Overdose
Management Of Overdosage
Cases of overdosage have been reported and rarely, deaths have occurred. The
following signs and symptoms may be observed following overdosage: stupor, coma,
diminished urine output and hypotension.
In the event of overdosage, the stomach should be emptied by inducing vomiting
or by gastric lavage, and the patient carefully observed and given symptomatic
and supportive treatment.
Animal studies show that absorption is decreased by the prompt administration
of activated charcoal and excretion is enhanced by alkalinization of the urine.
Contraindications
CLINORIL (sulindac) is contraindicated in patients with known hypersensitivity to sulindac
or the excipients (see DESCRIPTION).
CLINORIL (sulindac) should not be given to patients who have experienced asthma, urticaria,
or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely
fatal, anaphylactic/anaphylactoid reactions to NSAIDs have been reported in
such patients (see WARNINGS – Anaphylactic/Anaphylactoid Reactions, and PRECAUTIONS – Preexisting Asthma).
CLINORIL (sulindac) is contraindicated for the treatment of peri-operative pain in the
setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
Undesirable effects
The following adverse reactions were reported in clinical trials or have been
reported since the drug was marketed. The probability exists of a causal relationship
between CLINORIL (sulindac) and these adverse reactions. The adverse reactions which have
been observed in clinical trials encompass observations in 1,865 patients, including
232 observed for at least 48 weeks.
Incidence Greater Than 1%
Gastrointestinal
The most frequent types of adverse reactions occurring with CLINORIL (sulindac) are gastrointestinal;
these include gastrointestinal pain (10%), dyspepsia***, nausea*** with or without
vomiting, diarrhea***, constipation***, flatulence, anorexia and gastrointestinal
cramps.
Dermatologic
Rash***, pruritus.
Central Nervous System
Dizziness***, headache***, nervousness.
Special Senses
Tinnitus.
Miscellaneous
Edema (see WARNINGS).
Incidence Less Than 1 in 100
Gastrointestinal
Gastritis, gastroenteritis or colitis. Peptic ulcer and gastrointestinal bleeding
have been reported. GI perforation and intestinal strictures (diaphragms) have
been reported rarely.
Liver function abnormalities; jaundice, sometimes with fever; cholestasis;
hepatitis; hepatic failure.
There have been rare reports of sulindac metabolites in common bile duct “sludge”
and in biliary calculi in patients with symptoms of cholecystitis who underwent
a cholecystectomy.
Pancreatitis (see PRECAUTIONS).
Ageusia; glossitis.
Dermatologic
Stomatitis, sore or dry mucous membranes, alopecia, photosensitivity.
Erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome,
and exfoliative dermatitis have been reported.
Cardiovascular
Congestive heart failure, especially in patients with marginal cardiac function;
palpitation; hypertension.
Hematologic
Thrombocytopenia; ecchymosis; purpura; leukopenia; agranulocytosis; neutropenia;
bone marrow depression, including aplastic anemia; hemolytic anemia; increased
prothrombin time in patients on oral anticoagulants (see PRECAUTIONS).
Genitourinary
Urine discoloration; dysuria; vaginal bleeding; hematuria; proteinuria; crystalluria; renal impairment, including renal failure; interstitial nephritis; nephrotic syndrome.
Renal calculi containing sulindac metabolites have been observed rarely.
Metabolic
Hyperkalemia.
Musculoskeletal
Muscle weakness.
Psychiatric
Depression; psychic disturbances including acute psychosis.
Nervous System
Vertigo; insomnia; somnolence; paresthesia; convulsions; syncope; aseptic meningitis
(especially in patients with systemic lupus erythematosus (SLE) and mixed connective
tissue disease, see PRECAUTIONS).
Special Senses
Blurred vision; visual disturbances; decreased hearing; metallic or bitter
taste.
Respiratory
Epistaxis.
Hypersensitivity Reactions
Anaphylaxis; angioneurotic edema; urticaria; bronchial spasm; dyspnea.
