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1. Orlistat 60 Mg Capsules Hard
2. Orlistat 60 Mg Capsules Hard

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Orlistat 60 mg capsules, hard

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule, hard contains 60 mg orlistat.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Capsule, hard.

The capsule has a light blue cap and light blue body.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Orlistat 60 mg capsules 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.

4.2 Posology and method of administration Posology

Adults

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

Treatment should not exceed 6 months.

If patients have been unable to lose weight after 12 weeks of treatment with Orlistat 60 mg capsules, they should consult their doctor or a pharmacist. It may be necessary to discontinue treatment.

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 Orlistat 60 mg capsules.

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 Orlistat 60 mg capsules is stopped.

Special populations Paediatric population

Orlistat 60 mg capsules should not be used in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

Elderly (>65 years old)

There are limited data on the use of orlistat in the elderly.

However, as orlistat is minimally absorbed, no dosage adjustment is necessary in elderly.

Patients with hepatic and renal impairment

The effect of orlistat in individuals with hepatic and/or renal impairment has not been studied.

However, as orlistat is minimally absorbed, no dosage adjustment is necessary in individuals with hepatic and/or renal impairment.

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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

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).

4.4 Special warnings and precautions for use

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.

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.

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 Orlistat 60 mg capsules, in case it is necessary to adjust the dose of the antidiabetic medicinal product.

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 Orlistat 60 mg capsules, in case it is necessary to adjust the dose of these medicinal products.

Patients who are taking amiodarone should consult a doctor or pharmacist before starting treatment with Orlistat 60 mg capsules (see section 4.5).

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

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).

Patients with kidney disease should consult a doctor before starting treatment with Orlistat 60 mg capsules, as the use of orlistat may rarely be associated with hyperoxaluria and oxalate nephropathy (see section 4.8).

Patients taking levothyroxine should consult a doctor before starting treatment with Orlistat 60 mg capsules, as orlistat and levothyroxine may need to be taken at different times and the dose of levothyroxine may need to be adjusted. Hypothyroidism and/or reduced control of hypothyroidism may occur when orlistat and levothyroxine are co-administered (see section 4.5).

Patients taking an antiepileptic medicinal product should consult a doctor before starting treatment with Orlistat 60 mg capsules, 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).

4.5 Interaction with other medicinal products and other forms of interaction

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 Orlistat 60 mg capsules 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 Orlistat 60 mg capsules 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 (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, Orlistat 60 mg capsules 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 Orlistat 60 mg capsules. The dose of amiodarone may need to be adjusted during treatment with Orlistat 60 mg capsules.

4.6 Fertility, Pregnancy and lactation

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).

Orlistat 60 mg capsules is contraindicated in pregnancy (see section 4.3). Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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).

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000) and very rare (<1/10,000), 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, undesirable effects are presented in order of decreasing seriousness.

System organ class and Frequency	Adverse reaction
Blood and the lymphatic system disorders
	Decreased prothrombin and	increased
Not known:	INR (see sections 4.3 and 4.5).
Immune system disorders
Not known:	Hypersensitivity reactions anaphylaxis,	including
	bronchospasm, angioedema, rash, and urticaria.	pruritus,
Psychiatric disorders
Common:	Anxiety *
Gastrointestinal disorders
Very common:	Oily spotting Flatus with discharge Faecal urgency Fatty/oily stool Oily evacuation Flatulence Soft stools
Common:	Abdominal pain Faecal incontinence Liquid stools Increased defaecation
Not known:	Diverticulitis Pancreatitis

	Mild rectal bleeding (see section 4.4)
Renal and urinary disorders Not known:	Oxalate nephropathy
Hepato-biliary disorders Not known:	Hepatitis that may be serious 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.

4.9 Overdose

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 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

5.1    Pharmacodynamic properties

Pharmaco-therapeutic group: Anti obesity preparations, ex cl. 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 pretreatment 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	204	-3.24	-3.11
	Orlistat 60 mg	216	-5.55	-5.20a
Study 2	Placebo	183	-1.17	-1.05
	Orlistat 60 mg	191	-3.66	-3.59a
Pooled data	Placebo	387	-2.20	-2.09
	Orlistat 60 mg	407	-4.60	-4.40a
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	30.9	54.6a	10.3	21.3b
Study 2	21.3	37.7a	2.2	10.5b
Pooled data	26.4	46.7a	6.5	16.2a
Comparison versus placebo: a p<0.001; b p<0.01

The weight loss induced by orlistat 60 mg conferred other important health benefits after 6 months of treatment in addition to weight loss. The mean relative change in total cholesterol was -2.4% for orlistat 60 mg (baseline 5.20 mmol/l) and +2.8% for placebo (baseline 5.26 mmol/l). The mean relative change in LDL cholesterol was -3.5% for orlistat 60 mg (baseline 3.30 mmol/l) and +3.8% for placebo (baseline 3.41 mmol/l). For waist circumference, the mean change was -4.5 cm for orlistat 60 mg (baseline 103.7 cm) and -3.6 cm for placebo (baseline 103.5 cm). All comparisons against placebo were statistically significant.

5.2 Pharmacokinetic properties

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 pmol), 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 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.

The cumulative renal excretion of total orlistat-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 orlistat appeared to be similar between normal weight and obese volunteers. Orlistat, Ml and M3 are all subject to biliary excretion.

5.3 Preclinical safety data

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule filling:

Cellulose, microcrystalline Sodium starch glycolate (type A) Sillica, colloidal anhydrous Sodium lauryl sulphate

Capsule shell:

Gelatine

Indigo carmine (E132)

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Blisters: 2 years

Bottles: 2 years. After first opening: 6 months.

6.4 Special precautions for storage

Do not store above 25°C. Store in original package in order to protect from light and moisture.

6.5 Nature and contents of container

Al/PVC/PVDC blisters containing 42, 60, 84, 90 and 120 hard capsules.

Al/PVC/PCTFE blisters containing 42, 60, 84, 90 and 120 hard capsules.