Israel - English - Ministry of Health
" עעבקנהזןולעטמרופ " רשואוקדבנונכותותואירבהדרשמי ." רשואמןולע : רבמצד 2009
“This leaflet format has been determined by the Ministryof Healthand thecontent thereof has been
checked and approved.” Date of approval: December 2009
Physician’s Package Insert אפורלןולע
ךותהקרזהל דבלבתירירש INJECTION
Name of the medicinal product
ampoules 75 mg/3 ml solution for injection.
Qualitative and quantitative composition
Each ampoule of 3 ml contains:
Diclofenac sodium 75 mg
Propyleneglycol, benzyl alcohol, mannitol, sodium metabisulfite, sodium hydroxide,
water for injection.
Solution for injection.
Exacerbations of inflammatory and degenerative forms of rheumatism: rheumatoid
arthritis, ankylosing spondylitis, osteoarthritis,spondylarthritis,non-articular
Treatment of painful conditions due to inflammation of non rheumatic origin.
Renal colic and biliary colic.
Post-traumatic and post-operative pain, inflammation and swelling.
Posologyand method of administration
As a general recommendation, the dose should be individually adjusted andthe
lowest effective dose given for the shortest possible duration.
Abitren solution for injection should not be given formorethan2days;ifnecessary,
treatment can be continued with the tablets or suppositories.
The following directions for intramuscular injection must be followedinordertoavoid
damage to a nerve or other tissue at the injection site.
The dose is generally one 75 mg ampoule daily, given by deep intraglutealinjection
into the upper outer quadrant. In severe cases(e.g.colic),thedailydosecan
exceptionally be increased to two injections of 75 mg, separated by an interval of a
fewhours(one into each buttock). Alternatively, one ampoule of 75 mg can be
combinedwithother pharmaceutical forms of Abitren (e.g. tablets, suppositories) up
to a total maximum daily dose of 150 mg.
In migraine attacks, clinical experience is limited to initial use of one ampoule of
75mg administered as soon as possible, followed by suppositories upto100mgon
the same day if required. The total dose should not exceed 175 mg on the first day.
Children and adolescents
Because of their dosage strength, the Abitren solution for injection is not suitable for
children and adolescents.
Known hypersensitivity to the active substance, sodium metabisulfiteoranyofthe
Active gastric or intestinal ulcer, bleeding or perforation.
Last trimester of pregnancy (see Pregnancy and lactation).
Severe hepatic renal and cardiac failure (see Special warnings and special
precautions for use).
Like other non-steroidal anti-inflammatory drugs (NSAIDs), Abitrenisalso
contraindicatedinpatientsinwhomattacks of asthma, urticaria, or acute rhinitis are
precipitated by acetylsalicylic acid or other NSAIDs
Special warnings and special precautions for use
Gastrointestinal bleeding ulceration or perforation, whichcanbefatal,havebeen
reported with all NSAIDs and may occur at any time duringtreatment,withorwithout
warningsymptoms or a previous history of serious gastrointestinal events. They
generally have more serious consequences in the elderly. If gastrointestinalbleeding
or ulceration occurs in patients receiving Abitren, the medicinalproductshouldbe
Seriousskinreactions,some of them fatal, including exfoliative dermatitis, Stevens-
Johnsonsyndromeand toxic epidermal necrolysis, have been reported very rarely in
associationwith the use of NSAIDs, including diclofenac (see Undesirable effects).
Patients appear to be at highest risk of thesereactionsearlyinthecourseoftherapy,
the onset of the reaction occurring in the majority ofcaseswithinthefirstmonthof
treatment. Abitren should be discontinued at the firstappearanceofskinrash,
mucosal lesions or any other sign of hypersensitivity.
As with other NSAIDs, allergic reactions,includinganaphylactic/anaphylactoid
reactions,canalso occur in rare cases without earlier exposure to diclofenac. The
sodium metabisulphite in the solution for injection can also lead to isolated severe
hypersensitivity reactions and bronchospasm.
