New Zealand - English - Medsafe (Medicines Safety Authority)
NAME OF THE MEDICINE
The active ingredient of DUROTRAM ® XR is tramadol hydrochloride
Chemical name: (±)-cis-2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol
hydrochloride or (1RS,2RS)-2-[(Dimethylamino)methyl]-1-(3-
methoxyphenyl) cyclohexanol hydrochloride
Molecular formula: C
Molecular weight: 299.84
CAS registry no. 36282-47-0
Tramadol hydrochloride is a white crystalline powder with a melting point/range
approximately of 180 o C. It is readily soluble in water and ethanol and has a pKa of 9.41.
The water/n-octanol partition coefficient is 1.35 at pH 7.
DUROTRAM ® XR tablets are available in strengths of 100 mg, 200 mg and 300 mg
DUROTRAM ® XR tablets contain the following excipients: Contramid ® (Hydroxypropyl
distarch phosphate (E 1442)), polyvinyl acetate,povidone, sodium laurylsulfate, xanthan
gum, vegetable oil-hydrogenated, magnesium stearate, silica colloidal anhydrous,
Opacode monogramming ink S-1-17823 black.
DUROTRAM ® XR tablets are comprised of a dual-matrix delivery system with an outer
compression coat which releases tramadolhydrochloride immediately and a core
containing Contramid ® , which controls the release of tramadol hydrochloride.
Durotram-PI-NZ-01May08A Page 1 of 22
MECHANISM OF ACTION
The analgesic activity of tramadol hydrochloride is due to both parent drug and the M1
metabolite (O-desmethyl tramadol).
Tramadol is a centrally acting synthetic opioid analgesic. Although its mode of action is not
completely understood, from animal tests, atleast two complementary mechanisms appear
applicable: binding of parentand M1 metabolite to µ-opioid receptors and weak inhibition
of reuptake of norepinephrine and serotonin. Opioid activityis due to both low affinity
binding of the parent compound and higher affinity binding of the O-demethylated
metabolite M1 toμ-opioid receptors. In animal models,M1 is up to 6 times more potent
than tramadol in producing analgesia and 200 times more potent inμ-opioid binding.
Tramadol-induced analgesia is only partiallyantagonized by the opiate antagonist
naloxone in several animal tests. The relativecontribution of both tramadol and M1 to
human analgesia is dependent upon the plasmaconcentrations of each compound. (See
Tramadol has been shown to inhibit reuptake ofnorepinephrine and serotonin in vitro, as
have some other opioid analgesics. These mechanisms may contribute independently to
the overall analgesic profile of DUROTRAM ® XR.
Apart from analgesia, tramadoladministration may produce aconstellation of symptoms
(including dizziness, somnolence, nausea, constipation,sweating and pruritus) similar to
that of opioids. In contrastto morphine, tramadol has not been shown to cause histamine
release. At therapeuticdoses, tramadol has no effect on heart rate, left-ventricular function
or cardiac index. Orthostatic hypotension has been observed.
In a single-dose study, the dose adjusted bioavailability of the 100 mg, 200 mg and 300 mg
tablets were equivalent confirming a linear pharmacokinetic response (in relation to both
tramadol and O-desmethyltramadol) over this range of strengths. Doseproportionality of
the 100 mg, 200 mg and 300 mg tablets has been demonstrated.
Following oral administration ofa single dose, tramadol is almost completely absorbed and
the absolute bioavailability isapproximately 70%. There is nolag time in drug absorption
following administrationof DUROTRAM ® XR. DUROTRAM ® XR exhibits a plasma/time
concentration profile with a sharp initial slope similar toimmediate-release tramadol
capsules followed by a sustained release phase. This behaviour is due to the two phases
of drug release which work together to provide a smooth plasma concentration/time profile
(Figures 1 and 2).
Time (h) 0 6 12 18 24 30 36 42 48 Tramad ol co nce ntrati on (ng/mL)
Figure 1. Mean tramadol plasma concentrationsfollowing a single oral dose of DUROTRAM XR
100 mg (), 200 mg (), 300 mg (▲)
Time(h) 0 6 12 18 24 30 36 42 48 O -Desme thy ltramado l con cen tra tio n (ng/mL)
Figure 2. Mean O-desmethyltramadol plasmaconcentrations following a single oral dose of
DUROTRAM XR 100 mg (), 200 mg (), 300 mg (▲)
The mean peak steady-state plasma concentrationsof tramadol and M1after multiple dose
administration of DUROTRAM ® XR 200 mg tablets to healthy subjects are attained at
about 4.3 h and 7.4 h, respectively (Table 1).
Table 1.Mean (%CV) Steady-State Pharmacokinetic Parameter Values (n=26)
Parameter DUROTRAM XR 200 mg
Tablet Once-Daily DUROTRAM XR 200 mg Tablet
(ng·h/mL) 5185(28) 1358(23)
(ng/mL) 311 (25) 71 (24)
(ng/mL) 107 (49) 35 (23)
(hr)* 4.5 (2.0 –12.0) 5.0 (2.0 –16.0)
Fluctuation (%) 98 (22) 63 (27)
is presented as Median (Range)
Steady-state plasma concentrations with DUROTRAM ® XR were reached within 48 hours
Time (h) 0 4 8 12 16 20 24 Con centratio n (ng /mL )
0 100 200 300 400
Durotram ® XR 200mgOnceDaily
The effect of food was investigatedin a single dose study in which a DUROTRAM ® XR 200
mg tablet was given fasting and immediatelyfollowing a high fat meal. Food had no
significant effect on the area under the curve (AUC
0-∞ ) but increased the maximum plasma
) of both tramadol and itsmetabolite by 54% and 49% respectively.
