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DYLOJECT 75 MG/2 ML SOLUTION FOR INJECTION

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Dyloject® 75 mg/2 ml Solution for Injection

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
The active ingredient is diclofenac sodium [sodium-(o-[(2,6-dichlorophenyl)amino]-phenyl]-acetate)]. Each 2 ml vial contains 75 mg of diclofenac sodium.
For a full list of excipients, see Section 6.1.

3 PHARMACEUTI

CAL FORM

Solution for Injection

4 CLI

NICAL PARTICULARS

4.1 Therapeutic
indications
Intramuscular use
Dyloject 75 mg/2 ml Solution for Injection is effective in acute forms of pain,
including ren al colic, ex acerbations of os teo- and rheumatoid arthritis, a cute
back pain, acute gout, acute trauma and fractures, and post-operative pain.
Intravenous use
For treatment or prev ention of post-ope rative pa in in supe rvised he althcare
settings.
4.2

Posology and method of administration
Instructions on using the vial
1.
Remove the green flip cap
2.
Aseptically withdraw the appropriate amount (not more than 2 ml) for
either IV use or deep IM injection. As with all par enteral products, D yloject
should be inspected vis ually for pa rticulate matter or disc oloration prior to
administration.
Adults
Undesirable effects ma y be minimised by using the lowest effective dose for
the shortest duration necessary to control symptoms (see Section 4.4).
Dyloject 75 mg/2 ml Solution for Injection should not be given for more than
two days.

Intramuscular inje ction: The followin g directions for intra muscular injec tion
must be adhered to in orde r to avoid dama ge to a nerve or othe r tissue at the
injection site.
One vi al onc e (or i n s evere cas es t wice) dai ly, i ntramuscularly b y d eep
intragluteal injection into the upper out er q uadrant of the buttock. If two
injections daily are required, it is a dvised that the alternative buttock be used
for the second injection.

Recommended IM injection procedure
1.
The patient may lie down or stand, whichever is more comfortable.
2.
The ex posed buttocks s hould be inspected to fi nd the most suitable
injection site. Avoid scars and lumps and choose the buttock which is f ree
from an y problems. If more than one in jection needs to be g iven, the other
buttock should be used.
3.
The injection site should be thoroug hly disinfe cted, e. g. with alcohol,
and allowed to dry.
4.
To ensure deep intr amuscular injection, g ive hi gh into upper outer
quadrant of the buttock, taki ng particular c are t o a void the sciatic nerve and
blood vessels. Avoid inj ecting into an ar ea wher e resistance is felt. N.B . In
obese patients, avoid deposition of the drug into the subcutaneous fatty tissue.
In small thin patients with little muscle bulk, be especially aware of the sciatic
nerve, which may be quite superficial.
5.
Prior to injection of solution, draw back to ensure that no blood vessel
has been penetrated. If blood is drawn, withdraw the needle to another site and
check again.
Renal c olic: One 75 mg dose intra muscularly. A further dose ma y be
administered after 30 minutes if necessary. The recommended maximum daily
dose of Dyloject is 150 mg.
Intravenous use: D yloject 75 mg /2 ml Solution for Injection may be given as
an intravenous bolus injection. Two alternative regimens are recommended for
bolus injection.

For the trea tment of m oderate to sev ere post-o perative pain, 75 m g
should be injected intravenously. If necessary, treatment may be repeated after
4 to 6 hours, not exceeding 150 mg within any period of 24 hours.

For the prev ention of post-operative pain, a loadi ng dose of 25 m g to
50 mg administered as a 5 to 60 second intr avenous bolus after surg ery,
followed by additional injections up to a maximum daily dosage of 150 mg. If
necessary, treatment may be repeated after 4 to 6 hours, not ex ceeding 150 mg
within any period of 24 hours.
Phlebitis: Intravenous drug administra tion has been associat ed with the
occurrence of Thrombophlebitis. Clinical studies comparing Dyloject 75 mg/2
ml Solution for Injection to Voltarol® Ampoules have demonstrated r educed
severity and one fourth the incidence of phlebitis (p=0.0032).

