DICLOFENAC SODIUM DELAYED RELEASE
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diclofenac sodium tablet, delayed release
Med Health Pharma, LLC
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Cardiovascular Risk
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 (see Table 1).
Food has no significant effect on the extent of diclofenac absorption.
However, there is usually a delay in the onset of absorption of 1 to
4.5 hours and a reduction in peak plasma levels of less than 20%.
Table 1. Pharmacokinetic Parameters for Diclofenac
PK Parameter Normal PK Parameter Normal Healthy Adults (20-48 yrs.)
| Mean | Coefficient of Variation (%) |
Absolute bioavailability (%) [N = 7] | 55 | 40 |
Tmax (hr) [N = 56] | 2.3 | 69 |
Oral Clearance (CL/F; mL/min) [N = 56] | 582 | 23 |
Renal Clearance (% unchanged drug in urin) [N = 7] | Greater than 1 | -- |
Apparent Volume of Distribution (V/F; L/kg) [N = 56] | 1.4 | 58 |
Terminal Half-life (hr) [N = 56] | 2.3 | 48 |
Carefully consider the potential benefits and risks of diclofenac sodium delayed-release and other treatment options before deciding to use diclofenac sodium delayed-release. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).
Diclofenac sodium delayed-release tablets are indicated:
• For relief of signs and symptoms of osteoarthritis
• For relief of signs and symptoms of rheumatoid arthritis
• For acute or long-term use in the relief of signs and symptoms of ankylosing spondylitis
Diclofenac sodium delayed-release tablets are contraindicated in patients with known hypersensitivity to diclofenac. Diclofenac sodium delayed-release should not be given to 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, Anaphylactoid Reactions, and PRECAUTIONS, Preexisting Asthma).
Diclofenac sodium delayed-release is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
Cardiovascular Thrombotic Events
Clinical
trials of several COX-2 selective and nonselective NSAIDs of up to
three years duration have shown an increased risk of serious
cardiovascular (CV) thrombotic events, myocardial infarction, and
stroke, which can be fatal. All NSAIDs, both COX-2 selective and
nonselective, may have a similar risk. Patients with known CV disease
or risk factors for CV disease may be at greater risk. To minimize the
potential risk for an adverse CV event in patients treated with an
NSAID, the lowest effective dose should be used for the shortest
duration possible. Physicians and patients should remain alert for the
development of such events, even in the absence of previous CV
symptoms. Patients should be informed about the signs and/or symptoms
of serious CV events and the steps to take if they occur.
There
is no consistent evidence that concurrent use of aspirin mitigates the
increased risk of serious CV thrombotic events associated with NSAID
use. The concurrent use of aspirin and an NSAID does increase the risk
of serious GI events (see WARNINGS, GI Effects).
Two
large, controlled, clinical trials of a COX-2 selective NSAID for the
treatment of pain in the first 10-14 days following CABG surgery found
an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).
Hypertension
NSAIDs
can lead to onset of new hypertension or worsening of pre-existing
hypertension, either of which may contribute to the increased incidence
of CV events. Patients taking thiazides or loop diuretics may have
impaired response to these therapies when taking NSAIDs. NSAIDs,
including diclofenac sodium delayed-release, should be used with
caution in patients with hypertension.
Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
Caution should be
used when initiating treatment with diclofenac sodium delayed-release
in patients with considerable dehydration.
Long-term
administration of NSAIDs has resulted in renal papillary necrosis and
other renal injury. Renal toxicity has also been seen in patients in
whom renal prostaglandins have a compensatory role in the maintenance
of renal perfusion. In these patients, administration of a nonsteroidal
anti-inflammatory drug may cause a dose-dependent reduction in
prostaglandin formation and, secondarily, in renal blood flow, which
may precipitate overt renal decompensation. Patients at greatest risk
of this reaction are those with impaired renal function, heart failure,
liver dysfunction, those taking diuretics and ACE inhibitors, and the
elderly.
Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Advanced Renal Disease
No
information is available from controlled clinical studies regarding the
use of diclofenac sodium delayed-release in patients with advanced
renal disease. Therefore, treatment with diclofenac sodium
delayed-release is not recommended in these patients with advanced
renal disease. If diclofenac sodium delayed-release therapy must be
initiated, close monitoring of the patient's renal function
is advisable.
