/or oral diabetic medicinal products should be assessed to minimise the risk of hypoglycaemia, which could predispose patients to seizure;
concomitant administration of medicinal products that may lower the seizure threshold, including antipsychotics, antidepressants, antimalarials, tramadol, theophylline, systemic steroids, quinolones and sedating antihistamines.
Also see Section 4.3 Contraindications.
The consumption of alcohol during Contrave treatment should be minimised or avoided.

Patients receiving opioids.

Patients must be warned against the concomitant use of opioids during treatment with naltrexone/bupropion (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Contrave must not be administered to patients currently dependent on opioids, including opioid-containing medication or patients treated with opioid agonists used in opioid dependence (e.g. methadone, buprenorphine) or patients in acute opioid withdrawal (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Contrave may be used with caution after opioid use has been stopped for at least 7 to 10 days in order to prevent the precipitation of withdrawal symptoms.
When opioid use is suspected, a test may be performed to ensure clearance of opioid medication before starting treatment with Contrave. If opioid therapy is required after treatment initiation, Contrave treatment must be stopped. Serious life-threatening reactions, such as seizure and serotonin syndrome, have been observed after co-administration of Contrave and opioids. Insufficient intra-/post-operative opioid analgesia during treatment with Contrave has been reported.
In patients requiring intermittent treatment with opioids (e.g. due to a surgical procedure), Contrave should be discontinued for a minimum of 3 days before and the opioid dose should not be increased above the standard dose. During Contrave clinical studies, the use of concomitant opioid or opioid-like medicinal products, including analgesics or antitussives were excluded. However, approximately 12% of subjects took a concomitant opioid or opioid-like medicinal product while enrolled in the Contrave clinical studies, the majority of whom continued study treatment without interruption of Contrave dose, without untoward consequences.

Attempt to overcome blockade.

An attempt by a patient to overcome any naltrexone opioid blockade by administering large amounts of exogenous opioids is very dangerous and may lead to a fatal overdose or life endangering opioid intoxication (e.g. respiratory arrest, circulatory collapse). Patients should be advised that they may be more sensitive to opioids, even at lower doses, after Contrave treatment is discontinued.

Allergic reactions.

Anaphylactoid/ anaphylactic reactions characterised by symptoms such as pruritus, urticaria, angioedema, and dyspnoea requiring medical treatment have been reported in clinical trials with bupropion. In addition, there have been rare spontaneous post-marketing reports of erythema multiforme, and anaphylactic shock associated with bupropion. A patient should stop taking Contrave and consult a doctor if experiencing allergic or anaphylactoid/ anaphylactic reactions (e.g. skin rash, pruritus, hives, chest pain, oedema, and shortness of breath) during treatment. If a patient experiences anaphylactic reactions during treatment, medical attention should be sought immediately.
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity have been reported in association with bupropion. These symptoms may resemble serum sickness. Patients should be advised to notify their prescribing physician if they experience these symptoms. If serum sickness is suspected, Contrave should be discontinued.

Severe cutaneous adverse reactions (SCARs).

Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and acute generalised exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with Contrave treatment.
Patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, Contrave should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed a serious reaction such as SJS or AGEP with the use of Contrave, the treatment must not be restarted in this patient at any time.

Elevation of blood pressure and heart rate.

Contrave can cause an increase in systolic and/or diastolic blood pressure as well as an increase in resting heart rate. Early, transient mean increases from baseline in systolic and diastolic blood pressure of up to 1 mmHg were observed in Contrave phase 3 clinical trials. In clinical practice with other bupropion-containing products, hypertension, in some cases severe and requiring acute treatment, has been reported. Furthermore, post-marketing cases of hypertensive crisis have been reported during the initial titration phase with Contrave.
Blood pressure and pulse should be measured prior to initiation of therapy with Contrave and should be assessed at regular intervals consistent with usual clinical practice. If patients experience clinically relevant and sustained increases in blood pressure or pulse rate as a result of Contrave treatment, it should be discontinued.
Contrave should be given with caution to those patients with controlled hypertension and must not be given to patients with uncontrolled hypertension (see Section 4.3 Contraindications).

Cardiovascular disease.

There is no clinical experience establishing the safety of Contrave in patients with a recent history of myocardial infarction, unstable heart disease or NYHA class III or IV congestive heart failure. It is recommended that Contrave should not be used in this population.

