Go PLR Content Marketing Cocos (Keeling) Islands: August 2010

Saturday 28 August 2010

Barojectsol

Barojectsol may be available in the countries listed below.

Ingredient matches for Barojectsol

Barium Sulfate

Barium Sulfate is reported as an ingredient of Barojectsol in the following countries:

Japan

International Drug Name Search

Wednesday 18 August 2010

Amiodarone Sandoz

Amiodarone Sandoz may be available in the countries listed below.

Ingredient matches for Amiodarone Sandoz

Amiodarone

Amiodarone hydrochloride (a derivative of Amiodarone) is reported as an ingredient of Amiodarone Sandoz in the following countries:

Belgium

France

Italy

International Drug Name Search

Tamoxifène EG

Tamoxifène EG may be available in the countries listed below.

Ingredient matches for Tamoxifène EG

Tamoxifen

Tamoxifen citrate (a derivative of Tamoxifen) is reported as an ingredient of Tamoxifène EG in the following countries:

France

International Drug Name Search

Sunday 15 August 2010

Mahady

Mahady may be available in the countries listed below.

Ingredient matches for Mahady

Clobetasol

Clobetasol 17α-propionate (a derivative of Clobetasol) is reported as an ingredient of Mahady in the following countries:

Japan

International Drug Name Search

Friday 13 August 2010

Generic Name: Cabergoline
Class: Ergot-derivative Dopamine Receptor Agonists
VA Class: AU900
Chemical Name: 1-[(6-allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea
Molecular Formula: C₂₆H₃₇N₅O₂
CAS Number: 81409-90-7

Introduction

An ergot-derivative dopamine receptor agonist and prolactin inhibitor.¹ ² ³ ⁸ ¹⁰ ¹¹ ¹² ¹⁵

Uses for Dostinex

Hyperprolactinemic Disorders

Treatment of hyperprolactinemic disorders due to prolactinoma (prolactin-secreting adenomas) or idiopathic hyperprolactinemia.¹ ² ³ ¹² ¹³ ¹⁴ Suppresses prolactin secretion, restores gonadal function, and reduces the size of prolactinomas.¹ ² ³ ¹² ¹³ ¹⁴

At least as effective as bromocriptine in normalizing serum prolactin concentrations and restoring gonadal function in women with hyperprolactinemic amenorrhea.¹² ¹³ Fewer adverse effects, especially adverse GI effects, reported in cabergoline-treated women than in bromocriptine-treated women.¹² ¹³ ¹⁴ Bromocriptine preferred when restoration of fertility is the goal of therapy; this recommendation is based on the safety record of bromocriptine in pregnant women.¹⁴

Parkinsonian Syndrome

Has been used for the symptomatic management of parkinsonian syndrome†.⁴ ⁵ ⁶ ⁷ ⁸ ⁹ ¹⁰ ¹¹

Has been used as monotherapy for initial symptomatic management of parkinsonian syndrome†.⁸ ⁹ ¹¹ Most clinicians would use levodopa for initial therapy in individuals >70 years of age (less likely than younger individuals to develop levodopa-related motor complications and because of concerns about cognitive dysfunction), in patients with cognitive impairment, and in those with severe disease.⁷ A dopamine receptor agonist may be preferred for initial therapy in patients ≤70 years of age.⁷

Has been used as an adjunct to levodopa for the symptomatic management of parkinsonian syndrome† in patients with advanced disease.⁴ ⁵ ⁶ ⁸ ¹⁰

Dostinex Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.¹

Hyperprolactinemic disorders: Administer twice weekly.¹

Parkinsonian syndrome: Administer once daily.⁸

Dosage

Adults

Hyperprolactinemic Disorders

Oral

Initiate at low dosage and increase slowly (at ≥4 week intervals) until therapeutic response is achieved.¹

Initially, 0.25 mg twice weekly; increase in increments of 0.25 mg twice weekly up to 1 mg twice weekly.¹ Base dosage adjustments on serum prolactin concentrations; use lowest effective dosage.¹

Consider decreasing the dosage if normal serum prolactin concentrations maintained for 24 months and size of tumor decreased ≥50%; periodically monitor to determine whether retreatment is needed.¹⁴ ¹⁵ Some patients (e.g., those with microadenomas) may be able to discontinue the drug; discontinuance in those with macroadenomas should be undertaken with extreme caution.¹⁴ ¹⁵ The manufacturer states that efficacy >24 months not established.¹

Parkinsonian Syndrome†

Oral

Initiate at low dosage and increase slowly (at intervals of 7 or 14 days) until the maximum therapeutic response is achieved.⁸

2–6 mg daily has been used.⁸

Therapy has been initiated with 1 mg once daily, then increased in increments of 0.5–1 mg at 7 or 14 day intervals until control of symptoms obtained.⁸

When cabergoline is used as an adjunct to levodopa, the levodopa dosage may be decreased gradually as tolerated.⁸

When therapy with a dopamine receptor agonist is discontinued, the drug is discontinued gradually.¹⁸

Prescribing Limits

Adults

Hyperprolactinemic Disorders

Oral

Dosages >1 mg twice weekly have not been systematically evaluated.¹

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time; use with caution in patients with severe hepatic impairment.¹ (See Hepatic Impairment under Cautions and also see Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

No specific dosage recommendations at this time.¹ (See Elimination: Special Populations, under Pharmacokinetics.)

Geriatric Patients

Select dosage carefully; start at low dosage.¹ (See Geriatric Use under Cautions.)

