Clinoril

sulindac

Dosage Form: tablet
Clinoril®

TABLETS

(SULINDAC)

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.)


• Clinoril is 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.)

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.

Clinoril1 (Sulindac) is available in 200 mg tablets for oral administration. Each tablet contains the following inactive ingredients: cellulose, magnesium stearate, 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:

1

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COPYRIGHT © 1988, 2005 MERCK & CO., Inc.

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CLINICAL PHARMACOLOGY

Pharmacodynamics

Clinoril 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.

Pharmacokinetics

Absorption

The extent of sulindac absorption from Clinoril Tablets is similar as compared to sulindac solution.

There is no information regarding food affect 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)      (200 mg tablet)      3.38 ± 2.30 S 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	Age 65-87 (n=12) 400 mg qd       2.54± 1.52 S 5.75 ± 2.81 SF 6.83 ± 4.19 SP
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 (T1/2) is 7.8 and 16.4 hours, respectively, for sulindac and its active sulfide metabolite.

Because Clinoril 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, 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 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 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, 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 Clinoril 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 it 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 Clinoril is 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 Clinoril was evaluated in the following five conditions:

1. Osteoarthritis

In patients with osteoarthritis of the hip and knee, the anti-inflammatory and analgesic activity of Clinoril 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, Clinoril 200 to 400 mg daily was shown to be comparable in effectiveness to aspirin 2400 to 4800 mg daily. Clinoril was 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 Clinoril 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, Clinoril 300 to 400 mg daily was shown to be comparable in effectiveness to aspirin 3600 to 4800 mg daily. Clinoril was 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, Clinoril may be used in combination with gold salts at usual dosage levels. In clinical studies, Clinoril 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 Clinoril 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, Clinoril 200 to 400 mg daily was as effective as indomethacin 75 to 150 mg daily. In a second study, Clinoril 300 to 400 mg daily was comparable in effectiveness to phenylbutazone 400 to 600 mg daily. Clinoril was 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 Clinoril 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, Clinoril 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 Clinoril 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, Clinoril 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

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

Clinoril is indicated for acute or long-term use in the relief of signs and symptoms of the following:

1. Osteoarthritis


2. Rheumatoid arthritis2


3. Ankylosing spondylitis


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


5. Acute gouty arthritis

2

The safety and effectiveness of Clinoril 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

Clinoril is contraindicated in patients with known hypersensitivity to sulindac or the excipients (see DESCRIPTION).

Clinoril 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 is 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 Clinoril, 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, 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 should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including Clinoril, 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 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 Clinoril. 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. 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 should be discontinued.

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

Pregnancy

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

PRECAUTIONS

General

Clinoril cannot be expected to substitute for corticosteroids or to treate 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 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. 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, 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 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 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 should be used with caution in patients with a history of renal lithiasis, and they should be kept well hydrated while receiving Clinoril.

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 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. Clinoril, 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. Clinoril, 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. Clinoril, 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, Clinoril 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 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, monitor renal function periodically in patients receiving ACEIs or AIIAs and NSAIDs in combination therapy.

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 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; 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, 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 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 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 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 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 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.

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 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 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 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, 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

Diazepam 2mg / 5ml Syrup (Sandoz Limited)

1. Name Of The Medicinal Product

Diazepam Syrup 2mg/5ml.

2. Qualitative And Quantitative Composition

Each 5ml of syrup contains diazepam BP 2mg.

3. Pharmaceutical Form

Syrup.

4. Clinical Particulars

4.1 Therapeutic Indications

Diazepam has anti-convulsant, anxiolytic, sedative, muscle relaxant and amnesic properties.

It is indicated:

Adults:

i)	For the short-term relief (2 to 4 weeks only) of anxiety that is severe, disabling or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness;
ii)	As a sedative and premedicant;
iii)	As an anti-convulsant in the management of status epilepticus, febrile convulsions and poisoning;
iv)	In the control of muscle spasms as in tetanus;
v)	In the management of alcohol withdrawal symptoms; and
vi)	In selected cases it may be useful in the management of cerebral spasticity.

