Mysimba: composition and form
Mysimba is a two-ingredient tablet: one tablet contains 8 mg of naltrexone hydrochloride, equivalent to 7.2 mg of naltrexone, and 90 mg of bupropion hydrochloride, equivalent to 78 mg of bupropion. Each substance on its own has long been familiar from other areas of medicine, and what is distinctive about this medicine is precisely the pairing of the two in a single tablet.
The handling rules are strict: the tablet is swallowed whole with water, preferably with food, and must not be cut, chewed or bitten. The requirement is not cosmetic — a damaged coating changes how fast the bupropion is released, and as the warnings make clear, the risk of a seizure depends on exactly that.
How Mysimba works
The product information begins with an honest admission: the neurochemical mechanisms behind the appetite suppression produced by naltrexone plus bupropion are not precisely known. What the action consists of is known. Naltrexone is a µ-opioid receptor antagonist — that is, it blocks the receptor rather than stimulating it. Bupropion is a weak inhibitor of the neuronal reuptake of dopamine and noradrenaline.
Both substances act on two main areas of the brain: the arcuate nucleus of the hypothalamus and the mesolimbic dopaminergic reward system. The first governs appetite and energy balance; the second governs reinforcement, the sense of pleasure that fixes a behaviour in place. In other words, the medicine works not on the stomach and not on the absorption of food, but on the part of the brain where the wish to eat arises. That is also where the particular caution in people with a psychiatric history comes from.
Indications
The indication is written as an adjunct, not as a stand-alone treatment: the medicine is used in addition to a reduced-calorie diet and increased physical activity to reduce weight in adults from 18 years of age. Body mass index defines who the patients are: 30 kg/m² or more, that is obesity, or 27 to 30 kg/m², that is overweight, but only in the presence of one or more obesity-related conditions — for example type 2 diabetes, dyslipidaemia or controlled arterial hypertension.
A stopping rule is attached to the indication straight away, and in this the medicine is unusual: after 16 weeks of use it must be discontinued if weight has not fallen by at least 5% of the starting value. Treatment is therefore not continued "just in case" and not judged by eye — there is a deadline and there is a numerical threshold. If four months bring no result, taking it further is considered pointless.
Administration and dosage
The dose is raised gradually over four weeks, and the schedule is the same for everyone: the body is given time to get used to the bupropion. The maximum recommended daily dose is two tablets twice a day, which corresponds to 32 mg of naltrexone hydrochloride and 360 mg of bupropion hydrochloride per day.
| Week of treatment | Morning | Evening |
| Week 1 | 1 tablet | — |
| Week 2 | 1 tablet | 1 tablet |
| Week 3 | 2 tablets | 1 tablet |
| Week 4 onwards | 2 tablets | 2 tablets |
The need to continue is reviewed after 16 weeks and once a year thereafter. A missed dose is not taken later: the next one is taken at the usual time. Special groups are described in detail. Over the age of 65 the medicine is given with caution and above 75 it is not recommended. In end-stage renal disease and severe renal impairment it is contraindicated, in moderate impairment it is not recommended, and in mild impairment the dose is unchanged; in people at higher renal risk — above all those with diabetes and older patients — the estimated glomerular filtration rate is measured before starting. In severe hepatic impairment it is contraindicated, and in mild or moderate impairment it is not recommended. It is not given under the age of 18.
Contraindications
The list is long and falls into several groups by meaning. The first is the nervous system: current epilepsy or seizures in the past, a tumour of the central nervous system, and the period immediately following abrupt withdrawal of alcohol or benzodiazepines in a dependent person. The second is psychiatric: bipolar affective disorder in the history, and bulimia or anorexia nervosa, current or past.
The third group concerns opioids and follows from the mechanism of naltrexone: dependence on opioids or on long-term opiate agonists such as methadone, and the period immediately following abrupt withdrawal of opiates in a dependent person. The fourth is pharmacological: the use of MAO inhibitors, with at least 14 days required between stopping them and starting this treatment, and the use of bupropion or naltrexone for any indication other than weight reduction. The list closes with uncontrolled arterial hypertension, severe hepatic impairment, end-stage renal disease or severe renal impairment, and hypersensitivity to the active substances or to any of the excipients.
Special warnings and precautions
Safety and tolerability are assessed at regular intervals, and if there are safety or tolerability problems — including a rise in blood pressure — treatment is stopped. The first major theme of the section is suicide. The bupropion in the combination is a dopamine and noradrenaline reuptake inhibitor, close to some substances used in depression. A meta-analysis of placebo-controlled trials of antidepressants in adults with psychiatric disorders showed that in the subgroup under 25 the risk of suicidal behaviour was higher than on placebo. In the trials of this combination in obesity, lasting up to 52 weeks, not a single suicide or attempt was recorded, and suicidal ideation was no more frequent than on placebo. Even so, close observation is recommended at the start of treatment and after every dose change, particularly of young adults; the patient and those caring for them are told to seek medical help at once if low mood deepens, suicidal thoughts appear, or behaviour changes in an unusual way.
The second theme is seizures, and here the wording is especially careful. The seizure risk with bupropion is dose-proportional: for the prolonged-release form at 300 mg the estimated frequency is 0.1%. After a single dose of 180 mg of bupropion within this medicine, its plasma concentrations approach those given by a 150 mg dose of the SR form, but that comparison has not been made for repeated dosing. Since it is not known whether the risk is carried by bupropion itself or by one of its metabolites, there is no certainty that the seizure frequency will match. In clinical trials that frequency was about 0.06%, that is 2 cases out of 3239 people, against 0.00% on placebo — 0 out of 1515. From this risk follow the ban on splitting and chewing the tablet, the contraindication in epilepsy, and the caution around everything that lowers the seizure threshold.