Hypersensitivity vasculitis.
A potentially fatal apparent hypersensitivity syndrome has been reported. This
syndrome may include constitutional symptoms (fever, chills, diaphoresis, flushing),
cutaneous findings (rash or other dermatologic reactions - see above), conjunctivitis,
involvement of major organs (changes in liver function including hepatic failure,
jaundice, pancreatitis, pneumonitis with or without pleural effusion, leukopenia,
leukocytosis, eosinophilia, disseminated intravascular coagulation, anemia,
renal impairment, including renal failure), and other less specific findings
(adenitis, arthralgia, arthritis, myalgia, fatigue, malaise, hypotension, chest
pain, tachycardia).
Causal Relationship Unknown
A rare occurrence of fulminant necrotizing fasciitis, particularly in association
with Group A β-hemolytic streptococcus, has been described in persons treated
with non-steroidal anti-inflammatory agents, sometimes with fatal outcome (see
also PRECAUTIONS, General).
Other reactions have been reported in clinical trials or since the drug was
marketed, but occurred under circumstances where a causal relationship could
not be established. However, in these rarely reported events, that possibility
cannot be excluded. Therefore, these observations are listed to serve as alerting
information to physicians.
Cardiovascular
Arrhythmia.
Metabolic
Hyperglycemia.
Nervous System
Neuritis.
Special Senses
Disturbances of the retina and its vasculature.
Miscellaneous
Gynecomastia.
*** Incidence between 3% and 9%. Those reactions occurring in
1% to 3% of patients are not marked with an asterisk.
Therapeutic indications
Carefully consider the potential benefits and risks of CLINORIL (sulindac) and other treatment
options before deciding to use CLINORIL (sulindac). Use the lowest effective dose for the
shortest duration consistent with individual patient treatment goals (see WARNINGS).
CLINORIL (sulindac) is indicated for acute or long-term use in the relief of signs and
symptoms of the following:
- Osteoarthritis
- Rheumatoid arthritis**
- Ankylosing spondylitis
- Acute painful shoulder (Acute subacromial bursitis/supraspinatus tendinitis)
- Acute gouty arthritis
Pharmacodynamic properties
CLINORIL (sulindac) is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory,
analgesic and antipyretic activities in animal models. The mechanism of action,
like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.
Pharmacokinetic properties
Absorption
The extent of sulindac absorption from CLINORIL Tablets is similar as compared
to sulindac solution.
There is no information regarding food effect on sulindac absorption. Antacids
containing magnesium hydroxide 200 mg and aluminum hydroxide 225 mg per 5 mL
have been shown not to significantly decrease the extent of sulindac absorption.
TABLE 1
| PHARMACOKINETIC PARAMETERS |
NORMAL |
ELDERLY |
| Tmax |
Age 19-41 (n=24) |
Age 65-87 (n=12) 400 mg qd |
| (200 mg tablet) |
2.54 ± 1.52 S |
| 3.38 ± 2.30 S |
5.75 ± 2.81 SF |
| 4.88 ± 2.57 SP |
6.83 ± 4.19 SP |
| 4.96 ± 2.36 SF |
|
| (150 mg tablet) |
|
| 3.90 ± 2.30 S |
|
| 5.85 ±4.49 SP |
|
| 6.15 ± 3.07 SF |
|
| Renal Clearance |
200 mg tablet) |
|
| 68.12 ± 27.56 mL/min S |
|
| 36.58 ± 12.61 mL/min SP |
|
| 150 mg tablet) |
|
| 74.39 ± 34.15 mL/min S |
|
| 41.75 ± 13.72 mL/min SP |
|
| Mean effective Half life(h) |
7.8 S |
|
| 16.4 SF |
|
| S = Sulindac |
|
| SF = Sulindac Sulfide |
|
| SP = Sulindac Sulfone |
|
Distribution
Sulindac, and its sulfone and sulfide metabolites, are 93.1, 95.4, and 97.9%
bound to plasma proteins, predominantly to albumin. Plasma protein binding measured
over a concentration range (0.5-2.0 μg/mL) was constant. Following an oral,
radiolabeled dose of sulindac in rats, concentrations of radiolabel in red blood
cells were about 10% of those in plasma. Sulindac penetrates the blood-brain
and placental barriers. Concentrations in brain did not exceed 4% of those in
plasma. Plasma concentrations in the placenta and in the fetus were less than
25% and 5% respectively, of systemic plasma concentrations. Sulindac is excreted
in rat milk; concentrations in milk were 10 to 20% of those levels in plasma.