DUROTRAM ® XR was administered before breakfastin the phase III efficacy and safety
clinical trial. (See “CLINICAL TRIALS”.)
Tramadol is rapidly distributed inthe body with a volume of distribution of 2-3 L/kg in young
adults. The volume of distribution is reduced by about 25% in persons aged over 75 years.
The binding of tramadol to human plasma proteins is approximately 20%. Protein binding
is independent of concentration up to 10 µg/mL. Saturation of plasma protein binding
occurs only at concentrations outside the clinically relevant range.
Tramadol is extensively metabolized after oral administration. The major metabolic
pathways appear to be N- and O-demethylation andglucuronidation or sulfation in the liver.
One metabolite (O-desmethyltramadol, denoted M1)is pharmacologically active in animal
models. Formation of M1 is dependent on CYP2D6. Poor CYP2D6 metabolisers may
obtain reduced benefit from tramadol due to reduced formation of M1. N-demethylation is
catalysed by CYP3A4. The inhibition of oneor both of CYP2D6 orCYP3A4 may increase
plasma concentrations of tramadol orreduce plasma concentrations of M1.
Tramadol and its metabolites are primarily renally excreted, with a cumulative renal
excretion of approximately 95%. Inyoung adults, approximately 15-19% of an
administered dose is excreted unchanged in the urine, and in the elderly this increases to
about 35%. Biliary excretion is of little importance. The total clearance of tramadol is 430-
610 mL/min. After singleadministration of DUROTRAM ® XR, the mean terminal plasma
elimination half-lives of racemic tramadol and racemic M1are 6.5 ± 1.5 and 7.5 ± 1.4
SPECIAL POPULATIONS AND CONDITIONS
Impaired renal function results in a decreasedrate and extent of excretion of tramadol and
its active metabolite, M1. DUROTRAM ® XR has not been studied in patients with severe
renal impairment (creatinine clearance of less than 30 mL/min)and therefore should not be
used in these patients. (See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS,
Renal Impairment and DOSAGE AND ADMINISTRATION.) The total amount of tramadol
and M1 removed during a 4-hour dialysis periodis less than 7% of the administered dose.
DUROTRAM ® XR is contraindicated in patients with severe hepatic impairment. The
elimination half-life oftramadol and its activemetabolite may be prolonged in patients with
hepatic impairmentDUROTRAM ® XR has not been studied in patients with severe hepatic
impairment and, therefore, should not beused. (See CONTRAINDICATIONS, WARNINGS
AND PRECAUTIONS, Hepatic/Biliary/Pancreatic Impairment and DOSAGE AND
Healthy elderly subjects aged 65 to 75 yearswho are administered an immediate-release
formulation of tramadol have plasma concentrations and elimination half-lives comparable
to those observed in healthy subjects less than 65 years of age. In subjects aged over 75
years, the volume of distribution of tramadol is decreased by 25% and clearance is
decreased by 40%. As a result, tramadol C
and total exposure are increased by 30%
and 50% respectively, while the half-life is increased by 15%. The use of DUROTRAM ® XR
is not recommended in patients aged over 75 years. (See DOSAGE AND
Following a 100 mg IV dose of tramadol, plasma clearance was 6.4 mL/min/kg inmales
and 5.7 mL/min/kg in females. This difference is not likely to be clinically significant;
therefore, dosage adjustment based on gender is not recommended.
CHILDREN AND ADOLESCENTS (<18 YEARS)
Pharmacokinetics of DUROTRAM ® XR tablets have not been studied in paediatric patients
below 18 years of age.
In a Phase III, multi-centre, randomised, double-blind, double-dummy, parallel-design study
in 431 patients with painful osteoarthritis of the knee, DUROTRAM ® XR (once daily) was
compared with a tramadol twice daily formulation for three months. The dose was titrated
to an optimum dose (minimum effective/maximum tolerated dose) within the permitted
dose range of 100 mg to 400 mg daily. Inclusion criteria included patients of both sexes
aged 40-75 years with osteoarthritis of the knee confirmed in the previous yearby
arthroscopy or radiology, and an erythrocyte sedimentation rate (ESR) of <40 mm/hour. At
baseline, patients were required to have aWestern Ontario and McMaster University
Osteoarthritis (WOMAC) Index Pain subscale total score of≥150 mm and≤30 minutes
morning stiffness with or withoutcrepitus. The WOMAC Indexis a self-administered,
validated instrument used to assess pain, disability and joint stiffness in knee and hip
osteoarthritis. The WOMAC Index Pain subscaletotal score consists of the sum of the
patient’s Visual Analogue Scale (VAS) ratingson 5 items relating to the severity of pain.
Each response varies from unbearable pain (100 mm) tono pain (0 mm), with the subscale
total score being 0-500 mm. The mean ±SD baseline pain subscale total score for the
DUROTRAM ® XR group was 285±71 and 297±70 forthe tramadol twice daily group.
