Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: RUMATOR 30, 60, 90, 120 mg

Dosage form and strength: Film coated tablet and 30, 60, 90 & 120 mg etoricoxib respectively

PROPOSED PROFESSIONAL INFORMATION FOR RUMATOR 30, 60, 90 & 120 mg

SCHEDULING STATUS

S3

1 NAME OF THE MEDICINE

RUMATOR 30 mg (film coated tablets)

RUMATOR 60 mg (film coated tablets)

RUMATOR 90 mg (film coated tablets)

RUMATOR 120 mg (film coated tablets)

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

RUMATOR 30 mg:

Each film coated tablet contains 30 mg etoricoxib.

Contains sugar (lactose monohydrate) 0,56 mg per tablet.

RUMATOR 60 mg:

Each film coated tablet contains 60 mg etoricoxib.

Contains sugar (lactose monohydrate) 1,12 mg per tablet.

RUMATOR 90 mg:

Each film coated tablet contains 90 mg etoricoxib.

Contains sugar (lactose monohydrate) 1,68 mg per tablet.

RUMATOR 120 mg:

Each film coated tablet contains 120 mg etoricoxib.

Contains sugar (lactose monohydrate) 2,24 mg per tablet.

For full list of excipients, see section 6.1.

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Product proprietary name: RUMATOR 30, 60, 90, 120 mg

Dosage form and strength: Film coated tablet and 30, 60, 90 & 120 mg etoricoxib respectively

3 PHARMACEUTICAL FORM

RUMATOR 30 mg: Blue green coloured, apple shaped, biconvex film coated tablets, debossed with 96 on

one side and J on other side.

RUMATOR 60 mg: Blue green coloured, apple shaped, biconvex film coated tablets, debossed with 97 on

one side and J on other side.

RUMATOR 90 mg: White, apple shaped, biconvex film coated tablets, debossed with 98 on one side and J

on other side.

RUMATOR 120 mg: Pale green coloured, apple shaped, biconvex film coated tablets, debossed with 99 on

one side and J on other side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

RUMATOR is indicated for:

•

Symptomatic relief of osteoarthritis (OA) and rheumatoid arthritis (RA).

Treatment of ankylosing spondylitis (AS).

Treatment of acute gouty arthritis.

Short term relief of acute pain, treatment limited to a maximum period of 8 days.

Treatment of primary dysmenorrhoea.

Treatment of moderate to severe acute post-operative pain associated with dental surgery.

The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual

patient's overall risks (see section 4.4).

4.2 Posology and method of administration

Posology

RUMATOR should be administered for the shortest duration possible and the lowest effective daily dose

should be used.

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Product proprietary name: RUMATOR 30, 60, 90, 120 mg

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Osteo-Arthritis (OA): The recommended dose is 30 mg once daily. In some patients with insufficient relief

from symptoms, the dose may be increased to 60 mg once daily.

Rheumatoid Arthritis (RA): The recommended dose is 90 mg once daily. In some patients 60 mg once

daily may provide adequate therapeutic benefit.

Ankylosing Spondylitis: The recommended dose is 90 mg once daily. In some patients 60 mg once daily

may provide adequate therapeutic benefit.

Short term relief of Acute Pain: The recommended dose is 90 mg or 120 mg once daily, limited to a

maximum of 8 days’ treatment.

Acute Gouty Arthritis: The recommended dose is 120 mg once daily, limited to a maximum of 8 days’

treatment.

Primary Dysmenorrhoea: The recommended dose is 120 mg once daily.

Post-operative Dental Pain: The recommended dose is 90 mg once daily.

Doses greater than those recommended for each indication have either not demonstrated additional efficacy

or have not been studied.

Therefore:

The dose for OA should not exceed 60 mg daily.

The dose for RA should not exceed 90 mg daily.

The dose for ankylosing spondylitis should not exceed 90 mg daily.

The dose for acute gout should not exceed 120 mg daily.

The dose for acute pain and primary dysmenorrhoea should not exceed 120 mg daily.

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Product proprietary name: RUMATOR 30, 60, 90, 120 mg

Dosage form and strength: Film coated tablet and 30, 60, 90 & 120 mg etoricoxib respectively

The dose for Post-operative acute dental surgery pain should not exceed 90 mg dally.