Children: Dyloject 75 m g/2 ml Solution for Injection is not re commended for
use in children.
Elderly: The elderly are at i ncreased ri sk o f t he seri ous consequences of
adverse reactions. If an NSAID is considered necessary, the lowest effective
dose should be used and for the shortest possible duration. The patient should
be monitored re gularly for G I ble eding du ring NSA ID the rapy. The
recommended ma ximum da ily dose o f D yloject 75 m g/2 ml Solution for
Injection is 150 mg.
Patients with re nal impa irment: H ydroxypropylbetadex (HP βCD), whe n
administered intra venously, is pre dominantly e liminated throug h glomerular
filtration. Therefor e, pa tients with severe rena l impairment defined as
creatinine clearance belo w 30 ml/min shoul d not be treated with D yloject 75
mg/2 ml Solut ion for Injection. See Section 4.4, Special warning
s and
precautions for use.
4.3 Contraindications
Active, or histor y of re current peptic ulcer/haemorrhage (two or more dis tinct
episodes of proven ulceration or bleeding).
Severe heart failure, renal failure, and hepatic failure (see Section 4.4)
During the last trimester of pregnancy (see Section 4.6).
History of gastrointestinal bleeding or perforation, related to previous NSAIDs
therapy.
NSAIDs ar e cont raindicated i n pa tients wh o have previousl y sh own
hypersensitivity rea ctions (e .g. asthma, a ngioedema, urtic aria or rhinitis) in
response to ibuprofen, aspirin or other NSAIDs.
Hypersensitivity to diclofenac sodium, or to any of the excipients.
The ex cipient HP βCD i s pre dominantly eliminated throug h the kidney b y
glomerular filtration. Therefore, Dyloject 75 mg/2 ml Solution for Injection is
contraindicated in patients with severe renal impairment (defined as creatinine
clearance below 30
ml/min). See S ection 4.4, Special warning
s and
precautions for use.

Specifically for IV use
Concomitant NSA ID i ncluding c yclooxygenase-2 se lective inhibitors or
anticoagulant use (including low dose heparin).

A histor y o f haemor rhagic diathesis, a histor y of confirmed or suspe
cerebrovascular bleeding.

cted

Operations associated with a high risk of haemorrhage.
A history of asthma.
Moderate or severe renal impairment (serum creatinine > 160 µmol/l).
Hypovolaemia or dehydration from any cause.
4.4

Special warnings and precautions for use
Undesirable effects ma y be minimised by using the lowest effective dose for
the shortest duration ne cessary to control s ymptoms (see Section 4.2, and
gastrointestinal and cardiovascular risks below).
The use o f D yloject 75 mg /2 ml Solution for Injection with c oncomitant
NSAIDs including cyclooxygenase-2 s elective i nhibitors should be avoided
(see Section 4.5). Concomitant use durin g IV use is cont raindicated (see
Section 4.3).
Elderly: Th e el derly h ave an i ncreased frequency o f adv erse r eactions t o
NSAIDs especi ally gastrointestinal bleeding an d perforation which may be
fatal (see Section 4.2).
Gastrointestinal bleeding, ulceration a nd perfor ation: G I bleedin g, ulcerat ion
or per foration, which ca n be f atal, has b een reported with all NSA IDs. T hey
can occur at an y time during treatment, w ith or without warning symptoms or
a previous history of serious GI events.
The risk of G I ble eding, ulceration or perforation is hig her with incr easing
NSAID doses, in patients with a histor y of ulcer , particularl y if complica ted
with haemorrha ge or pe rforation (see Se ction 4.3), and in the elderl y. Th ese
patients should commence t
reatment on th e lowest dose
av ailable.
Combination therapy with protective agents (e.g. misoprostol or proton pu mp
inhibitors) should be c onsidered fo r these p atients, and also for
patients
requiring c oncomitant low dose a spirin, or othe r dru gs like ly to inc rease
gastrointestinal risk (see below and Section 4.5).
Patients with a histor y of GI toxicity, particularly when elderly, should r eport
any unusual abdominal s ymptoms (especially GI bleeding) particularly in the
initial stages of treatment.
Caution should be advi sed in patients r eceiving concomitant medic ations
which coul d i ncrease the ri sk of ul ceration or bl eeding, su ch as oral
corticosteroids, anticoagulants suc h a s wa rfarin, selective serotonin-r euptake
inhibitors or anti-platelet ag
ents such as a spirin (see Section 4.5).
Concomitant use with antic oagulants durin g IV tre atment is contraindicated
(see Section 4.3).