Children:

i)	Night terrors and somnambulism;
ii)	Premedication;
iii)	In the control of muscle spasms as in tetanus; and
iv)	In selected cases, it may be useful in controlling tension and irritability in cerebral spasticity.

The use of diazepam to treat short-term anxiety is inappropriate and unsuitable. Diazepam should be used to treat insomnia only when it is severe, disabling or subjecting the individual to extreme stress.

4.2 Posology And Method Of Administration

Adults:

Anxiety states: 2 mg, 3 times daily up to 30 mg daily in divided doses.

Insomnia associated with anxiety: 5 mg to 15 mg before retiring.

Muscle spasms: 2 mg to 15 mg daily in divided doses up to 60 mg in severe spastic disorders such as cerebral spasticity, epilepsy and muscle spasms associated with upper-motor neurone disease.

In the control of muscle spasms as in tetanus: 3 mg to 10 mg/kg body weight daily.

Alcohol withdrawal symptoms: 5 mg to 20 mg repeated within 2 to 4 hours if necessary.

Premedication in dental patients: 5 mg the night before, 5 mg on waking and another 5 mg 2 hours before the appointment.

Elderly or debilitated patients:

The dosage should be half that recommended in adults.

Children:

Night terrors and somnambulism: 1 mg to 5 mg daily before retiring.

Premedication: 2 mg to 10mg.

Management of cerebral spasticity: 2 mg to 40 mg daily in divided doses.

In the control of muscle spasms as in tetanus: 3 mg to 10mg/kg body weight daily.

Doses should be repeated only on medical advice. Long-term chronic use is not recommended and treatment should always be tapered off gradually. When a benzodiazepine is used as hypnotic, treatment should, if possible, be intermittent.

Method of administration: Oral.

4.3 Contraindications

Patients with a known sensitivity to benzodiazepines; acute pulmonary insufficiency; respiratory depression.

4.4 Special Warnings And Precautions For Use

The lowest dose that can control the symptoms should be used and treatment should not be continued beyond 4 weeks. The risk of dependence increases when high dosages are attained, especially when given over long periods. This is particularly so in patients with a history of alcoholism, drug abuse or in patients with marked personality disorders.

Treatment should always be tapered off gradually. Sudden cessation of treatment can result in symptoms such as depression, nervousness, rebound insomnia, irritability, sweating and diarrhoea even in patients receiving normal therapeutic doses for short periods of time. Abrupt withdrawal following high dosage may produce confusion, toxic psychosis, convulsions or a condition resembling delirium tremens.

Diazepam should not be used to treat chronic psychoses or phobic or obsessional states. Because diazepam-induced disinhibition may precipitate suicidal or aggressive behaviour, it should not be used alone to treat depression or anxiety related depression. Caution must be exercised when treating patients with personality disorders.

Elderly or debilitated patients may be more prone to adverse effects and care must be taken in patients with impaired liver or kidney function. Care is also required in patients with organic brain disease (particularly arteriosclerosis).

Diazepam should be avoided in cases of loss or bereavement as psychological adjustment may be inhibited by benzodiazepines.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Sedation, or respiratory or cardiovascular depression may be enhanced if diazepam is combined with centrally acting drugs such as anaesthetics, analgesics, antidepressants, hypnotics, neuroleptics and tranquillisers.

Concomitant intake with alcohol is not recommended since the sedative effect is increased.

Diazepam is primarily metabolised by hepatic microsomal oxidation and drugs which affect liver enzymes, such as cimetidine and phenobarbitone, may alter its pharmacokinetics.

Diazepam has been reported to be displaced from protein-binding sites by sodium valproate.

4.6 Pregnancy And Lactation

If the product is prescribed to a woman of child bearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspects that she is pregnant.

If, for compelling reasons, the product is administered during the late phase of pregnancy, or during labour at high doses, effects on the neonate, such as hypothermia, hypotonia and moderate respiratory depression, can be expected, due to the pharmacological action of the compound.

