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TRAMADOL HYDROCHLORIDE/PARACETAMOL 37.5MG/325 MG FILM-COATED TABLETS

Active substance(s): TRAMADOL HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Tramadol hydrochloride /Paracetamol 37.5mg/325 mg Film-coated Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains Tramadol Hydrochloride 37.5 mg and Paracetamol
325 mg.
For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Film-coated Tablet
(tablet)
Light yellow, capsule shaped, biconvex, film-coated tablets embossed with ‘C8’ on
one side and plain on other side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Tramadol hydrochloride/Paracetamol tablets are indicated for symptomatic treatment
of moderate to severe pain.
The use of Tramadol hydrochloride/Paracetamol tablets should be restricted to
patients whose moderate to severe pain is considered to require a combination of
Tramadol and Paracetamol (see section 5.1)

4.2
Posology and method of administration
Posology

The use of Tramadol hydrochloride/Paracetamol tablets should be restricted to
patients whose moderate to severe pain is considered to require a combination of
Tramadol and Paracetamol.
The dose should be individually adjusted according to intensity of pain and sensitivity
of the individual patient. The lowest effective dose for analgesia should generally be
selected. The total dose of 8 tablets (equivalent to 300 mg tramadol hydrochloride and
2600 mg paracetamol) per day should not be exceeded. The dosing interval should not
be less than six hours.
Adults and adolescents (12 years and older):
An initial dose of two tablets of Tramadol hydrochloride/Paracetamol tablets is
recommended. Additional doses can be taken as needed, not exceeding 8 tablets
(equivalent to 300 mg of Tramadol and 2600mg Paracetamol) per day.
The dosing interval should not be less than six hours.
Tramadol hydrochloride/Paracetamol tablets should under no circumstances be
administered for longer than is strictly necessary (see section 4.4). If repeated use or
long term treatment with Tramadol hydrochloride/Paracetamol tablets is required as a
result of the nature and severity of the illness, then careful, regular monitoring should
take place (with breaks in the treatment, where possible), to assess whether
continuation of the treatment is necessary.
Paediatric population
The effective and safe use of Tramadol hydrochloride/Paracetamol tablets has not
been established in children below the age of 12 years. Treatment is therefore not
recommended in this population.
Elderly A dose adjustment is not usually necessary in patients up to 75 years without
clinically manifest hepatic or renal insufficiency. In older people over 75 years
elimination may be prolonged. Therefore, if necessary the dosage interval is to be
extended according to the patient's requirements.
Renal impairment / dialysis
In patients with renal insufficiency the elimination of tramadol is delayed. In these
patients prolongation of the dosage intervals should be carefully considered according
to the patient's requirements.
Hepatic impairment
In patients with hepatic impairment the elimination of tramadol is delayed. In these
patients prolongation of the dosage intervals should be carefully considered according
to the patient's requirements (see section 4.4). Because of the presence of paracetamol
Tramadol hydrochloride/Paracetamol should not be used in patients with severe
hepatic impairment (see Section 4.3).
Method of administration:
For oral use only.
Tablets must be swallowed whole, with a sufficient quantity of liquid. They must not
be broken or chewed.
4.3

Contraindications


Hypersensitivity to tramadol, paracetamol or to any of the excipients listed in
section 6.1



Acute intoxication with alcohol, hypnotic drugs, centrally-acting analgesics,
opioids or psychotropic drugs



Tramadol/Paracetamol tablets should not be administered to patients who are
receiving monoamine oxidase inhibitors or within two weeks of their
withdrawal (see section 4.5)



Severe hepatic impairment



Epilepsy not controlled by treatment (see section4.4.).

