Voltaren suppository pil by pharmacia1.com

tb NOYARTISVoltareneAnti-inflammatory and anti-rheumatic product, non-steroid. acetic acid derivativ and related substance.

Cardiovascular Risk:• NSAIDs may cause an increased risk of seriouscardiovascular thrombotic events, myocardialinfarction, and stroke, which can be fatal. This riskmay increase with duration of use. Patients withcardiovascular disease or risk factors for cardiovas-cular disease may be at greater risk

• Voltaren is contraindicated for the treatment ofperi-operative pain in the setting of coronary arterybypass graft (CABG) Surgery .

Gastrointestinal Risk:• NSAIDs cause an increased risk of seriousgastrointestinal adverse events including bleedingulceration, and perforation of the stomach orintestines, which can be fatal. These events canoccur at any time during use and without warningsymptoms. Elder1y patients are at greater risk forserious gastrointestinal events.

COMPOSITION ANDPHARMACEUTICAL FORMThe active substance is sOdium-[0[(2,6-dichlorophenyl)-aminoj-phenyl)-acetale (= diclofenacSodium).One suppository contains 12.5 mg, 25 mg, 50 mg,or 100 mg of diclofenac sodium.For excipients, see section EXCIPIENTS.Certain dosage strengths may not be available inall countries.

INDICATIONSTreatment of:• Inflammatory and degenerative forms ofrheumatism; rheumatoid arthritis, juvenile rheumatoidarthritis, ankylosing spondylitis, osteoarthritis andspondylarthrttia. painful syndromes of the vertebralQumn, non-articular meumatism.• Acute attacks of gout.• Post-traumatic and post-operative pain,inflammation, and swelling, e.g. following dental ororthopaedic surgery.• Painful and/or inflammatory conditions ingynaecology, e.g. primary dysmenorrhoea oradnexitis.• Migraine attacks..As an adjuvant in severe painful inflammatory

infections of the ear, nose or throat, e.g. pharyngo-tonsillitis. otitis. In keeping with general therapeuUcprinciples, the u r1yingdisease should be treatedwith basic therapY,as appropriate. Fever alone is notan indication.

DOSAGE AND ADMINISTRATIONAs a general r mmendation, the dose should beindividually adju ted and the lowest effective dosegiven for the shortest possible duration.The suppositori s should be inserted well into therectum. It is r mmended to take the supposito-ries after passing stools.Not to be taken by mouth, as per rectal use only.

AdultsThe recommended initial daily dose is 100 to 150mg. In milder ases, as well as for long-termtherapy, 75 to 1 mg daily is usually sufficient.The total daily dose should generally be dividedinto 2 to 3 dose To suppress nocturnal pain andmorning stiffne ,treatment with tablets during theday can be supplemented by the administration ofa suppository at bedtime (up to a total maximumdaily dose of 150 rng).In primary dy norrhoea, the daily dose shouldbe individually adjusted and is generally 50 to 150mg. A dose of 50 to 100 mg should be given Initiallyand. if naces ,increased over the course ofseveral menstrual cycles up to a maximum of 200mglday. Treatm t should be started on appearanceof the first symptoms and, depending on thesymptomatology, continued for a few days.Treatment of migraine attacks with Voltarensuppositories should be started with a dose of 100mg at the first signs of an impending anack.Additional suppositories up to 100 mg may be takenon the same day if required. Should the patientrequire further therapy on the following days, themaximum daity dose should be limited to 150 mg individed doses.

Children and adolescentsChildren aged 1 year or over and adolescentsshould be given 0.5 102 mg/1<gbody weighl daily in2 to 3 divided doses, depending on the severity ofthe disorder.For treatment of juvenile rheumatoid arthritis, thedose can be raised up to a maximum of 3 mglkgdaily, given in divided doses.The maximum daily dose of 150 mg should not beexceeded.Voltaren 12.5 mg or 25 mg suppositories arerecommended for use in children and adolescentsbelow 14 years of age. Because of their dosage

strength, Voltaren 50 mg suppositories are notrecommended for children and adolescents below14 years of age.Vottaren 100 mg suppositories are not suitable forchildren and adolescents.

