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ORUVAIL 100 MG PROLONGED-RELEASE CAPSULES HARD

Active substance(s): KETOPROFEN

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Oruvail 100mg Prolonged-Release Capsules, Hard

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Ketoprofen 100 mg.

3.

PHARMACEUTICAL FORM
Controlled release capsules

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Oruvail is recommended in the management of rheumatoid arthritis,
osteoarthritis, ankylosing spondylitis, acute articular and periarticular
disorders, (bursitis, capsulitis, synovitis, tendinitis), cervical spondylitis, low
back pain (strain, lumbago, sciatica, fibrositis), painful musculoskeletal
conditions, acute gout, dysmenorrhoea and control of pain and inflammation
following orthopaedic surgery.
Oruvail reduces joint pain and inflammation and facilitates increase in
mobility and functional independence. As with other non-steroidal antiinflammatory agents, it does not cure the underlying disease.

4.2

Posology and method of administration
Adults: 100 - 200mg once daily, depending on patient weight and on
severity of symptoms.
The maximum daily dose is 200mg. The balance of risks and benefits should
be carefully considered before commencing treatment with 200mg daily, and
higher doses are not recommended (see also section 4.4).
Elderly: The elderly are at increased risk of the serious consequences of
adverse reactions. If an NSAID is considered necessary, the lowest effective

dose should be used and for the shortest possible duration. The patient should
be monitored regularly for GI bleeding during NSAID therapy.
Paediatric dosage not established.
Oruvail capsules are for oral administration. To be taken preferably
with or after food.
Undesirable effects may be minimised by using the lowest effective dose for
the shortest duration necessary to control symptoms (see section 4.4).
4.3

Contraindications
Ketoprofen is contraindicated in patients who have a history of hypersensitivity
reactions such as bronchospasm, asthmatic attacks, rhinitis, angioedema, urticaria or
other allergic-type reactions to ketoprofen, any other ingredients in this medicine,
ASA or other NSAIDs. Severe, rarely fatal, anaphylactic reactions have been reported
in such patients (see section 4.8 Undesirable effects).
Ketoprofen is contraindicated in patients with hypersensitivity to any of the
excipients of the drug.
Ketoprofen is also contraindicated in the third trimester of pregnancy.
Ketoprofen is contraindicated in the following cases:
- Severe heart failure
- active peptic ulcer, or any history of gastrointestinal bleeding, ulceration or
perforation
- haemorrhagic diathesis
- severe hepatic insufficiency
- severe renal insufficiency

4.4

Special warnings and precautions for use
Undesirable effects may be minimised by using the lowest effective dose for
the shortest duration necessary to control symptoms (see section 4.2 Posology
and method of administration, and GI and cardiovascular risks below).
The use of ketoprofen with concomitant NSAIDs including cyclooxygenase-2
selective inhibitors should be avoided (see section 4.5 Interactions).
Elderly:
The elderly have an increased risk of adverse reactions to NSAIDs, especially
gastrointestinal bleeding and perforation which may be fatal (see Section 4.2
Posology and method of administration).

Cardiovascular, Renal and Hepatic impairment:
At the start of treatment, renal function must be carefully monitored in patients
with heart impairment, heart failure, liver dysfunction, cirrhosis and nephrosis,
in patients receiving diuretic therapy, in patients with chronic renal
impairment, particularly if the patient is elderly. In these patients,
administration of ketoprofen may induce a reduction in renal blood flow
caused by prostaglandin inhibition and lead to renal decomposition. (see
Section 4.3 Contra-indications).
NSAIDs have also been reported to cause nephrotoxicity in various forms and
this can lead to interstitial nephritis, nephrotic syndrome and renal failure.
In patients with abnormal liver function tests or with a history of liver disease,
transaminase levels should be evaluated periodically, particularly during longterm therapy. Rare cases of jaundice and hepatitis have been described with
ketoprofen.
Cardiovascular and cerebrovascular effects
Appropriate monitoring and advice are required for patients with a history of
hypertension and/or mild to moderate congestive heart 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). There are insufficient data to exclude such a risk for
ketoprofen.
Patients with uncontrolled hypertension, congestive heart failure, established
ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular
disease should only be treated with ketoprofen after careful consideration.
Similar consideration should be made before initiating long-term treatment in
patients with risk factors for cardiovascular disease (e.g. hypertension,
hyperlipidaemia, diabetes mellitus, smoking).
Respiratory disorders:
Patients with asthma combined with chronic rhinitis, chronic sinusitis, and/or
nasal polyposis have a higher risk of allergy to aspirin and/or NSAIDs than the
rest of the population. Administration of this medicinal product can cause
asthma attacks or bronchospasm, particularly in subjects allergic to aspirin or
NSAIDs (see section 4.3).
Gastrointestinal bleeding, ulceration and perforation:
GI bleeding, ulceration or perforation, which can be fatal, has been reported
with all NSAIDs at any time during treatment, with or without warning
symptoms or a previous history of serious GI events.