As the cardiovascular risks of RUMATOR may increase with dose and duration of exposure, the shortest

duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic

relief and response to therapy should be re-evaluated periodically (see section 4.4).

Special populations

Elderly:

No dosage adjustment in RUMATOR is necessary for the elderly, although the elderly may be more

susceptible to renal, gastrointestinal and cardiovascular adverse effects (see sections 4.4 and 4.8).

Hepatic Insufficiency:

In patients with mild hepatic insufficiency (Child-Pugh score 5 to 6), a dose of 60 mg once dally should not

be exceeded.

In patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), the dose should be reduced; a dose

of 60 mg every other day should not be exceeded, administration of RUMATOR 30 mg once daily can also

be considered.

Clinical experience is limited particularly in patients with moderate hepatic dysfunction. In patients with

severe hepatic insufficiency (Child-Pugh score > 9), the use of RUMATOR is contraindicated (see section

4.3).

Renal Insufficiency:

No dosage adjustment is necessary for patients with lesser degrees of renal insufficiency (creatinine

clearance ≥ 30 ml/min). The use of RUMATOR in patients with creatinine clearance < 30 ml/min is

contraindicated (see section 4.3).

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Product proprietary name: RUMATOR 30, 60, 90, 120 mg

Dosage form and strength: Film coated tablet and 30, 60, 90 & 120 mg etoricoxib respectively

Method of administration

RUMATOR is administered orally. RUMATOR may be taken with or without food.

4.3 Contraindications

•

Known hypersensitivity to etoricoxib or to any of the excipients of RUMATOR (see section 6.1).

Pregnancy and lactation (see section 4.6).

Patients with active peptic ulceration or gastrointestinal (GI) bleeding.

Patients with severe hepatic dysfunction (Child-Pugh score > 9 or serum albumin < 25 g/L).

Patients with severe renal impairment (creatinine clearance < 30 mL/min).

Patients who have developed signs of asthma, acute rhinitis, nasal polyps, angioedema or urticaria

following the administration of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs)

including RUMATOR.

•

Uncontrolled hypertension.

Children and adolescents under 16 years of age.

Patients with inflammatory bowel disease.

Patients with congestive heart failure (NYHA II - IV).

Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease

(see section 4.4).

•

Peri-operative analgesia in the setting of coronary artery bypass surgery (CABG).

Lithium therapy: Concomitant administration with RUMATOR may lead to toxic blood concentrations

of lithium (see section 4.5).

•

Digoxin: There was an approximate increase of 33 % in digoxin C_maxin healthy volunteers (see

section 4.5).

4.4 Special warnings and precautions for use

RUMATOR may predispose to cardiovascular events, gastrointestinal events or cutaneous reactions which

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Product proprietary name: RUMATOR 30, 60, 90, 120 mg

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may be fatal. Medically appropriate supervision should be maintained when using RUMATOR in the elderly

and in patients with renal, hepatic or cardiac dysfunction. Clinical trials suggest that selective COX₂inhibitor

class of medicines, such as RUMATOR, are associated with increased risk of arterial thrombotic events,

(especially myocardial infarction (MI) and stroke.

Long-term administration of NSAIDs such as RUMATOR, has resulted in renal papillary necrosis and other

renal injury. Renal prostaglandins may play a compensatory role in the maintenance of renal perfusion.

Therefore, under conditions of compromised renal perfusion, administration of RUMATOR may cause a

reduction in prostaglandin formation and secondarily, in renal blood flow and thereby impair renal function.

Patients at greatest risk of this response are those with pre-existing significantly impaired renal function,

uncompensated heart failure or liver cirrhosis. Monitoring of renal and hepatic function in such patients is

indicated.

Caution should be used when initiating treatment with RUMATOR in patients with dehydration. It is advisable

to rehydrate patients prior to starting therapy with RUMATOR.

In view of RUMATOR’s inherent potential to cause fluid retention, heart failure may be precipitated in some

compromised patients.

Fluid retention, oedema and hypertension have been observed in patients taking RUMATOR. All non-

steroidal anti-inflammatory drugs (NSAIDs), including RUMATOR, can be associated with new onset or

recurrent congestive heart failure. Caution should be exercised in patients with a history of cardiac failure,

left ventricular dysfunction or hypertension, and in patients with pre-existing oedema from any other reason.