Brugada syndrome.

Bupropion may unmask Brugada syndrome, a rare hereditary disease of the cardiac sodium channel with characteristic ECG changes (right bundle branch block and ST segment elevation in right precordial leads), which may lead to cardiac arrest or sudden death. Caution is advised in patients with Brugada syndrome or a family history of cardiac arrest or sudden death.

Hepatotoxicity.

Naltrexone hydrochloride can cause hepatocellular injury in high doses; although this was not seen in Contrave with lower doses of naltrexone, care should be used when prescribing in patients in whom clearance may be reduced, or in whom underlying liver disease may be present.
In Contrave completed clinical studies, where naltrexone hydrochloride daily doses ranged from 16 mg to 48 mg, drug-induced liver injury (DILI) was reported. There have also been cases of elevated liver enzymes from post-marketing reporting. A patient with suspected DILI should stop taking Contrave and notify their prescribing physician.
Patients should be advised to seek medical attention if they experience symptoms of acute hepatitis. Use of Contrave should be discontinued in the event of symptoms and/or signs of acute hepatitis.

Serotonin syndrome.

Serotonin syndrome has been reported when bupropion is co-administered with drugs known to be associated with serotonin syndrome, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs) and opioids (e.g. tramadol, methadone). If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects)).
Serotonin syndrome has also been reported with overdosage (see Section 4.9 Overdose).

Neuropsychiatric symptoms and activation of mania.

Activation of mania and hypomania have been reported in patients with mood disorders who were treated with other similar medicinal products for major depressive disorder. No activation of mania or hypomania was reported in the clinical trials evaluating effects of Contrave in obese subjects, which excluded subjects receiving antidepressants. Contrave should be used cautiously in patients with a history of mania.
Panic attacks, particularly in patients with a history of psychiatric disorders, have been reported with Contrave. The cases occurred mostly during the initial titration phase and following dose changes. Contrave should be used with caution in patients with a history of psychiatric disorders.

Drug abuse and dependence.

Contrave has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. However, in outpatient clinical studies of up to 56-week duration, there was no evidence of euphoric drug intoxication, physical dependence, diversion or abuse. There was no evidence of an abstinence syndrome following abrupt or tapered drug discontinuation after 56 weeks of double-blind, placebo-controlled, randomised treatment.
However there have been reports of the inhalation of crushed tablets or injection of dissolved bupropion from use with single-ingredient products containing bupropion. This may lead to a rapid release, faster absorption and potential overdose. Seizures and/or cases of death have been reported when single-ingredient products containing bupropion have been administered intranasally or by parenteral injection.

Lactose.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Contrave.

Use in hepatic impairment.

Contrave has not been evaluated in subjects with hepatic impairment.
Based on information available for the individual constituents, systemic exposure is significantly higher for bupropion and metabolites (two- to three-fold), and naltrexone and their metabolites (up to 10-fold higher) in subjects with moderate-to-severe hepatic impairment. Therefore, Contrave should not be used in this population (see Section 4.3 Contraindications; Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

Contrave has not been extensively evaluated in subjects with renal insufficiency. Contrave is contraindicated in patients with end-stage renal failure. In patients with moderate or severe renal impairment, the maximum recommended daily dose for Contrave should be reduced, as these patients may have higher drug concentrations which could result in an increase in adverse drug reactions. For individuals who are at elevated risk for renal impairment, in particular, individuals with diabetes or elderly individuals, estimated glomerular filtration rate (eGFR) should be assessed prior to initiating therapy with Contrave (see Section 4.3 Contraindications; Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

Clinical studies of Contrave did not include sufficient numbers of subjects aged 65 and over, and none over 75 years, to determine whether they respond differently than younger subjects. Older individuals may be more sensitive to the central nervous system adverse effects of Contrave. Naltrexone and bupropion are known to be substantially excreted by the kidney, and the risk of adverse effects to Contrave may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Contrave should be used with caution in patients over 65 years of age and is not recommended in patients over 75 years of age.

Paediatric use.

The safety and efficacy of Contrave in children and adolescents below 18 years have not yet been established. Therefore, Contrave is not recommended in children and adolescents below 18 years of age.

Effects on laboratory tests.

False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Monoamine oxidase inhibitors (MAOI).