It is not known if sulindac is excreted in human milk.
Metabolism
Sulindac undergoes two major biotransformations of its sulfoxide moiety: oxidation
to the inactive sulfone and reduction to the pharmacologically active sulfide.
The latter is readily reversible in animals and in man. These metabolites are
present as unchanged compounds in plasma and principally as glucuronide conjugates
in human urine and bile. A dihydroxydihydro analog has also been identified
as a minor metabolite in human urine.
With the twice-a-day dosage regimen, plasma concentrations of sulindac and
its two metabolites accumulate: mean concentration over a dosage interval at
steady state relative to the first dose averages 1.5 and 2.5 times higher, respectively,
for sulindac and its active sulfide metabolite.
Sulindac and its sulfone metabolite undergo extensive enterohepatic circulation
relative to the sulfide metabolite in animals. Studies in man have also demonstrated
that recirculation of the parent drug sulindac and its sulfone metabolite is
more extensive than that of the active sulfide metabolite. The active sulfide
metabolite accounts for less than six percent of the total intestinal exposure
to sulindac and its metabolites.
Biochemical as well as pharmacological evidence indicates that the activity
of sulindac resides in its sulfide metabolite. An in-vitro assay for inhibition
of cyclooxygenase activity exhibited an EC50 of 0.02 μM for sulindac sulfide.
In-vivo models of inflammation indicate that activity is more highly correlated
with concentrations of the metabolite than with parent drug concentrations.
Elimination
Approximately 50% of the administered dose of sulindac is excreted in the urine
with the conjugated sulfone metabolite accounting for the major portion. Less
than 1% of the administered dose of sulindac appears in the urine as the sulfide
metabolite. Approximately 25% is found in the feces, primarily as the sulfone
and sulfide metabolites.
The mean effective half-life (T½) is 7.8 and 16.4 hours, respectively,
for sulindac and its active sulfide metabolite.
Because CLINORIL (sulindac) is excreted in the urine primarily as biologically inactive
forms, it may possibly affect renal function to a lesser extent than other non-steroidal
anti-inflammatory drugs; however, renal adverse experiences have been reported
with CLINORIL (see ADVERSE REACTIONS).
In a study of patients with chronic glomerular disease treated with therapeutic
doses of CLINORIL (sulindac) , no effect was demonstrated on renal blood flow, glomerular
filtration rate, or urinary excretion of prostaglandin E2 and the primary metabolite
of prostacyclin, 6-keto-PGF1α. However, in other studies in healthy volunteers
and patients with liver disease, CLINORIL (sulindac) was found to blunt the renal responses
to intravenous furosemide, i.e., the diuresis, natriuresis, increments in plasma
renin activity and urinary excretion of prostaglandins. These observations may
represent a differentiation of the effects of CLINORIL (sulindac) on renal functions based
on differences in pathogenesis of the renal prostaglandin dependence associated
with differing dose-response relationships of different NSAIDs to the various
renal functions influenced by prostaglandins (see PRECAUTIONS).
In healthy men, the average fecal blood loss, measured over a two-week period
during administration of 400 mg per day of CLINORIL (sulindac) , was similar to that for placebo, and was statistically significantly less than that resulting from 4800
mg per day of aspirin.
Fertility, pregnancy and lactation
In late pregnancy, as with other NSAIDs, CLINORIL (sulindac) should be avoided because
it may cause premature closure of the ductus arteriosus.
