Download PLR Content Marketing Grenada

Thursday, March 22, 2012

Multaq

Generic Name: Dronedarone Hydrochloride
Class: Class III Antiarrhythmics
VA Class: CV300
Chemical Name: N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-benzofuranyl]-methanesulfonamide monohydrochloride
Molecular Formula: C₃₁H₄₄N₂O₅S•HCl
CAS Number: 141625-93-6

Special Alerts:

[Posted 07/21/2011] ISSUE: FDA notified healthcare professionals that it is reviewing data from a clinical trial that evaluated the effects of the antiarrhythmic drug dronedarone (Multaq) in patients with permanent atrial fibrillation. The study was stopped early after the data monitoring committee found a two-fold increase in death, as well as two-fold increases in stroke and hospitalization for heart failure in patients receiving dronedarone compared to patients taking a placebo. FDA is evaluating whether and how the preliminary results of the PALLAS study apply to patients taking dronedarone for paroxysmal or persistent atrial fibrillation or atrial flutter. The PALLAS study results are considered preliminary at this time because the data have not undergone quality assurance procedures and have not been completely adjudicated. FDA will update the public when more information is available.

BACKGROUND: Dronedarone is approved for use to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted.

RECOMMENDATION: At this time, patients taking dronedarone should talk to their healthcare professional about whether they should continue to take dronedarone for non-permanent atrial fibrillation. Patients should not stop taking dronedarone without talking to a healthcare professional. Healthcare professionals should not prescribe dronedarone to patients with permanent atrial fibrillation. See the Data Summary in the Drug Safety Communication for additional details at: . For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for dronedarone hydrochloride to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of dronedarone hydrochloride and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Contraindicated in patients with NYHA class IV heart failure or NYHA class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic.¹ (See Heart Failure under Cautions.)

In the ANDROMEDA study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms, dronedarone therapy was associated with a greater than twofold increase in mortality rate relative to placebo;¹ ⁴ do not use dronedarone in such patients.¹

Introduction

Class III antiarrhythmic agent;⁵ ⁶ ⁷ also appears to exhibit activity in each of the 4 Vaughan-Williams antiarrhythmic classes.¹ ⁵ ⁶ ⁸

Uses for Multaq

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Supraventricular Tachyarrhythmias

Reduction of risk of hospitalization for cardiovascular events in patients with paroxysmal or persistent atrial fibrillation or atrial flutter who have had a recent episode of atrial fibrillation/flutter and who have associated cardiovascular risk factors (i.e., >70 years of age, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm, or left ventricular ejection fraction <40%); used in such patients who are in sinus rhythm or who will undergo cardioversion.¹ ⁹ (See Boxed Warningand also see Contraindications and see Heart Failure under Cautions.)

Less effective than amiodarone in preventing recurrence of atrial fibrillation but appears to have an improved safety profile (based on short-term data).⁴ ⁵ ⁸ ⁹ ¹⁴ ¹⁶ ¹⁹ ²⁴ Long-term data and experience needed to elucidate relative safety and tolerability of dronedarone versus amiodarone because of some late-onset adverse effects of amiodarone (e.g., pulmonary toxicity).⁶ ⁸ ¹⁴ ¹⁶ ¹⁸ ¹⁹

Efficacy of retreatment with dronedarone in patients who relapse after initial successful treatment or in those who fail therapy with amiodarone not established.¹⁷ ²¹

Individualize treatment of atrial fibrillation/flutter based on relative benefits and risks of various therapies (e.g., rhythm versus rate control, nondrug therapies such as ablation and pacemaker implantation), patient age, and patient preference and tolerance of the arrhythmia.¹⁵ ¹⁷ ¹⁸ ²⁰ ²¹ ²² ²³ ²⁴ ²⁶

Multaq Dosage and Administration

General

Risk Evaluation and Mitigation Strategy

FDA-required Risk Evaluation and Mitigation Strategy (REMS) implemented to assist healthcare professionals with identification of appropriate patients to receive dronedarone and ensure safe use while minimizing risk.¹⁰ ¹¹ ¹²

Goals of program (mPACT: MULTAQ Partnership for Appropriate Care and Treatment) are to educate prescribers about the increased risk of mortality associated with use of dronedarone in patients with NYHA class IV heart failure and in those who have NYHA class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic, and to prevent use of the drug in such patients.¹² Also designed to inform patients about serious risks associated with dronedarone, including an increased rate of mortality in patients with severe, unstable heart failure.¹² (See Contraindicationsand also see Heart Failure under Cautions.) REMS program consists of educational materials for healthcare professionals and patients, including a medication guide to be dispensed with every dronedarone prescription.¹ ¹⁰ ¹¹ ¹²

For additional information, consult the Multaq website at .¹⁰

Administration

Oral Administration

Administer orally twice daily with morning and evening meals (to enhance bioavailability).¹ (See Food under Pharmacokinetics.)

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as dronedarone hydrochloride; dosage expressed in terms of dronedarone.¹

Adults

Supraventricular Tachyarrhythmias

Oral

Reduction of risk of hospitalization due to cardiovascular events in selected patients with paroxysmal or persistent atrial fibrillation/flutter: 400 mg twice daily with morning and evening meals.¹

Must discontinue class I or III antiarrhythmic agents and drugs that are potent inhibitors of cytochrome P450 (CYP) isoenzyme 3A prior to initiating dronedarone.¹ ⁹ (See Contraindications under Cautions and also see Interactions.)

Special Populations

The manufacturer states that no dosage other than 400 mg twice daily of dronedarone is recommended for any population at this time.⁹

Hepatic Impairment

No dosage adjustment required in patients with moderate hepatic impairment.¹ Contraindicated in patients with severe hepatic impairment.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment required.¹ (See Renal Impairment under Cautions.)

Cautions for Multaq

Contraindications

NYHA Class IV heart failure or NYHA Class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic.¹ (See Boxed Warning and also see Heart Failure under Cautions.)

Second- or third-degree AV block or sick sinus syndrome (except in patients with a functioning pacemaker).¹

Bradycardia (<50 beats/minute).¹

QT interval corrected for rate, Bazett’s formula (QT_c) of ≥500 msec or PR interval >280 msec.¹ ⁹ (See Prolongation of QT Interval under Cautions.)

Concomitant use of potent inhibitors of CYP3A (e.g., clarithromycin, cyclosporine, itraconazole, ketoconazole, nefazodone, ritonavir, telithromycin, voriconazole).¹ (See Drugs Affecting Hepatic Microsomal Enzymes and also see Drugs Metabolized by Hepatic Microsomal Enzymes under Interactions.)

Concomitant use with drugs or herbal supplements that prolong the QT interval and may increase the risk of torsades de pointes (e.g., class I or III antiarrhythmic agents, phenothiazines, tricyclic antidepressants, certain oral macrolides).¹ ⁹ (See Drugs that Prolong the QT Interval under Interactions.)

Severe hepatic impairment.¹ (See Hepatic Impairment and also see Severe Hepatic Injury under Cautions.)

Women who are or may become pregnant.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Nursing women.¹

Warnings/Precautions

Heart Failure

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

In ANDROMEDA study, greater than twofold increase relative to placebo in rate of mortality in dronedarone-treated patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms; do not use dronedarone in such patients.¹ ⁴

Limited clinical experience available in patients with atrial fibrillation/flutter who develop worsening heart failure during therapy with dronedarone.¹ Worsening heart failure complicated by multiorgan dysfunction (e.g., acute renal and hepatic failure) in the setting of dronedarone initiation reported during postmarketing surveillance in at least one patient with atrial fibrillation and history of NYHA class III-IV heart failure and multiple recent hospitalizations for heart failure.²⁶

If heart failure develops or worsens, consider interrupting or discontinuing therapy.¹

Contraindicated in patients with NYHA class IV heart failure or NYHA class II or III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic.¹ (See Boxed Warningand also see Contraindications under Cautions.)

Severe Hepatic Injury

Severe hepatic injury reported rarely with dronedarone therapy.²⁸ Acute hepatic failure requiring liver transplantation reported in at least 2 patients; in both cases, explanted liver showed evidence of extensive hepatocellular necrosis.²⁸

Consider periodic monitoring of serum hepatic enzymes, especially during first 6 months of therapy.²⁸ If hepatic injury suspected (e.g., anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, itching), discontinue dronedarone therapy promptly and assess serum hepatic enzymes and bilirubin; initiate appropriate therapy if hepatic injury found.²⁸ Do not reinitiate dronedarone therapy in patients who experience hepatic injury without another explanation for such injury.²⁸

Hypokalemia and Hypomagnesemia

Possible hypokalemia and hypomagnesemia with concomitant use of potassium-depleting diuretics.¹ Ascertain that serum potassium and magnesium concentrations are within normal range prior to initiation of dronedarone; maintain within normal range during therapy.¹ ⁹ ²⁴

Prolongation of QT Interval

Moderate prolongation of QT_c interval reported; QT_c interval increased by an average of about 10 msec, however, greater prolongation reported.¹ Discontinue dronedarone if QT_c interval is ≥500 msec.¹ (See Contraindications under Cautions.)

