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Monday, March 12, 2012

Tikosyn

dofetilide

Dosage Form: capsule
Tikosyn ®

(dofetilide)

Capsules

To minimize the risk of induced arrhythmia, patients initiated or re-initiated on Tikosyn should be placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation. For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION. Tikosyn is available only to hospitals and prescribers who have received appropriate Tikosyn dosing and treatment initiation education; see DOSAGE AND ADMINISTRATION.

Tikosyn Description

Tikosyn® (dofetilide) is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties. Its empirical formula is C19H27N3O5S2 and it has a molecular weight of 441.6. The structural formula is

The chemical name for dofetilide is:

N - [4 - [2 - [methyl[2 - [4 - [(methylsulfonyl)amino]phenoxy]ethyl]amino]ethyl]phenyl] - methanesulfonamide.

Dofetilide is a white to off-white powder. It is very slightly soluble in water and propan-2-ol and is soluble in 0.1M aqueous sodium hydroxide, acetone, and aqueous 0.1M hydrochloric acid.

Tikosyn capsules contain the following inactive ingredients: microcrystalline cellulose, corn starch, colloidal silicon dioxide and magnesium stearate. Tikosyn is supplied for oral administration in three dosage strengths: 125 mcg (0.125 mg) orange and white capsules, 250 mcg (0.25 mg) peach capsules, and 500 mcg (0.5 mg) peach and white capsules.

Tikosyn - Clinical Pharmacology

Mechanism of Action

Tikosyn (dofetilide) shows Vaughan Williams Class III antiarrhythmic activity. The mechanism of action is blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr. At concentrations covering several orders of magnitude, dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents (e.g., IKs, IK1). At clinically relevant concentrations, dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors.

Electrophysiology

Tikosyn (dofetilide) increases the monophasic action potential duration in a predictable, concentration-dependent manner, primarily due to delayed repolarization. This effect, and the related increase in effective refractory period, is observed in the atria and ventricles in both resting and paced electrophysiology studies. The increase in QT interval observed on the surface ECG is a result of prolongation of both effective and functional refractory periods in the His-Purkinje system and the ventricles.

Dofetilide did not influence cardiac conduction velocity and sinus node function in a variety of studies in patients with or without structural heart disease. This is consistent with a lack of effect of dofetilide on the PR interval and QRS width in patients with pre-existing heart block and/or sick sinus syndrome.

In patients, dofetilide terminates induced re-entrant tachyarrhythmias (e.g., atrial fibrillation/flutter and ventricular tachycardia) and prevents their re-induction. Tikosyn does not increase the electrical energy required to convert electrically induced ventricular fibrillation, and it significantly reduces the defibrillation threshold in patients with ventricular tachycardia and ventricular fibrillation undergoing implantation of a cardioverter-defibrillator device.

Hemodynamic Effects

In hemodynamic studies, Tikosyn had no effect on cardiac output, cardiac index, stroke volume index, or systemic vascular resistance in patients with ventricular tachycardia, mild to moderate congestive heart failure or angina, and either normal or low left ventricular ejection fraction. There was no evidence of a negative inotropic effect related to Tikosyn therapy in patients with atrial fibrillation. There was no increase in heart failure in patients with significant left ventricular dysfunction (see CLINICAL STUDIES, Safety in Patients with Structural Heart Disease, DIAMOND Studies). In the overall clinical program, Tikosyn did not affect blood pressure. Heart rate was decreased by 4–6 bpm in studies in patients.

Pharmacokinetics, General

Absorption and Distribution

The oral bioavailability of dofetilide is >90%, with maximal plasma concentrations occurring at about 2–3 hours in the fasted state. Oral bioavailability is unaffected by food or antacid. The terminal half-life of Tikosyn is approximately 10 hours; steady state plasma concentrations are attained within 2–3 days, with an accumulation index of 1.5 to 2.0. Plasma concentrations are dose proportional. Plasma protein binding of dofetilide is 60–70%, is independent of plasma concentration, and is unaffected by renal impairment. Volume of distribution is 3 L/kg.

Metabolism and Excretion

Approximately 80% of a single dose of dofetilide is excreted in urine, of which approximately 80% is excreted as unchanged dofetilide with the remaining 20% consisting of inactive or minimally active metabolites. Renal elimination involves both glomerular filtration and active tubular secretion (via the cation transport system, a process that can be inhibited by cimetidine, trimethoprim, prochlorperazine, megestrol, and ketoconazole). In vitro studies with human liver microsomes show that dofetilide can be metabolized by CYP3A4, but it has a low affinity for this isoenzyme. Metabolites are formed by N-dealkylation and N-oxidation. There are no quantifiable metabolites circulating in plasma, but 5 metabolites have been identified in urine.

