Sulindac

Dosage Form: tablet
Sulindac TABLETS USP

Rx only

Cardiovascular Risk

• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (See WARNINGS.)


• Sulindac tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk

• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. (See WARNINGS.)

Sulindac Description

Sulindac is a non-steroidal, anti-inflammatory indene derivative designated chemically as (Z)-5-fluoro-2-methyl-1-[[p-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetic acid. It is not a salicylate, pyrazolone or propionic acid derivative. Its empirical formula is C20H17FO3S, with a molecular weight of 356.42. Sulindac, a yellow crystalline compound, is a weak organic acid practically insoluble in water below pH 4.5, but very soluble as the sodium salt or in buffers of pH 6 or higher.

Sulindac tablets are available in 150 and 200 mg tablets for oral administration. Each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, and pregelatinized starch.

Following absorption, Sulindac undergoes two major biotransformations — reversible reduction to the sulfide metabolite, and irreversible oxidation to the sulfone metabolite. Available evidence indicates that the biological activity resides with the sulfide metabolite.

The structural formulas of Sulindac and its metabolites are:

Sulindac - Clinical Pharmacology

Pharmacodynamics

Sulindac tablets are 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.

Pharmacokinetics

Absorption

The extent of Sulindac absorption from Sulindac 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
S   = Sulindac SF = Sulindac Sulfide SP = Sulindac Sulfone
Tmax	Age 19–41 (n=24)	Age 65–87 (n=12) (400 mg qd)
	(200 mg tablet)	2.54 ± 1.52 S
		5.75 ± 2.81 SF
	3.38 ± 2.30 S	6.83 ± 4.19 SP
	4.88 ± 2.57 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

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 (T1/2) is 7.8 and 16.4 hours, respectively, for Sulindac and its active sulfide metabolite.

Because Sulindac tablets are 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 Sulindac tablets (see ADVERSE REACTIONS).

In a study of patients with chronic glomerular disease treated with therapeutic doses of Sulindac tablets, 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, Sulindac tablets were 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 Sulindac tablets 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 Sulindac tablets, was similar to that for placebo, and was statistically significantly less than that resulting from 4800 mg per day of aspirin.

Special Populations

Pediatric

The pharmacokinetics of Sulindac have not been investigated in pediatric patients.

Race

Pharmacokinetic differences due to race have not been identified.

Hepatic Insufficiency

Patients with acute and chronic hepatic disease may require reduced doses of Sulindac tablets compared to patients with normal hepatic function since hepatic metabolism is an important elimination pathway.

Following a single dose, plasma concentrations of the active sulfide metabolite have been reported to be higher in patients with alcoholic liver disease compared to healthy normal subjects.

Renal Insufficiency

Sulindac pharmacokinetics have been investigated in patients with renal insufficiency. The disposition of Sulindac was studied in end-stage renal disease patients requiring hemodialysis. Plasma concentrations of Sulindac and its sulfone metabolite were comparable to those of normal healthy volunteers whereas concentrations of the active sulfide metabolite were significantly reduced. Plasma protein binding was reduced and the AUC of the unbound sulfide metabolite was about half that in healthy subjects.

Sulindac and its metabolites are not significantly removed from the blood in patients undergoing hemodialysis.

Since Sulindac tablets are eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored.

A lower daily dosage should be anticipated to avoid excessive drug accumulation.

In controlled clinical studies Sulindac tablets were evaluated in the following five conditions:

1. Osteoarthritis

In patients with osteoarthritis of the hip and knee, the anti-inflammatory and analgesic activity of Sulindac tablets was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; decrease in disease activity as assessed by both patient and investigator; improvement in ARA Functional Class; relief of night pain; improvement in overall evaluation of pain, including pain on weight bearing and pain on active and passive motion; improvement in joint mobility, range of motion, and functional activities; decreased swelling and tenderness; and decreased duration of stiffness following prolonged inactivity.

In clinical studies in which dosages were adjusted according to patient needs, Sulindac tablets 200 to 400 mg daily were shown to be comparable in effectiveness to aspirin 2400 to 4800 mg daily. Sulindac tablets were generally well tolerated, and patients on it had a lower overall incidence of total adverse effects, of milder gastrointestinal reactions, and of tinnitus than did patients on aspirin. (See ADVERSE REACTIONS.)

