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SKUDEXA 75 MG/25 MG FILM-COATED TABLETS

Active substance(s): DEXKETOPROFEN / TRAMADOL HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Skudexa 75 mg/25 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains: 75 mg of tramadol hydrochloride
and 25 mg of dexketoprofen.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet.
Skudexa: almost white to slightly yellow, oblong, film-coated tablets with a breakmark on one side and a debossed “M” on the other side. The dimension of the filmcoated tablet is ca. 14 mm lengths and ca. 6 mm width.
The score line is only to facilitate breaking for ease of swallowing and not to divide
into equal doses.

4
4.1

CLINICAL PARTICULARS
Therapeutic indications
Symptomatic short term treatment of moderate to severe acute pain in adult patients
whose pain is considered to require a combination of tramadol and dexketoprofen.

4.2

Posology and method of administration
Posology
Adults:
The recommended dosage is one tablet (corresponding to 75 mg of tramadol
hydrochloride and 25 mg of dexketoprofen). Additional doses can be taken as needed,
with a minimum dosing interval of 8 hours. The total daily dose should not exceed
three tablets per day (corresponding to 225 mg of tramadol hydrochloride and 75 mg
of dexketoprofen).

Skudexa is intended for short term use only and the treatment must be strictly limited
to the symptomatic period and in any case not more than 5 days. Switching to a single
agent analgesia should be considered according to pain intensity and response of the
patient.
Undesirable effects may be minimised by using the lowest number of doses for the
shortest duration necessary to control symptoms (see section 4.4).
Elderly:
In elderly patients the starting recommended dosage is one tablet; additional doses
can be taken as needed with the minimum dose interval of 8 hours and not exceeding
the total daily dose of 2 tablets (corresponding to 150 mg of tramadol hydrochloride
and 50 mg of dexketoprofen). The dosage may be increased to a maximum of 3 daily
tablets as recommended for the general population only after good general tolerance
has been ascertained.
Limited data are available in patients over 75 years, therefore SKUDEXA should be
used with caution in these patients (see section 4.4).
Hepatic impairment:
Patients with mild to moderate hepatic dysfunction should start therapy at reduced
number of doses (total daily dose 2 tablets Skudexa) and be closely monitored.
Skudexa should not be used in patients with severe hepatic dysfunction (see section
4.3).
Renal impairment:
The initial total daily dosage should be reduced to 2 tablets Skudexa in patients with
mildly impaired renal function (creatinine clearance 60 - 89 ml / min) (see section
4.4).
Skudexa should not be used in patients with moderate to severe renal dysfunction
(creatinine clearance ≤59 ml / min) (see section 4.3).
Paediatric population:
The safety and efficacy of Skudexa in children and adolescents have not been
established. No data are available.
Therefore Skudexa should not be used in children and adolescents.
Method of administration
Oral use.
Skudexa should be swallowed with a sufficient amount of fluid (e.g. one glass of
water). Concomitant administration with food delays the absorption rate of the drug

(see Section 5.2), for a faster effect the tablets may be taken at least 30 minutes before
meals.

4.3

Contraindications
The contraindications reported for dexketoprofen and tramadol as single agents
should be taken into account.
Dexketoprofen must not be administered in the following cases:


hypersensitivity to dexketoprofen, to any other NSAID, or to any of the
excipients listed in section 6.1;



patients in whom substances with a similar action (e.g. acetylsalicylic acid, or
other NSAIDs) precipitate attacks of asthma, bronchospasm, acute rhinitis, or
cause nasal polyps, urticaria or angioneurotic oedema;



known photoallergic or phototoxic reactions during treatment with ketoprofen
or fibrates;



patients with active peptic ulcer/gastrointestinal haemorrhage or any history
of gastrointestinal bleeding ulceration or perforation;



patients with history of gastrointestinal bleeding or perforation, related to
previous NSAIDs therapy;



patiens with chronic dyspepsia;



patients who have other active bleedings or bleeding disorders;



patients with Crohn’s disease or ulcerative colitis;



patients with a history of bronchial asthma (even if not drug-induced);



patients with severe heart failure;



patients with moderate to severe renal dysfunction (creatinine clearance <59
ml/min);



patients with severely impaired hepatic function (Child-Pugh C);



patients with haemorrhagic diathesis and other coagulation disorders;



patients with severe dehydration (caused by vomiting, diarrhoea or
insufficient fluid intake).

Tramadol must not be administered in the following cases:


hypersensitivity to tramadol or to any of the excipients listed in section 6.1;



in acute intoxication with alcohol, hypnotics, analgesics, opioids or
psychotropic medicinal products;



in patients receiving MAO inhibitors, or who have taken them within the last
14 days (see section 4.5);



in patients with epilepsy not adequately controlled by treatment (see section
4.4);



Severe respiratory depression

Skudexa is contraindicated during pregnancy and lactation (see section 4.6).

4.4

Special warnings and precautions for use
The special warnings and precautions reported for dexketoprofen and tramadol as
single agents should be taken into account.
Dexketoprofen
Administer with caution in patients with a history of allergic conditions.
The use of dexketoprofen with concomitant other NSAIDs including cyclooxygenase2 selective inhibitors should be avoided (see section 4.5).
Undesirable effects may be minimised by using the lowest effective dose for the
shortest duration necessary to control symptoms (see section 4.2, and gastrointestinal
and cardiovascular risks below).

