Summary of Product Characteristics (SmPC)

1. Name of the Medicinal Product

Naproxen Tablets BP, 500 mg

2. Qualitative and Quantitative Composition

Each tablet contains Naproxen 500 mg

3. Pharmaceutical Form

Tablet
A light yellow, oval and biconvex tablet, having ‘ARISTO’ mark on one side and a break line on
the other side.

4. Clinical Particulars

4.1 Therapeutic indications

Naproxen is indicated for the treatment of:

• Rheumatoid arthritis.
• Osteoarthritis (degenerative arthritis).
• Ankylosing spondylitis.
• Juvenile rheumatoid arthritis.
• Acute gout.
• Acute musculoskeletal disorders
• Dysmenorrhoea.

4.2 Posology and method of administration

Adults
Rheumatoid arthritis, osteoarthritis and ankylosing spondylitis
500mg-1g daily in two doses at twelve hour intervals, or alternatively, if 1g daily is needed this
can be administered as two 500mg doses or as a single dose. The size of the morning and evening
doses can be adjusted on the basis of the predominant symptoms (ie night time pain or morning
stiffness)
Acute gout
Initially 750mg followed by 250mg every 8 hours until the attack has passed.
Acute musculoskeletal disorders and dysmenorrhoea
Initially 500mg followed by 250mg every 6-8 hours as necessary to a maximum of 1250mg daily
after the first day.
Loading Dose
As a single administration of two tablets, morning or evening, a loading dose of 750mg-1g daily
for the acute phase is recommended in the following cases:
a) Patients reporting severe night time pain and/or morning stiffness.
b) Patients commencing naproxen therapy following a switch from a high dose of another
antirheumatic compound.
c) Osteoarthritis where pain is the predominant symptom.
Paediatric population
For juvenile rheumatoid arthritis in children over 5 years old, 10mg/kg a day taken in two doses
every 12 hours.
Elderly
The elderly are at increased risk of the serious 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 regularly for GI bleeding during NSAID therapy.
Studies indicate that although total plasma concentration of naproxen is unchanged, unbound
plasma fraction of naproxen is increased in the elderly. The implication of this finding for
naproxen dosing is unknown. As with other drugs used in the elderly it is prudent to use the lowest
effective dose. Dosage should be reduced in the elderly where there is an impairment of renal
function. (See other special warnings and precautions).
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration
necessary to control symptoms.
Method of administration
For oral administration preferably with or after food.

4.3 Contraindications

- Hypersensitivity to naproxen, naproxen sodium or any of the excipients listed in SMPC.

- Patients with active gastrointestinal bleeding or peptic ulceration.
- Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven
ulceration or bleeding).
- NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions
(e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-
steroidal anti-inflammatory drugs.
- Severe heart failure, hepatic failure and renal failure.
- During the third trimester of pregnancy.
- History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