Increased Serum Creatinine Concentrations

Increase in S_cr of about 0.1 mg/dL reported following initiation of drug; however, may not necessarily indicate decline in renal function.¹ ² ⁴ ⁵ ¹³ ¹⁶ Increase in S_cr and decrease in Cl_cr by about 10–15 or 18%, respectively, observed in clinical studies in healthy individuals and patients receiving the drug; however, no clinically important change in glomerular filtration rate, renal plasma flow or electrolyte exchanges, or any structural renal damage reported.¹ ² ³ ⁴ ¹³ Change in S_cr may result from a specific partial inhibition of tubular organic cation transporters and inhibition of tubular secretion of creatinine by dronedarone.¹ ⁵ ¹³ ¹⁶

Increases in S_cr appear to have a rapid onset, reach a plateau after 7 days, and are reversible following discontinuance of the drug.¹ ¹³ If an increase in the S_cr occurs and plateaus, use this increased value as the patient’s new baseline S_cr.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity demonstrated in animals.¹

Avoid pregnancy during therapy; women of childbearing potential (i.e., premenopausal women who have not undergone hysterectomy or oophorectomy) must use effective contraception.¹ If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.¹ (See Advice to Patients.)

Contraindicated in women who are or may become pregnant.¹

Specific Populations

Pregnancy

Category X.¹ (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications under Cautions.)

Lactation

Dronedarone and its metabolites distributed into milk in rats; not known whether distributed into milk in humans.¹ Discontinue nursing or the drug.¹ Contraindicated in nursing women.¹

Pediatric Use

Safety and efficacy not established in children or adolescents <18 years of age.¹

Geriatric Use

No substantial differences in safety and efficacy relative to those in younger adults.¹ (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

Not studied in patients with severe hepatic impairment; limited clinical experience available in patients with moderate hepatic impairment.¹ Severe liver injury reported rarely with dronedarone therapy.²⁸ (See Severe Hepatic Injury under Cautions.) Contraindicated in patients with severe hepatic impairment.¹ (See Special Populations under Pharmacokinetics.)

Renal Impairment

No dosage adjustment required because dronedarone undergoes minimal renal excretion.¹ (See Special Populations and also see Elimination Route under Pharmacokinetics.)

Common Adverse Effects

Increased S_cr (increase of ≥10% five days after initiation of drug),¹ prolonged QT_c interval (>450 msec [males] or >470 msec [females]),¹ diarrhea,¹ ² ¹⁴ asthenia,¹ nausea,¹ ² skin reactions (e.g., rash [generalized, macular, maculo-papular, erythematous], pruritus, eczema, dermatitis, allergic dermatitis),¹ ² abdominal pain,¹ bradycardia,¹ ² vomiting,¹ dyspepsia.¹ (See Contraindications and see Prolongation of QT Interval and also see Increased Serum Creatinine Concentrations under Cautions.)

Interactions for Multaq

Metabolized mainly by CYP isoenzyme 3A.¹

Moderate inhibitor of CYP isoenzymes 3A and 2D6; does not appear to substantially inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2C8, or 2B6.¹ May inhibit P-glycoprotein transport system.¹

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A: Pharmacokinetic interaction (increased exposure to and peak plasma concentrations of dronedarone).¹ Concomitant use contraindicated.¹

Inhibitors of CYP3A: Potential pharmacokinetic interaction (altered concentrations of dronedarone).¹

Inducers of CYP3A: Potential pharmacokinetic interaction (substantially decreased exposure to dronedarone).¹ Avoid concomitant use.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Potential pharmacokinetic interaction (possible increased plasma concentrations of the CYP3A substrate).¹ ⁹ ²⁵ Monitor plasma concentrations and appropriately adjust dosage of CYP3A substrates with a narrow therapeutic index when administered orally.¹ ⁹ Some clinicians state that dronedarone should be used with caution in patients receiving drugs with a narrow therapeutic index that are metabolized by CYP3A4.²⁵

Substrates of CYP2D6: Potential pharmacokinetic interaction (possible increased exposure to the CYP2D6 substrate).¹

Drugs that Prolong the QT Interval

Pharmacologic interaction (potential risk of torsades de pointes-type ventricular tachycardia) with drugs or herbal supplements that prolong the QT interval; concomitant use contraindicated.¹ ⁹ (See Contraindications under Cautions.)

Drugs Affected by the P-glycoprotein Transport System

Potential pharmacokinetic interaction (increased exposure to substrates of P-glycoprotein transport system [e.g., digoxin] expected) when used concomitantly with dronedarone.¹ Some clinicians state that dronedarone should be used with caution in patients receiving drugs with a narrow therapeutic index that are metabolized by the P-glycoprotein transport system.²⁵

Specific Drugs and Food

Drug	Interaction	Comments
Antiarrhythmic agents, class I or III (e.g., amiodarone, disopyramide, dofetilide, flecainide, propafenone, quinidine, sotalol)	Potential risk of torsades de pointes-type ventricular tachycardia¹	Concomitant use contraindicated¹
Anticoagulants, oral (e.g., warfarin)	Increased exposure to S-warfarin in healthy individuals; no change in exposure to R-warfarin or clinically important increases in the INR¹ No excess risk of bleeding observed with concomitant use of dronedarone and oral anticoagulants in patients with atrial fibrillation/flutter¹	Monitor INR according to manufacturers’ labeling for warfarin¹
Antidepressants, SSRI	Possible increased exposure to SSRI¹
Antidepressants, tricyclic	Potential risk of torsades de pointes-type ventricular tachycardia¹ Possible increased exposure to tricyclic antidepressants¹	Concomitant use contraindicated¹
β-Adrenergic blocking agents (e.g., metoprolol, propranolol)	Increased incidence of bradycardia observed¹ Increased exposure to metoprolol and propranolol; possible increased exposure to other β-adrenergic blocking agents that are CYP2D6 substrates¹	If used with β-adrenergic blocking agents, use lower initial dosage of the β-adrenergic blocking agent and increase dosage of β-adrenergic blocker only if well tolerated as documented by ECG¹ ⁹
Calcium-channel blocking agents (e.g., diltiazem, nifedipine, verapamil)	Calcium-channel blocking agents with depressant effects on the sinus and AV nodes may potentiate the conduction effects of dronedarone¹ Dronedarone increases exposure to calcium-channel blocking agents (verapamil, diltiazem, nifedipine); verapamil and diltiazem increase exposure to dronedarone¹	If used with calcium-channel blocking agents, use lower initial dosage of the calcium-channel blocking agent and increase dosage of calcium-channel blocker only if well tolerated as documented by ECG¹ ⁹
Carbamazepine	Substantially decreased exposure to dronedarone due to CYP3A induction¹	Avoid concomitant use¹
Cyclosporine	Increased peak plasma concentrations of, and exposure to, dronedarone¹	Concomitant use contraindicated¹
Digoxin	Possible potentiation of electrophysiologic effects of dronedarone (e.g., decreased AV node conduction)¹ Increased exposure to digoxin and increased digoxin concentrations¹ Increased incidence of GI disorders observed¹	When initiating dronedarone therapy, reassess need for continued digoxin therapy; discontinue digoxin or reduce digoxin dosage by 50%¹ Monitor serum digoxin concentrations; close observation for signs of digoxin toxicity recommended¹
Grapefruit juice	Increased peak plasma concentrations of, and exposure to, dronedarone¹	Avoid grapefruit juice during dronedarone therapy¹ ⁹
HMG-CoA reductase inhibitors (statins)	Increased exposure to simvastatin and simvastatin acid¹	Consult manufacturer’s labeling for the respective statin for specific recommendations regarding concomitant use with CYP3A or P-glycoprotein transport system inhibitors such as dronedarone¹
Itraconazole	Increased peak plasma concentrations of, and exposure to, dronedarone¹	Concomitant use contraindicated¹
Ketoconazole	Increased peak plasma concentrations of, and exposure to, dronedarone¹	Concomitant use contraindicated¹
Losartan	No drug interaction observed¹
Macrolides	Clarithromycin, telithromycin: Increase exposure to and peak plasma concentrations of dronedarone¹ Certain oral macrolides: Potential risk of torsades de pointes-type ventricular tachycardia¹	Clarithromycin, telithromycin, and certain oral macrolides: Concomitant use with dronedarone contraindicated¹
Nefazodone	Increased peak plasma concentrations of, and exposure to, dronedarone¹	Concomitant use contraindicated¹
Oral contraceptives	No decreases in ethinyl estradiol or levonorgestrel concentrations observed in healthy individuals¹
Pantoprazole	No clinically important effect on the pharmacokinetics of dronedarone¹
Phenobarbital	Substantially decreased exposure to dronedarone due to CYP3A induction¹	Avoid concomitant use¹
Phenothiazines	Potential risk of torsades de pointes-type ventricular tachycardia¹	Concomitant use contraindicated¹
Phenytoin	Substantially decreased exposure to dronedarone due to CYP3A induction¹	Avoid concomitant use¹
Potassium-depleting diuretics	Possible hypokalemia or hypomagnesemia¹	Ascertain that serum potassium and magnesium concentrations are within normal range prior to initiation of dronedarone; maintain within normal range during therapy¹
Rifampin	Decreased exposure to dronedarone due to CYP3A induction¹	Avoid concomitant use¹
Ritonavir	Increased peak plasma concentrations of, and exposure to, dronedarone¹	Concomitant use contraindicated¹
St. John’s wort	Substantially decreased exposure to dronedarone due to CYP3A induction¹	Avoid concomitant use¹
Sirolimus	Possible increased plasma concentrations of sirolimus;¹ initiation of dronedarone therapy in one patient receiving sirolimus post-kidney transplantation resulted in a threefold increase in trough sirolimus concentrations from baseline²⁵	Monitor plasma concentrations of sirolimus and adjust dosage appropriately when used concomitantly with dronedarone¹ Some clinicians recommend avoidance of concurrent use of sirolimus and dronedarone when possible. If concurrent administration cannot be avoided, a 50–75% reduction in sirolimus dosage prior to dronedarone initiation has been suggested; monitor trough sirolimus concentrations regularly (possibly even daily) during titration phase²⁵
Tacrolimus	Possible increased plasma concentrations of tacrolimus¹	Monitor plasma concentrations of tacrolimus and adjust dosage appropriately during concomitant use¹
Theophylline	No apparent increase in steady-state exposure to theophylline¹
Voriconazole	Increased peak plasma concentrations of, and exposure to, dronedarone¹	Concomitant use contraindicated¹