Pharmacokinetics in Special Populations

Renal Impairment

In volunteers with varying degrees of renal impairment and patients with arrhythmias, the clearance of dofetilide decreases with decreasing creatinine clearance. As a result, and as seen in clinical studies, the half-life of dofetilide is longer in patients with lower creatinine clearances. Because increase in QT interval and the risk of ventricular arrhythmias are directly related to plasma concentrations of dofetilide, dosage adjustment based on calculated creatinine clearance is critically important (see DOSAGE AND ADMINISTRATION). Patients with severe renal impairment (creatinine clearance <20 mL/min) were not included in clinical or pharmacokinetic studies (see CONTRAINDICATIONS).

Hepatic Impairment

There was no clinically significant alteration in the pharmacokinetics of dofetilide in volunteers with mild to moderate hepatic impairment (Child-Pugh Class A and B) compared to age- and weight-matched healthy volunteers. Patients with severe hepatic impairment were not studied.

Patients with Heart Disease

Population pharmacokinetic analyses indicate that the plasma concentration of dofetilide in patients with supraventricular and ventricular arrhythmias, ischemic heart disease, or congestive heart failure are similar to those of healthy volunteers, after adjusting for renal function.

Elderly

After correction for renal function, clearance of dofetilide is not related to age.

Women

A population pharmacokinetic analysis showed that women have approximately 12–18% lower dofetilide oral clearances than men (14–22% greater plasma dofetilide levels), after correction for weight and creatinine clearance. In females, as in males, renal function was the single most important factor influencing dofetilide clearance. In normal female volunteers, hormone replacement therapy (a combination of conjugated estrogens and medroxyprogesterone) did not increase dofetilide exposure.

Drug-Drug Interactions

(see PRECAUTIONS)

Dose-Response and Concentration Response for Increase in QT Interval

Increase in QT interval is directly related to dofetilide dose and plasma concentration. Figure 1 shows that the relationship in normal volunteers between dofetilide plasma concentrations and change in QTc is linear, with a positive slope of approximately 15–25 msec/(ng/mL) after the first dose and approximately 10–15 msec/(ng/mL) at Day 23 (reflecting a steady state of dosing). A linear relationship between mean QTc increase and dofetilide dose was also seen in patients with renal impairment, in patients with ischemic heart disease, and in patients with supraventricular and ventricular arrhythmias.

Figure 1: Mean QTc-Concentration Relationship in Young Volunteers Over 24 Days

Note: The range of dofetilide plasma concentrations achieved with the 500 mcg BID dose adjusted for creatinine clearance is 1–3.5 ng/mL.

The relationship between dose, efficacy, and the increase in QTc from baseline at steady state for the two randomized, placebo-controlled studies (described further below) is shown in Figure 2. The studies examined the effectiveness of Tikosyn in conversion to sinus rhythm and maintenance of normal sinus rhythm after conversion in patients with atrial fibrillation/flutter of >1 week duration. As shown, both the probability of a patient's remaining in sinus rhythm at six months and the change in QTc from baseline at steady state of dosing increased in an approximately linear fashion with increasing dose of Tikosyn. Note that in these studies, doses were modified by results of creatinine clearance measurement and in-hospital QTc prolongation.

Figure 2: Relationship Between Tikosyn Dose, QTc Increase and Maintenance of NSR

Number of patients evaluated for maintenance of NSR: 503 Tikosyn, 174 placebo.

Number of patients evaluated for QTc change: 478 Tikosyn, 167 placebo.

Clinical Studies

Chronic Atrial Fibrillation and/or Atrial Flutter

Two randomized, parallel, double-blind, placebo-controlled, dose-response trials evaluated the ability of Tikosyn 1) to convert patients with atrial fibrillation or atrial flutter (AF/AFl) of more than 1 week duration to normal sinus rhythm (NSR) and 2) to maintain NSR (delay time to recurrence of AF/AFl) after drug-induced or electrical cardioversion. A total of 996 patients with a one week to two year history of atrial fibrillation/atrial flutter were enrolled. Both studies randomized patients to placebo or to doses of Tikosyn 125 mcg, 250 mcg, 500 mcg, or in one study a comparator drug, given twice a day (these doses were lowered based on calculated creatinine clearance and, in one of the studies, for QT interval or QTc). All patients were started on therapy in a hospital where their ECG was monitored (see DOSAGE AND ADMINISTRATION).

Patients were excluded from participation if they had had syncope within the past 6 months, AV block greater than first degree, MI or unstable angina within 1 month, cardiac surgery within 2 months, history of QT interval prolongation or polymorphic ventricular tachycardia associated with use of antiarrhythmic drugs, QT interval or QTc >440 msec, serum creatinine >2.5 mg/mL, significant diseases of other organ systems; used cimetidine; or used drugs known to prolong the QT interval.

Both studies enrolled mostly Caucasians (over 90%), males (over 70%), and patients ≥65 years of age (over 50%). Most (>90%) were NYHA Functional Class I or II. Approximately one-half had structural heart disease (including ischemic heart disease, cardiomyopathies, and valvular disease) and about one-half were hypertensive. A substantial proportion of patients were on concomitant therapy, including digoxin (over 60%), diuretics (over 20%), and ACE inhibitors (over 30%). About 90% were on anticoagulants.