Concomitant use of MAOIs and bupropion is contraindicated. Bupropion inhibits the reuptake of dopamine and norepinephrine and can increase the risk for hypertensive reactions when used with medicines that also inhibit the reuptake of dopamine or norepinephrine. At least 14 days should elapse between discontinuation of MAOIs and initiation of treatment with Contrave. Conversely, at least 14 days should be allowed after stopping Contrave before starting an MAOI (see Section 4.3 Contraindications).

Opioids.

Contrave is contraindicated in patients currently dependent on opioids including opioid containing medication, patients treated with opioid agonists used in opioid dependence (e.g. methadone, buprenorphine), or patients in acute opioid withdrawal (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use). Due to the antagonistic effect of naltrexone at the opioid receptor, patients taking Contrave may not fully benefit from treatment with opioid-containing medicinal products, such as cough and cold remedies, anti-diarrhoeal preparations and opioid analgesics.

Potential for Contrave to affect other medicines.

Metabolised by CYP2D6 substrates.

In vitro human P450 studies have shown that bupropion and hydroxybupropion are inhibitors of CYP2D6. In a clinical study, Contrave (32 mg naltrexone hydrochloride/360 mg bupropion hydrochloride daily) was co-administered with a 50 mg dose of metoprolol (a CYP2D6 substrate). Contrave increased metoprolol AUC and C_max by approximately 4- and 2-fold, respectively, relative to metoprolol alone. Similar clinical drug interactions resulting in increased pharmacokinetic exposure of CYP2D6 substrates have also been observed with bupropion as a single medicinal product with desipramine and venlafaxine.
Co-administration of Contrave with drugs that are metabolised by CYP2D6 isozyme including certain antidepressants (SSRIs and many tricyclic antidepressants, e.g. desipramine, imipramine, paroxetine), antipsychotics (e.g. haloperidol, risperidone and thioridazine), beta-blockers (e.g. metoprolol) and Type 1C antiarrhythmics (e.g. flecainide), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication. If Contrave is added to the treatment regimen of a patient already receiving a drug metabolised by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index. When feasible, the option of therapeutic drug monitoring should be considered for medications with a narrow therapeutic index, such as tricyclic antidepressants.
Post-marketing data show a possible pharmacodynamics interaction between bupropion and SSRIs, SNRIs and opioids (e.g. tramadol, methadone) resulting in an increased risk of serotonin syndrome (see Section 4.4 Special Warnings and Precautions for Use, Serotonin syndrome; Section 4.8 Adverse Effects (Undesirable Effects)).

Potential for other drugs to affect Contrave.

Bupropion is primarily metabolised to its major active metabolite hydroxybupropion by the CYP2B6 isozyme. The potential exists for a drug interaction between Contrave and drugs that induce or are substrates of the CYP2B6 isozyme.

Inhibitors of CYP2B6.

Ticlopidine and clopidogrel: concomitant treatment with these drugs can increase bupropion exposure but decrease hydroxybupropion exposure. During concomitant use with CYP2B6 inhibitors, the Contrave dose should not exceed two tablets (one in the morning and evening) (see Section 4.2 Dose and Method of Administration).

Inducers of CYP2B6.

Ritonavir, lopinavir and efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure and may reduce efficacy. In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 100 mg plus lopinavir 400 mg twice daily reduced the exposure of bupropion and its major metabolites in a dose dependent manner by 20 to 80%. Similarly, efavirenz 600 mg once daily for two weeks reduced the exposure of bupropion by approximately 55% in healthy volunteers. Concomitant use with these drugs is not recommended.

OCT2 substrates.

Bupropion and its metabolites competitively inhibit the OCT2 in the basolateral membrane of the renal tubule responsible for creatinine secretion, in a manner similar to the OCT2 substrate cimetidine. Therefore, mild increases in creatinine observed after long-term treatment with naltrexone/ bupropion are likely due to inhibition of OCT2 and not indicative of changes in creatinine clearance. Use of naltrexone/ bupropion with other OCT2 substrates (e.g. metformin) in clinical trials did not indicate the need for dose adjustment or other precautions.

Drugs that lower the seizure threshold.

Use extreme caution when coadministering Contrave with other drugs that lower the seizure threshold (e.g. antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses and increase the dose gradually. Concomitant use of other bupropion containing products is contraindicated (see Section 4.3 Contraindications).