PRECAUTIONS
Qualitative and quantitative composition
No. 3353X - Tablets CLINORIL (sulindac) 200 mg are bright yellow, hexagon-shaped, compressed
tablets, one side full scored, the other side half scored and debossed MSD 942.
They are supplied as follows:
NDC 0006-0942-68 in bottles of 100. Storage
Store in a well-closed container at room temperature 15-30°C (59-86°F).
**The safety and effectiveness of CLINORIL (sulindac) have not been established
in rheumatoid arthritis patients who are designated in the American Rheumatism
Association classification as Functional Class IV (incapacitated, largely or
wholly bedridden, or confined to wheelchair; little or no self-care).
Manufactured for: By: Merck Sharp & Dohme Pty., Ltd. South
Granville, NSW, Australia 2142.
Special warnings and precautions for use
WARNINGS
Cardiovascular Effects
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 GI WARNINGS).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment
of pain in the first 1014 days following CABG surgery found an increased incidence
of myocardial infarction and stroke (see CONTRAINDICATIONS).
Hypertension
NSAIDs, including CLINORIL (sulindac) , 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 CLINORIL (sulindac) ,
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.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs.
CLINORIL (sulindac) should be used with caution in patients with fluid retention or heart
failure.
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including CLINORIL (sulindac) , can cause serious gastrointestinal (GI) adverse
events including inflammation, bleeding, ulceration, and perforation of the
stomach, small intestine, or large intestine, which can be fatal. These serious
adverse events can occur at any time, with or without warning symptoms, in patients
treated with NSAIDs. Only one in five patients, who develop a serious upper
GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding,
or perforation caused by NSAIDs occur in approximately 1% of patients treated
for 3-6 months, and in about 2-4% of patients treated for one year. These trends
continue with longer duration of use, increasing the likelihood of developing
a serious GI event at some time during the course of therapy. However, even
short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with prior history
of ulcer disease or gastrointestinal bleeding. Patients with a prior history
of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have
a greater than 10-fold increased risk for developing a GI bleed compared to
patients with neither of these risk factors. Other factors that increase the
risk for GI bleeding in patients treated with NSAIDs include concomitant use
of oral corticosteroids or anticoagulants, longer duration of NSAID therapy,
smoking, use of alcohol, older age, and poor general health status. Most spontaneous
reports of fatal GI events are in elderly or debilitated patients and therefore,
special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated
with an NSAID, the lowest effective dose should be used for the shortest possible
duration. Patients and physicians should remain alert for signs and symptoms
of GI ulceration and bleeding during NSAID therapy and promptly initiate additional
evaluation and treatment if a serious GI adverse event is suspected. This should
include discontinuation of the NSAID until a serious GI adverse event is ruled
out. For high risk patients, alternate therapies that do not involve NSAIDs
should be considered.
Hepatic Effects
In addition to hypersensitivity reactions involving the liver, in some patients
the findings are consistent with those of cholestatic hepatitis (see WARNINGS,
Hypersensitivity). As with other non-steroidal antiinflammatory drugs, borderline
elevations of one or more liver tests without any other signs and symptoms may
occur in up to 15% of patients taking NSAIDs including CLINORIL (sulindac). These laboratory
abnormalities may progress, may remain essentially unchanged, or may be transient
with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator
of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations
of SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1%
of patients. Notable elevations of ALT or AST (approximately three or more times
the upper limit of normal) have been reported in approximately 1% of patients
in clinical trials with NSAIDs. 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 CLINORIL (sulindac).
Although such reactions as described above are rare, if abnormal liver tests
persist or worsen, if clinical signs and symptoms consistent with liver disease
develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.),
CLINORIL (sulindac) should be discontinued.
In clinical trials with CLINORIL (sulindac) , the use of doses of 600 mg/day has been associated
with an increased incidence of mild liver test abnormalities (see DOSAGE
AND ADMINISTRATION for maximum dosage recommendation).