Cautions for Dostinex

Contraindications

Known hypersensitivity to cabergoline or other ergot derivatives.¹

Uncontrolled hypertension.¹

Warnings/Precautions

Warnings

Hypertension during Pregnancy

Should not be used in patients with pregnancy-induced hypertension (e.g., preeclampsia, eclampsia) unless potential benefits outweigh possible risks.¹

Fibrotic Effects

Pleural effusion, pulmonary fibrosis, and cardiac valvulopathy reported.¹ ¹⁶ Signs and symptoms have improved after discontinuance.¹

Use with caution in patients with history of, or current signs and/or symptoms of, respiratory or cardiac disorders linked to fibrotic tissue.¹

General Precautions

When used for parkinsonian syndrome, observe the usual precautions associated with dopamine receptor agonist therapy in this patient population.⁸ ⁹ ¹⁷ ¹⁸ Usual dosage for parkinsonian syndrome exceeds dosage used for hyperprolactinemia.¹ ¹⁷

Symptomatic Hypotension

Orthostatic hypotension reported, especially if initial doses >1 mg are used.¹ Exercise care in patients currently receiving drugs known to lower BP.¹

Postpartum Breast Engorgement

Not indicated for the inhibition or suppression of lactation.¹ Hypertension, cerebrovascular accidents, and seizures reported rarely when another dopamine receptor agonist (i.e., bromocriptine) was used for this indication.¹

Specific Populations

Pregnancy

Category B.¹ (See Hypertension during Pregnancy under Cautions.)

Lactation

Not known whether cabergoline is distributed into milk; drug is expected to interfere with lactation.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established.¹

Geriatric Use

Insufficient experience from clinical studies to determine whether patients ≥65 years of age respond differently than younger adults.¹ Other clinical experience has not identified age-related differences in responses.¹

Select dosage carefully, generally initiating therapy at low dosage.¹ Consider the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or drug therapy in geriatric patients.¹ ² ³

Hepatic Impairment

Cabergoline extensively metabolized in liver; use with caution and monitor carefully.¹ (See Absorption: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Patients with hyperprolactinemia: Nausea, constipation, abdominal pain, headache, dizziness, asthenia, fatigue, somnolence.¹

Patients with parkinsonian syndrome†: Dyskinesia, hallucinations, confusion, peripheral edema.¹

Interactions for Dostinex

Specific Drugs

Drug	Interaction	Comments
Dopamine antagonists (e.g., phenothiazines, butyrophenones, thioxanthenes, metoclopramide)	Possible reduced efficacy of cabergoline¹	Generally should not be used concomitantly¹ ⁸
Levodopa	Additive therapeutic and/or adverse (e.g., dyskinesia) effects⁸	Consider a reduction in levodopa dosage when cabergoline is added to levodopa therapy⁸

Dostinex Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations usually attained within 1–2 hours.¹ ¹⁷

Absolute bioavailability unknown.¹ ¹⁷

Onset

Following oral administration of a single 0.6-mg dose of cabergoline, time to maximum prolactin-lowering effect was 48 hours.¹

Duration

Prolactin-lowering effect persists for 14 days.¹

Food

Food does not alter the pharmacokinetics of cabergoline.¹

Special Populations

Peak plasma concentrations and AUC not altered in patients with mild to moderate hepatic impairment (Child Pugh score ≤10).¹ Peak plasma concentrations and AUC substantially increased in patients with severe impairment (Child Pugh score >10).¹

Distribution

Extent

Extensively distributed throughout the body, including the CNS.¹ ⁸

Plasma Protein Binding

40–42%.¹ ¹⁷

Elimination

Metabolism

Metabolized in the liver (minimal CYP involvement), mainly by hydrolysis of the acylurea bond;¹ ¹⁷ undergoes substantial first-pass metabolism.¹

Elimination Route

Excreted in feces (72%) and in urine (18% as metabolites and unchanged drug).¹⁷

Half-life

63–109 hours.¹ ¹⁷

Special Populations

Pharmacokinetic values not altered in patients with moderate to severe renal impairment.¹ ¹⁷

Stability

Storage

Oral

Tablets

20–25°C.¹

ActionsActions

A long-acting dopamine receptor agonist; has high binding affinity for dopamine D₂ receptors and lesser affinity for D₁, α₁- and α₂-adrenergic, and serotonin (5-HT₁ and 5-HT₂) receptors.¹ ⁸

Reduces serum prolactin concentrations by inhibiting release of prolactin from the anterior pituitary gland.¹ This effect on hypothalamic/pituitary function attributed to the drug's agonist activity at D₂ receptors.¹

Advice to Patients

Potential for hypotension.¹

Importance of patients informing clinicians if cough or dyspnea develop.¹

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., respiratory or cardiac disorders associated with fibrosis).¹

Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Cabergoline
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	0.5 mg	Dostinex (scored)	Pfizer
			Cabergoline	Teva, Par

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Pfizer Inc. Dostinex(cabergoline) tablets prescribing information. New York, NY; 2007 Feb.

2. Webster J, Piscitelli G, Polli A et al. Dose-dependent suppression of serum prolactin by carbergoline in hyperprolactinemia: a placebo controlled, double blind, multicentre study. Clin Endocrinol. 1992; 37:534-41.

3. Webster J, Piscitelli G, Polli A et al. The efficacy and tolerability of long-term cabergoline therapy in hyperprolactinemic disorders; an open, uncontrolled, multicentre study. Clin Endocrinol. 1993; 39:323-9.

4. Clarke CE, Deane KHO. Cabergoline versus bromocriptine for levodopa-induced complications in Parkinson's disease. Cochrane Database of Systematic Reviews 2001, Issue 1. Art. No.: CD001519. DOI: 10.1002/14651858.CD001519.

5. Clarke CE, Deane KHO. Cabergoline for levodopa-induced complications in Parkinson's disease. Cochrane Database of Systematic Reviews 2001, Issue 1. Art. No.: CD001518. DOI: 10.1002/14651858.CD001518.