Dopaminergic drugs (levodopa and amantadine).

Bupropion, levodopa and amantadine have dopamine agonist effects. CNS toxicity has been reported when bupropion was co-administered with levodopa or amantadine. Adverse effects have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use caution and monitor for such adverse effects when administering Contrave concomitantly with these drugs.

Use with alcohol.

In post-marketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients drinking alcohol during bupropion treatment. There are no known pharmacokinetic interactions between naltrexone and alcohol. The consumption of alcohol during Contrave treatment should be minimised or avoided.

Other interactions.

Coadministration of Contrave with digoxin may decrease plasma digoxin levels. Monitor plasma digoxin levels in patients treated concomitantly with Contrave and digoxin. Clinicians should be aware that digoxin levels may rise on discontinuation of Contrave and the patient should be monitored for possible digoxin toxicity. See Table 2.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on fertility from the combined use of naltrexone and bupropion. No effect on fertility was observed with bupropion in rats at oral doses up to 300 mg/kg/day (approximately 8 times the maximum recommended human dose of bupropion provided by Contrave, based on body surface area). Naltrexone administered orally to rats caused a significant increase in pseudopregnancy and a decrease in pregnancy rates at 100 mg/kg/day, approximately 30 times the naltrexone dose provided by Contrave. The relevance of these observations to human fertility is not known.
(Category B3)
Contrave is contraindicated in pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. Contrave should not be used during pregnancy or in women currently attempting to become pregnant. If Contrave is used during pregnancy, or if the patient becomes pregnant while taking this medicine, the patient should be apprised of the potential hazard of maternal weight loss to the fetus.
There are no or limited amounts of data from the use of naltrexone/bupropion in pregnant women. The combination has not been tested in reproductive toxicity studies.
Naltrexone increased the incidence of early fetal loss when administered to rats at oral doses ≥ 30 mg/kg/day (9 times the maximum recommended therapeutic dose, based on body surface area) and to rabbits at oral doses ≥ 60 mg/kg/day (36 times the maximum recommended therapeutic dose, based on body surface area). There was no evidence of teratogenicity when naltrexone was administered orally to rats and rabbits during the period of organogenesis at doses up to 200 mg/kg/day (approximately 60 and 120 times the maximum recommended therapeutic dose, based on body surface area, in the respective species).
Studies in pregnant mice, rats and rabbits showed no evidence of adverse effects on embryofetal development at oral doses up to 100, 450 and 150 mg/kg/day, respectively. In mice and rats, administration of bupropion in late gestation had no effects on parturition. The predictive value of these studies is limited by low exposure. In mice and rabbits, systemic exposure (based on AUC) to bupropion and its metabolites achieved at these dose levels is expected to be less than in humans at the maximum recommended therapeutic dose. In rats, exposure to bupropion was up to approximately twice, and to its metabolites was less than, human exposure.
Naltrexone and bupropion and their metabolites are excreted in human milk.
Since there is limited information on the systemic exposure to naltrexone and bupropion in infants/ newborns being breastfed, a risk to the newborns/ infants cannot be excluded.
Contrave is not recommended for nursing mothers.

4.7 Effects on Ability to Drive and Use Machines

Contrave may affect the ability to perform tasks that require judgment or motor and cognitive skills. When driving vehicles or using machines, it should be taken into account that dizziness, somnolence, loss of consciousness and seizure may occur during treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should therefore exercise caution before driving or use of machinery until they are reasonably certain Contrave does not adversely affect their performance.

4.8 Adverse Effects (Undesirable Effects)

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.
Contrave was evaluated for safety in five double-blind placebo-controlled studies in 4,754 overweight or obese subjects (3,239 subjects treated with Contrave and 1,515 subjects treated with placebo) for a treatment period up to 56 weeks.
In clinical studies, 23.8% of subjects receiving Contrave and 11.9% of subjects receiving placebo discontinued treatment due to an adverse event. The most frequent adverse reactions leading to discontinuation with Contrave were nausea, headache, dizziness and vomiting.

Tabulated summary of adverse reactions.

The safety profile of Contrave presented in Table 3 is based on clinical studies performed with the fixed-dose combination (adverse reactions at an incidence of at least 0.1% and twice that of placebo) and/or post marketing data sources.
The frequencies of adverse reactions are ranked according to the following: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Description of selected adverse reactions.