Renal Effects
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 non-steroidal 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, patients
who are volume-depleted, 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 CLINORIL (sulindac) in patients with advanced renal disease. Therefore, treatment
with CLINORIL (sulindac) is not recommended in these patients with advanced renal disease.
If CLINORIL (sulindac) therapy must be initiated, close monitoring of the patient's renal
function is advisable.
Anaphylactic/Anaphylactoid Reactions
As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients
without known prior exposure to CLINORIL (sulindac). CLINORIL (sulindac) 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 anaphylactic/anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including CLINORIL (sulindac) , 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.
Hypersensitivity
Rarely, fever and other evidence of hypersensitivity (see ADVERSE REACTIONS)
including abnormalities in one or more liver function tests and severe skin
reactions have occurred during therapy with CLINORIL (sulindac). Fatalities have occurred
in these patients. Hepatitis, jaundice, or both, with or without fever, may
occur usually within the first one to three months of therapy. Determinations
of liver function should be considered whenever a patient on therapy with CLINORIL (sulindac)
develops unexplained fever, rash or other dermatologic reactions or constitutional
symptoms. If unexplained fever or other evidence of hypersensitivity occurs,
therapy with CLINORIL (sulindac) should be discontinued. The elevated temperature and abnormalities
in liver function caused by CLINORIL (sulindac) characteristically have reverted to normal
after discontinuation of therapy. Administration of CLINORIL (sulindac) should not be reinstituted
in such patients.
Pregnancy
In late pregnancy, as with other NSAIDs, CLINORIL (sulindac) should be avoided because
it may cause premature closure of the ductus arteriosus.
PRECAUTIONS
General
CLINORIL (sulindac) 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 CLINORIL (sulindac) in reducing fever and inflammation
may diminish the utility of these diagnostic signs in detecting complications
of presumed noninfectious, painful conditions.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including CLINORIL (sulindac).
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 CLINORIL (sulindac) , 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
CLINORIL (sulindac) who may be adversely affected by alterations in platelet function,
such as those with coagulation disorders or patients receiving anticoagulants,
should be carefully monitored.
Preexisting Asthma
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 non-steroidal anti-inflammatory drugs has been reported in
such aspirin-sensitive patients, CLINORIL (sulindac) should not be administered to patients
with this form of aspirin sensitivity and should be used with caution in patients
with preexisting asthma.
Renal Calculi
Sulindac metabolites have been reported rarely as the major or a minor component
in renal stones in association with other calculus components. CLINORIL (sulindac) should
be used with caution in patients with a history of renal lithiasis, and they
should be kept well hydrated while receiving CLINORIL (sulindac).
Pancreatitis
Pancreatitis has been reported in patients receiving CLINORIL (see ADVERSE
REACTIONS). Should pancreatitis be suspected, the drug should be discontinued
and not restarted, supportive medical therapy instituted, and the patient monitored
closely with appropriate laboratory studies (e.g., serum and urine amylase,
amylase/creatinine clearance ratio, electrolytes, serum calcium, glucose, lipase,
etc.). A search for other causes of pancreatitis as well as those conditions
which mimic pancreatitis should be conducted.
Ocular Effects
Because of reports of adverse eye findings with non-steroidal anti-inflammatory
agents, it is recommended that patients who develop eye complaints during treatment
with CLINORIL (sulindac) have ophthalmologic studies.
Hepatic Insufficiency
In patients with poor liver function, delayed, elevated and prolonged circulating
levels of the sulfide and sulfone metabolites may occur. Such patients should
be monitored closely; a reduction of daily dosage may be required.
SLE and Mixed Connective Tissue Disease
In patients with systemic lupus erythematosus (SLE) and mixed connective tissue
disease, there may be an increased risk of aseptic meningitis (see ADVERSE
REACTIONS).
Information for Patients
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.
- CLINORIL (sulindac) , 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).