Gastrointestinal safety
Gastrointestinal bleeding, ulceration or perforation which can be fatal, have been
reported with all NSAIDs at anytime during treatment, with or without warning
symptoms or a previous history of serious gastrointestinal events. When
gastrointestinal bleeding or ulceration occurs in patients receiving dexketoprofen, the
treatment should be withdrawn.
The risk of gastrointestinal bleeding, ulceration or perforation is higher with
increasing NSAID doses, in patients with a history of ulcer, particularly if
complicated with haemorrhage or perforation (see section 4.3), and in older people.
As with all NSAIDs, any history of oesophagitis, gastritis and/or peptic ulcer must be
identified in order to ensure their total cure before starting treatment with
dexketoprofen. Patients with gastrointestinal symptoms or history of gastrointestinal
disease should be monitored for digestive disturbances, especially gastrointestinal
bleeding.
NSAIDs should be used with caution in patients with a history of gastrointestinal
disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated
(see section 4.8).
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 acetylsalicylic acid, or other drugs likely to increase
gastrointestinal risk (see below and section 4.5).
Patients with a history of gastrointestinal toxicity, particularly when elderly, should
report any unusual abdominal symptoms (especially gastrointestinal 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, anticoagulants
such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as
acetylsalicylic acid (see section 4.5).

Renal safety

Caution should be exercised in patients with impairment of renal functions. In these
patients, the use of NSAIDs may result in deterioration of renal function, fluid
retention and oedema. Caution is also required in patients receiving diuretic therapy
or those who could develop hypovolaemia as there is an increased risk of
nephrotoxicity.
Adequate fluid intake should be ensured during treatment to prevent dehydration and
possibly associated increased renal toxicity.
As with all NSAIDs, it can increase plasma urea nitrogen and creatinine. As with
other inhibitors of prostaglandin synthesis, it can be associated with adverse effects
on the renal system which can lead to glomerular nephritis, interstitial nephritis, renal
papillary necrosis, nephrotic syndrome and acute renal failure.

Liver safety
Caution should be exercised in patients with impairment of hepatic functions. As with
other NSAIDs, it can cause transient small increases in some liver parameters, and
also significant increases in aspartate transaminase (AST) also known as serum
glutamic oxaloacetic transaminase (SGOT) and Alanine transaminase (ALT), also
known as serum glutamic-pyruvic transaminase (SGPT). In case of a relevant
increase in such parameters, therapy must be discontinued.

Cardiovascular and cerebrovascular safety
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 NSAIDs therapy. Special caution
should be exercised in patients with a history of cardiac disease, in particular those
with previous episodes of heart failure as there is an increased risk of triggering heart
failure.
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 increase in
the risk of arterial thrombotic events (for example myocardial infarction or stroke).
There are insufficient data to exclude such a risk for dexketoprofen.
Patients with uncontrolled hypertension, congestive heart failure, established
ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease
should only be treated with dexketoprofen after careful consideration. Similar
consideration should be made before initiating long-term treatment of the patients
with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia,
diabetes mellitus, smoking).
All non-selective NSAIDs can inhibit platelet aggregation and prolong bleeding time
via inhibition of prostaglandin synthesis. Therefore, the use of dexketoprofen in
patients who are receiving other therapy that interferes with haemostasis, such as
warfarin or other coumarins or heparins is not recommended (see Section 4.5).

Skin reactions

Serious skin reactions, some of them fatal, including exfoliative dermatitis, StevensJohnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in
association with the use of NSAIDs (see section 4.8). 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. Dexketoprofen
should be discontinued at the first appearance of skin rash, mucosal lesions, or any
other sign of hypersensitivity.

Elderly
The elderly have an increased frequency of adverse reactions to NSAIDs especially
gastrointestinal bleeding and perforation which may be fatal (see section 4.2). These
patients should commence treatment on the lowest dose available.
Elderly are more likely to be suffering from impaired renal cardiovascular or hepatic
function (see section 4.2).

Other information:
Particular caution is required in patients with:
-

congenital disorder of porphyrin metabolism (e.g. acute intermittent porphyria)

-

dehydration

-

directly after major surgery.

Severe acute hypersensitivity reactions (anaphylactic shock, for example) have been
observed on very rare occasions. Treatment must be discontinued at the first signs of
severe hypersensitivity reactions following intake of dexketoprofen. Depending on
the symptoms, any medically required procedures must be initiated by specialist
healthcare professionals.
Patients with asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal
polyposis have a higher risk of allergy to acetylsalicylic acid 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 acetylsalicylic acid or
NSAIDs (see section 4.3).
Exceptionally, varicella can be at the origin of serious cutaneous and soft tissues
infectious complications. To date, the contributing role of NSAIDs in the worsening
of these infections cannot be ruled out. Thus, it is advisable to avoid use of
desketoprofen in case of varicella.
Dexketoprofen should be administered with caution to patients suffering from
haematopoietic disorders, systemic lupus erythematosus or mixed connective tissue
disease.
As other NSAIDs, dexketoprofen can mask the symptoms of infectious diseases.

Paediatric population

The safety and efficacy of Skudexa in children and adolescents have not been
established. Therefore Skudexa should not be used in children and adolescents.
Tramadol
Tramadol should be used with particular caution in addicted patients, patients with
head injury, shock, a reduced level of consciousness of uncertain origin, disorders of
the respiratory centre or function, or increased intracranial pressure.
In patients sensitive to opiates the product should be used with caution.
Care should be taken when treating patients with respiratory depression, or if
concomitant CNS depressant drugs are being administered (see section 4.5), or if the
recommended dosage is significantly exceeded (see section 4.9) as the possibility of
respiratory depression cannot be excluded in these situations.
Convulsions have been reported in patients receiving tramadol at the recommended
dose levels. The risk may be increased when doses of tramadol exceed the
recommended upper daily dose limit (400 mg).
In addition tramadol may increase the seizure risk in patients taking other medicinal
products that lower the seizure threshold (see section 4.5.). Patients with epilepsy or
those susceptible to seizures should only be treated with tramadol if there are
compelling circumstances.
With long-term use tolerance, psychic and physical addiction may develop. In
patients with a tendency to drug abuse or dependence, treatment with tramadol should
only be carried out for short periods under strict medical supervision.

