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OLDARAM 200 MG PROLONGED-RELEASE TABLETS

Active substance(s): TRAMADOL HYDROCHLORIDE / TRAMADOL HYDROCHLORIDE / TRAMADOL HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Oldaram 200 mg Prolonged-release tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 200mg tramadol hydrochloride
For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Prolonged-release tablet
Oldaram 200 mg Prolonged-release tablets are off-white, capsules shaped tablets.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of moderate to severe pain.

4.2

Posology and method of administration
Posology
The dose should be adjusted to the intensity of the pain and the sensitivity of
the individual patient. The lowest effective dose for analgesia should generally
be selected. The total daily dose of 400 mg active substance should not be
exceeded, except in special circumstances.
Unless otherwise prescribed, Oldaram Prolonged-release tablets should be
given as follows:
Adults and adolescents above the age of 12 years:
The usual initial dose is one 50-100mg tramadol hydrochloride twice daily, the
morning and evening. If the pain relief is insufficient, the dose may be titrated
upwards to 150mg or 200mg tramadol hydrochloride twice daily.
Paediatric population
Oldaram is not suitable for children below the age of 12 years.

Elderly patients
A dose adjustment is not usually necessary in patients up to 75 years without
clinically manifest hepatic or renal insufficiency. In elderly patients over 75
years elimination may be prolonged. Therefore, if necessary the dosage
interval is to be extended according to the patient's requirements.
Renal insufficiency/dialysis and hepatic insufficiency
In patients with renal and/or hepatic insufficiency the elimination of tramadol
is delayed. In these patients prolongation of the dosage interval should be
carefully considered according to the patients requirements. In cases of severe
renal and/or severe hepatic insufficiency Oldaram prolonged-release tablets
are not recommended.
Method of administration
The tablets are to be taken whole, not divided or chewed, with sufficient
liquid, independent of meals.
Duration of administration
Tramadol should under no circumstances be administered for longer than
absolutely necessary. If long-term pain treatment with tramadol is necessary in
view of the nature and severity of the illness, then careful and regular
monitoring should be carried out (if necessary with breaks in treatment) to
establish whether and to what extent further treatment is necessary.
4.3

Contraindications
Oldaram is contraindicated:
• in hypersensitivity to the active substance or to any of the
excipients listed in section 6.1
• in acute intoxication with alcohol, hypnotics, analgesics,
opioids, or other psychotropic medicinal products
• in patients who are 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
• for use in narcotic withdrawal treatment.

4.4

Special warnings and precautions for use
Tramadol may only be used with particular caution in opioid-dependent
patients, patients with head injury, shock, a reduced level of consciousness of
uncertain origin, disorders of the respiratory centre or function, increased
intracranial pressure.
In patients sensitive to opiates the product should only 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 lowers the seizure threshold (see section 4.5). Patients with
epilepsy or those susceptible to seizures should be only treated with tramadol
if there are compelling circumstances.
Tramadol has a low dependence potential. On long-term use tolerance, psychic
and physical dependence 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.
Tramadol is not suitable as a substitute in opioid-dependent patients. Although
it is an opioid agonist, tramadol cannot suppress morphine withdrawal
symptoms.
4.5

Interaction with other medicinal products and other forms of interaction
Tramadol should not be combined with 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
Oldaram.
Concomitant administration of tramadol with other centrally depressant
medicinal products including alcohol may potentiate the CNS 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.
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,
tehrahydrocannabinol) 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.
Caution should be exercised during concomitant treatment with tramadol and
coumarin derivatives (e.g. warfarin) due to reports of increased INR with
major bleeding and ecchymoses in some patients.
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 (see section
4.8).
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
Animal studies with tramadol revealed at very high doses effects on organ
development, ossification and neonatal mortality. Tramadol crosses the
placenta. There is inadequate evidence available on the safety of tramadol in
human pregnancy. Therefore tramadol should not be used 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. Chronic use during pregnancy may lead to
neonatal withdrawal symptoms.
Breast-feeding
During lactation about 0.1 % of the maternal dose is secreted into the milk.
Oldaram is not recommended during breast-feeding. After a single
administration of tramadol it is not usually necessary to interrupt breastfeeding.
Fertility
Post marketing surveillance does not suggest an effect of tramadol on fertility.
Animal studies did not show an effect of tramadol on fertility.

4.7

Effects on ability to drive and use machines
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 and other
psychotropic substances, particularly alcohol.
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:
- The medicine has been prescribed to treat a medical or dental
problem and
- You have taken it according to the instructions given by the
prescriber and in the information provided with the medicine
and
- It was not affecting your ability to drive safely
4.8

Undesirable effects
The most commonly reported adverse reactions are nausea and dizziness, both
occurring in more than 10 % of patients.
The frequencies are defined as follows:
Very common: ≥1/10
Common: ≥1/100, <1/10
Uncommon: ≥1/1000, <1/100
Rare: ≥1/10 000, <1/1000
Very rare: <1/10 000
Not known: cannot be estimated from the available data
Immune system disorders
Rare: allergic reactions (e.g. dyspnoea, bronchospasm, wheezing,
angioneurotic oedema) and anaphylaxis
Metabolism and nutrition disorders
Rare: changes in appetite
Not known: hypoglycaemia
Psychiatric disorders

