Venngel Ii (diclofenac sodium)

The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed. Dosage of diclofenac must be carefully adjusted according to individual requirements and response.

Different strengths and formulations of oral diclofenac are not interchangeable. Commercially available diclofenac sodium delayed-release tablets, diclofenac sodium extended-release tablets, and diclofenac potassium conventional tablets are not necessarily bioequivalent on a mg-per-mg basis. In addition, the frequency of administration may vary across available products; diclofenac potassium liquid-filled capsules are approved for administration 4 times daily, while diclofenac potassium conventional tablets can be administered 2-4 times daily.

Each actuation of the pump dispenser of diclofenac sodium 2% topical solution delivers 20 mg of diclofenac sodium in 1 g of solution. The 1.5% topical solution contains diclofenac sodium 16.05 mg/mL.

Each mL of 0.1% diclofenac sodium ophthalmic solution delivers 1 mg of diclofenac sodium.

The potential benefits and risks of diclofenac therapy as well as alternative therapies should be considered prior to initiating diclofenac therapy.

Diclofenac sodium, diclofenac sodium in fixed combination with misoprostol, and diclofenac potassium are administered orally. Diclofenac potassium is commercially available as a tablet (Lofena(R)) and as a liquid-filled capsule formulation (Zipsor(R)). Diclofenac sodium also is administered topically as a solution. Diclofenac epolamine is administered topically as a transdermal system. Diclofenac sodium is also available as a sterile, 0.1% solution for ophthalmic administration.

Diclofenac is not a substitute for corticosteroid therapy, and the drug is not effective in the management of adrenal insufficiency. Abrupt withdrawal of corticosteroids may exacerbate corticosteroid-responsive conditions. If corticosteroid therapy is to be discontinued after prolonged therapy, the dosage should be tapered gradually.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Selected Photosensitizers/Tretinoin-Mequinol

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Tretinoin, anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are all known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of tretinoin in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that tretinoin-mequinol should not be administered to patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides.(1)

DISCUSSION: Because of the risk of increased photosensitivity, the US manufacturer states that tretinoin-mequinol should not be administered to patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), methotrexate, phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Selected Photosensitizers/Aminolevulinic Acid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aminolevulinic acid, anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are all known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of aminolevulinic acid in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that aminolevulinic acid should be avoided in patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides for 24 hours before and after administration of aminolevulinic acid.(1)

DISCUSSION: Because of the risk of increased photosensitivity, the US manufacturer states that aminolevulinic acid should be avoided in patients receiving photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides for 24 hours before and after administration of aminolevulinic acid.(1)

Selected Photosensitizers/Methoxsalen

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Methoxsalen causes photosensitivity due to residual drug which is present in all parts of the skin from photopheresis. Anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are other known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of methoxsalen in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of methoxsalen states that concurrent use of methoxsalen with anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides should be avoided.(1)

DISCUSSION: All patients who have received methoxsalen become photosensitive. It is unknown what the risk of photosensitivity reactions is when methoxsalen is used concurrently with other photosensitizing agents.(1)

Selected Photosensitizers/Porfimer

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Porfimer causes photosensitivity due to residual drug which is present in all parts of the skin. Anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides are other known photosensitizers.(1)

CLINICAL EFFECTS: Concurrent use of porfimer in patients taking anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides may increase the risk of phototoxicity.(1)

PREDISPOSING FACTORS: Patients with any hepatic impairment and patients with severe renal impairment have reduced drug elimination and may remain photosensitive for 90 days or longer.(1)

PATIENT MANAGEMENT: The US manufacturer of porfimer states that concurrent use of porfimer with photosensitizers including anthralin, coal tar and derivatives, fluoroquinolones, griseofulvin, organic staining dyes (such as methylene blue, rose bengal, or toluidine blue), phenothiazines, selected NSAIDs (such as diclofenac, ketoprofen, nabumetone, naproxen, piroxicam, and tiaprofenic acid), methotrexate, St. John's wort, sulfonamides, sulfonylureas, tetracyclines, and thiazides should be avoided.(1) Since the photosensitive effect of porfimer may persist for at least 30 days (and for 90 days in some patients), it would be prudent to avoid other photosensitizing agents for at least 30 days after administration of porfimer.

DISCUSSION: All patients who have received porfimer become photosensitive. It is unknown what the risk of photosensitivity reactions is when porfimer is used concurrently with other photosensitizing agents. When porfimer was used in clinical trials, photosensitivity reactions occurred in about 20% of cancer patients and in 69% of high-grade dysplasia in Barretts esophagus patients. Most of the reactions were mild to moderate erythema, but they also included swelling, pruritus, burning sensation, feeling hot, or blisters. The majority of reactions occurred within 90 days of porfimer administration.(1)

There are no moderate interactions for this drug.

*Known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to diclofenac or any ingredient in the formulation.

*History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.

*In the setting of CABG surgery.

*Diclofenac sodium in fixed combination with misoprostol: Active GI bleeding.