CONTRAINDICATIONS• Known hypersensitivity to the active substanceor to any of the excipients.• Active gastric or intestinal ulcer, bleeding orperforation.• Last trimester of pregnancy (see sectionPREGNANCY AND LACTATION).• Severe h patic renal and cardiac failure (seeseclion SPECIAL WARNINGS AND PRECAU-TIONS FOR U ).• Like other non-steroidal ann-Inflammatory drugs(NSAIDs), Voltaren Is al 0 onlrolndlcaled inpatients in whom attacks of sthmo, urticaria, oracute rhinitis are precipitated by acetylsolicylic acidor other NSAIOs.• Proctitis.

SPECIAL WARNINGS ANDPRECAUTIONS FOR USE

WarningsGastrointestinal bleeding, ulceration or perforation,which can be fatal, have been reported wit~ allNSAIOs and may occur at any time duringtreatment, with or without warning symptoms or aprevious history of serious gastrOintestinal events.They generally have more serious consequences inthe elderly. If gastrOintestinal bleeding or ulcerationoccur in patients receiving Voltaren, the medicinalproduct should be withdrawn.Serious skin reactions, some of them fatal,including exfoliative dermatitis, Stevens-Johnsonsyndrome and toxic epidermal necrolysis, havebeen reported very rarely in association with theuse of NSAIOs, including Voltaren (see sectionUNDESIRABLE EFFECTS). Patients appear 10beat highest risk of these reactions early in the courseof therapy, the onset of the reaction occurring in themajority of cases within the first month oftreatment. Voltaren should be discontinued at thefirst appearance of skin rash, mucosal lesions orany other sign of hypersensitivity.As with other NSAIOs, allergic reactions, includinganaphylactic/anaphylactoid reactions, can alsooccur in rare cases without earlier exposure todiclofenac.Like other NSAIOs, Vottaren may mask the signsand symptoms of infection due to its pharmacody-namic properties.

PrecautionsGeneralThe concomitant use of Voltaren with systemicNSAIOs including cyclooxyg nase-2 selectiveinhibitors, should be avoided du to the absence ofany evidence demonstrating synergistic benefitsand the potential for additive undesirable effects.Caution is indicated in the elder1y on basic medicalgrounds. In particular. it is recommended that thelowest effective dose be used in frail elderlypatients or those with a low body weight.

Pre-exlstlng asthmaIn patlents with asthma, seasonal allergic rhinitis,swelling of the nasal mucosa (i.e. nasal polyps),chronic obstructive pulmonary diseases or chronicinfections of the respiratory tract (especially if linkedto allergic rhinitis-like symptoms), reactions onNSAIDs like asthma exacerbations (so-calledintolerance to analgesics/analgesics-asthma),Quincke's oedema or urticaria are more frequentthan In other patients. Therefore, special precautionis recommended in such patients (readiness foremergency). This is applicable as well for patientswho are allergtC to other substances. e.g. with skinreactions, pruritus or urticaria.

Gastrointestinal effectsAs with all NSAIDs, close medical surveillance isimperative and particular caution should beexercised when prescribing Voltaren in patientswith symptoms indicative of gastrOintestinal (GI)disorders or with a history suggestive of gastric orintestinal ulceration, bleeding or perforation (seeseclion UNDESIRABLE EFFECTS). The risk of GIbleeding is higher with increasing NSAIO dosesand in patients with a history of ulcer, particular1y ifcomplicated with haemorr11age or perforation andin the elderly.To reduce the risk of GI toxicity in patients with ahistory of ulcer, particularly jf complicated withhaemorr11age or perforation, and in the elderly, thetreatment should be initiated and maintained at thelowest effective dose.Combination therapy with protective agents (e.g.proton pump inhibitors or misoprostol) should beconsidered for these patients, and also forpatients requiring concomitant use of medicinalproducts containing iow-dose acetylsalicylic acid(ASA)laspirin or other medicinal products likely toincrease gastrOintestinal risk.Patients with a history of GI toxicity, particular1y theelderly, should report any unusual abdominalsymptoms (especially Gi bleeding). Caution isrecommended in patients receiving concomitant

111111medications which could increase the risk ofulceration or bleedi , such as systemic corticoste-roids, anticoagulants, anti-platelet agents orselective serotonin-reuptake inhibitors (see sectionINTERACTIONS).Close medical surveillance and caution shouldalso be exercised in patients with ulcerative colitisor Crohn's disease, as their condition may beexacerbated (see section UNDESIRABLEEFFECTS).