Multaq Pharmacokinetics

Absorption and Distribution

Bioavailability

Low systemic bioavailability; undergoes first-pass metabolism.¹ Absolute bioavailability about 4% when administered without food.¹

Steady-state concentrations achieved within 4–8 days following repeated oral administration of dronedarone 400 mg twice daily.¹

Food

Food increases bioavailability; bioavailability approximately 15% when administered with a high-fat meal.¹

Peak plasma concentrations of dronedarone and N-debutyl metabolite reached within 3–6 hours following oral administration with food.¹

Special Populations

Exposure to dronedarone increased by 23% in patients ≥65 years of age compared with that in younger adults.¹ (See Geriatric Use under Cautions.)

Mean exposure to dronedarone increased by 1.3-fold in patients with moderate hepatic impairment compared with individuals with normal hepatic function; mean exposure to N-debutyl metabolite decreased by about 50%.¹ (See Hepatic Impairment under Cautions.)

Pharmacokinetics not studied in patients with severe hepatic impairment; contraindicated in such patients.¹

No apparent differences in pharmacokinetics observed in healthy individuals with mild or moderate renal impairment versus those with normal renal function, or in patients with atrial fibrillation and mild to severe renal impairment versus those with normal renal function.¹ ⁹ (See Renal Impairment under Cautions.)

Exposure to dronedarone averages 30% higher in women than in men.¹

Pharmacokinetic differences related to race not formally studied.¹ However, based on a cross-study comparison, exposure to dronedarone twofold higher in Asian men (of Japanese ancestry) than in Caucasian men following single-dose administration of dronedarone 400 mg.¹

Distribution

Extent

Dronedarone and its metabolites distributed into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

Dronedarone and N-debutyl metabolite are >98% bound to plasma proteins (mainly albumin); binding not saturable.¹

Elimination

Metabolism

Extensively metabolized, mainly by CYP3A.¹

Initial metabolic pathway includes N-debutylation to form active N-debutyl metabolite, oxidative deamination to form inactive propanoic acid metabolite, and direct oxidation.¹ Metabolites further metabolized to >30 uncharacterized metabolites.¹ N-debutyl metabolite exhibits pharmacodynamic activity; only up to one-third as potent as dronedarone.¹

Elimination Route

Excreted in urine (6%) and in feces (84%) mainly as metabolites; no unchanged drug excreted in urine.¹

Half-life

13–19 hours following IV administration.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

Actions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Mechanism of antiarrhythmic action not fully elucidated; exact contribution of activities in each of the 4 Vaughan-Williams antiarrhythmic classes to the clinical effect of the drug unknown.¹ ⁵

Benzofuran derivative structurally related to amiodarone, but with structural modifications that include removal of the iodine group and addition of a methane-sulfonyl group.¹ ² ³ ⁵ ⁶ ⁷ ⁸ ¹⁶

Removal of the iodine group intended to reduce risk of nontarget organ (e.g., thyroid, pulmonary) adverse effects associated with amiodarone therapy; addition of the methane-sulfonyl group aimed at reducing lipophilicity, decreasing risk of neurotoxic adverse effects, and shortening half-life of dronedarone.² ³ ⁵ ⁶ ⁸ ¹⁶

Electrophysiologic profile similar to amiodarone, but with different relative effects on individual ion channels.² ³ ⁴ ⁵ ⁶

Prolongs action potential duration (APD) mainly by inhibition of potassium channels, including transmembrane delayed rectifier, ultrarapid delayed rectifier, inward rectifier, and transient outward potassium currents.⁵ ⁶

Inhibits sodium currents (at rapid pacing rates), calcium channels and slow L-type calcium currents, and demonstrates noncompetitive, antiadrenergic (α- and β-blocking) activity.⁵ ⁶ ⁸ ¹⁶

Prolongs PR interval and slows sinus rate by prolonging atrial and ventricular refractory periods.¹ ⁸

Prolongs RR and QT intervals.⁵ ⁶

Produces a dose-dependent increase in PR interval and a moderate prolongation of the QT_c interval similar to amiodarone.¹ ⁵ ⁸

Advice to Patients

Importance of instructing patients to carefully read the manufacturer’s patient information (medication guide) before initiating therapy and each time the prescription is refilled.¹

Importance of informing clinician if signs or symptoms of heart failure (e.g., weight gain, dependent edema, increasing shortness of breath) occur.¹

Importance of advising patients receiving dronedarone to immediately report symptoms suggesting hepatic injury (e.g., anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, itching).²⁸

Importance of taking dronedarone with a meal.¹

Importance of advising patients to avoid grapefruit juice while taking dronedarone.¹ (See Specific Drugs and Food under Interactions.)

Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity of advising women to avoid pregnancy and breast-feeding during dronedarone therapy.¹ ⁹ Necessity of advising women of childbearing potential to use an effective method of contraception while receiving therapy and importance of advising these patients regarding appropriate contraceptive choices (taking into consideration their underlying medical conditions and lifestyle preferences).¹ If pregnancy occurs, advise patient of risk to the fetus.¹

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses (e.g., heart failure, rhythm disturbance other than atrial fibrillation/flutter, uncorrected hypokalemia).¹

Importance of advising patients that if a dose of dronedarone is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled.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.

Dronedarone Hydrochloride
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	400 mg (of dronedarone)	Multaq	Sanofi-Aventis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Multaq 400MG Tablets (SANOFI-AVENTIS U.S.): 60/$276.00 or 180/$766.01

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 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Sanofi-Aventis. Multaq (dronedarone hydrochloride) tablets prescribing information. Bridgewater, NJ; 2009 Jul.

2. Hohnloser SH, Crijns HJ, van Eickels M et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009; 360:668-78. [PubMed 19213680]

3. Singh BN, Connolly SJ, Crijns HJ et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007; 357:987-99. [PubMed 17804843]

4. Køber L, Torp-Pedersen C, McMurray JJ et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008; 358:2678-87. [PubMed 18565860]

5. Hoy SM, Keam SJ. Dronedarone. Drugs. 2009; 69:1647-63. [PubMed 19678715]

6. Riera AR, Uchida AH, Ferreira C et al. Relationship among amiodarone, new class III antiarrhythmics, miscellaneous agents and acquired long QT syndrome. Cardiol J. 2008; 15:209-19. [PubMed 18651412]

7. Coletta AP, Cleland JG, Cullington D et al. Clinical trials update from Heart Rhythm 2008 and Heart Failure 2008: ATHENA, URGENT, INH study, HEART and CK-1827452. Eur J Heart Fail. 2008; 10:917-20. [PubMed 18678526]

8. Garcia D, Cheng-Lai A. Dronedarone: a new antiarrhythmic agent for the treatment of atrial fibrillation. Cardiol Rev. 2009 Sep-Oct; 17:230-4.

9. Sanofi-Aventis, Bridgewater, NJ: Personal communication.

10. Sanofi-Aventis. Healthcare professional information sheet for Multaq (dronedarone). 2009 Jul. Available from website. Accessed 2010 Mar 11.

11. Sanofi-Aventis. Prescribing Multaq: Information for health care professionals. 2009 Dec. Available from website. Accessed 2010 Mar 18.

12. Sanofi-Aventis. Risk evaluation and mitigation strategy (REMS): NDA 22-425 Multaq (dronedarone). 2009 Jun 9. Available from website. Accessed 2010 Mar 18.

