Single doses of 800 mg Orsoten and multiple doses of up to 400 mg three times daily for 15 days have been studied in normal weight and obese subjects without significant adverse findings. In addition, doses of 240 mg tid have been administered to obese patients for 6 months. The majority of Orsoten overdose cases received during post- marketing reported either no adverse events or adverse events that are similar to those reported with recommended dose.
Should a significant overdose of Orsoten occur, it is recommended that the patient be observed for 24 hours. Based on human and animal studies, any systemic effects attributable to the lipase-inhibiting properties of Orsoten should be rapidly reversible.
- Hypersensitivity to the active substance or to any of the excipients.
- Chronic malabsorption syndrome.
- Cholestasis.
- Breast-feeding.
Not applicable.
Adverse reactions to Orsoten are largely gastrointestinal in nature. The incidence of adverse events decreased with prolonged use of Orsoten.
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000) and very rare (<1/10,000) including isolated reports.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The following table of undesirable effects (first year of treatment) is based on adverse events that occurred at a frequency of > 2 % and with an incidence > 1 % above placebo in clinical trials of 1 and 2 years duration:
| System organ class | Adverse reaction/events |
| Nervous system disorders | |
| Very common: | Headache |
| Respiratory, thoracic and mediastinal disorders | |
| Very common: | Upper respiratory infection |
| Common: | Lower respiratory infection |
| Gastrointestinal disorders | |
| Very common: | Abdominal pain/discomfort Oily spotting from the rectum Flatus with discharge Faecal urgency Fatty/oily stool Flatulence Liquid stools Oily evacuation Increased defecation |
| Common: | Rectal pain/discomfort Soft stools Faecal incontinence Abdominal distension* Tooth disorder Gingival disorder |
| Renal and urinary disorders | |
| Common: | Urinary tract infection |
| Metabolism and nutrition disorders | |
| Very common: | Hypoglycemia* |
| Infections and infestations | |
| Very common: | Influenza |
| General disorders and administration site conditions | |
| Common: | Fatigue |
| Reproductive system and breast disorders | |
| Common: | Menstrual irregularity |
| Psychiatric disorders | |
| Common: | Anxiety |
* only unique treatment adverse events that occurred at a frequency of > 2 % and with an incidence > 1 % above placebo in obese type 2 diabetic patients.
In a 4 year clinical trial, the general pattern of adverse event distribution was similar to that reported for the 1 and 2 year studies with the total incidence of gastrointestinal related adverse events occurring in year 1 decreasing year on year over the four year period.
The following table of undesirable effects is based on post-marketing spontaneous reports, and therefore the frequency remains unknown:
| System organ class | Adverse reaction |
| Investigations | Increase in liver transaminases and in alkaline phosphatase. Decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in variations of haemostatic parameters have been reported in patients treated with anticoagulants in association with Orsoten |
| Gastrointestinal disorders | Rectal bleeding Diverticulitis Pancreatitis |
| Skin and subcutaneous tissue disorders | Bullous eruptions |
| Immune system disorders | Hypersensitivity (e.g. pruritus, rash, urticaria, angioedema, bronchospasm and anaphylaxis) |
| Hepatobiliary disorders | Cholelithiasis Hepatitis that may be serious. Some fatal cases or cases requiring liver transplantation have been reported. |
| Renal and urinary disorders | Oxalate nephropathy that may lead to renal failure |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the MHRA Yellow Card Scheme, Website - www.mhra.gov.uk/yellowcard.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.
In animal reproductive studies, no teratogenic effect was observed. In the absence of a teratogenic effect in animals, no malformative effect is expected in man. To date, active substances responsible for malformations in man have been found teratogenic in animals when well-conducted studies were performed in two species.
Orsoten is indicated in conjunction with a mildly hypocaloric diet for the treatment of obese patients with a body mass index (BMI) greater or equal to 30 kg/m2, or overweight patients (BMI > 28 kg/m2) with associated risk factors.
Treatment with Orsoten should be discontinued after 12 weeks if patients have been unable to lose at least 5 % of the body weight as measured at the start of therapy.
Pharmaco-therapeutic group: Peripherally acting antiobesity agent, ATC code A08AB01.
Orsoten is a potent, specific and long-acting inhibitor of gastrointestinal lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine site of the gastric and pancreatic lipases. The inactivated enzyme is thus unavailable to hydrolyse dietary fat, in the form of triglycerides, into absorbable free fatty acids and monoglycerides.