4.5

Interaction with other medicinal products and other forms of interaction
No clinical studies have been performed to evaluate the potential impact of drug-drug
interactions on safety profile of Skudexa. However, those reported for dexketoprofen
and Tramadol as single agents should be taken into account.
Dexketoprofen
The following interactions apply to non-steroidal antiinflammatory drugs (NSAIDs)
in general:
Concomitant use not recommended:


Other NSAIDs (including cyclooxygenase-2 selective inhibitors) including
high doses of salicylates (≥ 3 g/day): administration of several NSAIDs
together may increase the risk of gastrointestinal ulcers and bleeding, via a
synergistic effect.



Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as
warfarin, due to the high plasma protein binding of dexketoprofen and the
inhibition of platelet function and damage to the gastroduodenal mucosa. If
the combination cannot be avoided, close clinical observation and monitoring
of laboratory values should be carried out.



Heparins: increased risk of haemorrhage (due to the inhibition of platelet
function and damage to the gastroduodenal mucosa). If the combination
cannot be avoided, close clinical observation and monitoring of laboratory
values should be carried out.



Corticosteroids: there is an increased risk of gastrointestinal ulceration or
bleeding.



Lithium (described with several NSAIDs): NSAIDs increase blood lithium
levels, which may reach toxic values (decreased renal excretion of lithium).
This parameter therefore requires monitoring during the initiation, adjustment
and withdrawal of treatment with dexketoprofen.



Methotrexate, used at high doses of 15 mg/week or more: increased
haematological toxicity of methotrexate via a decrease in its renal clearance
by antiinflammatory agents in general.



Hydantoines (including phenytoin) and sulphonamides: the toxic effects of
these substances may be increased.

Combinations requiring precautions:


Diuretics, Angiotensin-converting-enzyme (ACE) inhibitors, antibacterial
aminoglycosides and angiotensin II receptor antagonists: dexketoprofen may
reduce the effect of diuretics and antihypertensive drugs. In some patients
with compromised renal function (e. g. dehydrated patients or elderly patients
with compromised renal function), the coadministration of agents that inhibit
cyclo-oxygenase and ACE inhibitors, angiotensin II receptor antagonists or
antibacterial aminoglycosides may result in further deterioration of renal
function, which is usually reversible. In case of combined prescription of
dexketoprofen and a diuretic, it is essential to ensure that the patient is
adequately hydrated and to monitor renal function at the start of the treatment
and periodically thereafter. Co-administration of dexketoprofen and
potassium-sparing diuretics can lead to hyperkalaemia. Monitoring of blood
potassium concentrations is required (see section 4.4).



Methotrexate, used at low doses, less than 15 mg/week: increased
haematological toxicity of methotrexate via a decrease in its renal clearance
by antiinflammatory agents in general. Weekly monitoring of blood count
during the first weeks of the combination. Increased surveillance in the
presence of even mildly impaired renal function, as well as in the elderly.



Pentoxyfilline: increased risk of bleeding. Increase clinical monitoring and
check bleeding time more often.



Zidovudine: risk of increased red cell line toxicity via action on reticulocytes,
with severe anaemia occurring one week after the NSAID is started. Check
complete blood count and reticulocyte count one to two weeks after starting
treatment with the NSAID.



Sulfonylureas: NSAIDs can increase the hypoglycaemic effect of
sulfonylureas by displacement from plasma protein binding sites.

Combinations needing to be taken into account:


Beta-blockers: treatment with a NSAID may decrease their antihypertensive
effect via inhibition of prostaglandin synthesis.



Cyclosporin and tacrolimus: nephrotoxicity may be enhanced by NSAIDs via
renal prostaglandin mediated effects. During combination therapy, renal
function has to be measured.



Thrombolytics: increased risk of bleeding.



Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs):
increased risk of gastrointestinal bleeding (see section 4.4).



Probenecid: plasma concentrations of dexketoprofen may be increased; this
interaction can be due to an inhibitory mechanism at the site of renal tubular
secretion and of glucuronoconjugation and requires adjustment of the dose of
dexketoprofen.



Cardiac glycosides: NSAIDS may increase plasma glycoside concentration.



Mifepristone: Because of a theoretical risk that prostaglandin synthetase
inhibitors may alter the efficacy of mifepristone, NSAIDS should not be used
for 8-12 days after mifepristone administration.

Limited evidence suggests that co-administration of NSAIDs on the day of
prostaglandin administration does not adversely influence the effects of mifepristone
or the prostaglandin on cervical ripening or uterine contractility and does not reduce
the clinical efficacy of medical termination of pregnancy.


Quinolone antibiotics: Animal data indicate that high doses of quinolones in
combination with NSAIDS can increase the risk of developing convulsions.



Tenofovir: concomitant use with NSAID can increase plasma urea nitrogen
and creatinine, renal function should be monitored in order to control a
potential synergic influence on renal function.



Deferasirox: concomitant use with NSAIDs can increase the risk of
gastrointestinal toxicity. Close clinical monitoring is required when
deferasirox is combined with these substances.



Pemetrexed: concomitant use with NSAIDs may decrease pemetrexed
elimination, therefore caution should be made when administering higher
doses of NSAIDs. In patients with mild to moderate renal insufficiency
(creatinine clearance from 45 to 79 ml/min), the concomitant administration
of pemetrexed with NSAIDs doses should be avoided for 2 days before and 2
days following pemetrexed administration.

Tramadol
Concomitant use not recommended:


Tramadol should not be combined with Monoamine Oxidasa (MAO)
inhibitors (see section 4.3). In patients treated with MAO inhibitors in the 14
days prior to the use of the opioid pethidine, life-threatening interactions on
the central nervous system, respiratory and cardiovascular function have been
observed. The same interactions with MAO inhibitors cannot be ruled out
during treatment with tramadol.