Hepatic effectsClose medical surveillance is required whenprescribing Voltaren to patients with impairedhepatic function, as their condition may beexacerbated.As with other NSAIDs, values of one or more liverenzymes may increase. During prolongedtreatment with Voltaren, regular monitoring ofhepatic function is indicated os 0 precautionarymeasure. If abnormal liver function tests persist orworsen, if clinical signs or symptoms consistentwith liver disease develop, or if other manifesta-tions occur (e.g. eosinophilia, rash), Voltarenshould be discontinued, Hepatitis may occurwithout prodromal symptoms.Caution is called for when using vottaren inpatients with hepatic porphyria, since it may triggeran attack.

Renal effectsAs fluid retention and oedema have been reportedin assoclalion with NSAID therapy, particularcaution Is called for In patients with impairedcardiac or renal function, history of hypertension,the elderly, patients receiving concomitanttreatment with diuretics or medicinal products thatcan significantly impact renal function, and in thosepatients with substantial extracellular volumedepletion from any cause, e.g. before or after majorsurgery (see section CONTRAINDICATIONS).Monitoring of renal function is recommended as aprecautionary measure when using Voltaren insuch cases. Discontinuation of therapy is usuallyfollOwed by recovery to the pre-treatment state.

Haematologlcal effectsDuring prolonged treatment with Voltaren, as withother NSAIDs, monitoring of the blood count isrecommended.Like other NSAIDs, Voltaren may temporarilyinhibit platelet aggregation. Patients with defects ofhaemostasis should be carefully monitored.

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INTERACTIONSThe fOil 'ng interactions include those observedWithVoUarensuppositories and/or other pharmaceu-tical forms of diclofenac.Lithium: If used concomitantly, diclofenac mayraise plasma concentrations of lithium. MonitOringof the serum lithium level is recommended.Digoxin: If used concomitantly, diclofenac mayraise plasma concentrations of digoxin. Monitoringof the serum digoxin level Is recommended.Diuretics and antihypertensive agents: Like otherNSAIDs, concomitant use of diclofenac withdiuretics or antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE)Inhibitors) may cause a decrease in theirantihypertensive effect. Therefore, the combinationshould be administered with caution and patients,especially the elderly should have their bloodpressure periodically monitored. Patients should beadequately hydrated and consideration should begiven to monitoring of renal function after initiationof concomitant therapy and periodically thereafter,particular1y for diuretics and ACE inhibitors due tothe increased risk of nephrotoxicity. Concomitanttreatment with potassium-sparing drugs may beassociated with increased serum potassium levels,which should therefore be monitored frequently(see section SPECIAL WARNINGS AND PRECAU-TIONS F<;>RUSE).Other NSAIDs and corticosteroids: Concomitantadministration of diclofenac and other systemicNSAIDs or corticosteroids may increase thefrequency of gastrOintestinal undesirable effects(see section SPECIAL WARNINGS AND PRECAU-TIONS FOR USE).Anticoagulants and anti-platelet agents: Caution isrecommended since concomitant administrationcould increase the risk of bleeding (see sectionSPECIAL WARNINGS AND PRECAUTIONS FORUSE). Although clinical investigations do notappear to indicate that diclofenac affects the actionof anticoagulants, there are isolated reports of anincreased risk of haemorr11age in patients receivingdiclofenac and anticoagulants concomitantly.Close monitoring of such patients is thereforerecommended.Selective serotonin reuptake inhibitors (SSRls):Concomitant M1ministration of systemic NSAIOsand SSRls ~ i,gcrease the risk of gastrointestinalbleeding (see s«Olion SPECIAL WARNINGS ANDPRECAUTIONS FOR USE).Antidiabetics: Clinical studies have shown thatdiclofenac can be given together with oralantidiabetic agents without influencing their clinicaleffect. However, there have been isolated reports