Acute conversion rates are shown in Table 1 for randomized doses (doses were adjusted for calculated creatinine clearance and, in Study 1, for QT interval or QTc). Of patients who converted pharmacologically, approximately 70% converted within 24–36 hours.

Table 1: Conversion of Atrial Fibrillation/Flutter to Normal Sinus Rhythm
	Tikosyn Dose			Placebo
	125 mcg BID	250 mcg BID	500 mcg BID
Study 1	5/82(6%)	8/82(10%)	23/77(30%)		1/84(1%)
Study 2	8/135(6%)	14/133(11%)	38/129(29%)	2/137(1%)

Patients who did not convert to NSR with randomized therapy within 48–72 hours had electrical cardioversion. Those patients remaining in NSR after conversion in hospital were continued on randomized therapy as outpatients (maintenance period) for up to one year unless they experienced a recurrence of atrial fibrillation/atrial flutter or withdrew for other reasons.

Table 2 shows, by randomized dose, the percentage of patients at 6 and 12 months in both studies who remained on treatment in NSR and the percentage of patients who withdrew because of recurrence of AF/AFl or adverse events.

Table 2: Patient Status at 6 and 12 Months Post Randomization
	Tikosyn Dose
	125 mcg BID	250 mcg BID	500 mcg BID	Placebo
Note that columns do not add up to 100% due to discontinuations for "other" reasons.
Study 1
Randomized	82	82	77	84
Achieved NSR	60	61	61	68
6 months
Still on treatment in NSR	38%	44%	52%	32%
D/C for recurrence	55%	49%	33%	63%
D/C for AEs	3%	3%	8%	4%
12 months
Still on treatment in NSR	32%	26%	46%	22%
D/C for recurrence	58%	57%	36%	72%
D/C for AEs	7%	11%	8%	6%
Study 2
Randomized	135	133	129	137
Achieved NSR	103	118	100	106
6 months
Still on treatment in NSR	41%	49%	57%	22%
D/C for recurrence	48%	42%	27%	72%
D/C for AEs	9%	6%	10%	4%
12 months
Still on treatment in NSR	25%	42%	49%	16%
D/C for recurrence	59%	47%	32%	76%
D/C for AEs	11%	6%	12%	5%

Table 3 and Figures 3 and 4 show, by randomized dose, the effectiveness of Tikosyn in maintaining NSR using Kaplan Meier analysis, which shows patients remaining on treatment.

Table 3: P-Values and Median Time (days) to Recurrence of AF/AFl
	Tikosyn Dose
	125 mcg BID	250 mcg BID	500 mcg BID	Placebo
Median time to recurrence of AF/AFl could not be estimated accurately for the 250 mcg BID treatment group in Study 2 and the 500 mcg BID treatment groups in Studies 1 and 2 because Tikosyn maintained >50% of patients (51%, 58%, and 66%, respectively) in NSR for the 12 months duration of the studies.
Study 1
p-value vs. placebo	P=0.21	P=0.10	P<0.001
Median time to recurrence (days)	31	179	>365	27
Study 2
p-value vs. placebo	P=0.006	P<0.001	P<0.001
Median time to recurrence (days)	182	>365	>365	34

Figure 3: Maintenance of Normal Sinus Rhythm, Tikosyn Regimen vs. Placebo (Study 1)

The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 62% and 58%, respectively, for Tikosyn 500 mcg BID; 50% and 37%, respectively, for Tikosyn 250 mcg BID; and 37%, and 25%, respectively, for placebo.

Figure 4: Maintenance of Normal Sinus Rhythm, Tikosyn Regimen vs. Placebo (Study 2)

The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 71% and 66%, respectively, for Tikosyn 500 mcg BID; 56% and 51%, respectively, for Tikosyn 250 mcg BID; and 26% and 21%, respectively, for placebo.

In both studies, Tikosyn resulted in a dose-related increase in the number of patients maintained in NSR at all time periods and delayed the time of recurrence of sustained AF. Data pooled from both studies show that there is a positive relationship between the probability of staying in NSR, Tikosyn dose, and increase in QTc (see Figure 2 in CLINICAL PHARMACOLOGY, Dose-Response and Concentration Response for Increase in QT Interval).

Analysis of pooled data for patients randomized to a Tikosyn dose of 500 mcg twice daily showed that maintenance of NSR was similar in both males and females, in both patients aged <65 years and patients ≥65 years of age, and in both patients with atrial flutter as a primary diagnosis and those with a primary diagnosis of atrial fibrillation.

During the period of in-hospital initiation of dosing, 23% of patients in Studies 1 and 2 had their dose adjusted downward on the basis of their calculated creatinine clearance, and 3% had their dose down-titrated due to increased QT interval or QTc. Increased QT interval or QTc led to discontinuation of therapy in 3% of patients.