2. Rheumatoid arthritis

In patients with rheumatoid arthritis, the anti-inflammatory and analgesic activity of Sulindac tablets was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; decrease in disease activity as assessed by both patient and investigator; reduction in overall joint pain; reduction in duration and severity of morning stiffness; reduction in day and night pain; decrease in time required to walk 50 feet; decrease in general pain as measured on a visual analog scale; improvement in the Ritchie articular index; decrease in proximal interphalangeal joint size; improvement in ARA Functional Class; increase in grip strength; reduction in painful joint count and score; reduction in swollen joint count and score; and increased flexion and extension of the wrist.

In clinical studies in which dosages were adjusted according to patient needs, Sulindac tablets 300 to 400 mg daily were shown to be comparable in effectiveness to aspirin 3600 to 4800 mg daily. Sulindac tablets were generally well tolerated, and patients on it had a lower overall incidence of total adverse effects, of milder gastrointestinal reactions, and of tinnitus than did patients on aspirin. (See ADVERSE REACTIONS.)

In patients with rheumatoid arthritis, Sulindac tablets may be used in combination with gold salts at usual dosage levels. In clinical studies, Sulindac tablets added to the regimen of gold salts usually resulted in additional symptomatic relief but did not alter the course of the underlying disease.

3. Ankylosing spondylitis

In patients with ankylosing spondylitis, the anti-inflammatory and analgesic activity of Sulindac tablets was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; decrease in disease activity as assessed by both patient and investigator; improvement in ARA Functional Class; improvement in patient and investigator evaluation of spinal pain, tenderness and/or spasm; reduction in the duration of morning stiffness; increase in the time to onset of fatigue; relief of night pain; increase in chest expansion; and increase in spinal mobility evaluated by fingers-to-floor distance, occiput to wall distance, the Schober Test, and the Wright Modification of the Schober Test. In a clinical study in which dosages were adjusted according to patient need, Sulindac tablets 200 to 400 mg daily were as effective as indomethacin 75 to 150 mg daily. In a second study, Sulindac tablets 300 to 400 mg daily were comparable in effectiveness to phenylbutazone 400 to 600 mg daily. Sulindac tablets were better tolerated than phenylbutazone. (See ADVERSE REACTIONS.)

4. Acute painful shoulder (Acute subacromial bursitis/supraspinatus tendinitis)

In patients with acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), the anti-inflammatory and analgesic activity of Sulindac tablets was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; relief of night pain, spontaneous pain, and pain on active motion; decrease in local tenderness; and improvement in range of motion measured by abduction, and internal and external rotation. In clinical studies in acute painful shoulder, Sulindac tablets 300 to 400 mg daily and oxyphenbutazone 400 to 600 mg daily were shown to be equally effective and well tolerated.

5. Acute gouty arthritis

In patients with acute gouty arthritis, the anti-inflammatory and analgesic activity of Sulindac tablets was demonstrated by clinical measurements that included: assessments by both the patient and investigator of overall response; relief of weight-bearing pain; relief of pain at rest and on active and passive motion; decrease in tenderness; reduction in warmth and swelling; increase in range of motion; and improvement in ability to function. In clinical studies, Sulindac tablets at 400 mg daily and phenylbutazone at 600 mg daily were shown to be equally effective. In these short-term studies in which reduction of dosage was permitted according to response, both drugs were equally well tolerated.

Indications and Usage for Sulindac

Carefully consider the potential benefits and risks of Sulindac tablets and other treatment options before deciding to use Sulindac tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Sulindac tablets are indicated for acute or long-term use in the relief of signs and symptoms of the following:

1. Osteoarthritis


2. Rheumatoid arthritis1


3. Ankylosing spondylitis


4. Acute painful shoulder (Acute subacromial bursitis/supraspinatus tendinitis)


5. Acute gouty arthritis

1

The safety and effectiveness of Sulindac tablets 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).

Contraindications

Sulindac tablets are contraindicated in patients with known hypersensitivity to Sulindac or the excipients (see DESCRIPTION).