13. Tschuppert Y, Buclin T, Rothuizen LE et al. Effect of dronedarone on renal function in healthy subjects. Br J Clin Pharmacol. 2007; 64:785-91. [PubMed 17662087]

14. Le Heuzey JY, De Ferrari GM, Radzik D et al. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation. The DIONYSOS study. J Cardiovasc Electrophysiol. 2010 Jun; 21:597-605. [PubMed 20384650]

15. Savelieva I, Camm J. Update on atrial fibrillation: part II. Clin Cardiol. 2008; 31:102-8. [PubMed 18383050]

16. Zimetbaum PJ. Dronedarone for atrial fibrillation—an odyssey. N Engl J Med. 2009 Apr; 360:1811-3. Commentary. [PubMed 19403901]

17. Schafer JA, Kjesbo NK, Gleason PP. Dronedarone: current evidence and future questions. Cardiovasc Ther. 2010; 28:38-47. [PubMed 20074258]

18. Singh D, Cingolani E, Diamond GA et al. Dronedarone for atrial fibrillation. Have we expanded the therapeutic armamentarium? JACC. 2010; 55:1569-76. Commentary. [PubMed 20378073]

19. Ezekowitz MD. Maintaining sinus rhythm—making treatment better than the disease. N Engl J Med. 2009; 357:1039-41. Editorial. [PubMed 17804851]

20. Wyse DG, Waldo AL, DiMarco JP et al, for theAtrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002 Dec 5;347:1825-33. [PubMed 12466506]

21. Falk RH. Management of atrial fibrillation—ra

Monday, March 12, 2012

Simethicone

Class: Antiflatulents
VA Class: GA900
CAS Number: 8050-81-5
Brands: Alka-Seltzer Gas Relief, Flatulex, GasAid, Gas-X, Genasyme, Imodium Advanced, Maalox Anti-Gas, Mylanta Gas Relief, Mylicon, Phazyme

Introduction

Antiflatulent; antifoaming agent.^a

Uses for Simethicone

Flatulence, Functional Gastric Bloating, and Postoperative Gas Pains

Adjunct for symptomatic treatment of flatulence, functional gastric bloating, and postoperative gas pain.^a

Self-medication as an antiflatulent to relieve symptoms of gas (e.g., upper GI bloating, pressure, fullness, stuffed feeling).¹⁰² ¹⁰³ ¹⁰⁴ ¹⁰⁵

Has been used prior to gastroscopy to enhance visualization and prior to radiography of the intestine to reduce gas shadows.^a

Infant Colic

Not recommended for treatment of infant colic.^a (See Pediatric Use under Cautions.)

Immediate Postprandial Upper Abdominal Distress

Efficacy not established for the symptomatic relief of immediate postprandial upper abdominal distress (IPPUAD);¹⁰¹ ¹⁰² no conclusive evidence that excessive gas causes IPPUAD.¹⁰⁰ ¹⁰¹

Intestinal Distress

Efficacy not established for symptomatic relief of intestinal distress; ¹⁰⁰ ¹⁰¹ no conclusive evidence that gas causes intestinal distress symptoms.¹⁰⁰ ¹⁰¹

Simethicone Dosage and Administration

Administration

Oral Administration

Administer orally after meals and at bedtime, usually in up to 4 divided doses daily; infant drops (oral suspension) can be administered in up to 12 doses daily.^a ^b

Chewable Tablets

Chew thoroughly before swallowing.^a

Oral Suspension

Generally used in infants.^b Shake drops well before use; use dosing device provided by manufacturer for measurement of the dose.^b

Dose may be mixed with 1 ounce cool water, infant formula, or other suitable liquids prior to administration.^b

Orally Dissolving Strips

Place strips on tongue to dissolve.^g

Dosage

Pediatric Patients

Flatulence, Functional Gastric Bloating, and Postoperative Gas Pain

Oral

Usual dosage in children >12 years of age: 40–125 mg 4 times daily as needed after meals and at bedtime.^a

Self-medication in children <2 years of age (<10.9 kg): 20 mg (0.3 mL) as needed after meals and at bedtime as oral drops; do not exceed 12 doses (i.e., 240 mg) daily.^b

Self-medication in children 2–12 years of age (>10.9 kg): 40 mg as needed after meals and at bedtime; do not exceed 12 doses (i.e., 480 mg) daily.^b

Self-medication in children >12 years of age: 40–125 mg as needed after meals and at bedtime; do not exceed 500 mg daily.^a

Adults

Flatulence, Functional Gastric Bloating, and Postoperative Gas Pain

Oral

Usual dosage: 40–125 mg 4 times daily as needed after meals and at bedtime.^a

Self-medication: 40^a –250^c mg as needed after meals and at bedtime; do not exceed 500 mg daily.^a ¹⁰⁵

Diagnostic Aid Prior to Gastroscopy or Radiography of the Intestine

Oral

67 mg as a single dose of oral suspension, in 2.5 mL of water.^a

Prescribing Limits

Pediatric Patients

Flatulence, Functional Gastric Bloating, and Postoperative Gas Pain

Oral

Self-medication in children <2 years of age (weight <10.9 kg): Maximum 12 doses (i.e., 240 mg) daily.^b

Self-medication in children 2–12 years of age (weight >10.9 kg): Maximum 12 doses (i.e., 480 mg) daily.^b

Self-medication in children >12 years of age: Maximum 500 mg daily.^a

Adults

Flatulence, Functional Gastric Bloating, and Postoperative Gas Pain

Oral

Self-medication: Maximum 500 mg daily.^a ¹⁰⁵

Special Populations

No special population dosage recommendations at this time.^a

Cautions for Simethicone

Warnings/Precautions

General Precautions

Simethicone is apparently nontoxic; no adverse effects reported.^a

Use of Fixed Combination

When used in fixed combination with other agents, consider the cautions, precautions, and contraindications associated with the concomitant agents.

Specific Populations

Pregnancy

Category C.^d

Lactation

Distribution into milk not expected; simethicone not orally absorbed.^d

Pediatric Use

Safety information in infants and children limited; not recommended for treatment of infant colic.^a

Simethicone Pharmacokinetics

Absorption

Bioavailability

Not absorbed following oral administration.^a

Food

Does not interfere with the absorption of nutrients or with gastric secretion.^a

Elimination

Elimination Route

Excreted unchanged in feces.^a

Stability

Storage

Oral

Capsules, Liquid-filled

20–25°C; avoid temperatures >40°C.^e ^f Protect from moisture.^f

Strips, Orally Dissolving

20–25°C.^g Protect from moisture.^g

Tablets and Chewable Tablets

Tight, well-closed containers at <40°C; preferably 15–30°C.^a Avoid high humidity.^c

Suspension

Tight, light resistant containers at <40°C; preferably 15–30°C.^a Avoid freezing.^a ^b

ActionsActions

Silicone antifoams spread on the surface of aqueous liquids, forming a low surface tension film and causing collapse of foam bubbles.^a

May allow mucus-surrounded gas bubbles in the GI tract to coalesce and be expelled.^a

Advice to Patients

Importance of not exceeding recommended self-medication dosage, unless otherwise instructed by a clinician.^b

Advise patients to dispense recommended dose of infant drops (oral suspension) slowly into the infant's mouth with enclosed dropper, toward the inner cheek.^b

Advise patients that oral suspension may be mixed with 1 ounce cool water, infant formula, or other suitable liquids.^b

Importance of not chewing liquid-filled capsules.^a

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

Preparations

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

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Simethicone
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules, liquid-filled	125 mg	Alka-Seltzer Gas Relief Maximum Strength Softgels	Bayer
			GasAid Maximum Strength Softgels	McNeil
			Gas-X Extra Strength Softgels	Novartis
			Mylanta Gas Maximum Strength Softgels	J&J-Merck
		180 mg	Phazyme-Ultra Strength Gas Relief Softgels	GlaxoSmithKline
	Strips, orally dissolving	62.5 mg	Gas-X Thin Strips	Novartis
	Suspension	40 mg/0.6 mL*	Baby Gas-X Infant Drops	Novartis
			Flatulex Drops	Dayton
			Genasyme Drops	Teva
			Mylicon Infant’s Drops	J&J-Merck
	Tablets, chewable	80 mg*	Gas-X (scored)	Novartis
			Genasyme	Teva
			Maalox Anti-Gas Regular Strength	Novartis
		125 mg	Gas-X Extra Strength (scored)	Novartis
			Mylanta Gas Relief Maximum Strength (scored)	J&J-Merck
			Simethicone Tablets	Rugby
		150 mg	Maalox Anti-Gas Extra Strength	Novartis

Simethicone is also commercially available in combination with antacids, antispasmodics, and digestants.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Simethicone Combinations
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	125 mg with Loperamide Hydrochloride 2 mg	Imodium Advanced Caplets	McNeil
	Tablets, chewable	125 mg with Loperamide Hydrochloride 2 mg*	Imodium Advanced Chewable Tablets	McNeil

Disclaimer

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

References

Only references cited for selected revisions after 1984 are available electronically.

100. Food and Drug Administration. Digestive aid products for over-the-counter human use; establishment of a monograph. [21 CFR Part 357; Docket No. 81N-0106] Fed Regist. 1982; 47:454-87.

101. Food and Drug Administration. Digestive aid products for over-the-counter human use; tentative final monograph. [21 CFR Part 357; Docket No. 81N-0106] Fed Regist. 1988; 53:2706-14. (IDIS 240339)

102. Food and Drug Administration. Antiflatulent drug products for over-the-counter human use; proposed amendment of monograph. [21 CFR Part 332; Docket No. 87N-0053] Fed Regist. 1988; 53:2716-7. (IDIS 240340)

103. Food and Drug Administration. Over-the-counter drugs: proposal establishing a monograph for antacid products. [21 CFR Part 130] Fed Regist. 1973; 38:8714-24.

104. Food and Drug Administration. Over-the-counter drugs generally recognized as safe and effective and not misbranded: tentative final order for antacid products. [21 CFR Part 130] Fed Regist. 1973; 38:31258-69.