Some epidemiological evidence suggests that ketoprofen may be associated
with a high risk of serious gastrointestinal toxicity, relative to some other
NSAIDs, especially at high doses (see also section 4.2 and 4.3).
The risk of GI bleeding, ulceration or perforation is higher with increasing
NSAlD doses, in patients with a history of ulcer, particularly if complicated
with haemorrhage or perforation, and in the elderly. Elderly patients should
commence treatment on 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 below
and section 4.5). Ketoprofen should not be used in patients with any history of
peptic ulceration (see section 4.3).
NSAIDs should be given with care to patients with a history of gastrointestinal
disease (e.g. ulcerative colitis, Crohn’s disease) as these conditions may be
exacerbated (see Section 4.8 Undesirable effects).
Patients with a history of gastrointestinal toxicity, particularly when elderly,
should report any unusual abdominal symptoms (especially GI bleeding),
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, or anticoagulants such as warfarin, selective serotoninreuptake inhibitors or anti-platelet agents such as aspirin (see Section 4.5).
When GI bleeding or ulceration occurs in patients receiving ketoprofen, the
treatment should be withdrawn.
SLE and mixed connective tissue disease:
In patients with systemic lupus erythematosis (SLE) and mixed connective
tissue disorders, there may be an increased risk of aseptic meningitis (see
Section 4.8 Undesirable effects).
Female fertility:
The use of ketoprofen, as with other NSAIDs, may impair female fertility and
is not recommended in women attempting to conceive. In women who have
difficulty conceiving or who are undergoing investigation of infertility,
withdrawal of ketoprofen should be considered.
Skin reactions:
Serious skin reactions, 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 NSAIDs. Patients appear to
be at highest risk of these reactions early in the course of therapy, the onset of
the reaction occurring in the majority of cases within the first month of
treatment. Treatment should be discontinued at the first appearance of skin
rash, mucosal lesions, or any other sign of hypersensitivity.

Infectious disease:
As with other NSAIDs, in the presence of an infectious disease, it should be
noted that the anti-inflammatory, analgesic and the antipyretic properties of
ketoprofen may mask the usual signs of infection progression such as fever.
Visual disturbances:
If visual disturbances such as blurred vision occur, treatment should be
discontinued.

4.5

Interaction with other medicinal products and other forms of interaction
Anticoagulants (heparin and warfarin) and platelet aggregation inhibitors
(i.e. ticlopidine, clopidogrel):
Increased risk of bleeding (see section 4.4).
If coadministration is unavoidable, patient should be closely monitored.
Lithium:
Risk of elevation of lithium plasma levels, sometimes reaching toxic levels
due to decreased lithium renal excretion. Where necessary, plasma lithium
levels should be closely monitored and the lithium dosage levels adjusted
during and after NSAIDs therapy.
Other analgesics/NSAIDs (including cyclooxygenase-2 selective inhibitors)
and high dose salicylates:
Avoid concomitant use of two or more NSAIDs (including aspirin) as this may
increase the risk of adverse effects, particularly gastrointestinal ulceration and
bleeding. (see Section 4.4 Special warnings and precautions for use).
Methotrexate:
Serious interactions have been recorded after the use of high dose
methotrexate with NSAIDs, including ketoprofen, due to decreased
elimination of methotrexate. At doses greater than 15mg/week:
Increased risk of haematologic toxicity of methotrexate, particularly if
administered at high doses (> 15 mg/week), possibly related to displacement
of protein-bound methotrexate and to its decreased renal clearance. At doses
lower than 15mg/week: During the first weeks of combination treatment, full
blood count should be monitored weekly. If there is any alteration of the renal
function or if the patient is elderly, monitoring should be done more
frequently.
Mifepristone:
NSAIDs should not be used for 8-12 days after mifepristone administration as
NSAIDs can reduce the effect of mifepristone.
Pentoxifylline:
There is an increased risk of bleeding. More frequent clinical monitoring and
monitoring of bleeding time is required.