4.4
Special warnings and precautions for use
Warnings:
• In adults and adolescents 12 years and older, the maximum dose of 8
tablets of Tramadol hydrochloride/Paracetamol tablets should not be
exceeded. In order to avoid inadvertent overdose, patients should be
advised not to exceed the recommended dose and not to use any other
paracetamol (including over the counter) or tramadol containing products
concurrently without the advice of a physician.
• In severe renal insufficiency (creatinine clearance <10 ml/mm),
Tramadol hydrochloride/Paracetamol tablets is not recommended.
• In patients with severe hepatic impairment, Tramadol
hydrochloride/Paracetamol tablets should not be used (See section 4.3).
The hazards of paracetamol overdose are greater in patients with noncirrhotic alcoholic liver disease. In moderate cases prolongation of
dosage interval should be carefully considered.
• In severe respiratory insufficiency, Tramadol hydrochloride/Paracetamol
tablet is not recommended.
• Tramadol is not suitable as a substitute in opioid-dependent patients.
Although it is an opioid agonist, tramadol cannot suppress morphine
withdrawal symptoms.
• Convulsions have been reported in tramadol-treated patients susceptible
to seizures or taking other medications that lower the seizure threshold,
especially selective serotonin re-uptake inhibitors, tricyclic
antidepressants, antipsychotics, centrally acting analgesics or local
anaesthesia. Epileptic patients controlled by a treatment or patients
susceptible to seizures should be treated with Tramadol/ Paracetamol
tablets only if there are compelling circumstances. 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 dose limit.
• Concomitant use of opioid agonists-antagonists (nalbuphine,
buprenorphine, pentazocine) is not recommended (see section 4.5).
Precautions for use
Tolerance and physical and/or psychological dependence may develop, even at
therapeutic doses. The clinical need for analgesic treatment should be reviewed
regularly (see 4.2). In opioid-dependent patients and patients with a history of drug
abuse or dependence, treatment should only be for short period and under medical
supervision. Tramadol hydrochloride/Paracetamol tablets should be used with caution
in patients with cranial trauma, in patients prone to convulsive disorder, biliary tract

disorders, in a state of shock, in an altered state of consciousness for unknown
reasons, with problems affecting the respiratory center or the respiratory function, or
with an increased intracranial pressure.
Paracetamol in over dosage may cause hepatic toxicity in some patients.
Symptoms of withdrawal reactions, similar to those occurring during opiate
withdrawal, may occur even at therapeutic doses and for short term treatment (see
section 4.8). Withdrawal symptoms may be avoided by tapering it at the time of
discontinuation especially after long treatment periods. Rarely, cases of dependence
and abuse have been reported (see section 4.8).
In one study, use of tramadol during general anaesthesia with enflurane and nitrous oxide was
reported to enhance intra-operative recall. Until further information is available, use of
tramadol during light planes of anaesthesia should be avoided.

4.5
Interaction with other medicinal products and other forms of interaction
Concomitant use is contraindicated with:
• Non-selective MAO Inhibitors
Risk of serotonergic syndrome: diarrhoea, tachycardia, sweating, trembling,
confusion, even coma.
• Selective-A MAO Inhibitors
Extrapolation from non-selective MAO inhibitors
Risk of serotonergic syndrome: diarrhoea, tachycardia, sweating, trembling,
confusion, even coma.
• Selective-B MAO Inhibitors
Central excitation symptoms evocative of a serotonergic syndrome: diarrhoea,
tachycardia, sweating, trembling, confusion, even coma.
In case of recent treatment with MAO inhibitors, a delay of two weeks should occur
before treatment with tramadol
Concomitant use is not recommended with:
• Alcohol
Alcohol increases the sedative effect of opioid analgesics.
The effect on alertness can make driving of vehicles and the use of machines
dangerous.
Avoid intake of alcoholic drinks and of medicinal products containing alcohol.
• Carbamazepine and other enzyme inducers
Risk of reduced efficacy and shorter duration due to decreased plasma concentrations
of tramadol.
• Opioid agonists-antagonists (buprenorphine, nalbuphine, pentazocine)
Decrease of the analgesic effect by competitive blocking effect at the receptors, with
the risk of occurrence of withdrawal syndrome.
Concomitant use which needs to be taken into consideration:
• Tramadol can induce convulsions and increase the potential for selective
serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake
inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and seizure
threshold-lowering medicinal products (such as bupropion, mirtazapine,
tetrahydrocannabinol) to cause convulsions.
• Concomitant therapeutic use of tramadol and serotonergic drugs such as
selective serotonin re-uptake inhibitors (SSRIs) serotonin-norepinephrine

reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.2), tricyclic
antidepressants and mirtazapine may cause serotonin toxicity.
• Serotonin Syndrome is likely when one of the following is observed:
o Spontaneous clonus
o Inducible or ocular clonus with agitation or diaphoresis ,
o Tremor and hyperreflexia
o Hypertonia and body temperature > 38°C and inducible or ocular
clonus.
• Withdrawal of the serotonergic drugs usually brings about a rapid
improvement. Treatment depends on the type and severity of the
symptoms.
• Other opioid derivatives (including antitussive drugs and substitutive
treatments), benzodiazepines and barbiturates
Increased risk of respiratory depression which can be fatal in cases of overdose.
• Other central nervous system depressants, such as other opioid
derivatives (including antitussive drugs and substitutive treatments),
barbiturates, benzodiazepines, other anxiolytics, hypnotics, sedative
antidepressants, sedative antihistamines, neuroleptics, centrally-acting
antihypertensive drugs, thalidomide and baclofen.
These drugs can cause increased central depression. The effect on alertness can make
driving of vehicles and the use of machines dangerous.
• As medically appropriate, periodic evaluation of prothrombin time
should be performed when Tramadol/Paracetamol tablets and warfarin
like compounds are administered concurrently due to reports of
increased INR.
• In a limited number of studies the pre- or postoperative application of the
antiemetic 5-HT3 antagonist ondansetron increased the requirement of
tramadol in patients with postoperative pain.

4.6

Fertility, pregnancy and lactation
Pregnancy
Since Tramadol hydrochloride/Paracetamol tablet is a fixed combination of active
ingredients including tramadol, it should not be used during pregnancy.


Data regarding paracetamol:

Epidemiological studies in human pregnancy have shown no ill effects due to
paracetamol used in the recommended dosages.


Data regarding tramadol:

Tramadol should not be used during pregnancy as there is inadequate evidence
available to assess the safety of tramadol in pregnant women. 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. Long-term
treatment during pregnancy may lead to withdrawal symptoms in the newborn after
birth, as a consequence of habituation.
Breast-feeding

Since Tramadol hydrochloride/Paracetamol tablet is a fixed combination of active
ingredients including tramadol, it should not be ingested during breast feeding.


Data regarding paracetamol:

Paracetamol is excreted in breast milk but not in a clinically significant amount.
Available published data do not contraindicate breast feeding by women using single
ingredient medicinal products containing only paracetamol.


Data regarding tramadol:

Approximately 0.1% of the maternal dose of tramadol is excreted in breast milk. In
the immediate post-partum period, for maternal oral daily dosage up to 400 mg, this
corresponds to a mean amount of tramadol ingested by breast-fed infants of 3% of the
maternal weight-adjusted dosage. For this reason tramadol should not be used during
lactation or alternatively, breast-feeding should be discontinued during treatment with
tramadol. Discontinuation of breast-feeding is generally not necessary following a
single dose of tramadol.
Fertility
Post marketing surveillance does not suggest an effect of tramadol on fertility.
Animal studies did not show an effect of tramadol on fertility. No study on fertility
was accomplished with the combination of tramadol and paracetamol.

4.7

Effects on ability to drive and use machines
Tramadol may cause drowsiness or dizziness, which may be enhanced by alcohol or
other CNS depressants. If affected, the patient should not drive or operate
machinery.
This medicine can impair cognitive function and can affect a patient’s ability
to drive safely. This class of medicine is in the list of drugs included in
regulations under 5a of the Road Traffic Act 1988. When prescribing this
medicine, patients should be told:
• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
• However, you would not be committing an offence (called ‘statutory
defence’) if:
o The medicine has been prescribed to treat a medical or dental problem
and
o You have taken it according to the instructions given by the prescriber
and in the information provided with the medicine and
o It was not affecting your ability to drive safely
The most commonly reported undesirable effects during the clinical trials performed

4.8

Undesirable effects
The most commonly reported undesirable effects during the clinical trials performed
with the paracetamol/tramadol hydrochloride combination were nausea, dizziness and
somnolence, observed in more than 10 % of the patients.
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
Unknown: Frequency cannot be estimated from the available data
Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
Cardiac disorders:
• Uncommon: palpitations, tachycardia, arrythmia.
Eye disorders:
• Rare: vision blurred, miosis, mydriasis
Ear and labyrinth disorders:
• Uncommon: tinnitus
Gastro-intestinal disorders:
• Very common: nausea
• Common: vomiting, constipation, dry mouth, diarrhoea abdominal pain, dyspepsia,
flatulence
• Uncommon: dysphagia, melaena
General disorders and administration site conditions:
• Uncommon: chills, chest pain
Investigations:
• Uncommon: transaminases increased
Metabolism and nutrition disorders:
• Unknown: hypoglycaemia
Nervous system disorders:
• Very common: dizziness, somnolence
• Common: headache trembling
• Uncommon: involuntary muscular contractions, paraesthesia, amnesia
• Rare: ataxia, convulsions, syncope, speech disorders.
Psychiatric disorders:
• Common: confusional state, mood altered, anxiety, nervousness, euphoric mood),
sleep disorders
• Uncommon: depression, hallucinations, nightmares
• Rare: delirium, drug dependence.