Sulindac tablets 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).

Sulindac tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

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 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

NSAIDs, including Sulindac tablets, 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 Sulindac tablets, 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. Sulindac tablets should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including Sulindac tablets, 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 a 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 anti-inflammatory 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 Sulindac tablets. 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 Sulindac tablets. 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.), Sulindac tablets should be discontinued.

In clinical trials with Sulindac tablets, 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 Sulindac tablets in patients with advanced renal disease. Therefore, treatment with Sulindac tablets is not recommended in these patients with advanced renal disease. If Sulindac tablets 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 Sulindac tablets. Sulindac tablets 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 Sulindac tablets, 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 Sulindac tablets. 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 Sulindac tablets develops unexplained fever, rash or other dermatologic reactions or constitutional symptoms. If unexplained fever or other evidence of hypersensitivity occurs, therapy with Sulindac tablets should be discontinued. The elevated temperature and abnormalities in liver function caused by Sulindac tablets characteristically have reverted to normal after discontinuation of therapy. Administration of Sulindac tablets should not be reinstituted in such patients.

Pregnancy

In late pregnancy, as with other NSAIDs, Sulindac tablets should be avoided because it may cause premature closure of the ductus arteriosus.

Precautions

General

Sulindac 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 Sulindac tablets 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 Sulindac tablets. 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 Sulindac tablets, 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 Sulindac tablets 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, Sulindac tablets 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. Sulindac tablets should be used with caution in patients with a history of renal lithiasis, and they should be kept well hydrated while receiving Sulindac tablets.

Pancreatitis

Pancreatitis has been reported in patients receiving Sulindac tablets (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 Sulindac tablets 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.

1. Sulindac tablets, 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. Sulindac tablets, 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).


3. Sulindac tablets, 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 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).


7. In late pregnancy, as with other NSAIDs, Sulindac tablets 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, Sulindac tablets should be discontinued.

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 Sulindac tablets 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 Sulindac tablets; 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 Sulindac tablets, 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 Sulindac tablets 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 Sulindac tablets 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 Sulindac tablets 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 Sulindac tablets were 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 Sulindac tablets were 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.

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. Sulindac tablets 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. Sulindac tablets prolong 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 Sulindac tablets 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 Sulindac tablets, 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).

Sulindac tablets are 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).

Adverse Reactions

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 Sulindac tablets 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 Sulindac tablets are gastrointestinal; these include gastrointestinal pain (10%), dyspepsia2, nausea2 with or without vomiting, diarrhea2, constipation2, flatulence, anorexia and gastrointestinal cramps.

Dermatologic

Rash2, pruritus.

Central Nervous System

Dizziness2, headache2, nervousne

Lithium

Pronunciation: LITH-ee-um
Generic Name: Lithium
Brand Name: Eskalith

Lithium toxicity is closely related to blood lithium levels and can occur at doses close to normal blood lithium levels. Do not exceed the recommended dose. Your doctor should monitor your blood lithium levels routinely to help prevent lithium toxicity. Contact your doctor immediately if you experience symptoms of toxicity, such as nausea, diarrhea, vomiting, blurred vision, ringing in the ears, drowsiness, giddiness, muscle weakness, tremor, twitching, seizures, loss of consciousness, back and forth eye movements, loss of coordination, or increased urination.

Lithium is used for:

Treating manic episodes in patients with bipolar disorder. It is also used to reduce the frequency and decrease the severity of manic episodes in patients with bipolar disorder. It may also be used for other conditions as determined by your doctor.

Lithium is an antimanic agent. Exactly how Lithium works is unknown, but it may work by altering the balance of certain chemicals in the brain.

Do NOT use Lithium if:

• you are allergic to any ingredient in Lithium


• you have moderate to severe kidney or heart problems


• you have low blood sodium levels


• you are severely dehydrated, ill, or weakened

Contact your doctor or health care provider right away if any of these apply to you.

Video: Treatment for Depression

Treatments for depression are getting better everyday and there are things you can start doing right away.