of both hypoglycaemic and hyperglyca mic effectsnecessitating changes in the dosage of theantidiabetic agents during treatment with diclofenac.For this reason, monitoring of the blood glucoselevel is recommended as a precautionary measureduring concomitant therapy.Methotrexate: Caution is recommended whenNSAIDs are administered less than 24 hoursbefore or after treatment with methotr xate, sinceblood concentrations of methotrexate may rise andthe toxicity of this substance be increased.Ciclosporin: Dielofenae, like other NSAIDs, mayincrease the nephrotoxicity of cidosporin due to theeffect on renal prostaglandins. Therefore. it shouldbe given at doses lower than those that would beused in patients not receiving cidosporin.Quinalone antibacterials: There have n isolatedreports of convulsions which may have been due toconcomitant use of quinolones and NSAIOs.

PREGNANCY AND LACTATIONPregnancyThe use of didofenac in pregnant women has notbeen studied. Therefore, Voltaren should not beused during the first two trimesters of pregnancyunless the potential benefit to the mother outweightsthe risk to the foetus. As with other NSAIDs, useduring the third trimester of pregnancy is contraindi-cated owing to the possibility of uterine intertiaand/or premature dosure of the ductus arteriosus(see section CONTRAINDICATIONS). Animalstudies have not shown any directly or indirectlyharmful effects on pregnancy, embryonal/fetaldevelopment, parturition or postnatal development(see section PRECLINICAL SAFETY DATA).LactationLike other NSAIDs, diclofenac passes into thebreast milk in small amounts. Therefore, Voltarenshould not be administered during breast feeding inorder to avoid undesirable effects in the infant.FertilityAs with other NSAIDs, the use of Voltaren mayimpair female fertility and is not recommended inwomen attempting to conceive. In women whohave difficulties conceiving or who are undergoinginvestigation of infertility, withdrawal of Voltarenshould be considered.

EFFECTS ON ABILITY TODRIVE AND USE MACHINESPatients experiencing visual disturbances, dizziness,vertigo, somnolence or other central nervous systemdisturbances while taking Voltaren should refrainfrom driving or using machines.

IlllfnUNDESIRABLE EFFECTSAdverse reactions (Table 1) are ranked underheading of frequency, the most frequent first, usingthe following convention: common (0:: 1/100, <1/10); uncommon (. 1/1,000, < 1/100); rare (.1110,000, < 111,000); very rare « 1/10,000),including isolated reports.The following undesirable effects indude thosereported with Voltaren su sitories and/or otherpharmaceutical forms of didofenac, with eithershort-term or long-term use.

Table 1

Blood and lymphatic system disordersVery rare: Thrombocytopenia, leukopenia,anaemia (including haemolytic and aplasticanaemia), agranulocytosis.Immune system disordersRare: Hypersensitivfty, anaphylactic andanaphylactoid reactions (Including hypotensionand shock).Very rare: Angioneurotic oedema (includingface oedema).Psychiatric disordersVery rare: Disorientation, depression, insomnia,nightmare, irritability, psychotic disorder.Nervous system disordersCommon: Headache, dizziness.Rare: Somnolence.Very rare: Paraesthesia, memory impairment,convulsion, anxiety, tremor, aseptic meningitis,taste disturbances, cerebrovascular accident.Eye disordersVery rare: Visual disturbance,vision blurred,dlplopia..Ear and labyrinth disordersCommon: Vertigo.Very rare: Tinnitus, hearing impaired.Cardiac disordersVery rare: Palpitations, chest pain, cardiacfailure, myocardial infarction.Vascular disordersVery rare: Hypertension, vasculitis.Respiratory, thoracic and mediastinal disordersRare: Asthma (including dyspnoea).Very rare: Pneumonitis.Gastrointestinal disordersCommon Nausea, vomiting, diarrhoea,dyspepsia, abdominal pain, flatulence, anorexia.Rare: Gastritis, gastrointestinalhaemorrhage, haematemesis, melaena, diarrhoeahaemorrhagic, gastrointe tinal ulcer (with orwithout bleeding or perforation), proctitis.Very rare: Colitis (induding haemorrhagic and