- CLINORIL (sulindac) , like other NSAIDs, can cause GI discomfort and, rarely, 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).
- CLINORIL (sulindac) , 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.
- Patients should promptly report signs or symptoms of unexplained weight
gain or edema to their physicians.
- 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.
- Patients should be informed of the signs of an anaphylactic/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).
- In late pregnancy, as with other NSAIDs, CLINORIL (sulindac) should be avoided because
it may cause premature closure of the ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning
symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients
on long-term treatment with NSAIDs should have their CBC and a chemistry profile
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, CLINORIL (sulindac) should be discontinued.
Pregnancy
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. CLINORIL (sulindac) should be used in pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Because of the known effects of non-steroidal anti-inflammatory drugs on the
fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy
(particularly late pregnancy) should be avoided.
The known effects of drugs of this class on the human fetus during the third
trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary hypertension; non-closure of the ductus
arteriosus postnatally which may be resistant to medical management; myocardial
degenerative changes, platelet dysfunction with resultant bleeding, intracranial
bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result
in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding
or perforation, and increased risk of necrotizing enterocolitis.
In reproduction studies in the rat, a decrease in average fetal weight and
an increase in numbers of dead pups were observed on the first day of the postpartum
period at dosage levels of 20 and 40 mg/kg/day (2½ and 5 times the usual maximum
daily dose in humans), although there was no adverse effect on the survival
and growth during the remainder of the postpartum period. CLINORIL (sulindac) prolongs
the duration of gestation in rats, as do other compounds of this class. Visceral
and skeletal malformations observed in low incidence among rabbits in some teratology
studies did not occur at the same dosage levels in repeat studies, nor at a
higher dosage level in the same species.
Labor and Delivery
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 CLINORIL (sulindac) on labor and delivery in pregnant
women are unknown.
Nursing Mothers
It is not known whether this drug is excreted in human milk; however, it is
secreted in the milk of lactating rats. Because many drugs are excreted in human
milk and because of the potential for serious adverse reactions in nursing infants
from CLINORIL (sulindac) , 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.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly (65
years and older) since advancing age appears to increase the possibility of
adverse reactions. Elderly patients seem to tolerate ulceration or bleeding
less well than other individuals and many spontaneous reports of fatal GI events
are in this population (see WARNINGS, Gastrointestinal Effects -Risk of Ulceration,
Bleeding, and Perforation).
CLINORIL (sulindac) is known to be substantially excreted by the kidney and the risk of
toxic reactions to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal function,
care should be taken in dose selection and it may be useful to monitor renal
function (see WARNINGS, Renal Effects).
Dosage (Posology) and method of administration
Carefully consider the potential benefits and risks of CLINORIL (sulindac) and other treatment
options before deciding to use CLINORIL (sulindac). 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 CLINORIL (sulindac) , the dose and
frequency should be adjusted to suit an individual patient's needs.
CLINORIL (sulindac) should be administered orally twice a day with food. The maximum dosage
is 400 mg per day. Dosages above 400 mg per day are not recommended.
In osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, the recommended
starting dosage is 150 mg twice a day. The dosage may be lowered or raised depending
on the response.
A prompt response (within one week) can be expected in about one-half of patients
with osteoarthritis, ankylosing spondylitis, and rheumatoid arthritis. Others
may require longer to respond.
In acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis)
and acute gouty arthritis, the recommended dosage is 200 mg twice a day. After
a satisfactory response has been achieved, the dosage may be reduced according
to the response. In acute painful shoulder, therapy for 714 days is usually
adequate. In acute gouty arthritis, therapy for 7 days is usually adequate.
Interaction with other medicinal products and other forms of interaction
SIDE EFFECTS
The following adverse reactions were reported in clinical trials or have been
reported since the drug was marketed. The probability exists of a causal relationship
between CLINORIL (sulindac) and these adverse reactions. The adverse reactions which have
been observed in clinical trials encompass observations in 1,865 patients, including
232 observed for at least 48 weeks.