Like other NSAIDs, diclofenac may mask the signs and symptoms of infection due to
its pharmacodynamic properties.
The concomitant use of diclofenacwithsystemicNSAIDsincluding
cyclooxygenase-2selective inhibitors, should be avoided due to the absence of any
evidence demonstrating synergistic benefits and the potentialforadditiveundesirable
Caution is indicated in the elderly on basic medical grounds. In particular it is
recommendedthatthelowesteffectivedose be used in frail elderly patients or those
with a low body weight.
In patients with asthma, seasonal allergic rhinitis, swelling ofthenasalmucosa(i.e.
nasalpolyps),chronicobstructivepulmonary diseases or chronic infections of the
respiratorytract(especiallyif linked to allergic rhinitis-like symptoms), reactions on
NSAIDs like asthma exacerbations (so-called intolerance toanalgesics/analgesic-
asthma), Quincke’s edema or urticaria are more frequent than inotherpatients.
Therefore special precaution is recommended insuchpatients(readinessfor
emergency). This is applicable as well for patients who are allergic toother
substances, e.g. with skin reactions, pruritus or urticaria.
Special caution is recommended when Abitren injection is used parenterally in
patients with bronchial asthma because symptoms may be exacerbated.
AswithallNSAIDs,close medical surveillance is imperative and particular caution
should be exercised when prescribing Abitren in patients with symptoms indicative of
gastrointestinal (GI) disorders or with a history suggestive of gastricorintestinal
ulceration, bleeding or perforation, (see Undesirable effects). The risk ofGIbleeding
is higher with increasing NSAID doses and inpatientswithahistoryofulcer,
particularly if complicated with hemorrhage or perforation and in the elderly.
To reduce the risk of GI toxicity in patients with a historyofulcer,particularlyif
complicatedwithhaemorrhageorperforation, and in the elderly, the treatment should
be initiated and maintained at the lowest effective dose.
Combination therapy with protective agents (e.g. proton pumpinhibitorsor
misoprostol) should be considered for these patients, and also for patientsrequiring
concomitant use of medicinal products containing low-dose acetylsalicylic acid
(ASA)/aspirin, or other medicinal products likely to increase gastrointestinal risk .
Patients with a history of GI toxicity, particularly the elderly, should report anyunusual
abdominal symptoms (especially GI bleeding). Cautionisrecommendedinpatients
receiving concomitant medications which could increase theriskofulcerationor
bleeding, such as systemic corticosteroids,anticoagulants,anti-plateletagentsor
selectiveserotonin-reuptake inhibitors (see Interaction with other medicinal products
and other forms of interaction).
Closemedical surveillance and caution should also be exercised in patients with
ulcerativecolitis or Crohn’s disease, as their condition may by exacerbated (see
Elevations of one or more liver tests may occur during therapy withdiclofenacsodium.
Theselaboratory abnormalities may progress, may remain unchanged, or may be
transient with continued therapy. Borderline elevations (i.e. less than3timestheULN
[ULN = the upper limit of normal range]) or greaterelevationsoftransaminases
occurredinabout15%ofdiclofenac-treated patients. Of the markers of hepatic
function, ALT (SGPT) is recommended for the monitoring of liver injury.
Inclinicaltrials,meaningfulelevations (i.e., more than 3 times the ULN) of AST (GOT)
(ALT was not measured in all studies) occurred in about 2% of approximately 5,700
patients at some time during diclofenac treatment. In a large,open-label,controlled
trialof3,700 patients treated for 2-6 months, patients were monitored first at 8 weeks
and1,200patientsweremonitored again at 24 weeks. Meaningful elevations of ALT
and/or AST occurred in about 4% of patients andincludedmarkedelevations(i.e.,
more than 8 times the ULN) in about 1% of the 3,700 patients.
Inthatopen-labelstudy,ahigherincidence of borderline (less than 3 times the ULN),
moderate(3-8timestheULN),andmarked(> 8 times the ULN) elevations of ALT or
ASTwasobserved in patients receiving diclofenac when compared to other NSAIDs.