Post marketing surveillance
Very rare: abuse.
Renal and urinary disorders:
• Uncommon: albuminuria, micturition disorders (dysuria and urinary retention)
Respiratory, thoracic and mediastinal disorders:
• Uncommon: dyspnoea
Skin and subcutaneous tissue disorders:
• Common: hyperhidrosis, pruritus
• Uncommon: dermal reactions (e.g.rash, urticaria).
Vascular disorders:
• Uncommon: hypertension, hot flush
Although not observed during clinical trials, the occurrence of the following
undesirable effects known to be related to the administration of tramadol or
paracetamol cannot be excluded:
Tramadol
• Postural hypotension, bradycardia, collapse (tramadol).
• Post-marketing surveillance of tramadol has revealed rare alterations of warfarin
effect, including elevation of prothrombin times.
• Rare cases (≥ 1/10000 to < 1/1000): allergic reactions with respiratory symptoms
(e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis
• Rare cases (≥ 1/10000 to < 1/1000): changes in appetite, motor weakness, and
respiratory depression
• Psychic side-effects may occur following administration of tramadol which vary
individually in intensity and nature (depending on personality and duration of
medication). These include changes in mood, (usually euphoric mood occasionally
dysphoria), changes in activity (usually suppression occasionally increase) and
changes in cognitive and sensorial capacity (e.g. decision behaviour perception
disorders).
• Worsening of asthma has been reported though a causal relationship has not been
established.
• Symptoms of drug withdrawal syndrome, 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 if tramadol hydrochloride
is discontinued abruptly include: panic attacks, severe anxiety, hallucinations,
paraesthesia, tinnitus and unusual CNS symptoms.
Paracetamol
• Adverse effects of paracetamol are rare but hypersensitivity including skin rash may
occur. There have been reports of blood dyscrasias including thrombocytopenia and
agranulocytosis, but these were not necessarily causally related to paracetamol.

• There have been several reports that suggest that paracetamol may produce
hypoprothrombinemia when administered with warfarin-like compounds. In other
studies, prothrombin time did not change.
• Very rare cases of serious skin reactions have been reported.
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 at: www.mhra.gov.uk/yellowcard.

4.9

Overdose
Tramadol hydrochloride/Paracetamol is a fixed combination of active ingredients. In
case of overdose, the symptoms may include the signs and symptoms of toxicity of
tramadol or paracetamol or of both
these active ingredients.
Symptoms of overdose from tramadol:
In principle, on intoxication with tramadol, symptoms similar to those of other
centrally acting analgesics (opioids) are to be expected. These include in particular,
miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma,
convulsions and respiratory depression up to respiratory arrest.
Symptoms of overdose from paracetamol:
An overdose is of particular concern in young children. Symptoms of paracetamol
over dosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal
pain. Liver damage may become apparent 12 to 48 hours after ingestion.
Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe
poisoning, hepatic failure may progress to encephalophathy, coma and death. Acute
renal failure with acute tubular necrosis may develop even in the absence of severe
liver damage. Cardiac arrhythmias and pancreatitis have been reported.
Liver damage is possible in adults who have taken 7.5-10 g or more of paracetamol. It
is considered that excess quantities of a toxic metabolite (usually adequately
detoxified by glutathione when normal doses of paracetamol are ingested); become
irreversibly bound to liver tissue.
Emergency treatment:


Transfer immediately to a specialized unit.



Maintain respiratory and circulatory functions



Prior to starting treatment, a blood sample should be taken as soon as possible
after overdose in order to measure the plasma concentration of paracetamol and
tramadol and in order to perform hepatic tests.



Perform hepatic tests at the start (of overdose) and repeat every 24 hours. An
increase in hepatic enzymes (ASAT, ALAT) is usually observed, which
normalizes after one or two weeks.



Empty the stomach by causing the patient to vomit (when the patient is
conscious) by irritation or gastric lavage.



Supportive measures such as maintaining the patency of the airway and
maintaining cardiovascular function should be instituted; naloxone should be
used to reverse respiratory depression; fits can be controlled with diazepam.



Tramadol is minimally eliminated from the serum by haemodialysis or
haemofiltration. Therefore treatment of acute intoxication with Tramadol
hydrochloride/Paracetamol tablets with haemodialysis or haemofiltration alone is
not suitable for detoxification.