When g astrointestinal b leeding o r ul ceration o ccurs i n pat ients r eceiving
Dyloject 75 mg/2 ml Solution for Injection, the drug should be withdrawn.
NSAIDs should be given with care to patients with a history of gastrointestinal
disease (ul cerative colit is, Crohn’s di sease) as these conditions may be
exacerbated (see Section 4.8).
SLE and mix ed connective tissue di sease: In p atients with s ystemic lupus
erythematosus (S LE) an d m ixed connect ive t issue di sorders t here m ay be an
increased risk of aseptic meningitis (see Section 4.8).
Dermatological: Se rious skin re actions, som e of the m fa tal, inc luding
exfoliative dermatitis, Stevens-J ohnson s yndrome, and tox ic epidermal
necrolysis, have b een reported ve ry ra rely in association with the use of
NSAIDs (see Se ction 4.8). Patients appear to be at hig hest risk fo r these
reactions early in the course of therapy: the onset of the rea ction occurring in
the majority of cases within the first month of treatment. Dyloject 75 mg/2 ml
Solution for I njection should be disconti nued at the first appearan ce of s kin
rash, mucosal lesions, or any other sign of hypersensitivity.
Hepatic: Close me dical surve illance is a lso imp erative in pa tients suffe ring
from severe impairment of hepatic function.
Hypersensitivity rea ctions: As with othe r NSA IDs, a llergic re actions,
including anaphylactic/anaphylactoid reactions, can also occur without ea rlier
exposure to the drug.
Like other NSAIDs, Dyloject 75 mg/2 ml Solution for Injection may mask the
signs and symptoms of infection due to its pharmacodynamic properties.
Renal impa irment: HPβCD, when admi
nistered intravenousl y, is
predominantly eliminated throu gh the kidney b y g lomerular filtration.
Therefore, pat ients wi th renal i mpairment (defi ned as cre atinine cl earance
below 30 ml/min) should not be treated with Dyloject 75 mg/2 ml Solution for
Injection. See Section 5.2, Pharmacokinetic properties.
Precautions
Cardiovascular, Ren al a nd He patic Impairment: The a dministration of a n
NSAID may cause a dose dependent reduction in prostaglandin formation and
precipitate renal failure. Patients at greatest risk of this reaction are those with
impaired renal function, cardiac impairm ent, liver d ysfunction, those taking
diuretics or those recov ering f rom ma jor surg ery and the elderl y. Renal
function should be monitored in these patients (see also Section 4.3).
Renal impa irment: HPβCD, when admi
nistered intravenousl y, is
predominantly eliminated throu gh the kidney b y g lomerular filtration.
Therefore, pat ients wi th renal i mpairment (defi ned as cre atinine cl earance

below 30 ml/min) should not be treated with Dyloject 75 mg/2 ml Solution for
Injection. See Section 5.2, Pharmacokinetic properties.
Hepatic: I f abnormal liver fun ction tests pe rsist or wors en, clinic al sig ns or
symptoms consistent wi th liver diseas e develop, or if other manifestati ons
occur (eosinophilia, rash , etc.), D yloject 75 mg /2 ml Solution for Injection
should be discontinued. Hepatitis may occur without prodromal symptoms.
Use of D yloject 75 m g/2 ml Solut ion for Injection in pa tients with he patic
porphyria may trigger an attack.
Haematological: Dyloject 75 mg /2 ml Solution for Injection ma y reversibly
inhibit platelet agg regation (see Anticoa gulants in Section 4.5). Patients with
defect of h aemostasis, bleeding diat hesis or h aematological abnormalities
should be carefully monitored.
Long-term tre atment: D yloject 75 m g/2 ml Solution for
Injection is not
recommended for long term use. Prescribers should select follow-on treatm ent
based on prescribing information for the specific product selected. All patients
who are receiving non-steroidal anti-inflammatory agents long term, should be
monitored as a precauti onary me asure, e.g. r enal functi on, hepatic function
(elevation of liver enzymes may occur) and blood counts. This is pa rticularly
important in the elderly.
Respiratory disorders: Caution is requi red if administered to patients suffering
from, or with a previous history of, bronchial asthma since NSAIDs have been
reported to precipitate bronchospasm in such pati ents. IV use in patients with
history of asthma is contraindicated (see Section 4.3).
Cardiovascular and cerebrovascular e ffects: A ppropriate monitorin g and
advice are required fo r patients with a hi story of h ypertension and/or mild to
moderate congestive h eart fa ilure a s fluid reten tion and oedema have been
reported in association with NSAID therapy.
Clinical tria l a nd e pidemiological d ata su ggest tha t use of dic lofenac,
particularly at hig h dose (150 m g dail y) and in long te rm treatment m ay be
associated wi th a sm all i ncreased ri sk of a rterial thrombotic e vents (for
example myocardial infarction or stroke).
Patients with uncontroll ed h ypertension, congestive heart failure, established
ischaemic h eart di sease, peri pheral a rterial di sease, and/ or c erebrovascular
disease should onl y be treated with di clofenac afte r c areful consid eration.
Similar consideration shoul d be made befor e initia ting longer-t erm treat ment
of patients with risk fa ctors for c ardiovascular events (e. g. h ypertension,
hyperlipidaemia, diabetes mellitus, smoking).
Impaired female fertility : Th e use of D yloject 75 mg /2 ml Solution for
Injection may impa ir fe male fe rtility a nd is not re commended in wome n
attempting to conceive. In women who have difficulties conceiving or who are

