orlistat: prescribing information – dosing, contraindications, interactions, side effects

alli is indicated for weight loss in adults who are overweight (body mass index, BMI, ≥28 kg/m2) and should be taken in conjunction with a mildly hypocaloric, lower-fat diet.

Posology

Adults
The recommended treatment dose is one 60 mg capsule to be taken three times daily. No more than three 60 mg capsules should be taken in 24 hours.

Diet and exercise are important parts of a weight loss programme. It is recommended that a diet and exercise programme is started before beginning treatment with alli.

While taking orlistat, the patient should be on a nutritionally balanced, mildly hypocaloric diet that contains approximately 30% of calories from fat (e.g. in a 2,000 kcal/day diet, this equates to <67 g of fat). The daily intake of fat, carbohydrate and protein should be distributed over three main meals.

The diet and exercise programme should continue to be followed when treatment with alli is stopped.

Treatment should not exceed 6 months.

If patients have been unable to lose weight after 12 weeks of treatment with alli, they should consult their doctor or a pharmacist. It may be necessary to discontinue treatment.

Special populations

Elderly (>65 years old)
There are limited data on the use of orlistat in the elderly. However, as orlistat is minimally absorbed, no dose adjustment is necessary in the elderly.

Hepatic and renal impairment
The effect of orlistat in individuals with hepatic and/or renal impairment has not been studied (see section 4.4). However, as orlistat is minimally absorbed, no dose adjustment is necessary in individuals with hepatic and/or renal impairment.

Paediatric population
The safety and efficacy of alli in children below 18 years of age has not been established. No data are available.

Method of administration

The capsule should be taken with water immediately before, during or up to 1 hour after each main meal. If a meal is missed or contains no fat, the dose of orlistat should be omitted.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Concurrent treatment with ciclosporin (see section 4.5)

• Chronic malabsorption syndrome
• Cholestasis
• Pregnancy (see section 4.6)
• Breast-feeding (see section 4.6)
• Concurrent treatment with warfarin or other oral anticoagulants (see sections 4.5 and 4.8)

Summary of the safety profile

Adverse reactions to orlistat are largely gastrointestinal in nature and related to the pharmacologic effect of the medicinal product on preventing the absorption of ingested fat.

The gastrointestinal adverse reactions identified from clinical trials with orlistat 60 mg of 18 months to 2 years duration were generally mild and transient. They generally occurred early in treatment (within 3 months) and most patients experienced only one episode. Consumption of a diet low in fat will decrease the likelihood of experiencing adverse gastrointestinal reactions (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions 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), very rare (<1/10,000) and not known (cannot be estimated from the available data).

The frequencies of adverse reactions identified during post-marketing use of orlistat are not known as these reactions were reported voluntarily from a population of uncertain size.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System organ class and frequency
Adverse reaction
Blood and lymphatic system disorders

Not known

Decreased prothrombin and increased INR
(see sections 4.3 and 4.5)
Immune system disorders

Not known

Hypersensitivity reactions including anaphylaxis, bronchospasm, angioedema, pruritus, rash, and urticaria Psychiatric disorders

Common

Anxiety†

System organ class and frequency
Adverse reaction
Gastrointestinal disorders
Very common

Common

Not known

Oily spotting
Flatus with discharge
Faecal urgency
Fatty oily stool
Oily evacuation
Flatulence
Soft stools

Abdominal pain
Faecal incontinence
Liquid stools
Increased defaecation

Diverticulitis
Pancreatitis
Mild rectal bleeding (see section 4.4)
Renal and urinary disorders

Not known

Oxalate nephropathy that may lead to renal failure
Hepatobiliary disorders

Not known

Hepatitis that may be serious. Some fatal cases or cases requiring liver transplantation have been reported.
Cholelithiasis
Increase in transaminases and in alkaline phosphatase
Skin and subcutaneous tissue disorders

Not known

Bullous eruption

†It is plausible that treatment with orlistat can lead to anxiety in anticipation of or secondary to gastrointestinal adverse reactions.

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 national reporting system listed in Appendix V.

Gastrointestinal symptoms

Patients should be advised to adhere to the dietary recommendations they are given (see section 4.2). The possibility of experiencing gastrointestinal symptoms (see section 4.8) may increase when orlistat is taken with an individual meal or a diet high in fat.

Fat-soluble vitamins

Treatment with orlistat may potentially impair the absorption of fat-soluble vitamins (A, D, E and K) (see section 4.5). For this reason, a multivitamin supplement should be taken at bedtime.

Antidiabetic medicinal products

As weight loss may be accompanied by improved metabolic control in diabetes, patients who are taking a medicinal product for diabetes should consult a doctor before starting treatment with alli, in case it is necessary to adjust the dose of the antidiabetic medicinal product.