Safety in Patients with Structural Heart Disease: DIAMOND Studies (The Danish Investigations of Arrhythmia and Mortality on Dofetilide)

The two DIAMOND studies were 3-year trials comparing the effects of Tikosyn and placebo on mortality and morbidity in patients with impaired left ventricular function (ejection fraction ≤35%). Patients were treated for at least one year. One study was in patients with moderate to severe (60% NYHA Class III or IV) congestive heart failure (DIAMOND CHF) and the other was in patients with recent myocardial infarction (DIAMOND MI) (of whom 40% had NYHA Class III or IV heart failure). Both groups were at relatively high risk of sudden death. The DIAMOND trials were intended to determine whether Tikosyn could reduce that risk. The trials did not demonstrate a reduction in mortality; however, they provide reassurance that, when initiated carefully, in a hospital or equivalent setting, Tikosyn did not increase mortality in patients with structural heart disease, an important finding because other antiarrhythmics [notably the Class IC antiarrhythmics studied in the Cardiac Arrhythmia Suppression Trial (CAST) and a pure Class III antiarrhythmic, d-sotalol (SWORD)] have increased mortality in post-infarction populations. The DIAMOND trials therefore provide evidence of a method of safe use of Tikosyn in a population susceptible to ventricular arrhythmias. In addition, the subset of patients with AF in the DIAMOND trials provide further evidence of safety in a population of patients with structural heart disease accompanying the AF. Note, however, that this AF population was given a lower (250 mcg BID) dose (see CLINICAL STUDIES, DIAMOND Patients with Atrial Fibrillation).

In both DIAMOND studies, patients were randomized to 500 mcg BID of Tikosyn, but this was reduced to 250 mcg BID if calculated creatinine clearance was 40–60 mL/min, if patients had AF, or if QT interval prolongation (>550 msec or >20% increase from baseline) occurred after dosing. Dose reductions for reduced calculated creatinine clearance occurred in 47% and 45% of DIAMOND CHF and MI patients, respectively. Dose reductions for increased QT interval or QTc occurred in 5% and 7% of DIAMOND CHF and MI patients, respectively. Increased QT interval or QTc (>550 msec or >20% increase from baseline) resulted in discontinuation of 1.8% of patients in DIAMOND CHF and 2.5% of patients in DIAMOND MI.

In the DIAMOND studies, all patients were hospitalized for at least 3 days after treatment was initiated and monitored by telemetry. Patients with QTc greater than 460 msec, second or third degree AV block (unless with pacemaker), resting heart rate <50 bpm, or prior history of polymorphic ventricular tachycardia were excluded.

DIAMOND CHF studied 1518 patients hospitalized with severe CHF who had confirmed impaired left ventricular function (ejection fraction ≤35%). Patients received a median duration of therapy of greater than one year. There were 311 deaths from all causes in patients randomized to Tikosyn (n=762) and 317 deaths in patients randomized to placebo (n=756). The probability of survival at one year was 73% (95% CI: 70% – 76%) in the Tikosyn group and 72% (95% CI: 69% – 75%) in the placebo group. Similar results were seen for cardiac deaths and arrhythmic deaths. Torsade de Pointes occurred in 25/762 patients (3.3%) receiving Tikosyn. The majority of cases (76%) occurred within the first 3 days of dosing. In all, 437/762 (57%) of patients on Tikosyn and 459/756 (61%) on placebo required hospitalization. Of these, 229/762 (30%) of patients on Tikosyn and 290/756 (38%) on placebo required hospitalization because of worsening heart failure.

DIAMOND MI studied 1510 patients hospitalized with recent myocardial infarction (2–7 days) who had confirmed impaired left ventricular function (ejection fraction ≤35%). Patients received a median duration of therapy of greater than one year. There were 230 deaths in patients randomized to Tikosyn (n=749) and 243 deaths in patients randomized to placebo (n=761). The probability of survival at one year was 79% (95% CI: 76% – 82%) in the Tikosyn group and 77% (95% CI: 74% – 80%) in the placebo group. Cardiac and arrhythmic mortality showed a similar result. Torsade de Pointes occurred in 7/749 patients (0.9%) receiving Tikosyn. Of these, 4 cases occurred within the first 3 days of dosing and 3 cases occurred between Day 4 and the conclusion of the study. In all, 371/749 (50%) of patients on Tikosyn and 419/761 (55%) on placebo required hospitalization. Of these, 200/749 (27%) of patients on Tikosyn and 205/761 (27%) on placebo required hospitalization because of worsening heart failure.

DIAMOND Patients with Atrial Fibrillation (the DIAMOND AF subpopulation). There were 506 patients in the two DIAMOND studies who had atrial fibrillation (AF) at entry to the studies (249 randomized to Tikosyn and 257 randomized to placebo). DIAMOND AF patients randomized to Tikosyn received 250 mcg BID; 65% of these patients had impaired renal function, so that 250 mcg BID represents the dose they would have received in the AF trials, which would give drug exposure similar to a person with normal renal function given 500 mcg BID. In the DIAMOND AF subpopulation, there were 111 deaths (45%) in the 249 patients in the Tikosyn group and 116 deaths (45%) in the 257 patients in the placebo group. Hospital readmission rates for any reason were 125/249 or 50% on Tikosyn and 156/257 or 61% for placebo. Of these, readmission rates for worsening heart failure were 73/249 or 29% on Tikosyn and 102/257 or 40% for placebo.

