Dyloject

1. Dyloject

DYLOJECT is indicated in adults for the:

• management of mild to moderate pain
• management of moderate to severe pain alone or in combination with opioid analgesics.

Mechanism Of Action

Diclofenac has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of DYLOJECT, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Pharmacodynamics

The effect of DYLOJECT on QTc prolongation was evaluated in a randomized, double-blind, positive (moxifloxacin 400 mg) - and placebo-controlled crossover study in healthy subjects. A total of 70 subjects was administered diclofenac sodium 37.5 mg and 75 mg. In a study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on Fridericia correction method (QTcF) was below 10 ms, the threshold for regulatory concern.

Pharmacokinetics

Following intravenous administration of DYLOJECT to healthy volunteers, plasma concentrations of diclofenac exceed that of immediate-release oral diclofenac for the first 45 minutes reaching a maximum of 4.8-fold 5 minutes after administration.

The pharmacokinetics of diclofenac following intravenous administration of DYLOJECT and oral doses of immediate-release diclofenac are compared in Table 3.

Table 3: Single-dose and Multiple-dose Pharmacokinetics of DYLOJECT (diclofenac sodium) Injection and Oral Immediate Release (IR) Diclofenac Potassium

DYLOJECT administered as an intravenous bolus dose of 37.5 mg every 6 hours for 4 doses to healthy subjects (N=36) showed minimal accumulation with mean values for Cmax and AUC equivalent between the first and the fourth dose.

DYLOJECT exhibits linear pharmacokinetics over intravenous doses ranging from 18.75 to 75 mg and injection times ranging from a bolus (less than 5 seconds) to 60 seconds.

Following administration of DYLOJECT, the apparent volume of distribution during the terminal elimination phase (Vz) of diclofenac is 40.1 ± 9.77 L.

Diclofenac is more than 99% bound to human serum proteins, primarily albumin. Serum binding is constant over the concentration range (0.15-105 mcg/mL) achieved with the recommended doses.

Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac.

HPβCD is distributed in the extracellular fluids following administration of DYLOJECT, and has a volume of distribution during the terminal elimination phase (Vz) of 21.8 ±7.36 L.

Metabolism

Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4', 5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4'hydroxy diclofenac is primarily mediated by CYP2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy- diclofenac.

In patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy- and 5-hydroxydiclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects.

Excretion

Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites.

Plasma concentrations of DYLOJECT decline from peak levels in a biexponential fashion, with a terminal phase half-life of approximately 1.4 hours following intravenous administration.

Total systemic clearance of diclofenac in plasma following administration of DYLOJECT is 324 ± 63 mL/min.

Little or no free unchanged diclofenac is excreted in the urine following administration of DYLOJECT. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Less than 1% is excreted as unchanged substance.

The terminal half-life of HPβCD in plasma following administration of DYLOJECT is approximately 2.7 ± 1.4 hours.

Specific Populations

The pharmacokinetics of DYLOJECT have not been established in pediatric subjects [see Use in Specific Populations].

The effect of aging on the pharmacokinetics of DYLOJECT was studied in 88 subjects from 18 to 86 years old. The terminal half-life for subjects aged 65 to 74 years was 1.4 hours and for subjects greater than or equal to 75 years was 2.1 hours. Clearance of diclofenac following administration of DYLOJECT was not affected by age [see Use in Specific Populations].

Pharmacokinetics of diclofenac following injection of DYLOJECT was studied in Caucasian, Black/African and Asian subjects. After taking body weight into account there was no difference in pharmacokinetics of diclofenac with respect to race [see Pharmacokinetics].

Systemic exposure of diclofenac was 30% higher in females compared to males following DYLOJECT administration. However, this is possibly due to the effect of body weight on clearance of diclofenac. After taking body weight into account there was no difference in pharmacokinetics of diclofenac with respect to sex [see Pharmacokinetics].