Moreover, infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.

Since benzodiazepines are found in the breast milk, benzodiazepines should not be given to breast feeding mothers.

4.7 Effects On Ability To Drive And Use Machines

The side-effects of diazepam, such as sedation and impaired muscle function, may adversely affect the ability to drive or use machines. Insufficient sleep may also increase the likelihood of impaired alertness.

4.8 Undesirable Effects

Diazepam may cause drowsiness, sedation, blurring of vision, unsteadiness and ataxia. These may occur after a single as well as repeated doses and persist to the following day.

Less common effects include vertigo, headache, confusion, slurred speech, visual disturbance, tremor, changes in libido, skin rashes and gastro-intestinal upset. Jaundice or blood dyscrasias have been reported rarely. High doses may be associated with respiratory depression or hypotension.

Abnormal psychological reactions to benzodiazepines have been reported. Rare behavioural adverse effects include paradoxical aggressive outbursts, excitement, confusion and the uncovering of depression with suicidal tendencies.

4.9 Overdose

Symptoms

Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Coma, hypotension and respiratory depression occasionally occur but are seldom serious if these drugs are taken alone. Coma usually lasts only a few hours but in elderly people it may be more protracted and cyclical. Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic respiratory disease.

Benzodiazepines potentiate the effects of other central nervous system depressants, including alcohol.

Management

Consider activated charcoal in adults or children who have taken more than 1 mg/kg within 1 hour, provided they are not too drowsy. Gastric lavage is unnecessary if these drugs have been taken alone. Patients who are asymptomatic at four hours are unlikely to develop symptoms. Institute supportive measures as indicated by the patient's clinical state.

If CNS depression is severe consider the use of flumazenil (Anexate), a benzodiazepine antagonist. This should rarely be required. It has a short half-life (about an hour) and should NOT TO BE USED IN MIXED OVERDOSE OR AS A "DIAGNOSTIC" TEST. It is contraindicated in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Diazepam has potent anxiolytic anti-convulsant and central muscle relaxant properties, these effects are probably mediated through special areas of the central nervous system. Diazepam has little autonomic activity.

5.2 Pharmacokinetic Properties

The following results were obtained with 10mg of Lagap Diazepam Syrup 2 mg/5 ml in healthy volunteers:

Cmax. (mean ± SD)	250 + 60 ng/ml.
Tmax. (mean)	1 hour.

5.3 Preclinical Safety Data

There are no preclinical safety data of relevance to the prescriber.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Glycerin, Sucrose, microcrystalline cellulose, methyl-p-hydroxybenzoate, propyl-p-hdroxybenzoate, alcohol (96%), sodium carboxymethylcellulose, flavouring agent(framboise 50969A), ponceau 4R (E124), potassium sorbate and purified water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Store below 25^oC. Protect from light.

6.5 Nature And Contents Of Container

Amber glass bottles with screw caps with plastic inserts. Pack sizes: 50 ml, 100 ml,

150 ml, 250 ml, 300 ml and 500 ml.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Sandoz Ltd

Woolmer Way

Bordon

Hampshire

GU35 9QE

8. Marketing Authorisation Number(S)

PL 04416/0026

9. Date Of First Authorisation/Renewal Of The Authorisation

13/03/2009

10. Date Of Revision Of The Text

13/03/2009

Pseudox M Syrup

Pronunciation: KAR-bin-OX-a-meen/METH-skoe-POL-a-meen/SOO-doe-e-FED-rin
Generic Name: Carbinoxamine/Methscopolamine/Pseudoephedrine
Brand Name: Examples include Pannaz S and Pseudox M

Pseudox M Syrup is used for:

Relieving congestion, sneezing, runny nose, and itchy, watery eyes due to colds, flu, or hay fever. It may also be used for other conditions as determined by your doctor.