Elevationsin transaminases were seen more frequently in patients with osteoarthritis
than in those with rheumatoid arthritis.
Almost all meaningful elevations in transaminases were detected beforepatients
becamesymptomatic. Abnormal tests occurred during the first 2 months of therapy
withdiclofenac in 42 of the 51 patients in all trials who developed marked
In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in
thefirstmonth, and in some cases, the first 2 months of therapy, but can occur at any
timeduring treatment with diclofenac. Postmarketing surveillance has reported cases
of severe hepatic reactions, including liver necrosis,jaundice,fulfillmenthepatitiswith
and without jaundice, and liver failure. Some of these reported cases resultedin
fatalities or liver transplantation.
Physiciansshould measure transaminases periodically in patients receiving long-term
therapy with diclofenac, because severe hepatotoxicity may develop without a
prodromeofdistinguishingsymptoms.Theoptimum times for making the first and
subsequenttransaminase measurements are not known. Based on clinical trial data
andpostmarketing experiences, transaminases should be monitored within 4 to
8weeksafterinitiating treatment with diclofenac. However, severe hepatic reactions
can occur at any time during treatment with diclofenac.
If abnormal liver tests persist or worsen, if clinical signs and/or symptomsconsistent
with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia,
rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium should be
discontinuedimmediately.Tominimize the possibility that hepatic injury will become
severe between transaminase measurements,physicians should inform patients of
the warning signs and symptoms of hepatotoxicity (e.g.,nausea,fatigue,lethargy,
diarrhea,pruritus,jaundice,right upper quadrant tenderness, and “flu-like”
symptoms), and the appropriate action patients should takeifthesesignsand
To minimize the potential risk for an adverse liver relatedeventinpatientstreatedwith
diclofenac sodium, the lowest effective dose should be usedfortheshortestduration
possible. Caution should be exercised in prescribing diclofenacsodiumwith
concomitant drugs that are known to be potentially hepatotoxic (e.g.,antibiotics,anti-
As fluid retention and edema have been reported in association with NSAID therapy,
particular caution is called for in patients withimpairedcardiacorrenalfunction,
history of hypertension, the elderly, patientsreceivingconcomitanttreatmentwith
diureticsormedicinal products that can significantly impact renal function, and in
those patients with substantial extracellular volume depletion of anycause,e.g.
beforeorafter major surgery (see Contraindications). Monitoring of renal function is
recommendedasa precautionary measure when using Abitren in such cases.
Discontinuation of therapy is normally followedby recovery to the pre-treatment state.
During prolonged treatment with diclofenac, as with otherNSAIDs,monitoringofthe
blood count is recommended.
Likeother NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Patients
with defects of hemostasis, should be carefully monitored.
Interaction with other medicinal products and other forms of interaction
Thefollowinginteractionsincludethose observed with Abitren for injection and/or
other pharmaceutical forms of diclofenac.
If used concomitantly, diclofenac may raise plasma concentrations oflithium.
Monitoring of the serum lithium level is recommended.
Ifusedconcomitantly, diclofenac may raise plasma concentrations of digoxin.
Monitoring of the serum digoxin level is recommended.
Diuretics and antihypertensive agents:
LikeotherNSAIDs,concomitant use of diclofenac with diuretics or antihypertensive
agents(e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors) may
cause a decrease in their antihypertensive effect. Therefore, the combination should
beadministeredwithcautionandpatients, especially the elderly, should have their
bloodpressureperiodically monitored. Patients should be adequately hydrated and
considerationshouldbe given to monitoring of renal function after initiation of
concomitanttherapyand periodically thereafter, particularly for diuretics and ACE
inhibitors due to the increased risk of nephrotoxicity. Concomitanttreatmentwith
potassium-sparing drugs may be associated with increased serum potassium levels,
whichshouldthereforebemonitored frequently (see Special warnings and special
precaution for use).