Medicinal products for hypertension or hypercholesterolaemia

Weight loss may be accompanied by an improvement in blood pressure and cholesterol levels. Patients who are taking a medicinal product for hypertension or hypercholesterolaemia should consult a doctor or pharmacist when taking alli, in case it is necessary to adjust the dose of these medicinal products.

Amiodarone

Patients who are taking amiodarone should consult a doctor before starting treatment with alli (see section 4.5).

Rectal bleeding

Cases of rectal bleeding have been reported in patients taking orlistat. If this occurs, the patient should consult a doctor.

Oral contraceptives

The use of an additional contraceptive method is recommended to prevent possible failure of oral contraception that could occur in case of severe diarrhoea (see section 4.5).

Kidney disease

Patients with kidney disease should consult a doctor before starting treatment with alli, as the use of orlistat 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.

Levothyroxine

Hypothyroidism and/or reduced control of hypothyroidism may occur when orlistat and levothyroxine are co-administered (see section 4.5). Patients taking levothyroxine should consult a doctor before starting treatment with alli, as orlistat and levothyroxine may need to be taken at different times and the dose of levothyroxine may need to be adjusted.

Antiepileptic medicinal products

Patients taking an antiepileptic medicinal product should consult a doctor before starting treatment with alli, as they should be monitored for possible changes in the frequency and severity of convulsions. If this occurs, consideration could be given to administering orlistat and antiepileptic medicinal products at different times (see section 4.5).

Antiretrovirals for HIV

Patients should consult a physician before taking alli concomitantly with antiretroviral medicinal products. Orlistat may potentially reduce the absorption of antiretroviral medicinal products for HIV and could negatively affect the efficacy of antiretroviral medicinal products for HIV (see section 4.5).

Information concerning excipients

alli 60 mg hard capsules contain less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

Ciclosporin

A decrease in ciclosporin plasma levels has been observed in a drug-drug interaction study and also reported in several cases, when orlistat was administered concomitantly. This could potentially lead to a decrease of immunosuppressive efficacy.
Concurrent use of alli and ciclosporin is contraindicated (see section 4.3).

Oral anticoagulants

When warfarin or other oral anticoagulants are given in combination with orlistat, international normalised ratio (INR) values could be affected (see section 4.8). Concurrent use of alli and warfarin or other oral anticoagulants is contraindicated (see section 4.3).

Oral contraceptives

The absence of an interaction between oral contraceptives and orlistat has been demonstrated in specific drug-drug interaction studies. However, orlistat may indirectly reduce the availability of oral contraceptives and lead to unexpected pregnancies in some individual cases. An additional contraceptive method is recommended in case of severe diarrhoea (see section 4.4).

Levothyroxine

Hypothyroidism and/or reduced control of hypothyroidism may occur when orlistat and levothyroxine are taken at the same time (see section 4.4). This could be due to a decreased absorption of iodine salts and/or levothyroxine.

Antiepileptic medicinal products

Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic medicinal products e.g.
valproate, lamotrigine, for which a causal relationship to an interaction cannot be excluded. Orlistat may decrease the absorption of antiepileptic medicinal products, leading to convulsions.

Antiretroviral medicinal products

Based on reports from literature and post-marketing experience orlistat may potentially reduce the absorption of antiretroviral medicinal products for HIV and could negatively affect the efficacy of antiretroviral medicinal product for HIV (see section 4.4).

Fat-soluble vitamins

Treatment with orlistat may potentially impair the absorption of fat-soluble vitamins (A, D, E and K).

The vast majority of subjects receiving up to 4 full years of treatment with orlistat in clinical studies had vitamin A, D, E and K and beta-carotene levels that stayed within normal range. However, patients should be advised to use a multivitamin supplement at bedtime to help ensure adequate vitamin intake (see section 4.4).

Acarbose

In the absence of pharmacokinetic interaction studies, alli is not recommended to be used by patients receiving acarbose.

Amiodarone

A decrease in plasma levels of amiodarone, when given as a single dose, has been observed in a limited number of healthy volunteers who received orlistat concomitantly. The clinical relevance of this effect in patients receiving amiodarone treatment remains unknown. Patients who are taking amiodarone should consult a doctor before starting treatment with alli.
The dose of amiodarone may need to be adjusted during treatment with alli.

Antidepressants, antipsychotics (including lithium) and benzodiazepines

There are some case reports of reduced efficacy of antidepressants, antipsychotics (including lithium) and benzodiazepines coincidental to the initiation of orlistat treatment in previously well controlled patients. Therefore orlistat treatment should only be initiated after careful consideration of the possible impact in these patients.

Women of childbearing potential / Contraception in males and females
The use of an additional contraceptive method is recommended to prevent possible failure of oral contraception that could occur in case of severe diarrhoea (see sections 4.4 and 4.5).

Pregnancy
For orlistat, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

alli is contraindicated in pregnancy (see section 4.3).

