Durotram XR

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Active ingredient:
Tramadol hydrochloride 300 mg
Available from:
iNova Pharmaceuticals (New Zealand) Limited
INN (International Name):
Tramadol hydrochloride 300 mg
Dosage:
300 mg
Pharmaceutical form:
Modified release tablet
Composition:
Active: Tramadol hydrochloride 300 mg Excipient: Colloidal silicon dioxide Distarch phosphate Hydrogenated vegetable oil Magnesium stearate Opacode black S-1-17823 Polyvinyl acetate Povidone Sodium laurilsulfate Xanthan gum
Units in package:
Blister pack, PVC/PVDC/Al, 2 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Perrigo API Ltd
Therapeutic indications:
Relief of moderate to severe pain
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/PVDC/Al - 2 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, PVC/PVDC/Al - 3 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, PVC/PVDC/Al - 5 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, PVC/PVDC/Al - 10 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, PVC/PVDC/Al - 20 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, PVC/PVDC/Al - 30 tablets - 36 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-8145b
Authorization date:
2008-06-24

PRODUCT INFORMATION

DUROTRAM ®

XR

Tramadol Hydrochloride

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

Chemical structure:

.HCl

Molecular formula: C

.HCl

Molecular weight: 299.84

CAS registry no. 36282-47-0

DESCRIPTION

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

tramadol hydrochloride.

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

PHARMACOLOGY

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

Pharmacokinetics.)

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.

PHARMACOKINETICS

ABSORPTION

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 (ƒ), 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 (ƒ), 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)

TramadolM1 Metabolite

Pharmacokinetic

Parameter DUROTRAM XR 200 mg

Tablet Once-Daily DUROTRAM XR 200 mg Tablet

Once-Daily

0-24

(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

(Figure 3).

Time (h) 0 4 8 12 16 20 24 Con centratio n (ng /mL )

0 100 200 300 400

Tramadol

M1

Figure3. MeanTramadolPlasmaConcentrationsatSteady-StateFollowingOralAdministrationof

Durotram ® XR 200mgOnceDaily

FOOD EFFECT

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

concentration (C

) 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”.)

DISTRIBUTION

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.

METABOLISM

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.

ELIMINATION

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

hours, respectively.

SPECIAL POPULATIONS AND CONDITIONS

RENAL IMPAIRMENT

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.

HEPATIC IMPAIRMENT

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

ADMINISTRATION.)

ELDERLY

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

ADMINISTRATION.)

SEX

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.

CLINICALTRIALS

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.

INDICATIONS

Relief of moderate to severe pain.

CONTRAINDICATIONS

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

opioid analgesics)

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

PRECAUTIONS

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

Other opioids.

Administration of tramadol may enhance the seizure risk in patients taking:

MAO inhibitors (see CONTRAINDICATIONS),

Neuroleptics, or

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

machinery.

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

area basis).

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

pregnancy.

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

maternotoxic dose.

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

are unknown.

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

Overview

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.

Drug-Drug Interactions

MAO Inhibitors

Tramadol is contraindicated in patients receiving MAO inhibitors or who have used them

within the previous14 days. (See CONTRAINDICATIONS, WARNINGS AND

PRECAUTIONS.)

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

PRECAUTIONS.)

CNS Depressants

Concurrent administration of tramadol with other centrally actingdrugs, including alcohol,

centrally acting analgesics, opioids and psychotropic drugs may potentiateCNS

depressanteffects.

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

concentrations.

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.

Other Interactions

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-

operative pain.

ADVERSE EVENTS

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%)

Cardiac disorders

Angina pectoris 4 (1.9%)

Ear and labyrinth disorders

Vertigo 5 (2.3%)

Gastrointestinal disorders

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

Hypersensitivity3 (1.4%)

Metabolism and nutrition disorders

Anorexia 16 (7.4%)

Musculoskeletal and connective tissue disorders

Arthralgia 3 (1.4%)

Nervous systemdisorders

Dizziness 51 (23.7%)

Dysgeusia 8 (3.7%)

Headache 27 (12.6%)

Somnolence 65 (30.2%)

Psychiatric disorders

Insomnia 6 (2.8%)

Skin and subcutaneous tissue disorders

Pruritus 7 (3.3%)

Sweating increased 16 (7.4%)

Vascular disorders

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

discomfort, toothache.

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,

weight decreased.

Metabolismand nutrition disorders: appetite increased, hypercholesterolemia,

hyperuricaemia.

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,

tension.

Renal and urinary disorders: bacteriuria, difficulty in micturition, dysuria, nephritis

interstitial, leukocyturia.

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

suicidal tendency.

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

MAOIs.

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

Cardiovascular

Uncommon: orthostatic dysregulation (tendency to collapse and cardiovascularcollapse),

acute myocardial infarction, anginapectoris, anginaunstable, atrial fibrillation,

bradycardia, cardiovascular disorder, palpitations, sinus tachycardia,

tachycardia

Ear and labyrinth disorders

Uncommon: cerumen impaction, ear congestion,ear discomfort, ear pain, labyrinthitis,

tinnitus

Endocrine disorders

Uncommon: hypothyroidism

Very rare: Syndrome of inappropriate antidiuretic hormone secretion characterised by

hyponatraemia secondary to decreased free water excretion

Eye disorders

Uncommon:cataract, dry eyes, eye pain, eyelid disorder, lacrimation increased,

photopsia, scleral haemorrhage, blurred vision

Gastrointestinal

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

Hepatobiliary disorders

Uncommon: cholelithiasis

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

Investigations

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,

tendonitis

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon:benign breast neoplasm, breast cancer invasive, breast cancer, thyroid

neoplasm, uterine fibroids

Neurological

Common: sedation

Uncommon: trembling, ataxia, burning sensation, disturbance in attention, dysarthria,

dysgeusia, gait abnormal, headache aggravated, hypoaesthesia, mental

impairment, migraine, neuralgia, paraesthesia, sinus headache, sleep

apnoea syndrome

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,

perception disorders),syncope

Psychiatric disorders

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

retention

Reproductive system and breast disorders

Uncommon:dysmenorrhoea, erectile dysfunction, genital pruritus female,

menometrorrhagia, prostatitis, sexualdysfunction, vaginal cyst, vaginal

discharge

Respiratory

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.

Rare: dyspnoea

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

Vascular disorders

Uncommon:aortic aneurysm, deep venous thrombosis, haematoma, hot flushes

aggravated, hypertension aggravated, hypertension, hypotension, orthostatic

hypotension, poor peripheral circulation, vascular insufficiency, wound

haemorrhage

Special senses

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

performed.

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

CNS symptoms.

DOSAGE AND ADMINISTRATION

General Advice

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.

Adults

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

PRECAUTIONS.)

Renal impairment

DUROTRAM ® XR iscontraindicatedpatients with severe renal impairment (creatinine

clearance <30 mL/min). (See also PHARMACOKINETICS, CONTRAINDICATIONS and

PRECAUTIONS.)

Hepatic impairment

DUROTRAM ® XR is contraindicated in patientswith severe hepatic impairment. (See also

PHARMACOKINETICS, CONTRAINDICATIONS and PRECAUTIONS.)

Missed Dose

If a patient forgets to take one or more doses, they should take their next dose atthe

normal time and in the normal amount.

OVERDOSAGE

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.

Storage

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

POISONSCHEDULE

S4 Prescription Only Medicine

Date of TGA Approval:

1 May 2008

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