The primary objective ofthe study was to show non-inferiority of DUROTRAM ® XR
compared with tramadol twice daily on the percentage improvementin the WOMAC Index
Pain subscale total score between baseline and day 84. The per-protocol population was
used as the primary analysis set to test non-inferiority. The minimalclinically important
difference between the two treatmentswas set at 15%. To conclude that DUROTRAM ® XR
was not inferior to tramadol twice daily with a2.5% type I error, thelower bound of the 95%
confidence interval (two-sided test) forthe mean difference between treatments was
required to be greater than -15%. The mean change from baseline to last visit in the
WOMAC IndexPain subscale total score was 58%±30% for DUROTRAM ® XR and
59%±27% for tramadol twice daily. The 95%confidence interval between the two
treatments was -7.6 %to 3.82%. Consequently, as thelower bound interval (-7.6%) was
greater than the pre-specified lower bound interval of -15%, DUROTRAM ® XR was shown to
be non-inferior to tramadol twice daily for the treatment ofosteoarthritic knee pain. The
median optimum dose in the per-protocol population was 200 mg daily in both treatment
groups. The statistical analysis of the primaryefficacy outcome in the intention-to-treat
population produced similar results. There werea number of secondary efficacy endpoints
including WOMAC Stiffness and Physical Function Subscales, patient pain rating at the
end of each 24 hour dosing interval (diaries),patient global assessment of pain over 24
hours (VAS) and walking time for 15 metres.The analysis of the secondary endpoints
confirmed the similarity of both treatments.
Relief of moderate to severe pain.
Known hypersensitivity to tramadol or to any of the excipients
Acute intoxication or overdose with psychotropic medicines
Acute intoxication or overdose with CNSdepressants (alcohol, hypnotics, other
Patients receiving concomitant treatment with MAOinhibitorsor who have been
treated with MAO inhibitors during the past 2 weeks
Concomitant treatment with linezolid
Severe renal or hepatic impairment (creatinine clearance of lessthan 30 mL/min
and/or Child-Pugh Class C)
Epilepsy not adequately controlled by treatment
Tramadol must not be administered during breastfeeding if long-term treatment,
i.e. more than 2 to 3 days, is necessary.
Not to be used to treat opioid withdrawal
Known sensitivity to opioids
Seizure risk: Seizures have been reported in patients receiving tramadol hydrochloride
within the recommended dosage range. Spontaneouspostmarketing reports indicate that
seizure risk is increased with doses above the recommended range. Concomitant use of
tramadol hydrochloride increasesthe seizure risk in patients taking:
Selective serotonin reuptake inhibitors(SSRI antidepressants or anorectics),
Tricyclic antidepressants (TCAs)and other tricyclic compounds or
Administration of tramadol may enhance the seizure risk in patients taking:
MAO inhibitors (see CONTRAINDICATIONS),
Other medicines that lower theseizure threshold (see WARNINGS AND
PRECAUTIONS: Interactionswith other medicines)
Risk of convulsions may alsoincrease in patients with epilepsy, those with a history of
seizures, or in patients with a recognized riskfor seizure (such as head trauma, metabolic
disorders, alcohol and drug withdrawal, CNS infections). Intramadol overdose, naloxone
administration may increase the risk of seizures.
Patients with controlled epilepsy or patientswith a known risk of seizure should only be
treated with tramadol in cases of absolute necessity.
Use with alcohol: Consumption of alcohol isnotrecommended duringtreatment with
tramadol due to the potential for additive effects on central nervous system depression.
Dependency: Tramadol has a low potential for dependence. However, with long-term use,
tolerance and psychological and/or physical dependence may develop.At therapeutic
doses, withdrawal symptoms have been reported with a frequency of1 in 8,000 while
reports of dependence and abuse have been less frequent.
Because of the potential for dependence or withdrawal to occur, the clinical need for
continued analgesia should bereviewed regularly in patients being treated with
DUROTRAM ® XR. In patients with ahistory of drug abuse ordependence, tramadol should
only be used for short periods understrict medical surveillance.
WithdrawalSymptoms: Withdrawal symptoms may occur if DUROTRAM ® XR is
discontinued abruptly. These symptoms may include:anxiety, sweating, insomnia, rigors,
pain, nausea, tremors, diarrhoea, upper respiratory symptoms,piloerection and, rarely,
hallucinations. Other symptoms that havebeen seen lessfrequently with tramadol
discontinuation include: panic attacks,severeanxiety and paresthesias.
Clinical experience suggests that signs and symptoms of withdrawal may be avoided by
tapering medication when discontinuing tramadol therapy. Patients on prolonged therapy
should be withdrawn gradually fromthe drug if it is no longerrequired for pain control.
Clinical experience suggests thatwithdrawal symptoms may be relieved by reinstitution of
tramadol therapy followed by a gradual,tapered dose reductionof the medication
combined with symptomatic support.
Tramadol is not suitable asa substitute opioid in opioid-dependent patients. Although it is
an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.
Intra-operative use: In one study using nitrous oxide/ tramadol anaesthetic technique
(with only intermittent administration of enflurane 'as required'), tramadolwas reported to
enhance intraoperative recall. Hence its use during potentiallyvery light planes of general
anaesthesia should be avoided.
Two recentstudies of tramadol administration during anaesthesia comprising continuous
administration of isoflurane didnot show clinically significant lightening of anaesthetic
depth or intraoperative recall. Therefore, if the current practiceof administering continuous,
potent (volatile or intravenous) anaestheticagent is followed, tramadol may be used
intraoperatively in the same way as other analgesic agents are routinely used.
Intracranial PressureandHead Trauma: Tramadol should be usedwith caution in
patients with head trauma or increased intra-cranial pressure and in patients who are in
shock or in an altered state of consciousness (with no obvious cause).
