Physician’s Prescribing Information

Etopan XL 400 and 600 mg

Extended Release Tablets

1. Name of the medicinal product

Etopan XL 400 mg Extended Release Tablets
Etopan XL 600 mg Extended Release Tablets

2. Qualitative and quantitative composition

Each tablet of Etopan XL 400 mg contains 400 mg etodolac.
Each tablet of Etopan XL 600 mg contains 600 mg etodolac.
For excipients, see 6.1.

3. Pharmaceutical form
Extended Release Tablets

4. Clinical particulars
5.
4.1 Therapeutic indications
For the management of signs and symptoms of osteoarthritis and
rheumatoid arthritis.

4.2 Posology and method of administration

400mg XL - One to two tablets twice daily but no more than three tablets
a day
600mg XL - One tablet once or twice daily
The total daily dose of Etopan XL should not exceed 1,200mg.

As with other NSAIDs, the lowest dose and longest interval should be
sought for each patient. Therefore, after observing the response to initial
therapy with Etopan XL, the dose and frequency should be adjusted to
suit individual patient’s needs (tolerance and response). In responsive
patients, partial symptomatic relief of symptoms usually occurs within 1
or 2 weeks, although maximum effectiveness may occur only after
several weeks of therapy.
During long-term administration the dose of Etopan XL may be adjusted,
up or down, depending on the patient’s clinical response (maximum dose
1200 mg/day).
As with other NSAIDs, Etopan XL is preferably taken after meals or with
food or antacids to reduce gastrointestinal irritation, especially during
chronic use. However, for faster absorption when a rapid initial effect is
required, the first 1 or 2 doses may be taken 30 minutes before meals or
at least 2 hours after meals. If an antacid is taken concurrently, an

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 aluminum and magnesium-containing formulation may be preferred. It is
recommended to take Etopan XL tablets with a full glass of water and
that the patient remains in an upright position for 15-30 minutes after
administration. Patients should be advised to avoid alcoholic beverages
while under treatment with this medicine.

4.3 Contraindications
• Hypersensitivity to etodolac or to any of the excipients.
NSAIDs are contraindicated in patients who have previously shown
hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria)
in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory
drugs.
• History of gastrointestinal bleeding or perforation, related to previous
NSAID's therapy.
• Active or history of recurrent peptic ulcer/haemorrhage (two or more
distinctepisodes of proven ulceration or bleeding).
• Severe heart failure, hepatic failure and renal failure (see section 4.4).
• During the last trimester of pregnancy (see section 4.6).

4.4 Special warnings and precautions for use

Undesirable effects may be minimized by using the minimum effective
dose for the shortest duration necessary to controlsymptoms (see
section 4.2, and GI and cardiovascular risks below).
The use of Etopan XL with concomitant NSAIDs including
cyclooxygenase-2 selective inhibitors should beavoided (see section
4.5).
Although non-steroidal anti-inflammatory drugs do not have the same
direct effects on platelets as aspirin, all drugs which inhibitthe
biosynthesis of prostaglandins may interfere, to some extent, with
platelet function. Patients receiving Etopan XL who may be adversely
affected by such actions should be carefully observed.
Patients with rare hereditary problems or galactose intolerance, the Lap
lactase deficiency or glucose-galactose malabsorption should not take
this medicine.
Elderly: The elderly have an increased frequency of adverse reactions to
NSAIDs especially gastrointestinal bleeding andperforation, which may
be fatal (see section 4.2).
Cardiovascular, Renal and Hepatic Impairment:
The administration of an NSAID may cause a dose dependent reduction
in prostaglandin formation and precipitate renal failure.Patients at
greatest risk of this reaction are those with impaired renal function,
cardiac impairment, liver dysfunction, those takingdiuretics and the
elderly. Renal function should be monitored in these patients and the
dose should be kept as low as possible(see also section 4.3). However,
impairment of renal or hepatic functions due to other causes may alter
drug metabolism;patients receiving concomitant long term therapy,