Interactions with other medicines
There is one absolute prohibition: MAO inhibitors. They strengthen transmission along catecholaminergic pathways, though by a mechanism different from bupropion, so concurrent use is unacceptable and at least 14 days are left after stopping them. The second group in importance is opioids, and here the interaction runs both ways. Because naltrexone antagonises opioid receptors, the patient may not get the full benefit of opioid-containing medicines: cough and cold preparations, antidiarrhoeals, opioid analgesics. If urgent opiate analgesia is needed, the medicine is withdrawn for that period and the opiate dose is not raised above the standard one; if long-term opiate treatment is needed, it is withdrawn altogether. Starting it after prolonged opioid use is possible only after 7 to 10 days, so as not to provoke a withdrawal syndrome.
The third group is set by metabolic pathways. Bupropion is converted into its main active metabolite, hydroxybupropion, with the involvement of the CYP2B6 isoenzyme, so interactions with medicines that induce or inhibit that isoenzyme are possible. Bupropion itself is not metabolised by CYP2D6, but both it and hydroxybupropion slow the conversions that run along that route and therefore affect the action of medicines metabolised by it. The scale of that effect is shown by a study with metoprolol: on co-administration, the area under the metoprolol concentration curve rose roughly fourfold. That is not a theoretical figure — it means that a usual dose of a beta-blocker, on top of Mysimba, behaves as though it had been multiplied.
Pregnancy and breastfeeding
There are no data, or only very limited data, on the use of the naltrexone and bupropion combination in pregnant women, and the combination has not been studied for reproductive toxicity. By substance the picture differs: animal studies of naltrexone showed reproductive toxicity, whereas for bupropion no clear evidence of a harmful effect was obtained. The potential risk to humans is unknown, and the conclusion in the product information is categorical: the medicine must not be used during pregnancy or in women trying to become pregnant.
Naltrexone and bupropion, together with their metabolites, pass into breast milk, and since information on systemic exposure in newborns and infants is scant, a risk to them cannot be ruled out: during breastfeeding the medicine must not be used. There are no data on the effect of the combination on fertility. For bupropion, reproductive toxicity studies showed no effect on fertility. Naltrexone, however, given orally to female rats at a dose about thirty times that supplied by the combination, caused a marked increase in pseudopregnancies and a fall in the pregnancy rate; whether those observations carry over to humans is unknown.
Adverse reactions
Safety was assessed in five placebo-controlled trials involving 4754 people with overweight or obesity; 3239 of them received the naltrexone and bupropion combination and 1515 received placebo, and treatment lasted no longer than 56 weeks. One figure speaks for itself: an adverse event led to discontinuation in 23.8% of participants in the medicine group and in 11.9% of the placebo group. That is, roughly one in four did not reach the end because of tolerability.
The most frequent adverse reactions are nausea, constipation, vomiting, dizziness and dry mouth. The ones that most often led to stopping treatment were nausea, headache, dizziness and vomiting. Among the less common are: commonly, a fall in the lymphocyte count in blood and hypersensitivity reactions such as urticaria; uncommonly, cold sores, athlete's foot and enlarged lymph nodes; rarely, idiopathic thrombocytopenic purpura; very rarely, more severe hypersensitivity reactions, among them angioedema, breathlessness with bronchospasm and anaphylactic shock. Joint and muscle pain have also been described.
Overdose
There are no data on cases of simultaneous overdose of bupropion and naltrexone in everyday practice. In clinical trials the maximum daily dose of the combination was 50 mg of naltrexone hydrochloride and 400 mg of bupropion hydrochloride. The gravest consequences of an overdose will in all likelihood be due to the bupropion.
On bupropion the data are specific: single doses more than ten times the maximum therapeutic dose have been described, and in about a third of those cases a seizure followed. Also reported are hallucinations, loss of consciousness, sinus tachycardia and ECG changes, among them widening of the QRS complex and arrhythmias. Fever, muscle rigidity, rhabdomyolysis, a fall in blood pressure, stupor, coma and respiratory failure were described mainly in poisonings involving several medicines at once. Most patients recovered fully, but fatal outcomes occurred only with high doses of bupropion. On naltrexone there is little data: in one study patients received 800 mg of the hydrochloride a day — twenty-five times the recommended daily dose of the combination — for no more than a week, with no signs of toxicity. Help consists of keeping the airway open, maintaining adequate oxygenation and ventilation, and monitoring heart rhythm and vital signs; ECG monitoring is recommended for the first 48 hours after an overdose.
How to get a prescription for Mysimba online
A weight-loss medicine is not something chosen on a whim: the indication is set by body mass index and by accompanying illnesses, and the list of contraindications is among the longest of any prescription drug. At e-zdrowie.com you fill in a medical questionnaire, the doctor examines the answers and, if the medicine is suitable, issues an electronic prescription: the code arrives by message, and with it any Polish pharmacy will dispense the tablets.
In the questionnaire give your height and weight, so the doctor can calculate body mass index, and list the accompanying conditions: diabetes, lipid disorders, hypertension and whether it is controlled. Be sure to report seizures, epilepsy, head injuries and tumours, bipolar disorder, depression and eating disorders, dependence on alcohol, benzodiazepines or opioids, liver and kidney disease, pregnancy and breastfeeding. List every medicine, including opioid painkillers, cough preparations, antidepressants, MAO inhibitors and beta-blockers. And remember the 16-week rule: if weight has not dropped by 5% by then, the medicine is withdrawn — that is part of the prescription, and not a reason to change the dose.