Anaphylactoid Reactions and Allergic Reactions:Serious and rarely fatal anaphylactoid
reactions have been reported in patients receiving therapy with tramadol. When these
events occur, it is often following the first dose. Other reported allergic reactions include
pruritus, hives, bronchospasm, angioedema,toxic epidermal necrolysis and Stevens-
Johnson syndrome. Patients witha history of anaphylactoid reactions to codeine and other
opioids may be at increased risk and therefore should not receive DUROTRAM ® XR.
Respiratory Depression: Administer DUROTRAM ® XR cautiously in patients at risk for
respiratory depression, such aspatients with significant chronic obstructive pulmonary
disease or cor pulmonale, and in patients having a substantiallydecreased respiratory
reserve, hypoxia or hypercapnia. In these patients, alternative non-opioid analgesics
should be considered and opioidsshouldbe employed only under careful medical
supervision at the lowest effective dose. When large doses oftramadol are administered
with anesthetic medications or alcohol, respiratory depression may result. Respiratory
depression should be treated asan overdose. If naloxone isto be administered, use
cautiously because it may precipitate seizures.
Acute abdominal conditions:The administration of DUROTRAM ® XR may complicate
the clinical assessment of patients with acute abdominal conditions.
Renal impairment: DUROTRAM ® XR iscontraindicated inpatients with severe renal
impairment (creatinine clearance <30mL/min, see CONTRAINDICATIONSand
PHARMACOKINETICS). Caution is advised inpatients with moderate renal impairment.
Impaired renal function results in a decreasedrate and extent of excretion of tramadol and
its active metabolite, M1. The total amountof tramadol and M1 removed during a 4-hour
dialysis period is less than 7% of the administered dose.
Hepatic Impairment: DUROTRAM ® XR is contraindicated in patients with severe hepatic
impairment. (See CONTRAINDICATIONS.) Metabolism of tramadol and M1 is reduced in
patients with advanced cirrhosis of the liver,resulting in both a greater systemic exposure
to tramadol and longertramadol and M1 elimination half-lives (13 hours for tramadol and
19 hours for M1).
Use in the Elderly (> 65 years of age): Dose adjustments in elderly patients up to
75 years of age without clinically relevant hepatic or renal impairment is not normally
necessary. However, in patients aged over 75 years, the elimination half-life of tramadol
may be prolonged. The use of DUROTRAM ® XR in patients over the age of 75 years is not
recommended. (See PHARMACOKINETICS, DOSAGE AND ADMINISTRATION.)
Use in Children and Adolescents (< 18 years of age):The safety and effectiveness of’
DUROTRAM ® XR in children and adolescents less than 18 years of age has not been
established. The use of DUROTRAM ® XR in this age group is not recommended,
Effects on ability todrive and use machines: Tramadol maycause dizziness and/or
drowsinessand has, even when used according to the directions, an influence on the
ability to drive and use machines. This effectmay occur at the beginning oftreatment and
may be potentiated by alcohol and concomitantuse of other CNS-depressants or anti-
histamines. If patients are affected they should bewarned not to drive or operate
Carcinogenicity: A slight but statisticallysignificant increase in two common murine
tumours, pulmonaryand hepatic,was observed in a mouse carcinogenicity study,
particularlyin aged mice, at doses less thanthe maximum clinicaldose on a body surface
basis, but this finding is not believed to suggest risk in humans. No such findings occurred
in a rat carcinogenicity study.
Genotoxicity: The weight of evidence from an extensive battery of genotoxicity assays
indicates that tramadol does notpossess a genotoxic risk to humans.
Effects on Fertility: There were no effects on fertility inrats treated with tramadol at oral
doses up to 50 mg/kg/day (approximately themaximum clinical dose on a body surface
Use in Pregnancy. (Category C): There are no adequate and wellcontrolled studies with
tramadol in pregnant women and, therefore, the drugshould not be used during
Tramadol has been shown to be embryotoxicand fetotoxic in rats and rabbitsat
maternotoxic doses (2 to 4 times the maximum clinical dose on a body surface area basis),
but there was no evidence of teratogenicity inrats (75 mg/kg/day, or twice the maximum
clinical dose on a body surface area basis) orrabbits (175 mg/kg/day, or 8 times the
maximum clinical dose on a body surface area basis). There was no fetal harm observed at
doses that were not maternotoxic. Embryo and fetal toxicityconsisted primarily of reduced
fetal weight, skeletal ossification and increased supernumerary ribs. Transient delays in
development or behavioural parameters were also seenin pups from rat dams allowed to
deliver. Embryo and fetal lethality were reported in only one rabbit study at an extreme
Labour and delivery. Tramadol should not be used in pregnant women prior to or during
labour unless the potential benefits outweigh the risks, because safe use in pregnancy has
not been established. The use of tramadolduring labour may cause neonatal respiratory
depression. Tramadol crosses the placenta and, in women during labour, the mean
umbilical vein concentration is similar to the maternal vein concentration.
The effects of tramadol on later growth, development and functional maturation of the child
Use in Lactation: Tramadol and its metabolites have beendetected in human breast milk
in small amounts. An infant could ingest 0.1%of the single dose given to their mother. A
single administration of tramadoldoes not usually require breastfeeding to be interrupted. If
repeated administration is needed for several days, i.e. more than 2 to 3 days,
breastfeeding should be suspended.If long-term treatmentafter birth is necessary,
breastfeeding is contraindicated.
In perinatal and postnatal studiesin rats, progenyof dams receiving oral doses of tramadol
(1 to 2 times the maximum clinical dose based on body surface area) had reduced weights
and pup survival in early lactation. There was no offspring toxicity at lower doses, although
maternotoxicity was observed at all dose levels.