Pseudox M Syrup is an antihistamine, decongestant, and anticholinergic combination. It works by blocking histamine, a substance in the body that causes sneezing, runny nose, and watery eyes. It also relieves nasal congestion by shrinking the nasal mucous membranes, which promotes nasal drainage, and dries the chest by decreasing lung secretions.

Do NOT use Pseudox M Syrup if:

• you are allergic to any ingredient in Pseudox M Syrup


• you are pregnant or breast-feeding


• you take sodium oxybate (GHB) or you have taken furazolidone or a monoamine oxidase inhibitor (MAOI) (eg, phenelzine) within the last 14 days


• you have severe heart blood vessel disease; severe high blood pressure; narrow-angle glaucoma; severe bleeding; severe irritation of the esophagus or other serious problems with the esophagus (eg, esophageal achalasia); peptic ulcer; a blockage of your stomach, bowel, or bladder; bowel motility problems; severe bowel inflammation (eg, ulcerative colitis); certain muscle problems (eg, myasthenia gravis); or uncontrolled bleeding


• you are unable to urinate or are having an asthma attack

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

Before using Pseudox M Syrup:

Some medical conditions may interact with Pseudox M Syrup. 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 a history of diabetes, an enlarged prostate or other prostate problems, bladder or kidney problems, severe bowel problems, trouble urinating, high blood pressure, diarrhea, asthma, nerve problems, heart problems, blood vessel problems, blood clots, a hiatal hernia, an adrenal gland tumor, glaucoma, breathing problems during sleep, seizures, stroke, myasthenia gravis (muscle weakness), or an overactive thyroid

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

• Alpha-blockers (eg, guanethidine, methyldopa, prazosin), beta-blockers (eg, atenolol), diuretics (eg, furosemide, hydrochlorothiazide), furazolidone, or MAOIs (eg, phenelzine) because the risk of high or low blood pressure may be increased


• Alkalizers (eg, calcium or magnesium antacids), anticholinergics (eg, atropine, benztropine, dicyclomine), carbonic anhydrase inhibitors (eg, acetazolamide), ergotamine, sodium bicarbonate, or tricyclic antidepressants (eg, amitriptyline) because they may increase the risk of Pseudox M Syrup's side effects


• Bromocriptine, catechol-O-methyltransferase (COMT) inhibitors (eg, entacapone), certain stimulants (eg, doxapram, pseudoephedrine), cocaine, digoxin, droxidopa, potassium chloride, or sodium oxybate (GHB) because the risk of their side effects may be increased by Pseudox M Syrup


• Guanadrel, guanethidine, mecamylamine, methyldopa, or reserpine because their effectiveness may be decreased by Pseudox M Syrup

This may not be a complete list of all interactions that may occur. Ask your health care provider if Pseudox M Syrup 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 Pseudox M Syrup:

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

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


• Do not take Pseudox M Syrup at the same time as an antacid, certain medicines for diarrhea (eg, attapulgite, bismuth, kaolin, pectin), or ketoconazole. Take these medicines 2 or 3 hours before or after you take Pseudox M Syrup.


• Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose.


• If you miss a dose of Pseudox M Syrup and you are taking it regularly, 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 Pseudox M Syrup.

Important safety information:

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


• If your symptoms do not get better within 7 days or if they get worse or you develop a high fever or persistent headache, check with your doctor.


• Pseudox M Syrup may cause dry mouth. To relieve dry mouth, suck on sugarless hard candy or ice chips, chew sugarless gum, drink water, or use a saliva substitute.


• Pseudox M Syrup may make your eyes more sensitive to sunlight. It may help to wear sunglasses.


• Pseudox M Syrup may reduce sweating. Do not become overheated in hot weather or while you are being active; heatstroke may occur.


• Do not take diet or appetite control medicines while you are taking Pseudox M Syrup without checking with your doctor.


• Pseudox M Syrup has pseudoephedrine in it. Before you start any new medicine, check the label to see if it has pseudoephedrine in it too. If it does or if you are not sure, check with your doctor or pharmacist.