Before using Lithium:

Some medical conditions may interact with Lithium. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have diarrhea, vomiting, excessive sweating, dehydration, fever, infection, or illness, or you are in a weakened state


• if you have psoriasis or kidney, heart, or thyroid problems


• if you have or are suspected to have a certain genetic heart disease (Brugada syndrome), or you have risk factors for it (eg, unexplained fainting; family history of Brugada syndrome; family history of sudden, unexplained death before the age of 45 years)


• if you have brain or nerve problems (eg, organic brain syndrome)


• if you are on a low-salt (sodium) diet

Some MEDICINES MAY INTERACT with Lithium. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Angiotensin-converting enzyme (ACE) inhibitors (eg, enalapril), angiotensin II receptor antagonists (eg, losartan), calcium channel blockers (eg, verapamil), carbamazepine, diuretics (eg, furosemide, hydrochlorothiazide), hydantoins (eg, phenytoin), methyldopa, metronidazole, nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, indomethacin, celecoxib), selective serotonin reuptake inhibitor (SSRI) antidepressants (eg, fluoxetine), or serotonin-norepinephrine reuptake inhibitors (SNRIs) (eg, venlafaxine) because the risk of toxicity of Lithium may be increased


• Butyrophenones (eg, haloperidol) or other medicines for mental or mood problems because the risk of a severe and sometimes permanent nervous system problem (encephalopathic syndrome) characterized by weakness, fever, tremor, confusion, sluggishness, or uncontrolled muscle movements may be increased


• Iodide preparations (eg, potassium iodide) because the risk of low thyroid levels may be increased


• Acetazolamide, urea, urinary alkalinizers (eg, sodium bicarbonate), or xanthines (eg, theophylline) because they may decrease Lithium's effectiveness

This may not be a complete list of all interactions that may occur. Ask your health care provider if Lithium may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Lithium:

Use Lithium as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Lithium by mouth with or without food. If stomach upset occurs, take with food to reduce stomach irritation.


• Drinking extra fluids while you are taking Lithium is recommended. Check with your doctor for instructions.


• Do not change your diet, including the amount of salt in your diet, unless instructed by your doctor.


• If you miss a dose of Lithium, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Lithium.

Important safety information:

• Lithium may cause drowsiness or dizziness. These effects may be worse if you take it with alcohol or certain medicines. Use Lithium with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do NOT take more than the recommended dose without checking with your doctor.


• It may take 1 to 3 weeks for Lithium to work. Do not stop using Lithium or change your dose without checking with your doctor.


• Tell your doctor or dentist that you take Lithium before you receive any medical or dental care, emergency care, or surgery.


• Fever, infection, vomiting, diarrhea, or excessive sweating may affect the levels of Lithium in your blood. If you experience any of these conditions, contact your doctor. Talk to your doctor about how to replace the salt lost through sweating during exercise.


• Do not change the amount of salt in your diet unless instructed by your doctor. Check with your doctor before restricting your salt intake. Tell your doctor if you are on a low-salt diet.


• Lab tests, including blood lithium levels and kidney function tests, may be performed while you use Lithium. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Lithium with caution in the ELDERLY; they may be more sensitive to its effects.


• Lithium should not be used in CHILDREN younger than 12 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Lithium may cause harm to the fetus. If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of using Lithium while you are pregnant. Lithium is found in breast milk. Do not breast-feed while taking Lithium.

Possible side effects of Lithium:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Drying or thinning of the hair; hair loss; mild hand tremor; mild loss of appetite; mild thirst; mild tiredness; temporary, mild nausea and general discomfort at the beginning of treatment.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); back and forth eye movements; confusion; diarrhea; dizziness or light-headedness; drowsiness; dry mouth or eyes; fainting; giddiness; inability to control the bladder or bowels; increased or decreased urination; increased thirst; involuntary twitching or muscle movements; loss of consciousness; loss of coordination; muscle weakness; numbness of the skin; restlessness; ringing in the ears; seizures; severe or persistent headache or nausea; shortness of breath; slow or irregular heartbeat; sluggishness; slurred speech; swelling of the ankles or wrists; tremor; unsteadiness; vision changes (eg, blurred vision); vomiting; weight changes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Lithium side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include back and forth eye movements; blurred vision; diarrhea; drowsiness; giddiness; increased urination; loss of consciousness; loss of coordination; muscle weakness; nausea; ringing in the ears; seizures; tremor; twitching; vomiting.

