ROFENAC LP

Diclofenac is a phenylacetic acid derivative and non-steroidal anti-inflammatory drug (NSAID).

NSAIDs inhibit cyclooxygenase (COX)-1 and-2 which are the enzyme responsible for producing prostaglandins (PGs).

PGs contribute to inflammation and pain signalling.

Diclofenac, like other NSAIDs, is often used as first line therapy for acute and chronic pain and inflammation from a variety of causes.

Diclofenac was the product of rational drug design based on the structures of phenylbutazone, mefenamic acid, and indomethacin.

The addition of two chlorine groups in the ortho position of the phenyl ring locks the ring in maximal torsion which appears to be related to increased potency.

It is often used in combination with misoprostol to prevent NSAID-induced gastric ulcers.

Diclofenac was first approved by the FDA in July 1988 under the trade name Voltaren, marketed by Novartis (previously Ciba-Geigy).

Diclofenac is indicated for use in the treatment of pain and inflammation from varying sources including inflammatory conditions such as osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, as well as injury-related inflammation due to surgery and physical trauma.

It is often used in combination with misoprostol as a gastro-protective agent in patients with high risk of developing NSAID-induced ulcers.

Diclofenac reduces inflammation and by extension reduces nociceptive pain and combats fever.

Label, 17 It also increases the risk of developing a gastrointestinal ulcer by inhibiting the production of protective mucus in the stomach.

G/H synthase 2 Inhibitor Prostaglandin G/H synthase 1 Inhibitor.

Diclofenac is completely absorbed from the

GI tract but likely undergoes significant first pass metabolism with only 60% of the drug reaching systemic circulation unchanged Label, 7, 8.

Many topical formulations are absorbed percutaneous and produce clinically significant plasma concentrations.

Absorption is dose proportional over the range of 25-150 mg.

Tmax varies between formulations with the oral solution reaching peak plasma concentrations in 10-40min, the enteric coated tablet in 1.5-2h, and the sustained.

• and extended-release formulations prolonging Tmax even further.

Administration with food has no significant effects on AUC but does delay Tmax to 2.5-12h. 7, 8.

Diclofenac has a total volume of distribution of 5-10 L or 0.1-0.2 L/kg.

The volume of the central compartment is 0.04 L/kg.

Diclofenac distributes to the synovial fluid reaching peak concentration 2-4h after administration.

There is limited crossing of the blood brain barrier and cerebrospinal fluid concentrations only reach 8.22% of plasma concentrations.

Doses of 50 mg delivered via intramuscular injection produced no detectable diclofenac concentrations in breast milk, however metabolite concentrations were not investigated.

Diclofenac has been shown to cross the placenta in mice and rats but human data is unavailable.

Diclofenac undergoes oxidative metabolism to hydroxy metabolites as well as conjugation to glucuronic acid, sulfate, and taurine.

Label, 7 The primary metabolite is 4'-hydroxy diclofenac which is generated by CYP2C9.

This metabolite is very weakly active with one thirtieth the activity of diclofenac.

Other metabolites include 3'-hydroxy diclofenac, 3'-hydroxy-4'methoxy diclofenac, 4',5-dihydroxy diclofenac, an acylglucuronide conjugate, and other conjugate metabolites.

Hover over products below to view reaction partners Diclofenac 4'-Hydroxydiclofenac 4'-hydroxy-2'-glutathione conjugated monoclofenac 4'-hydroxy-3'-glutathione conjugated diclofenac Diclofenac acyl glucuronide 3'-Hydroxydiclofenac 3',4'-hydroxy diclofenac 3'-hydroxy-4'-methoxy diclofenac 5-hydroxy diclofenac 5-hydroxy-6-glutathione conjugated diclofenac 5-hydroxy-4-glutathione conjugated diclofenac 4',5-Dihydroxydiclofenac 5,N-dihydroxy diclofenac diclofenac o-imine methine 2-(2,6-dichlorophenylamino)-benzyl-S-thioether glutathione diclofenac 2',3'-oxide 3'-hydroxy-2'glutathione conjugated monoclofenac 2'-hydroxy-3'-glutathione conjugated diclofenac Diclofenac radical 2'-(glutathion-S-yl)-deschloro-diclofenac.