If there is clinical evidence of deterioration in the condition of these patients, appropriate measures including

discontinuation of RUMATOR should be taken.

RUMATOR may be associated with more frequent and severe hypertension than other NSAIDs and other

selective COX-2 inhibitors. Therefore, special attention should be paid to blood pressure monitoring during

treatment with RUMATOR. If blood pressure rises significantly, alternative treatment should be considered.

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Product proprietary name: RUMATOR 30, 60, 90, 120 mg

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Clinical trials suggest that the selective COX-2 inhibitor class of medicines such as RUMATOR, are

associated with an increased risk of thrombotic events [especially myocardial infraction (Ml) and stroke]. As

the cardiovascular risks of selective COX-2 inhibitors such as RUMATOR may increase with dose and

duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The

patient's need for symptomatic relief and response to therapy should be re-evaluated periodically.

Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes

mellitus, smoking) should only be treated with RUMATOR after careful consideration.

RUMATOR is not a substitute for aspirin for cardiovascular prophylaxis because of its lack of effect

on platelets. Because RUMATOR does not inhibit platelet aggregation, anti-platelet therapies should not be

discontinued and if indicated, should be considered in patients at risk for or with a history of cardiovascular

or other thrombotic events. There is no evidence that concurrent use of aspirin mitigates the increased risk of

serious cardiovascular thrombotic events associated with RUMATOR.

For more details, refer to section 4.5.

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and

toxic epidermal necrolysis, have been reported in association with the use of selective COX-2 inhibitors such

as RUMATOR during post-marketing surveillance (see section 4.8). Serious hypersensitivity reactions (such

as anaphylaxis and angioedema) have been reported in patients receiving RUMATOR (see section 4.8).

Selective COX-2 inhibitors have been associated with an increased risk of skin reactions in patients with a

history of any allergy. RUMATOR should be discontinued at the first appearance of skin rash, mucosal

lesions or any other sign of hypersensitivity.

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When using RUMATOR in the elderly and in patients with renal, hepatic or cardiac dysfunction, medically

appropriate supervision should be intensified. If these patients show deterioration during treatment,

appropriate measures should be taken, including discontinuation of RUMATOR.

Gastrointestinal Effects:

Upper gastrointestinal complications [perforations, ulcers or bleedings (PUBs)], some of them resulting in

fatal outcome, have occurred in patients treated with RUMATOR.

Caution is advised with treatment of patients at risk of developing a gastrointestinal complication with

RUMATOR; the elderly, patients using any other NSAIDs or acetylsalicylic acid concomitantly or patients

with a prior history of gastrointestinal disease, such as perforation, ulceration and gastrointestinal bleeding.

There is an increase in risk of gastrointestinal adverse effects (gastrointestinal ulceration or other

gastrointestinal complications) when RUMATOR is taken concomitantly with aspirin (even at low doses).

Elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (approximately 3 or

more times the upper limit of normal) have been reported in approximately 1 % of patients in clinical trials,

treated for up to 1 year with RUMATOR 60 mg and 90 mg daily.

Any patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function

test has occurred, should be evaluated for persistently abnormal liver function tests. If persistently abnormal

liver function tests (3 times the upper limit of normal) are detected, RUMATOR should be discontinued.

RUMATOR may mask fever and other signs of inflammation or infection.

The use of RUMATOR is not recommended in fertile women attempting to conceive.

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Product proprietary name: RUMATOR 30, 60, 90, 120 mg

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Due to inhibition of prostaglandin synthesis, fluid retention and oedema have been observed in patients

taking RUMATOR; therefore RUMATOR should be used with caution in patients with compromised cardiac

function, and other conditions predisposing to or worsened by fluid retention. Patients with pre-existing

congestive heart failure or hypertension should be closely monitored. All non-steroidal anti-inflammatory

drugs (NSAIDs), including etoricoxib, can be associated with new onset or recurrent congestive heart failure

(see section 4.8).

RUMATOR contains lactose. Patients with hereditary problems of galactose intolerance, e.g. galactosaemia,

the Lapp lactase deficiency or glucose galactose malabsorption should not take RUMATOR.