The pharmacokinetics of DYLOJECT were evaluated in 8 subjects with mild hepatic impairment (Child-Pugh Classification A, Score of 5 to 6 and a bilirubin of less than or equal to 2.5 mg/dL) compared to matched healthy subjects. The pharmacokinetics of diclofenac following administration of DYLOJECT in mild hepatic impaired subjects were not altered. Pharmacokinetics of DYLOJECT has not been evaluated in moderate or severe hepatic impaired subjects [see Use in Specific Populations].

The pharmacokinetics of DYLOJECT in mild (n = 8), and moderate (n = 5) renal impaired subjects were not significantly altered compared to healthy subjects (n = 7) [see WARNINGS AND PRECAUTIONS and Use in Specific Populations].

Pharmacokinetics of diclofenac following DYLOJECT injection appear to be dependent on body weight. The pharmacokinetics of DYLOJECT were studied in 88 subjects ranging in weight from 53 to 156.2 kg. Clearance of diclofenac in subjects weighing below 95 kg is 282±68 mL/min compared to 356±53 mL/min in subjects above 95 kg body weight (approximately 30% higher clearance). The volume of distribution increased with increased body weight and the proportional increase in clearance resulted in no change in elimination half-life with increased body weight [see Use in Specific Populations].

Drug Interaction Studies

When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [see DRUG INTERACTIONS].

Clinical Studies

The effect of DYLOJECT in the short-term treatment of acute pain was evaluated in two double-blind, placebo and active-controlled, multiple-dose clinical trials in patients with postoperative pain. In both trials, intravenous morphine was permitted as rescue medication for pain management.

In a controlled, multiple-dose study of adult patients with postoperative pain who had undergone elective abdominal or pelvic surgery, 245 patients were treated with DYLOJECT, a positive NSAID control (ketorolac tromethamine), or placebo administered every 6 hours starting within 6 hours after surgery and for up to 5 days. The study population consisted of patients with a mean age of 43 years (range 18 to 65 years) and a minimum pain intensity of 50 mm on a 100-mm visual analog scale (VAS) at baseline. The mean baseline pain intensity on the VAS was 68 mm (range 50 to 100 mm). Approximately 63% of subjects in the DYLOJECT 37.5 mg group and 92% of subjects in the placebo group took rescue medication within the first 48 hours of the treatment phase. Efficacy was demonstrated by a reduction in pain intensity as measured by the sum of the pain intensity differences over 0 to 48 hours in patients receiving DYLOJECT as compared to placebo. The average pain intensities over time are depicted for the treatment groups in Figure 1.

In a second controlled, multiple-dose study of adult patients with postoperative pain who had undergone elective orthopedic surgery, 277 patients were treated with DYLOJECT, a positive NSAID control (ketorolac tromethamine), or placebo administered every 6 hours starting within 6 hours postsurgery and for up to 5 days. The study population consisted of patients with a mean age of 55 years (range 19 to 84 years) and a minimum pain intensity of 50 mm on a 100-mm VAS at baseline. The mean baseline pain intensity on the VAS was 69 mm (range 50 to 100 mm). Approximately 74% of subjects in the DYLOJECT group and 92% of subjects in the placebo group took rescue medication within the first 48 hours of the treatment phase. Efficacy was demonstrated by a reduction in pain intensity as measured by the sum of the pain intensity differences over 0 to 48 hours in patients receiving DYLOJECT as compared to placebo. The average pain intensities over time are depicted for the treatment groups in Figure 2.

Figure 1: Pain Intensity Score Versus Time

Figure 2: Pain Intensity Score Versus Time

Oral:

• Capsule: take 3 times a day, with or without food.
• Tablet: take 3 or 4 times a day, with or without food.
• Extended-release tablet: take 1 or 2 times a day, with or without food. Do not crush, chew, split, or break extended-release tablets. Swallow tablets whole.
• Powder for oral solution: mix with 1 to 2 ounces (30 to 60 mL) of water and taken by mouth once a day, without food.