Interaction with other Medicines
In vitro studies indicatethat tramadol is unlikelyto inhibitthe CYP3A4-mediated
metabolismof other drugs whenit is administered concomitantly attherapeutic doses.
Tramadol does not appear to induce its own metabolism inhumans, since observed
maximal plasma concentrations after multipleoral doses are higher than expected based
on single dose data. Tramadol is a mildinducer of selected drug metabolism pathways
measured in animals.
Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers,
such as rifampin and St. John’s Wort, with DUROTRAM ® XR may affect the metabolism of
tramadol leading to altered tramadol exposure.
Tramadol is contraindicated in patients receiving MAO inhibitors or who have used them
within the previous14 days. (See CONTRAINDICATIONS, WARNINGS AND
Drugs that Lower Seizure Threshold
Tramadol can induce convulsionsand increase the potential for selective serotonin
reuptake inhibitors (SSRIs),tricyclic anti-depressants (TCAs), anti-psychotics and other
seizure threshold loweringdrugs to cause convulsions. (See WARNINGS AND
Concurrent administration of tramadol with other centrally actingdrugs, including alcohol,
centrally acting analgesics, opioids and psychotropic drugs may potentiateCNS
The combination of tramadol with mixed opiate agonists/antagonists(eg. buprenorphine,
pentazocine) is not advisable because the analgesic effect of a pure agonist may be
theoretically reduced in such circumstances.
Use with Inhibitors of CYP2D6
In vitro drug interaction studiesinhuman liver microsomes indicate thatconcomitant
administration with inhibitors ofCYP2D6 such as fluoxetine, paroxetine, amitryptiline and
phenothiazines may inhibit the metabolismoftramadol resulting in increased plasma
Use with Quinidine
Tramadol is metabolized to M1 by CYP2D6. Asquinidine is a selective inhibitor of that
isoenzyme, concomitant administration of quinidine and tramadol results in increased
concentrations of tramadol and reduced concentrations of M1. The clinical consequences
of these findings are unknown. In vitro drug interaction studies in human livermicrosomes
indicate that tramadol has noeffect on quinidine metabolism.
Use with Inhibitors orInducers of CYP3A4
Administration of CYP3A4 inhibitors, such asketoconazole and erythromycin, or inducers,
such as rifampin and St. John’s Wort, may affect the metabolism of tramadol, leading to
altered tramadol exposure.
Use with Carbamazepine
Concomitant administration oftramadol with carbamazepine causes a significant increase
in tramadol metabolism, presumably through metabolicinduction by carbamazepine.
Patients receiving chronic carbamazepine dosesof up to 800 mg daily may require up to
twice the recommended dose of tramadol.
Use with Cimetidine
Concomitant administration oftramadol immediate-release capsules with cimetidine does
not result in clinically significant changes in tramadol pharmacokinetics. No alteration ofthe
DUROTRAM ® XR dosage regimen with cimetidine is recommended.
Use with Warfarin-Like Compounds
Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin
effect, including an increased international normalised ratio (INR).
While suchchangeshave beengenerally of limited clinical significance for tramadol,
periodic evaluation of prothrombin time should beperformed when DUROTRAM ® XR
tablets and warfarin-like compoundsare administered concurrently.
Use with Serotonergic Agents
The presence of another drug that increases serotonin by any mechanism should alert the
treating doctor to the possibilityof an interaction. In isolated cases,there have been reports
of serotonin syndrome in a temporal connection with the therapeuticuse of tramadol in
combination with other serotonergic medicines, e.g. selectiveserotonin reuptake inhibitors
(SSRIs). Signs of serotonin syndrome may be,for example, confusion, agitation, fever,
sweating, ataxia, hyper-reflexia, myoclonus anddiarrhoea. Withdrawal of the serotonergic
medicines usually bringsabout a rapid improvement. Drug treatment dependson the
nature and severity of the symptoms.
In a limited number of studies,the pre- or post-operative application of the anti-emetic 5-
HT3 antagonist ondansetron increased the requirement of tramadol in patients with post-
DUROTRAM ® XR was administered to a total of 215patients during a clinical study. This
was a randomized double-blind parallel-group studyof 431patients with moderate to
moderately severe pain due to osteoarthritis ofthe knee. A titration phase (4 – 12 days)
was followed by a maintenance phase (12 weeks). A summary of adverse events
occurring at an incidence of 1% or more is given in Table 2, whichincludes all events,
whether considered by the clinical investigator tobe related to the study drug or not.
Table 2.Percentage of Patientswith Incidence ofAdverse Events≥1%in 12-weekStudyMDT3-001/E1
Durotram ® XR Total
Adverse Events N = 215
Any TEAE 175 (81.4%)
Angina pectoris 4 (1.9%)
Ear and labyrinth disorders
Vertigo 5 (2.3%)
Abdominalpain 3 (1.4%)
Abdominalpainupper 9 (4.2%)
Aptyalism 5 (2.3%)
Constipation 73 (34.0%)
Diarrhoea 5 (2.3%)
Drymouth 20 (9.3%)
Dyspepsia 3 (1.4%)
Nausea 70 (32.6%)
Vomiting 18 (8.4%)
General disorders and administration site conditions
Fatigue 9 (4.2%)
Weakness 24 (11.2%)
Immune system disorders
Metabolism and nutrition disorders
Anorexia 16 (7.4%)
Musculoskeletal and connective tissue disorders
Arthralgia 3 (1.4%)
Dizziness 51 (23.7%)
Dysgeusia 8 (3.7%)
Headache 27 (12.6%)
Somnolence 65 (30.2%)
Insomnia 6 (2.8%)
Skin and subcutaneous tissue disorders
Pruritus 7 (3.3%)
Sweating increased 16 (7.4%)
Hypertension 5 (2.3%)
Hypertension aggravated 4 (1.9%)
The majority (67%) of patients who experienced the most commonadverse events (≥1%)
reported mild to moderate symptoms. Overall, onset ofthese adverse events usually
occurred within the firsttwo weeks of treatment.