Seizures.

The incidence of seizure in Contrave over the course of the clinical program was 0.06% (2/3239 subjects). Among the group of subjects treated with Contrave, both cases of seizures were considered as serious and led to treatment discontinuation (see Section 4.4 Special Warnings and Precautions for Use). There were no cases of seizures in the placebo group.

Gastrointestinal adverse reactions.

The incidence of the most common gastrointestinal adverse reactions for Contrave versus placebo was as follows: nausea (31.8% vs. 6.7%), constipation (18.1% vs. 7.2%), and vomiting (9.9% vs. 2.9%). The incidence of severe nausea constipation, or vomiting was low, but was higher in subjects treated with Contrave compared to subjects treated with placebo (severe nausea: Contrave 1.9%, placebo < 0.1%; severe constipation: Contrave 0.6%, placebo 0.1%; severe vomiting: Contrave 0.7%, placebo 0.3%). No events of nausea, constipation, or vomiting were considered serious.
Most subjects treated with Contrave who experienced nausea reported the event within 4 weeks of starting treatment. Events were generally self-limited; the majority of events resolved within 4 weeks and almost all resolved by week 24. Similarly, most constipation events were reported during the dose escalation phase. The time to resolution of constipation was similar between subjects treated with Contrave and subjects treated with placebo. Approximately half of the subjects treated with Contrave who experienced vomiting first reported the event during the dose escalation phase. Time to resolution for vomiting was typically rapid (within one week) and almost all events resolved within 4 weeks.

Other frequent adverse reactions.

The majority of subjects treated with Contrave who reported dizziness, headache, insomnia, or dry mouth, first reported these events during the dose escalation phase. Dry mouth may be associated with toothache and dental caries; in the subset of patients with dry mouth, a higher incidence of toothache and dental caries were observed in subjects treated with Contrave compared to subjects treated with placebo. The incidence of severe headache, severe dizziness, and severe insomnia was low, but was higher in subjects treated with Contrave compared to subjects treated with placebo (severe headache: Contrave 1.1%, placebo 0.3%; severe dizziness: Contrave 0.6%, placebo 0.2%; severe insomnia: Contrave 0.4%, placebo < 0.1%). No events of dizziness, dry mouth, headache, or insomnia in subjects treated with Contrave were considered serious.

Elderly patients.

Elderly patients may be more sensitive to some of the central nervous system-related adverse reactions of Contrave (primarily dizziness and tremor). There is an increased incidence of gastrointestinal disorders with higher age categories. Common events leading to withdrawal among elderly were nausea, vomiting, dizziness, constipation.

Type 2 diabetes.

Patients with type 2 diabetes treated with Contrave demonstrated a higher incidence of gastrointestinal adverse events, primarily nausea, vomiting, and diarrhoea, than subjects without diabetes. Patients with type 2 diabetes may be more prone to these events due to concomitant medicinal product use (e.g. metformin) or may be more likely to have underlying gastrointestinal disorders (e.g. gastroparesis) predisposing to gastrointestinal symptoms.

Renal impairment.

Patients with moderate renal impairment had a higher incidence of gastrointestinal and central nervous system-related adverse events, thus these patients generally had lower tolerability of Contrave at a total daily dose of 32 mg naltrexone/360 mg bupropion, which is thought to be due to higher plasma concentrations of active metabolites. The types of tolerability events were similar to the events observed in patients with normal renal function (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 5 Pharmacological Properties).

Post-marketing data.

Nervous system disorders.

Rare frequency: loss of consciousness, syncope.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
There is no clinical experience with overdose with Contrave. The maximum daily dose of Contrave administered in clinical trials contained 50 mg naltrexone hydrochloride and 400 mg bupropion hydrochloride. The most serious clinical implications of Contrave overdose are likely those related to bupropion.

Bupropion.

Overdoses of up to 30 grams or more of bupropion (equivalent of up to 83 times the recommended daily dose of Contrave 32 mg/360 mg) have been reported. Seizure was reported in approximately one third of these overdose cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses.
Although most subjects recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in subjects ingesting large doses of the drug.
Serotonin syndrome has also been reported.

Naltrexone.