Of the 506 patients in the DIAMOND studies who had atrial fibrillation or flutter at baseline, 12% of patients in the Tikosyn group and 2% of patients in the placebo group had converted to normal sinus rhythm after one month. In those patients converted to normal sinus rhythm, 79% of the Tikosyn group and 42% of the placebo group remained in normal sinus rhythm for one year.

In the DIAMOND studies, although Torsade de Pointes occurred more frequently in the Tikosyn-treated patients (see ADVERSE REACTIONS), Tikosyn, given with an initial 3-day hospitalization and with dose modified for reduced creatinine clearance and increased QT interval, was not associated with an excess risk of mortality in these populations with structural heart disease in the individual studies or in an analysis of the combined studies. The presence of atrial fibrillation did not affect outcome.

Indications and Usage for Tikosyn

Maintenance of Normal Sinus Rhythm (Delay in AF/AFl Recurrence)

Tikosyn is indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm. Because Tikosyn can cause life threatening ventricular arrhythmias, it should be reserved for patients in whom atrial fibrillation/atrial flutter is highly symptomatic.

In general, antiarrhythmic therapy for atrial fibrillation/atrial flutter aims to prolong the time in normal sinus rhythm. Recurrence is expected in some patients (see CLINICAL STUDIES).

Conversion of Atrial Fibrillation/Flutter

Tikosyn is indicated for the conversion of atrial fibrillation and atrial flutter to normal sinus rhythm.

Tikosyn has not been shown to be effective in patients with paroxysmal atrial fibrillation.

Contraindications

Tikosyn is contraindicated in patients with congenital or acquired long QT syndromes. Tikosyn should not be used in patients with a baseline QT interval or QTc >440 msec (500 msec in patients with ventricular conduction abnormalities). Tikosyn is also contraindicated in patients with severe renal impairment (calculated creatinine clearance <20 mL/min).

The concomitant use of verapamil or the cation transport system inhibitors cimetidine, trimethoprim (alone or in combination with sulfamethoxazole), or ketoconazole with Tikosyn is contraindicated (see WARNINGS and PRECAUTIONS, Drug-Drug Interactions), as each of these drugs cause a substantial increase in dofetilide plasma concentrations. In addition, other known inhibitors of the renal cation transport system such as prochlorperazine and megestrol should not be used in patients on Tikosyn.

The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with Tikosyn is contraindicated (see PRECAUTIONS, Drug-Drug Interactions) because this has been shown to significantly increase dofetilide plasma concentrations and QT interval prolongation.

Tikosyn is also contraindicated in patients with a known hypersensitivity to the drug.

Warnings

Ventricular Arrhythmia

Tikosyn (dofetilide) can cause serious ventricular arrhythmias, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to dofetilide plasma concentration. Factors such as reduced creatinine clearance or certain dofetilide drug interactions will increase dofetilide plasma concentration. The risk of TdP can be reduced by controlling the plasma concentration through adjustment of the initial dofetilide dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval.

Treatment with dofetilide must therefore be started only in patients placed for a minimum of three days in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Calculation of the creatinine clearance for all patients must precede administration of the first dose of dofetilide. For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION.

The risk of dofetilide induced ventricular arrhythmia was assessed in three ways in clinical studies: 1) by description of the QT interval and its relation to the dose and plasma concentration of dofetilide; 2) by observing the frequency of TdP in Tikosyn-treated patients according to dose; 3) by observing the overall mortality rate in patients with atrial fibrillation and in patients with structural heart disease.

Relation of QT Interval to Dose

The QT interval increases linearly with increasing Tikosyn dose (see Figures 1 and 2 in CLINICAL PHARMACOLOGY and Dose-Response and Concentration Response for Increase in QT Interval).

Frequency of Torsade de Pointes

In the supraventricular arrhythmia population (patients with AF and other supraventricular arrhythmias), the overall incidence of Torsade de Pointes was 0.8%. The frequency of TdP by dose is shown in Table 4. There were no cases of TdP on placebo.

Table 4: Summary of Torsade de Pointes in Patients Randomized to Dofetilide by Dose; Patients with Supraventricular Arrhythmias
	Tikosyn Dose
	<250 mcg BID	250 mcg BID	>250–500 mcg BID	>500 mcg BID	All Doses
Number of Patients	217	388	703	38	1346
Torsade de Pointes	0	1 (0.3%)	6 (0.9%)	4 (10.5%)	11 (0.8%)

As shown in Table 5, the rate of TdP was reduced when patients were dosed according to their renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations, Renal Impairment and DOSAGE AND ADMINISTRATION).