105. Food and Drug Administration. Antacid products for over-the-counter (OTC) human use. Antiflatulent products for over-the-counter (OTC) human use. Final order for antacid and antiflatulent products generally recognized as safe and effective and not misbranded. [21 CFR Parts 331 and 332] Fed Regist. 1974; 39:19862-77.

a. AHFS drug information 2007. McEvoy GK, ed. Simethicone. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2918-9.

b. Johnson & Johnson. Infants' Mylicon Drops (simethicone) product information. 2006 June. From Mylicon webiste.

c. Johnson & Johnson. Mylanta Gas Maximum Strength Chewable Tablets (simethicone) product information. 2006 June. From Mylanta website.

d. Simethicone. In: Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:1469.

e. Bayer Consumer Care. Alka-Seltzer Gas Relief (simethicone) Liquid Softgels product information. Undated. From product website. Accessed 2007 Jul 12.

f. Novartis Consumer Health. Gas-X (simethicone) Maximum Strength Softgels product information. Undated. From product website. Accessed 2007 Jul 12.

g. Novartis Consumer Health. Gas-X (simethicone) Thin Strips product information. Undated. From product website. Accessed 2007 Jul 12.

More Simethicone resources

Simethicone Use in Pregnancy & Breastfeeding
Drug Images
Simethicone Support Group
2 Reviews for Simethicone - Add your own review/rating

Simethicone MedFacts Consumer Leaflet (Wolters Kluwer)

Simethicone Professional Patient Advice (Wolters Kluwer)

simethicone Concise Consumer Information (Cerner Multum)

simethicone Advanced Consumer (Micromedex) - Includes Dosage Information

Bicarsim MedFacts Consumer Leaflet (Wolters Kluwer)

Gas-X Chewable Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Gas-X Infant Drops Liquid Drops MedFacts Consumer Leaflet (Wolters Kluwer)

Genasyme Suspension MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Simethicone with other medications

Endoscopy or Radiology Premedication
Functional Gastric Disorder
Gas
Postoperative Gas Pains

Saturday, March 10, 2012

Temazepam 10mg / 5ml Oral Solution

1. Name Of The Medicinal Product

Temazepam 10mg/5ml Oral Solution

2. Qualitative And Quantitative Composition

Temazepam BP 10mg/5ml

3. Pharmaceutical Form

An elixir containing 10mg Temazepam BP per 5ml for oral administration.

4. Clinical Particulars

4.1 Therapeutic Indications

Temazepam is indicated for the short term treatment of sleep disturbances, considered severe or disabling or where insomnia is subjecting the individual to extreme distress. This product is especially useful in those patients for whom particularly rapid onset of hypnotic action is required and for whom the persistence of hypnotic effect after rising would be undesirable.

Temazepam is particularly suitable for patients with transient sleep disorders in whom re-establishment of normal sleep patterns is expected following the resolution of precipitating factors.

It is also indicated for pre-medication for minor surgical and investigative procedures, especially in the case of outpatients.

4.2 Posology And Method Of Administration

For oral administration only.

Adults:

Insomnia: Each 5ml dose of Temazepam Elixir is equivalent to 10mg Temazepam. The usual dose is 5 - 15ml orally on retiring; a dose of 10ml will be found to be satisfactory for most patients. This may be increased to 15 - 20ml (30 - 40mg Temazepam) in patients who do not respond to the lower dose. Lower doses may be adequate for some patients, as for the elderly.

Pre- medication

10 - 20ml from half an hour to one hour prior to surgery or investigative procedures.

Elderly:

Elderly patients or those suffering from cerebral vascular changes such as arteriosclerosis are likely to respond to smaller doses. Half the normal dose, 2.5 to 7.5ml (5 - 15mg) may be sufficient for a therapeutic response.

Children:

Insomnia: Not recommended

Pre-medication:

1mg (0.5ml)/Kg one hour prior to surgery or investigative procedures.

Treatment should if possible be intermittent. The lowest dose which can control symptoms should be used. It should not be continued beyond 4 weeks.

Long term chronic use is not recommended.

Treatment should always be tapered off gradually. Patients who have taken benzodiazepines for a long time may require a longer period during which doses are reduced.

4.3 Contraindications

Myasthenia gravis

Known hypersensitivity to Benzodiazepines.

Severe respiratory insufficiency.

Sleep apnoea syndrome.

Severe hepatic insufficiency.

Phobic or obsessional state; chronic psychosis

Mild anxiety states

Acute narrow angle glaucoma

As monotherapy in patients with depression or those with anxiety and depression (suicide may be precipitated in these patients)

4.4 Special Warnings And Precautions For Use

Doses of 30mg and above are more likely to cause hangover effects to persist into the following day than lower doses, particularly in patients unused to hypnotics and in the elderly. As with all compounds which have an effect on the CNS, patients should be advised not to consume alcohol whilst taking temazepam.

An underlying cause for insomnia should be sought before deciding upon the use of benzodiazepines for symptomatic relief.

Temazepam should be given with caution to patients with chronic pulmonary insufficiency, or those with renal or hepatic dysfunction.

Where Temazepam is used as a medication before surgical or investigative procedures, the patients should be accompanied home.

Tolerance: Some loss of efficacy to the hypnotic effects of short acting benzodiazepines may develop after repeated use for a few weeks

Psychiatric and 'paradoxical' reactions: reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. Should this occur, use of the product should be discontinued. These reactions are more likely to occur in the elderly.

Benzodiazepines are not recommended for the primary treatment of psychotic illness.

Dependence potential and withdrawal symptoms: In general, the dependence potential of benzodiazepines is low, but this increases when high dosage is used, 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. Regular monitoring of treatment in such patients is essential and routine repeat prescriptions should be avoided.

Treatment in all patients should be withdrawn gradually as symptoms such as depression, nervousness, rebound insomnia, irritability, sweating, headaches, dizziness, impaired concentration, tinnitus, loss of appetite, tremor, perceptual disturbances, nausea, vomiting, abdominal cramps, palpitations, mild systolic hypertension, tachycardia, orthostatic hypotension, photophobia, hyperacusis, muscle pain, extreme anxiety, tension, restlessness, confusion and diarrhoea have been reported following abrupt cessation of treatment with benzodiazepines in patients receiving even normal therapeutic doses for short periods of time. Abrupt withdrawal following excessive dosage may produce confusion, toxic psychosis, convulsions, derealisation, depersonalisation, tingling of extremities, hypersensitivity to light, noise and physical contact, hallucinations, epileptic seizures or a condition resembling delirium tremens. Broken sleep with vivid dreams may persist for some weeks after withdrawal.

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.

In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.

Extreme caution should be used in prescribing benzodiazepines in patients with personality disorders.

Excipient Warnings

This product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

This product contains 10%v/v ethanol, i.e. up to 395mg per dose equivalent to 10ml of beer or 4ml of wine per dose. It is harmful for those suffering from alcoholism. It should be taken into account in high-risk groups such as patients with liver disease or epilepsy. It may modify or increase the effect of other medicines.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The concurrent use of other CNS depressants such as general anaesthetics, antipsychotics, monoamine oxidase inhibitors, anxiolytics/sedatives, sedative antihistamines, anti-depressants and hypnotics, lofexidine and nabilone should be avoided as it will result in an enhancement of the central depressive effect. In the case of narcotic analgesics enhancement of the euphoria may also occur leading to an increase in psychotic dependence.

Alcohol - Concomitant intake is not recommended.

The sedative effects may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.

Antiepileptic drugs– plasma phenytoin concentrations may be increased or decreased by temazepam. Phenytoin levels may need monitoring during temazepam withdrawal. Side effects may be more evident with hydantoins or barbiturates.

Antihypertensives– enhanced hypotensive effects. Enhances sedative effect with alpha blockers or moxonidine.

Antivirals– concurrent use of zidovudine with benzodiazepines may decrease zidovudine clearance. Ritonavir may inhibit benzodiazepine hepatic metabolism

Clozapine– reports of cardiorespiratory collapse. Also increase in hypersalivation with both drugs.

Disulfiram– inhibits the metabolism of benzodiazepines and enhances sedative effect. May cause temazepam toxicity.

Dopaminergics– concurrent use with benzodiazepines may decrease the therapeutic effects of levodopa.

Muscle relaxants– Baclofen and Tizanidine – enhanced sedative effect.

4.6 Pregnancy And Lactation

Insufficient data are available on temazepam to assess its safety during pregnancy and lactation. If the product is prescribed to a woman of child bearing age, she should be warned to contact her physician about stopping the product if she intends to become, or suspects that she is, pregnant. If for compelling medical reasons, temazepam is administered during the late phase of pregnancy, or during labour, effects on the neonate, such as hypothermia, hypotonia, and moderate respiratory depression, can be expected due to the pharmacological action of the product. Moreover, infants born to mothers who took benzodiazepines chronically during the later stages of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.

Since benzodiazepines are found in breast milk, temazepam should not be administered to breast feeding mothers.

4.7 Effects On Ability To Drive And Use Machines

Sedation, amnesia and impaired muscular function may adversely affect the ability to drive or use machines. If insufficient sleep occurs, the likelihood of impaired alertness may be increased (see also Interactions).

4.8 Undesirable Effects

Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnesia may be associated with inappropriate behaviour. In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.