There is limited experience with overdose of naltrexone monotherapy in humans. In one study, subjects received 800 mg naltrexone hydrochloride daily (equivalent to 25 times the recommended daily dose of Contrave 32 mg/360 mg) for up to one week showing no evidence of toxicity.

Overdose management.

In case of an overdose, provide supportive care, including close medical supervision and monitoring. An adequate airway, oxygenation, and ventilation should be ensured. Cardiac rhythm and vital signs should be monitored. EEG monitoring is also recommended for the first 48 hours post-ingestion. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended.
Activated charcoal may reduce absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
No antidotes are known.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: A08AA Centrally acting anti-obesity products.
ATC code: A08AA62 bupropion and naltrexone.

Mechanism of action.

The exact neurochemical appetite suppressant effects of naltrexone/bupropion (NB) are not fully understood. The medicinal product has two components: naltrexone, a mu-opioid antagonist, and bupropion, a moderately weak inhibitor of neuronal reuptake of dopamine and norepinephrine. These components affect two principal areas of the brain, specifically the arcuate nucleus of the hypothalamus and the mesolimbic dopaminergic reward system. Combined, bupropion and naltrexone increased the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons in vitro, which are associated with regulation of appetite. The combination of bupropion and naltrexone also reduced food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, the area associated with regulation of reward pathways.
In the arcuate nucleus of the hypothalamus, bupropion stimulates pro-opiomelanocortin (POMC) neurons that release alpha-melanocyte stimulating hormone (α-MSH), which in turn binds to and stimulates melanocortin 4 receptors (MC4-R). When α-MSH is released, POMC neurons simultaneously release β-endorphin, an endogenous agonist of the mu-opioid receptors. Binding of β-endorphin to mu-opioid receptors on POMC neurons mediates a negative feedback loop on POMC neurons leading to a decrease in the release of α-MSH. Blocking this inhibitory feedback loop with naltrexone is proposed to facilitate a more potent and longer lasting activation of POMC neurons, thereby amplifying the effects of bupropion on energy balance. In vitro and in vivo data in mice suggest that naltrexone and bupropion may have greater than additive effects in this region to reduce food intake when administered together.

Clinical trials.

The effects of Contrave on weight loss in conjunction with reduced caloric intake and increased physical activity, were examined in double-blind, placebo-controlled trials (BMI range 27 to 45 kg/m²) with study durations of 16 to 56 weeks randomised to naltrexone hydrochloride (16 to 50 mg/day) and/or bupropion hydrochloride (300 to 400 mg/day) or placebo.

Effect on weight loss and weight maintenance.

Four 56-week phase 3 multicentre, double-blind, placebo-controlled obesity trials (NB-301, NB-302, NB-303 and NB-304) were conducted to evaluate the effect of Contrave in conjunction with lifestyle modification in 4,536 subjects randomised to Contrave or placebo. The NB-301, NB-302 and NB-303 trials enrolled patients with obesity (BMI 30 kg/m² or greater), or overweight (BMI 27 kg/m² or greater) and at least one comorbidity (hypertension or dyslipidaemia). The NB-304 trial enrolled patients with BMI greater than 27 kg/m² with type 2 diabetes with or without hypertension and/or dyslipidaemia.
Treatment was initiated with a 3-week dose escalation period followed by approximately 1 year of continued therapy. Patients were instructed to take Contrave with food. NB-301 and NB-303 included a program consisting of a reduced-calorie diet, behavioural counselling, and increased physical activity. NB-302 included an intensive behavioural modification program as well as a prescribed diet and exercise regimen. NB-304 evaluated patients with type 2 diabetes not achieving glycaemic goal of HbA_1c less than 7% either with oral antidiabetic agents or with diet and exercise alone. Of the overall population of 4,536 subjects in these trials, 25% had hypertension, 33% had fasting glucose levels ≥ 5.6 mmol/L at baseline, 54% had dyslipidaemia at study entry, and 11% had type 2 diabetes. The mean age was 46 years, 83% were female and 77% Caucasian. At baseline, mean BMI was 36 kg/m² and mean waist circumference was 110 cm. The two co-primary endpoints were percent change from baseline body weight and the proportion of subjects achieving ≥ 5% total decreased body weight.
NB-301 study subjects had a mean percent body weight loss of -5.4% while receiving Contrave compared to -1.3% in placebo-treated subjects (see Table 4). Weight loss of at least 5% baseline body weight was observed more frequently for subjects treated with Contrave (31%) compared to placebo (12%) (see Table 5). More pronounced weight loss was observed in the cohort of subjects who completed 56 weeks of treatment with Contrave (-8.1%) compared to placebo (-1.8%). Comparable results were seen in NB-303, which was of similar design, with significant weight loss observed in Contrave-treated subjects compared to placebo at the week 28 primary endpoint, and sustained through 56 weeks from baseline (see Table 5).
Contrave was also evaluated in combination with intensive behavioural modification counselling in NB-302. There was greater mean weight loss from baseline for Contrave treatment (-8.1%) compared to NB-301 (-5.4%) at week 56, and for placebo (-4.9%) compared to NB-301 (-1.3%).
The treatment effects observed in obese and overweight subjects with type 2 diabetes mellitus (study NB-304) were less pronounced than those observed in the other phase 3 studies. However, Contrave (-3.7%) was significantly (p < 0.001) more efficacious than placebo (-1.7%) treatment in this population.