undergoing investigation of infertilit y, withdraw al of D yloject 75 m g/2 ml
Solution for Injection should be considered.
4.5

Interaction with other medicinal products and other forms of interaction
Lithium and digoxin: Decreased elimination of lithium and digoxin.
Anticoagulants: NS AIDs m ay enhance t he eff ects of ant i-coagulants, such as
warfarin (see Section 4.4).
Antidiabetic agents: Clinical studies have shown that diclofenac can be given
together with oral antidiabetic agents without influencing thei r clinical effect.
However, there h ave been isolated repo
rts of h ypoglycaemic and
hyperglycaemic eff ects which have re quired a djustment to the dosage of
hypoglycaemic agents.
Ciclosporin: Increased risk of nephrotoxicity.
Methotrexate: Decreased the elimination of methotrexate.
Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk
of convulsions associated with quinolone antibiotics. Patients taking NSAIDs
and quinolones may have an increased risk of developing convulsions.
Other an algesics i ncluding c yclooxygenase-2 sel ective i nhibitors and
corticosteroids: Avoid c oncomitant use of two or more NSA IDs (inc luding
aspirin) or cort icosteroids as t his may increase the risk of advers e effects (see
Section 4.4).
Diuretics: R educed di uretic eff ect. Di uretics can i ncrease t he ri sk of
nephrotoxicity of NSAIDs.
Cardiac g lycosides: N SAIDs may exacerbate ca rdiac failure, red uce
glomerular filtration rate and increase plasma glycoside and HPβCD levels.
Mifepristone: NSAIDs should not be used for 8 t o 12 da ys after mifepristone
administration, as NSAIDs can reduce the effect of mifepristone.
Anti-hypertensives: Reduced anti-hypertensive effect.
Corticosteroids: Increased risk of g astrointestinal ulc eration or ble eding (se e
Section 4.4).
Anti-platelet a gents and sel ective s erotonin r euptake i nhibitors (S SRIs):
Increased risk of gastrointestinal bleeding (see Section 4.4).
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given
with tacrolimus.
Zidovudine: Increased risk of haematological toxicity when NSAIDs are given
with zidovudine. There is evidence of an increased risk of haemarthroses and
haematoma i n H IV(+) haemophiliacs re ceiving concurr ent t reatment with
zidovudine and ibuprofen.

4.6

Pregnancy and lactation
Pregnancy
Congenital a bnormalities ha ve bee n re ported i n a ssociation with NSA ID
administration in man; however, these are low in frequen cy and do not appear

to follow any discernible pattern. In view of the known effe cts of NSAIDs on
the foetal cardiovascular system (risk of closure of the ductus arteriosus), use
in the last trimester of pre gnancy is contraindicated. The onset of labou r may
be delayed and t he duration increased with an i ncreased bleeding tendency in
both mother and child (s ee Section 4.3). NSAIDs should not be used dur ing
the first two trime sters o f pregnancy or la bour u nless the potential benefit to
the patient outweighs the potential risk to the foetus.
Lactation
In limited studies so fa r available, NSAIDs can appear in brea st milk in v ery
low concentr ations. NSA IDs shoul d, if possible, be avoided when
breastfeeding.
See Section 4.4 Special warnin gs and pr ecautions for use, re garding f emale
fertility.
4.7

Effects on ability to drive and use machines
Undesirable effects su ch as di zziness, drowsiness, fatig ue and vi sual
disturbances are possible after taking NSAIDs. If affected, patients should not
drive or operate machinery.