Common adverse effects of benzodiazepines include drowsiness, sedation, blurring of vision, unsteadiness, numbed emotions, reduced alertness, dizziness, muscle weakness, ataxia, fatigue, respiratory depression or slurred speech. These phenomena occur predominantly at the start of therapy and usually disappear thereafter. These symptoms are likely to be potentiated by alcohol. The elderly are more liable to experience such effects.

Abnormal psychological reaction to benzodiazepines has been reported.

Rare behavioural adverse effects include paradoxical aggressive outbursts, excitement, confusion, restlessness, agitation, irritability, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and the uncovering of depression with suicidal tendencies. Should this occur, use of the product should be discontinued. Extreme caution should therefore be used in prescribing benzodiazepines in patients with personality disorders. These reactions are more likely to occur in the elderly.

Other adverse effects, including hypotension, gastro-intestinal and visual disturbances, skin rashes, urinary retention, headache, vertigo, changes in libido, dry mouth, restless sleep, dysarthria, tremor, hypersalivation, hypersensitivity, incontinence, blood dyscrasias and jaundice have been reported occasionally.

Dependence: Use (even at therapeutic doses) may lead to the development of physical dependence: Discontinuation of therapy may result in withdrawal of rebound phenomena (See warnings and precautions). Psychotic dependence may occur. Abuse has been reported in polydrug users.

4.9 Overdose

Symptoms

Benzodiazepines commonly cause drowsiness, ataxia, dysarthria, mental confusion and nystagmus. Coma, hypotension, hypotonia 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 1mg/kg within 1 hour, provided they are not too drowsy. The benefit of gastric decontamination is uncertain. Gastric lavage is unnecessary if these drugs have been taken alone. The value of dialysis has not been determined for temazepam. 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

Temazepam has a similar pharmacological action to Oxazepam and Diazepam, that is central nervous system sedation, anxiolysis and muscle relaxation. Animal studies show anticonvulsant activity. These effects are likely to be due to potentiation of gamma-aminobutyric acid (GABA) although other neurotransmitters may also be affected. Evidence suggests a close molecular association between the sites and action for GABA and the benzodiazepines.

5.2 Pharmacokinetic Properties

Reported elimination half-life values for Temazepam after night time administration in young volunteers vary from 5.3 - 11.5 hours. There is, however, an approximately 30% increase in the half-life of Temazepam when taken in the morning. The mean elimination half-life values in young volunteers after morning administration vary from 8.3 - 13.6 hours. In the elderly the half-life may be longer with a mean value of about 15 hours. The half-life in elderly women may be longer than in elderly men.

5.3 Preclinical Safety Data

None

6. Pharmaceutical Particulars

6.1 List Of Excipients

Ethanol

Propylene Glycol

Peppermint Oil

Caramel E150

Trometamol

Citric Acid Monohydrate

Patent Blue V E131

Glycerol

Sorbitol Solution 70%

Purified Water

6.2 Incompatibilities

None known

6.3 Shelf Life

24 months

After opening 3 months

6.4 Special Precautions For Storage

Store between 4°C and 25°C and protect from light.

6.5 Nature And Contents Of Container

100ml, 150ml, 200ml, 300ml, 450ml and 500ml amber glass bottles. Aluminium, wadded, roll-on pilfer proof closures or HDPE, EPE wadded, tamper evident child resistant closures or HDPE, EPE wadded, tamper evident closures.

6.6 Special Precautions For Disposal And Other Handling

Keep out of the reach of children.

Administrative Data

7. Marketing Authorisation Holder

Rosemont Pharmaceuticals Ltd

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

8. Marketing Authorisation Number(S)

PL 00427/0089

9. Date Of First Authorisation/Renewal Of The Authorisation

26.9.95

10. Date Of Revision Of The Text

13 Jan 2010

Wednesday, March 7, 2012

Chenodal

chenodiol

Dosage Form: tablet, film coated
Chenodal 250 mg (chenodiol tablets)

Rx only

NDC 45043-876-40

Chenodal 250 mg

(Chenodiol Tablets)

100 Tablets

Manchester Pharmaceuticals, Inc.

Each Film-Coated Tablet Contains: Chenodiol 250 mg



Usual Adult Dosage: Please see package insert for detailed prescribing information.



Store and Dispense: Store at 200 to 250C (680 to 770F). [see USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.



KEEP THIS AND ALL MEDICATION OUT OF THE REACH OF CHILDREN.



Manufactured for: Manchester Pharmaceuticals, Inc.

                                    Fort Collins, CO 80525

                                    866-758-7068

Bar code

45043 87640

Lot No.:

Exp. Date:

SPECIAL NOTE

Because of the potential hepatoxicity of Chenodal, poor response rate in

some subgroups of Chenodal treated patients, and an increased rate of a need

for cholecystectomy in other Chenodal treated subgroups, Chenodal is not an

appropriate treatment for many patients with gallstones. Chenodal should be

reserved for carefully selected patients and treatment must be accompanied by

systematic monitoring for liver function alterations. Aspects of patient

selection, response rates and risks versus benefits are given in the insert.

Chenodal Description

Chenodiol is the non-proprietary name for chenodeoxycholic acid,

a naturally occurring human bile acid. It is a bitter-tasting white powder

consisting of crystalline and amorphous particles freely soluble in methanol,

acetone and acetic acid and practically insoluble in water. Its chemical name is

3α, 7α-dihydroxy-5β-cholan-24-oic acid (C24H40O4), it has a molecular weight of

392.58, and its structure is shown below;

Chenodiol film-coated tablets for oral administration contain 250 mg of

chenodiol.

Inactive ingredients: pregelatinized starch; silicon dioxide;

microcrystalline cellulose, sodium starch glycollate; and magnesium stearate;

the thin-film coating contains: opadry YS-2-7035 [consisting of methylcellulose

and glycerin] and sodium lauryl sulfate

Chenodal - Clinical Pharmacology

At therapeutic doses, chenodiol suppresses hepatic synthesis of

both cholesterol and cholic acid, gradually replacing the latter and its

metabolite, deoxycholic acid in an expanded bile acid pool. These actions

contribute to biliary cholesterol desaturation and gradual dissolution of

radiolucent cholesterol gallstones in the presence of a gall-bladder visualized

by oral cholecystography. Chenodiol has no effect on radiopaque (calcified)

gallstones or on radiolucent bile pigment stones.

Chenodiol is well absorbed from the small intestine and taken up by the liver

where it is converted to its taurine and glycine conjugates and secreted in

bile. Owing to 60 % to 80% first-pass hepatic clearance, the body pool of

chenodiol resides mainly in the enterohepatic circulation; serum and urinary

bile acid levels are not significantly affected during chenodiol therapy.

At steady-state, an amount of chenodiol near the daily dose escapes to the

colon and is converted by bacterial action to lithocholic acid. About 80% of the

lithocholate is excreted in the feces; the remainder is absorbed and converted

in the liver to its poorly absorbed sulfolithocholyl conjugates. During

chenodiol therapy there is only a minor increase in biliary lithocholate, while

fecal bile acids are increased three- to fourfold.

Chenodiol is unequivocally hepatotoxic in many animal species, including

sub-human primates at doses close to the human dose. Although the theoretical

cause is the metabolite, lithocholic acid, an established hepatotoxin, and man

has an efficient mechanism for sulfating and eliminating this substance, there

is some evidence that the demonstrated hepatotoxicity is partly due to chenodiol

per se. The hepatotoxicity of

lithocholic acid is characterized biochemically and morphologically as

cholestatic.

Man has the capacity to form sulfate conjugates of lithocholic acid.

Variation in this capacity among individuals has not been well established and a

recent published report suggests that patients who develop chenodiol-induced

serum aminotransferase elevations are poor sulfators of lithocholic acid (see ADVERSE

REACTIONS and WARNINGS).

General Clinical Results

Both the desaturation of bile and the clinical dissolution of cholesterol gallstones are dose-related. In

the National Cooperative Gallstone Study (NCGS) involving 305 patients in each

treatment group, placebo and chenodiol dosages of 375 mg and 750 mg per day were

associated with complete stone dissolution in 0.8%, 5.2% and 13.5%,

respectively, of enrolled subjects over 24 months of treatment. Uncontrolled

clinical trials using higher doses than those used in the NCGS have shown

complete dissolution rates of 28 to 38% of enrolled patients receiving body

weight doses of from 13 to 16 mg/kg/day for up to 24 months. In a prospective

trial using 15 mg/kg/day, 31% enrolled surgical-risk patients treated more than

six months (n = 86) achieved complete confirmed dissolutions.

Observed stone dissolution rates achieved with chenodiol treatment are higher

in subgroups having certain pretreatment characteristics. In the NCGS, patients

with small {less than 15 mm in diameter} radiolucent stones, the observed rate

of complete dissolution was approximately 20% on 750 mg/day. In the uncontrolled

trails using 13 to 16 mg/kg/day doses of chenodiol, the rates of complete

dissolution for small radiolucent stones ranged from 42% to 60%. Even higher

dissolution rates have been observed in patients with small floatable stones.