4.4 Special warnings and precautions for use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration
necessary to control symptoms (GI cardiovascular risks below).
Cardiovascular and cerebrovascular effects
Appropriate monitoring and advice are required for patients with a history of hypertension and/or
mild to moderate congestive heart failure as fluid retention and oedema have been reported in
association with NSAID therapy.
Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly
at high doses and in long term treatment) may be associated with a small increased risk of arterial
thrombotic events (for example myocardial infarction or stroke). Although data suggest that the
use of naproxen (1000mg daily) may be associated with a lower risk, some risk cannot be
excluded.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart
disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with
naproxen after careful consideration. Similar consideration should be made before initiating
longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension,
hyperlipidaemia, diabetes mellitus, smoking).
Gastrointestinal bleeding, ulceration and perforation
GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at
any time during treatment, with ot without warning symptoms or a previous history of serious GI
events.
The risk of GI bleeding, ulceration or perforation is higher
- with increasing NSAID doses
- in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation.
- in the elderly
- when used with alcohol
- in smoking
These patients should commence treatment on the lowest dose available. Combination therapy
with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these
patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to
increase gastrointestinal risk.
Patients with a history of GI toxicity, particularly the elderly, should report any unusual
abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.
Caution should be advised in patients receiving concomitant medications which could increase the
risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin,
selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin.
When GI bleeding or ulceration occurs in patients receiving naproxen, the treatment should be
withdrawn.
NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative
colitis, Crohn's disease) as these conditions may be exacerbated.
Cardiovascular, Renal and Hepatic Impairment
The administration of an 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 impairment, liver dysfunction, those taking diuretics and the
elderly. Renal function should be monitored in these patients.
Impaired renal function:
Naproxen should be used with great caution where there is impairment of renal function as it is
eliminated to a large extent (95%) via glomerular filtration; the monitoring of serum creatinine
and/or creatinine clearance should be conducted in these patients.
Naproxen is not recommended in patients having baseline creatinine clearance less than
20ml/minute.
Certain patients, specifically those whose renal blood flow is compromised, because of
extracellular volume depletion, cirrhosis of the liver, sodium restriction, congestive heart failure,
and pre-existing renal disease, should have renal function assessed before and during naproxen
therapy. Some elderly patients in whom impaired renal function may be expected, as well as
patients using diuretics, may also fall within this category. A reduction in daily dosage should be
considered to avoid the possibility of excessive accumulation of naproxen metabolites in these
patients.
Impaired liver function
Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma
concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The
implication of this finding for naproxen dosing is unknown but it is prudent to use the lowest
effective dose. The product should be used with caution in patients with a history of, or in those
with impaired liver function.
Elderly
The elderly have an increased frequency of adverse reactions to NSAIDs especially
gastrointestinal bleeding and perforation which may be fatal.
Respiratory disorders
Caution is required if administered to patients suffering from, or with a previous history of,
bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.
SLE and mixed connective tissue disease
In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there
may be an increased risk of aseptic meningitis.
Dermatological
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson
syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the
use of NSAIDs. 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. Naproxen should be discontinued at the first appearance of skin rash, mucosal lesions,
or any other sign of hypersensitivity.
Impaired female fertility
The use of naproxen may impair female fertility and is not recommended in women attempting to
conceive. In women who have difficulties conceiving or who are undergoing investigation of
fertility, withdrawal of naproxen should be considered.
Anaphylactic (anaphylactoid) reactions
Hypersensitivity reactions may occur in susceptible individuals. Anaphylactic (anaphylactoid)
reactions may occur both in patients with and without a history of hypersensitivity or exposure to
aspirin, other non-steroidal anti-inflammatory drugs or naproxen-containing products. They may
also occur in individuals with a history of angioedema, bronchospastic reactivity (eg asthma),
rhinitis and nasal polyps.
Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.
Naproxen, in common with other NSAIDs, decreases platelet aggregation and prolongs bleeding
time. This effect should be kept in mind when bleeding times are determined. Patients who have
coagulation disorders or who are receiving drug therapy that affects haemostasis should be
carefully observed when given naproxen.
Patients on full anticoagulant therapy (eg heparin or warfarin) may be at an increased risk of
bleeding if given naproxen concurrently. Therefore, the benefits should be weighed against these
risks.
Mild peripheral oedema has been observed in a few patients receiving naproxen. Although sodium
retention has not been reported in metabolic studies, it is possible that patients with questionable
or compromised function may be at a greater risk when taking naproxen.
Steroids
If steroid dosage is reduced or eliminated during therapy, the steroid dosage should be reduced
slowly and the patients must be observed closely for any evidence of adverse effects, including
adrenal insufficiency and exacerbation of symptoms of arthritis.
Ocular effects
Studies have not shown changes in the eye attributable to naproxen administration. In rare cases,
adverse ocular disorders including papillitis, retrobulbar optic neuritis and papilledema, have been
reported in users of NSAIDs including naproxen, although a cause-and-effect relationship cannot
be established; accordingly, patients who develop visual disturbances during treatment with
naproxen-containing products should have an ophthalmological examination.
Combination with other NSAIDs
The combination of naproxen-containing products and others NSAIDs is not recommended,
because of the cummulative risks of inducing serious NSAID-related adverse events.
The use of Naproxen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors
should be avoided.
The antipyretic and anti-inflammatory activities of naproxen may reduce fever and inflammation
thereby diminishing their utility as diagnostic signs.
Interference in tests:
Naproxen therapy should be temporarily withdrawn 48 hours before adrenal function tests are
performed as it may artifactually interfere with some tests for 17-ketogenic steroids. Similarly,
naproxen may interfere with some assays of urinary 5-hydroxyindoleacetic acid.
Sporadic abnormalities in laboratory tests (e.g. liver function test) have occurred in patients on
naproxen therapy, but no definite trend was seen in any test indicating toxicity.
Medication Overuse Headache (MOH)
After long term treatment with analgesics, headache may develop or aggravate. Headache caused
by overuse of analgesics (MOH - medication-overuse headache) should be suspected in patients
who have frequent or daily headaches despite (or because of) regular use of analgesics. Patients
with medication overuse headache should not be treated by increasing the dose. In such cases the
use of analgesics should be discontinued in consultation with a doctor.
Contains Lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