Topical:

• Gel
  • Diclofenac gel is to be applied to the skin twice daily for 60 to 90 days. Use exactly as prescribed. Do not use more or less of it, or use it more often than prescribed by your doctor.
  • Wash your hands.
  • Apply a small amount of gel on the affected skin, covering it completely, gently smoothing the gel on affected area.
  • Use this gel twice daily; apply it in the morning before dressing and at night before going to bed.
  • Wash your hands after applying the gel. Do not rub or touch your eyes before washing your hands.
    • What to avoid:
      • Be careful not to get this medication in your eyes if you are applying it to your face.
      • Do not apply to open wounds (broken skin), infections, or red, scaly skin.
      • Wear protective clothing, and avoid prolonged sun exposure.
      • Do not use sunscreens, cosmetics, or other medications applied to the skin during treatment.
      • Do not cover treated areas with dressings or bandages.
• Patch
  • Diclofenac also comes in patch form to be applied to the most painful area twice a day. Be sure to remove the old patch before applying the next one.
  • If diclofenac patch begins to peel-off, the edges of the patch may be taped down. If problems with adhesion persist, you may cover the patch with a mesh netting sleeve, where appropriate (e.g. to secure patches applied to ankles, knees, or elbows). The mesh netting sleeve (e.g. Curad Hold Tite, Surgilast Tubular Elastic Dressing) must allow air to pass through and not be occlusive (non-breathable).
  • Do not apply diclofenac patch to non-intact or damaged skin (e.g. exudative dermatitis, eczema, infected lesion, burns, or wounds).
  • Do not wear a diclofenac patch when bathing or showering.
  • Wash your hands after applying, handling or removing the patch.
  • Avoid eye contact.
• Topical Liquid
  • Apply diclofenac topical liquid to clean, dry skin.
  • Dispense diclofenac topical liquid 10 drops at a time either directly onto the knee or first into the hand and then onto the knee. Spread diclofenac topical liquid evenly around front, back and sides of the knee. Repeat this procedure until 40 drops have been applied and the knee is completely covered with solution.
  • Wash hands completely after administering the product.
  • Wait until the area is completely dry before covering with clothing or applying sunscreen, insect repellent, cosmetics, topical medications, or other substances.
  • Do not get diclofenac topical liquid in your eyes, nose or mouth.
• Eye drop solutions
  • One drop should be applied to the affected eye, 4 times daily beginning 24 hours after cataract surgery and continuing throughout the first 2 weeks of the postoperative period.
  • One or two drops should be applied to the operative eye within the hour prior to corneal refractive surgery. Within 15 minutes after surgery, one or two drops should be applied to the operative eye and continued 4 times daily for up to 3 days.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of diclofenac injection in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of diclofenac injection in the elderly. However, elderly patients are more likely to have age-related kidney or stomach problems, which may require caution for patients receiving diclofenac injection.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Ketorolac