(See Floatable versus Nonfloatable Stones, below). Some

obese patients and occasional normal weight patients fail to achieve bile

desaturation even with doses of chenodiol up to 19 mg/kg/day for unknown

reasons. Although dissolution is generally higher with increased dosage of

chenodiol, doses that are too low are associated with increased cholecystectomy

rates (see ADVERSE REACTIONS).

Stones have recurred within five years in about 50% of patients following

complete confirmed dissolutions. Although retreatment with chenodiol has proven

successful in dissolving some newly formed stones, the indications for and

safety of retreatment are not well defined. Serum aminotransferase elevations

and diarrhea have been notable in all clinical trials and are dose-related

(refer to ADVERSE REACTIONS and WARNINGSsections

for full information).

Floatable versus Nonfloatable Stones

A major finding in clinical trials was a difference between floatable and nonfloatable stones,

with respect to both natural history and response to chenodiol. Over the

two-year course of the National Cooperative Gallstone Study (NCGS), placebo –

treated patients with floatable stones (n = 47) had significantly higher rates

of biliary pain and cholecystectomy than patients with nonfloatable stones (n =

258) (47% versus 27% and 19%versus 4%, respectively). Chenodiol treatment (750

mg/day) compared to placebo was associated with a significant reduction in both

biliary pain and the cholecystectomy rates in the group with floatable stones

(27% versus 47% and 1.5% versus 19%, respectively). In an uncontrolled clinical

trial using 15 mg/kg/day, 70% of the patients with small (less than 15 mm)

floatable stones (n = 10) had complete confirmed dissolution.

In the NCGS in patients with nonfloatable stones, chenodiol produced no

reduction in biliary pain and showed a tendency to increase the cholecystectomy

rate (8% versus 4%). This finding was more pronounced with doses of chenodiol

below 10 mg/kg. The subgroup of patients with nonfloatable stones and a history

of biliary pain had the highest rates of cholecystectomy and aminotransferase

elevations during chenodiol treatment. Except for the NCGS subgroup with

pretreatment biliary pain, dose-related aminotransferase elevations and diarrhea

have occurred with equal frequency in patients with floatable or nonfloatable

stones. In the uncontrolled clinical trial mentioned above, 27% of the patients

with nonfloatable stones (n = 59) had complete confirmed dissolutions, including

35% with small (less than 15 mm)(n= 40) and only 11% with large, nonfloatable

stones (n= 19).

Of 916 patients enrolled NCGS, 17.6% had stones seen in upright form

(horizontal X-ray beam) to float in the dye-laden bile during oral

cholecystography using iopanoic acid. Other investigators report similar

findings. Floatable stones are not detected by ultrasonography in the absence

for dye. Chemical analysis has shown floatable stones to be essentially pure

cholesterol).

Other Radiographic and Laboratory Features

Radiolucent stones may have rims or centers of opacity representing

calcification. Pigment stones and partially calcified radiolucent stones do not

respond to chenodiol. Subtle calcification can sometimes be detected in flat

film X-rays, if not obvious in the oral cholecystogram. Among nonfloatable

stones, cholesterol stones are more apt than pigment stones to be smooth

surfaced, less than 0.5 cm in diameter, and to occur in numbers less than 10. As

stone size number and volume increase, the probability of dissolution within 24

months decreases. Hemolytic disorders, chronic alcoholism, biliary cirrhosis and

bacterial invasion of the biliary system predispose to pigment gallstone

formation. Pigment stones of primary biliary cirrhosis should be suspected in

patients with elevated alkaline phosphates, especially if positive

anti-mitochondrial antibodies are present. The presence of microscopic

cholesterol crystals in aspirated gallbladder bile, and demonstration of

cholesterol super saturation by bile lipid analysis increase the likelihood that

the stones are cholesterol stones.

PATIENT SELECTION

Evaluation of Surgical Risk

Surgery offers the advantage of immediate and permanent stone removal, but carries a fairly high risk. In some patients, about 5% of cholecystectomized patients have residual symptoms or retained common duct stones. The spectrum to surgical risk varies as a function of age and the presence of disease other than cholelithiasis. Selected tabulation of results from the National Halothane Study (JAMA, 1968, 197:775-778) is shown below: the study included 27,600 cholecystectomies.

Women in good health, or having only moderate systemic disease, under 49 years of age have the lowest rate (0.054%); men in all categories have a surgical mortality rate twice that of women; common duct exploration quadruples the rates in all categories; the rates rise with each decade of life and increase tenfold or more in all categories with severe or extreme systemic disease.

Relatively young patients requiring treatment might be better treated by surgery than with chenodiol, because treatment with chenodiol, even if successful, is associated with a high rate of recurrence. The long-term consequences of repeated courses of chenodiol in terms of liver toxicity, neoplasia and elevated cholesterol levels are not known. Watchful waiting has the advantage that no therapy may ever be required. For patients with silent or minimally symptomatic stones, the rate of moderate to severe symptoms or gallstone complications is estimated to be between 2% and 6% per year, leading to a cumulative rate of 7% and 27% in five years. Presumably the rate is higher for patients already having symptoms.

Indications and Usage for Chenodal

Chenodal (chenodiol tablets) is indicated for patients with radiolucent stones in well-opacifying gallbladders, in whom selective surgery would be undertaken except for the presence of increased surgical risk due to systemic disease or age. The likelihood of successful dissolution is far greater if the stones are floatable or small. For patients with nonfloatable stones, dissolution is less likely and added weight should be given to the risk that more emergent surgery might result form a delay due to unsuccessful treatment. Safety of use beyond 24 months is not established. Chenodiol will not dissolve calcified (radiopaque) or radiolucent bile pigment stones.

Contraindications

Chenodal (chenodiol tablets) is contraindicated in the presence of know hepatocyte

dysfunction or bile ductal abnormalities such as intrahepatic cholestasis,

primary biliary cirrhosis or sclerosing cholangitits (see Warnings); a

gallbladder confirmed as nonvisualizing after two consecutive single doses of

dye; radiopaque stones; or gallstone complications or compelling reasons for

gallbladder surgery including unremitting acute cholecystitis, cholangitis,

biliary obstruction, gallstone pancreatitis, or biliary gastrointestinal

fistula.

Pregnancy Category X

Chenodal (chenodiol tablets) may cause fetal harm when administered to a pregnant woman. Serious

hepatic, renal and adrenal lesions occurred in fetuses of female Rhesus monkeys

given 60 to 90 mg/kg/day (4 to 6 times the maximum recommended human dose, MRHD)

from day 21 to day 45 of pregnancy. Hepatic lesions also occurred in neonatal

baboons whose mothers had received 18 to 38 mg/kg ( 1 to 2 times the MRHD), all

during pregnancy. Fetal malformations were not observed. Neither fetal liver

damage nor fetal abnormalities occurred in reproduction studies in rats and

hamsters. No human data are available at this time. Chenodal (chenodiol tablets) is contraindicated

in women who are or may become pregnant. If this drug is used during pregnancy,

or if the patient becomes pregnant while taking this drug, the patient should be

apprised of the potential hazard to the fetus.

Warnings

Safe use of chenodiol depends upon selection of patients without

pre-existing liver disease and upon faithful monitoring of serum

aminotransferase levels to detect drug-induced liver toxicity. Aminotransferase

elevations over three times the upper limit of normal have required

discontinuation of chenodiol in 2% to 3% of patients. Although clinical and

biopsy studies have not shown fulminant lesions, the possibility remains that an

occasional patient may develop serious hepatic disease. Three patients with

biochemical and histologic pictures of chronic active hepatitis while on

chenodiol, 375 mg/day or 750 mg/day, have been reported. The biochemical

abnormalities returned spontaneously to normal in two of the patients within 13

and 17 months; and after 17 months’ treatment with prednisone in the third.

Follow-up biopsies were not done; and the causal relationship of the drug could

not be determined. Another biopsied patient was terminated from therapy because

of elevated aminotransferase levels and a liver biopsy was interpreted as

showing active drug hepatitis.

One patient with sclerosing cholangitis, biliary cirrhosis and history of

jaundice died during chenodiol treatment for hepatic duct stones. Before

treatment, serum aminotransferase and alkaline phosphate levels were over twice

the upper limit of normal; within one month they rose to over 10 time normal.

Chenodiol was discontinued at seven weeks, when the patient was hospitalized

with advanced hepatic failure and E. coli peritonitis; death ensued at the eight

week. A contribution of chenodiol to the fatal outcome could not be ruled

out.

Epidemiologic studies suggest that bile acids might contribute to human colon

cancer, but direct evidence is lacking. Bile acids, including chenodiol and

lithocholic acid, have no carcinogenic potential in animal models, but have been

shown to increase the number of tumors when administered with certain know

carcinogens. The possibility that chenodiol therapy might contribute to colon

cancer in otherwise susceptible individuals cannot be ruled out.

Precautions

Information for patients

Patients should be counseled on the importance of periodic visits

for liver function tests and oral cholecystograms (or ultrasonograms) for

monitoring stone dissolution; they should be made aware of the symptoms of

gallstone complications and be warned to report immediately such symptoms to the

physician. Patients should be instructed on ways to facilitate faithful

compliance with the dosage regimen throughout the usual long term of therapy,

and on temporary doses reduction if episodes of diarrhea occur.