Anaphylactoid Reactions
As
with other NSAIDs, anaphylactoid reactions may occur in patients
without known prior exposure to diclofenac sodium delayed-release.
Diclofenac sodium delayed-release should not be given to patients with
the aspirin triad. This symptom complex typically occurs in asthmatic
patients who experience rhinitis with or without nasal polyps, or who
exhibit severe, potentially fatal bronchospasm after taking aspirin or
other NSAIDs. (See CONTRAINDICATIONS and PRECAUTIONS, Preexisting
Asthma.)
Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs,
including diclofenac sodium delayed-release, can cause serious skin
adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome
(SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These
serious events may occur without warning.
Patients should be
informed about the signs and symptoms of serious skin manifestations
and use of the drug should be discontinued at the first appearance of
skin rash or any other sign of hypersensitivity.
Pregnancy
In
late pregnancy, as with other NSAIDs, diclofenac sodium delayed-release
should be avoided because it may cause premature closure of the ductus
arteriosus.
Diclofenac sodium
delayed-release tablets cannot be expected to substitute for
corticosteroids or to treat corticosteroid insufficiency. Abrupt
discontinuation of corticosteroids may lead to disease exacerbation.
Patients on prolonged corticosteroid therapy should have their therapy
tapered slowly if a decision is made to discontinue corticosteroids.
The
pharmacological activity of diclofenac sodium delayed-release in
reducing fever and inflammation may diminish the utility of these
diagnostic signs in detecting complications of presumed noninfectious,
painful conditions.
Borderline
elevations of one or more liver tests may occur in up to 15% of
patients taking NSAIDs including diclofenac sodium delayed-release.
These laboratory abnormalities may progress, may remain unchanged, or
may be transient with continuing therapy. Based on this experience, in
patients on chronic treatment with diclofenac sodium delayed-release,
periodic monitoring of transaminases is recommende. (see PRECAUTIONS,
Laboratory Tests).Notable elevations of ALT or AST (approximately three
or more times the upper limit of normal) have been reported in
approximately 2%-4% of patients, including marked elevations (eight or
more times the upper limit of normal) in about 1% of patients in
clinical trials with diclofenac. In addition, rare cases of severe
hepatic reactions, including jaundice and fatal fulminant hepatitis,
liver necrosis and hepatic failure, some of them with fatal outcomes
have been reported.
A patient with symptoms and/or signs
suggesting liver dysfunction, or in whom an abnormal liver test has
occurred, should be evaluated for evidence of the development of a more
severe hepatic reaction while on therapy with diclofenac sodium
delayed-release.
If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), diclofenac sodium delayed-release should be discontinued.
Anemia
is sometimes seen in patients receiving NSAIDs, including diclofenac
sodium delayed-release. This may be due to fluid retention, occult or
gross GI blood loss, or an incompletely described effect upon
erythropoiesis. Patients on long-term treatment with NSAIDs, including
diclofenac sodium delayed-release, should have their hemoglobin or
hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs
inhibit platelet aggregation and have been shown to prolong bleeding
time in some patients. Unlike aspirin, their effect on platelet
function is quantitatively less, of shorter duration, and reversible.
Patients receiving diclofenac sodium delayed-release who may be
adversely affected by alterations in platelet function, such as those
with coagulation disorders or patients receiving anticoagulants, should
be carefully monitored.
Patients with
asthma may have aspirin-sensitive asthma. The use of aspirin in
patients with aspirin-sensitive asthma has been associated with severe
bronchospasm which can be fatal. Since cross-reactivity, including
bronchospasm, between aspirin and other nonsteroidal anti-inflammatory
drugs has been reported in such aspirin-sensitive patients, diclofenac
sodium delayed-release should not be administered to patients with this
form of aspirin sensitivity and should be used with caution in patients
with preexisting asthma.
Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
1. Diclofenac sodium delayed-release, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
2. Diclofenac sodium delayed-release, like other NSAIDs, 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, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects-Risk of Ulceration, Bleeding, and Perforation).