• Naproxen is highly protein-bound hence patients receiving hydantoins, anticoagulants or a

highly protein-bound sulphonamide should be closely monitored for signs of overdosage of these
drugs. No interactions have beern observed in clinical studies with naproxen or sulphonylureas,
but caution is nevertheless advised since interaction has been seen with other non-steroidal agents
of this class.
• NSAIDs, including naproxen, have been reported to increase steady state plasma lithium levels
by inhibition of renal lithium clearance. Decreased elimination of lithium. It is recommended that
these levels are monitored whenever initiating, adjusting or discontinuing naproxen.
• Anti-hypertensives: Reduced anti-hypertensive effect. Concomitant administration of naproxen
with beta blockers may reduce their antihypertensive effect and may increase the risk of renal
impairment associated with the use of ACE inhibitors or angiotensin II receptor antagonists.
• Probenecid given concurrently increases naproxen plasma levels and extends its half-life
considerably.
• Decreased elimination of methotrexate. Caution is advised when methotrexate is administered
concurrently, due to the possible enhancement of its toxicity as naproxen, like other NSAIDs, has
been reported to reduce tubular secretion of methotrexate in an animal model.
• The natriuretic effect of furosemide has been reported to be inhibited by some drugs of this class.
• NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside
levels when co-administered with cardiac glycosides..
• As with all NSAIDs, caution is advised when ciclosporin is co-administered because of the
increased risk of nephrotoxicity.
• NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can
reduce the effects of mifepristone.
• As with all NSAIDs, caution should be taken when co-administering with corticosteroids
because of the increased risk of gastrointestinal ulceration or bleeding.
• Other analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two
or more NSAIDs as this may increase the risk of adverse effects.
• Acetylsalicylic acid: Clinical pharmacodynamic data suggest that concomitant naproxen usage
for more than one day consecutively may inhibit the effect of low-dose acetylsalicylic acid on
platelet activity and this inhibition may persist for up to several days after stopping naproxen
therapy. The clinical relevance of this interaction is not known.
• Diuretics: NSAIDs may reduce the effect of diuretics and antihypertensive medicinal products.
The risk of acute renal insufficiency, which is usually reversible, may be increased in some
patients with compromised renal function (e.g. dehydrated patients or elderly patients) when
angiotensin II receptor antagonists are combined with NSAIDs. Therefore, the combination should
be administered with caution, especially in the elderly. Patients should be adequately hydrated and
consideration should be given to monitoring of renal function after initiation of concomitant
therapy, and periodically thereafter. Diuretics can increase the risk of nephrotoxicity of NSAIDs.
• Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin.
• 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.
• Anti-platelet agents and selective serotonin reuptake inhibitors (SSRls): Increased risk of
gastrointestinal bleeding.
• 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 haem arthroses and haematoma in HIV(+)
haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen
• Bisphosphonates: concomitant use of bisphosphonates and NSAIDs may increase the risk of
gastric mucosal damage.
• Colestyramine: colestyramine delays the absorption of naproxen. Naproxen should be taken at
least one hour before or four to six hours after colestyramine.