Drug interactions

Bile acid sequestering agents, such as cholestyramine and

colestipol, may interfere with the action of Chenodiol by reducing its

absorption. Aluminum-based antacids have been shown to absorb bile acids in

vitro and may be expected to interfere with Chenodiol in the same manner as the

sequestering agents. Estrogen, oral contraceptive and collaborate (and perhaps

other lipid-lowering drugs) increase biliary cholesterol secretion, and the

incidence of cholesterol gallstones hence may counteract the effectiveness of

Chenodiol.

Due to its hepatotoxicity, chenodiol can affect the pharmacodynamics of

coumarin and its derivatives, causing unexpected prolongation of the prothrombin

time and hemorrahages. Patients on concommitant therapy with chenodiol and

coumarin or its derivatives should be monitored carefully. If prolongation of

prothrombin time is observed, the coumarin dosage should be readjusted to give a

prothrombin time 1½ to 2 times normal. If necessary Chenodal (chenodiol tablets) should be

discontinued.

Carcinogenesis, mutagenesis, impairment of fertility

A two-year oral study of chenodiol in rats failed to show a

carcinogenic potential at the tested levels of 15 to 60 mg/kg/day (1 to 4 times

the maximum recommended human dose, MRHD). It has been reported that chenodiol

given in long-term studies at oral doses up to 600 mg/kg/day (40 times the MRHD)

to rats and 1000 mg/kg/day (65 times the MRHD) to mice induced benign and

malignant liver cell tumors in female rats and cholangiomata in female rats and

male mice. Two-year studies of lithocholic acid ( a major metabolite of

chenodiol) in mice (125 to 250 mg/kg/day) and rats (250 and 500 mg/kg/day) found

it not to be carcinogenic. The dietary administration of Lithocholic acid to

chickens is reported to cause hepatic adenomatous hyperplasia.

Pregnancy

Pregnancy Category X: See CONTRAINDICATIONS

Nursing mothers

It is not known whether chenodiol is excreted in human mild.

Because many drugs are excreted in human milk, caution should be exercised when

Chenodal (chenodiol tablets) is administered to a nursing mother.

Pediatric use

The safety and effectiveness of chenodiol in children have not been established.

Adverse Reactions

Hepatobiliary

Dose-related serum aminotransferase (mainly SGPT) elevations, usually not accompanied by rises in

alkaline phosphatase or bilirubin, occurred in 30% or more of patients treated with the recommended dose of Chenodiol. In most cases, these elevations were

minor (1 ½ to 3 times the upper limit of laboratory normal) and transient, returning to within the normal range within six months despite continued

administration of the drug. In 2% to 3% of patients, SGPT levels rose to over three times the upper limit of laboratory normal, recurred on rechallenge with

the drug, and required discontinuation of chenodiol treatment. Enzyme levels have returned to normal following withdrawal of chenodiol (see WARNINGS).

Morphologic studies of liver biopsies taken before and after 9 and 24 months of treatment with chenodiol have shown that 63% of the patients prior to

chenodiol treatment had evidence of intrahepatic cholestasis. Almost all pretreatment patients had electron microscopic abnormalities. By the ninth month

of treatment, reexamination of two-thirds of the patients showed an 89% incidence of the signs of intrahepatic cholestasis. Two of 89 patients at the

ninth month had lithocholate-like lesions in the canalicular membrane, although there were not clinical enzyme abnormalities in the face of continued treatment

and no change in Type 2 light microscopic parameters.

Increased Cholecystectomy Rate

NCGS patients with a history of biliary pain prior to treatment had higher cholecystectomy rates

during the study if assigned to low dosage chenodiol (375 mg/day) than if

assigned to either placebo or high dosage chenodiol (750 mg/day). The

association with low dosage chenodiol though not clearly a causal one, suggests

that patients unable to take higher doses of chenodiol may be at greater risk of

cholecystectomy.

Gastrointestinal

Dose-related diarrhea has been encountered in 30% to 40% of chenodiol-treated patients and may occur at any

time during treatment, but is most commonly encountered when treatment is initiated. Usually, the diarrhea is mild, translucent, well-tolerated and does

not interfere with therapy. Dose reduction has been required in 10% to 15% of patients, and in a controlled trial about half of these required a permanent

reduction in dose. Anti-diarrhea agents have proven useful in some patients.

Discontinuation of Chenodal (chenodiol tablets) because of failure to control diarrhea is to be expected in approximately 3% of patients treated. Steady epigastric pain with

nausea typical of lithiasis (biliary colic) usually is easily distinguishable from the crampy abdominal pain of drug-induced diarrhea.

Other less frequent, gastrointestinal side effects reported include urgency, cramps, heartburn, constipation, nausea, and vomiting, anorexic, epigastric

distress, dyspepsis, flatulence and nonspecific abdominal pain.

Serum Lipids

Serum total cholesterol and low-density lipoprotein (LDL) cholesterol may rise 10% or more during administration of

chenodiol: no change has been seen in the high-density lipoprotein (HDL) fraction; small decreases in serum triglyceride levels for females have been

reported.

Hematologic

Decreases in white cell count, never below 3000, have been noted in a few patients treated with chenodiol; the drug

was continued in all patients without incident.

Drug Abuse and Dependence

Overdosage

Accidental or intentional overdoses of chenodiol have not been reported. One patient tolerated 4 gm/day (58 mg/kg/day) for six months without

incident

Chenodal Dosage and Administration

The recommended dose range for Chenodal (chenodiol tablets) is 13 to 16 mg/kg/day in two divided doses, morning and night, starting with 250 mg b.i.d. the first two

weeks and increasing by 250 mg/day each week thereafter until the recommended or maximum tolerated dose is reached. If diarrhea occurs during dosage buildup or

later in treatment, it usually can be controlled by temporary dosage adjustment until symptoms abate, after which the previous dosage usually is tolerated.

Dosage less than 10 mg/kg usually is ineffective and may be associated with increased risk of cholecystectomy, so is not recommended.

The optimal frequency of monitoring liver function tests is not known. It is suggested that serum aminotransferase levels should be monitored monthly for the

first three months and every three months thereafter during Chenodal (chenodiol tablets) administration. Under NCGS guidelines, if a minor, usually transient elevations

(1 ½ to3 three times the upper limit of normal) persisted longer than three to six months. Chenodiol was discontinued and resumed only after the

aminotransferase level returned to normal; however, allowing the elevations to persist over such an interval is not know to be safe. Elevations over three

times the upper limit of normal require immediate discontinuation of Chenodal (chenodiol tablets) and usually reoccur on challenge.

Serum cholesterol should be monitored at six months intervals. It may be advisable to discontinue Chenodal (chenodiol tablets) if cholesterol rises above the acceptable

age-adjusted limit for given patient.

Oral cholecystograms or ultrasonograms are recommend at six to nine month intervals to monitor response. Complete dissolutions should be confirmed by a

repeat test after one to three months continued Chenodal (chenodiol tablets) administration. Most patients who eventually achieve complete dissolution will show partial (or

complete) dissolution at the first on-treatment test. If partial dissolution is not seen by nine to 12 months, the likelihood of success of treating loner is

greatly reduced; Chenodal (chenodiol tablets) should be discontinued if there is no response by 18 months. Safety of use beyond 24 months is not established.

Stone recurrence can be expected within five years in 50% of cases. After confirmed dissolution, treatment generally should be stopped. Serial

cholecystograms or ultrasonograms are recommended to monitor for recurrence, keeping in mind that radiolucency and gallbladder function should be established

before starting another course of Chenodal (chenodiol tablets). A prophylactic doses is not established; reduced doses cannot be recommended; stones have recurred on 500

mg/day. Low cholesterol or carbohydrate diets, and dietary bran, have been reported to reduce biliary cholesterol; maintenance of reduced weight is

recommended to forestall stone recurrence.

How is Chenodal Supplied

Chenodal™ 250 mg (chenodiol tablets) is available as white film-coated 250 mg tablets imprinted “MP” on one side and "250" on the other in bottles of 100,

NDC 45043-876-40.

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].

Dispense in a tight container.

Manufactured for:

Manchester Pharmaceuticals, Inc.™

Fort Collins, CO 80525

866-758-7068 7121

Rev. 9/09

Chenodal
chenodiol tablet, film coated

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	NDC Product Code (Source)	45043-876 (0722-7121)
Route of Administration	ORAL	DEA Schedule

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
Chenodiol (Chenodiol)	Chenodiol	250 mg

Inactive Ingredients
Ingredient Name	Strength
No Inactive Ingredients Found

Product Characteristics
Color	white (White to Off-White)	Score	no score
Shape	ROUND	Size	10mm
Flavor		Imprint Code	MP;250
Contains

Packaging
#	NDC	Package Description	Multilevel Packaging
1	45043-876-40	100 TABLET In 1 BOTTLE, PLASTIC	None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA091019	10/01/2009

Labeler - Manchester Pharmaceuticals Inc. (832417641)

Registrant - Manchester Pharmaceuticals Inc. (832417641)

Establishment
Name	Address	ID/FEI	Operations
Manchester Pharmaceuticals Inc.		832417641	relabel

Revised: 01/2010Manchester Pharmaceuticals Inc.

More Chenodal resources

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

Chenodal Monograph (AHFS DI)

Chenodal Advanced Consumer (Micromedex) - Includes Dosage Information

Chenodal MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Chenodal with other medications

Gallbladder Disease