• Pseudox M Syrup may interfere with skin allergy tests. If you are scheduled for a skin test, talk to your doctor. You may need to stop taking Pseudox M Syrup for a few days before the tests.


• If you have trouble sleeping, ask your doctor or pharmacist about the best time of the day to take Pseudox M Syrup.


• Pseudox M Syrup may interfere with certain lab tests. Be sure your doctor and lab personnel know that you are taking Pseudox M Syrup.


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


• Diabetes patients - Pseudox M Syrup may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


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


• Caution is advised when using Pseudox M Syrup in CHILDREN; they may be more sensitive to its effects.


• PREGNANCY and BREAST-FEEDING: It is not known if Pseudox M Syrup can cause harm to the fetus. If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Pseudox M Syrup while you are pregnant. Pseudox M Syrup is found in breast milk. Do not breast-feed while taking Pseudox M Syrup.

Possible side effects of Pseudox M Syrup:

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:

Constipation; diarrhea; dizziness; drowsiness; dry mouth, nose, or throat; excitability; headache; loss of appetite; nausea; nervousness or anxiety; trouble sleeping; upset stomach; vomiting; weakness.

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); difficulty urinating or inability to urinate; fast or irregular heartbeat; hallucinations; mental or mood changes; seizures; severe dizziness, lightheadedness, or headache; tremor; vision 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: Pseudox M 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 deep sleep or loss of consciousness; hot or cool skin; irregular heartbeat; irritability, anxiety, or panic; large pupils; numbness or tingling in the arms or legs; seizures; slowed or shallow breathing.

Proper storage of Pseudox M Syrup:

Store Pseudox M Syrup between 59 and 86 degrees F (15 and 30 degrees C) in a tightly closed container. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Pseudox M Syrup out of the reach of children and away from pets.

General information:

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


• Pseudox M Syrup 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 Pseudox M Syrup. 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 Pseudox M resources

• Pseudox M Side Effects (in more detail)
• Pseudox M Use in Pregnancy & Breastfeeding
• Pseudox M Drug Interactions
• Pseudox M Support Group
• 0 Reviews for Pseudox M - Add your own review/rating

Compare Pseudox M with other medications

• Rhinitis

Exelon Transdermal

Generic Name: rivastigmine (Transdermal route)

riv-a-STIG-meen

Commonly used brand name(s)

In the U.S.

• Exelon

Available Dosage Forms:

• Patch, Extended Release

Therapeutic Class: Central Nervous System Agent

Pharmacologic Class: Cholinesterase Inhibitor, Centrally Acting

Uses For Exelon

Rivastigmine is used to treat mild to moderate dementia (memory loss) associated with Alzheimer's disease or Parkinson's disease. Rivastigmine will not cure these diseases and it will not stop these diseases from getting worse. However, rivastigmine can improve thinking ability in some patients with these diseases.

In Alzheimer's disease, many chemical changes take place in the brain. One of the earliest and biggest changes is that there is a decrease in a chemical called acetylcholine (ACh). ACh helps the brain to work properly. Rivastigmine is an acetylcholinesterase inhibitor. It slows the breakdown of ACh, so it can build up and have a greater effect. However, as Alzheimer's disease gets worse, there will be less and less ACh, so rivastigmine may not work as well.

This medicine is available only with your doctor's prescription.

Before Using Exelon

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of rivastigmine in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of rivastigmine in the elderly.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Metoclopramide

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Oxybutynin


• Tolterodine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Asthma, history of or


• Chronic obstructive pulmonary disease (COPD), history of or


• Heart block or


• Seizures or tremors or


• Sick-sinus syndrome (heart rhythm problem) or


• Stomach or bowel ulcers or


• Urinary tract blockage or difficult urination—Use with caution. This medicine may worsen these conditions.

• Low body weight (below 50 kilograms)—Use with caution. The side effects of this medicine may be increased in this condition.

Proper Use of Exelon

This medicine comes with patient instructions. Read and follow these instructions carefully. Ask your doctor or pharmacist if you have any questions.