4.6 Pregnancy and lactation

Pregnancy
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal
development. Data from epidemiological studies suggest an increased risk of miscarriage and of
cardiac malformation after use of a prostaglandin synthesis inhibitor in early pregnancy. The
absolute risk for cardiovascular malformation was increased from less than 1%, up to
approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In
animals, administration of a prostaglandin synthesis inhibitor has been shown to result in
increased pre- and post- implantation loss and embryo-foetal lethality. In addition, increased
incidences of various malformations, including cardiovascular, have been reported in animals
given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and
second trimester of pregnancy, naproxen should not be given unless clearly necessary. If naproxen
is used by a woman attempting to conceive, or during the first and second trimester of pregnancy,
the dose should be kept as low and duration of treatment as short as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the
foetus to:
- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary
hypertension);
- renal dysfunction, which may progress to renal failure with oligo-hydramniosis; the mother and
the neonate, at the end of pregnancy to:
- possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very
low doses.
- inhibition of uterine contractions resulting in delayed or prolonged labour.
Consequently naproxen is contraindicated during the last trimester of pregnancy.
Lactation
In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations.
NSAIDs should, if possible, be avoided when breastfeeding.

4.7 Effects on ability to drive and use machines

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible
after taking NSAIDs. If affected, patients should not drive or operate machinery.

4.8 Undesirable effects

System Organ Common Uncommon Rare Very Rare Frequency not

Class known (cannot
(≥ 1/100 < (≥ 1/1000 < (≥ 1/10,000 < (< 1/10,00) be estimated
1/10) 1/100) 1/1000) from the
available data)

Blood and haemolytic granulo- aplastic anaemia,

lymphatic anaemia cyctopenia, neutropenia
system thrombo-
disorders cytopenia,
agranulocytosis

Immune system allergic and

disorders hyper-sensitivity
reactions,
anaphylaxis

Endocrine
disorders

Metabolism and hyperkalaemia

nutrition
disorders

Psychiatric depression, hallucinations

disorders cognitive
dysfunction,
insomnia, loss of
concentration,
abnormal dreams

Nervous system confusion, convulsions, vertigo,

disorders dizziness, aseptic paraesthesia,
drowsiness, meningitis* malaise,
headache exacerbation of
Parkinson's
disease
Eye disorders visual optic neuritis,
disturbances papilloedema

Ear and tinnitus hearing

labyrinth impairment
disorders

Cardiac palpitations cardiac failure

disorders

Vascular vasculitis arterial hypertension

disorders thrombotic events
e.g. myocardial
infarction or
stroke

Respiratory, aggravated bronchospasm,

thoracic and asthma, dyspnoea,
mediastinal eosinophilic rhinitis,
disorders pneumontitis pulmonary
oedema

Gastro- pancreatitis thirst, peptic

intestinal ulcers,
disorders perforation or GI
bleeding**,
nausea,
vomiting,
diarrhoea,
flatulence,
constipation,
dyspepsia,
abdominal pain,
melaena,
haematemesis,
ulcerative
stomatitis,
exacerbation of
colitis and
Crohn's disease,
gastritis

Hepatobiliary hepatitis abnormal liver

(sometimes function,
fatal), jaundice

Skin and rash, pruritis, urticaria, photo- alopecia, erythema angio-oedema,

subcutaneous purpura sensitivity pseudo- multiforme, epidermal
tissue disorders porphyria Stevens Johnsons necrosis,
syndrome, toxic exfoliative and
epidermal bullous
necrosis, dermatoses,
epidermolysis lichen planus
 bullosa

