Contrave vs Orlistat in Australia

No randomised trial has compared naltrexone-bupropion with orlistat. A Europe PMC search for randomised controlled trials mentioning both, run on 6 October 2026, returned 34 records, none a trial comparing the two. Everything below is indirect.

Contrave's evidence is four 56-week phase 3 trials (4,536 randomised, all in the United States, all funded by the then sponsor, Orexigen), reported intention-to-treat in the Australian Product Information: COR-I, 5.4% loss against 1.3% on placebo (538 and 536 people); COR-BMOD, 8.1% against 4.9% with 28 sessions of intensive behaviour modification in both groups (565 and 196); COR-Diabetes, 3.7% against 1.7% in type 2 diabetes (321 and 166); COR-II at week 28, 5.7% against 1.9% (943 and 474). Completion was 50% in COR-I and 54% in COR-II. None ran beyond 56 weeks.

Orlistat's largest trial is XENDOS: 3,305 adults with a BMI of 30 or more, four years, published in 2004 with Roche-affiliated authors. Loss was 10.6 kg against 6.2 kg on placebo at one year and 5.8 kg against 3.0 kg at four years; 52% completed against 34%. The 2007 BMJ update of the Cochrane review pooled 16 orlistat trials of one to four years (10,631 people): 2.9 kg, or 2.9% of body weight, more than placebo.

Contrave's side effects are nausea, constipation, vomiting and effects on the nervous system and blood pressure. Orlistat's follow from the third of dietary fat it stops the gut absorbing.

Contrave: in the pooled trials (3,239 people on Contrave, 1,515 on placebo, up to 56 weeks) nausea affected 31.8% against 6.7%, constipation 18.1% against 7.2% and vomiting 9.9% against 2.9%. Most nausea began within four weeks and almost all had resolved by week 24. 23.8% stopped for an adverse event against 11.9%, usually for nausea, headache, dizziness or vomiting. The Product Information warns on suicidal thoughts (post-marketing reports, none in the trials; close supervision early in treatment and after dose changes); seizures (two of 3,239 trial participants, 0.06%; stop permanently after one); hypertensive crises during the step-up, so blood pressure and pulse must be measured before starting and monitored; serotonin syndrome with SSRI or SNRI antidepressants, added after six TGA reports linked to bupropion up to June 2021; and severe skin reactions. The September 2026 revision added that cardiovascular risk beyond one year has not been fully determined, requiring an annual cardiovascular assessment before continuing, and that prescribers must have read the sponsor's educational material. Alcohol should be minimised or avoided.

Orlistat: oily spotting, flatus with discharge, faecal urgency, fatty or oily stools, oily evacuation, liquid stools, more frequent bowel movements and faecal incontinence are listed as commonly or very commonly observed. They occur within the first three months, most people have one episode, 3% have more than two episodes of any one effect, and they worsen with the fat eaten; the diet is meant to keep fat to about 30% of energy, or no more than 67 g a day. The Australian document gives no percentages; the United States label, reporting the same seven trials, gives oily spotting in 26.6% against 1.3% on placebo in year one, faecal urgency 22.1% against 6.7% and faecal incontinence 7.7% against 0.9%. 8.8% stopped for an adverse event in year one against 4.9%. A multivitamin is advised, at least two hours apart or at bedtime, because fat-soluble vitamin absorption falls. Severe diarrhoea may reduce the reliability of the oral contraceptive pill; an additional method is advised when it occurs. Rare post-marketing reports include hepatitis and severe liver injury, with no causal relationship established, and oxalate kidney damage.

Contrave is a Schedule 4 prescription-only medicine. A GP, a specialist or a nurse practitioner within their scope of practice can prescribe it; the Product Information says every prescriber must be familiar with the sponsor's educational material. The criteria are a BMI of 30 or more, or 27 to 30 with a weight-related condition such as type 2 diabetes, dyslipidaemia or controlled hypertension, alongside a reduced-calorie diet and more physical activity. The dose steps up over four weeks from one tablet in the morning to two tablets twice a day, taken with food and swallowed whole. Two stopping rules: at 16 weeks if less than 5% of starting weight has been lost, and at one year if a 5% loss has not been maintained.

Orlistat 120 mg is a Schedule 3 pharmacist-only medicine under the Poisons Standard (June 2026 instrument): "ORLISTAT in oral preparations for weight-control purposes containing 120 mg or less of orlistat per dosage unit". A pharmacist can supply it without a prescription after assessing whether it is appropriate. The Product Information's criteria are a BMI of 30 or more, or 27 or more with other risk factors; it is not recommended under 18. Online, the three retailers differ: Chemist Warehouse requires a phone call with its pharmacists within five business days or removes the item from the order; Chemist Outlet requires a call within 48 hours unless a prescription is supplied, and sells one pack per order; Your Discount Chemist labels Xenical "Prescription Only Medicine" and will not dispatch without a script, the retailer's policy rather than the legal schedule.

There is no 60 mg orlistat product in Australia. Alli 60 mg was cancelled from the ARTG at the sponsor's request on 22 June 2021, and no other 60 mg product is registered.

On the indirect evidence, Contrave produces more weight loss than orlistat and is stopped more often for side effects: Khera's 2016 network meta-analysis puts the one-year difference from placebo at 5.0 kg against 2.6 kg, and Shi's 2024 analysis gives discontinuation odds of 2.69 against 1.71. The BMJ 2026 analysis does not find either convincingly different from a lifestyle program at one year. Contrave costs 2.6 times as much per month at Chemist Warehouse.

Australian guidance does not rank one above the other for everyone. The RACGP's journal (April 2025) says incretin-based injections should be considered first line for people with type 2 diabetes, cardiovascular disease, knee osteoarthritis, sleep apnoea or fatty liver disease; that phentermine-topiramate or naltrexone-bupropion are reasonable options for people without cardiovascular disease or hypertension; and that orlistat can be considered in people with cardiovascular disease or hypertension where incretin therapy is not tolerated or unaffordable. It also says to stop and try another agent if less than 5% has been lost after 12 weeks on the maximum dose, and that most people need lifelong treatment.

No Australian guideline covers moving from one to the other, and neither Product Information mentions the other medicine or gives a washout period. Contrave's step-up takes four weeks from one tablet a day; orlistat has no step-up and starts at the full dose with the first main meal.

No trial has tested using them together. The orlistat Product Information says that, in the absence of interaction studies, "concomitant administration with other anti-obesity agents is not recommended". The Contrave Product Information says nothing about other weight-loss medicines; its own restrictions are other bupropion or naltrexone products, MAOIs and opioids. Australian Prescriber (April 2022, by an author with declared advisory roles for the sponsors of liraglutide and Contrave) said phentermine must not be combined with Contrave and a GLP-1 medicine "could be", citing no trial, and said nothing about orlistat. The only combination evidence found for Contrave is a 2024 retrospective study from one Canadian clinic that added it to a GLP-1 medicine, not to orlistat.

Regain after stopping is documented for both. In the four orlistat trials with a second year of maintenance, the orlistat and placebo groups regained weight at similar rates while the gap between them held; the Product Information says weight regain or a slowing of loss may occur after one year. No Contrave extension study was found; the RACGP's journal says regain on stopping is the norm for weight-loss medicines generally.