Other NSAIDs and corticosteroids:
Concomitant administration of diclofenac and other systemic NSAIDsor
corticosteroids may increase the frequency of gastrointestinal undesirableeffects(see
Special warnings and special precautions for use).
Anticoagulants and anti-platelet agents:
Caution is recommended since concomitant administration could increase the risk of
bleeding(see Special warnings and special precautions for use) . Although clinical
investigations do not appear to indicate that diclofenac affectstheactionof
anticoagulants,there are isolated reports of an increased risk of haemorrhage in
patientsreceiving diclofenac and anticoagulants concomitantly. Close monitoring of
such patients is therefore recommended.
Selective serotonin reuptake inhibitors (SSRIs):
Concomitant administration of systemicNSAIDs and SSRIs may increase the riskof
gastrointestinal bleeding (see Special warnings and special precautions for use).
Clinical studies have shown that diclofenac can be given togetherwithoral
antidiabetic agents without influencing their clinical effect. However, there havebeen
isolated reports of both hypoglycemic and hyperglycemic effectsnecessitating
changes in the dosage of the antidiabetic agents during treatment with diclofenac. For
thisreason, monitoring of the blood glucose level is recommended as a precautionary
measure during concomitant therapy.
Caution is recommended when NSAIDs are administered less than 24 hours before or
after treatment with methotrexate, since blood concentrations of methotrexate may
rise and the toxicity of this substance be increased.
Diclofenac, like other NSAIDs may increase the nephrotoxicity of ciclosporin due to
the effect on renal prostaglandins. Therefore, it should be given at doses lower than
those that would be used in patients not receiving ciclosporin.
There have been isolated reports of convulsions which may have been due to
concomitant use of quinolones and NSAIDs.
Theuseofdiclofenac in pregnant women has not been studied. Therefore, Abitren
shouldnotbeusedduringthefirst two trimesters of pregnancy unless the potential
benefit to the mother outweighs the risk to the fetus.AswithotherNSAIDs,useduring
the third trimester of pregnancy is contraindicated owing tothepossibilityofuterine
inertia and/or premature closure of the ductus arteriosus (see Contraindications).
Animal studies have not shown any directlyor indirectly harmful effects on pregnancy,
embryonal/fetaldevelopment, parturition orpostnatal development (see Preclinical
Like other NSAIDs, diclofenac passes into the breastmilkinsmallamounts.
Therefore, Abitren should not be administered during breast feeding in order to avoid
undesirable effect in the infant.
Aswithother NSAIDs, the use of Abitren may impair female fertility and is not
recommendedinwomen attempting to conceive. In women who have difficulties
conceiving or who are undergoing investigation of infertility,withdrawalofAbitren
should be considered.
Effects on abilityto drive and use machines
Patients experiencing visual disturbances,dizziness, vertigo, somnolence, or other
central nervous systemdisturbances while taking diclofenac should refrain from
driving or using machines.
Adverse reactions are ranked under heading offrequency, the most frequent first,
using the following convention: common (≥1/100, < 1/10); uncommon (≥1/1,000, <
1/100); rare (≥1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports.
The following undesirable effects include those reported with Abitren solution for
injection and/or other pharmaceutical forms ofdiclofenac, with either short-termor
Infections and infestations
Very rare: Injection site abscess.
Blood and lymphatic system disorders
Very rare: Thrombocytopenia, leukopenia, anemia (including hemolytic and aplastic
Immune system disorders
Rare: Hypersensitivity, anaphylactic and anaphylactoid reactions (including
hypotension and shock).
Very rare: Angioneurotic edema (including face edema).
Very rare: Disorientation, depression, insomnia, nightmare, irritability, psychotic
Nervous system disorders
Common: Headache, dizziness.
Very rare: Paresthesia, memory impairment, convulsion, anxiety, tremor, aseptic
meningitis, taste disturbances, cerebrovascular accident.