4.5 Interaction with other medicines and other forms of interaction

Ciclosporin and Tacrolimus: Co-administration of ciclosporin or tacrolimus with any NSAID may increase

the nephrotoxic effect of ciclosporin or tacrolimus. Renal function should be monitored when RUMATOR and

either of these medicines are used in combination.

Warfarin: In subjects stabilised on chronic warfarin therapy, the administration of etoricoxib 120 mg daily

was associated with an approximate 13 % increase in prothrombin time International Normalised Ratio

(INR). Standard monitoring of INR values should be conducted when therapy with RUMATOR is initiated or

changed in patients receiving warfarin or similar medicines.

Etoricoxib is metabolised by the cytochrome P450 isoenzymes, such as CYP3.Use of RUMATOR with other

medicines that inhibit or induce this isoenzyme, may result in changes in plasma concentration of

RUMATOR.

Rifampicin: Co-administration of etoricoxib with rifampicin, a potent inducer of hepatic metabolism by CYP

isoenzymes, produced a 65 % decrease in etoricoxib plasma area under the curve (AUC). This interaction

should be considered when RUMATOR is co-administered with rifampicin.

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Methotrexate: Two studies investigated the effects of etoricoxib 60, 90 or 120 mg administered once daily

for 7 days, in patients receiving once-weekly methotrexate doses of 7,5 mg to 20 mg for rheumatoid arthritis.

Etoricoxib 60 and 90 mg had no effect on methotrexate plasma concentrations (as measured by AUC) or

renal clearance. In one study, etoricoxib 120 mg had no effect on methotrexate plasma concentrations (as

measured by AUC) or renal clearance. In the other study, etoricoxib 120 mg increased methotrexate plasma

concentrations by 28 % (as measured by AUC) and reduced renal clearance of methotrexate by 13 %.

Monitoring for methotrexate-related toxicity should be considered, when RUMATOR at doses > 90 mg daily

and methotrexate are administered concomitantly.

Diuretics, Angiotensin Converting Enzyme (ACE) Inhibitors and Angiotensin Receptor Blockers

(ARBs): Reports suggest that nonselective NSAIDs and COX-2 selective inhibitors such as etoricoxib may

diminish the antihypertensive effect of diuretics, ACE inhibitors and Angiotensin Receptor Blockers (ARBs).

This interaction should be given consideration in patients taking RUMATOR concomitantly with these

products.

In patients with compromised renal function (e.g. elderly patients or patients who are volume depleted,

including those on diuretic therapy) who are being treated with RUMATOR, the co-administration of ACE

inhibitors or ARBs may result in a further deterioration of renal function, including possible acute renal failure.

These effects may be reversible. Therefore, the combination should be administered with caution, especially

in the elderly and in patients with impaired renal function. Patients should be adequately hydrated and

consideration should be given to monitoring of renal function after initiation of concomitant therapy, and

periodically thereafter.

Lithium: Reports suggest that etoricoxib may increase plasma lithium levels. This interaction should be

given consideration in patients taking RUMATOR concomitantly with lithium.

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Product proprietary name: RUMATOR 30, 60, 90, 120 mg

Dosage form and strength: Film coated tablet and 30, 60, 90 & 120 mg etoricoxib respectively

Aspirin: In a study in healthy subjects, at steady state, etoricoxib 120 mg once daily had no effect on the

anti-platelet activity of aspirin (81 mg once daily). RUMATOR may be used concomitantly with aspirin at

doses used for cardiovascular prophylaxis (low-dose aspirin). However, concomitant administration of low-

dose aspirin with etoricoxib increases the rate of gastrointestinal ulceration, and other complications

compared to use of etoricoxib alone. Concomitant administration of RUMATOR with doses of aspirin above

those for cardiovascular prophylaxis or with other NSAIDs should be avoided (see section 4.4).