Caution should be exercised during concomitant treatment with tramadol and
coumarin derivatives (e.g. warfarin) due to reports of elevated International
Normalized Ratio (INR) with major bleeding and ecchymoses in some
patients.



The combination of mixed agonists/antagonists opioid receptors (e.g.
buprenorphine, nalbuphine, pentazocine) and tramadol is not advisable
because the analgesic effect of a pure agonist may be theoretically reduced in
such circumstances.
Combinations requiring precautions:



Tramadol can induce convulsions and increase the potential for selective
serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake
inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other seizure
threshold-lowering medicinal product (such as bupropion, mirtazapine,
tethrahydrocannabinol) to cause convulsions.



Concomitant therapeutic use of tramadol and serotonergic drugs, such as
selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine
reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), tricyclic
antidepressants and mirtazapine may cause serotonin toxicity. Serotonin
syndrome is likely when one of the following is observed: spontaneous
clonus, inducible or ocular clonus with agitation or diaphoresis, tremor and
hyperreflexia, hypertonia and body temperature > 38˚C and inducible ocular
clonus. Withdrawal of the serotonergic drugs usually brings about a rapid
improvement. Treatment depends on the type and severity of the symptoms.

Combinations needing to be taken into account:

4.6



Concomitant administration of tramadol with other centrally depressant
medicinal products or alcohol may potentiate the central nervous system
effects (see section 4.8).



The results of pharmacokinetic studies have so far shown that on the
concomitant or previous administration of cimetidine (enzyme inhibitor)
clinically relevant interactions are unlikely to occur.



Simultaneous or previous administration of carbamazepine (enzyme inducer)
may reduce the analgesic effect and shorten the duration of action.



In a limited number of studies the pre- or postoperative administration of the
antiemetic 5-HT3 antagonist ondansetron increased the requirement of
tramadol in patients with postoperative pain.



Other active substances known to inhibit CYP3A4, such as ketoconazole and
erythromycin, might inhibit the metabolism of tramadol (N-demethylation)
probably also the metabolism of the active O-demethylated metabolite. The
clinical importance of such an interaction has not been studied.

Fertility, pregnancy and lactation
Pregnancy
No cases of pregnancy occurred during the Skudexa clinical development. The safety
profile of Skudexa during pregnancy has not been established in the clinical studies
included in this section. Data reported for dexketoprofen and tramadol as single
agents should be taken into account.

Dexketoprofen
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the
embryo/foetal development. Data from epidemiological studies raise concern about
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 pre- and 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. Nevertheless, animal studies with dexketoprofen haven’t shown reproductive
toxicity (see section 5.3).
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;

At the end of pregnancy, the mother and the neonate may be exposed to:


possible prolongation of bleeding time, an anti-platelet effect which may
occur even at very low doses;



inhibition of uterine contractions resulting in delayed or prolonged labour.

Tramadol
Animal studies with tramadol revealed at very high doses effects on organ
development, ossification and neonatal mortality. Teratogenic effects were not
observed. Tramadol crosses the placenta. There is inadequate evidence available on
the safety of tramadol in human pregnancy.
Tramadol – administered before or during birth – does not affect uterine contractility.
In neonates it may induce changes in the respiratory rate which are usually not
clinically relevant. Chronic use during pregnancy may lead to neonatal withdrawal
symptoms.
Considering the above Skudexa is contraindicated in pregnancy (see section 4.3).
Breastfeeding
No controlled trials have been conducted to study the excretion of Skudexa in human
milk. Data reported for dexketoprofen and tramadol as single agents should be taken
into account.
Dexketoprofen

It is not known whether dexketoprofen is excreted in human milk.
Tramadol
Tramadol and its metabolites are found in small amounts in human breast milk.
An infant could ingest about 0.1% of the dose given to the mother. Tramadol should
not be ingested during breast feeding.
Considering the above Skudexa is contraindicated during breastfeeding (see section
4.3).
Fertility
As with other NSAIDs, the use of dexketoprofen may impair female fertility and is
not recommended in women attempting to conceive. In women who have difficulties
conceiving or who are undergoing investigation of infertility, withdrawal of
dexketoprofen should be considered.

4.7

Effects on ability to drive and use machines
The effects known for the single components of Skudexa apply to the fixed
combination.
Dexketoprofen
Dexketoprofen has minor or moderate influence on the ability to drive and use
machines, due to possible occurrence of dizziness or somnolence.
Tramadol
Even when taken according to instructions, tramadol may cause effects such as
somnolence and dizziness and therefore may impair the reactions of drivers and
machine operators.
This applies particularly in conjunction with other psychotropic substances and
alcohol.

4.8

Undesirable effects
The adverse events at least possibly related reported in the clinical trials performed
with Skudexa and the adverse reactions reported in dexketoprofen and tramadol
tablets SmPCs are tabulated below, classified by system organ class.
The frequencies are defined as follows:
Very common: ≥ 1/10
Common: ≥ 1/100 to <1/10

Uncommon: ≥1/1000 to <1/100
Rare: ≥ 1/10 000 to <1/1000
Very rare (< 1/10,000)
Not known: cannot be estimated from the available data

MedDRA
SYSTEM
ORGAN CLASS

Adverse Reaction

Blood and
lymphatic
system disorders

Thrombocytosis

Uncommon

Neutropenia,

-

Very rare

-

Thrombocytopenia

-

Very rare

-

Hypersensitivity
(e.g. dyspnoea,
bronchospasm,
wheezing,
Angioedema)