The percentages of subjects with ≥ 5% or ≥ 10% body weight loss from baseline were greater with Contrave compared to placebo in all four phase 3 obesity trials (see Table 5).

Of the subjects with observed data at week 16 in the four phase 3 clinical trials, 50.8% of those randomised to receive Contrave had lost ≥ 5% of their baseline body weight, compared to 19.3% of placebo-treated subjects (week 16 responders). At one year, the average weight loss (using LOCF methodology) among these week 16 responders who received Contrave was 11.3%, with 55% losing ≥ 10% bodyweight. Additionally, week 16 responders who received Contrave had a high retention rate with 87% completing 1 year of treatment.

Effect on cardiovascular and metabolic parameters.

Improvements were observed for waist circumference (including subjects with type 2 diabetes), triglycerides, HDL-C and LDL-C/HDL-C ratio for subjects treated with Contrave vs. placebo in all phase 3 studies. Improvements in triglycerides, HDL-C and LDL-C/HDL-C ratio were seen in Contrave-treated subjects diagnosed with baseline dyslipidaemia irrespective of dyslipidaemia treatment. Changes in mean blood pressure are described in Section 4.4 Special Warnings and Precautions for Use. In addition, in subjects who did not have type 2 diabetes, there were reductions in fasting insulin and HOMA-IR, a measure of insulin resistance, in Contrave treated subjects.

Effects on glycaemic control in obese subjects with type 2 diabetes.

After 56 weeks of treatment in subjects with type 2 diabetes (NB-304), Contrave exhibited improvements in glycaemic control parameters compared to placebo. Greater HbA_1c improvement compared to placebo was observed at the first post-baseline measurement (week 16, p < 0.001). Mean HbA_1c change from baseline at week 56 was -0.63% for subjects treated with Contrave compared to subjects on placebo -0.14% (p < 0.001). In subjects with baseline HbA_1c > 8% (64 mmol/mol), HbA_1c changes at endpoint were -1.1% and -0.5% for Contrave compared to placebo, respectively. Improvements were observed for fasting glucose, fasting insulin, HOMA-IR and percent of subjects requiring rescue diabetes medicinal products for subjects treated with Contrave vs. placebo.

Effect on body composition.

In a subset of 124 subjects (79 Contrave, 45 placebo), body composition was measured using dual energy X-ray absorptiometry (DEXA). The DEXA assessment showed that treatment with Contrave was associated with a significantly greater decrease from baseline in total fat mass than placebo (p < 0.001).

Long-term use.

Pivotal studies evaluated the use of Contrave for up to 52 weeks. Long-term efficacy and safety data is limited.

5.2 Pharmacokinetic Properties

The results of a single dose relative bioavailability study in healthy subjects demonstrated that naltrexone/bupropion tablets, when dose adjusted, are bioequivalent based on AUC_0-∞ mean ratio and 90% confidence intervals to naltrexone immediate release (IR) or bupropion prolonged release (PR) administered as single agents.

Absorption.