Table 5: Incidence of Torsade de Pointes Before and After Introduction of Dosing According to Renal Function
	Total	Before	After
Population:	n/N %	n/N %	n/N %
Supraventricular Arrhythmias	11/1346 (0.8%)	6/193 (3.1%)	5/1153 (0.4%)
DIAMOND CHF	25/762 (3.3%)	7/148 (4.7%)	18/614 (2.9%)
DIAMOND MI	7/749 (0.9%)	3/101 (3.0%)	4/648 (0.6%)
DIAMOND AF	4/249 (1.6%)	0/43 (0%)	4/206 (1.9%)

The majority of the episodes of TdP occurred within the first three days of Tikosyn therapy (10/11 events in the studies of patients with supraventricular arrhythmias; 19/25 and 4/7 events in DIAMOND CHF and DIAMOND MI, respectively; 2/4 events in the DIAMOND AF subpopulation).

Mortality

In a pooled survival analysis of patients in the supraventricular arrhythmia population (low prevalence of structural heart disease), deaths occurred in 0.9% (12/1346) of patients receiving Tikosyn and 0.4% (3/677) in the placebo group. Adjusted for duration of therapy, primary diagnosis, age, gender, and prevalence of structural heart disease, the point estimate of the hazard ratio for the pooled studies (Tikosyn/placebo) was 1.1 (95% CI: 0.3, 4.3). The DIAMOND CHF and MI trials examined mortality in patients with structural heart disease (ejection fraction ≤35%). In these large, double-blind studies, deaths occurred in 36% (541/1511) of Tikosyn patients and 37% (560/1517) of placebo patients. In an analysis of 506 DIAMOND patients with atrial fibrillation/flutter at baseline, one year mortality on Tikosyn was 31% vs. 32% on placebo (see CLINICAL STUDIES).

Because of the small number of events, an excess mortality due to Tikosyn cannot be ruled out with confidence in the pooled survival analysis of placebo-controlled trials in patients with supraventricular arrhythmias. However, it is reassuring that in two large placebo-controlled mortality studies in patients with significant heart disease (DIAMOND CHF/MI), there were no more deaths in Tikosyn-treated patients than in patients given placebo (see CLINICAL STUDIES).

Drug-Drug Interactions

(see CONTRAINDICATIONS)

Because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant drugs that interfere with the metabolism or renal elimination of dofetilide may increase the risk of arrhythmia (Torsade de Pointes). Tikosyn is metabolized to a small degree by the CYP3A4 isoenzyme of the cytochrome P450 system and an inhibitor of this system could increase systemic dofetilide exposure. More important, dofetilide is eliminated by cationic renal secretion, and three inhibitors of this process have been shown to increase systemic dofetilide exposure. The magnitude of the effect on renal elimination by cimetidine, trimethoprim, and ketoconazole (all contraindicated concomitant uses with dofetilide) suggests that all renal cation transport inhibitors should be contraindicated.

Hypokalemia and Potassium-Depleting Diuretics

Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting diuretics, increasing the potential for Torsade de Pointes. Potassium levels should be within the normal range prior to administration of Tikosyn and maintained in the normal range during administration of Tikosyn (see DOSAGE AND ADMINISTRATION).

Use with Drugs that Prolong QT Interval and Antiarrhythmic Agents

The use of Tikosyn in conjunction with other drugs that prolong the QT interval has not been studied and is not recommended. Such drugs include phenothiazines, cisapride, bepridil, tricyclic antidepressants, certain oral macrolides, and certain fluoroquinolones. Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to dosing with Tikosyn. In clinical trials, Tikosyn was administered to patients previously treated with oral amiodarone only if serum amiodarone levels were below 0.3 mg/L or amiodarone had been withdrawn for at least three months.

Precautions

Renal Impairment

The overall systemic clearance of dofetilide is decreased and plasma concentration increased with decreasing creatinine clearance. The dose of Tikosyn must be adjusted based on creatinine clearance (see DOSAGE AND ADMINISTRATION). Patients undergoing dialysis were not included in clinical studies, and appropriate dosing recommendations for these patients are unknown. There is no information about the effectiveness of hemodialysis in removing dofetilide from plasma.

Hepatic Impairment

After adjustment for creatinine clearance, no additional dose adjustment is required for patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment have not been studied. Tikosyn should be used with particular caution in these patients.

Cardiac Conduction Disturbances

Animal and human studies have not shown any adverse effects of dofetilide on conduction velocity. No effect on AV nodal conduction following Tikosyn treatment was noted in normal volunteers and in patients with 1st degree heart block. Patients with sick sinus syndrome or with 2nd or 3rd degree heart block were not included in the Phase 3 clinical trials unless a functioning pacemaker was present. Tikosyn has been used safely in conjunction with pacemakers (53 patients in DIAMOND studies, 136 in trials in patients with ventricular and supraventricular arrhythmias).

Information for Patients

Please refer patient to the Medication Guide.

Prior to initiation of Tikosyn therapy, the patient should be advised to read the Medication Guide and reread it each time therapy is renewed in case the patient's status has changed. The patient should be fully instructed on the need for compliance with the recommended dosing of Tikosyn and the potential for drug interactions, and the need for periodic monitoring of QTc and renal function to minimize the risk of serious abnormal rhythms.