Adverse Events with an Incidence of <1.0%(whether considered bythe clinical
investigator to be relatedto the studydrug or not):
Cardiac disorders: extrasystoles, palpitations, coronary artery insufficiency.
Eye disorders: visual acuityreduced, visual disturbance.
Gastrointestinal disorders: abdominal tenderness, duodenal ulcer aggravated, eructation,
flatulence, gastric irritation, gastritis,gastritis aggravated,gastroduodenitis, stomach
General disorders and administration site conditions: asthenia, chest pain, lethargy,
oedema peripheral, rigors, thirst.
Hepatobiliary disorders: biliarytract disorder, cholecystitis.
Infections and infestations: bronchitis acute,genitourinary tract infection, herpangina,
nasopharyngitis, pharyngitis, pyelonephritis chronic, sinusitis acute.
Injury, poisoning and proceduralcomplications: arthropod bite.
Investigations: blood cholesterol abnormal, blood pressure increased, gamma-
glutamyltransferase increased, liver functiontests abnormal, respiratory rate increased,
Metabolismand nutrition disorders: appetite increased, hypercholesterolemia,
Musculoskeletal and connective tissue disorders: Arthrosis, back pain, muscle cramps,
muscle spasms, neck pain, pain in limb.
Nervous system disorders: disturbance inattention, encephalopathy, hypersomnia,
hypoaesthesia, hypotonia, ischaemic stroke,parkinsonism aggravated,sciatica, tremor.
Psychiatric disorders: anxiety, crying, dyssomnia, dysthymic disorder, food aversion, libido
decreased,listless, nervousness, neurosis, restlessness, sleep disorder, stress symptoms,
Renal and urinary disorders: bacteriuria, difficulty in micturition, dysuria, nephritis
Reproductive system and breastdisorders: breast pain.
Respiratory,thoracic and mediastinal disorders: pharyngolaryngeal pain, rhinitis.
Skin and subcutaneous tissue disorders: photodermatosis, rash.
Vascular disorders: essential hypertension,flushing, hot flushes, thrombophlebitis
superficial, vein pain.
Other Adverse Experiences PreviouslyReportedin Clinical Trialsor Post-Marketing
Reports with Tramadol Hydrochloride
Adverse events which have beenreported with the use oftramadol products include
convulsions. Other adverse events whichhave been reported with the use of tramadol
products and for which a causal association has not been determined include: difficulty
concentrating, hepatitis, liver failure, pulmonary oedema, Stevens-Johnson syndrome and
Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia,
fever, shivering, tremor, agitation, diaphoresis, seizuresand coma) has been reported with
tramadol when used concomitantly with otherserotonergic agents such as SSRIs and
Adverse reactions that may occur after administration of tramadol resemble those known to
occur with opioids. Adverse reactions were recorded in 13,802 patientsfrom trials with
different formulations of tramadol. The nature and incidence ofreactions (in CIOMS format
where very common = > 1/10; common = >1/100 and <1/10; uncommon = >1/1000 and
<1/100; rare = >1/10,000 and <1/1000; and very rare = <1/10,000) were as follows:
Blood and lymphatic system disorders
Uncommon: anaemia, lymphadenopathy, thrombocytopenia
Uncommon: orthostatic dysregulation (tendency to collapse and cardiovascularcollapse),
acute myocardial infarction, anginapectoris, anginaunstable, atrial fibrillation,
bradycardia, cardiovascular disorder, palpitations, sinus tachycardia,
Ear and labyrinth disorders
Uncommon: cerumen impaction, ear congestion,ear discomfort, ear pain, labyrinthitis,
Very rare: Syndrome of inappropriate antidiuretic hormone secretion characterised by
hyponatraemia secondary to decreased free water excretion
Uncommon:cataract, dry eyes, eye pain, eyelid disorder, lacrimation increased,
photopsia, scleral haemorrhage, blurred vision
Uncommon:abdominal discomfort, lower abdominal pain, abdominal tenderness, change
in bowel habit, constipation aggravated,diverticulitis, dyspepsia aggravated,
dysphagia, faecal impaction, faeces discoloured, food poisoning,
gastrointestinal haemorrhage, gastrointestinal irritation, gastro-oesophageal
reflux disease, hiccups, lip blister,loose stools, pancreatitis aggravated,
rectal haemorrhage, rectal prolapse, retching, small intestinal obstruction,
urge to vomit
Very rare: elevated liver enzymes
General disorders and administration site conditions
Uncommon:chest tightness, fall, feeling abnormal, feelingcold, inflammation localised,
inflammation, influenza like illness,malaise, mass, pain
Hypersensitivity and skin
Rare: shock reactions, anaphylaxis
Immune system disorders
Uncommon:hypersensitivity, seasonal allergy
Infections and infestations
Uncommon:abscess limb, bladder infection, bronchitis, ear infection, erysipelas, foot
infection fungal, fungal infection, gastroenteritis, gastroenteritis viral,
gastrointestinal infection, helicobacter infection, herpes simplex, herpes
zoster, laryngitis acute, nail fungal infection,otitis externa, otitis media, otitis
media serous, respiratory tract infection viral, sinusitis, stye, tooth abscess,
tooth infection, tracheitis, vaginosisfungal, viral infection,wound infection
Injury, poisoning and procedural complications