-

Very rare

Rare

Anaphylactic
reaction, including
anaphylactic shock

-

Very rare

Rare

Laryngeal oedema

Uncommon

Rare

-

Immune system
disorders

Metabolism and
nutrition
disorders

Frequency
Skudexa

Dexketoprofen

Appetite disorder

Decreased appetite

Rare

-

Rare

Hypoglycaemia
Hypokalaemia
Psychiatric
disorders

-

not known
Uncommon

Anxiety

Uncommon

Rare

Cognitive disorder

Rare

Confusional state

Rare

Dependence

Rare

Hallucination

Rare

Insomnia

Uncommon

Mood altered

Rare

Nightmare

Rare

Psychotic disorder

Nervous system
disorders

Tramadol

Uncommon

Sleep disorder

Rare

Coordination
abnormal

Rare

MedDRA
SYSTEM
ORGAN CLASS

Adverse Reaction

Frequency
Skudexa

Dizziness

Common

Dexketoprofen
Uncommon

Epilepsy
Headache

Uncommon

Uncommon

Rare

Sensory
disturbance
Uncommon

Uncommon

Rare

Tremor

Rare
Rare

Blurred vision

Very rare

Rare

Mydriasis

Not known

Miosis

Rare

Periorbital oedema
Ear and
labyrinth
disorders

Tinnitus

Cardiac
disorders

Bradycardia

Vertigo

Uncommon
Very rare
Uncommon

Uncommon
Rare

Palpitations
Tachycardia

Uncommon

Uncommon

Uncommon

Very rare

Uncommon

Circulatory
collapse

Uncommon

Flushing

Uncommon

Hypertensive crisis

Uncommon

Hypotension

Uncommon

Very rare

Orthostatic
hypotension

Gastrointestinal
disorders

Common
Not known

Syncope

Respiratory,
thoracic and
mediastinal
disorders

Rare
Rare

Speech disorder

Vascular
disorders

Common
Rare

Paraesthesia

Eye disorders

Very common
Rare

Muscle
contractions
involuntary

Somnolence

Tramadol

Uncommon

Bradypnoea,

Rare

Bronchospasm

Very rare

Dyspnoea

Very rare

Rare

Respiratory
depression

Uncommon

Abdominal
discomfort

Uncommon

MedDRA
SYSTEM
ORGAN CLASS

Adverse Reaction

Frequency
Skudexa

Abdominal
distension

Uncommon

Abdominal pain
Constipation

Dexketoprofen

Uncommon
Common
Uncommon

Common

Diarrhoea

Common

Uncommon

Dry mouth

Uncommon

Common

Dyspepsia

Uncommon

Uncommon

Common

Flatulence

Uncommon

Gastritis

Uncommon

Gastrointestinal
tract irritation

Uncommon

Nausea

Common

Common

Pancreatitis

Very rare

Peptic ulcer
haemorrhage

Rare

Peptic ulcer
perforation

Rare

Peptic ulcer,

Rare

Retching
Vomiting
Hepatobiliary
disorders

Very common

Uncommon
Common

Common

Hepatitis

Rare

Hepatocellular
injury

Rare

Hepatic enzyme
increased including
Liver function test
abnormal and
Gamma-glutamyl
transferase
increased)
Skin and
subcutaneous
tissue disorders

Tramadol

Uncommon

Acne

Rare

Common

Very rare

Rare

Face oedema

Uncommon

Very rare

Hyperhidrosis

Uncommon

Rare

Common

Photosensitivity
reaction

Very rare

Pruritus

Very rare

Uncommon

Rash

Uncommon

Uncommon

Stevens Johnson

Very rare

MedDRA
SYSTEM
ORGAN CLASS

Adverse Reaction

Frequency
Skudexa

Dexketoprofen

Tramadol

syndrome
Toxic epidermal
necrolysis (Lyell's
syndrome)
Urticaria

Very rare

Uncommon

Rare

Uncommon

Musculoskeletal
and connective
tissue disorders

Back pain
Weakness

Rare

Renal and
urinary
disorders

Dysuria

Rare

Haematuria

Rare

Uncommon

Micturition
disorder

Rare

Nephritis

Very rare

Nephrotic
syndrome

Very rare

Polyuria

Rare

Renal failure acute

Rare

Urinary retention

Rare

Reproductive
system and
breast disorders

Menstrual disorder

Rare

Prostatic disorder

Rare

General
disorders and
administration
site conditions

Asthenia

Uncommon

Uncommon

Chills

Uncommon

Uncommon

Discomfort

Uncommon

Feeling abnormal

Uncommon

Drug withdrawal
syndrome
(agitation, anxiety,
nervousness,
insomnia,
hyperkinesia,
tremor and
gastrointestinal
symptoms: rare;
panic attacks,
severe anxiety,
hallucinations,
paraesthesias,
tinnitus, and
unusual CNS
symptoms i.e.
confusion,

Rare/very rare

MedDRA
SYSTEM
ORGAN CLASS

Adverse Reaction

Frequency
Skudexa

Dexketoprofen

Tramadol

delusions,
depersonalisation,
derealisation,
paranoia)

Investigations

Fatigue

Uncommon

Malaise

Uncommon

Oedema peripheral

Rare

Pain

Uncommon

Blood pressure
increased

Uncommon

Blood alkaline
phosphatase
increased

Uncommon

Blood lactate
dehydrogenase
increased

Uncommon

Rare

Common

Rare

Dexketoprofen-tramadol
In clinical studies the most commonly observed adverse reactions were vomiting,
nausea and dizziness (2.9%, 2.7% and 1.1% of patients, respectively).
Dexketoprofen
Gastrointestinal: The most commonly-observed adverse events are gastrointestinal in
nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal,
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
Special warnings and precautions for use) have been reported following
administration. Less frequently, gastritis has been observed. Oedema, hypertension
and cardiac failure have been reported in association with NSAIDs treatment.
As with other NSAIDs the following undesirable effects may appear aseptic
meningitis, which might predominantly occur in patients with systemic lupus
erythematosus or mixed connective tissue disease; haematological reactions (purpura,
aplastic and haemolytic anaemia, and rarely agranulocytosis and medullar
hypoplasia).
Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal
Necrolysis (very rare).
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 increase in
the risk of arterial thrombotic events (for example myocardial infarction or stroke)
(see section 4.4).