4.8 Undesirable
effects
Side effects observed following parenteral diclofenac administration
If serious side effects occur, Dyloject 75 mg/2 ml Solution for Injection should
be withdrawn. Frequ ency estimate: frequent: >1 0%; occasional: > 1 to 10%;
rare: > 0.001 to 1%; isolated cases: < 0.001%.
Gastrointestinal tract
Occasional: epi gastric pain, ot her gastrointestinal di sorders (e. g. n ausea,
vomiting, diarrhoea, dyspepsia, flatulence, anorexia).
Rare: gastrointestinal bl eeding (hae matemesis, melaena, blood y diarrh oea),
abdominal pain/tenderness, gastrointestinal ulcers with or without bleedin g or
perforation, mouth ulcerations, tooth and tongue disorders or dysphagia.
In isolated cases: aphthous stomatitis, glossitis, esophageal lesions, low er gut
disorders (e. g. non -specific haemo rrhagic colitis and ex acerbations or
ulcerative colitis or Crohn’s proctoco
litis, colonic damage and stricture
formation), pancreatitis, or constipation.
Central nervous system
Occasional: headache, dizziness or vertigo.
Rare: drowsi ness, t iredness, d ysgeusia, pa raesthesia, bal ance i mpairment,
aponia, hypoaesthesia, migraine, speech disorder, or trismus.
In isolated
cases: d isturbances o f sens ation, memor y disturba nce,
disorientation, insomnia, irritabilit y, convuls ions, depression, anx iety,
nightmares, tremor, psychotic reactions, or aseptic meningitis.
General disorders
Rare: pa in, c hest pa in, c hest tig htness, mal aise, ri gors, blood y discha rge,
feeling abnormal, feeling hot, or pyrexia.

Musculoskeletal and connective tissue disorders
Occasional: pain in jaw.
Rare: f acial pai n, j oint stiffness, m yalgia, b ack pai n, chest w all pai n, neck
pain, muscle cramp, or muscle tightness.
Special senses
Rare: eyelid oedema, eyelid pruritus, increased lacrimation, or eye pain.
In isolated cas es: disturbances of vision (blurre d vision, diplopia), imp aired
hearing, tinnitus, or taste disturbances.
Skin
Occasional: rashes or skin eruptions.
Rare: urticaria, pruritus, or sweating increased.
In isola ted ca ses: bullou s e ruptions, ec zema, er ythema multiforme , Ste vensJohnson s yndrome, Ly ell’s s yndrome (a cute tox ic epidermol ysis),
erythroderma ( exfoliative derm atitis), loss of hai r, photosensitivit y r eactions,
or purpura including allergic purpura.
Kidney
Rare: oedema, renal pain.
In isola ted ca ses: ac ute re nal insuffic iency, urinary a bnormalities (e .g.
haematuria, proteinuria), interstitial nephritis, nephrotic syndrome, or papillary
necrosis.
Liver
Occasional: elevation of serum aminotransferase enzymes (ALT, AST).
Rare: liver function disorders including hepatitis (in isolated cases fulminant)
with or without jaundice, or increased lipase.
Blood
Rare: neutrophilia.
In i solated cases: t hrombocytopenia, leucopenia, ag ranulocytosis, hemoly tic
anaemia, or aplastic anaemia.
Hypersensitivity
Rare: h ypersensitivity reactions
(e.g. br onchospasm, anaph ylactic/
anaphylactoid s ystemic reactions including h ypotension), respiratory disorder
NOS, or rhinorrhoea.
In isolated cases: vasculitis, or pneumonitis.
Cardiovascular and cerebrovascular
Occasional: haemorrhage
Rare: phlebitis, hypotension, bradycardia, or flushing.
In isolated cas es: palpitations, chest pain, h ypertension, or cong estive h eart
failure.
Laboratory abnormalities
Rare: elevated creatine phosphokinase, ke tonuria, haematuria, or bilirubin in
urine.
Other organ systems
In isolated cases: impotence.
Reactions to the intramuscular injection

