Pennsaid info from emc.vhn.net
Provalis Healthcare
Newtech Square
Deeside Industrial Park
Deeside
Flintshire CH5 2NT
Telephone: 01244 288 888 Facsimile: 01244 280 342
Document last updated on the eMC: Tue Jul 31 15:19:39 2001
Pennsaid Topical Solution
Table of Contents
1. Trade Name of the Medicinal Product
2. Qualitative and Quantitative Composition
3. Pharmaceutical Form
4. Clinical Particulars
4.1 Therapeutic Indications
4.2 Posology and Method of Administration
4.3 Contra-indications
4.4 Special Warnings and Precautions for Use
4.5 Interactions with other Medicaments and other forms of interaction
4.6 Pregnancy and Lactation
4.7 Effects on Ability to Drive and Use Machines
4.8 Undesirable Effects
4.9 Overdose
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
5.2 Pharmacokinetic Properties
5.2 Preclinical Safety Data
6. Pharmaceutical Particulars
6.1 List of Excipients
6.2 Incompatibilities
6.3 Shelf-Life
6.4 Special Precautions for Storage
6.5 Nature and Contents of Container
6.6 Instructions for Use/Handling
7. Marketing Authorisation Holder
8. Marketing Authorisation Number
9. Date of First Authorisation/Renewal of Authorisation
10. Date of (Partial) Revision of the Text
1. Trade Name of the Medicinal Product:
Pennsaid® Topical Solution.
2. Qualitative and Quantitative Composition:
1.5% (w/w) diclofenac sodium.
3. Pharmaceutical Form:
Cutaneous solution.
The solution is a clear, colourless to pink or orange liquid.
4. Clinical Particulars
4.1 Therapeutic Indications:
Pennsaid® (1.5% w/w diclofenac sodium) is indicated for the treatment of pain
associated with osteoarthritis of superficial joints of medium to large size, including the
knee and elbow. There is no data on the use of Pennsaid® for large, deep joints covered
by layers of muscle or other soft tissues, such as the hip or spine.
4.2 Posology and Method of Administration:
Pennsaid® is applied topically to the painful joint.
After washing the treatment site with soap and water and allowing it to dry, apply a total
of about 20 or 40 drops (approximately 0.5 or 1 ml) of Pennsaid® (1.5% w/w diclofenac
sodium) topical solution to a medium or large joint, respectively. To ensure that product
does not run off the treatment site, apply the solution in several aliquots of 5 or 10 drops
to the medium or large joint. Spread Pennsaid® evenly over the treatment area with a
hand or fingers with as little rubbing as possible. Repeat this procedure until the total
amount of Pennsaid® has been applied. Follow the same procedure 4 times a day.
Use in Children:
Since no experience has been acquired with Pennsaid® in paediatric use, it is not
recommended for use in this group of patients.
4.3 Contra-indications:
Pennsaid® (1.5% w/w diclofenac sodium) is contraindicated in pregnant and lactating
women and in patients with hypersensitivity to diclofenac. Since there exists the potential
for cross-sensitivity with other NSAIDs, even from different groups, diclofenac should not
be used in patients whom acute asthmatic attacks, urticaria, rhinitis or other allergic
manifestations have been precipitated by oral use of acetylsalicylic acid (ASA) or other
non-steroidal, anti-inflammatory agents.
Allergy or Skin Sensitivity: Pennsaid® also contains dimethyl sulphoxide (DMSO) as a skin
penetrant. It should not be used in patients with known history of allergy or skin
sensitivity to DMSO.
4.4 Special Warnings and Precautions for Use:
The occurrence of adverse systemic events associated with the use of Pennsaid® should
be very rare.
Gastrointestinal System:
Peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and
occasionally (rarely) fatal, in either the presence or absence of previous symptoms have
been known to occur during oral and rectal therapy with non-steroidal anti-inflammatory
drugs (NSAIDs). However, the maximum serum level of diclofenac, after topical application
of Pennsaid® , is low (50 times lower than that achieved after 25 mg of orally
administered diclofenac). Therefore, Pennsaid® (diclofenac sodium) can reasonably be
given to patients prone to gastrointestinal tract irritation, including those with a history of
previous NSAID-induced peptic ulcer, or other inflammatory disease of the gastrointestinal
tract (such as ulcerative colitis or Crohn's disease), under close medical supervision. In
these cases the physician must weigh the benefits of treatment against the possible
hazards (See Contraindications and Adverse Events). The patient should be instructed to
contact a physician immediately if symptoms or signs suggestive of peptic ulceration or
gastrointestinal bleeding occur. These reactions may occur at any time during treatment
without warning symptoms or signs.