Diclofenac is mainly eliminated via metabolism. 7, 8 Of the total dose, 60-70% is eliminated in the urine and 30% is eliminated in the feces.

No significant enterohepatic recycling occurs.

The terminal half-life of diclofenac is approximately 2 h, however the apparent half-life including all metabolites is 25.8-33 h.

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Symptoms of overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain, and gastrointestinal bleeding.

Hypertension, acute renal failure, respiratory depression and coma occur rarely.

In case of overdose, provide supportive care and consider inducing emesis and administering activated charcoal if overdose occurred less than 4 hours prior.

For external use only Allergy alert

Diclofenac may cause a severe allergic reaction, especially in people allergic to aspirin.

Symptoms may include: hives asthma (wheezing) skin reddening blisters facial swelling shock rash If an allergic reaction occurs, stop use and seek medical help right away.

Liver warning

This product contains diclofenac.

Liver damage may occur if you apply more or for a longer time than directed when using other drugs containing diclofenac Stomach bleeding warning: This product contains an NSAID, which may cause severe stomach bleeding.

The chance is small but higher if you are age 60 or older have had stomach ulcers or bleeding problems take a blood thinning (anticoagulant) or steroid drug take other drugs containing prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others) have 3 or more alcoholic drinks every day while using this product apply more or for longer than directed Heart attack and stroke warning: NSAIDs, except aspirin, increase the risk of heart attack, heart failure, and stroke.

These can be fatal.

The risk is higher if you use more than directed or for longer than directed.

Do not use if you have ever had an allergic reaction to any other pain reliever or to a fever reducer for strains, sprains, bruises or sports injuries.

This product has not been shown to work for these types of injuries. right before or after heart surgery on more than 2 body areas at the same time in the eyes, nose or mouth Ask a doctor before us if you have problems or serious side effects from taking pain relievers or fever reducers stomach bleeding warning applies to you you have a history of stomach problems, such as heartburn you have high blood pressure, heart disease, liver cirrhosis, kidney disease, asthma, or had a stroke you are taking a diuretic you are under age 18 years.

It is not known if this drug works or is safe in children under age 18 years.

Ask a doctor or pharmacist before use if you are under a doctor’s care for any serious condition taking any other drug When using this product avoid contact with eyes, nose, or mouth if eye contact occurs, rinse thoroughly with water Stop use and ask a doctor if pain gets worse or lasts more than 21 days redness or swelling is present in the painful area fever occurs skin irritation occurs any new symptoms appear.

These could be signs of a serious condition. you experience any of the following signs of stomach bleeding: feel faint have bloody or black stools vomit blood have stomach pain that does not get better you have symptoms of heart problems or stroke: chest pain trouble breathing leg swelling weakness in one part or side of body slurred speech If pregnant or breast-feeding, ask a health professional before use.

It is especially important not to use this product during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery.

Keep out of reach of children.

If swallowed, get medical help or contact a Poison Control Center right away.

Use up to 21 days unless directed by your doctor Not for strains, sprains, bruises or sports injuries.

This product has not been shown to work for these types of injuries.

Daily Per Dose For your arthritis pain: Use 4 times per day every day Do not use on more than 2 body areas at the same time Use ENCLOSED DOSING CARD to measure a dose For each upper body area (hand, wrist, or elbow) – Squeeze out 2.25 inches (2 grams) For each lower body area (foot, ankle or knee) –Squeeze out 4.5 inches (4 grams) Read the enclosed User Guide for complete instructions: use only as directed do not use more than directed or for longer than directed apply only to clean, dry skin that does not have any cuts, open wounds, infections or rashes do not apply in same area as any other product do not apply with external heat such as heating pad do not apply a bandage over the treated area store ENCLOSED DOSING CARD with your Diclofenac Sodium Topical Gel, 1% product.

The dosing card is re-usable.

Other information store at 20-25°C (68-77°F).

Keep from freezing. read all product information before using.

Keep the dosing card, this carton and accompanying User Guide for important information.