Antihypertensive agents (beta blockers, angiotensin converting enzyme
inhibitors, diuretics):
Risk of decreased antihypertensive potency (inhibition of vasodilator
prostaglandins by NSAIDs.
Diuretics:
Risk of reduced diuretic effect. Patients and particularly dehydrated patients
taking diuretics are at a greater risk of developing renal failure secondary to a
decrease in renal blood flow caused by prostaglandin inhibition. Such patients
should be rehydrated before initiating coadministration therapy and renal
function monitored when the treatment is started (see section 4.4 Special
warnings and precautions for use).
Cardiac glycosides:
NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma
glycoside levels.
Ciclosporin:
Increased risk of nephrotoxicity, particularly in elderly subjects.
Corticosteroids:
Increased risk of gastrointestinal ulceration or bleeding. (see Section 4.4
Special warnings and precautions for use).
Quinolone antibiotics:
Animal data indicate that NSAIDs can increase the risk of convulsions
associated with quinolone antibiotics. Patients taking NSAIDs and quinolones
may have an increased risk of developing convulsions.
Tacrolimus:
Possible increased risk of nephrotoxicity when NSAIDs are given with
tacrolimus, particularly in elderly subjects.
Thrombolytics:
Increased risk of bleeding.
Probenecid:
Concomitant administration of probenecid may markedly reduce the plasma
clearance of ketoprofen.
Anti-platelet agents and Selective serotonin reuptake inhibitors (SSRIs):
Increased risk of gastrointestinal bleeding (Section 4.4 Special warnings and
precautions for use).
ACE inhibitors and Angiotensin II Antagonists:
In patients with compromised renal function (e.g. dehydrated patients or
elderly patients the co-administration of an ACE inhibitor or Angiotensin II
antagonist and agents that inhibit cyclooxygenase may result in further
deterioration of renal function, including possible acute renal failure.

Zidovudine:
Increased risk of haematological toxicity when NSAlDs 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

Inhibition of prostaglandin synthesis may adversely affect the pregnancy
and/or the embryo/foetal development. Data from epidemiological studies
suggest an increased risk of miscarriage and of cardiac malformation and
gastroschisis after use of a prostaglandin synthesis inhibitor in early
pregnancy. The absolute risk for cardiovascular malformation was increased
from less than 1%, up to approximately 1.5%. The risk is believed to increase
with dose and duration of therapy. In animals, administration of a
prostaglandin synthesis inhibitor has been shown to result in increased preand post-implantation loss and embryo-foetal lethality. In addition, increased
incidences of various malformations, including cardiovascular, have been
reported in animals given a prostaglandin synthesis inhibitor during the
organogenetic period. During the first and second trimester of pregnancy,
ketoprofen should not be given unless clearly necessary. If ketoprofen is used
by a woman attempting to conceive, or during the first and second trimester of
pregnancy, the dose should be kept as low and duration of treatment as short
as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors
may expose the foetus to:
- cardiopulmonary toxicity (with premature closure of the ductus arteriosus
and pulmonary hypertension);
- renal dysfunction, which may progress to renal failure with oligohydroamniosis; the mother and the neonate, at the end of the pregnancy,
to:
- possible prolongation of bleeding time, an anti-aggregating effect which
may occur even at very low doses.
- Inhibition of uterine contractions resulting in delayed or prolonged labour.
Consequently, ketoprofen is contraindicated during the third trimester of
pregnancy.
Lactation
No data are available on excretion of ketoprofen in human milk. Ketoprofen is
not recommended in nursing mothers.
4.7

Effects on ability to drive and use machines

Patients should be warned about the potential for somnolence, dizziness or
convulsions, drowsiness, fatigue and visual disturbances and be advised not to
drive or operate machinery if these symptoms occur.