Oral Contraceptives: Etoricoxib 60 mg given concomitantly with an oral contraceptive containing 35 mcg

ethinyl oestradiol (EE) and 0,5 mg to 1 mg norethindrone (NET) for 21 days, increased the steady state

AUC_0-24hof EE by 37 %. Etoricoxib 120 mg given with the same oral contraceptive concomitantly or

separated by 12 hours, increased the steady state AUC_0-24hof EE by 50 % to 60 %; however, (NET)

concentrations generally did not increase to a clinically relevant degree. This increase in EE concentration

should be considered when selecting an appropriate oral contraceptive for use with RUMATOR. An increase

in EE exposure can increase the incidence of adverse events associated with oral contraceptives (e.g.

venous thromboembolic events in women at risk).

Furosemide: Clinical studies have shown that NSAIDs such as etoricoxib, contained in RUMATOR reduce

the natriuretic and antihypertensive effect of furosemide and thiazides in patients. This response has been

attributed to inhibition of renal prostaglandin synthesis.

Hormone Replacement Therapy: Administration of etoricoxib 120 mg, contained in RUMATOR 120 mg

with hormone replacement therapy consisting of conjugated oestrogens (0,625 mg conjugated oestrogens

for 28 days, increased the mean steady state AUC_0-24hof unconjugated oestrone (41 %), equilin (76 %) and

17-beta-oestradiol (22 %). The effect of the recommended chronic doses of RUMATOR (60 mg and 90 mg)

has not been studied. The effects of etoricoxib 120 mg on the exposure (AUC_0-24h) to these oestrogenic

components of conjugated oestrogens were less than half of those observed, when conjugated oestrogens

was administered alone, and the dose was increased from 0,625 mg to 1,25 mg. The clinical significance of

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these increases is unknown, and higher doses of conjugated oestrogens were not studied in combination

with etoricoxib.

These increases in oestrogenic concentration should be taken into consideration when selecting post-

menopausal hormone therapy for use with RUMATOR, because the increase in oestrogen exposure might

increase the risk of adverse events associated with Hormone Replacement Therapy (HRT).

Effects of RUMATOR on medicines metabolised by sulfotransferases:

Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and has been shown to

increase the serum concentrations of ethinyl oestradiol. While knowledge about effects of multiple

sulfotransferases is presently limited and the clinical consequences for many medicines are still being

examined, it may be prudent to exercise care when administering RUMATOR concurrently with other

medicines primarily metabolised by human sulfotransferases (e.g. oral salbutamol and minoxidil).

Other: In interaction studies, RUMATOR did not have clinically significant effects on the pharmacokinetics of

prednisone/prednisolone. The risk of GI perforation, bleeding and ulceration (PUBs) is increased when taken

with corticosteroids.

Digoxin: RUMATOR etoricoxib 120 mg once daily for 10 days in healthy volunteers did not alter the steady

state plasma AUC_0-24hor renal elimination of digoxin. There was an increase in digoxin C_max(approximately

33 %). This increase is not generally important for most patients. Patients at high risk of digoxin toxicity

should be monitored for this when RUMATOR and digoxin are administered concomitantly.

Antacids did not have clinically significant effects on the pharmacokinetics of etoricoxib, such as contained in

RUMATOR.

Ketoconazole, a potent inhibitor of CYP3A4, dosed at 400 mg once a day for 11 days to healthy volunteers

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did not have any clinically important effect on the single-dose pharmacokinetics of 60 mg etoricoxib, such as

contained in RUMATOR 60 (43 % increase in AUC).

4.6 Fertility, pregnancy and lactation

RUMATOR is contraindicated in pregnancy and lactation. Regular use of non-steroidal anti-inflammatory

substances during the third trimester of pregnancy, may result in premature closure of the foetal ductus

arteriosus in utero, and possibly, in persistent pulmonary hypertension of the new-born. The onset of labour

may be delayed and its duration increased (see section 4.4).

Etoricoxib is excreted in the milk of lactating rats. Safety in human lactation has not been established.

Mothers should not breastfeed their infants while taking RUMATOR.

The use of RUMATOR is not recommended in women attempting to conceive.

4.7 Effects on ability to drive and use machines

RUMATOR may cause side effects such as dizziness. Patients should be advised not to drive or operate

machines until it is established that their ability to perform such activities is not affected.