Following single oral administration of naltrexone/bupropion tablets to healthy subjects, peak concentrations of naltrexone and bupropion occurred approximately 2 and 3 hours post administration of naltrexone/bupropion, respectively. There were no differences in bioavailability, as measured by AUC, of naltrexone or bupropion when administered in combination compared to each administered alone. However, given the prolonged nature of the drug release for naltrexone/bupropion, C_max for naltrexone was markedly reduced compared to the 50 mg naltrexone hydrochloride IR administered alone (about 2-fold difference after dose adjustment). The bupropion C_max from naltrexone/bupropion (180 mg bupropion hydrochloride) was equivalent to the C_max of bupropion PR (150 mg bupropion hydrochloride), indicating that the bupropion C_max achieved with naltrexone/bupropion (360 mg bupropion hydrochloride/day) is comparable to that achieved with commercially available bupropion PR (300 mg bupropion hydrochloride/day) administered alone.
Naltrexone and bupropion are well absorbed from the gastrointestinal tract (> 90% absorbed), however, naltrexone has a significant first pass effect thereby limiting systemic bioavailability, with only 5-6% reaching the systemic circulation intact.

Distribution.

The mean volume of distribution at steady state of oral naltrexone and bupropion given as naltrexone/bupropion, V_SS/F, was 5697 litres and 880 litres, respectively.
Plasma protein binding is not extensive for naltrexone (21%) or bupropion (84%) indicating low potential for drug interactions by displacement.

Metabolism.

Following single oral administration of naltrexone/bupropion tablets to healthy subjects, mean t_1/2 elimination half-life was approximately 5 hours for naltrexone and 21 hours for bupropion.
When naltrexone/bupropion was given with a high-fat meal the AUC and C_max for naltrexone increased 2.1-fold and 3.7-fold and the AUC and C_max for bupropion increased 1.4-fold and 1.8-fold, respectively. At steady state, the food effect resulted in AUC and C_max increases of 1.7- and 1.9-fold for naltrexone, and 1.1- and 1.3-fold for bupropion, respectively. Clinical experience included varying prandial conditions and supports the use of naltrexone/bupropion tablets with food.

Naltrexone.

The major metabolite of naltrexone is 6-beta-naltrexol. Naltrexone is primarily metabolised to 6-beta-naltrexol by the dihydrodiol dehydrogenases (DD1, DD2 and DD4). The activity of naltrexone is believed to be the result of both the parent and the 6-beta-naltrexol metabolite. Though less potent, 6-beta-naltrexol is eliminated more slowly and thus circulates at much higher concentrations than naltrexone.
Other major metabolic routes are the formation of the metabolites 2-hydroxy-3-O-methyl naltrexone and 2-hydroxy-3-O-methyl-6-beta-naltrexol, believed to be mediated by catechol-O-methyl transferases (COMT), and glucuronidation, thought to be mediated by UGT1A1 and UGT2B7.

Bupropion.

Bupropion is extensively metabolised with three active metabolites: hydroxybupropion, threohydrobupropion and erythrohydrobupropion. The metabolites have longer elimination half-lives than bupropion and accumulate to a greater extent. Following bupropion administration, more than 90% of the exposure is a result of metabolites.
In vitro findings suggest that CYP2B6 is the principal isozyme involved in the formation of hydroxybupropion, while CYP1A2, 2A6, 2C9, 3A4 and 2E1 are less involved. In contrast, formation of threohydrobupropion has been reported in the literature to be mediated by 11-beta-hydroxysteroid dehydrogenase 1. The metabolic pathway responsible for the formation of erythrohydrobupropion is unknown.

Excretion.

Following twice daily administration of Contrave, naltrexone does not accumulate, while 6-beta-naltrexol accumulates over time. Based on its half-life, 6-beta-naltrexol is estimated to reach steady state concentrations in approximately 3 days. Metabolites of bupropion, and to a lesser extent unchanged bupropion, accumulate and reach steady-state concentrations in approximately one week.

Naltrexone.

Naltrexone and its metabolites are excreted primarily by the kidney (37 to 60% of the dose). The derived value for renal excretion of naltrexone after oral administration, adjusting for plasma protein binding, is 89 mL/min. The enzyme responsible for the main elimination pathway is not known. Faecal excretion is a minor elimination pathway.

Bupropion.

Following oral administration of 200 mg of ¹⁴C-bupropion hydrochloride in humans, 87% and 10% of the radioactive dose were recovered in the urine and faeces, respectively. The fraction of the oral dose of bupropion excreted unchanged was 0.5%, a finding consistent with the extensive metabolism of bupropion.