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PENNSAID 16MG/ML CUTANEOUS SOLUTION

Active substance(s): DICLOFENAC SODIUM / DICLOFENAC SODIUM / DICLOFENAC SODIUM

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1

Name of the medicinal product
PENNSAID® 16 mg/ml cutaneous solution

2

Qualitative and quantitative composition
1 ml cutaneous solution contains: 16.05 mg diclofenac sodium
For excipients, see 6.1

3

Pharmaceutical form
Cutaneous solution.
The cutaneous solution is a clear, colourless to pink or orange liquid.

4.1

Therapeutic indications
PENNSAID® (16 mg/ml diclofenac sodium) is a cutaneous solution that is
indicated for the symptomatic relief of pain associated with osteoarthritis in
superficial joints, including the knee. 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® (16 mg/ml diclofenac sodium) to a medium (e.g. wrist) or large
joint (e.g. knee), respectively. Patients should use up to a maximum of 40
drops four times per day per joint as recommended by the physician. 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. Repeat
this procedure until the total amount of PENNSAID® has been applied.
Follow the same procedure 4 times a day.

Patients with renal and hepatic impairment:
For the use of PENNSAID® in patients with hepatic or renal impairment see
section 4.4.
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® (16 mg/ml diclofenac sodium) is contraindicated in pregnant
and lactating women and in patients with hypersensitivity to diclofenac or
other ingredients of the solution.
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 Special Precautions for Use
Undesirable effects may be minimised by using the minimum effective dose for the
shortest duration necessary to control symptoms.
Elderly: The elderly have an increased frequency of adverse reactions to oral NSAIDs
especially gastrointestinal bleeding and perforation, which may be fatal.
Patients with a history of GI toxicity, particularly when elderly, should report any
unusual abdominal symptoms (especially GI bleeding) particularly in the initial
stages of treatment.
Serious skin reactions, some of them fatal, including exfoliative dermatitis, StevensJohnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in
association with the use of NSAIDSs (see 4.8). Patients appear to be at highest risk
for these reactions early in the course of therapy: the onset of the reaction occurring
in the majority of cases within the first month of treatment. PENNSAID® should be
discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of
hypersensitivity.
Patients should be instructed to wash their hands after the administration procedure to
avoid contact with eyes, mucous membranes and skin not intended for treatment.
No other medicinal products should be applied to the affected area simultaneously
with PENNSAID®.

The likelihood of systemic side effects occurring following the topical
application of PENNSAID® is very small compared to the frequency of side
effects with oral diclofenac, owing to low systemic absorption with
PENNSAID®. This product should be used with caution in patients with
impaired renal function, since isolated cases of systemic reactions resulting in

deterioration of renal function have been reported with topically or orally
administered NSAIDs. The lower dose of PENNSAID® per joint should be
considered.
Hepatic System
Mild elevation of liver function tests may occur during treatment with PENNSAID®.
If abnormal liver function tests persist or worsen, clinical signs or symptoms
consistent with liver disease develop, or if other manifestations occur (e.g.
eosinophilia, rash), PENNSAID® should be discontinued. If there is a need to
prescribe this drug in the presence of severe impairment of liver function, it must be
done under strict observation.

Caution is called for when using diclofenac sodium in patients with hepatic
porphyria, since diclofenac sodium may trigger an attack.
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 antiinflammatory 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. Do not use PENNSAID® in joint areas
where there is a previous skin disease (e.g. psoriasis) unless advised by your
physician.] 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.

PENNSAID® contains dimethyl sulphoxide (DMSO) which can cause
drowsiness and headache and may be irritant to the skin.
4.5 Interactions with other medicaments and other forms of interaction
The listed interactions in this section of the SPC have been observed after systemic
administration of diclofenac sodium. The risk associated with the topical use of
PENNSAID® formulation is not known, but probably low.
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 might 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:

NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see
section 4.4).
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 prostaglandin.
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 β-blockers, as well as other antihypertensive agents.
Other Drugs
Diclofenac sodium should not be used concomitantly with diclofenac potassium since
both exist in plasma as the same active organic ion.
Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (See section
4.4).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs):
increased risk of gastrointestinal bleeding (see section 4.4).

4.6

Use during pregnancy and lactation
PENNSAID® is contraindicated during pregnancy and lactation (see sections
4.3 and 5.3).

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 six double-blind, clinical trials with significantly increased frequency in the
PENNSAID®-treated group compared with placebo. At the site of application, dry
skin (35.80% compared to 6.86% in placebo treated group) and rash (10.44%
compared to 2.86% in placebo treated group) were statistically significant. Other
Pennsaid undesirable effects statistically significant compared to placebo are
constipation (3.83% compared to 0.57%), dyspepsia (8.98% compared to 4%) and
flatulence (4.49% compared to 0.57%).
Photoallergic reaction and contact dermatitis have been reported following
application of topical diclofenac.
Systemic absorption of diclofenac sodium after topical application of PENNSAID® is
very low compared with use of diclofenac sodium tablets. However, where
PENNSAID® is applied to a relatively large area of skin over a prolonged period, the
possibility of systemic side-effects similar to systemic effects from oral diclofenac
(see below) cannot be completely excluded. Possible systemic side-effects are
described below.

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 (StevensJohnson syndrome and Lyell syndrome). Fatalities have occurred on occasion,
particularly in the elderly.
Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal
Necrolysis (very rare)

Oedema, hypertension and cardiac failure have been reported in association with
NSAID treatment
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 paraesthesia, 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 gastrointestinal 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 asthma in patients sensitive to ASA e.g.,
bronchospasm; anaphylactic/anaphylactoid systemic reactions including hypotension.
Isolated: vasculitis and pneumonitis.

4.9

Overdose symptoms, emergency procedures, antidotes
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 gastrointestinal condition for possible irritation or
bleeding. Supportive and symptomatic treatment should be given for
complications including, for example: hypotension, gastrointestinal
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 of >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.

5.1

Pharmacodynamic properties
Pharmaco-Therapeutic Group
Topical products for Joints and Muscular Pain (M02).
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
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-hydroxydiclofenac, 3’hydroxydiclofenac, 3’-hydroxy-4’-methoxy diclofenac and 4’,5dihydroxydiclofenac.
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.
5.3

Preclinical safety data
Diclofenac sodium has not been shown to be mutagenic in standard in vitro
and in vivo tests. No increase in tumourgenicity has been observed in longterm animal studies with diclofenac sodium.
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.

6.1

List of Excipients
dimethyl sulphoxide
ethanol
glycerine
propylene glycol
purified water

6.2

Major incompatibilities
Not applicable

6.3

Shelf life
30 ml, 60 ml, 120 ml and 150 ml: 3 years
15 ml: 18 months
After first opening: 12 weeks

6.4

Special precautions for storage
Do not store above 25°C. Do not refrigerate.

6.5

Nature and contents of container
PENNSAID® is packaged in 20, 40, 75, 140 and 170 ml white, oval high-density
polyethylene bottles (which correspond to fill volumes of 15 ml, 30 ml, 60 ml, 120 ml
and 150 ml respectively), and are sealed with an 18 mm, white, low-density
polyethylene screw cap with a plastic dropper spout. Not all pack sizes may be
marketed.

6.6

Special precautions for disposal
No special requirements.

7

Marketing authorisation holder
DIMETHAID (UK) LIMITED
2 Bloomsbury Street
London, WC1B 3ST
United Kingdom

8

Marketing authorisation number
PL 18329/0001

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
21/11/2005

10

DATE OF REVISION OF THE TEXT
14/04/2010

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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