4.8

Undesirable effects
The following CIOMS frequency rating is used, when applicable:
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), not known (cannot be estimated
from the available data).
The following adverse reactions have been reported with Ketoprofen in adults:
Blood and lymphatic system disorders
-

rare: haemorrhagic anaemia, anaemia due to bleeding

-

not known: agranulocytosis, thrombocytopenia, bone marrow failure, neutropenia

Immune system disorders
-

rare: anaphylactic reactions (including shock)

Psychiatric disorders
-

not known: mood altered

Nervous system disorders
-

uncommon: headache, dizziness, somnolence

-

rare: paraesthesia

-

not known: convulsions, dysgeusia, depression, confusion, hallucinations,
vertigo, malaise, drowsiness, reports of aseptic meningitis (especially in patients
with existing auto-immune disorders such as systemic lupus erythematosis, mixed
connective tissue disease) with symptoms such as stiff neck, headache, nausea,
vomiting, fever or disorientation (see section 4.4 Special warnings and
precautions for use).

Eye disorders
-

rare: visual disturbances such as blurred vision (see section 4.4 Special warnings
and precautions for use)

-

not known: optic neuritis

Ear and labyrinth disorders
-

rare: tinnitus

Cardiac disorders
-

not known: heart failure, oedema

Vascular disorders
-

not known: hypertension, vasodilatation

Respiratory, thoracic and mediastinal disorders
-

rare: asthma, asthmatic attack

-

not known: bronchospasm (particularly in patients with known hypersensitivity to
ASA and other NSAIDs), rhinitis, non-specific allergic reactions, dyspnoea

Gastrointestinal disorders
-

common: dyspepsia, nausea, abdominal pain, vomiting

-

uncommon: constipation, diarrhoea, flatulence, gastritis

-

rare: stomatitis, peptic ulcer

-

very rare: pancreatitis (very rare reports of pancreatitis have been noted with
NSAIDs)

-

not known: exacerbation of colitis and Crohn’s disease, gastrointestinal
haemorrhage and perforation, gastralgia, melaena, haematemesis

Gastrointestinal bleeding may sometimes be fatal, particularly in the elderly (see
section 4.4 Special warnings and precautions for use).
Hepatobiliary disorders
-

rare: hepatitis, transaminases increased, elevated serum bilirubin due to hepatitis
disorders

-

not known: abnormal liver function, jaundice

Skin and subcutaneous disorders
-

uncommon: rash, pruritis

-

not known: photosensitivity reactions, alopecia, urticaria, angioedema, bullous
eruption including Stevens-Johnson syndrome and toxic epidermal necrolysis,
exfoliative and bullous dermatoses (including epidermal necrolysis, erythema
multiforme), purpura

Renal and urinary disorders
-

not known: renal failure acute, tubulointerstitial nephritis, nephritic syndrome,
renal function tests abnormal

General disorders and administration site conditions

-

uncommon: oedema, fatigue

-

not known: headache, taste perversion

Investigations
-

rare: weight increased

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly
at high doses and in long term treatment) may be associated with an increased risk of
arterial thrombotic events (for example myocardial infarction or stroke) (see section
4.4 Special warnings and precautions for use).
In all cases of major adverse effects Oruvail should be withdrawn at once.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9