Incidence Greater Than 1%
Gastrointestinal
The most frequent types of adverse reactions occurring with CLINORIL (sulindac) are gastrointestinal;
these include gastrointestinal pain (10%), dyspepsia***, nausea*** with or without
vomiting, diarrhea***, constipation***, flatulence, anorexia and gastrointestinal
cramps.
Dermatologic
Rash***, pruritus.
Central Nervous System
Dizziness***, headache***, nervousness.
Special Senses
Tinnitus.
Miscellaneous
Edema (see WARNINGS).
Incidence Less Than 1 in 100
Gastrointestinal
Gastritis, gastroenteritis or colitis. Peptic ulcer and gastrointestinal bleeding
have been reported. GI perforation and intestinal strictures (diaphragms) have
been reported rarely.
Liver function abnormalities; jaundice, sometimes with fever; cholestasis;
hepatitis; hepatic failure.
There have been rare reports of sulindac metabolites in common bile duct “sludge”
and in biliary calculi in patients with symptoms of cholecystitis who underwent
a cholecystectomy.
Pancreatitis (see PRECAUTIONS).
Ageusia; glossitis.
Dermatologic
Stomatitis, sore or dry mucous membranes, alopecia, photosensitivity.
Erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome,
and exfoliative dermatitis have been reported.
Cardiovascular
Congestive heart failure, especially in patients with marginal cardiac function;
palpitation; hypertension.
Hematologic
Thrombocytopenia; ecchymosis; purpura; leukopenia; agranulocytosis; neutropenia;
bone marrow depression, including aplastic anemia; hemolytic anemia; increased
prothrombin time in patients on oral anticoagulants (see PRECAUTIONS).
Genitourinary
Urine discoloration; dysuria; vaginal bleeding; hematuria; proteinuria; crystalluria; renal impairment, including renal failure; interstitial nephritis; nephrotic syndrome.
Renal calculi containing sulindac metabolites have been observed rarely.
Metabolic
Hyperkalemia.
Musculoskeletal
Muscle weakness.
Psychiatric
Depression; psychic disturbances including acute psychosis.
Nervous System
Vertigo; insomnia; somnolence; paresthesia; convulsions; syncope; aseptic meningitis
(especially in patients with systemic lupus erythematosus (SLE) and mixed connective
tissue disease, see PRECAUTIONS).
Special Senses
Blurred vision; visual disturbances; decreased hearing; metallic or bitter
taste.
Respiratory
Epistaxis.
Hypersensitivity Reactions
Anaphylaxis; angioneurotic edema; urticaria; bronchial spasm; dyspnea.
Hypersensitivity vasculitis.
A potentially fatal apparent hypersensitivity syndrome has been reported. This
syndrome may include constitutional symptoms (fever, chills, diaphoresis, flushing),
cutaneous findings (rash or other dermatologic reactions - see above), conjunctivitis,
involvement of major organs (changes in liver function including hepatic failure,
jaundice, pancreatitis, pneumonitis with or without pleural effusion, leukopenia,
leukocytosis, eosinophilia, disseminated intravascular coagulation, anemia,
renal impairment, including renal failure), and other less specific findings
(adenitis, arthralgia, arthritis, myalgia, fatigue, malaise, hypotension, chest
pain, tachycardia).
Causal Relationship Unknown
A rare occurrence of fulminant necrotizing fasciitis, particularly in association
with Group A β-hemolytic streptococcus, has been described in persons treated
with non-steroidal anti-inflammatory agents, sometimes with fatal outcome (see
also PRECAUTIONS, General).
Other reactions have been reported in clinical trials or since the drug was
marketed, but occurred under circumstances where a causal relationship could
not be established. However, in these rarely reported events, that possibility
cannot be excluded. Therefore, these observations are listed to serve as alerting
information to physicians.
Cardiovascular
Arrhythmia.
Metabolic
Hyperglycemia.