4.8 Undesirable effects

b) Tabulated summary of adverse reactions

Infections and Infestations

Frequent: Alveolar osteitis

Less frequent: Gastroenteritis, upper respiratory infection, urinary tract infection

Blood and lymphatic system disorders

Less frequent: Anaemia, neutropenia, eosinophilia, agranulocytosis

Frequency unknown: Thrombocytopenia

Immune system disorders

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Frequency unknown: Hypersensitivity reactions, anaphylactic/anaphylactoid reactions including shock,

angioedema

Metabolism and nutrition disorders

Frequent: Oedema/fluid retention

Less frequent: Appetite increase or decrease, weight gain

Psychiatric disorders

Less frequent: Anxiety, depression, mental acuity decreased

Frequency unknown: Nervousness, confusion, hallucinations

Nervous system disorders

Frequent: Dizziness, headache

Less frequent: Insomnia, paraesthesia/hypaesthesia, dysgeusia

Frequency unknown: Somnolence, cerebrovascular incidents (strokes)

Eye disorders

Less frequent: Conjunctivitis

Frequency unknown: Blurred vision

Ear and labyrinth disorders

Less frequent: Tinnitus, vertigo

Cardiac disorders

Frequent: Palpitations

Less frequent: Atrial fibrillation, congestive heart failure, non-specific ECG changes, myocardial infarction,

angina pectoris, myocardial infarction, cardiovascular thrombotic events

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Dosage form and strength: Film coated tablet and 30, 60, 90 & 120 mg etoricoxib respectively

Frequency unknown: Dysrhythmia and tachycardia

Vascular disorders

Frequent: Hypertension

Less frequent: Flushing, transient ischaemic attack, vasculitis

Frequency unknown: Hypertensive crisis, peripheral oedema

Respiratory, thoracic and mediastinal disorders

Less frequent: Cough, dyspnoea, epistaxis

Frequency unknown: Bronchospasms

Gastrointestinal disorders

Frequent: Gastrointestinal disorders (e.g. abdominal pain, flatulence, heartburn), diarrhoea, dyspepsia,

epigastric discomfort, nausea, vomiting, oesophagitis, oral ulcer

Less frequent: Abdominal distension, acid reflux, bowel movement pattern change, constipation, dry mouth,

gastro duodenal ulcer, irritable bowel syndrome, pancreatitis, gastritis, peptic ulcer including GI perforation

and bleeding (sometimes fatal)

Frequency unknown: Melaena, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease,

haematemesis, gastritis

Hepato-biliary disorders

Frequent: Increased ALT, increased AST

Less frequent: Hepatitis, hepatic failure, jaundice

Skin and subcutaneous tissue disorders

Frequent: Ecchymosis

Less frequent: Facial oedema, pruritus, rash, erythema, urticaria, bulbous reactions including Stevens-

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Johnson syndrome, toxic epidermal necrolysis, fixed drug eruptions

Musculoskeletal and connective tissue disorders

Less frequent: Muscular cramp/spasm, musculoskeletal pain/stiffness

Renal and urinary disorders

Less frequent: Proteinuria, increased serum creatinine, renal insufficiency, renal failure, maybe reversible

upon discontinuation of treatment (see section 5.2)

Frequency unknown: Nephrotoxicity (such as interstitial nephritis and nephrotic syndrome)

General disorders and administrative site conditions

Frequent: Asthenia/fatigue, flu-like disease

Less frequent: Chest pain

Investigations

Less frequent: Blood urea increased, creatine phosphokinase increased, haematocrit decreased,

haemoglobin decreased, hyperkalaemia, leukocytes decreased, platelets decreased, uric acid increased,

blood sodium decreased

c) Description of selected adverse reactions

Serious undesirable effects have been reported associated with the use of NSAIDs and cannot be ruled out:

nephrotoxicity including interstitial.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued

monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any

suspected adverse reactions via the “6.04 Adverse Drug Reactions Reporting Form”, found online under

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SAHPRA’s publications: https://www.sahpra.org.za or to the Holder of certificate of registration through the

mail: pvg.cdma@heterogroups.com

4.9 Overdose

Overdosage:

The most frequently observed adverse experiences were gastrointestinal events, renovascular events.