Uncommon:abrasion, back injury, blister,concussion, eye injury, face injury, hand
fracture, head injury, joint sprain, laceration, ligament injury, limb injury,
muscle injury, muscle strain, neck injury, postoperative wound complication,
soft tissue injury, tendon injury, wrist fracture
Uncommon:alanine aminotransferase decreased, alanineaminotransferase increased,
aspartate aminotransferase decreased, aspartate aminotransferase
increased, blood amylase increased,blood calcium increased, blood
cholesterol increased, blood creatinineincreased, blood glucose abnormal,
blood glucose increased, blood in stool, blood potassium abnormal, blood
urea increased, body temperature increased, cardiac murmur, c-reactive
protein increased, haematocrit decreased, haematocrit increased,
haemoglobin decreased, haemoglobin increased, low density lipoprotein
increased, lymphocyte count increased, mammogram abnormal, mean
platelet volume decreased, neutrophil count decreased,protein total
decreased,red blood cell count decreased, red blood cell count increased,
red blood cell sedimentation rate increased, red cell distribution width
increased, white blood cell count increased
Metabolismand nutrition disorders
Uncommon:decreasedappetite,dehydration,diabetes mellitus, gout, hyperglycaemia,
hyperlipidemia, hypertriglyceridaemia, hypocalcaemia, hypokalaemia
Musculoskeletal and connective tissue disorders
Uncommon:back disorder, bone pain, bone spur, bursitis, ganglion, groin pain, joint
crepitation, joint disorder, joint stiffness, joint swelling, musculoskeletal
discomfort, musculoskeletal stiffness,myalgia, neck pain, neck stiffness,
osteoarthritis aggravated, osteopenia,osteoporosis, plantar fasciitis,
polyarthralgia, rheumatoid arthritis,temporomandibular joint arthralgia,
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Uncommon:benign breast neoplasm, breast cancer invasive, breast cancer, thyroid
neoplasm, uterine fibroids
Uncommon: trembling, ataxia, burning sensation, disturbance in attention, dysarthria,
dysgeusia, gait abnormal, headache aggravated, hypoaesthesia, mental
impairment, migraine, neuralgia, paraesthesia, sinus headache, sleep
Rare: changes in mood (usually elevation,occasionally dysphoria) paraesthesia,
hallucinations, confusion, coordination disturbance, sleep disturbance,
nightmares, respiratory depression, seizures, involuntarymuscle
contractions, changes in activity (usually suppression, occasionallyincrease),
changes in cognitive and sensorial capacity (eg. Decision behaviour,
Uncommon:abnormal behaviour, agitation, bipolar disorder, confusion, depression,
emotional disturbance,euphoricmood, indifference, irritability
Renal and urinary disorders
Uncommon:calculus renal, haematuria, micturition urgency, nocturia, renal impairment,
renal pain, urinary frequency,urinary hesitation, urinary incontinence, urinary
Reproductive system and breast disorders
Uncommon:dysmenorrhoea, erectile dysfunction, genital pruritus female,
menometrorrhagia, prostatitis, sexualdysfunction, vaginal cyst, vaginal
Uncommon:asthma, chest wall pain, cough,crackles lung, dry throat, dyspnoea,
epistaxis, nasal congestion, nasal oedema,productive cough, rhinitis allergic,
rhinorrhea, rhonchi, sinus congestion,sinus pain, throat irritation.
Very rare: worsening of asthma (causality not established), respiratory depression
(when the recommended doses are considerably exceeded and other
respiratory depressantsubstancesare administered concomitantly)
Skin and subcutaneous tissue disorders
Uncommon:acne, cold sweat, contusion, dermatitis allergic, dermatitiscontact, dermatitis,
dermatitis aggravated, dermatosis, dryskin, eczema exacerbated, eczema,
erythema, hyperkeratosis,ingrowing nail, night sweat, pallor, piloerection,
prurigo, pruritus generalised, rash pruritic, rosacea, skin ulcer, urticaria
Surgical and medical procedures
Uncommon:cardiac pacemaker replacement,colon polypectomy,endodontic procedure,
foot operation, hernia repair, lesion excision, tumour excision
Uncommon:aortic aneurysm, deep venous thrombosis, haematoma, hot flushes
aggravated, hypertension aggravated, hypertension, hypotension, orthostatic
hypotension, poor peripheral circulation, vascular insufficiency, wound
The incidence of “CNS irritation” (dizziness), “autonomic nervous effects” (perspiration),
“orthostatic dysregulation” (tendency to collapse and cardiovascularcollapse) and
tachycardia and “nausea/urge to vomit/vomiting”can be increased with rapid intravenous
administration and alsotends to be dosedependent. No tests of significance have been
Drug abuse and dependence
Although tramadol can producedrug dependence of the µ-opioidtype (like codeine or
dextropropoxyphene) andpotentially may be abused, there has been little evidence of
abuse in clinical experience to date. In clinical trials, tramadol produced some effects
similar to an opioid, and at supratherapeuticdoses was recognised as an opioid in
subjective/behavioural studies. Part of the activity of tramadol is thought to be derived from
its active metabolite which is responsible for some delayin onset of activity and some
extension of the duration of µ-opioid activity. Delayed µ-opioid activity is believed to reduce
a drug’s abuse liability.