Proper storage of Lithium:

Store Lithium at 77 degrees F (25 degrees C) in a tightly closed container. Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, light, and moisture. Keep Lithium out of the reach of children and away from pets.

General information:

• If you have any questions about Lithium, please talk with your doctor, pharmacist, or other health care provider.


• Lithium is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Lithium. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Lithium resources

• Lithium Side Effects (in more detail)
• Lithium Dosage
• Lithium Use in Pregnancy & Breastfeeding
• Drug Images
• Lithium Drug Interactions
• Lithium Support Group
• 88 Reviews for Lithium - Add your own review/rating

• Lithium Prescribing Information (FDA)


• Lithium Professional Patient Advice (Wolters Kluwer)


• lithium Advanced Consumer (Micromedex) - Includes Dosage Information


• lithium Concise Consumer Information (Cerner Multum)


• Eskalith Prescribing Information (FDA)


• Lithium Salts Monograph (AHFS DI)


• Lithobid Prescribing Information (FDA)

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• Mania
• Schizoaffective Disorder

Chlorothiazide Injection

Dosage Form: injection, powder, lyophilized, for solution
Chlorothiazide Sodium for Injection, USP

FOR THE PREPARATION OF INTRAVENOUS SOLUTIONS

Chlorothiazide Injection Description

Chlorothiazide sodium is a diuretic and antihypertensive. It is 6-chloro-2 H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide monosodium salt and its molecular weight is 317.71. Its molecular formula is C7H5ClN3NaO4S2 and its structural formula is:

Chlorothiazide sodium for injection, USP is a sterile lyophilized white powder and is supplied in a vial containing:

 

Chlorothiazide sodium equivalent to chlorothiazide USP........................................ 500 mg

 

Inactive ingredients:

Mannitol .................................................................................................................. 250 mg

Sodium hydroxide to adjust pH.

 

Chlorothiazide is a diuretic and antihypertensive. It is 6-chloro-2 H-1,2,4- benzothiadiazine-7-sulfonamide 1,1-dioxide. Its molecular formula is C7H6ClN3O4S2 and its structural formula is:

It is a white, or practically white, crystalline powder with a molecular weight of 295.72, which is insoluble in water, but readily soluble in dilute aqueous sodium hydroxide. It is soluble in urine to the extent of about 150 mg per 100 mL at pH 7.

Chlorothiazide Injection - Clinical Pharmacology

The mechanism of the antihypertensive effect of thiazides is unknown. Chlorothiazide does not usually affect normal blood pressure.

 

Chlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic efficacy.

 

Chlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.

 

After oral use diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours. Following intravenous use of chlorothiazide sodium, onset of the diuretic action occurs in 15 minutes and the maximal action in 30 minutes.

Pharmacokinetics and Metabolism

Chlorothiazide is not metabolized but is eliminated rapidly by the kidney; 96 percent of an intravenous dose is excreted unchanged in the urine within 23 hours. The plasma half-life of chlorothiazide is 45 to 120 minutes. Chlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Indications and Usage for Chlorothiazide Injection

Chlorothiazide sodium for injection is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.

 

Chlorothiazide sodium for injection has also been found useful in edema due to various forms of renal dysfunction such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

 

Use in Pregnancy

 

Routine use of diuretics during normal pregnancy is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia.

 

Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. Thiazides are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy (see PRECAUTIONS, Pregnancy). Dependent edema in pregnancy, resulting from restriction of venous return by the gravid uterus, is properly treated through elevation of the lower extremities and use of support stockings. Use of diuretics to lower intravascular volume in this instance is illogical and unnecessary. During normal pregnancy there is hypervolemia which is not harmful to the fetus or the mother in the absence of cardiovascular disease. However, it may be associated with edema, rarely generalized edema. If such edema causes discomfort, increased recumbency will often provide relief. Rarely this edema may cause extreme discomfort which is not relieved by rest. In these instances, a short course of diuretic therapy may provide relief and be appropriate.