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 especially the elderly, should be observed for potential side effects and
theirdrug doses adjusted as needed, or the drug discontinued.
Patients on long-term treatment with Etopan XL should be regularly
reviewed as a precautionary measure e.g.for changes in renal function,
haematological parameters, or hepatic function.
Cardiovascular and cerebrovascular effects:
Appropriate monitoring and advice are required for patients with a history
of hypertension and/or mild to moderate congestiveheart failure as fluid
retention and oedema have been reported in association with NSAID
therapy.
Clinical trial and epidemiological data suggest that use of some NSAIDs
(particularly at high doses and in long term treatment)may be associated
with a small increased risk of arterial thrombotic events (for example
myocardial infarction or stroke). Thereare insufficient data to exclude
such a risk for Etodolac.
Patients with uncontrolled hypertension, congestive heart failure,
established ischaemic heart disease, peripheral arterialdisease, and/or
cerebrovascular disease should only be treated with EtopanXL after
careful consideration. Similar considerationshould be made before
initiating long-term treatment of patients with risk factors for
cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes
mellitus, smoking).
Dermatological:
Serious skin reaction some of them fatal, including exfoliative dermatitis,
Stevens-Johnson syndrome, and toxic epidermal necrolysis have been
reported very rarely in association with the use of NSAID's (see section
4.8). Patients appear to be athighest risk of these reactions early in the
course of therapy: the onset of the reaction occurring in the majority of
cases withinthe first month of treatment. Etodolac XL should be
discontinued at the first appearance of skin rash, mucosal lesions, orany
other signs of hypersensitivity.
Respiratory disorders:
Caution is required if Etopan XL are administered to patients suffering
from, or with a previous history of bronchial asthma, since NSAIDs have
been reported to precipitate bronchospasm in such patients.
SLE and mixed connective tissue disease:
In patients with systemic lupus erythematosus (SLE) and mixed
connective tissue disorders there may be an increased risk ofaseptic
meningitis (see section 4.8).
Impaired female fertility:
The use of Etopan XL may impair female fertility and is not recommended
in women attempting to conceive. Inwomen who have difficulties
conceiving or who are undergoing investigation of infertility, withdrawal of
Etopan XL should be considered.
Gastrointestinal bleeding, ulceration and perforation:

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 GI bleeding, ulceration or perforation, which can be fatal, has been
reported with all NSAIDs at anytime during treatment, with orwithout
warning symptoms or a previous history of serious GI events.
The risk of bleeding, ulceration or perforation is higher with increasing
NSAID doses, in patients with a history of ulcer, particular if complicated
with haemorrhage or perforation (see section 4.3), and in the elderly.
These patients should commence treatmenton the lowest dose available.
Combination therapy with protective agents (e.g. misoprostol or proton
pump inhibitors) should be considered for these patients,and also for
patients requiring concomitant low dose aspirin or other drugs likely to
increase gastrointestinal risk (see section 4.5).
Patients with a history of GI toxicity, particularly when elderly, should
report any unusual abdominal symptoms (especially GIbleeding)
particularly in the initial stages of treatment.
Caution should be advised in patients receiving concomitant medications
which could increase the risk of ulceration or bleeding,such as oral
corticosteroids, anticoagulants such as warfarin, selective serotonin-
reuptake inhibitors or anti-platelet agents suchas aspirin (see section
4.5).
When GI bleeding or ulceration occurs in patients receiving etodolac, the
treatment should be withdrawn.
NSAIDs should be given with care to patients with a history of
gastrointestinal disease (ulcerative colitis, Crohn's disease) as their
condition may be exacerbated (see section 4.8 – undesirable effects).

4.5 Interaction with other medicinal products and other forms of

interaction
Corticosteroids: increased risk of gastrointestinal ulceration or bleeding
(see section 4.4).
Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants,
such as warfarin (see section 4.4).
Since etodolac is extensively protein bound, it may be necessary to
modify the dosage of other highly protein-bound drugs.
The concomitant administration of warfarin and Etopan XL should not
require a dosage adjustment of eitherdrug, however it has rarely led to
prolonged prothrombin times, therefore caution should be exercised
when Etopan XL are administered with warfarin.
Bilirubin tests can give a false positive result due to the presence of
phenolic metabolites of etodolac in the urine.
Care should also be taken in patients treated with any of the following
drugs as interactions have been reported in some patientsincluding
increase in serum levels of these compounds and associated toxicities:
• Anti-hypertensives: Reduced anti-hypertensive effect
• Mifepristone: NSAIDs should not be used for 8 – 12 days after
mifepristone administration as NSAIDs can reduce the effect of
mifepristone.