6. Pahwa R, Factor SA, Lyons KE et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): Report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2006; 66:983-95. [PubMed 16606909]

7. Olanow CW, Watts, RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease: treatment guidelines (2001). Neurology. 2001; 56 (Suppl):S1-88. [PubMed 11402154]

8. Curran MP, Perry CM. Cabergoline: a review of its use in the treatment of Parkinson's disease. Drugs. 2004; 64:2125-41. [PubMed 15341508]

9. Miyasaki JM, Martin W, Suchowersky O et al. Practice parameter: initiation of treatment for Parkinson's disease: an evidence-based review: Report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2002; 58:11-7. [PubMed 11781398]

10. Marsden CD. Clinical experience with cabergoline in patients with advanced Parkinson's disease treated with levodopa. Drugs. 1998; 55 (Suppl 1):17-22. [PubMed 9483166]

11. Rinne UK, Bracco F, Chouza C et al. Early treatment of Parkinson's disease with cabergoline delays the onset of motor complications: results of a double-blind levodopa controlled trial: The PKDS009 Study Group. Drugs. 1998; 55 (Suppl 1):23-30. [PubMed 9483167]

12. Webster J, Piscitelli G, Polli A et al. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea: carbergoline comparative study group. N Engl J Med. 1994; 331:904-9. [PubMed 7915824]

13. Webster J. Dopamine agonist therapy in hyperprolactinemia. J Reprod Med. 1999; 44:1105-10. [PubMed 10649819]

14. Schlechte JA. Prolactinoma. N Engl J Med. 2003; 349:2035-41. [PubMed 14627789]

15. Colao A, Di Sarno A, Cappabianca P et al. Withdrawl of long-term cabergoline therapy for tumoral and nontumoral hyperprolactinemia. N Engl J Med. 2003; 349:2023-33. [PubMed 14627787]

16. Ling LH, Ahlskog JE, Munger TM et al. Constrictive pericarditis and pleuropulmonary disease linked to ergot dopamine agonist therapy (cabergoline) for Parkinson's disease. Mayo Clin Proc. 1999; 74:371-5. [PubMed 10221467]

17. Del Dotto P, Bonuccelli U. Clinical pharmacokinetics of cabergoline. Clin Pharmacokinet. 2003; 42:633-45. [PubMed 12844325]

18. Valeant Pharmaceuticals. Permax (pergolide mesylate) tablets prescribing information. Costa Mesa, CA; 2003 Nov 11.

More Dostinex resources

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

Dostinex Prescribing Information (FDA)

Dostinex MedFacts Consumer Leaflet (Wolters Kluwer)

Dostinex Concise Consumer Information (Cerner Multum)

Dostinex Advanced Consumer (Micromedex) - Includes Dosage Information

Cabergoline Prescribing Information (FDA)

Compare Dostinex with other medications

Hyperprolactinemia

Tuesday 10 August 2010

Mexlo

Mexlo may be available in the countries listed below.

Ingredient matches for Mexlo

Lomefloxacin

Lomefloxacin hydrochloride (a derivative of Lomefloxacin) is reported as an ingredient of Mexlo in the following countries:

Bangladesh

International Drug Name Search

Diflunisal

Diflunisal TABLETS USP

0755

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).

Diflunisal 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).

*Throughout this package insert, the term NSAID refers to a non-aspirin non-steroidal anti-inflammatory drug.

Diflunisal Description

Diflunisal is 2',4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid. Its structural formula is:

C13H8F2O3 M.W. 250.20

Diflunisal is a stable, white, crystalline compound with a melting point of 211° to 213°C. It is practically insoluble in water at neutral or acidic pH. Because it is an organic acid, it dissolves readily in dilute alkali to give a moderately stable solution at room temperature. It is soluble in most organic solvents including ethanol, methanol, and acetone.

Each tablet, for oral administration, contains 500 mg Diflunisal. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, FD&C Blue #2 aluminum lake, hypromellose, microcrystalline cellulose, pregelatinized starch, propylene glycol, sodium stearyl fumarate, and titanium dioxide.

Diflunisal - Clinical Pharmacology

Action

Diflunisal is a non-steroidal drug with analgesic, anti-inflammatory and antipyretic properties. It is a peripherally-acting non-narcotic analgesic drug. Habituation, tolerance, and addiction have not been reported.

Diflunisal is a difluorophenyl derivative of salicylic acid. Chemically, Diflunisal differs from aspirin (acetylsalicylic acid) in two respects. The first of these two is the presence of a difluorophenyl substituent at carbon 1. The second difference is the removal of the O-acetyl group from the carbon 4 position. Diflunisal is not metabolized to salicylic acid, and the fluorine atoms are not displaced from the difluorophenyl ring structure.

The precise mechanism of the analgesic and anti-inflammatory actions of Diflunisal is not known. Diflunisal is a prostaglandin synthetase inhibitor. In animals, prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain. Since prostaglandins are known to be among the mediators of pain and inflammation, the mode of action of Diflunisal may be due to a decrease of prostaglandins in peripheral tissues.

Pharmacokinetics and Metabolism

Diflunisal is rapidly and completely absorbed following oral administration with peak plasma concentrations occurring between 2 to 3 hours. The drug is excreted in the urine as two soluble glucuronide conjugates accounting for about 90% of the administered dose. Little or no Diflunisal is excreted in the feces. Diflunisal appears in human milk in concentrations of 2 to 7% of those in plasma. More than 99% of Diflunisal in plasma is bound to proteins.