Contraindications

Anuria.


Hypersensitivity to any component of this product or to other sulfonamide-derived drugs.

Warnings

Intravenous use in infants and children has been limited and is not generally recommended.

 

Use with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

 

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

 

Thiazides may add to or potentiate the action of other antihypertensive drugs.

 

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

 

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

 

Lithium generally should not be given with diuretics (see PRECAUTIONS, Drug Interactions).

Precautions

General

All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

 

Hypokalemia may develop especially with brisk diuresis, when severe cirrhosis is present or after prolonged therapy.

 

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmias and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may be avoided or treated by use of potassium-sparing diuretics or potassium supplements such as foods with a high potassium content. Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

 

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

 

Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazides.

 

In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required.

 

Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.

 

The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.

 

If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.

 

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

 

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

 

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Laboratory Tests

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals.

Drug Interactions

When given concurrently the following drugs may interact with thiazide diuretics.

 

Alcohol, barbiturates, or narcotics - potentiation of orthostatic hypotension may occur.

 

Antidiabetic drugs - (oral agents and insulin) - dosage adjustment of the antidiabetic drug may be required.

 

Other antihypertensive drugs - additive effect or potentiation.

 

Corticosteroids, ACTH - intensified electrolyte depletion, particularly hypokalemia.

 

Pressor amines (e.g., norepinephrine) - possible decreased response to pressor amines but not sufficient to preclude their use.

 

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) - possible increased responsiveness to the muscle relaxant.

 

Lithium - generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with chlorothiazide sodium.

 

Non-steroidal Anti-inflammatory Drugs - In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when chlorothiazide sodium and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Drug/Laboratory Test Interactions

Thiazides should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS, General).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with chlorothiazide.

 

Chlorothiazide was not mutagenic in vitro in the Ames microbial mutagen test (using a maximum concentration of 5 mg/plate and Salmonella typhimurium strains TA98 and TA100) and was not mutagenic and did not induce mitotic nondisjunction in diploid-strains of Aspergillus nidulans.

 

Chlorothiazide had no adverse effects on fertility in female rats at doses up to 60 mg/kg/day and no adverse effects on fertility in male rats at doses up to 40 mg/kg/day. These doses are 1.5 and 1 times1 the recommended maximum human dose, respectively, when compared on a body weight basis.

 

1 Calculations based on a human body weight of 50 kg.

Pregnancy

Teratogenic Effects


Pregnancy Category C: Although reproduction studies performed with chlorothiazide doses of 50 mg/kg/day in rabbits, 60 mg/kg/day in rats and 500 mg/kg/day in mice revealed no external abnormalities of the fetus or impairment of growth and survival of the fetus due to chlorothiazide, such studies did not include complete examinations for visceral and skeletal abnormalities. It is not known whether chlorothiazide can cause fetal harm when administered to a pregnant woman; however, thiazides cross the placental barrier and appear in cord blood. Chlorothiazide should be used during pregnancy only if clearly needed (see INDICATIONS AND USAGE).

 

Nonteratogenic Effects:


Chlorothiazide may cause fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult.

Nursing Mothers

Because of the potential for serious adverse reactions in nursing infants from chlorothiazide sodium, 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 of chlorothiazide sodium in pediatric patients have not been established.

Geriatric Use

Clinical studies of chlorothiazide sodium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

 

This drug 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).

Adverse Reactions

The following adverse reactions have been reported and, within each category, are listed in order of decreasing severity.

 

Body as a Whole: Weakness.

 

Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics or antihypertensive drugs).

 

Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia.

 

Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia.

 

Hypersensitivity: Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura.

 

Metabolic: Electrolyte imbalance (see PRECAUTIONS), hyperglycemia, glycosuria, hyperuricemia.

 

Musculoskeletal: Muscle spasm.

 

Nervous System/Psychiatric: Vertigo, paresthesias, dizziness, headache, restlessness.

 

Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia.

 

Special Senses: Transient blurred vision, xanthopsia.

 

Renal: Renal failure, renal dysfunction, interstitial nephritis, (see WARNINGS); hematuria (following intravenous use).