Occasional: reactions such as local pain and induration.
In isolated cases: abscesses and local necrosis at the injection site.
Reactions to the intravenous injection
Occasional: thrombophlebitis.
Rare: cannula site r eaction, infusion site discomfort or burnin g, injection site
stinging, or pyrexia.
Additional adverse r eactions have b een docum ented following diclof enac
administration
Cardiovascular a nd c erebrovascular: Clinic al tria l a nd e pidemiological da ta
suggest that use of diclofenac, particularly at high doses (150 mg daily) and in
long t erm t reatment m ay be associ ated wi th a smal l i ncreased ri sk of art erial
thrombotic event s (for ex ample m yocardial infar ction or stroke) (see Sec tion
4.4).
Additional adverse reactions have be en docume nted following non -selective
NSAIDs therapy
Hypersensitivity: H ypersensitivity r eactions ha ve been r eported follo wing
treatment with NSA IDs. These m ay c onsist of (a ) non-sp ecific alle rgic
reactions a nd a naphylaxis (b) re spiratory trac t rea ctivity c omprising a sthma,
aggravated asthma, bronchospasm or d yspnoea, or (c) assort ed skin disord ers,
including rashes of vario us types, pruritus, urticaria, purpura, an giodema and,
more ra rely exfoliative a nd bullous de rmatoses (inc luding e pidermal
necrolysis and erythema multiforme).
Other adverse reactions reported less commonly include:
Renal: Renal failure.
Neurological a nd sp ecial se nses: Optic ne uritis, re ports of a septic me ningitis
(especially in pa tients with e xisting a utoimmune disorde rs, suc h a s s ystemic
lupus erythematosus, mixed connective tissue disease), with symptoms such as
stiff ne ck, hea dache, n ausea, vomiting , fe ver or disorie ntation (see Sec tion
4.4).
4.9 Overdose
Symptoms
Symptoms inc lude headache, n ausea, v omiting, e pigastric pain,
gastrointestinal ble eding, rarel y dia rrhoea, disor ientation, ex citation, coma,
drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of
significant poisoning acute renal failure and liver damage are possible.
Therapeutic measure
Patients should be treated symptomatically as required.
Within one hour of ing estion of a poten tially toxic amount, activated ch arcoal
should be consider ed. Alternativel y, in adult s, g astric lava ge shoul d be
considered within one hour of in gestion of a potentiall y lif e-threatening
overdose.
Good urine output should be ensured.

Renal and liver function should be closely monitored.
Patients should be observed for at least four hours after ingestion of potentially
toxic amounts.
Frequent or prolon ged convulsions should b e tre ated with intrave nous
diazepam.
Other measures may be indicated by the patient's clinical condition.

5 PHARMACOLOGI

CAL PROPERTIES

5.1 P

harmacodynamic properties
Pharmacotherapeutic group
Non-steroidal anti-inflammatory drugs (NSAIDs). ATC code M01AB.
Mechanism of action
Dyloject 75 m g/2 ml Solution for Injection is a non-ste roidal a gent with
marked analgesic/anti-inflammatory prop erties. It is
an inhibitor of
prostaglandin s ynthetase (c yclo-oxygenase). Dicl ofenac sodium in vitro does
not suppress proteo glycan bios ynthesis in cartilage at con centrations
equivalent to the c oncentrations re ached i n human bei ngs. W hen used
concomitantly with opioids for the
ma nagement of post-ope rative pa in,
diclofenac sodium often reduces the need for opioids.

5.2 P

harmacokinetic properties
Absorption
Intramuscular injection: After administration of Dyloject 75 mg/2 ml Solution
for Injection intramuscularly, absorption sets in imme diately, and m ean p eak
plasma concentrations of about 2.569 ± 1.09 2 µ g/ml (2.5 µ g/ml eq uals
approximately 8 µ mol/l) are r eached in 39 minutes. In comparative clinical
studies, the rate of a bsorption for D yloject 75 m g/2 ml Solution for Injection
was more rapid than V oltarol® Ampoules - peak plasma conc entration for
Voltarol® was 1.541 ± 0.419 µg/ml at 48 minutes. The extent of absorption of
Dyloject 75 mg /2 ml Solution for Injection wa s bioequivalent to Voltarol®
Ampoules. The amount of diclofenac absorbed a fter IM administration is in
linear proportion to the size of the dose.
Intravenous injection: After administr ation of Dy loject 75 mg /2 ml Solu tion
for Injection intra venously, a bsorption s ets in imme diately, and me an peak
plasma concentrations of about 15.147 ± 2.8 29 µ g/ml (2.5 µ g/ml equals
approximately 8 µ mol/l) are r eached in 3 minutes. In comparative clinical
studies, the rate of a bsorption for D yloject 75 m g/2 ml Solution for Injection
was more rapid than V oltarol® Ampoules - peak plasma conc entration for
Voltarol® was 5.668 ± 0.974 µg/ml at 30 minutes. The ex tent of absorption of
Dyloject 75 mg /2 ml Solution for Injection wa s bioequivalent to Voltarol®
Ampoules.
In clinical studies comparing the analgesic efficacy of Dyloject to Voltarol®,
Dyloject was found to have a more r apid onset of anal gesic action. At the 15and 30-minute post-dose time s, D yloject 75 mg /2 ml So lution for I njection