Medications and Supplements

Assessment of patients' medication history should include all over-the-counter, prescription, and herbal/natural preparations with emphasis on preparations that may affect the pharmacokinetics of Tikosyn such as cimetidine (see CONTRAINDICATIONS), trimethoprim alone or in combination with sulfamethoxazole (see WARNINGS, CONTRAINDICATIONS), prochlorperazine (see WARNINGS, CONTRAINDICATIONS), megestrol (see WARNINGS, CONTRAINDICATIONS), ketoconazole (see WARNINGS, CONTRAINDICATIONS), hydrochlorothiazide (alone or in combinations such as with triamterene) (see CONTRAINDICATIONS), other cardiovascular drugs (especially verapamil – see CONTRAINDICATIONS), phenothiazines, and tricyclic antidepressants (see WARNINGS). If a patient is taking Tikosyn and requires anti-ulcer therapy, omeprazole, ranitidine, or antacids (aluminum and magnesium hydroxides) should be used as alternatives to cimetidine, as these agents have no effect on the pharmacokinetics of Tikosyn. Patients should be instructed to notify their health care providers of any change in over-the-counter, prescription, or supplement use. If a patient is hospitalized or is prescribed a new medication for any condition, the patient must inform the health care provider of ongoing Tikosyn therapy. Patients should also check with their health care provider and/or pharmacist prior to taking a new over-the-counter preparation.

Electrolyte Imbalance

If patients experience symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, or vomiting or loss of appetite or thirst, these conditions should immediately be reported to their health care provider.

Dosing Schedule

Patients should be instructed NOT to double the next dose if a dose is missed. The next dose should be taken at the usual time.

Drug/Laboratory Test Interactions

None known.

Drug-Drug Interactions

Cimetidine

(see WARNINGS, CONTRAINDICATIONS) Concomitant use of cimetidine is contraindicated. Cimetidine at 400 mg BID (the usual prescription dose) co-administered with Tikosyn (500 mcg BID) for 7 days has been shown to increase dofetilide plasma levels by 58%. Cimetidine at doses of 100 mg BID (OTC dose) resulted in a 13% increase in dofetilide plasma levels (500 mcg single dose). No studies have been conducted at intermediate doses of cimetidine. If a patient requires Tikosyn and anti-ulcer therapy, it is suggested that omeprazole, ranitidine, or antacids (aluminum and magnesium hydroxides) be used as alternatives to cimetidine, as these agents have no effect on the pharmacokinetic profile of Tikosyn.

Verapamil

(see CONTRAINDICATIONS) Concomitant use of verapamil is contraindicated. Co-administration of Tikosyn with verapamil resulted in increases in dofetilide peak plasma levels of 42%, although overall exposure to dofetilide was not significantly increased. In an analysis of the supraventricular arrhythmia and DIAMOND patient populations, the concomitant administration of verapamil with dofetilide was associated with a higher occurrence of Torsade de Pointes.

Sunday, March 11, 2012

Eskalith-CR

Generic Name: lithium (Oral route)

LITH-ee-um

Oral route(Tablet;Tablet, Extended Release;Capsule)

Lithium toxicity is closely related to serum lithium levels, and can occur at doses close to therapeutic levels. Facilities for prompt and accurate serum lithium determinations should be available before initiating therapy .

Oral route(Solution)

Commonly used brand name(s)

In the U.S.

Eskalith

Eskalith-CR

Lithobid

Available Dosage Forms:

Capsule

Solution

Tablet, Extended Release

Tablet

Syrup

Therapeutic Class: Antimanic

Uses For Eskalith-CR

Lithium is used to treat mania that is part of bipolar disorder (manic-depressive illness). It is also used on a daily basis to reduce the frequency and severity of manic episodes. Manic-depressive patients experience severe mood changes, ranging from an excited or manic state (e.g., unusual anger or irritability or a false sense of well-being) to depression or sadness.

It is not known how lithium works to stabilize a person's mood. However, it does act on the central nervous system. It helps you to have more control over your emotions and helps you cope better with the problems of living.

It is important that you and your family understand all the effects of this medicine. These effects depend on your individual condition and response and the amount of lithium you use. You also must know when to contact your doctor if there are problems with using the medicine.

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

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, lithium is used in certain patients with the following medical conditions:

Cluster headaches.

Mental depression.

Neutropenia (a blood condition where there is a decreased number of a certain type of white blood cells).

Before Using Eskalith-CR

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

Allergies

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

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of lithium extended-release tablets in children younger than 12 years of age. Safety and efficacy have not been established.

No information is available on the relationship of age to the effects of lithium capsules, solution, and tablets in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies on the relationship of age to the effects of lithium have not been performed in the geriatric population. However, elderly patients are more likely to have age-related heart and kidney problems, which may require caution and an adjustment in the dose for patients receiving lithium.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	D	Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

Breast Feeding

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

Interactions with Medicines

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

Using this medicine with any of the following medicines is 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.