 

Urogenital: Impotence.

 

Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.

Overdosage

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

 

In the event of overdosage, symptomatic and supportive measures should be employed. Correct dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures. If required, give oxygen or artificial respiration for respiratory impairment.

 

The degree to which chlorothiazide sodium is removed by hemodialysis has not been established.

 

The intravenous LD50 of chlorothiazide in the mouse is 1.1 g/kg.

Chlorothiazide Injection Dosage and Administration

Chlorothiazide sodium for injection should be reserved for patients unable to take oral medication or for emergency situations.

 

Therapy should be individualized according to patient response. Use the smallest dosage necessary to achieve the required response.

 

Intravenous use in infants and children has been limited and is not generally recommended.

 

When medication can be taken orally, therapy with chlorothiazide tablets or oral suspension may be substituted for intravenous therapy, using the same dosage schedule as for the parenteral route.

 

Chlorothiazide sodium for injection may be given slowly by direct intravenous injection or by intravenous infusion.

 

Extravasation must be rigidly avoided. Do not give subcutaneously or intramuscularly.

 

The usual adult dosage is 500 mg to 1 g once or twice a day. Many patients with edema respond to intermittent therapy, i.e., administration on alternate days or on three to five days each week. With an intermittent schedule, excessive response and the resulting undesirable electrolyte imbalance are less likely to occur.

Directions for Reconstitution

Use aseptic technique. Because chlorothiazide sodium for injection contains no preservative, a fresh solution should be prepared immediately prior to each administration, and the unused portion should be discarded.

 

Add 18 mL of Sterile Water for Injection to the vial to form an isotonic solution for intravenous injection. Never add less than 18 mL. When reconstituted with 18 mL of Sterile Water, the final concentration of intravenous chlorothiazide sodium is 28 mg/mL. The reconstituted solution is clear and essentially free from visible particles. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use whenever solution and container permit. The solution is compatible with dextrose or sodium chloride solutions for intravenous infusion. Avoid simultaneous administration of solutions of chlorothiazide with whole blood or its derivatives.

How is Chlorothiazide Injection Supplied

Chlorothiazide sodium for injection, USP is a dry, sterile lyophilized white to off white powder usually in cake form, supplied in vials containing chlorothiazide sodium equivalent to 500 mg of chlorothiazide USP.

 

NDC 47335-330-40

 

Storage

 

Store lyophilized powder at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].

 

For single dose only. Use solution immediately after reconstitution. (See DOSAGE AND ADMINISTRATION, Directions for Reconstitution.) Discard unused portion of the reconstituted solution.

Distributed by:

Caraco Pharmaceutical Laboratories, Ltd.

1150 Elijah McCoy Drive, Detroit, MI 48202

 

Manufactured by:

Sun Pharmaceutical Ind. Ltd.

Halol-Baroda Highway,

Halol-389 350, Gujarat, India.

 

ISS. 07/2011

PJPI0259

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - CARTON

NDC 47335-330-40

Chlorothiazide Sodium for Injection, USP

500 mg/vial

STERILE

LYOPHILIZED

FOR THE PREPARATION OF INTRAVENOUS SOLUTIONS

Rx only

One Single Dose Vial

SUN PHARMACEUTICAL INDUSTRIES LTD.

CHLOROTHIAZIDE SODIUM  chlorothiazide sodium  injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 47335-330 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CHLOROTHIAZIDE SODIUM (CHLOROTHIAZIDE) CHLOROTHIAZIDE 500 mg  in 18 mL

Inactive Ingredients Ingredient Name Strength MANNITOL 250 mg  in 18 mL SODIUM HYDROXIDE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 47335-330-40 1 VIAL In 1 CARTON contains a VIAL, SINGLE-DOSE 1 18 mL In 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (47335-330-40)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA091546	08/05/2011

Labeler - Sun Pharma Global FZE (864347344)

Establishment
Name	Address	ID/FEI	Operations
Sun Pharmaceutical Industries Limited		725959238	MANUFACTURE, ANALYSIS

Revised: 08/2011Sun Pharma Global FZE

More Chlorothiazide Injection resources

• Chlorothiazide Injection Side Effects (in more detail)
• Chlorothiazide Injection Use in Pregnancy & Breastfeeding
• Drug Images
• Chlorothiazide Injection Drug Interactions
• Chlorothiazide Injection Support Group
• 1 Review for Chlorothiazide Injection - Add your own review/rating

Compare Chlorothiazide Injection with other medications

• Edema
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Aluvea

urea

Dosage Form: cream
Aluvea

(39% Urea Cream)

RX ONLY

Aluvea Description

Aluvea™ (urea) cream, 39% is a keratolytic emollient, which is a gentle, yet effective, tissue softener for skin.