was sta tistically superior to Voltarol® a
s me asured on th e VAS and
categorical pain intensity and pain relief scales (p < 0.05). At 15 minutes after
dosing, the proportion of patients reporting a 30 % reduction in pain inte nsity
differed si gnificantly for those given Dyloject and Voltarol® (52% ve rsus
21%, respectively;
p = 0.0022). D yloject was statistically superior to Voltarol® over the initial 02 hour TOTPAR inte rval both on th e VAS scale (p
= 0.009) and the
categorical scale (p = 0.019). The mag nitude of pain relief after two hours and
the duration of action of Dyloject were found to be similar to Voltarol®.
Bioavailability
The relative bioavailability of Dyloject 75 mg/2 ml Solution for Injection after
IM administration is appr oximately 100%. Th e abso lute bioavailability of
Dyloject 75 mg /2 ml Solution for Injection after IV administration relative to
Voltarol® Ampoules IV is approximately 100%.
The bioa vailability of dic lofenac after ora l or re ctal administration is
approximately one half that of IM or IV administration, as thes e latter routes
avoid “first-pass” metabolism.
Distribution
The active substance is 99.7% protein bound, mainly to albumin (99.4%).
Diclofenac ent ers t he s ynovial fl uid, whe re m aximum concent rations are
measured 2 to 4 h ours a fter the peak pl asma val ues have be en attain ed. The
apparent half -life for el imination from the s ynovial fluid is 3 - 6 hours. Two
hours afte r re aching th e peak plasma valu es, concentrations of the active
substance are already higher in the s ynovial fluid than the y are in the plasma,
and remain higher for up to 12 hours.
Metabolism
Biotransformation of dic lofenac tak es pl ace partly b y g lucuronidation of the
intact mole cule, but mainly b y sin gle a nd multiple h ydroxylation a nd
methoxylation, resulting in several phenolic metabolites, most of which are
converted to
glucuronide conjuga tes. Two phenolic metabolites are
biologically active, but to a much lesser extent than diclofenac.
Elimination
The terminal half-life of Dyloject 75 mg/2 ml Solution for Injection in plasma
is 1.17 ± 0.32 hours. In comparative clinical studies, the rate of clearance was
more rapid than for Voltarol® Ampoules ( IM: 1. 17 ± 0.29 hours, I V: 1.23 ±
0.31 hours). F or D yloject and Voltarol®, renal cl earance and excretion were
found to be bioequivalent. Total systemic clearance of diclofenac in plasma is
263 ± 56 ml/min (mean value ± SD). F our of t he metabolites, including the
two active ones, also have short plasma half-lives of 1 - 3 hours.
About 60% of the admin istered dose is ex creted in the urine in the form of the
glucuronide c onjugate o f the inta ct mole cule and a s me tabolites, most of
which are also converted to g lucuronide conjugates. Less than 1% is ex creted
as unc hanged subst ance. The rest o f the dose is e liminated a s me tabolites
through the bile in the faeces.
Previous studies with HP βCD at higher doses than what is present in Dyloject
75 mg (667 mg p er dos e) hav e shown that the t erminal half-lif e followi ng a

single-dose of 2 g of HPβCD administered b y a o ne-hour IV infusion is 1. 5 ±
0.3 hours. HP βCD is primaril y r enally ex creted with 93% to 101% ex creted
unchanged in the u rine within 12 hours of adm inistration. In subjects with
severe ren al i mpairment (cr eatinine cl earance ≤ 19 ml/min), c learance of
HPβCD was reduced 6-fold compared to subjects with normal renal function.
Characteristics in patients
Elderly: No r elevant a ge-dependent diff erences in the dru g’s abso rption,
metabolism or excretion have been reported.
Patients with re nal impairme nt: In pa tients suffering from re nal impa irment,
no accum ulation of t he unchan ged a ctive subst ance can be i nferred f rom t he
single-dose kinetics when appl ying the usual dosage schedul e. At a cr eatinine
clearance of < 10 ml/min, the ca lculated ste ady-state pla sma le vels o f the
hydroxyl metabolites ar e about 4 times hi gher than in normal subjects.
However, the metabolites are ultimately cleared through the bile.
Patients with hepatic d isease: In patients with chr onic hepatitis or nondecompensated c irrhosis, the kine tics a nd me tabolism of dic lofenac are the
same as in patients without liver disease.
5.3