Musculo- myalgia, muscle

skeletal and weakness
connective
tissue disorders

Renal and glomerular renal failure,

urinary nephritis, nephropathy,
disorders haematuria, increase in
interstitial serum creatinine
nephritis,
nephritic
syndrome, renal
papillary necrosis

Reproductive impaired female

system and fertility
breast disorders

General fatigue mild peripheral

disorders and oedema, pyrexia
administration
site
complications
*especially in patients with existing auto-immune disorders, such as system lupus erythematosus,
mixed connective tissue disease, with symptoms such as stiff neck headache, nausea, vomiting,
fever and disorientation.
** sometimes fatal, particularly in the elderly, may occur.
Clinical trial and epidemiological data suggests that use of some NSAIDs (particularly at high
doses and in long term treatment) may be associated with an increased risk of arterial thrombotic
events (for example myocardial infarction or stroke.

4.9 Overdose

Symptoms
Headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea,
disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally
convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.
Treatment
Patients should be treated symptomatically as required. Within one hour of ingestion of a
potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric
lavage should be considered within one hour of ingestion of a potentially life-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 prolonged convulsions should be treated with intravenous diazepam.
Other measures may be indicated by the patient's clinical condition.
 5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Naproxen reduces the synthesis of prostaglandins primarily by inhibiting the enzyme cyclo-
oxygenase. Naproxen has been shown to have anti-inflammatory activity in a number of
experimental models. Naproxen inhibits prostaglandin E2 synthesis in vitro by human rheumatoid
synovial microsomes. It also inhibits prostaglandin E2 production by phytohaemagglutin-
stimulated peripheral blood mononuclear cells. At 10-4 M (23mg.1-1) naproxen inhibits neutral
protease activity derived from human polymorphonuclear leucocytes. Naproxen also inhibits in
vitro the activity of cathepsin-β and other hydrolytic enzymes derived from lysosomes. Naproxen
is a potent in inhibitor of leucocyte migration.

5.2 Pharmacokinetic Properties

Absorption
Naproxen is readily absorbed from the gastrointestinal tract.
Distribution
Peak plasma concentrations are attained 2-4 hours after ingestion. Plasma concentrations of
naproxen increase proportionally with dose up to about 500mg daily; at higher doses there is an
increase in clearance caused by saturation of plasma proteins. At therapeutic concentrations
naproxen is more than 99% bound to plasma proteins and has a plasma half-life of about 13 hours.
Elimination
Approximately 95% of a dose is excreted in urine as naproxen and 6-O-desmethylnaproxen and
their conjugates. Less than 3% of a dose has been recovered in the faeces. Naproxen crosses the
placenta and is excreted in breast milk.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already
included in other sections of the SMPC.

6. Pharmaceutical Particulars

6.1 List of excipients

▪ Microcrystalline Cellulose (Avicel PH 101) BP

▪ Crospovidone USP
▪ Povidone (K – 30) BP
▪ Lemon Yellow Colour Ph. Gr.
▪ Microcrystalline Cellulose (Avicel PH 102) BP
▪ Magnesium Stearate BP
6.2 Incompatibilities

Not applicable.
6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store below 30°C.

Discard 30 days first opening.

6.5 Nature and contents of container

Aluminium – PVDC

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.

7. Marketing Authorisation Holder

Name : Aristopharma Ltd.

Physical Address : Aristopharma Ltd., Plot # 14-22 Road #11 & 12
Shampur-Kadamtali I/A, Dhaka-1204, Bangladesh.
Telephone number : +880-2-9351691-93
Fax number : +880-2-8317005
e-mail : [email protected]

8. Marketing Authorization Numbers

Napro 500 Tablet: 143–072–064

9. Date of first Authorization/renewal of Authorization

Date of first authorization: 10.09.1996

10. Date of revision of the text

To be given after approval of the product