As is the case with salicylic acid, concentration-dependent pharmacokinetics prevail when Diflunisal is administered; a doubling of dosage produces a greater than doubling of drug accumulation. The effect becomes more apparent with repetitive doses. Following single doses, peak plasma concentrations of 41 ± 11 mcg/mL (mean ± S.D.) were observed following 250 mg doses, 87 ± 17 mcg/mL were observed following 500 mg and 124 ± 11 mcg/mL following single 1000 mg doses. However, following administration of 250 mg b.i.d., a mean peak level of 56 ± 14 mcg/mL was observed on day 8, while the mean peak level after 500 mg b.i.d. for 11 days was 190 ± 33 mcg/mL. In contrast to salicylic acid which has a plasma half-life of 2 1/2 hours, the plasma half-life of Diflunisal is 3 to 4 times longer (8 to 12 hours), because of a difluorophenyl substituent at carbon 1. Because of its long half-life and nonlinear pharmacokinetics, several days are required for Diflunisal plasma levels to reach steady state following multiple doses. For this reason, an initial loading dose is necessary to shorten the time to reach steady-state levels, and 2 to 3 days of observation are necessary for evaluating changes in treatment regimens if a loading dose is not used.

Studies in baboons to determine passage across the blood-brain barrier have shown that only small quantities of Diflunisal, under normal or acidotic conditions are transported into the cerebrospinal fluid (CSF). The ratio of blood/CSF concentrations after intravenous doses of 50 mg/kg or oral doses of 100 mg/kg of Diflunisal was 100:1. In contrast, oral doses of 500 mg/kg of aspirin resulted in a blood/CSF ratio of 5:1.

Mild to Moderate Pain

Diflunisal is a peripherally-acting analgesic agent with a long duration of action. Diflunisal produces significant analgesia within 1 hour and maximum analgesia within 2 to 3 hours.

Consistent with its long half-life, clinical effects of Diflunisal mirror its pharmacokinetic behavior, which is the basis for recommending a loading dose when instituting therapy. Patients treated with Diflunisal, on the first dose, tend to have a slower onset of pain relief when compared with drugs achieving comparable peak effects. However, Diflunisal produces longer lasting responses than the comparative agents.

Comparative single dose clinical studies have established the analgesic efficacy of Diflunisal at various dose levels relative to other analgesics. Analgesic effect measurements were derived from hourly evaluations by patients during eight and twelve hour postdosing observation periods. The following information may serve as a guide for prescribing Diflunisal.

Diflunisal 500 mg was comparable in analgesic efficacy to aspirin 650 mg, acetaminophen 600 mg or 650 mg, and acetaminophen 650 mg with propoxyphene napsylate 100 mg. Patients treated with Diflunisal had longer lasting responses than the patients treated with the comparative analgesics.

Diflunisal 1000 mg was comparable in analgesic efficacy to acetaminophen 600 mg with codeine 60 mg. Patients treated with Diflunisal had longer lasting responses than the patients who received acetaminophen with codeine.

A loading dose of 1000 mg provides faster onset of pain relief, shorter time to peak analgesic effect, and greater peak analgesic effect than an initial 500 mg dose.

In contrast to the comparative analgesics, a significantly greater proportion of patients treated with Diflunisal did not remedicate and continued to have a good analgesic effect eight to twelve hours after dosing. Seventy-five percent (75%) of patients treated with Diflunisal continued to have a good analgesic response at four hours. When patients having a good analgesic response at four hours were followed, 78% of these patients continued to have a good analgesic response at eight hours and 64% at twelve hours.

Chronic Anti-Inflammatory Therapy in Osteoarthritis and Rheumatoid Arthritis

In the controlled, double-blind clinical trials in which Diflunisal (500 mg to 1000 mg a day) was compared with anti-inflammatory doses of aspirin (2 to 4 grams a day), patients treated with Diflunisal had a significantly lower incidence of tinnitus and of adverse effects involving the gastrointestinal system than patients treated with aspirin (see also Effect on Fecal Blood Loss).

Osteoarthritis

The effectiveness of Diflunisal for the treatment of osteoarthritis was studied in patients with osteoarthritis of the hip and/or knee. The activity of Diflunisal was demonstrated by clinical improvement in the signs and symptoms of disease activity.

In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient response, Diflunisal 500 or 750 mg daily was shown to be comparable in effectiveness to aspirin 2000 or 3000 mg daily. In open-label extensions of this study to 24 or 48 weeks, Diflunisal continued to show similar effectiveness and generally was well tolerated.

Rheumatoid Arthritis

In controlled clinical trials, the effectiveness of Diflunisal was established for both acute exacerbations and long-term management of rheumatoid arthritis. The activity of Diflunisal was demonstrated by clinical improvement in the signs and symptoms of disease activity.

In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient response, Diflunisal 500 or 750 mg daily was comparable in effectiveness to aspirin 2600 or 3900 mg daily. In open-label extensions of this study to 52 weeks, Diflunisal continued to be effective and was generally well tolerated.

Diflunisal 500, 750, or 1000 mg daily was compared with aspirin 2000, 3000, or 4000 mg daily in a multicenter study of 8 weeks' duration in which dosages were adjusted according to patient response. In this study, Diflunisal was comparable in efficacy to aspirin.

In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient needs, Diflunisal 500 or 750 mg daily and ibuprofen 1600 or 2400 mg daily were comparable in effectiveness and tolerability.

In a double-blind multicenter study of 12 weeks' duration, Diflunisal 750 mg daily was comparable in efficacy to naproxen 750 mg daily. The incidence of gastrointestinal adverse effects and tinnitus was comparable for both drugs. This study was extended to 48 weeks on an open-label basis. Diflunisal continued to be effective and generally well tolerated.