Tramadol
The most commonly reported adverse reactions due to tramadol are nausea and
dizziness, both occurring in more than 10% of patients.
If the recommended doses are considerably exceeded and other centrally depressant
substances are administered concomitantly (see section 4.5) respiratory depression
may occur.
Worsening of asthma has been reported, though a causal relationship has not been
established.
Epileptiform convulsions occurred mainly after administration of high doses of
tramadol or after concomitant treatment with drugs, which can lower the seizure
threshold or themselves induce cerebral convulsions (see section 4.4 and section 4.5).
Symptoms of withdrawal reactions, similar to those occurring during opiate
withdrawal, may occur as follows; agitation, anxiety, nervousness, insomnia,
hyperkinesia, tremor and gastrointestinal symptoms.
Other symptoms that have very rarely been seen with tramadol discontinuation
include: panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus, and
unusual CNS symptoms (i.e. confusion, delusions, depersonalisation, derealisation,
paranoia).
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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

4.9

Overdose
No cases of overdose have been reported in the clinical studies. Data reported for
dexketoprofen and tramadol as single agents should be taken into account.
Symptoms
Dexketoprofen
The symptomatology following overdose due to dexketoprofen is not known.
Medicinal products containing dexketoprofen have produced gastrointestinal
(vomiting, anorexia, abdominal pain) and neurological (somnolence, vertigo,
disorientation, headache) disorders.
Tramadol

In tramadol overdose, in principle, the same symptoms occur as for all other central
acting analgesics (opioids). In particular, these include miosis, vomiting,
cardiovascular collapse, consciousness disorders up to coma, convulsions and
respiratory depression up to respiratory arrest.
Management
Dexketoprofen
In case of accidental or excessive intake, immediately initiate symptomatic therapy
according to the patient’s clinical condition.
If more than 5 mg/kg has been ingested by an adult or a child, activated charcoal
should be administered within the first hour after ingestion. Dexketoprofen may be
removed by dialysis.
Tramadol
Keep the respiratory tract open (and avoid aspiration), maintain respiration and
circulation depending on the symptoms. The antidote for respiratory depression is
naloxone. In animal experiments naloxone had no effect on convulsions. In such case
diazepam should be given intravenously.
In case of orally intoxication, gastrointestinal decontamination with activated
charcoal is recommended within two hours after tramadol intake.
Tramadol may be removed by dialysis, but it is minimally eliminated from the serum
by haemodialysis or haemofiltration. Therefore treatment of acute intoxication with
tramadol with haemodialysis or haemofiltration alone is not suitable for
detoxification.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Opioids in combination with non-opioid analgesics
ATC code: N02AJ14
Mechanism of action
Dexketoprofen is the tromethamine salt of S-(+)-2-(3-benzoylphenyl)propionic acid,
an analgesic, anti-inflammatory and antipyretic drug, which belongs to the nonsteroidal anti-inflammatory group of drugs (M01AE).
The mechanism of action of non-steroidal antiinflammatory drugs is related to the
reduction of prostaglandin synthesis by the inhibition of cyclooxygenase pathway.
Specifically, there is an inhibition of the transformation of arachidonic acid into
cyclic endoperoxides, PGG2 and PGH2, which produce prostaglandins PGE1, PGE2,
PGF2α and PGD2 and also prostacyclin PGI2 and thromboxanes (TxA2 and TxB2).

Furthermore, the inhibition of the synthesis of prostaglandins could affect other
inflammation mediators such as kinins, causing an indirect action which would be
additional to the direct action.
Dexketoprofen has been demonstrated to be an inhibitor for COX-1 and COX-2
activities in experimental animals and humans.
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic. It is a nonselective, partial agonist of μ-, δ- and κ-opioid receptors with a higher affinity for μreceptors. Opioid activity is due to both low affinity binding of the parent compound
and higher affinity binding of the O-demethylated metabolite M1 to µ-opioid
receptors. In animal models, M1 is up to 6 times more potent than tramadol in
producing analgesia and 200 times more potent in µ-opioid binding. Tramadolinduced analgesia is only partially antagonized by the opiate antagonist naloxone in
several animal tests. The relative contribution of both tramadol and M1 to human
analgesia is dependent upon the plasma concentrations of each compound.
Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in
vitro, as have some other opioid analgesics. These mechanisms may contribute
independently to the overall analgesic profile of tramadol.
Tramadol has an antitussive action. In contrast to morphine, analgesic doses of
tramadol over a wide range have no respiratory depressant effect. Also
gastrointestinal motility is less affected. Effects on the cardiovascular system tend to
be slight. The potency of tramadol is reported to be 1/10 (one tenth) to 1/6 (one sixth)
that of morphine
Pharmacodynamic effects
Preclinical studies have shown a synergistic interaction between the active ingredients
observed during both acute and chronic inflammation models and suggest that lower
doses of each active ingredient allow to obtain effective analgesia.
Clinical efficacy and safety
Clinical studies performed on several models of moderate to severe nociceptive pain
(including dental pain, somatic pain and visceral pain) demonstrated effective
analgesic activity of Skudexa.
In a multiple-dose, double-blind, randomised, parallel group study in 606 patients
with moderate to severe pain after abdominal hysterectomy, mean age 47.6 (range 25
to 73), the analgesic efficacy of the combination versus the individual components
was assessed by means of the sum of pain intensity difference values over the interval
of 8 hours (SPID8) after the first dose of study medication, with pain intensity been
assessed on a 100mm visual analogue scale (VAS). Higher value of SPID indicates
greater pain relief. The treatment with Skudexa resulted in an analgesic effect
significantly greater than those of the individual components given at the same dose
(dexketoprofen 25 mg) or at a higher dose (tramadol 100mg), being the results as
follows: Skudexa (241.8), dexketoprofen 25 mg (184.5), tramadol 100 mg (157.3).
Over the first 8 hours following Skudexa, patients reported a significantly lower Pain
Intensity (mean PI-VAS= 33.6) with a statistically significant (p< 0.0001) difference
over dexketoprofen 25 mg (mean PI-VAS= 42.6) and tramadol 100 mg (mean PIVAS= 42.9). Superior analgesia was also demonstrated over 56 hours following
repeated doses administered according to the posology scheme in an ITT population
in which patients, who did not receive active treatment as first single dose were