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abciximab
• Aceclofenac
• Acemetacin
• Acenocoumarol
• Amiloride
• Amineptine
• Amitriptyline
• Amitriptylinoxide
• Amoxapine
• Amtolmetin Guacil
• Anagrelide
• Apixaban
• Ardeparin
• Argatroban
• Aspirin
• Balsalazide
• Bemiparin
• Bendroflumethiazide
• Benzthiazide
• Betamethasone
• Betrixaban
• Bismuth Subsalicylate
• Bivalirudin
• Bromfenac
• Budesonide
• Bufexamac
• Bumetanide
• Cangrelor
• Celecoxib
• Ceritinib
• Certoparin
• Chlorothiazide
• Chlorthalidone
• Choline Magnesium Trisalicylate
• Choline Salicylate
• Cilostazol
• Citalopram
• Clomipramine
• Clonixin
• Clopamide
• Clopidogrel
• Cortisone
• Cyclopenthiazide
• Cyclosporine
• Dabigatran Etexilate
• Dalteparin
• Danaparoid
• Deferiprone
• Deflazacort
• Desipramine
• Desirudin
• Desmopressin
• Desvenlafaxine
• Dexamethasone
• Dexibuprofen
• Dexketoprofen
• Diazoxide
• Dibenzepin
• Diclofenac
• Diflunisal
• Digoxin
• Dipyridamole
• Dipyrone
• Dothiepin
• Doxepin
• Droxicam
• Duloxetine
• Edoxaban
• Enoxaparin
• Eplerenone
• Epoprostenol
• Eptifibatide
• Escitalopram
• Ethacrynic Acid
• Etodolac
• Etofenamate
• Etoricoxib
• Felbinac
• Fenoprofen
• Fepradinol
• Feprazone
• Feverfew
• Floctafenine
• Flufenamic Acid
• Fluocortolone
• Fluoxetine
• Flurbiprofen
• Fluvoxamine
• Fondaparinux
• Furosemide
• Ginkgo
• Gossypol
• Heparin
• Hydrochlorothiazide
• Hydrocortisone
• Hydroflumethiazide
• Ibuprofen
• Iloprost
• Imipramine
• Indapamide
• Ketoprofen
• Lepirudin
• Levomilnacipran
• Lithium
• Lofepramine
• Lornoxicam
• Loxoprofen
• Lumiracoxib
• Magnesium Salicylate
• Meadowsweet
• Meclofenamate
• Mefenamic Acid
• Melitracen
• Meloxicam
• Mesalamine
• Methotrexate
• Methyclothiazide
• Methylprednisolone
• Metolazone
• Milnacipran
• Morniflumate
• Nabumetone
• Nadroparin
• Naproxen
• Nefazodone
• Nepafenac
• Niflumic Acid
• Nimesulide
• Nimesulide Beta Cyclodextrin
• Nortriptyline
• Olsalazine
• Opipramol
• Oxaprozin
• Oxyphenbutazone
• Paramethasone
• Parecoxib
• Parnaparin
• Paroxetine
• Pemetrexed
• Pentosan Polysulfate Sodium
• Pentoxifylline
• Phenindione
• Phenprocoumon
• Phenylbutazone
• Phenyl Salicylate
• Piketoprofen
• Piroxicam
• Polythiazide
• Pralatrexate
• Prasugrel
• Prednisolone
• Prednisone
• Proglumetacin
• Propyphenazone
• Proquazone
• Protein C
• Protriptyline
• Reboxetine
• Reviparin
• Rivaroxaban
• Rofecoxib
• Salicylamide
• Salicylic Acid
• Salsalate
• Sertraline
• Sibutramine
• Sodium Salicylate
• Spironolactone
• Sulfasalazine
• Sulindac
• Tacrolimus
• Tenoxicam
• Tianeptine
• Tiaprofenic Acid
• Ticagrelor
• Ticlopidine
• Tinzaparin
• Tirofiban
• Tolfenamic Acid
• Tolmetin
• Torsemide
• Treprostinil
• Triamterene
• Trichlormethiazide
• Trimipramine
• Trolamine Salicylate
• Valdecoxib
• Venlafaxine
• Vilazodone
• Vorapaxar
• Vortioxetine
• Warfarin
• Xipamide

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol
• Alacepril
• Atenolol
• Azilsartan
• Azilsartan Medoxomil
• Benazepril
• Betaxolol
• Bisoprolol
• Candesartan
• Captopril
• Carteolol
• Carvedilol
• Celiprolol
• Cilazapril
• Ciprofloxacin
• Delapril
• Enalapril
• Enalaprilat
• Eprosartan
• Esmolol
• Fosinopril
• Imidapril
• Irbesartan
• Labetalol
• Levobunolol
• Lisinopril
• Losartan
• Metipranolol
• Metoprolol
• Moexipril
• Nadolol
• Nebivolol
• Olmesartan
• Oxprenolol
• Penbutolol
• Pentopril
• Perindopril
• Pindolol
• Practolol
• Propranolol
• Quinapril
• Ramipril
• Sotalol
• Spirapril
• Telmisartan
• Temocapril
• Timolol
• Trandolapril
• Valsartan
• Zofenopril