Preclinical safety data
Nonclinical da ta on dic lofenac, HP CD a nd the ir c ombination in D yloject
revealed no special hazard for humans based on conventional studies of safety
pharmacology, rep eated dose t oxicity, genotoxicity, c arcinogenic pote ntial,
toxicity to reproduction , and local to lerance studies with the fol lowing
provisions for pote ntial gastrointestinal to xicity and foet al risk of p remature
closure of the ductus arteriosus in late pregnancy.
A single or al dose of 0. 1 mg/kg of di clofenac t o pre gnant r ats on p regnancy
day 21 caused a constriction of the ductus arteriosus in the offsprin g, a known
effect of prostag landin-inhibiting drug s. Admini stration of dic lofenac in la te
pregnancy is therefore not recommended.
In the 4-w eek IV tox icity studies conducted with diclofenac in r ats (3, 7 and
15 mg /kg/day) and dic lofenac and HP CD in monke ys (3, 15 and 60
mg/kg/day and 533 mg /kg/day respectively) observed effects were essentially
similar for both species and were all considered expected. Diclofenac induced
a low inc idence of morta lity/premature sa crifice (due to pe ritonitis),
gastrointestinal toxicity and regenerative anaemia in ra ts at a dose level of 15
mg/kg/day. Recovery was complete after a 9-week treatment-free period.
In monke ys, diclofenac caused gastrointestinal t oxicity, regenerative anaemia
and ex acerbation of m inor t ail ski n lesions at dose l evels of 15 and 60
mg/kg/day. Re solution of the se findi ngs could not be assessed in
th e 60
mg/kg/day dos e group, due to premature sacr ifice. F indings attributed to
HP CD included ver y mild to mild renal tubular vacuolization in rats and
very mild to mild granular appearance of the renal tubular cells in the medullar
rays in monke ys. F ollowing a relativel y long treatment- free period as
compared to the du ration of tre atment, p artial a nd c omplete re covery of
HP CD-associated fi ndings has b een d emonstrated i n r ats and m onkeys,
respectively.

The No Adverse E ffect Level for HP CD-related effe cts after 4 we eks of
administration is lower than 26.6 mg HP CD/kg/day in both species.
The solubilising ag ent HP βCD has been fo und to produce panc reatic
hyperplasia and n eoplasia when administe red o rally to rats at doses of 500,
2000 or 5000 mg /kg per day for 25 months. Adenocarcinomas of the ex ocrine
pancreas produced in the treated animals were not seen in the untreated group
and ar e not repo rted i n the histori cal control s. These findin gs we re not
observed in the mouse c arcinogenicity study, nor in a 12-month to xicity study
in dogs or in a 2-year toxicity study in female cynomolgous monkeys.
In the D yloject nonclinical studies diclofenac and HP CD alone and in
combination we re not mutagenic or clastogenic. Diclofen ac h as show n no
carcinogenic pot ential. The adenoca rcinomas observed in the ex
ocrine
pancreas in the 2-year oral carcinogenicity study with HP CD in rats were not
considered a cl inical ha zard for D yloject be cause HP CD i s not g enotoxic.
Dyloject is inte nded for short-te rm tr eatment on ly, and no p ancreatotrophic
changes were observed in the 4 week intravenous studies in r ats and monkeys
described above.

6 PHARMACEUTI
6.1

CAL PARTICULARS

List of excipients
Dyloject 75 mg/2 ml Solution for Injection also contain
•H
ydroxypropylbetadex (HP CD)
• Monothiog
lycerol
•W
ater for Injection

Sodium hydroxide and/or hydrochloric acid (to adjust pH)
• Nitrog
en

6.2 Incom patibilities
The vials used IM or IV as a bolus s hould not b e mixed with other injection
solutions.
6.3 Shelf
life
30 months.
6.4

Special precautions for storage
Store below 30°C. Do n ot freez e. Keep vi als in the outer carton in o rder to
protect from light.
Keep Dyloject out of reach and sight of children.

6.5

Nature and contents of container
The vials are 2 m l Ph. Eur. T ype I bo rosilicate glass vials with 13 m m caps.
The vials contain colourless liquid and are supplied in packs of 10.

6.6

Special precautions for disposal
The dose should be fr eshly withdrawn from the vial and used immediatel y.
Once withdrawn, the dose should not be stored.
The product should not be used if crystals or precipitates are observed.

7 MARKETI

NG AUTHORISATION HOLDER

Therabel Pharma UK Limited
Compass House, Vision Park
Chivers Way, Histon
Cambridge CB24 9AD
United Kingdom

8 MARKETI

NG AUTHORISATION NUMBER

PL 25053/0001

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
30/10/2007

10

DATE OF REVISION OF THE TEXT
22/09/2009

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