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

Antipyretic Activity

Diflunisal tablets are not recommended for use as an antipyretic agent. In single 250 mg, 500 mg, or 750 mg doses, Diflunisal produced measurable but not clinically useful decreases in temperature in patients with fever; however, the possibility that it may mask fever in some patients, particularly with chronic or high doses, should be considered.

Uricosuric Effect

In normal volunteers, an increase in the renal clearance of uric acid and a decrease in serum uric acid was observed when Diflunisal was administered at 500 mg or 750 mg daily in divided doses. Patients on long-term therapy taking Diflunisal at 500 mg to 1000 mg daily in divided doses showed a prompt and consistent reduction across studies in mean serum uric acid levels, which were lowered as much as 1.4 mg%. It is not known whether Diflunisal interferes with the activity of other uricosuric agents.

Effect on Platelet Function

As an inhibitor of prostaglandin synthetase, Diflunisal has a dose-related effect on platelet function and bleeding time. In normal volunteers, 250 mg b.i.d. for 8 days had no effect on platelet function, and 500 mg b.i.d., the usual recommended dose, had a slight effect. At 1000 mg b.i.d., which exceeds the maximum recommended dosage, however, Diflunisal inhibited platelet function. In contrast to aspirin, these effects of Diflunisal were reversible, because of the absence of the chemically labile and biologically reactive O-acetyl group at the carbon 4 position. Bleeding time was not altered by a dose of 250 mg b.i.d., and was only slightly increased at 500 mg b.i.d. At 1000 mg b.i.d., a greater increase occurred, but was not statistically significantly different from the change in the placebo group.

Effect on Fecal Blood Loss

When Diflunisal was given to normal volunteers at the usual recommended dose of 500 mg twice daily, fecal blood loss was not significantly different from placebo. Aspirin at 1000 mg four times daily produced the expected increase in fecal blood loss. Diflunisal at 1000 mg twice daily (NOTE: exceeds the recommended dosage) caused a statistically significant increase in fecal blood loss, but this increase was only one-half as large as that associated with aspirin 1300 mg twice daily.

Effect on Blood Glucose

Diflunisal did not affect fasting blood sugar in diabetic patients who were receiving tolbutamide or placebo.

Indications and Usage for Diflunisal

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

Diflunisal tablets are indicated for acute or long-term use for symptomatic treatment of the following:

Mild to moderate pain

Osteoarthritis

Rheumatoid arthritis

Contraindications

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

Diflunisal 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/analphylactoid reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactic/Anaphylactoid Reactions and PRECAUTIONS, Preexisting Asthma).

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

Hypertension

NSAIDs, including Diflunisal tablets, can lead to onset of new hypertension or worsening of preexisting 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 Diflunisal 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. Diflunisal tablets should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects – Risk of Ulceration, Bleeding and Perforation

NSAIDs, including Diflunisal 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 to 6 months, and in about 2 to 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.

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 Diflunisal tablets in patients with advanced renal disease. Therefore, treatment with Diflunisal tablets is not recommended in these patients with advanced renal disease. If Diflunisal tablet 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 Diflunisal tablets. Diflunisal 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 Diflunisal 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 Syndrome

A potentially life-threatening, apparent hypersensitivity syndrome has been reported. This multisystem syndrome includes constitutional symptoms (fever, chills), and cutaneous findings (see ADVERSE REACTIONS, Dermatologic). It may also include involvement of major organs (changes in liver function, jaundice, leukopenia, thrombocytopenia, eosinophilia, disseminated intravascular coagulation, renal impairment, including renal failure), and less specific findings (adenitis, arthralgia, myalgia, arthritis, malaise, anorexia, disorientation). If evidence of hypersensitivity occurs, therapy with Diflunisal tablets should be discontinued.

Pregnancy

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

Precautions

General

Diflunisal 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 Diflunisal tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Diflunisal tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. 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 Diflunisal tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Diflunisal tablets should be discontinued.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including Diflunisal 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 Diflunisal 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 Diflunisal 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, Diflunisal tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Ocular Effects

Because of reports of adverse eye findings with agents of this class, it is recommended that patients who develop eye complaints during treatment with Diflunisal tablets have ophthalmologic studies.

Reye’s Syndrome

Acetylsalicylic acid has been associated with Reye’s syndrome. Because Diflunisal is a derivative of salicylic acid, the possibility of its association with Reye’s syndrome cannot be excluded.

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.

Diflunisal 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 signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).

Diflunisal 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 signs 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).

Diflunisal tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.

Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.

Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.

Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).

In late pregnancy, as with other NSAIDs, Diflunisal tablets should be avoided because they 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, Diflunisal tablets should be discontinued.

Drug Interactions

ACE-inhibitors and Angiotensin II Anagonists

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, the coadministration 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.

Acetaminophen

In normal volunteers, concomitant administration of Diflunisal and acetaminophen resulted in an approximate 50% increase in plasma levels of acetaminophen. Acetaminophen had no effect on plasma levels of Diflunisal. Since acetaminophen in high doses has been associated with hepatotoxicity, concomitant administration of Diflunisal tablets and acetaminophen should be used cautiously, with careful monitoring of patients.

Concomitant administration of Diflunisal and acetaminophen in dogs, but not in rats, at approximately 2 times the recommended maximum human therapeutic dose of each (40 to 52 mg/kg/day of Diflunisal/acetaminophen), resulted in greater gastrointestinal toxicity than when either drug was administered alone. The clinical significance of these findings has not been established.

Antacids

Concomitant administration of antacids may reduce plasma levels of Diflunisal. This effect is small with occasional doses of antacids, but may be clinically significant when antacids are used on a continuous schedule.

