Orlistat teva 60 mg

SUMMARY OF PRODUCT CHARACTERISTICS
1.
NAME OF THE MEDICINAL PRODUCT
[Invented name] 60 mg capsules, hard
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule, hard contains 60 mg orlistat.
For the 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
[Invented name] 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 [Invented name] 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 [Invented name], 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 [Invented name].
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 [Invented name] is
stopped.
Special populations
Paediatric population
The safety and efficacy of [Invented name] in children and adolescents below 18 years of age has not been
established. No data are available.
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.
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 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 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).
4.4
Special warnings and precautions for use
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 [Invented name], 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 [Invented name], 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 [Invented name]
(see section 4.5).
Rect al bl eedi ng
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).
Ki dney di sease
Patients with kidney disease should consult a doctor before starting treatment with [Invented name], 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
(see section 4.8).
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 [Invented name], as orlistat and levothyroxine may need to be taken at different times and the
dose of levothyroxine may need to be adjusted.
Anti epil eptic medi ci nal pr oducts
Patients taking an antiepileptic medicinal product should consult a doctor before starting treatment with
[Invented name], 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 orlistat concomitantly with antiretroviral medications.
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)
Excipient (s)
Sodium
This medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially `sodium-
free'.
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 [Invented name] 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 [Invented name] 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, [Invented name] 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 [Invented name]. The dose of amiodarone may need to be
adjusted during treatment with [Invented name].
Antiretrovirals for HIV
Based on reports from literature and post-marketing experience orlistat may potentially reduce the absorption
of antiretroviral medicines for HIV and could negatively affect the efficacy of antiretroviral medications for
HIV (see section 4.4).
Antidepressants, antipsychotics, 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.
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).
[Invented name] 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 or negligible influence on the ability to drive and use machines.
4.8
Undesirable effects
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) and 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, undesirable effects 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 *
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 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.
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 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
5.1
Pharmacodynamic properties
Pharmaco-therapeutic 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
N
Relative mean Mean change (kg)
group
change (%)
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 mol), 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.
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, M1 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 fertility, reproduction and
development.
The medicinal use of orlistat is unlikely to represent a risk to the aquatic or terrestrial environment.
However, any possible risk should be avoided (see section 6.6).
6.
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
Capsule filling:
Cellulose, microcrystalline
Sodium starch glycolate (type A)
Silica, hydrophobic colloidal
Sodium laurilsulfate
Capsule shell:
Gelatin
Indigo carmine (E132)
Titanium dioxide (E171)
6.2
Incompatibilities
Not applicable.
6.3
Shelf life
Blisters: 2 years
Bottles: 2 years. After first opening of the bottle: 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.
HDPE tamper-evident bottles sealed with Paper-Wax-Aluminium- Polyethylene terephthalate-Polyethylene
membrane with PE push-fit tamper evident cap containing 42 and 84 hard capsules.
HDPE tamper-evident bottles with PE push-fit tamper evident caps equipped with silica gel, molecular
sieves desiccant containing 42 and 84 hard capsules.
HDPE tamper-evident bottles with PE push-fit tamper evident caps equipped with wide-porous silica gel
desiccant containing 42 and 84 hard capsules.
HDPE tamper-evident bottles with PE push-fit tamper evident caps equipped with narrow-porous silica gel
desiccant containing 42 and 84 hard capsules.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
MARKETING AUTHORISATION HOLDER
<[To be completed nationally]>
8.
MARKETING AUTHORISATION NUMBERS
<[To be completed nationally]>
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
<[To be completed nationally]>
10.
DATE OF REVISION OF THE TEXT
<[To be completed nationally]>