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Voltaren ampoules
Antirheumatic, anti-inflammatory, analgesic
Composition
Active substance:
Diclofenac sodium (phenylacetic acid derivative)
Presentation and amount of active substance per unit:
i.m.: injection solution; i.v.: concentrate for infusion
One 3 mL ampoule of Voltaren contains 75 mg diclofenac sodium
Excipients:
Mannitol, propylene glycol, water, antioxidant: sodium metabisulfite (E 223)
2.0 mg;
Preservative: benzyl alcohol 120 mg.
Description
Clear, colourless to faintly yellow liquid.
Properties/effects
Mechanism of action
Voltaren ampoules contain diclofenac sodium, a non-steroidal compound with
pronounced antirheumatic, antiinflammatory, analgesic, and antipyretic
properties.
Inhibition of prostaglandin biosynthesis, which has been demonstrated in
experiments, is considered to be fundamental to its mechanism of action.
Prostaglandins play an important role in causing inflammation, pain, and
fever. Diclofenac sodium in vitro does not suppress proteoglycan
biosynthesis in cartilage at concentrations equivalent to the concentrations
reached in humans.
Therapeutic effect
In rheumatic diseases, the anti-inflammatory and analgesic properties of
Voltaren elicit a clinical response characterised by marked relief from
signs and symptoms such as pain at rest, pain on movement, morning
stiffness, and swelling of the joints, as well as by an improvement in
function. In post-traumatic and postoperative inflammatory conditions,
Voltaren rapidly relieves both spontaneous pain and pain on movement and
reduces inflammatory swelling and wound oedema. When used concomitantly with
opioids for the management of postoperative pain, Voltaren significantly
reduces the need for opioids.
In clinical trials, the pronounced analgesic effect has also been
demonstrated in moderate and severe pain of nonrheumatic origin, an effect
which sets in within 15-30 minutes. Voltaren has also been shown to have a
beneficial effect in migraine attacks. Voltaren ampoules are particularly
suitable for initial treatment of inflammatory and degenerative rheumatic
diseases, and of painful conditions due to inflammation of non-rheumatic
origin.
Pharmacokinetics
Absorption
After administration of 75 mg diclofenac by intramuscular injection, mean
peak plasma concentrations of about 2.5 µg/mL (8 µmol/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 an intravenous infusion
over 2 hours, mean peak plasma concentrations are about 1.9 µ/mL (5.9 µmol/L).
Shorter infusions result in higher peak plasma concentrations, while longer
infusions give plateau concentrations proportional to the infusion rate
after 3 to 4 hours. In contrast, plasma concentrations decline rapidly once
peak levels have been reached following intramuscular injection or
administration of gastro-resistant tablets or suppositories. The area under
the concentration curve (AUC) after intramuscular or intravenous
administration is about twice as large as it is following oral or rectal
administration, because about half the active substance is metabolised
during its first passage through the liver ("first pass" effect) when
administered via the oral or rectal route. Pharmacokinetic behaviour does
not change after repeated administration. No accumulation occurs provided
the recommended dosage intervals are observed.
Distribution
Altogether 99.7% of diclofenac binds to serum proteins, mainly to albumin
(99.4%). The apparent volume of distribution calculated is 0.12-0.17 L/kg.
Diclofenac enters the synovial fluid, where maximum concentrations are
measured. 2-4 hours after peak plasma values have been reached. The apparent
half-life for elimination from the synovial fluid is 3-6 hours. Two hours
after reaching peak plasma levels, 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.
Metabolism
Biotransformation of diclofenac takes place partly by glucuronidation of the
intact molecule, but mainly by single and multiple hydroxylation and
methoxylation, resulting in several phenolic metabolites (3'hydroxy-, 4'-hydroxy-,
5-hydroxy-, 4',5dihydroxy-, and 3'-hydroxy-4' methoxydiclofenac), most of
which are converted to glucuronide conjugates. Two of these phenolic
metabolites are biologically active, but to a much lesser extent than
diclofenac.
Elimination
Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean
value± SD). The terminal half-life in plasma is 1-2 hours.
Four of the metabolites, including the two active ones, also have short
plasma half-lives of 1-3 hours. One metabolite,
3'-hydroxy-4'-methoxy-diclofenac, has a much longer plasma half-life.
However, this metabolite is virtually inactive. About 60% of the
administered dose is excreted in the urine in the form of metabolites. Less
than 1% is excreted as unchanged substance. The rest of the dose is
eliminated as metabolites through the bile in the faeces.
Kinetics in special clinical situations
No relevant age-dependent differences in the drug's absorption,
metabolism, or excretion have been observed after oral administration.
However, in elderly patients a 15-minute intravenous infusion resulted in
50% higher plasma concentrations than expected from the data on young
healthy subjects.
In patients suffering from renal impairment, no accumulation of the
unchanged active substance can be inferred from the single-dose kinetics when
applying the usual dosage schedule. At a creatinine clearance of less than
10 mL/min, the calculated steady-state plasma levels of the hydroxy
metabolites are about 4 times higher than in healthy subjects. However, the
metabolites are ultimately cleared through the bile.
In patients with impaired liver function (chronic hepatitis or non-decompensated
cirrhosis), the kinetics and metabolism of diclofenac are the same as in
patients without liver disease.
Indications
Intramuscular injection
Initial treatment of:
- Exacerbations of inflammatory and degenerative forms of rheumatism:
rheumatoid arthritis, ankylosing spondylitis, osteoarthritis,
spondylarthritis, painful syndromes of the vertebral column, non-articular
rheumatism.
- Acute attacks of gout.
- Renal colic and biliary colic.
- Post-traumatic and postoperative pain, inflammation, and swelling.
Intravenous infusion
Treatment or prevention of post-operative pain in a hospital setting.
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