Breast-feeding
As it is not known whether orlistat is secreted into human milk, alli is contraindicated during breast-feeding (see section 4.3).

Fertility
Animal studies do not indicate harmful effects with respect to fertility.

Orlistat has no or negligible influence on the ability to drive and use machines.

Single doses of 800 mg orlistat 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 clinical findings. In addition, doses of 240 mg three times daily have been administered to obese patients for 6 months. The majority of orlistat overdose cases received during post-marketing reported either no adverse reactions or adverse reactions that are similar to those reported with recommended doses of orlistat.

In the event of an overdose, medical advice should be sought. Should a significant overdose of orlistat 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 orlistat should be rapidly reversible.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: antiobesity preparations, excl. diet products, peripherally acting antiobesity products, ATC code:
A08AB01.

Orlistat 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. From clinical studies, it has been estimated that orlistat 60 mg taken three times daily blocks the absorption of approximately 25% of dietary fat. The effect of orlistat results in an increase in faecal fat as early as 24 to 48 hours after dosing. Upon discontinuation of therapy, faecal fat content returns to pre-treatment levels, usually within 48 to 72 hours.

Two double-blind, randomised, placebo-controlled studies in adults with a BMI ≥28 kg/m2 support the efficacy of orlistat 60 mg taken three times daily in conjunction with a hypocaloric, lower-fat diet. The primary parameter, change in body weight from baseline (time of randomisation), was assessed for body weight over time (Table 1) and the percentage of

subjects who lost ≥5% or ≥10% of body weight (Table 2). Although weight loss was assessed during 12 months of treatment in both studies, most weight loss occurred within the first 6 months.

Table 1: Effect of 6 months treatment on body weight measured at baseline

Treatment group
N
Relative mean change (%)
Mean change (kg)
Study 1
Placebo
Orlistat 60 mg
-3.24
-5.55
-3.11
-5.20 a
Study 2
Placebo
Orlistat 60 mg
-1.17
-3.66
-1.05
-3.59 a
Pooled data
Placebo
Orlistat 60 mg
-2.20
-4.60
-2.09
-4.40 a a p<0.001 versus placebo

Table 2: Responder analysis at 6 months

Lost ≥5% of baseline body weight (%)
Lost ≥10% of baseline body weight (%)

Placebo
Orlistat 60 mg
Placebo
Orlistat 60 mg
Study 1

Absorption
Studies in normal weight and obese volunteers have shown that the extent of absorption of orlistat was minimal. Plasma concentrations of intact orlistat were non-measurable (<5 ng/ml) 8 hours following oral administration of orlistat 360 mg.

In general, at therapeutic doses, detection of intact orlistat 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 active substance is minimally absorbed and has no defined systemic pharmacokinetics. In vitro, orlistat is >99% bound to plasma proteins (lipoproteins and albumin were the major binding proteins). Orlistat minimally partitions into erythrocytes.

Biotransformation
Based on animal data, it is likely that the metabolism of orlistat 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 (1,000- and 2,500-fold less than orlistat, 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 active substance was the major route of elimination. Approximately 97% of the administered dose was excreted in faeces and 83% of that as unchanged orlistat.

Xenical 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 orlistat 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.

Adults
The recommended dose of orlistat 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 orlistat 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 orlistat above 120 mg three times daily have not been shown to provide additional benefit.
The effect of orlistat 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 orlistat in patients with hepatic and/or renal impairment, children and elderly patients has not been studied.

There is no relevant indication for use of Xenical in children.

• Hypersensitivity to the active substance or to any of the excipients.
• Chronic malabsorption syndrome.
• Cholestasis.
• Breast-feeding.

Adverse reactions to orlistat are largely gastrointestinal in nature. The incidence of adverse events decreased with prolonged use of orlistat.

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/event
Nervous system disorders
Very common:

Headache
Respiratory, thoracic and mediastinal disorders
Very common:

Common:

Upper respiratory infection

Lower respiratory infection
Gastrointestinal disorders
Very common:

Common:

Abdominal pain/discomfort
Oily spotting from the rectum
Flatus with discharge
Faecal urgency
Fatty/oily stool
Flatulence
Liquid stools
Oily evacuation
Increased defecation

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 orlistat (see section 4.4 and 4.5) 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 national reporting system listed in Appendix V*.

In clinical trials, the decrease in bodyweight with orlistat 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 orlistat.

Co-administration of orlistat with ciclosporin is not recommended (see section 4.5).

Patients should be advised to adhere to the dietary recommendations they are given (see section 4.2).

The possibility of experiencing gastrointestinal adverse reactions (see section 4.8) may increase when orlistat 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 orlistat 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 Xenical. 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 (see section 4.5).

Coagulation parameters should be monitored in patients treated with concomitant oral anticoagulants (see section 4.5 and 4.8).