excluded, with statistically significant (p< 0.0001) difference between Skudexa and
dexketoprofen 25 mg (-8.4) and tramadol 100 mg (-5.5).
Patients treated with Skudexa were in need of less rescue medication to control pain
(11.8% of patients in comparison with 21.3% (p= 0.0104) and 21.4% (p= 0.0097)
under dexketoprofen 25 mg and tramadol 100 mg, respectively). When the impact of
rescue medication use is taken into account, the superior analgesic effect of Skudexa
in the repeat use over 56 hours becomes more evident, reaching a difference in PIVAS favouring Skudexa over dexketoprofen (-11.0) and tramadol (-9.1) with a
statistical significance of p= <0.0001.
In a multiple-dose, double-blind, randomised, parallel group study in 641 patients
with moderate to severe pain after total hip arthroplasty, mean age 61.9 (range 29 to
80), the analgesic efficacy of the combination versus the individual components was
assessed over 8 hours after the first dose of study medication (SPID8). The treatment
with Skudexa resulted in an analgesic effect significantly greater than those of the
individual components given at the same dose (dexketoprofen 25mg) or at a higher
dose (tramadol 100mg); Skudexa (246.9), dexketoprofen 25 mg (208.8), tramadol 100
mg (204.6). Over the first 8 hours following Skudexa, patients reported a
significantly lower Pain Intensity (mean PI-VAS= 26.3) with a statistically significant
(p< 0.0001) difference over dexketoprofen 25 mg (mean PI-VAS= 33.6) and tramadol
100 mg (mean PI-VAS= 33.7).
Superior analgesia was also demonstrated over 56 hours following repeated doses
administered according to the posology scheme in an ITT population in which
patients who did not receive active treatment as first single dose were excluded, with
statistically significant (p< 0.0001) difference between Skudexa and dexketoprofen
25 mg (-8.1) and tramadol 100 mg (-6.3), respectively.
Rescue medication to control pain was required by 15.5% of patients under Skudexa,
in comparison with 28.0% (p= 0.0017) and 25.2% (p=0.0125) under dexketoprofen
25 mg and tramadol 100 mg, respectively. When the impact of rescue medication use
is taken into account, the superior analgesic effect of Skudexa in the repeat use over
56 hours becomes more evident, reaching a statistical (p= <0.0001) difference in PIVAS favouring Skudexa over dexketoprofen (-10.4) and tramadol (-8.3).
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of
studies with Skudexa in all subsets of the paediatric population in the treatment of
moderate to severe acute pain (see section 4.2 for information on paediatric use).

5.2

Pharmacokinetic properties
Concomitant administration of dexketoprofen and tramadol had no effects on the
pharmacokinetic parameters of either component in healthy subjects.
In normal healthy adults, peak plasma concentrations of dexketoprofen and tramadol
are reached in about 30 min (range 15 to 60 min) and 1.6 to 2 hours, respectively.
Dexketoprofen

Absorption
After oral administration of dexketoprofen to humans, the Cmax is reached at 30 min
(range 15 to 60 min).
When administered concomitantly with food, the AUC does not change, however the
Cmax of dexketoprofen decreases and its absorption rate is delayed (increased tmax).
Distribution
The distribution half-life and elimination half-life values of dexketoprofen are 0.35
and 1.65 hours, respectively. As with other drugs with a high plasma protein binding
(99%), its volume of distribution has a mean value below 0.25 l/kg.
In multiple-dose pharmacokinetic studies, it was observed that the AUC after the last
administration is not different from that obtained following a single dose, indicating
that no drug accumulation occurs.
Biotransformation and Elimination
After administration of dexketoprofen only the S-(+) enantiomer is obtained in urine,
demonstrating that no conversion to the R-(-) enantiomer occurs in humans.
The main elimination route for dexketoprofen is glucuronide conjugation followed by
renal excretion.
Tramadol
Absorption
More than 90% of tramadol is absorbed after oral administration. The mean absolute
bioavailability is approximately 70%, irrespective of concomitant intake of food.
The difference between absorbed and non-metabolised available tramadol is probably
due to low first-pass effect. The first-pass effect after oral administration is a
maximum of 30%.
Tramadol has a high tissue affinity (Vd,β=203±40l). Protein binding is about 20%.
Following a single oral dose administration of tramadol 100 mg as capsules or tablets
to young healthy volunteers, plasma concentrations were detectable within
approximately 15 to 45 minutes within a mean Cmax of 280 to 208 mcg/L and Tmax of
1.6 to 2h.
Distribution
Tramadol passes the blood-brain and placenta barrier. Very small amounts of the
substance and its O-desmethyl derivative are found in the breast milk (0.1 % and 0.02
% respectively of the applied dose).
Biotransformation