Each gram of Aluvea Cream contains 39% Urea as the active ingredient, and the following inactive ingredients: dimethyl isosorbide, emulsifying wax NF, glycerin 99.7% USP, isopropyl myristate, purified water, sorbitol 70% Solution USP, tridecyl stearate and neopentyl glycol dicaprylate/dicaprate and tridecyl trimellitate.

CHEMICAL STRUCTURE

Urea is diamide of Carbonic acid with the following structure:

Aluvea - Clinical Pharmacology

Urea gently dissolves the intracellular matrix which results in loosening of the horny layer of the skin and shedding of scaly skin at regular intervals, thereby softening hyperkeratotic areas of the skin.

PHARMACOKINETICS

The exact mechanism of action of topically applied urea is not known.

INDICATION AND USAGE

Urea is useful for the treatment of hyperkeratotic conditions such as dry, rough skin, xerosis, ichthyosis, skin cracks and fissures, dermatitis, eczema, psoriasis, keratoses and calluses.

Contraindications

Known hypersensitivity to any of the listed ingredients

Warnings

For external use only. Avoid contact with eyes, lips or mucous membranes.

Precautions

Urea should be used as directed by a physician and should not be used to treat conditions other than those for which it was prescribed. If redness or irritation occurs, discontinue use.

Pregnancy

Category C

Animal reproduction studies have not been conducted with Aluvea. It is also not known whether Aluvea can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Aluvea should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether Aluvea is excreted in human milk, therefore caution should be exercised when administering to a nursing mother.

Adverse Reactions

Transient stinging, burning, itching or irritation is possible and normally resolves upon discontinuing the medication.

DOSAGE AND ADMINISTRATIONS

Apply Aluvea to affected skin twice per day, or as directed by your physician. Rub in until completely absorbed.

KEEP THIS AND ALL OTHER MEDICATIONS OUT OF REACH OF CHILDREN

How is Aluvea Supplied

Aluvea is supplied in an 8oz. bottle.

NDC 0259-1139-80

Store at room temperature 15°C -30°C (59°F-86°F).

Protect from freezing.

Manufactured for:

Merz Pharmaceuticals, LLC

Greensboro, NC 27410

5011457 12/10

PRINCIPAL DISPLAY PANEL - 227g Carton

NDC 0259-1139-80

Aluvea™

39% Urea Cream

WITH UNIQUE

CSP ™

VEHICLE

TECHNOLOGY

FOR EXTERNAL USE ONLY

8 oz. (227g)

Rx ONLY

Aluvea  urea  cream

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0259-1139 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Urea (Urea) Urea 39 g  in 100 g

Inactive Ingredients Ingredient Name Strength Dimethyl isosorbide   Glycerin   Isopropyl Myristate   Sorbitol   Tridecyl Stearate   Neopentyl Glycol Dicaprate   Tridecyl Trimellitate

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0259-1139-80 1 BOTTLE In 1 CARTON contains a BOTTLE 1 227 g In 1 BOTTLE This package is contained within the CARTON (0259-1139-80)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
UNAPPROVED DRUG OTHER		04/15/2011

Labeler - Merz Pharmaceuticals, LLC (126209282)

Establishment
Name	Address	ID/FEI	Operations
Crown Laboratories, Inc.		079035945	MANUFACTURE

Revised: 04/2011Merz Pharmaceuticals, LLC

More Aluvea resources

• Aluvea Side Effects (in more detail)
• Aluvea Use in Pregnancy & Breastfeeding
• Aluvea Support Group
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