In the 2-year studies and the 4-year study, a hypocaloric diet was used in association with treatment in both the Orsoten and the placebo treated groups.
Pooled data from five 2 year studies with Orsoten and a hypocaloric diet showed that 37 % of Orsoten patients and 19 % of placebo patients demonstrated a loss of at least 5 % of their baseline body weight after 12 weeks of treatment. Of these, 49 % of Orsoten treated patients and 40 % of placebo treated patients went on to lose > 10 % of their baseline body weight at one year. Conversely, of patients failing to demonstrate a loss of 5 % of their baseline body weight after 12 weeks of treatment, only 5 % of Orsoten
treated patients and 2 % of placebo treated patients went on to lose > 10 % of their baseline body weight at one year. Overall, after one year of treatment, the percentage of patients taking 120 mg Orsoten who lost 10 % or more of their body weight was 20 % with Orsoten 120 mg compared to 8 % of patients taking placebo. The mean difference in weight loss with the drug compared to placebo was 3.2 kg.
Data from the 4-year XENDOS clinical trial showed that 60 % of Orsoten patients and 35 % of placebo patients demonstrated a loss of at least 5 % of their baseline body weight after 12 weeks of treatment. Of these, 62 % of Orsoten treated patients and 52 % of placebo treated patients went on to lose > 10 % of their baseline body weight at one year. Conversely, of patients failing to demonstrate a loss of 5 % of their baseline body weight after 12 weeks of treatment, only 5 % of Orsoten treated patients and 4 % of placebo treated patients went on to lose > 10 % of their baseline body weight at one year. After 1 year of treatment, 41 % of the Orsoten treated patients versus 21 % of placebo treated patients lost > 10 % of body weight with a mean difference of 4.4 kg between the two groups. After 4 years of treatment 21 % of the Orsoten treated patients compared to 10 % of the placebo treated patients had lost > 10 % of body weight, with a mean difference of 2.7 kg.
More patients on Orsoten or placebo lost baseline body weight of at least 5 % at 12 weeks or 10 % at one year in the XENDOS study than in the five 2-year studies. The reason for this difference is that the five 2-year studies included a 4-week diet and placebo lead-in period during which patients lost on average 2.6 kg prior to commencing treatment.
Data from the 4-year clinical trial also suggested that weight loss achieved with Orsoten delayed the development of type 2 diabetes during the study (cumulative diabetes cases incidences: 3.4 % in the Orsoten group compared to 5.4 % in the placebo-treated group). The great majority of diabetes cases came from the subgroup of patients with impaired glucose tolerance at baseline, which represented 21 % of the randomised patients. It is not known whether these findings translate into long-term clinical benefits.
In obese type 2 diabetic patients insufficiently controlled by antidiabetic agents, data from four one year clinical trials showed that the percentage of responders (> 10 % of body weight loss) was 11.3 % with Orsoten as compared to 4.5 % with placebo. In Orsoten-treated patients, the mean difference from placebo in weight loss was 1.83 kg to 3.06 kg and the mean difference from placebo in HbA1c reduction was 0.18 % to 0.55 %. It has not been demonstrated that the effect on HbA1c is independent from weight reduction.
In a multi-centre (US, Canada), parallel-group, double-blind, placebo-controlled study, 539 obese adolescent patients were randomised to receive either 120 mg Orsoten (n=357) or placebo (n=182) three times daily as an adjunct to a hypocaloric diet and exercise for 52 weeks. Both populations received multivitamin supplements. The primary endpoint was the change in body mass index (BMI) from baseline to the end of the study.
The results were significantly superior in the Orsoten group (difference in BMI of 0.86 kg/m2 in favour of Orsoten). 9.5 % of the Orsoten treated patients versus 3.3 % of the placebo treated patients lost > 10 % of body weight after 1 year with a mean difference of 2.6 kg between the two groups. The difference was driven by the outcome in the group of patients with > 5 % weight loss after 12 weeks of treatment with Orsoten representing 19 % of the initial population. The side effects were generally similar to those observed in adults. However, there was an unexplained increase in the incidence of bone fractures (6 % versus 2.8 % in the Orsoten and placebo groups, respectively).
Absorption
Studies in normal weight and obese volunteers have shown that the extent of absorption of Orsoten was minimal. Plasma concentrations of intact Orsoten were non- measurable (< 5 ng/ml) eight hours following oral administration of Orsoten.