Dermatological:
Pennsaid® should not be used under occlusive dressings.
Pennsaid® should not be applied to open, abraded or infected skin.
Application of Pennsaid® to mucus membranes is not advisable.
Hypersensitivity:
The dimethyl sulphoxide (DMSO) in Pennsaid® may initiate the liberation of histamine and
occasional hypersensitivity reactions have been reported with topical administration. If
anaphylactoid symptoms develop, appropriate therapy should be instituted and further use
of Pennsaid® discontinued.
Ophthalmology:
In animal studies, heavy DMSO dosage, particularly by the oral route, has resulted in
abnormal changes to the lens of the eye. In studies of primates and humans, following
both ocular and oral dosage of DMSO, no such changes have been observed.
Infection:
The anti-inflammatory and analgesic effects of diclofenac sodium may mask the usual
signs of infection. Hence, the physician should be alert to the development of localised
skin infection in the area that the patient has applied the drug.
The maximum concentration of diclofenac in the blood, after application of the maximum
dosage of Pennsaid® (1ml), was found to be less than 10 ng/ml. This value is 50 times
lower than the maximum concentration of diclofenac in the blood after oral administration
of 25 mg of diclofenac.
4.5 Interactions with other Medicaments and other forms of interaction:
Acetylsalicylic Acid (ASA):
Serum levels of diclofenac may be reduced when taken with ASA simultaneously. The
bioavailability of ASA is reduced by the presence of diclofenac. Although these
pharmacokinetic interactions do not appear to be clinically relevant, there is no proven
advantage in using these two medications together.
Digoxin:
Diclofenac may increase the plasma concentration of digoxin.
Dosage adjustment may be required.
Lithium:
Lithium plasma concentrations will increase when administered concomitantly with
diclofenac (which affects lithium renal clearance).
Dosage adjustment of lithium may be required.
Oral hypoglycaemic drugs:
Pharmacodynamic studies have shown no potentiation of effect with concurrent
administration with diclofenac: however, there are isolated reports of both hypoglycaemic
and hyperglycaemic effects in the dosage of hypoglycaemic agents.
Anticoagulants:
Although clinical investigations would appear to indicate that diclofenac has no influence
on the effect of anticoagulants, there have been isolated reports of an increased risk of
haemorrhage with the combined use of diclofenac and acenocoumarol anticoagulant
therapy. Special caution is therefore recommended and frequent laboratory tests should
be performed to check that the desired response to the anticoagulant is being maintained.
Although diclofenac, as with other NSAIDs, is an inhibitor of induced platelet aggregation
in vitro and in vivo, it has little effect on spontaneous platelet aggregation at usual
therapeutic dosages.
Diuretics:
NSAIDs have been reported to decrease the activity of diuretics.
Concomitant treatment with potassium-sparing diuretics may be associated with increased
serum potassium, thus it is necessary to monitor blood/plasma levels regularly.
Glucocorticoids:
Concomitant administration may aggravate gastrointestinal side effects.
NSAIDs:
Concurrent oral treatment with two or more NSAIDs may promote the occurrence of side
effects (see Special Warnings and Precautions for Use).
Methotrexate:
Caution should be exercised when NSAIDs are administered less than 24 hours before or
after treatment with methotrexate. Elevated blood concentrations of methotrexate may
occur, hence toxicity is increased.
Cyclosporine:
Nephrotoxicity of cyclosporine may be increased because of the effect of NSAIDs on renal
prostaglandins.
Quinolone Antibacterials:
There have been isolated reports of convulsions, which may have been due to
concomitant use of quinolones and NSAIDs.
Antihypertensive Agents:
Like other NSAIDs, diclofenac can reduce the antihypertensive effects of propranolol and
other ß-blockers, as well as other anti-hypertensive agents.
Other Drugs:
Diclofenac sodium must not be used concomitantly with diclofenac potassium since both
exist in plasma as the same active organic ion.
4.6 Pregnancy and Lactation:
Pennsaid® is contraindicated during pregnancy and lactation.
4.7 Effects on Ability to Drive and Use Machines:
Headache, dizziness, light-headedness, and mental confusion have been reported
following oral diclofenac therapy. Patients should be aware that these side effects may
occur, and be cautioned against operating machinery or motor vehicles should they
experience any of these.
4.8 Undesirable Effects:
Topical:
Undesirable effects are divided into those occurring at the site of application and those
occurring as a systemic effect. The following undesirable effects were observed in two
double-blind clinical trials with significantly increased frequency in the Pennsaid® -treated
group compared with placebo. At the site of application, dry skin (40.8% compared to
1.6% in placebo treated group) and rash (12.0% compared to 3.3% in placebo treated
group) were statistically significant.