Very rare: Visual disturbances, vision blurred, diplopia.
Ear and labyrinth disorders
Very rare: Tinnitus, hearing impaired.
Very rare: Palpitations, chest pain, cardiac failure, myocardial infarction.
Very rare: Hypertension, vasculitis.
Respiratory, thoracic and mediastinal disorders
Rare:Asthma (including dyspnea).
Very rare: Pneumonitis.
Common:Nausea, vomiting, diarrhea, dyspepsia, abdominalpain,flatulence,
Rare:Gastritis, gastrointestinal haemorrhage,hematemesis,diarrheahemorrhagic,
melena, gastrointestinal ulcer (with or without bleeding or perforation).
Very rare: Colitis (including hemorrhagic colitis and exacerbation of ulcerative colitis
orCrohn'sdisease), constipation, stomatitis, glossitis, esophageal disorder,
diaphragm-like intestinal strictures, pancreatitis.
Rare:Hepatitis, jaundice, liver disorder.
Very rare: Fulminant hepatitis.
Skin and subcutaneous tissue disorders
Very rare: Bullous eruptions, eczema, erythema, erythema multiforme, Stevens-
Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), dermatitis
exfoliative, loss of hair, photosensitivity reaction, purpura, allergic purpura, pruritus.
Renal and urinarydisorders
Very rare: Acute renal failure, haematuria, proteinuria, nephrotic syndrome, interstitial
nephritis, renal papillary necrosis.
General disorders and administration site conditions
Common: Injection site reaction, injection site pain, injection site induration
Rare:Edema, injection site necrosis.
There is no typical clinical picture resulting from diclofenac overdosage. Overdosage
can cause symptoms such as vomiting, gastrointestinalhaemorrhage,diarrhea,
dizziness, tinnitus or convulsions. In the event of significant poisoning,acuterenal
failure and liver damage are possible.
Managementofacutepoisoningwith NSAIDs essentially consists of supportive
measures and symptomatic treatment. Supportive measures andsymptomatic
treatment should be given for complications such as hypotension, renalfailure,
convulsions, gastrointestinal disorder, and respiratory depression.
Specialmeasuressuchasforced diuresis, dialysis or haemoperfusion are probably of
nohelp in eliminating NSAIDs due to the high protein binding and extensive
Pharmacotherapeutic group: Anti-inflammatory andantirheumaticproducts,non
steroids, acetic acid derivatives and related substances (ATC code: M01A B05).
Mechanism of action
Diclofenac is a non-steroidal compoundwithpronouncedantirheumatic,anti-
inflammatory, analgesic, and antipyretic properties.Inhibitionofprostaglandin
biosynthesis, which has been demonstrated in experiments, is consideredtobe
fundamentaltoitsmechanismof action. Prostaglandins play an important role in
causing inflammation, pain and fever.
Diclofenacin vitrodoes not suppress proteoglycan biosynthesis incartilageat
concentrations equivalent to the concentrations reached in humans.
Inrheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac
elicit a clinical response characterized by marked relief from signsandsymptoms
such as pain at rest, pain on movement, morning stiffness, andswellingofthejoints,
as well as by an improvement in function.
Diclofenac has also been found to exert a pronounced analgesic effect inmoderate
andseverepainof non-rheumatic origin, an effect which sets in within 15 to 30
Diclofenac has also been shown to have a beneficial effect in migraine attacks.
In post-traumatic and post-operative inflammatory conditions, diclofenac rapidly
relieves both spontaneous pain and pain on movement andreducesinflammatory
swelling and wound edema.
When used concomitantly with opioids for themanagementofpost-operativepain,
diclofenac significantly reduces the need for opioids.
Abitreninjection is particularly suitable for initial treatment of inflammatory and
degenerativerheumaticdiseases,andof painful conditions due to inflammation of
After administration of 75 mg diclofenac by intramuscular injection, absorption sets in
immediately, and mean peak plasma concentrations of about 2.5 micrograms/mL
(8 micromol/L) are reached after about 20 minutes. The amount absorbed is in linear
proportion to the size of the dose.