Aspirin

When Diflunisal is administered with aspirin, its protein binding is reduced, although the clearance of free Diflunisal is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of Diflunisal tablets and aspirin is not generally recommended because of the potential of increased adverse effects.

In normal volunteers, a small decrease in Diflunisal levels was observed when multiple doses of Diflunisal and aspirin were administered concomitantly.

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.

Diuretics

Clinical studies, as well as postmarketing observations, have shown that Diflunisal can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.

In normal volunteers, concomitant administration of Diflunisal and hydrochlorothiazide resulted in significantly increased plasma levels of hydrochlorothiazide. Diflunisal decreased the hyperuricemic effect of hydrochlorothiazide. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

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 administration of Diflunisal to normal volunteers receiving indomethacin decreased the renal clearance and significantly increased the plasma levels of indomethacin. In some patients the combined use of indomethacin and Diflunisal has been associated with fatal gastrointestinal hemorrhage. Therefore, indomethacin and Diflunisal tablets should not be used concomitantly.

The concomitant use of Diflunisal tablets and other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy. The following information was obtained from studies in normal volunteers.

Sulindac

The concomitant administration of Diflunisal and sulindac in normal volunteers resulted in lowering of the plasma levels of the active sulindac sulfide metabolite by approximately one-third.

Naproxen

The concomitant administration of Diflunisal and naproxen in normal volunteers had no effect on the plasma levels of naproxen, but significantly decreased the urinary excretion of naproxen and its glucuronide metabolite. Naproxen had no effect on plasma levels of Diflunisal.

Oral Anticoagulants

In some normal volunteers, the concomitant administration of Diflunisal and warfarin, acenocoumarol, or phenprocoumon resulted in prolongation of prothrombin time. This may occur because Diflunisal competitively displaces coumarins from protein binding sites. Accordingly, when Diflunisal tablets are administered with oral anticoagulants, the prothrombin time should be closely monitored during and for several days after concomitant drug administration. Adjustment of dosage of oral anticoagulants may be required. 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.

Tolbutamide

In diabetic patients receiving Diflunisal and tolbutamide, no significant effects were seen on tolbutamide plasma levels or fasting blood glucose.

Drug/Laboratory Test Interactions

Serum Salicylate Assays

Caution should be used in interpreting the results of serum salicylate assays when Diflunisal is present. Salicylate levels have been found to be falsely elevated with some assay methods.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Diflunisal did not affect the type or incidence of neoplasia in a 105 week study in the rat given doses up to 40 mg/kg/day (equivalent to approximately 1.3 times the maximum recommended human dose), or in long-term carcinogenic studies in mice given Diflunisal at doses up to 80 mg/kg/day (equivalent to approximately 2.7 times the maximum recommended human dose). It was concluded that there was no carcinogenic potential for Diflunisal.

Diflunisal passes the placental barrier to a minor degree in the rat. Diflunisal had no mutagenic activity after oral administration in the dominant lethal assay, in the Ames microbial mutagen test or in the V-79 Chinese hamster lung cell assay.

No evidence of impaired fertility was found in reproduction studies in rats at doses up to 50 mg/kg/day.

Pregnancy

Teratogenic Effects

Pregnancy category C

A dose of 60 mg/kg/day of Diflunisal (equivalent to two times the maximum human dose) was maternotoxic, embryotoxic, and teratogenic in rabbits. In three of six studies in rabbits, evidence of teratogenicity was observed at doses ranging from 40 to 50 mg/kg/day. Teratology studies in mice, at doses up to 45 mg/kg/day, and in rats at doses up to 100 mg/kg/day, revealed no harm to the fetus due to Diflunisal. Aspirin and other salicylates have been shown to be teratogenic in a wide variety of species, including the rat and rabbit, at doses ranging from 50 to 400 mg/kg/day (approximately one to eight times the human dose). Animal reproduction studies are not always predictive of human response. There are no adequate and well controlled studies with Diflunisal in pregnant women. Diflunisal 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 rats at a dose of one and one-half times the maximum human dose, there was an increase in the average length of gestation. Similar increases in the length of gestation have been observed with aspirin, indomethacin, and phenylbutazone, and may be related to inhibition of prostaglandin synthetase.

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 Diflunisal tablets on labor and delivery in pregnant women are unknown.

Nursing Mothers

Diflunisal is excreted in human milk in concentrations of 2 to 7% of those in plasma. Because of the potential for serious adverse reactions in nursing infants from Diflunisal, 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 Diflunisal in pediatric patients below the age of 12 have not been established. Use of Diflunisal tablets in pediatric patients below the age of 12 is not recommended.

The adverse effects observed following Diflunisal administration to neonatal animals appear to be species, age, and dose-dependent. At dose levels approximately 3 times the usual human therapeutic dose, both aspirin (200 to 400 mg/kg/day) and Diflunisal (80 mg/kg/day) resulted in death, leukocytosis, weight loss, and bilateral cataracts in neonatal (4 to 5-day-old) beagle puppies after 2 to 10 doses. Administration of an 80 mg/kg/day dose of Diflunisal to 25-day-old puppies resulted in lower mortality, and did not produce cataracts. In newborn rats, a 400 mg/kg/day dose of aspirin resulted in increased mortality and some cataracts, whereas the effects of Diflunisal administration at doses up to 140 mg/kg/day were limited to a decrease in average body weight gain.

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).

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, Renal Effects).

Adverse Reactions

The adverse reactions observed in controlled clinical trials encompass observations in 2,427 patients.

Listed below are the adverse reactions reported in the 1,314 of these patients who received treatment in studies of two weeks or longer. Five hundred thirteen patients were treated for at least 24 weeks, 255 patients were treated for at least 48 weeks, and 46 patients were treated for 96 weeks. In general, the adverse reactions listed below were 2 to 14 times less frequent in the 1,113 patients who received short-term treatment for mild to moderate pain.