*Diclofenac sodium in fixed combination with misoprostol: Pregnancy.

*Diclofenac potassium liquid-filled capsules: Hypersensitivity to bovine protein.

*Diclofenac epolamine transdermal system: Use on nonintact or damaged skin, regardless of etiology (e.g., exudative dermatitis, eczema, infected lesions, burns, wounds).

• Aspirin exacerbated respiratory disease
• Post-operative from CABG surgery
• Pregnancy

• Acute myocardial infarction
• Alcohol use disorder
• Cerebrovascular accident
• Chronic heart failure
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Debilitation
• Disease of liver
• Gastrointestinal ulcer
• Hemorrhage
• Increased risk of bleeding
• Peptic ulcer
• Systemic mastocytosis
• Tobacco smoker

• Anemia
• Asthma
• Edema
• Hypertension

Adverse effects reported in 1-10% of patients receiving diclofenac sodium delayed-release tablets, diclofenac potassium conventional tablets, or other NSAIAs, include GI effects (abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers, and vomiting). Other common adverse effects include abnormal renal function, anemia, dizziness, edema, elevations in hepatic transaminases, headaches, increased bleeding time, pruritic, rashes, and tinnitus.

Adverse effects reported in >=2% of patients receiving diclofenac in fixed combination with misoprostol include abdominal pain, diarrhea, dyspepsia, nausea, flatulence, gastritis, vomiting, constipation, headache, dizziness, increases in ALT, and decreases in hematocrit.

The most common adverse effects reported in adults receiving diclofenac epolamine transdermal system (Flector(R)) include pruritis (5%) and nausea (3%). The most common adverse effects in pediatric patients were headache (9%) and application site pruritis (7%). Application site pruritis and application site reactions were also common adverse effects in patients receiving diclofenac epolamine transdermal system (Licart(R)).

Adverse effects reported with diclofenac potassium for oral solution include nausea and dizziness (>=1% of patients).

Adverse effects reported with diclofenac sodium ophthalmic solution include transient burning and stinging (15%), elevated intraocular pressure following cataract surgery (15%) and keratitis in up to 28% of patients, although keratitis was noted prior to treatment in many of these patients. Lacrimation complaints were also reported in approximately 30% of cases undergoing incisional refractive surgery. Other adverse effects reported in <=10% of patients include abnormal vision, acute elevated intraocular pressure, blurred vision, conjunctivitis, corneal deposits, corneal edema, corneal opacity, corneal lesions, discharge, eyelid swelling, eye pain, injection (redness), iritis, irritation, itching, lacrimation disorder, and ocular allergy.

Rare or Very Rare

• Abnormal hepatic function tests
• Acute myocardial infarction
• Allergic dermatitis
• Anaphylaxis
• Anemia
• Asthma
• Body fluid retention
• Bullous dermatitis
• Cerebrovascular accident
• DRESS syndrome
• Exfoliative dermatitis
• Gastric ulcer
• Gastroenteritis
• Gastrointestinal hemorrhage
• Gastrointestinal perforation
• Gastrointestinal ulcer
• Heart failure
• Hepatic failure
• Hepatic necrosis
• Hepatitis
• Jaundice
• Platelet aggregation inhibition
• Rectal bleeding
• Renal papillary necrosis
• Stevens-johnson syndrome
• Tongue swelling
• Toxic epidermal necrolysis

More Frequent

• Dry skin
• Pruritus of skin

Less Frequent

• Bruising
• Contact dermatitis
• Drowsy
• Dysgeusia
• Dyspepsia
• Edema
• Headache disorder
• Nausea
• Paresthesia
• Skin inflammation
• Skin rash
• Skin ulcer
• Stinging of skin
• Treatment site sequelae

Rare or Very Rare

• Acute eruptions of skin
• Application site skin reactions
• Cataracts
• Cramps in legs
• Depression
• Diarrhea
• Dizziness
• Eczema
• Gastritis
• Halitosis
• Hyperkinesis
• Hypertension
• Hypoesthesia
• Increased urinary frequency
• Localized edema
• Myalgia
• Palpitations
• Sinusitis
• Skin photosensitivity
• Urinary tract infection
• Urticaria
• Visual changes
• Xerostomia

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Safety and efficacy of diclofenac epolamine transdermal system (Flector(R)) have been established in pediatric patients >=6 years of age based on quality evidence in adults and an open-label study conducted in 104 pediatric patients >=6 years of age with minor soft tissue injuries. The available evidence indicates that the safety of diclofenac epolamine transdermal system (Flector(R)) is similar in pediatric patients compared to adults. Safety and efficacy of diclofenac epolamine transdermal system (Flector(R)) have not been established in pediatric patients <6 years of age.