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exacerbratlon of ulcerative colitis or Crohn'sdisease), constipation, stomatitis, glossitis,oesophageal disorder, diaphragm-like intestinalstrictures, pancreatitis, haemorrhoids aggravated.Hepatoblllary disordersCommon: Transaminases increased.Rare: Hepatitis, jaundice, liver disorder.Very rare: Fulminant hepatitis.Skin and subcutaneous tissue disordersCommon: Rash.Rare: Urticaria.Very rare: Buttous eruptions, eczema, erythema,erythema multiforme, Stevens-Johnson syndrome,toxic epidermal necrolysis (Lyell's syndrome),dermatitis exfoliative, loss of hair, photosensitivityreaction, purpura, allergic purpura, pruritus.Renal and urinary disordersVery rare: Acute renal failure acute, haematuria,proteinuria, nephrotic syndrome, interstitialnephritis, renal papillary necrosis.General disorders andadministration site conditionsCommon: Application site irritationRare: Oedema.

OVERDOSESymptomsThere is no typical clinical picture resulting fromdiclofenac overdosage. Overdosage can causesymptoms such as vomiting, gastrointestinalhaemorrhage, diarrhoea, dizziness, tinnitus orconvulsions. In the event of significant poisoning,acute renal failure and liver damage are possible.

Therapeutic measuresManagement of acute poisoning with NSAIDsessentially consists of supportive measures andsymptomatic treatment. Supportive measures andsymptomatic treatment should be given forcomplications such as hypotension, renal failure,convulsions, gastrointestinal disorder, and respiratorydepression.Special measures such as forced diuresis, dialysisor haemoperfusion are probably of no help ineliminating NSAIDs due to the high protein bindingand extensive metabolism.

PHARMACODYNAMICSMechanism of actionVoitaren contains didofenac sodium, a non-steroidalcompound with pronounced antirheumatic, anti-inflammatory, ana~esic, and antipyretic properties.Inhibition of prostaglandin biosynthesis, which hasbeen demonstrated in experiments, is consideredfundamental to its mechanism of action. Prostaglan

dins playa major role in causing inflammation, pain,and fever.Oiclofenac sodium in vitro does not suppressproteoglycan biosynthesis in cartilage at co ntra-tions equivalent to those reached in humans.

Pharmacodynamic effectsIn rheumatic diseases, the anti-inflammatory andanalgesic properties of Voltaren elicit a clinicalresponse characterised by marked relief from signsand symptoms such as pain at rest, pain onmovement, morning stiffness, and swelling of thejoints, as well as by an improvement in function.In post- traumatic and post-operative inflammatoryconditions, Voitaren rapidly relieves both spontane-ous pain and pain on movement and reducesinflammatory swelling and wound oedema.In clinical trials Voltaren has also been found toexert a pronounced analgesic effect in moderateand severe pain of non-rheumatic origin Clinicalstudies have also revealed that, in primarydy'smenorrhoea, Voltaren is capable of rallevingt pain and reducing the extent of bleeding.V, Itaren also has beneficial effects on thes ptoms of migraine attacks.

PHARMACOKINETICSAbsorptionOlclofenac shows a rapid onset of absorption fromsuppositories, although the rate of absorption isslower than from gastro-resistant tabletsadministered orally. After the administration of 50mg suppositories, peak plasma concentrations areattained on average within 1 hour, but maximumconcentrations per dose unit are about two thirds ofthose reached after administration of gastro-resistant tablets. The amount absorbed is linearlyrelated to the size of the dose.Since about half of diclofenac is metabolised duringits first passage through the liver ("first pass" effect),the area under the concentration curve (AUC)following oral or rectal administration is about halfthat following an equivalent parenteral dose.Pharmacokinetic behaviour does not change afterrepeated administration. No accumulation occursprovided the recommended dosage intervals areobserved.The plasma concentrations attained in childrengiven equivalent doses (mglkg body weight) aresimilar to those obtained in adults.