Nervous System
Neuritis.
Special Senses
Disturbances of the retina and its vasculature.
Miscellaneous
Gynecomastia.
*** Incidence between 3% and 9%. Those reactions occurring in
1% to 3% of patients are not marked with an asterisk.
DRUG INTERACTIONS
ACE-Inhibitors and Angiotensin II Antagonists
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors
and angiotensin II antagonists. These interactions should be given consideration
in patients taking NSAIDs concomitantly with ACE-inhibitors or angiotensin II
antagonists. In some patients with compromised renal function (e.g., elderly
patients or patients who are volume-depleted, including those on diuretic therapy)
who are being treated with non-steroidal anti-inflammatory drugs, the co-administration
of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result
in further deterioration of renal function, including possible acute renal failure,
which is usually reversible. Therefore, the combination should be administered
with caution in patients with compromised renal function.
Acetaminophen
Acetaminophen had no effect on the plasma levels of sulindac or its sulfide
metabolite.
Aspirin
The concomitant administration of aspirin with sulindac significantly depressed
the plasma levels of the active sulfide metabolite. A double-blind study compared
the safety and efficacy of CLINORIL (sulindac) 300 or 400 mg daily given alone or with
aspirin 2.4 g/day for the treatment of osteoarthritis. The addition of aspirin
did not alter the types of clinical or laboratory adverse experiences for CLINORIL (sulindac) ;
however, the combination showed an increase in the incidence of gastrointestinal
adverse experiences. Since the addition of aspirin did not have a favorable
effect on the therapeutic response to CLINORIL (sulindac) , the combination is not recommended.
Cyclosporine
Administration of non-steroidal anti-inflammatory drugs concomitantly with
cyclosporine has been associated with an increase in cyclosporine-induced toxicity,
possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be
used with caution in patients taking cyclosporine, and renal function should
be carefully monitored.
Diflunisal
The concomitant administration of CLINORIL (sulindac) and diflunisal in normal volunteers
resulted in lowering of the plasma levels of the active sulindac sulfide metabolite
by approximately one-third.
Diuretics
Clinical studies, as well as post marketing observations, have shown that CLINORIL (sulindac)
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.
DMSO
DMSO should not be used with sulindac. Concomitant administration has been
reported to reduce the plasma levels of the active sulfide metabolite and potentially
reduce efficacy. In addition, this combination has been reported to cause peripheral neuropathy.
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.
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.
NSAIDs
The concomitant use of CLINORIL (sulindac) with other NSAIDs is not recommended due to
the increased possibility of gastrointestinal toxicity, with little or no increase
in efficacy.
Oral anticoagulants
Although sulindac and its sulfide metabolite are highly bound to protein, studies
in which CLINORIL (sulindac) was given at a dose of 400 mg daily have shown no clinically
significant interaction with oral anticoagulants. However, patients should be
monitored carefully until it is certain that no change in their anticoagulant
dosage is required. Special attention should be paid to patients taking higher
doses than those recommended and to patients with renal impairment or other
metabolic defects that might increase sulindac blood levels. 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.
Oral hypoglycemic agents
Although sulindac and its sulfide metabolite are highly bound to protein, studies
in which CLINORIL (sulindac) was given at a dose of 400 mg daily, have shown no clinically
significant interaction with oral hypoglycemic agents. However, patients should
be monitored carefully until it is certain that no change in their hypoglycemic
dosage is required. Special attention should be paid to patients taking higher
doses than those recommended and to patients with renal impairment or other
metabolic defects that might increase sulindac blood levels.
Probenecid
Probenecid given concomitantly with sulindac had only a slight effect on plasma
sulfide levels, while plasma levels of sulindac and sulfone were increased.
Sulindac was shown to produce a modest reduction in the uricosuric action of
probenecid, which probably is not significant under most circumstances.
Propoxyphene hydrochloride
Propoxyphene hydrochloride had no effect on the plasma levels of sulindac or
its sulfide metabolite.