Safety and efficacy of diclofenac potassium liquid-filled capsules have been established in pediatric patients 12-17 years of age. Use of the drug in this age group is based on quality evidence in adults and pharmacokinetic and safety data from 2 open-label studies in a total of 125 pediatric patients ranging from 12-17 years of age. The plasma concentrations and safety profile of diclofenac were found to be similar in adolescents compared to healthy adults. Safety and efficacy of diclofenac potassium liquid-filled capsules have not been established in pediatric patients <12 years of age.

The manufacturers state that safety and efficacy of other formulations of diclofenac in children have not been established.

Oral diclofenac has been used with good results for the management of juvenile rheumatoid arthritis+ in a limited number of children 3-16 years of age.

Use of NSAIAs during pregnancy at about >=30 weeks' gestation can cause premature closure of the fetal ductus arteriosus, and use at about >=20 weeks' gestation has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, use of NSAIAs should be avoided in pregnant women at about >=30 weeks' of gestation; if NSAIA therapy is necessary between about 20-30 weeks' gestation, the lowest effective dosage and shortest possible duration of treatment should be used. Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice. Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they should be informed that NSAIAs should be avoided beginning at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus and that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20-30 weeks of gestation.

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy. Oligohydramnios is often, but not always, reversible following discontinuance of NSAIA therapy. Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation. A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios. Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis. Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use. Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.

There are no studies evaluating the effects of diclofenac on labor and delivery in humans. In animal studies, NSAIAs, including diclofenac, inhibit prostaglandin synthesis, delay parturition, and increase the incidence of stillbirth.

Diclofenac sodium in fixed combination with misoprostol is contraindicated in women who are pregnant because misoprostol exhibits abortifacient activity and can cause serious fetal harm. In addition, it is recommended that diclofenac in fixed combination with misoprostol be used in women of reproductive potential only if they require NSAIA therapy and are considered at high risk of complications resulting from NSAIA-induced gastric or duodenal ulceration or at high risk of developing gastric or duodenal ulceration.

Diclofenac may be distributed into human milk. While diclofenac was not detectable in breast milk in 12 women who received diclofenac 100 mg orally daily for 7 days or a single 50-mg IM dose administered in the immediate postpartum period, the drug was detected in breast milk at a concentration of 100 mcg/L (equivalent to an infant dose of about 0.03 mg/kg daily) in one woman receiving a diclofenac salt at a dosage of 150 mg daily.

The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for diclofenac and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

Geriatric patients >=65 years of age are at an increased risk for NSAIA-associated serious cardiovascular, gastrointestinal, and/or renal adverse effects compared to younger adults. The risk of these adverse effects may be increased in geriatric patients with renal impairment or receiving concomitant ACE inhibitor or angiotensin II receptor antagonist therapy. If the anticipated benefits of therapy outweigh the potential risks, it is recommended to initiate therapy at the lower end of the dosage range and monitor for adverse effects.

The manufacturer states that commercially available combination of diclofenac in fixed combination with misoprostol should be avoided in geriatric patients with cardiovascular and/or renal risk factors. If use of the combination product cannot be avoided, the manufacturer recommends the lowest recommended dosage for the shortest possible duration, in addition to monitoring for cardiac and renal adverse effects. Monitor renal function in geriatric patients receiving diclofenac in fixed combination with misoprostol, particularly during concomitant therapy with an ACE inhibitor or angiotensin II receptor antagonist.

Geriatric patients are at increased risk for NSAIA-associated serious adverse cardiovascular, GI, and renal effects. The risk of these adverse effects may be increased in geriatric patients with renal impairment or receiving concomitant ACE inhibitor or angiotensin II receptor antagonist therapy. Many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involve geriatric individuals. If the anticipated benefits of diclofenac therapy outweigh the potential risks, diclofenac should be initiated at the lower end of the dosing range and patients should be monitored for adverse effects.

Diclofenac sodium in fixed combination with misoprostol should be avoided in geriatric patients with cardiovascular and/or renal risk factors. In clinical trials of diclofenac sodium in fixed combination with misoprostol, 25.5% of patients were >=65 years of age. No overall differences in efficacy were observed between geriatric patients and younger adults. Other clinical experience has not identified differences in response compared to younger adults, although a greater sensitivity to the drug cannot be ruled out in older individuals. No clinically meaningful differences in diclofenac and misoprostol pharmacokinetics were observed in geriatric patients compared to younger adults.

In phase 3 clinical trials of diclofenac sodium 1.5% topical solution, 49% of patients receiving the drug were >=65 years of age. In an open-label, long-term safety study, 42% of patients receiving diclofenac sodium 1.5% topical solution were >=65 years of age, while 13% were >=75 years of age. No age-related differences in the incidence of adverse effects were observed in these studies.

Clinical trials of diclofenac epolamine transdermal system or diclofenac potassium oral solution did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently than younger adults. Other clinical experience has not identified differences in response between geriatric and younger patients.

Diclofenac is substantially excreted by the kidneys, and the risk of toxicity may be greater in patients with renal impairment. Because geriatric patients are more likely to have decreased renal function, diclofenac should be used with caution; it may be useful to monitor renal function in such patients.