In humans tramadol is mainly metabolised by means of N- and O-demethylation and
conjugation of the O-demethylation products with glucuronic acid. Only Odesmethyltramadol is pharmacologically active. There are considerable
interindividual quantitative differences between the other metabolites. So far, eleven
metabolites have been found in the urine. Animal experiments have shown that Odesmethyltramadol is more potent than the parent substance by the factor 2 – 4. Its
half life t½β (6 healthy volunteers) is 7.9 h (range 5.4–9.6 h) and is approximately that
of tramadol.
The inhibition of one or both cytochrome P450 isoenzymes, CYP3A4 and CYP2D6
involved in the metabolism of tramadol, may affect the plasma concentration of
tramadol or its active metabolite. Up to now, clinically relevant interactions have not
been reported.
Elimination
Elimination half-life t½β is approximately 6 h, irrespective of the mode of
administration. In patients above 75 years of age it may be prolonged by a factor of
approximately 1.4.
Tramadol and its metabolites are almost completely excreted via the kidneys.
Cumulative urinary excretion is 90 % of the total radioactivity of the administered
dose. In cases of impaired hepatic and renal function the half-life may be slightly
prolonged. In patients with cirrhosis of the liver, elimination half-lives of 13.3 ± 4.9 h
(tramadol) and 18.5 ± 9.4 h (O-desmethyltramadol), in an extreme case 22.3 h and 36
h respectively have been determined. In patients with renal insufficiency (creatinine
clearance < 5 ml / min) the values were 11 ± 3.2 h and 16.9 ± 3 h, in an extreme case
19.5 h and 43.2 h, respectively.
Linearity/non-linearity
Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.
The relationship between serum concentrations and the analgesic effect is dosedependent, but varies considerably in isolated cases. A serum concentration of 100 –
300 ng/ml is usually effective.

5.3

Preclinical safety data
Tramadol hydrochloride-dexketoprofen Combination
Preclinical data with the combination revealed no special hazard for humans based on
conventional studies of safety pharmacology and repeated dose toxicity.
The combination of dexketoprofen and tramadol had not significant effect on
cardiovascular system as assessed by both in vitro and in vivo tests. Less effect on
gastrointestinal transit were observed with the combination as compared to tramadol
alone.
A 13-week chronic toxicity study in rats, gave No Observed Adverse Effect Levels
(NOAELs) of 6 mg/kg/day for dexketoprofen and 36 mg/kg/day for tramadol (highest
tested doses), when administered both singularly or in combination (corresponding to
AUC-based exposures at the NOAEL after single doses of 25.10 times and 1.38 times
the human exposure to dexketoprofen and tramadol, respectively, at a single clinical
dose of 25 mg dexketoprofen and 75 mg tramadol).

No new toxicities, different from those previously described for dexketoprofen or
tramadol were observed.
Dexketoprofen
Preclinical data on dexketoprofen revealed no special hazard for humans based on
conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity,
toxicity to reproduction and immunopharmacology. The chronic toxicity studies
carried out in mice and monkeys gave a No Observed Adverse Effect Level
(NOAEL) of 3 mg/kg/day. The main adverse effect observed at high doses was
gastrointestinal erosions and ulcers that developed dose-dependently.
The active substance dexketoprofen trometamol shows an environmental risk for
algae.
Tramadol
In repeated oral and parenteral administration of tramadol during 6 to 26 weeks to rats
and dogs and oral administration for 12 months in dogs haematological, clinicochemical and histological investigations showed no evidence of any substance-related
changes. Central nervous manifestations only occurred after high doses considerably
above the therapeutic range: restlessness, salivation, convulsions, and reduced weight
gain. Rats and dogs tolerated oral doses of 20 mg/kg and 10 mg/kg body weight
respectively, and dogs rectal doses of 20 mg/kg body weight without any reactions.
In rats tramadol dosages from 50 mg/kg/day upwards caused toxic effects in dams
and raised neonate mortality. In the offspring retardation occurred in the form of
ossification disorders and delayed vaginal and eye opening. Male fertility was not
affected. After higher doses (from 50 mg/kg/day upwards) females exhibited a
reduced pregnancy rate. In rabbits there were toxic effects in dams from 125 mg/kg
upwards and skeletal anomalies in the offspring.
In some in-vitro test systems there was evidence of mutagenic effects. In-vivo studies
showed no such effects.
According to knowledge gained so far, tramadol can be classified as non-mutagenic.
Studies on the tumorigenic potential of tramadol hydrochloride have been carried out
in rats and mice. The study in rats showed no evidence of any substance-related
increase in the incidence of tumours. In the study in mice there was an increased
incidence of liver cell adenomas in male animals (a dose-dependent, non-significant
increase from 15 mg/kg upwards) and an increase in pulmonary tumours in females
of all dosage groups (significant, but not dose-dependent).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet Core:


Microcrystalline cellulose;



Maize Starch, pregelatinised;



Croscarmellose sodium;



Sodium stearyl fumarate;



Silica colloidal, anhydrous.

Film-coating:

6.2



Polyvinyl alcohol;



Titanium dioxide;



Macrogol/PEG 3350;



Talc.

Incompatibilities
Not applicable.

6.3

Shelf life
30 months if the product is packed in PA/Aluminium/PVC //Aluminium and
PVC/PVDC//Aluminium blister;
24 months if the product is packed in PVC/PE/PVDC//Aluminium blister.

6.4

Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Store in the original package in order to protect from light.

6.5

Nature and contents of container
Tablets are provided in blister packs, in three alternative materials:
PA/Aluminium/PVC //Aluminium blister;
PVC/PE/PVDC//Aluminium blister;
PVC/PVDC//Aluminium blister
Skudexa tablets: 2, 4, 10, 15, 20, 30, 50, 100 film-coated tablets/pack or multipacks
containing 500 (5 packs of 100) film-coated tablets/pack.

6.6

Special precautions for disposal
No special requirements.

Any unused product or waste material should be disposed of in accordance with local
requirements.

7

MARKETING AUTHORISATION HOLDER
Menarini International Operations Luxembourg S.A.
1, Avenue de la Gare
L-1611 Luxembourg
Luxembourg

8

MARKETING AUTHORISATION NUMBER(S)
PL 16239/0041

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
02/02/2016

10

DATE OF REVISION OF THE TEXT
04/09/2016

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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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