3. Diclofenac sodium delayed-release, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
5. Patients should be informed 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, patients should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, diclofenac sodium delayed-release should be avoided because it may cause premature closure of the ductus arteriosus.
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. In patients on long-term treatment with NSAIDs, including diclofenac sodium delayed-release, the CBC and a chemistry profile (including transaminase levels) should be checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, diclofenac sodium delayed-release should be discontinued.
Aspirin:When diclofenac sodium delayed-release is administered with aspirin, its protein binding is reduced. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects.
Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
Cyclosporine: Diclofenac sodium delayed-release, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with diclofenac sodium delayed-release may increase cyclosporine’s nephrotoxicity.
Caution should be used when diclofenac is administered concomitantly with cyclosporine.
ACE-inhibitors:Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.
Furosemide:Clinical studies, as well as post-marketing observations, have shown that diclofenac sodium delayed-release can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.
Lithium:NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
Warfarin:The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Teratogenic Effects
Pregnancy category C
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women.
Nonteratogenic Effects
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of diclofenac sodium delayed-release on labor and delivery in pregnant women are unknown.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from diclofenac sodium delayed-release, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
In patients taking diclofenac sodium delayed-release tablets, or 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 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, 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
OVERDOSAGE
Symptoms following acute NSAID overdoses are usually limited to 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, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific antidotes.
Emesis and/or 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.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of diclofenac sodium delayed-release tablets and other treatment options before deciding to use diclofenac sodium delayed-release. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with diclofenac sodium delayed-release tablets, the dose and frequency should be adjusted to suit an individual patient’s needs.
For the relief of osteoarthritis, the recommended dosage is 100-150 mg/day in divided doses (50 mg b.i.d. or t.i.d., or 75 mg b.i.d.).
For the relief of rheumatoid arthritis, the recommended dosage is 150-200 mg/day in divided doses (50 mg t.i.d. or q.i.d., or 75 mg b.i.d.).
For the relief of ankylosing spondylitis, the recommended dosage is 100-125 mg/day, administered as 25 mg q.i.d., with an extra 25-mg dose at bedtime if necessary.
Different formulations of diclofenac (diclofenac sodium delayed-release tablets; diclofenac sodium extended-release tablets; diclofenac potassium immediate-release tablets) are not necessarily bioequivalent even if the milligram strength is the same.
HOW SUPPLIED
Diclofenac Sodium Delayed-Release Tablets, USP are available as follows:
50 mg — Each white, round, enteric-coated tablet printed with on one side and 550 on the other side with black ink contains 50 mg of Diclofenac Sodium, USP. Tablets are supplied in bottles of 30 (NDC 51138-020-30).
75 mg — Each white, round, enteric-coated tablet printed with on one side and 551 on the other side with black ink contains 75 mg of Diclofenac Sodium, USP. Tablets are supplied in bottles of 30 (NDC 51138-021-30).
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Protect from moisture.
Dispense in a tight, light-resistant container as defined in the USP.
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:
with longer use of NSAID medicines
in people who have heart disease
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:
can happen without warning symptoms
may cause death
The chance of a person getting an ulcer or bleeding increases with:
taking medicines called “corticosteroids” and “anticoagulants”
longer use
smoking
drinking alcohol
older age
having poor health
NSAID medicines should only be used:
exactly as prescribed
at the lowest dose possible for your treatment
for the shortest time needed
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:
different types of arthritis
menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
for pain right before or after heart bypass surgery
Tell your healthcare provider:
about all your medical conditions.
about
all of the medicines you take. NSAIDs and some other medicines can
interact with each other and cause serious side effects.
DICLOFENAC SODIUM
DELAYED RELEASE
diclofenac sodium tablet, delayed release |
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Marketing Information | |||
Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
ANDA | ANDA074514 | 01/01/2011 | 03/19/2012 |
DICLOFENAC SODIUM
DELAYED RELEASE
diclofenac sodium tablet, delayed release |
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Marketing Information | |||
Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
ANDA | ANDA074514 | 01/01/2011 | 03/19/2012 |
Labeler - Med Health Pharma, LLC (962603812) |
Establishment | |||
Name | Address | ID/FEI | Operations |
Med Health Pharma, LLC | 962603812 | repack |
Revised: 01/2011 Med Health Pharma, LLC