The use of orlistat 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 (see section 4.8).

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 (see section 4.5).

Antiepileptics patient: Orlistat may unbalance anticonvulsant treatment by decreasing the absorption of antiepileptic drugs, leading to convulsions (see section 4.5).

Antiretrovirals for HIV: Orlistat may potentially reduce the absorption of antiretroviral medicines for HIV and could negatively affect the efficacy of antiretroviral medications for HIV (see section 4.5).

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

Ciclosporin
A decrease in ciclosporin plasma levels has been observed in a drug-drug-interaction study and also reported in several cases, when orlistat was administered concomitantly. This can lead to a decrease of immunosuppressive efficacy. Therefore the combination is not recommended (see section 4.4).
However, if such concomitant use is unavoidable, more frequent monitoring of ciclosporin blood levels should be performed both after addition of orlistat and upon discontinuation of orlistat in ciclosporin treated patients. Ciclosporin blood levels should be monitored until stabilised.

Acarbose
In the absence of pharmacokinetic interaction studies, the concomitant administration of orlistat with acarbose should be avoided.

Oral anticoagulants

When warfarin or other anticoagulants are given in combination with orlistat, international normalised ratio (INR) values should be monitored (see section 4.4).

Fat soluble vitamins
Treatment with orlistat may potentially impair the absorption of fat-soluble vitamins (A, D, E and K).
The vast majority of patients receiving up to four full years of treatment with orlistat in clinical studies had vitamin A, D, E and K and beta-carotene levels that stayed within normal range. In order to ensure adequate nutrition, patients on a weight control diet should be advised to have a diet rich in fruit and vegetables and use of a multivitamin supplement could be considered. If a multivitamin supplement is recommended, it should be taken at least two hours after the administration of orlistat or at bedtime.

Amiodarone
A slight decrease in plasma levels of amiodarone, when given as a single dose, has been observed in a limited number of healthy volunteers who received orlistat concomitantly. In patients receiving amiodarone treatment, the clinical relevance of this effect remains unknown but may become clinically relevant in some cases. In patients receiving concomitant amiodarone treatment, reinforcement of clinical and ECG monitoring is warranted.

Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs e.g. valproate, lamotrigine, for which a causal relationship to an interaction cannot be excluded.
Therefore, these patients should be monitored for possible changes in the frequency and/or severity of convulsions.

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 (see section 4.4).

There are some case reports of reduced efficacy of antiretroviral HIV medicines, antidepressants antipsychotics (including lithium) and benzodiazepines coincidental to the initiation of orlistat treatment in previously well-controlled patients. Therefore orlistat treatment should only be initiated after careful consideration of the possible impact in these patients.

Lack of interactions
No interactions with amitriptyline, atorvastatin, biguanides, digoxin, fibrates, fluoxetine, losartan, phenytoin, phentermine, pravastatin, nifedipine Gastrointestinal Therapeutic System (GITS), nifedipine slow release, sibutramine or alcohol have been observed. The absence of these interactions has been demonstrated in specific drug-drug-interaction studies.

The absence of an interaction between oral contraceptives and orlistat has been demonstrated in specific drug-drug interaction studies. However, orlistat may indirectly reduce the availability of oral contraceptives and lead to unexpected pregnancies in some individual cases. An additional contraceptive method is recommended in case of severe diarrhoea (see section 4.4).

For orlistat no clinical data on exposed pregnancies are available.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).
Caution should be exercised when prescribing to pregnant women.

As it is not known whether orlistat is secreted into human milk, orlistat is contra-indicated during breast-feeding.

Xenical has no influence on the ability to drive and use machines.

Single doses of 800 mg orlistat 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 orlistat 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 orlistat 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 orlistat should be rapidly reversible.

5.
PHARMACOLOGICAL PROPERTIES

Pharmaco-therapeutic group: Peripherally acting antiobesity agent, ATC code A08AB01.

Orlistat 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 orlistat and the placebo treated groups.

Pooled data from five 2 year studies with orlistat and a hypocaloric diet showed that 37 % of orlistat 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 orlistat 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 orlistat 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 orlistat who lost 10 % or more of their body weight was 20 % with orlistat 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 orlistat 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 orlistat 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 orlistat 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 orlistat 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 orlistat 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 orlistat 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.

Absorption
Studies in normal weight and obese volunteers have shown that the extent of absorption of orlistat was minimal. Plasma concentrations of intact orlistat were non-measurable (< 5 ng/ml) eight hours following oral administration of orlistat.

In general, at therapeutic doses, detection of intact orlistat 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 orlistat is > 99 % bound to plasma proteins (lipoproteins and albumin were the major binding proteins). Orlistat minimally partitions into erythrocytes.

Metabolism
Based on animal data, it is likely that the metabolism of orlistat 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 orlistat 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 orlistat.