To use the skin patch:

• Apply the patch right away after removing it from the protective pouch. Do not cut it into smaller pieces and do not touch the sticky surface of the patch.


• Apply the patch to a clean, dry, and hairless skin area on your upper or lower back, upper arm, or chest. Do not put the patch over rashes, cuts, or irritated skin. Avoid putting the patch on areas where it could be rubbed off by tight clothing.


• Press the patch firmly in place with the palm of your hand to make sure that the edges of the patch stick well.


• The patch should stay in place, even when you are showering, bathing, or swimming. Apply a new patch if it falls off.


• After 24 hours, remove the patch. Choose a different place on your skin to apply the new patch. Do not put a new patch in the same place for at least 14 days. Do not leave the patch on for more than 24 hours. It will not work as well after that time and it may irritate your skin.


• After removing a used patch, fold the patch in half with the sticky sides together. Place the folded, used patch in its protective pouch. Make sure to dispose of it out of the reach of children and pets.


• Try to change the patch at the same time each day. If you forget to change the patch at the usual time, remove the patch you are wearing and put on a new patch. After that, apply a fresh patch at the usual time on the next day.


• Do not put cream, lotion, ointment, oil, or powder on the skin area where the patch will be placed.


• Do not touch your eyes after you touch the patch.


• Do not expose the patch to direct sources of heat, such as heating pads, electric blankets, heat lamps, saunas, hot tubs, heated water beds, or direct sunlight for long periods of time.


• Make sure you wash your hands with soap and water before and after applying the patch.

Do not stop using this medicine without asking your doctor. If you have not used your medicine for several days in a row, do not start using it again without talking to your doctor first. You may need to start the medicine again using a lower dose.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For transdermal dosage form (patch):
  
  • For dementia associated with Alzheimer's disease or Parkinson's disease:
    
    • Adults—At first, one 4.6 milligram (mg) patch once a day. After at least 4 weeks, your doctor will increase your dose to one 9.5 mg patch once a day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you forget to wear or change a patch, put one on as soon as you can. If it is almost time to put on your next patch, wait until then to apply a new patch and skip the one you missed. Do not apply extra patches to make up for a missed dose.

Storage

Store the patches at room temperature in a closed container, away from heat, moisture, and direct light.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Exelon

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and to check for unwanted effects.

Having more than one patch on your body at the same time can cause you to get too much of this medicine. Make sure you remove the used patch before wearing a new one to decrease your risk of having serious side effects. If you accidentally use more than one patch at a time, call your doctor right away.

This medicine may cause nausea, severe vomiting, loss of appetite, diarrhea, and weight loss. Talk with your doctor before using this medicine if you have any concerns.

Before you have any kind of surgery or dental treatment, tell the medical doctor or dentist in charge that you are taking this medicine. Using rivastigmine together with medicines that are sometimes used during surgery or dental treatments may increase the effects of these medicines.

This medicine may cause some people to become dizzy, drowsy, or less alert than they are normally. If any of these side effects occur, do not drive, use machines, or do anything else that could be dangerous if you are dizzy or are not alert.

Exelon Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Bladder pain


• bloody or cloudy urine


• difficult, burning, or painful urination


• frequent urge to urinate


• lower back or side pain

Rare

• Abdominal or stomach pain or tenderness


• arm, back, or jaw pain


• chest pain or discomfort


• chest tightness or heaviness


• confusion


• convulsion


• decreased urine


• difficult or troubled breathing


• dilated neck veins


• extreme fatigue


• false beliefs that cannot be changed by facts


• fast, slow, or irregular heartbeat


• irregular breathing


• loss of consciousness


• rapid breathing


• seizures


• severe nausea or vomiting


• shortness of breath


• sunken eyes


• swelling of face, fingers, feet, or lower legs


• wheezing


• wrinkled skin

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Blurred vision


• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position


• increasing muscle weakness


• irregular, fast or slow, or shallow breathing


• pale or blue lips, fingernails, or skin


• slow or irregular heartbeat


• sweating


• watering of mouth


• unusual tiredness or weakness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Diarrhea