Since systemic absorption of diclofenac sodium after topical application of Pennsaid® is
low compared with use of diclofenac sodium tablets, the likelihood of those systemic
side-effects which frequently occur with tablets is small with Pennsaid®. However, where
Pennsaid® is applied to a relatively large area of skin over a prolonged period, the
possibility of systemic side-effects cannot be completely excluded. Any adverse events
due to systemic absorption from Pennsaid® may be similar to systemic effects from oral
diclofenac (see below).
Isolated cases:
Hypersensitivity reaction may occur including asthmatic attacks and angio-oedema.
Oral:
Oral administration of diclofenac results in adverse events due to systemic and local
gastrointestinal reactions.
The most severe gastrointestinal adverse reactions observed were ulceration and bleeding
while the most severe albeit rare dermatological reactions observed were erythema
multiforme (Stevens-Johnson syndrome and Lyell syndrome). Fatalities have occurred on
occasion, particularly in the elderly.
Gastrointestinal:
Occasional:
epigastric, gastric, or abdominal pain, abdominal cramps, nausea, dyspepsia, anorexia,
diarrhoea, vomiting and flatulence.
Rare:
gastrointestinal bleeding (bloody diarrhoea, melaena, haematemesis) gastric and intestinal
ulcerations with or without bleeding or perforation.
Isolated:
lower gut disorders (e.g. non-specific haemorrhagic colitis and exacerbation of ulcerative
colitis or Crohn's disease), diaphragm-like intestinal strictures, hyperacidity, stomatitis,
glossitis, coated tongue, oesophageal lesions, constipation and pancreatitis.
CNS:
Occasional:
dizziness, headache and vertigo.
Rare:
drowsiness, malaise, impaired concentration and tiredness.
Isolated:
sensory disturbances including paresthesia, memory disturbance, disorientation, insomnia,
irritability, convulsions, depression, anxiety, nightmares, tremor, psychotic reactions and
aseptic meningitis.
Special Senses:
Isolated:
vision disturbances (blurred vision, diplopia), impaired hearing, tinnitus and taste alteration
disorders.
Cardiovascular:
Rare:
palpitation, angina and arrhythmias.
Isolated:
exacerbation of cardiac failure and hypertension.
Dermatologic:
Occasional:
rash and pruritus.
Rare:
urticaria.
Isolated:
bullous eruption, erythema, eczema, erythema multiforme, Stevens-Johnson syndrome,
Lyell Syndrome (toxic epidermal necrolysis), erythroderma (exfoliative dermatitis), loss of
hair, photosensitivity reactions and purpura including allergic purpura.
Renal System:
Rare:
Oedema (facial, general, peripheral).
Isolated:
acute renal failure, nephrotic syndrome, urinary abnormalities (e.g. haematuria and
proteinuria), interstitial nephritis and papillary necrosis.
Haematologic:
Isolated:
thrombocytopaenia, leukopaenia, agranulocytosis, haemolytic anaemia, aplastic anaemia
and anaemia secondary to gastro-intestinal bleeding.
Hepatic:
Occasional:
elevations ( 3 times the upper normal limit) of AST, ALT.
Rare:
liver function disorders including hepatitis with or without jaundice.
Isolated:
fulminant hepatitis.
Hypersensitivity:
Rare:
hypersensitivity reaction such as as asthma in patients sensitive to ASA e.g.,
bronchospasm; anaphylactic/anaphylactoid systemic reactions including hypotension.
Isolated:
vasculitis and pneumonitis.
4.9 Overdose:
Pennsaid® is intended for external use only. The low systemic absorption of diclofenac
from Pennsaid® suggests that toxicity from topical overdose is extremely unlikely.
In the event of accidental ingestion, the amount of diclofenac sodium (900 mg) contained
in one 60 ml bottle of Pennsaid ® could cause stomach upset and/or transient renal
dysfunction. Absorption should be minimised as soon as possible by administration of
activated charcoal. Renal function should be monitored as should gastro-intestinal
condition for possible irritation or bleeding. Supportive and symptomatic treatment should
be given for complications including for example: hypotension, gastro-intestinal
haemorrhage and renal failure. Forced diuresis may be of limited use. The amount of DMSO
(36 g) would be far below any level dangerous to humans (based on an LD50 in monkeys
o>11 g/kg).