Tolerance and withdrawal
Tolerance development has beenreported to be relatively mild. Symptoms of withdrawal
reactions, similar to those occurring duringopiate withdrawal, may occur as follows:
agitation, anxiety, nervousness, insomnia,hyperkinesia, tremor and gastrointestinal
symptoms. Other symptoms thathave very rarely been seen with tramadol discontinuation
include panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus and unusual
DOSAGE AND ADMINISTRATION
DUROTRAM ® XR tablets must be swallowed wholewith liquid and not broken, chewed,
dissolved or crushed.
DUROTRAM ® XR can be taken with or without food. DUROTRAM ® XR dosage should be
individualised according to patient need usingthe lowest effective dose. The maximum
recommended dose of 400 mg once daily should not be exceeded.
Before using DUROTRAM ® XR for longer than three months, re-assessment of the patient
should be undertaken in order to determine whether ongoing treatment is required. If long-
term tramadol treatmentis required, careful and regularmonitoring should be undertaken
to establish whether, and towhat extent, ongoing treatmentwith the medicine is necessary.
Alternative tablet strengths of DUROTRAM ® XR are available.Where necessary,
appropriate tablet strengths should be used to achieve the required dose.
The starting dose is one 100 mgprolonged-release tablet once daily. The usual dose is
one 200 mg prolonged-release tablet once daily,to be taken preferably in the evening.
If this doesnot provide sufficientpain relief, the dosage can be increased in 100 mg dose
increments to a maximum of 400 mg once daily.
In general, the lowest effective analgesic dose should be chosen.
DUROTRAM ® XR should not be usedfora period longer thanabsolutelynecessary. If
continued pain treatment is necessary due tothe nature and severity of the illness, careful
regular surveillance should becarried out(including periods without treatment, if
necessary) in order to determinethe need for continued treatment.
Children and Adolescents (<18 years)
DUROTRAM ® XR is not recommended for the treatment of children (under 18 years of age).
(See also PHARMACOKINETICS and PRECAUTIONS.)
Elderly patients (>65 YEARS)
Dose adjustment in elderlypatients (up to75 years of age)without clinically relevant
hepatic or renal impairment isnormally not necessary. In patients over 75 years, the
elimination half-lifeof tramadol may be prolonged. The use of DUROTRAM ® XRinpatients
over 75 years of age is not recommended. (See also PHARMACOKINETICS and
DUROTRAM ® XR iscontraindicatedpatients with severe renal impairment (creatinine
clearance <30 mL/min). (See also PHARMACOKINETICS, CONTRAINDICATIONS and
DUROTRAM ® XR is contraindicated in patientswith severe hepatic impairment. (See also
PHARMACOKINETICS, CONTRAINDICATIONS and PRECAUTIONS.)
If a patient forgets to take one or more doses, they should take their next dose atthe
normal time and in the normal amount.
Acute tramadol overdosage canresult in respiratory depression, somnolence progressing
to stupor or coma, skeletalmuscle flaccidity, cold and clammy skin, constricted pupils,
bradycardia, hypotension and death.
Deaths due to overdose have been reported with abuse and misuse of tramadol, by
ingesting, inhaling or injecting the crushed tablets. Review of case reports has indicated
that the risk of fatal overdoseis further increased whentramadol is abused concurrently
with alcohol or other CNS depressants, including other opioids.
In the treatment of tramadoloverdosage, primary attention should be given to the re-
establishment of a patent airwayand institution ofassisted or controlled ventilation.
General treatment measures should be employed in the management ofrespiratory failure
and/or circulatory shock accompanying overdose.
While naloxone will reverse some, but not all, symptoms caused by overdosage with
tramadol, the risk of seizures isalso increased with naloxone administration. In animals,
convulsions following the administration of toxic doses oftramadol could be suppressed
with barbiturates or benzodiazepinesbutwere increased with naloxone. Naloxone
administration did not change the lethality of an overdose in mice. Hemodialysis isnot
expected to be helpful in an overdose because itremoves less than 7% of the administered
dose in a 4-hour dialysis period.
The use of activated charcoal should be considered within the first 1-2 hours after
ingestion. As release of tramadol can be sustained following ingestion of DUROTRAM ® XR,
gastric lavage and other procedures to decontaminate the bowel should be considered.
Information on the treatment of overdosage should be obtained from the Poisons
Information Centre (Phone 13 12 26).
PRESENTATION AND STORAGE CONDITIONS
DUROTRAM ® XR is available as 100 mg, 200 mg and300 mg tablets. They are white to
off-white, plain, bevelled edge round biconvextablets. The 100 mg tablets are marked
“LP100”, the 200 mg tablets are marked “LP200” and the 300 mg tablets are marked
“LP300” in black ink.
Supplied in blister packs containing 2*, 3, 5*, 10, 20* and 30* tablets.
* Not currently marketed.
Store below 30°C.
NAME AND ADDRESS OFTHE SPONSOR
iNova Pharmaceuticals (Australia) Pty Limited
9 – 15 Chilvers Road
Thornleigh NSW 2120
® = Registered Trademark
DUROTRAM ® XR is a trademark licensed to iNova Pharmaceuticals
S4 Prescription Only Medicine
Date of TGA Approval:
1 May 2008