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Anemia or
• Bleeding problems or
• Blood clots or
• Congestive heart failure or
• Dehydration or
• Edema (fluid retention) or
• Heart attack, recent or history of or
• Heart disease or
• Hyperkalemia (high potassium in the blood) or
• Hypertension (high blood pressure) or
• Kidney disease or
• Stomach ulcers or bleeding, history of or
• Stroke, history of—Use with caution. May make these conditions worse.

• Aspirin-sensitive asthma, history of or
• Aspirin (or other NSAIDs) sensitivity, history of or
• Kidney disease, moderate to severe—Should not be used in patients with these conditions.

• Heart surgery (eg, coronary artery bypass graft [CABG] surgery)—Should not be used to relieve pain right before or after the surgery.

• If you have an allergy to diclofenac or any other part of Dyloject.
• If you have an allergy to aspirin or NSAIDs.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are pregnant or may be pregnant. Do not take this medicine if you are in the third trimester of pregnancy. You may also need to avoid Dyloject at other times during pregnancy. Talk with your doctor to see when you need to avoid taking this medicine during pregnancy.
• If you have any of these health problems: GI (gastrointestinal) bleeding or kidney problems.
• If you are having trouble getting pregnant or you are having your fertility checked.
• If you are taking any other NSAID.
• If you are taking a salicylate drug like aspirin.
• If you are taking pemetrexed.

This is not a list of all drugs or health problems that interact with Dyloject.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Signs of high potassium levels like a heartbeat that does not feel normal; feeling confused; feeling weak, lightheaded, or dizzy; feeling like passing out; numbness or tingling; or shortness of breath.
• Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Chest pain or pressure or a fast heartbeat.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Feeling very tired or weak.
• Very bad belly pain.
• Swelling, warmth, numbness, change of color, or pain in a leg or arm.
• A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Upset stomach.
• Hard stools (constipation).
• Dizziness.
• Pain where the shot was given.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Applies to diclofenac: oral capsule, oral capsule liquid filled, oral powder for solution, oral tablet, oral tablet enteric coated, oral tablet extended release

Other dosage forms:

• intravenous solution

Along with its needed effects, diclofenac (the active ingredient contained in Dyloject) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking diclofenac:

• Abdominal or stomach bloating, burning, cramping, or pain
• belching
• bloody or black, tarry stools
• cloudy urine
• constipation
• decrease in urine output or decrease in urine-concentrating ability
• diarrhea
• dizziness
• feeling of indigestion
• headache
• increased bleeding time
• itching skin or rash
• loss of appetite
• nausea and vomiting
• pain in the chest below the breastbone
• pale skin
• severe stomach pain
• swelling
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting of blood or material that looks like coffee grounds
• weight loss

Get emergency help immediately if any of the following symptoms of overdose occur while taking diclofenac:

• Agitation
• blurred vision
• change in consciousness
• change in the ability to see colors, especially blue or yellow
• confusion
• depression
• difficult or troubled breathing
• hives
• hostility
• irregular, fast or slow, or shallow breathing
• irritability
• loss of consciousness
• muscle twitching
• nervousness
• pain or discomfort in the chest, upper stomach, or throat
• pale or blue lips, fingernails, or skin
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• rapid weight gain
• seizures
• sleepiness
• slow or fast heartbeat
• stupor
• swelling of the face, ankles, or hands
• tightness in the chest
• trouble sleeping
• unusual drowsiness, dullness, or feeling of sluggishness

Some side effects of diclofenac may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Continuing ringing or buzzing or other unexplained noise in the ears
• excess air or gas in the stomach or intestines
• hearing loss
• lack or loss of strength
• passing gas