Immediate treatment is essential in the management of paracetamol overdose. Despite
a lack of significant early symptoms, patients should be referred to hospital urgently
for immediate medical attention and any adult or adolescent who had ingested around
7.5 g or more of paracetamol in the preceding 4 hours or any child who has ingested ≥
150 mg/kg of paracetamol in the preceding 4 hours should undergo gastric lavage.
Paracetamol concentrations in blood should be measured later than 4 hours after
overdose in order to be able to assess the risk of developing liver damage (via the
paracetamol overdose nomogram). Administration of oral methionine or intravenous
N-acetylcysteine (NAC) which may have a beneficial effect up to at least 48 hours
after the overdose may be required. Administration of intravenous NAC is most
beneficial when initiated within 8 hours of overdose ingestion. However, NAC should
still be given if the time to presentation is greater than 8 hours after overdose and
continued for a full course of therapy. NAC treatment should be started immediately
when massive overdose is suspected. General supportive measures must be available.
Irrespective of the reported quantity of paracetamol ingested, the antidote for
paracetamol, NAC, should be administered orally or intravenously, as quickly as
possible, if possible, within 8 hours following the overdose.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
ATC Code: N02A X 52
Pharmacotherapeutic group: Tramadol, combinations
ANALGESICS
Tramadol is an opioid analgesic that acts on the central nervous system. Tramadol is
pure non selective agonists of the μ, δ, and κ opioid receptors with a higher affinity
for the µ receptors. Other mechanisms which contribute to its analgesic effect are
inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin
release. Tramadol has an antitussive effect. Unlike morphine, a broad range of
analgesic doses of tramadol has no respiratory depressant effect. Similarly, the gastrointestinal motility is not modified. The cardiovascular effects are generally slight. The
potency of tramadol is considered to be one-tenth to one-sixth that of morphine.
The precise mechanism of the analgesic properties of paracetamol is unknown and
may involve central and peripheral effects.
Tramadol hydrochloride/Paracetamol tablets are positioned as a step II analgesic in
the WHO pain ladder and should be utilised accordingly by the physician.

5.2

Pharmacokinetic properties
Tramadol is administered in racemic form and the [-] and [+] forms of tramadol and
its metabolite M1, are detected in the blood. Although tramadol is rapidly absorbed
after administration, its absorption is slower (and its half-life longer) than that of
paracetamol.
After a single oral administration of a tramadol/paracetamol (37.5 mg/325 mg) tablet,
peak plasma concentrations of 64.3/55.5 ng/ml [(+)-tramadol/(-)-tramadol] and 4.2
µg/ml (paracetamol) are reached after 1.8 h [(+)-tramadol/(-)-tramadol] and 0.9 h
(paracetamol) respectively. The mean elimination half-lives t1/2 are 5.1/4.7 h [(+)tramadol/(-)-tramadol] and 2,5 h (paracetamol).
During pharmacokinetic studies in healthy volunteers after single and repeated oral
administration of Tramadol/Paracetamol 37.5/325 mg film-coated tablets, no clinical
significant change was observed in the kinetic parameters of each active ingredient
compared to the parameters of the active ingredients used alone.
Absorption:
Racemic tramadol is rapidly and almost completely absorbed after oral
administration. The mean absolute bioavailability of a single 100 mg dose is
approximately 75 %. After repeated administration, the bioavailability is increased
and reaches approximately 90 %.
After administration of Tramadol hydrochloride/Paracetamol tablets, the oral
absorption of paracetamol is rapid and nearly complete and takes place mainly in the
small intestine. Peak plasma concentrations of paracetamol are reached in one hour
and are not modified by concomitant administration of tramadol.
The oral administration of Tramadol hydrochloride/Paracetamol tablets with food has
no significant effect on the peak plasma concentration or extent of absorption of
either tramadol or paracetamol so that Tramadol /Paracetamol 37.5/325 mg filmcoated tablets can be taken independently of meal times.
Distribution:
Tramadol has a high tissue affinity (Vd,β=203 ± 40 l). It has a plasma protein binding
of about 20%.
Paracetamol appears to be widely distributed throughout most body tissues except fat.
Its apparent volume of distribution is about 0.9 l/kg. A relative small portion (~20%)
of paracetamol is bound to plasma proteins.
Metabolism:
Tramadol is extensively metabolized after oral administration. About 30 % of the
dose is excreted in urine as unchanged drug, whereas 60% of the dose is excreted as
metabolites.
Tramadol is metabolised through O-demethylation (catalyzed by the enzyme
CYP2D6) to the metabolite M1, and through N-demethylation (catalyzed by CYP3A)
to the metabolite M2. M1 is further metabolised through N-demethylation and by
conjugation with glucuronic acid. The plasma elimination half-life of M1 is 7 hours.
The metabolite M1 has analgesic properties and is more potent than the parent drug.
The plasma concentrations of M1 are several-fold lower than those of tramadol and
the contribution to the clinical effect are unlikely to change on multiple dosing.
Paracetamol is principally metabolized in the liver through two major hepatic routes:
glucuronidation and sulphation. The latter route can be rapidly saturated at doses
above the therapeutic doses. A small fraction (less than 4%) is metabolized by
cytochrome P 450 to an active intermediate (the N-acetyl benzoquinoneimine) which,