In general, at therapeutic doses, detection of intact Orsoten in plasma was sporadic and concentrations were extremely low (< 10 ng/ml or 0.02 μmol), with no evidence of accumulation, which is consistent with minimal absorption.
Distribution
The volume of distribution cannot be determined because the drug is minimally absorbed and has no defined systemic pharmacokinetics. In vitro Orsoten is > 99 % bound to plasma proteins (lipoproteins and albumin were the major binding proteins). Orsoten minimally partitions into erythrocytes.
Metabolism
Based on animal data, it is likely that the metabolism of Orsoten occurs mainly within the gastrointestinal wall. Based on a study in obese patients, of the minimal fraction of the dose that was absorbed systemically, two major metabolites, M1 (4-member lactone ring hydrolysed) and M3 (M1 with N-formyl leucine moiety cleaved), accounted for approximately 42 % of the total plasma concentration.
M1 and M3 have an open beta-lactone ring and extremely weak lipase inhibitory activity (1000 and 2500 fold less than Orsoten respectively). In view of this low inhibitory activity and the low plasma levels at therapeutic doses (average of 26 ng/ml and 108 ng/ml respectively), these metabolites are considered to be pharmacologically inconsequential.
Elimination
Studies in normal weight and obese subjects have shown that faecal excretion of the unabsorbed drug was the major route of elimination. Approximately 97 % of the administered dose was excreted in faeces and 83 % of that as unchanged Orsoten.
The cumulative renal excretion of total Orsoten-related materials was < 2 % of the given dose. The time to reach complete excretion (faecal plus urinary) was 3 to 5 days. The disposition of Orsoten appeared to be similar between normal weight and obese volunteers. Orsoten, M1 and M3 are all subject to biliary excretion.
In clinical trials, the decrease in bodyweight with Orsoten treatment was less in type II diabetic patients than in non-diabetic patients. Antidiabetic medicinal product treatment may have to be closely monitored when taking Orsoten.
Co-administration of Orsoten with ciclosporin is not recommended.
Patients should be advised to adhere to the dietary recommendations they are given.
The possibility of experiencing gastrointestinal adverse reactions may increase when Orsoten is taken with a diet high in fat (e.g. in a 2000 kcal/day diet, > 30 % of calories from fat equates to > 67 g of fat). The daily intake of fat should be distributed over three main meals. If Orsoten is taken with a meal very high in fat, the possibility of gastrointestinal adverse reactions may increase.
Cases of rectal bleeding have been reported with Orsoten. Prescribers should investigate further in case of severe and/or persistent symptoms.
The use of an additional contraceptive method is recommended to prevent possible failure of oral contraception that could occur in case of severe diarrhoea.
Coagulation parameters should be monitored in patients treated with concomitant oral anticoagulants.
The use of Orsoten may be associated with hyperoxaluria and oxalate nephropathy leading sometimes to renal failure. This risk is increased in patients with underlying chronic kidney disease and/or volume depletion.
Rare occurrence of hypothyroidism and/or reduced control of hypothyroidism may occur. The mechanism, although not proven, may involve a decreased absorption of iodine salts and/or levothyroxine.
Antiepileptics patient: Orsoten may unbalance anticonvulsivant treatment by decreasing the absorption of antiepileptic drugs, leading to convulsions.
Antiretrovirals for HIV: Orsoten may potentially reduce the absorption of antiretroviral medicines for HIV and could negatively affect the efficacy of antiretroviral medications for HIV.
Orsoten has no influence on the ability to drive and use machines.
Posology
Adults
The recommended dose of Orsoten is one 120 mg capsule taken with water immediately before, during or up to one hour after each main meal. If a meal is missed or contains no fat, the dose of Orsoten should be omitted.
The patient should be on a nutritionally balanced, mildly hypocaloric diet that contains approximately 30 % of calories from fat. It is recommended that the diet should be rich in fruit and vegetables. The daily intake of fat, carbohydrate and protein should be distributed over three main meals.
Doses of Orsoten above 120 mg three times daily have not been shown to provide additional benefit. The effect of Orsoten results in an increase in faecal fat as early as 24 to 48 hours after dosing. Upon discontinuation of therapy, faecal fat content usually returns to pre-treatment levels, within 48 to 72 hours.
Special populations
The effect of Orsoten in patients with hepatic and/or renal impairment, children and elderly patients has not been studied.
There is no relevant indication for use of Orsoten in children.
No special requirements.