Overdose
Symptoms
Cases of overdose have been reported with doses up to 2.5g of ketoprofen. In
most instances the symptoms observed have been benign and limited to
lethargy, drowsiness, nausea, vomiting and epigastric pain. Headache, rarely
diarrhoea, disorientation, excitation, coma, dizziness, tinnitus, fainting,
occasionally convulsions may also occur. Adverse effects seen after overdose
with propionic acid derivatives such as hypotension, bronchospasm and
gastro-intestinal haemorrhage should be anticipated.
In cases of significant poisoning, acute renal failure and liver damage are
possible.
If renal failure is present, haemodialysis may be useful to remove circulating
medicinal product.
Therapeutic measures:
There are no specific antidotes to ketoprofen overdosages. In cases of
suspected massive overdosages, a gastric lavage is recommended and
symptomatic and supportive treatment should be instituted to compensate for
dehydration, to monitor urinary excretion and to correct acidosis, if present.
Owing to the slow release characteristics of Oruvail, it should be expected that
ketoprofen will continue to be absorbed for up to 16 hours after ingestion.

Within one hour of ingestion, consideration should be given to administering
activated charcoal in an attempt to reduce absorption of slowly-released
ketoprofen.
Alternatively, in adults, gastric lavage, aimed at recovering pellets that may
still be in the stomach, should be considered if the patient presents within 1
hour of ingesting a potentially toxic amount.
It should be possible to identify the pellets in the gastric contents. Correction
of severe electrolyte abnormalities may need to be considered.
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.
The benefit of gastric decontamination is uncertain.
Other measures may be indicated by the patient’s clinical condition.
5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Ketoprofen overall has the properties of a potent non-steroidal anti-inflammatory agent. It has the following pharmacological effects:
Anti-inflammatory It inhibits the development of carageenan-induced
abscesses in rats at 1 mg/kg and UV-radiation induced erythema in guinea pigs
at 6mg/kg. It is also a potent inhibitor of PGE2 and PGF2oc synthesis in guinea
pig and human
chopped lung preparations.
Analgesic Ketoprofen effectively reduced visceral pain in mice caused by
phenyl benzoquinone or by bradykinin following p.o. administration at about
6mg/kg.
Antipyretic Ketoprofen (2 and 6mg/kg) inhibited hyperthermia caused by s.c
injection of brewer's yeast in rats and, at 1 mg/kg hyperthermia caused by i.v.
administration of anticoagulant vaccine to rabbits.
Ketoprofen at 10mg/kg i.v. did not affect the cardiovascular, respiratory,
central nervous system or autonomic nervous systems.

5.2

Pharmacokinetic properties
Ketoprofen is slowly but completely absorbed from Oruvail capsules.
Maximum plasma concentration occurs after 6 - 8 hours. It declines thereafter
with a half-life of about 8 hours. There is no accumulation on continued daily
dosing. Ketoprofen is very highly bound to plasma protein.

5.3

Preclinical safety data
No additional data of relevance to the prescriber.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Pellets
Sugar Spheres
Colloidal Silicon Dioxide
Shellac
Ethyl Cellulose
Talc

NF
EP
NF
NF
EP

Capsule shell -body
Erythrocine (EEC 127)
Gelatin
Capsule shell - Cap
Erythrocine (EEC 127)
Patent Blue V (EEC 131)
Titanium Dioxide (EEC 171)
Gelatin
6.2

Incompatibilities
None.

6.3

Shelf life
36 months

6.4

Special precautions for storage
Securitainer and HDPE bottle: Store below 30 C in a dry place. Blister
pack: Store below 25°C in a dry place. Protect from light.

6.5

Nature and contents of container
Securitainer or HDPE bottle containing 100 capsules.
UPVC/Aluminium foil blister or UPVC coated with PVDC aluminium foil
blister containing either 8, 28, 30 or 56 capsules
Not all pack sizes may be marketed.

6.6

Instructions for use and handling
None stated.

7

MARKETING AUTHORISATION HOLDER
Aventis Pharma Limited also trading as Aventis Pharma
One Onslow Street
Guildford
Surrey
GU1 4YS
UK
Or trading as
Sanofi-aventis or Sanofi
One Onslow Street
Guildford
Surrey
GU1 4YS
UK

8.

MARKETING AUTHORISATION NUMBER
PL 04425/0597

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF
AUTHORISATION
01/09/1998 / 13/03/2001

10

DATE OF REVISION OF THE TEXT
11/10/2013

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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