Rare: hallucinations, confusion, sleep disturbance, delirium, anxiety and
nightmares. Psychic adverse reactions may occur following administration of
tramadol which vary individually in intensity and nature (depending on
personality and duration of treatment). These include changes in mood
(usually elation, occasionally dysphoria), changes in activity (usually
suppression, occasionally increase) and changes in cognitive and sensorial
capacity (e.g. decision behaviour, perception disorders). Drug dependence
may occur.
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 with tramadol discontinuation
include: panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus
and unusual CNS symptoms (i.e. confusion, delusions, depersonalisation,
derealisation, paranoia).
Nervous system disorders
Very common: dizziness
Common: headache, somnolence
Rare: paraesthesia, tremor, epileptiform convulsions, involuntary muscle
contractions, abnormal coordination, syncope, speech disorders.
Convulsions occurred mainly after administration of high doses of tramadol or
after concomitant treatment with medicinal products which can lower the
seizure threshold (see sections 4.4 and 4.5).
Eye disorders
Rare: miosis, mydriasis, blurred vision
Cardiac disorders
Uncommon: cardiovascular regulation (palpitation, tachycardia. These adverse
reactions may occur especially on intravenous administration and in patients
who are physically stressed.
Rare: bradycardia
Vascular disorders
Uncommon: cardiovascular regulation (postural hypotension or cardiovascular
collapse). These adverse reactions may occur especially on intravenous
administration and in patients who are physically stressed.
Respiratory, thoracic and mediastinal disorders
Rare: respiratory depression, dyspnoea
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.

Gastrointestinal disorders
Very common: nausea
Common: vomiting, constipation, dry mouth
Uncommon: retching; gastrointestinal discomfort (a feeling of pressure in the
stomach, bloating), diarrhoea
Hepatobiliary disorders
In a few isolated cases an increase in liver enzyme values has been reported in
a temporal connection with the therapeutic use of tramadol.
Skin and subcutaneous tissue disorders
Common: hyperhidrosis
Uncommon: dermal reactions (e.g. pruritus, rash, urticaria)
Musculoskeletal and connective tissue disorders
Rare: motorial weakness
Renal and urinary disorders
Rare: micturition disorders (dysuria and urinary retention)
General disorders
Common: fatigue
Investigations
Rare: increase in blood pressure

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
Symptoms
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.
Treatment
The general emergency measures apply. Keep open the respiratory tract
(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 cases diazepam should be
given intravenously.
In case of intoxication orally, gastrointestinal decontamination with activated
charcoal or by gastric lavage is only recommended within 2 hours after
tramadol intake. Gastrointestinal decontamination at a later time point may be
useful in case of intoxication with exceptionally large quantities or prolongedrelease formulation.
Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore treatment of acute intoxication with Oldaramwith
haemodialysis or haemofiltration alone is not suitable for detoxification.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: other opioids; ATC-code N 02 AX 02
Tramadol is a centrally acting opioid analgesic. It is a non-selective pure
agonist at µ, ō and ĸ opiod receptors with a higher affinity for µ-receptors.
Other mechanisms which contribute to its analgesic effect are the inhibition of
neuronal reuptake of noradrenaline and enhancement of serotonin release.
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.

5.2

Pharmacokinetic properties
More than 90% of Oldaram is absorbed after oral administration.
The mean absolute bioavailability is approximately 70 %, irrespective of
concomitant intake of food. The difference between absorbed and nonmetabolised 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 ± 40 I). It has a plasma protein
binding of about 20%.
After administration of Oldaram 100mg the peak plasma concentration Cmax
141 ± 40 ng/ml is reached after 4.9 hours. After administration of Oldaram
200mg a Cmax 260 ± 62 ng/ml is reached after 4.8 hours.

Tramadol passes the blood-brain and placenta barriers. 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).
Elimination of 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.
In humans tramadol is mainly metabolised by means of N- and Odemethylation and conjugation of the O-demethylation products with
glucuronic acid. Only O-desmethyltramadol 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 O-desmethyltramadol 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 types of the isoenzymes CYP3A4 and CYP2D6
involved in the biotransformation of tramadol may affect the plasma
concentration of tramadol or its active metabolite. Up to now, clinically
relevant interactions have not been reported.
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.
Tramadol has a linear pharmacokinetic profile within the therapeutic dosage
range.
The relationship between serum concentrations and the analgesic effect is
dose-dependent, but varies considerably in isolated cases. A serum
concentration of 100 - 300 ng/ml is usually effective.
5.3

Preclinical safety data
On repeated oral and parenteral administration of tramadol for 6 - 26 weeks in
rats and dogs and oral administration for 12 months in dogs haematological,
clinico-chemical 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
Calcium hydrogen phosphate (E341)
Hydroxypropylcellulose (E463)
Colloidal anhydrous silica (E551)
Magnesium stearate (E470b)

6.2

Incompatibilities
Not applicable

6.3

Shelf life
3 years

6.4

Special precautions for storage
Do not store above 25°C.

6.5

Nature and contents of container
PVC/Aluminium blisters (clear polyvinylchloride (PVC) film and aluminium foil.
Pack size of 60 tablets.

6.6

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

7

MARKETING AUTHORISATION HOLDER
Ranbaxy (UK) Limited
Building 4, Chiswick Park
566 Chiswick High Road
London, W4 5YE
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 14894/0341

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
04/02/2008

10

DATE OF REVISION OF THE TEXT
23/11/2015

11

DOSIMETRY (IF APPLICABLE)

12

INSTRUCTIONS FOR PREPARATION OF
RADIOPHARMACEUTICALS (IF APPLICABLE)

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

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