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 • Other analgesics including cyclooxygenase-2 selective inhibitors:
Avoid concomitant use of two or more NSAIDs (includingaspirin) as
this may increase the risk of adverse effects (see section 4.4).
• Quinolone antibiotics: Animal data indicate that NSAIDs can increase
the risk of convulsions associated with quinoloneantibiotics. Patients
taking NSAIDs and quinolones may have an increased risk of
developing convulsions.
• Diuretics: Reduced diuretic effect. Diuretics can increase the risk of
nephrotoxicity of NSAIDs.
• Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce
GFR and increase plasma glycoside levels.
• Lithium: Decreased elimination of lithium.
• Methotrexate: Decreased elimination of methotrexate.
• Cyclosporin: Increased risk of nephrotoxicity.
• Anti-platelet agents and selective serotonin reuptake inhibitors
(SSRIs): Increased risk of gastrointestinal bleeding (see section4.4).
• Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs
are given with tacrolimus.
• Zidovudine: Increased risk of haematological toxicity when NSAIDs
are given with zidovudine. There is evidence of an increased risk of
haemarthroses and haematoma in HIV(+) haemophiliacs receiving
concurrent treatment with zidovudine and ibuprofen.

4.6 Pregnancy and lactation

Pregnancy:
Drugs which inhibit prostaglandin biosynthesis may cause dystocia and
delayed parturition as evidenced by studies in pregnantanimals.
Congenital abnormalities have been reported in association with NSAID
administration in man; however, these are low infrequency and do not
appear to follow any discernible pattern. In view of the known effects of
NSAIDs on the foetal cardiovascular system (risk of closure of the ductus
arteriosus), use in the last trimester of pregnancy is contraindicated. The
onset of labour may be delayed and the duration increased with an
increased bleeding tendency in both mother and child (seesection 4.3).
NSAIDs should not be used during the first two trimesters of pregnancy
or labour unless the potential benefit to thepatient outweighs the potential
risk to the foetus.
Lactation:
In limited studies so far available, NSAIDs can appear in breast milk in
very low concentrations. NSAIDs should, if possible, beavoided when
breastfeeding.
See section 4.4 Special warnings and precautions for use, regarding
female fertility.

4.7 Effects on ability to drive and use machines

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 Undesirable effects such as dizziness, drowsiness, fatigue and visual
disturbances are possible after taking NSAIDs. If affected,patients should
not drive or operate machinery.

4.8 Undesirable effects

Gastrointestinal:
The most commonly observed adverse events are gastrointestinal in
nature. Peptic ulcers, perforation or GI bleeding, sometimesfatal,
particularly in the elderly, may occur (see section 4.4). Nausea, vomiting,
diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena,
haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's
disease (see section 4.4)have been reported following administration.
Less frequently, gastritis has been observed. Pancreatitis has been
reported veryrarely.
Hypersensitivity:
Hypersensitivity reactions have been reported following treatment with
NSAIDs. These may consist of (a) nonspecificallergic reactions and
anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated
asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders,
including rashes of various types, pruritus, urticaria, purpura, angiodema
and, more rarely exfoliative and bullous dermatoses (including epidermal
necrolysis and erythema multiforme).
Cardiovascular and cerebrovascular:
Oedema, hypertension and cardiac failure have been reported in
association with NSAID treatment.
Clinical trial and epidemiological data suggests that use of some NSAID's
(particularly at high doses and in long term treatment)may be associated
with an increased risk of arterial thrombotic events (for example
myocardial infarction of stroke) (see section4.4).
Other adverse reactions reported less commonly include:
Endocrine disorders:
Oedema, pyrexia
Musculoskeletal connective tissue and bone disorders:
Weakness/malaise
Respiratory, thoracic and mediastinal disorders:
Dyspnoea
Neurological and special senses:
Visual disturbances, optic neuritis, headaches, paraesthesia, reports of
aseptic meningitis (especially in patients with existingauto-immune
disorders, such as systemic lupus erythematosus, mixed connective
tissue disease), with symptoms such as stiffneck, headache, nausea,
vomiting, fever or disorientation (see section 4.4), depression, confusion,
hallucinations, tinnitus,vertigo, dizziness, malaise, fatigue, tremor,
insomnia, and drowsiness.
Dermatological:

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 Bullous reactions including Stevens-Johnson syndrome, and Toxic
Epidermal Necrolysis (very rare).Photosensitivity.
Haematological:
Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and
haemolyticanaemia.
Hepatic:
Abnormal liver function, hepatitis and jaundice.
Renal:
Bilirubinuria, urinary frequency, dysuria, Nephrotoxicity in various forms
including interstitial nephritis, nephrotic syndrome, renal failure.