• discouragement


• fear or nervousness


• feeling of constant movement of self or surroundings


• feeling sad or empty


• headache


• irritability


• lack of appetite


• lack or loss of strength


• loss of interest or pleasure


• nausea


• sensation of spinning


• sleeplessness


• stomach pain


• tiredness


• trouble concentrating


• trouble sleeping


• unable to sleep


• upper stomach pain


• vomiting


• weight loss

Rare

• Blindness


• blurred vision


• burning, stinging, or pain at application site


• continuing ringing or buzzing or other unexplained noise in the ears


• decreased vision


• difficulty in moving


• eye pain


• headache


• hearing loss


• itchy skin


• muscle pain or stiffness


• pain in joints


• pale skin


• tearing


• troubled breathing with exertion


• unusual bleeding or bruising

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Exelon Transdermal side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Exelon Transdermal resources

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

Compare Exelon Transdermal with other medications

• Alzheimer's Disease
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Levall

Generic Name: carbetapentane, guaifenesin, and phenylephrine (kar BET a PEN tane, gwye FEN e sin, and FEN il EFF rin)

Brand Names: Carbetaplex, MonteCough

What is Levall (carbetapentane, guaifenesin, and phenylephrine)?

Carbetapentane is a cough suppressant. It affects the signals in the brain that trigger cough reflex.

Guaifenesin is an expectorant. It helps loosen congestion in your chest and throat, making it easier to cough out through your mouth.

Phenylephrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of carbetapentane, guaifenesin, and phenylephrine is used to treat stuffy nose, sinus congestion, cough, and chest congestion caused by sinusitus, bronchitis, or the common cold or flu.

Carbetapentane, guaifenesin, and phenylephrine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Levall (carbetapentane, guaifenesin, and phenylephrine)?

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. You should not use this medication if you have severe high blood pressure, severe colitis or toxic megacolon, or if you are unable to urinate. Do not use cough and cold medicine if you have untreated or uncontrolled diseases such as high blood pressure, heart disease, coronary artery disease, or overactive thyroid. Do not use a cough or cold medicine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

What should I discuss with my healthcare provider before taking Levall (carbetapentane, guaifenesin, and phenylephrine)?

Do not use a cough or cold medicine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects. You should not use this medication if you have severe constipation, severe colitis or toxic megacolon, or if you are unable to urinate. Do not use cough and cold medicine if you have untreated or uncontrolled diseases such as glaucoma, asthma or COPD, high blood pressure, heart disease, coronary artery disease, or overactive thyroid.

Ask a doctor or pharmacist if it is safe for you to take this medication if you have ever had:

• 
  

  glaucoma;

  
  


• 
  

  asthma or COPD;

  
  


• 
  

  diabetes;

  
  


• 
  

  epilepsy or other seizure disorder;

  
  


• 
  

  cough with mucus, or cough caused by emphysema or chronic bronchitis;

  
  


• 
  

  enlarged prostate or urination problems;

  
  


• 
  

  an adrenal gland tumor or disorder (such as pheochromocytoma or Addison's disease); or

  
  


• 
  

  if you take potassium (Cytra, Epiklor, K-Lyte, K-Phos, Kaon, Klor-Con, Polycitra, Urocit-K).

  
  

FDA pregnancy category C. It is not known whether carbetapentane, guaifenesin, and phenylephrine will harm an unborn baby. Do not use cold or cough medicine without medical advice if you are pregnant. This medicine may pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using carbetapentane, guaifenesin, and phenylephrine.

Artificially sweetened liquid cough or cold medicine may contain phenylalanine. If you have phenylketonuria (PKU), check the medication label to see if the product contains phenylalanine.

How should I take Levall (carbetapentane, guaifenesin, and phenylephrine)?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Cough or cold medicine is usually taken only for a short time until your symptoms clear up.

Do not take for longer than 7 days in a row. Talk with your doctor if your symptoms do not improve after 7 days of treatment, or if you have a fever with a headache or skin rash.