Treatment:

In the event of overdose, it is reasonable to employ the usual supportive measures e.g. remove unabsorbed

material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if

required. Etoricoxib is not dialysable by haemodialysis; it is not known whether etoricoxib is dialysable by

peritoneal dialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacological classification: A 3.1 Anti-Rheumatics (Anti-inflammatory Agents)

Etoricoxib is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and

antipyretic activities in animal models. Etoricoxib is an orally active, selective cyclo-oxygenase-2 (COX-2)

inhibitor.

5.2 Pharmacokinetic properties

Absorption:

Orally administered etoricoxib is absorbed with a mean oral bioavailability of approximately 100 %. Following

120 mg once-daily dosing to steady state, the peak plasma concentration (geometric mean C_max= 3,6

mcg/mL) was observed at approximately 1 hour (T_max) after administration to fasted adults. The geometric

mean AUC_0-24hwas 37,8 mcg/h/mL. The pharmacokinetics of etoricoxib are linear across the clinical dose

range.

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Dosage form and strength: Film coated tablet and 30, 60, 90 & 120 mg etoricoxib respectively

A standard meal had no clinically meaningful effect on the extent or rate of absorption of a dose of etoricoxib

120 mg. In clinical trials, etoricoxib was administered without regard to food.

The pharmacokinetics of etoricoxib in 12 healthy subjects (40 to 65 years of age) were similar (comparable

AUC, C_maxwithin approximately 20 %) when administered alone or a calcium carbonate antacid

(approximately 50 mEq acid-neutralising capacity).

Distribution:

In humans, etoricoxib is approximately 92 % bound to plasma protein over the range of concentrations of

0,05 mcg/mL to 5 mcg/mL. The volume of distribution at steady state (V_dss) is approximately 120 litre.

Etoricoxib crosses the placenta and the blood-brain barrier.

Biotransformation:

Etoricoxib is extensively metabolised in the liver with < 1 % of a dose recovered in urine as the parent drug

compound. The major route of metabolism to form the 6' hydroxymethyl derivative is catalysed by

cytochrome P450 (CYP) enzymes.

Five metabolites have been identified in man. The principal metabolite is the 6'-carboxylic acid derivative of

etoricoxib formed by further oxidation of the 6'-hydroxymethyl derivative. These principal metabolites either

demonstrate no measurable activity or are only weakly active as COX-2 inhibitors.

Elimination:

Following administration of a single 25 mg radio-labelled intravenous dose of etoricoxib to healthy subjects,

70 % of radioactivity was recovered in urine and 20 % in faeces, mostly as metabolites. Plasma and urine

were collected for 7 days and stool collected for 10 days, post-dose. Less than 2 % was recovered as

unchanged.

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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: RUMATOR 30, 60, 90, 120 mg

Dosage form and strength: Film coated tablet and 30, 60, 90 & 120 mg etoricoxib respectively

Elimination of etoricoxib occurs almost exclusively through metabolism followed by renal excretion. Steady

state concentrations of etoricoxib are reached within 7 days of once-daily administration of 120 mg, with an

accumulation ratio of approximately 2, corresponding to an accumulation half-life of approximately 22 hours.

The plasma clearance is estimated to be approximately 50 mL/min.

Characteristics in specific groups of subjects or patients

Elderly:

Pharmacokinetics in the elderly (65 years of age and older) with normal renal function are similar to those in

the young. In clinical studies, a higher incidence of adverse experiences was seen in older patients

compared to younger patients (see section 4.2).

Hepatic Insufficiency:

Patients with mild hepatic insufficiency (Child-Pugh score 5 to 6) administered etoricoxib 60 mg once daily

(for 21 days), had an approximately 16 % higher mean AUC as compared to healthy subjects given the

same regimen. Patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9) administered

etoricoxib 60 mg every other day (for 21 days), had similar mean AUC to the healthy subjects given

etoricoxib 60 mg once daily. There are no available clinical or pharmacokinetic data in patients with severe

hepatic insufficiency (Child-Pugh score > 9) (see sections 4.3 and 4.2, Hepatic Insufficiency).

Renal Insufficiency:

The pharmacokinetics of a single dose of etoricoxib 120 mg in patients with moderate (creatinine clearance

30 to 50 mL/min) to severe (creatinine clearance of < 30 mL/min) renal insufficiency, and patients with end-

stage renal disease on haemodialysis, were not significantly different from those in healthy subjects.