under normal conditions of use, is rapidly detoxified by reduced glutathione and
excreted in urine after conjugation to cysteine and mercapturic acid. However, during
massive overdose, the quantity of this metabolite is increased.
Elimination:
Tramadol and its metabolites are eliminated mainly by the kidneys. The half-life of
paracetamol is approximately 2 to 3 hours in adults. It is shorter in children and
slightly longer in the newborn and in cirrhotic patients. Paracetamol is mainly
eliminated by dose-dependent formation of glucuro- and sulpho-conjugate
derivatives. Less than 9 % of paracetamol is excreted unchanged in urine. In renal
insufficiency, the half-life of both compounds is prolonged.

5.3

Preclinical safety data
Tramadol/Paracetamol
No preclinical study has been performed with the fixed combination (tramadol and
paracetamol) to evaluate its carcinogenic or mutagenic effects or its effects on
fertility.
No teratogenic effect that can be attributed to the medicine has been observed in the
progeny of rats treated orally with the combination tramadol/paracetamol.
The combination tramadol/paracetamol has proven to be embryotoxic and foetotoxic
in the rat at materno-toxic dose (50/434 mg/kg tramadol/paracetamol), i.e., 8.3 times
the maximum therapeutic dose in man. No teratogenic effect has been observed at this
dose. The toxicity to the embryo and the foetus results in a decreased foetal weight
and an increase in supernumerary ribs. Lower doses, causing less severe maternotoxic effect (10/87 and 25/217 mg/kg tramadol/paracetamol) did not result in toxic
effects in the embryo or the foetus.
Tramadol
Animal studies with tramadol revealed, at very high doses, effects on organ
development, ossification and neonatal mortality, associated with maternotoxicity.
Fertility reproductive performance and development of offspring were unaffected.
Tramadol crosses the placenta. No effect on fertility has been observed after oral
administration of tramadol up to doses of 50 mg/kg in the male rat and 75 mg/kg in
the female rat. Results of standard mutagenicity tests did not reveal a potential
genotoxic risk for tramadol in man. Results of carcinogenicity tests do not suggest a
potential risk of tramadol for man.
Paracetamol
Extensive investigations showed no evidence of a relevant genotoxic risk of
paracetamol at therapeutic (i.e. non-toxic) doses.
Long-term studies in rats and mice yielded no evidence of relevant tumorigenic
effects at non-hepatotoxic dosages of paracetamol.
Animal studies and extensive human experience to date yield no evidence of
reproductive toxicity.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core:
Powdered cellulose
Pregelatinised maize starch
Sodium starch glycolate (Type A)
Maize starch
Magnesium stearate
Film-coating:
Hypromellose
Titanium dioxide (E171)
Macrogol 400
Iron oxide yellow (E172)
Polysorbate 80

6.2

Incompatibilities
Not applicable

6.3

Shelf life
3 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
Tramadol/Paracetamol 37.5mg/325mg Film Coated Tablets are packed in Opaque
PVC/aluminium blister packs of 2, 10, 20, 30, 40, 50, 60, 70, 80, 90 and 100 tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.
Any unused product or waste should be disposed of in accordance with local
requirements.

7

MARKETING AUTHORISATION HOLDER
BRISTOL LABORATORIES LIMITED
Unit 3, Canalside, Northbridge Road
Berkhamsted, Herts, HP4 1EG
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 17907/0392

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
11/05/2016

10

DATE OF REVISION OF THE TEXT
06/06/2017

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