Acute exposure to DMSO through inhalation of high vapour concentrations through the
use or abuse of Pennsaid® is remote. In the event that exposure should occur, it may
lead to irritation of the mucous membranes of the upper respiratory tract, wheezing,
nausea or vomiting. Treatment includes administration of oxygen or other symptomatic
measures as necessary.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties:
Pharmaco-Therapeutic Group:
Topical products for Joints and Muscular Pain (MO2).
Mechanism of Action:
Diclofenac sodium is a non-steroidal anti-inflammatory drug of the arylacanoic acid group,
with analgesic and antipyretic properties.
Diclofenac inhibits prostaglandin biosynthesis by irreversibly inactivating prostaglandin
synthetase. This decreased formation of prostaglandins results from the competition
between diclofenac and arachidonic acid for binding to cyclooxygenase (prostaglandin
synthetase). This may partially explain its mechanism of action.
Since the anti-inflammatory activity of diclofenac is maintained even in adrenalectomised
animals, it does not act through the pituitary-adrenal axis. Diclofenac is considered to be
a peripherally acting analgesic.
Pennsaid® contains diclofenac sodium in a solution base containing 45% (w/w) dimethyl
sulphoxide (DMSO), which enhances drug penetration through the skin into underlying
tissue and joint spaces. There are many mechanisms of action suggested for DMSO, and it
is likely that a combination of mechanisms is operational.
5.2 Pharmacokinetic Properties:
Absorption:
Diclofenac sodium is rapidly absorbed when administered as an oral solution, rectal
suppository, or by intramuscular injection. It is absorbed more slowly when administered
as enteric-coated tablets, especially when this dosage form is given with food. Diclofenac
is also absorbed percutaneously.
After the topical application of 1.0 ml of Pennsaid® (15 mg of diclofenac sodium), the
mean peak plasma concentration (Cmax) of diclofenac in plasma is 9.7 ng/ml. This
concentration is reached at 24 to 48 hours (Tmax).
Distribution and Metabolism:
Although orally administered diclofenac is almost completely absorbed, it undergoes first
pass metabolism so that only 50-60% of the drug reaches the systemic circulation in the
unchanged form. At therapeutic concentrations it is more than 99% bound to plasma
proteins. Diclofenac penetrates synovial fluid and has been detected in breast milk. The
terminal plasma half-life is about 1 to 2 hours. Diclofenac is metabolised to
4'-hydroxydiclofenac, 5-hydroxydi-clofenac, 3'-hydroxydiclofenac, 3'-hydroxy-4'methoxy
diclofenac and 4',5-dihydroxydiclofenac.
Elimination:
Diclofenac sodium is excreted in the form of glucuronide and sulphate conjugates, mainly
in the urine and the bile.
The mean total urinary recovery of diclofenac after 120 hours is 3.68%. The peak urinary
excretion rate is reached within 24 hours and is maintained until 48-72 hours.
Diclofenac sodium and its metabolites are eliminated primarily (60%) by the kidneys.
5.2 Preclinical Safety Data:
The excipient DMSO can produce local toxicity, particularly when administered in undiluted
form (muscle necrosis, inflammation and oedema, scaling and flaking of skin following
intramuscular, subcutaneous, or topical administration, respectively). DMSO has produced
teratogenic lesions in a number of mammalian species at doses of approximately
2.5g/kg/day or above and by different routes of administration.
6. Pharmaceutical Particulars
6.1 List of Excipients:
Pennsaid® (1.5% w/w diclofenac sodium topical solution) contains:
dimethyl sulphoxide, ethanol, glycerine, propylene glycol, purified water.
6.2 Incompatibilities:
Diclofenac sodium should not be used concomitantly with diclofenac potassium since both
exist in plasma as the same active organic ion.
6.3 Shelf-Life:
The produce can be stored for 24 months for the 30 ml and 60 ml bottle sizes and 18
months for the 15 ml bottle size. After opening, the product can be kept for up to 12
weeks.
6.4 Special Precautions for Storage:
Do not store above 25°C.
6.5 Nature and Contents of Container:
Pennsaid® Topical Solution is packaged in 15 ml, 30 ml or 60 ml, white, oval low-density
polyetheylene bottles, sealed with an 18 mm, white, low-density polyethylene screw cap
with a plastic dropper, spout.
6.6 Instructions for Use/Handling:
Wash hands after application.
Administrative Data
7. Marketing Authorisation Holder:
DIMETHAID (UK) LIMITED
Spectrum House, 20/26 Cursitor Street
London EC4A 1HY
United Kingdom
8. Marketing Authorisation Number:
PL 18329/0001
9. Date of First Authorisation/Renewal of Authorisation:
02 August 2000.
10. Date of (Partial) Revision of the Text:
22 December 2000.
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