Distribution99.7% of didofenac is bound to serum proteins,mainly to albumin 99.4%).The apparent volume of distribution calculated is

0.12 to 0.17 Ukg.Oicfofenac enters the synovial fluid, where maximumconcentrations are measured 2 t 4 hours after peakplasma values have been attair)ed. The apparenthalf-life for elimination from the svpovial fluid is 3 to 6hours. Two hours after reachllg peak plasmavalues, concentrations of the active substance arealready higher in the synovial fluid than in theptasma, and they remain higher for up to 12 hours.

BiotransformationBiotransformation of dtdofenac takes place partlyby glucuronidation of the intact ecule, but mainlyby single and multiple hydroxylation andmethoxylation, resulting in several phenolicmetabolites(3'-hydroxy-, 4'-hydroXY-,5-hydroXY-,4',5-<lihydroxy-and 3'-hydroxy-4'-methoxy-diclofenac), most ofwhich are converted to glucuronide conjugates.Two of these phenolic metabolites are btologicallyactive, but to a much smaller extent than dtdofenac.

EliminationTotal systemic dearance of diclofenac from plasmais 263 -56 mUmin (mean value *50). The terminalhalf-life in plasma is 1 to 2 hours. Four of themetabolites, including the two active ones, alsohave short plasma half-lives of 1 to 3 hours. Onemetabolite, 3'-hydroxy-4' -methoxy-diclofenac hasa much longer plasma half-life. However, thismetabolite is virtually inactive.About 60% of the administered dose is excreted inthe urine as the glucuronide conjugate of the intactmolecule and as metabolites, most of which arealso converted to glucuronide conjugates. Lessthan 1% is excreted as unchanged substance. Therest of the dose is eliminated as metabolitesthrough the bile in the faeces.

Characteristics in patientsNo reievant age-dependent differences in thedrug's absorption, metabolism, or excretion havebeen observed.In patients suffering from renal impairment, noaccumulation of the unchanged active substancecan be inferred from the single-dose kinetics whenapplYing the usual dosage schedule. At acreatinine clearance of < 10 mUmin, the calculatedsteady-state plasma levels of the hydroxymetabolites are about 4 times higher than in normalsubjects. However, the metabolites are ultimatelydeared through the bile.In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics andmetabolism of didofenac are the same as inpatients without liver disease.

PRECLINICAL SAFETY DATAPreclinical data from acute and repeated dosetoxicity studies, as well as from genotoxicity,mutagenicity, and carcinogenicity studies withdk:lofenac revealed no Specific hazard for humans atthe intended therapeutic doses. There was noevKJence that dtdofenac had a teratogenic potentialin mice, rats or rabbfts.Oidofenac had no influence on the fertility of parentanimals in rats. The prenatal, perinatal and postnataldevelopment of the offspring was not affected.

EXCIPIENTSHard fat.Pharmaceutical formulations may vary betweencountries.

INCOMPATIBILITIESNot applicable.

STORAGESee folding box.Voltaren suppositories shoutd not be used after thedate marked ·EXp· on the pack.

INSTRUCTIONS FORUSE AND HANDLINGThe suppositories should not be cut apart, asincorrect storage conditions may lead to unevendistribution of the active substance.Note: Voltaren suppositories should be kept out ofthe reach and sight of children.

Manufacturer:See folding box.

International Package LeafletInformation issued: February 2006~= registered trademark

Novartis Pharma AG, Basel, Switzerland

Council of Arab Health Ministers Union Of ArabPharmacistsTHIS IS A MEDICAMENT• A medicament is a product which affects yourhealth and consumption contrary to instructions isdangerous for you.• Follow strictly the doctor's prescription, themethod of use and the instructions of thepharmacist who sold the medicament.• The doctor and the pharmacist are experts inmedicine, its benefits and risks.• 00 not by yourself interrupt the period oftreatment prescribed for you.• 00 not repeat the same prescription withoutconsulting your doctor. 1330830 SA 08 AlH