Incidence Greater Than 1%

Gastrointestinal

The most frequent types of adverse reactions occurring with Diflunisal are gastrointestinal: these include nausea*, vomiting, dyspepsia*, gastrointestinal pain*, diarrhea*, constipation, and flatulence.

Psychiatric

Somnolence, insomnia.

Central Nervous System

Dizziness.

Special Senses

Tinnitus.

Dermatologic

Rash*.

Miscellaneous

Headache*, fatigue/tiredness.

* Incidence between 3% and 9%. Those reactions occurring in 1% to 3% are not marked with an asterisk.

Incidence Less Than 1 in 100

The following adverse reactions, occurring less frequently than 1 in 100, were reported in clinical trials or since the drug was marketed. The probability exists of a causal relationship between Diflunisal and these adverse reactions.

Dermatologic

Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, pruritus, sweating, dry mucous membranes, stomatitis, photosensitivity.

Gastrointestinal

Peptic ulcer, gastrointestinal bleeding, anorexia, eructation, gastrointestinal perforation, gastritis. Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis.

Monday 9 August 2010

oxymorphone

ox-i-MOR-fone

Oral route(Tablet, Extended Release)

Opana(R) ER contains oxymorphone, a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. Opana(R) ER is an extended-release oral formulation of oxymorphone indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time; not indicated for use as an as needed analgesic. Extended release tablets should be swallowed whole; not cut, broken, chewed, dissolved, or crushed. Avoid alcohol and alcohol-containing medications as consumption of alcohol may result in increased plasma levels and a potentially fatal overdose of oxymorphone .

Commonly used brand name(s)

In the U.S.

Opana

Opana ER

Available Dosage Forms:

Tablet, Extended Release

Tablet

Therapeutic Class: Analgesic

Chemical Class: Opioid

Uses For oxymorphone

Oxymorphone tablets are used to relieve pain. The extended-release tablets are used to relieve moderate to severe pain.

Oxymorphone belongs to the group of medicines called narcotic analgesics (pain medicines). It acts in the central nervous system (CNS) to relieve pain. Many of its side effects are also caused by actions in the CNS.

When oxymorphone is used for a long time, it may become habit-forming (causing mental or physical dependence). However, people who have continuing pain should not let the fear of dependence keep them from using narcotics to relieve their pain. Mental dependence (addiction) is not likely to occur when narcotics are used for this purpose. Physical dependence may lead to withdrawal side effects if treatment is stopped suddenly. However, severe withdrawal side effects can usually be prevented by gradually reducing the dose over a period of time before treatment is stopped completely.

oxymorphone is available only with your doctor's prescription.

Before Using oxymorphone

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 oxymorphone, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to oxymorphone 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 oxymorphone in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of oxymorphone in the elderly. However, elderly patients are more likely to have age-related liver, kidney or heart problems, which may require caution and an adjustment in the dose for patients receiving oxymorphone.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

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 oxymorphone, 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 oxymorphone 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.

Naltrexone

Using oxymorphone with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Adinazolam

Alfentanil

Alprazolam

Amobarbital

Anileridine

Aprobarbital

Bromazepam

Brotizolam

Buprenorphine

Butabarbital

Butalbital

Butorphanol

Carisoprodol

Chloral Hydrate

Chlordiazepoxide

Chlorzoxazone

Clobazam

Clonazepam

Clorazepate

Codeine

Dantrolene

Dezocine

Diazepam

Estazolam

Ethchlorvynol

Fentanyl

Flunitrazepam

Flurazepam

Fospropofol

Halazepam

Hydrocodone

Hydromorphone

Ketazolam

Levorphanol

Lorazepam

Lormetazepam

Medazepam

Meperidine

Mephenesin

Mephobarbital

Meprobamate

Metaxalone

Methocarbamol

Methohexital

Midazolam

Morphine

Morphine Sulfate Liposome

Nalbuphine

Nitrazepam

Nordazepam

Opium

Oxazepam

Oxycodone

Oxymorphone

Pentazocine

Pentobarbital

Phenobarbital

Prazepam

Propoxyphene

Quazepam

Remifentanil

Secobarbital

Sodium Oxybate

Sufentanil

Tapentadol

Temazepam

Thiopental

Triazolam

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. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using oxymorphone with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use oxymorphone, or give you special instructions about the use of food, alcohol, or tobacco.

Ethanol

Proper Use of oxymorphone

Take oxymorphone only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. This is especially important for elderly patients, who may be more sensitive to the effects of pain medicines. If too much of oxymorphone is taken for a long time, it may become habit-forming (causing mental or physical dependence).

It is best to take oxymorphone on an empty stomach, at least 1 hour before or 2 hours after a meal.

If you are using the extended-release tablets:

Take the tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. Do not break, cut, crush, dissolve, lick, or chew it.

While taking oxymorphone, part of the tablet may pass into your stools. This is normal and is nothing to worry about.

oxymorphone comes with a medication guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Dosing

The dose of oxymorphone 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 oxymorphone. 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 oral dosage form (extended-release tablets):
- For moderate to severe pain:
  - For patients who are not taking narcotic medicines:
    - Adults—At first, 5 milligrams (mg) every 12 hours. Your doctor may adjust your dose as needed.
    - Children—Use and dose must be determined by your doctor.
  - For patients switching from Opana® to Opana® ER:
    - Adults—At first, the dose is half of the total oral Opana® that you are taking per day, every 12 hours. Your doctor may adjust your dose as needed.
    - Children—Use and dose must be determined by your doctor.
  - For patients switching from oxymorphone injection to Opana® ER:
    - Adults—At first, the dose is 10 times the total oxymorphone injection dose that you are receiving per day divided into two equal doses. Your doctor may adjust your dose as needed.
    - Children—Use and dose must be determined by your doctor.
  - For patients switching from oral opioids to Opana® ER:
    - Adults—At first, the dose is half of the total daily dose that you are taking per day, every 12 hours. Your doctor may adjust your dose as needed.
    - Children—Use and dose must be determined by your doctor.

