Zipsor 25 mg

ZIPSOR  - diclofenac sodium capsule, liquid filled 
Lake Erie Medical DBA Quality Care Products LLC

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Zipsor 25 mg

11. DESCRIPTION Zipsor (diclofenac potassium) Liquid Filled Capsule is a benzeneacetic acid derivative NSAID. Zipsor is available as liquid-filled capsules of 25 mg for oral administration. The chemical name is 2-[(2,6- dichlorophenyl) amino] benzeneacetic acid monopotassium salt. The molecular weight is 334.24. Its molecular formula is C14H10Cl2NKO2, and it has the following structural formula.

The inactive ingredients in Zipsor include ProSorb® (a proprietary combination of polyethylene glycol 400, glycerin, sorbitol, povidone, polysorbate 80, and hydrochloric acid), isopropyl alcohol, and mineral oil. The capsule shells contain gelatin, sorbitol, isopropyl alcohol, glycerin, and mineral oil. The imprinting on the gelatin capsules is black edible ink.



12. CLINICAL PHARMACOLOGY
12.1 Mechanism of Action Zipsor is an NSAID that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Zipsor, like that of other NSAIDs, is not completely understood but may involve inhibition of the cyclooxygenase (COX-1 and COX-2) pathways. Diclofenac's mechanism may also be related to prostaglandin synthetase inhibition. The analgesic mechanism of action needs further elucidation.

12.3 Pharmacokinetics

The pharmacokinetics of Zipsor was assessed in 24 healthy, normal volunteers who received 25 mg Zipsor under fasting conditions. The mean pharmacokinetic parameters for Zipsor are shown in Table 2.


Absorption

Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. After repeated oral administration, no accumulation of diclofenac in plasma occurred.

The extent of diclofenac absorption is not significantly affected when Zipsor is taken with food. However, the rate of absorption is reduced by food, as indicated by a two-fold increase of Tmax and a 47% decrease in Cmax.

Distribution

The apparent volume of distribution (V/F) of diclofenac potassium is 1.3 L/kg.

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

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 CPY2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 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-hydroxy-diclofenac 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. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine, and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 1 hour.


1. INDICATIONS AND USAGE

Zipsor is indicated for relief of mild to moderate acute pain in adults (18 years of age or older).

4. CONTRAINDICATIONS

Zipsor is contraindicated in patients with known hypersensitivity (e.g., anaphylactoid reactions and serious skin reactions) to diclofenac [see Warnings and Precautions (5.7, 5.8)].

Zipsor is contraindicated in patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.13)].

Zipsor is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)].

Zipsor contains gelatin and is contraindicated in patients with known hypersensitivity to bovine protein.

6. ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:


6.1 Clinical Study Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with the rates in clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Zipsor was evaluated in 965 subjects. In patients treated with Zipsor 25 mg (N=345) or a higher dose, three or four times a day, for 4 to 5 days, the most common adverse reactions (i.e., reported in ≥ 1% of Zipsor treated patients) were as follows: gastrointestinal experiences including abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, dizziness, headache, somnolence, pruritus, and increased sweating. (see Table 1)

In patients taking other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1%-10% of patients are:

Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal) and vomiting.

Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, and tinnitus.

Additional adverse experiences reported in patients taking other NSAIDs occasionally include:

Body as a Whole: fever, infection, sepsis

Cardiovascular System: congestive heart failure, hypertension, tachycardia, syncope

Digestive System: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice

Hemic and Lymphatic System: ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia

Metabolic and Nutritional: weight changes

Nervous System: anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo

Respiratory System: asthma, dyspnea

Skin and Appendages: alopecia, photosensitivity, sweating increased

Special Senses: blurred vision

Urogenital System: cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure

Other adverse reactions in patients taking other NSAIDs, which occur rarely are:

Body as a Whole: anaphylactic reactions, appetite changes, death

Cardiovascular System: arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis

Digestive System: colitis, eructation, liver failure, pancreatitis

Hemic and Lymphatic System: agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia

Metabolic and Nutritional: hyperglycemia

Nervous System: convulsions, coma, hallucinations, meningitis

Respiratory System: respiratory depression, pneumonia

Skin and Appendages: angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome, urticaria

Special Senses: conjunctivitis, hearing impairment



10. OVERDOSAGE

Symptoms following acute NSAID overdoses include lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur.

Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

For additional information about overdose treatment, call the poison control center at 1-800-222-1222.

2. DOSAGE AND ADMINISTRATION 2.1 Initiating Therapy

For treatment of mild to moderate acute pain, the dosage is 25 mg four times a day. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

2.2 Non-Interchangeability with Other Formulations of Diclofenac

Different formulations of oral diclofenac are not bioequivalent even if the milligram strength is the same. Therefore, it is not possible to convert dosing from any other formulation of diclofenac to Zipsor. The only approved dosing regimen for Zipsor is 25 mg four times a day.

16. HOW SUPPLIED/STORAGE AND HANDLING

Zipsor 25 mg is supplied as translucent, pale yellow, liquid-filled capsules printed with ”X592” in black ink. Bottles of 100 Capsules NDC# 66479-592-10.

Store at 25ºC (77ºF); excursions permitted to 15ºC-30ºC (59ºF-86ºF). [See USP Controlled Room Temperature]

Protect from moisture.

Dispense in tight container (USP).

17. PATIENT COUNSELING INFORMATION

Inform patients of the availability of a Medication Guide for NSAIDs that accompanies each prescription dispensed, and instruct them to read the NSAID Medication Guide prior to using Zipsor [see Medication Guide].

17.1 Cardiovascular Effects

NSAIDs, including diclofenac, may cause serious CV events, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, advise patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and to ask for medical advice when observing any indicative sign or symptoms. Inform patients of the importance of this follow-up [see Warnings and Precautions (5.1)].

17.2 Gastrointestinal Effects

NSAIDs, including diclofenac, can cause GI discomfort and, rarely, more serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, advise patients to be alert for the signs and symptoms of ulcerations and bleeding, and to ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Inform patients of the importance of this follow-up [see Warnings and Precautions (5.2)].

17.3 Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop therapy with Zipsor and seek immediate medical therapy [see Warnings and Precautions (5.3)].

17.4 Adverse Skin Reactions

NSAIDs can cause serious skin reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, advise patients to be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and to ask for medical advice when observing any indicative signs or symptoms. Advise patients to stop Zipsor immediately if they develop any type of rash and contact their physicians as soon as possible [see Warnings and Precautions (5.8)].

17.5 Weight Gain and Edema

Advise patients to promptly report to their physicians signs or symptoms of unexplained weight gain or edema during treatment with Zipsor [see Warnings and Precautions (5.5)].

17.6 Anaphylactoid Reactions

Inform patients of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Warnings and Precautions (5.7)].

17.7 Effects During Pregnancy

Starting at 30 weeks gestation, Zipsor and other NSAIDs, should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur [see Use in Specific Populations (8.1)].

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

Cardiovascular Risk

Gastrointestinal Risk

ZIPSOR - diclofenac potassium capsule, liquid filled 
Xanodyne Pharmaceuticals, Inc.

Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)

What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases:


NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG)."

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:


The chance of a person getting an ulcer or bleeding increases with:


NSAID medicines should only be used:


What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:


Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?

Do not take an NSAID medicine:


Tell your healthcare provider:


What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?


Get emergency help right away if you have any of the following symptoms:


Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:

These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or Xanodyne Pharmaceuticals, Inc. at 1-877-773-7793.

Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)



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ZIPSOR 
diclofenac potassium   capsule, liquid filled
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)35356-537 (66479-592)
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
DICLOFENAC SODIUM (DICLOFENAC ) DICLOFENAC SODIUM25 mg
Inactive Ingredients
Ingredient NameStrength
POLYETHYLENE GLYCOL 400 
GLYCERIN 
SORBITOL 
POVIDONE 
POLYSORBATE 80 
HYDROCHLORIC ACID 
ISOPROPYL ALCOHOL 
MINERAL OIL 
GELATIN 
Product Characteristics
Coloryellow (pale yellow) Score no score
ShapeCAPSULESize15mm
FlavorImprint Code X592
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
135356-537-6060 BOTTLE In 1 BOTTLE, PLASTICNone

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02220211/05/2010

Labeler - Lake Erie Medical DBA Quality Care Products LLC (831276758)
Establishment
NameAddressID/FEIOperations
Lake Erie Medical DBA Quality Care Products LLC831276758repack
Establishment
NameAddressID/FEIOperations
Accucaps Industries LTD248441727manufacture
Revised: 11/2010Lake Erie Medical DBA Quality Care Products LLC