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children.

Measure liquid medicine with a special dose measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose measuring device, ask your pharmacist for one.

Drink extra fluids to help loosen the congestion and lubricate your throat while you are taking this medication.

If you need surgery or medical tests, tell the surgeon or doctor ahead of time if you have taken a cough or cold medicine within the past few days. Store at room temperature away from moisture, heat, and light. Do not freeze.

What happens if I miss a dose?

Since cough or cold medicine is taken when needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include extreme dizziness or restless feeling, severe stomach pain, vomiting, diarrhea, loss of appetite, rapid heart rate, flushing (warmth, redness, or tingly feeling).

What should I avoid while taking Levall (carbetapentane, guaifenesin, and phenylephrine)?

This medicine may cause blurred vision or impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly. Drinking alcohol can increase certain side effects of carbetapentane, guaifenesin, and phenylephrine. Avoid becoming overheated or dehydrated during exercise and in hot weather. Carbetapentane, guaifenesin, and phenylephrine can decrease sweating and you may be more prone to heat stroke. Ask a doctor or pharmacist before using any other cold, allergy, cough, or sleep medicine. Antihistamines, decongestants, and cough suppressants are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine, decongestant, or cough suppressant.

Avoid taking this medication if you also take diet pills, caffeine pills, or other stimulants (such as ADHD medications). Taking a stimulant together with a decongestant can increase your risk of unpleasant side effects.

Levall (carbetapentane, guaifenesin, and phenylephrine) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Stop using carbetapentane, guaifenesin, and phenylephrine and call your doctor at once if you have a serious side effect such as:

• 
  

  fast or pounding heartbeats;

  
  


• 
  

  confusion, hallucinations, unusual thoughts or behavior;

  
  


• 
  

  severe dizziness, anxiety, restless feeling, or nervousness;

  
  


• 
  

  urinating less than usual or not at all;

  
  


• 
  

  easy bruising or bleeding, unusual weakness, fever, chills, body aches, flu symptoms; or

  
  


• 
  

  dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, chest pain, shortness of breath, uneven heartbeats, seizure).

  
  

Less serious side effects may include:

• 
  

  dizziness, drowsiness, headache, weakness;

  
  


• 
  

  dry mouth, nose, or throat, increased sweating or urination;

  
  


• 
  

  nausea, mild stomach pain;

  
  


• 
  

  sleep problems (insomnia); or

  
  


• 
  

  feeling restless or excited (especially in children).

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Levall (carbetapentane, guaifenesin, and phenylephrine)?

Ask a doctor or pharmacist before using this medicine if you regularly use other medicines that make you sleepy (such as narcotic pain medication, sedatives, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety). They can add to sleepiness caused by brompheniramine.

Ask a doctor or pharmacist if it is safe for you to take carbetapentane, guaifenesin, and phenylephrine if you are also using any of the following drugs:

• 
  

  an antidepressant such as amitriptyline (Elavil, Vanatrip, Limbitrol), doxepin (Sinequan, Silenor), nortriptyline (Pamelor), and others; or

  
  


• 
  

  heart or blood pressure medication such as atenolol (Tenormin, Tenoretic), carvedilol (Coreg), labetalol (Normodyne, Trandate), mecamylamine (Inversine), methyldopa (Aldomet), metoprolol (Dutoprol, Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal, InnoPran), reserpine, sotalol (Betapace), and others.

  
  

This list is not complete and other drugs may interact with carbetapentane, guaifenesin, and phenylephrine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Levall resources

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

• Levall Solution MedFacts Consumer Leaflet (Wolters Kluwer)


• Aquatab C MedFacts Consumer Leaflet (Wolters Kluwer)


• Carbatab-12 Sustained-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Levall with other medications

• Cough and Nasal Congestion

Where can I get more information?

• Your pharmacist can provide more information about carbetapentane, guaifenesin, and phenylephrine.

See also: Levall side effects (in more detail)