For oral dosage form (tablets):
- For pain:
  - Adults—At first, 5 milligrams (mg) every 4 to 6 hours. Your doctor may adjust your dose if needed.
  - Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of oxymorphone, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

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

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.

Oxymorphone can cause serious unwanted effects if taken by adults who are not used to strong narcotic pain medicines, children, or pets. Make sure you store the medicine in a safe and secure place to prevent others from getting it.

Flush all unused medicine down the toilet after you have finished your treatment. Also flush old medicine after the expiration date has passed. oxymorphone is one of only a few medicines that should be disposed of this way.

Precautions While Using oxymorphone

If you will be taking oxymorphone for a long time, it is very important that your doctor check you at regular visits for any problems or unwanted effects that may be caused by oxymorphone.

Oxymorphone may increase your risk of having serious breathing problems. Check with your doctor right away if you are having difficult or troubled breathing; irregular, fast, slow, or shallow breathing; pale or blue lips, fingernails, or skin; or shortness of breath.

oxymorphone will add to the effects of alcohol and other CNS depressants (medicines that can make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for hay fever, other allergies, or colds; sedatives, tranquilizers, or sleeping medicine; other prescription pain medicine or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the other medicines listed above while you are using oxymorphone.

Oxymorphone may cause some people to become drowsy, dizzy, or lightheaded, or to feel a false sense of well-being. Make sure you know how you react to oxymorphone before you drive, use machines, or do anything else that could be dangerous if you are dizzy, not alert, or lightheaded.

Dizziness, lightheadedness, or even fainting may occur when you get up suddenly from a lying or sitting position. Getting up slowly may help lessen this problem. Also, lying down for a while may relieve dizziness or lightheadedness.

Using oxymorphone for a long time can cause severe constipation. To prevent this, your doctor may direct you to take laxatives, drink a lot of fluids, or increase the amount of fiber in your diet. Be sure to follow the directions carefully, because continuing constipation can lead to more serious problems.

Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are using oxymorphone. Serious side effects can occur if your medical doctor or dentist gives you certain other medicines without knowing that you are using oxymorphone.

If you have been using oxymorphone regularly for several weeks or more, do not change your dose or suddenly stop using it without first checking with your doctor. Your doctor may want you to gradually reduce the amount you are taking before stopping it completely. Withdrawal side effects may occur when the medicine is stopped suddenly because your body has become used to oxymorphone.

Using oxymorphone while you are pregnant may cause neonatal withdrawal syndrome in your newborn babies. Tell your doctor right away if your baby has the following symptoms: abnormal sleep pattern, diarrhea, high-pitched cry, irritability, shakiness or tremor, weight loss, vomiting, or failure to gain weight.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

oxymorphone 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:

Less common

Blurred vision

confusion

decreased urination

difficult or labored breathing

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

dry mouth

fast, pounding, racing, or irregular heartbeat or pulse

headache

nervousness

pounding in the ears

rapid breathing

shortness of breath

sunken eyes

sweating

swelling of the hands, ankles, or feet

thirst

tightness in the chest

unusual tiredness or weakness

wheezing

wrinkled skin

Rare

Abdominal or stomach pain

chest pain or discomfort

chills

cold sweats

cough

decrease in consciousness

decrease in urine volume

difficulty in passing urine (dribbling)

difficulty with sleeping

difficulty with swallowing

disorientation

drowsiness to profound coma

fear

fever

hallucination

hives

hyperventilation

hoarseness

irregular, slow, or shallow breathing

irritability

irritation

itching

joint pain, stiffness, or swelling

lethargy

mood or other mental changes

painful urination

pale or blue lips, fingernails, or skin

puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue

redness of the skin

restlessness

severe constipation

severe vomiting

shaking

shortness of breath

skin rash

swelling of the eyelids, face, or lips

trouble in holding or releasing urine

trouble with sleeping

troubled breathing or swallowing

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

Symptoms of overdose

Cold and clammy skin

constricted, pinpoint, or small pupils (black part of the eye)

decreased awareness or responsiveness

muscle weakness

no blood pressure or pulse

not breathing

severe sleepiness or unusual drowsiness

stopping of heart

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

Difficulty having a bowel movement (stool)

feeling of constant movement of self or surroundings

increased sweating

nausea or vomiting

relaxed and calm

sensation of spinning

sleepiness

Less common

Acid or sour stomach

belching

decreased appetite

decreased weight

diarrhea

discouragement

excess air or gas in the stomach or intestines

feeling of warmth

feeling sad or empty

full or bloated feeling

heartburn

indigestion

lack of appetite

loss of interest or pleasure

passing gas

pressure in the stomach

redness of the face, neck, arms, and occasionally, upper chest

sleeplessness

stomach discomfort or upset

swelling of the abdominal or stomach area

tiredness

trouble concentrating

unable to sleep

Rare

Blistering, crusting, irritation, itching, or reddening of the skin

cracked, dry, scaly skin

difficulty with thinking or concentrating

disturbed color perception

double vision

false or unusual sense of well-being

feeling jittery

halos around lights

loss of vision

mental depression

night blindness

nightmares or unusually vivid dreams

overbright appearance of lights

sudden sweating

tunnel vision

welts

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: oxymorphone side effects (in more detail)

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