When 75 mg diclofenac is administered as anintravenousinfusionover2hours,
meanpeakplasmaconcentrationsare about 1.9 micrograms/mL (5.9 micromol/L).
Shorter infusions result in higher peak plasma concentrations, whilelongerinfusions
giveplateauconcentrationsproportionalto the infusion rate after 3 to 4 hours. In
contrast, plasma concentrations decline rapidly once peak levels have beenreached
following intramuscular injection or administration of tablets or suppositories.
The area under the concentration curve (AUC) after intramuscular orintravenous
administration is about twice as large as itisfollowingoralorrectaladministration,
becauseabout half the active substance is metabolised during its first passage
through the liver ("first pass" effect) when administered via the oral or rectal routes.
Pharmacokineticbehavior does not change after repeated administration. No
accumulation occurs provided the recommended dosage intervals are observed.
99.7% of diclofenac binds to serum proteins, mainlytoalbumin(99.4%).Theapparent
volume of distribution calculated is 0.12 to 0.17 L/kg.
Diclofenac enters the synovial fluid, where maximum concentrations are measured
2to4hoursafterpeak plasma values have been reached. The apparent half-life for
elimination from the synovial fluidis3 to 6 hours. Two hours after reaching peak
plasmalevels,concentrations of the active substance are already higher in the
synovial fluid than in the plasma, and they remain higher for up to 12 hours.
Biotransformation of diclofenac takes place partlybyglucuronidationoftheintact
molecule,butmainlyby single and multiple hydroxylation and methoxylation, resulting
in several phenolic metabolites (3'-hydroxy-,4'-hydroxy-,5-hydroxy-,4',5-dihydroxy-,
and 3'- methoxy-diclofenac), most of which are converted toglucuronideconjugates.
Twoofthesephenolic metabolites are biologically active, but to a much lesser extent
Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min(meanvalue±
SD). The terminal half-life in plasma is 1 to 2hours.Fourofthemetabolites,including
the two active ones, also have short plasma half-lives of 1to3hours.Onemetabolite,
3'-hydroxy- 4'-methoxy-diclofenac, has a muchlonger plasma half-life. However, this
metabolite is virtually inactive.
About60%ofthe administered dose is excreted in the urine as the glucuronide
conjugate of the intact molecule and as metabolites, most of which are alsoconverted
to glucuronide conjugates. Less than 1% is excreted asunchangedsubstance.The
rest of the dose is eliminated as metabolites through the bile in the feces.
Characteristics in patients
Norelevant age-dependent differences in the drug’s absorption, metabolism, or
excretionhavebeenobserved.However, in a few elderly patients a 15-minute
intravenous infusion resulted in 50% higher plasma concentrationsthanexpected
from the data on young healthy subjects.
In patients suffering from renal impairment, no accumulation of the unchanged active
substancecan be inferred from the single-dose kinetics when applying the usual
dosageschedule.Atacreatinine clearance of less than 10 mL/min, the calculated
steady-state plasma levels of the hydroxy metabolites are about 4 times higherthanin
normal subjects. However, the metabolites are ultimately cleared through the bile.
Inpatients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and
metabolism of diclofenac are the same as in patients without liver disease.
Preclinical data from acute and repeated dose toxicity studies, aswellasfrom
genotoxicity, mutagenicity, and carcinogenicity studieswithdiclofenacrevealedno
specifichazard for humans at the intended therapeutic doses. There was no evidence
that diclofenac had a teratogenic potential in mice, rats or rabbits.
Diclofenachad no influence on the fertility of parent animals in rats. The prenatal,
perinatal and postnatal development of the offspring was not affected.
As a rule, Abitren solution for injection should not be mixed with otherinjection
Protect from light.
Drug Registration Number:
015 57 24238 00
Teva Pharmaceutical Works Private Limited Company,
P.O.Box 8077, Netanya.