Haemodialysis contributed negligibly to elimination (dialysis clearance approximately 50 mL/min).

Paediatric population

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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: RUMATOR 30, 60, 90, 120 mg

Dosage form and strength: Film coated tablet and 30, 60, 90 & 120 mg etoricoxib respectively

The pharmacokinetics of etoricoxib in paediatric patients (< 12 years of age) has not been studied.

In a pharmacokinetic study (n=16) conducted in adolescents (aged 12 to 17) the pharmacokinetics in

adolescents weighing 40 kg to 60 kg given etoricoxib 60 mg once daily and in adolescents > 60 kg given

etoricoxib 90 mg once daily, were similar to the pharmacokinetics in adults given etoricoxib 90 mg once

daily. Safety and efficacy of etoricoxib in paediatric and adolescent patients have not been established (see

section 4.3).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

•

Calcium hydrogen phosphate anhydrous

Croscarmellose sodium

Lactose monohydrate

Magnesium stearate

Microcrystalline cellulose

Film coating and colourants:

•

RUMATOR 30 mg: Opadry II Green 32K510001 (containing FD&C Blue #2/Indigo Carmine

Aluminium Lake, hypromellose, iron oxide yellow, lactose monohydrate, titanium dioxide, triacetin),

Opadry Clear 02K19253 (containing hypromellose, triacetin).

•

RUMATOR 60 mg: Opadry II Green 32K510001 (containing FD&C Blue #2/Indigo Carmine

Aluminium Lake, hypromellose, iron oxide yellow, lactose monohydrate, titanium dioxide, triacetin),

Opadry Clear 02K19253 (containing hypromellose, triacetin).

•

RUMATOR 90 mg: Opadry II White 32K580000 (containing hypromellose, lactose monohydrate,

titanium dioxide, triacetin), Opadry Clear 02K19253 (containing hypromellose, triacetin).

RUMATOR 120 mg: Opadry II Green 32K510001 (containing FD&C Blue #2/Indigo Carmine

Aluminium Lake, hypromellose, iron oxide yellow, lactose monohydrate, titanium dioxide, triacetin),

Opadry Clear 02K19253 (containing hypromellose, triacetin).

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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: RUMATOR 30, 60, 90, 120 mg

Dosage form and strength: Film coated tablet and 30, 60, 90 & 120 mg etoricoxib respectively

6.2 Incompatibilities

Not applicable

6.3 Shelf life

24 months

6.4 Special precautions for storage

Store at or below 25 °C. Protect from light and moisture.

Keep the tablets in the original container until required for use.

This medicine does not require any special storage conditions.

6.5 Nature and contents of container

HDPE bottles:

White opaque HDPE container, with a white opaque polypropylene, ribbed, child-resistant plastic cap with

opening illustrations embossed on top. Each bottle contains a silica gel desiccant and purified cotton ball.

Pack sizes: 30 or 90 film coated tablets per bottle.

Blister strips:

PVC/Aluminium/OPA cold form foil (forming film) / plain Aluminium hard tempered foil (lidding foil) blisters,

containing 7 or 10 film coated tablets per blister.

Pack sizes: 7 film coated tablets per blister. 7, 14, 28 tablets per pack.

Pack sizes: 10 film coated tablets per blister. 10, 20, 30, 60, 90 tablets per pack.

HDPE bottle and blister strips are kept in an outer carton box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd

Product proprietary name: RUMATOR 30, 60, 90, 120 mg

Dosage form and strength: Film coated tablet and 30, 60, 90 & 120 mg etoricoxib respectively

No special requirements

7 HOLDER OF CERTIFICATE OF REGISTRATION

Hetero Drugs South Africa (Pty) Ltd.

Waterfall Corporate Campus

Building No. 2, First floor

74 Waterfall Drive

Midrand, 2066

8 REGISTRATION NUMBER(S)

RUMATOR 30 mg: 52/3.1/0420

RUMATOR 60 mg: 52/3.1/0421

RUMATOR 90 mg: 52/3.1/0422

RUMATOR 120 mg: 52/3.1/0423

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13 April 2021

10 DATE OF REVISION OF THE TEXT

07 April 2021

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