Reporting suspected adverse reactions after authorization of the

medicinal product is important. It allows continued monitoring of the
benefit/risk balance of the medicinal product. Any suspected adverse
events should be reported to the Ministry of Health according to the
National Regulation by using an online form:
http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=
[email protected]

4.9 Overdose
a) Symptoms
Symptoms include headache, nausea, vomiting, epigastric pain,
gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation,
coma, drowsiness, dizziness, tinnitus, fainting, and occasionally
convulsions. In cases of significant poisoning acuterenal failure and liver
damage are possible.
b) Therapeutic measure
Patients should be treated symptomatically as required.
Within one hour of ingestion of a potentially toxic amount, activated
charcoal should be considered. Alternatively, in adults,gastric lavage
should be considered within one hour of ingestion of a potentially life-
threatening overdose.
Good urine output should be ensured.
Renal and liver function should be closely monitored.
Patients should be observed for at least four hours after ingestion of
potentially toxic amounts.
Frequent or prolonged convulsions should be treated with intravenous
diazepam. Other measures may be indicated by thepatient's clinical
condition.

6. Pharmacological properties
5.1 Pharmacodynamic properties
ATC code: M01A B08

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 Pharmacotherapeutic group: anti-inflammatory and anti-rheumatic
products, non-steroids, acetic acid derivatives and relatedsubstances
Inhibition of prostaglandin synthesis and COX-2 selectivity: All non-
steroidal anti-inflammatory drugs (NSAIDs) have been shownto inhibit the
formation of prostaglandins. It is this action which is responsible both for
their therapeutic effects and some of theirside effects. The inhibition of
prostaglandin synthesis observed with etodolac differs from that of other
NSAIDs. In an animalmodel at an established anti-inflammatory dose,
cytoprotective PGE concentration in the gastric mucosa have been
shown to bereduced to a lesser degree and for a shorter period than
other NSAIDs. This finding is consistent with subsequent in-vitro
studieswhich have found etodolac to be selective for induced cyclo-
oxygenase 2 (COX-2, associated with inflammation) over COX-
1(cytoprotective).
Furthermore, studies in human cell models have confirmed that etodolac
is selective for the inhibition of COX-2.
The clinical benefit of preferential COX-2 inhibition over COX-1 has yet to
be proven.
Anti-inflammatory effects: Experiments have shown etodolac to have
marked anti-inflammatory activity, being more potent thanseveral
clinically established NSAIDs.

5.2 Pharmacokinetic properties

In man, etodolac is well absorbed following oral administration.
Etodolac is highly bound to serum proteins.
The elimination half-life averages seven hours in man. The primary route
of excretion is in the urine, mostly in the form ofmetabolites.
In subjects receiving daily doses of Etopan XL 600 mg Tabletsto steady
state levels over a three day period, the peak plasma concentrations was
11.9 μg/ml at 7.8 hours

5.3 Preclinical safety data

Preclinical data reveal no special hazard based on conventional studies
of safety, pharmacology, repeated dose toxicity, genotoxicity and
carcinogenic potential.

7. Pharmaceutical particulars
6.1 List of excipients
Microcrystalline cellulose, Hypromellose, Lactose anhydrous, Povidone,
Magnesium stearate, Polydextrose, Titanium Dioxide, Triacetin,
Macrogol, FD&C Red #40 Aluminum Lake (E129), FD&C Yellow #6
Aluminum Lake (E110), FD&C Blue #2 Aluminum Lake (E132), black iron
oxide (E172) and yellow iron oxide (E172)

6.2 Incompatibilities

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 Not applicable

6.3 Shelf life

Etopan XL 400 mg (Blisters) – 36 months
Etopan XL 600 mg(Bottles) –36months;Etopan XL 600 mg (Blisters) – 48
months

6.4 Special precautions for storage

Store below25°C.

6.5 Nature and contents of container

Etopan XL 400 mg
PVC/PVDC/Aluminium blister packs in outer cardboard cartons.
Available in pack sizes of 2, 4, 20 and 30 tablets.
Etopan XL 600 mg
PVC/PVDC/Aluminium blister packs in outer cardboard cartons.
Available in pack sizes of 10, 12, 18, 20 and 24 tablets.
White round HDPE container with PP safety cap with aluminium foil inner
seal and purified cotton fill.
Available in pack sizes of 30, 100 and 1,000 tablets.
Not all packs may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

8. Manufacturer and registration holder

Taro Pharmaceutical Industries Ltd., P.O.Box 10347, Haifa Bay 2624761

The content of this leaflet was approved by the Ministry of Health in June
2013 and updated according to the guidelines of the Ministry of Health in
April 2018.

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