Acetophenazine

Azosemide

Bemetizide

Bendroflumethiazide

Benzthiazide

Bromperidol

Bumetanide

Buthiazide

Candesartan Cilexetil

Canrenoate

Chlorothiazide

Chlorpromazine

Chlorprothixene

Chlorthalidone

Clozapine

Cyclothiazide

Domperidone

Droperidol

Duloxetine

Ethacrynic Acid

Ethopropazine

Flupenthixol

Fluphenazine

Furosemide

Haloperidol

Hydrochlorothiazide

Hydroflumethiazide

Indapamide

Linezolid

Losartan

Loxapine

Melperone

Mesoridazine

Methotrimeprazine

Methyclothiazide

Metolazone

Milnacipran

Molindone

Olanzapine

Penfluridol

Periciazine

Perphenazine

Phenelzine

Pimozide

Pipamperone

Pipotiazine

Piretanide

Polythiazide

Prochlorperazine

Promazine

Promethazine

Quinethazone

Remoxipride

Risperidone

Sertindole

Sibutramine

Spironolactone

Sulpiride

Thiopropazate

Thioproperazine

Thioridazine

Thiothixene

Tiapride

Torsemide

Trichlormethiazide

Trifluoperazine

Triflupromazine

Trimeprazine

Valsartan

Xipamide

Zotepine

Zuclopenthixol

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

Alacepril

Benazepril

Bromfenac

Calcitonin

Carbamazepine

Celecoxib

Cilazapril

Citalopram

Clometacin

Clovoxamine

Diclofenac

Diltiazem

Dipyrone

Escitalopram

Femoxetine

Fluoxetine

Fluvoxamine

Fosinopril

Ibuprofen

Indomethacin

Ketoprofen

Ketorolac

Lisinopril

Lurasidone

Mazindol

Mefenamic Acid

Meloxicam

Metronidazole

Naproxen

Paroxetine

Perindopril

Piroxicam

Quinapril

Rofecoxib

Sertraline

Spirapril

Succinylcholine

Sulindac

Telmisartan

Tenidap

Tenoxicam

Tiaprofenic Acid

Tolmetin

Trandolapril

Valdecoxib

Verapamil

Yohimbine

Zimeldine

Zofenopril

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.

Proper Use of lithium

This section provides information on the proper use of a number of products that contain lithium. It may not be specific to Eskalith-CR. Please read with care.

Take this medicine exactly as directed by your doctor. Do not take more or less of it, do not take it more or less often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

You might have to take this medicine for several weeks before you begin to feel better. Talk to your doctor if you have any questions.

Make sure that your doctor knows if you are on a low-sodium or low-salt diet. Too little salt in your diet could lead to serious side effects.

Talk to your doctor about the correct amount of fluid to take with this medicine. Some people need to drink extra fluid every day with the lithium.

Swallow the extended-release tablet whole. Do not break, crush, or chew it.

Measure the oral solution with a marked measuring spoon, oral syringe, or medicine cup. A regular teaspoon may not measure the correct amount of medicine.

There are several different forms of lithium. The dose for each is different and they are used at different times of the day. Do not change the type of medicine you take without talking to your doctor first.

In order for lithium to work properly, it must be taken every day in regularly spaced doses as ordered by your doctor. This is necessary to keep a constant amount of lithium in your blood. To help keep the amount constant, do not miss any doses and do not stop taking the medicine even if you feel better.

Use only the brand of this medicine that your doctor prescribed. Different brands may not work the same way.

Dosing

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

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

For oral dosage forms (capsules, solution, and tablets):
- For acute mania:
  - Adults—600 milligrams (mg) or 10 milliliters (mL) three times a day. Your doctor may adjust your dose if needed.
  - Children—Use and dose must be determined by your doctor.
- For long-term treatment of mania:
  - Adults—300 milligrams (mg) or 5 milliliters (mL) three or four times a day. Your doctor may adjust your dose if needed.
  - Children—Use and dose must be determined by your doctor.

For oral dosage form (extended-release tablets):
- For acute mania:
  - Adults—900 milligrams (mg) two times a day, or 600 mg three times a day.
  - Teenagers and children 12 years of age—Use and dose must be determined by your doctor.
  - Children younger than 12 years of age—Use is not recommended.
- For long-term treatment of mania:
  - Adults—600 milligrams (mg) two times a day, or three times a day up to 1200 mg per day.
  - Teenagers and children 12 years of age—Use and dose must be determined by your doctor.
  - Children younger than 12 years of age—Use is not recommended.

Missed Dose

If you miss a dose of this medicine, 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.

Precautions While Using Eskalith-CR

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood and urine tests may be needed to check for unwanted side effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

Stop using this medicine and call your doctor right away if you have diarrhea, vomiting, drowsiness, muscle weakness, tremors, unsteadiness, or other problems with muscle control or coordination.

Make sure your doctor knows if you have a heart disorder called Brugada syndrome. Brugada syndrome can be life-threatening and requires immediate medical attention. Call your doctor or the emergency department right away if you have a fast, pounding, or uneven heartbeat; unexplained fainting; lightheadedness; shortness of breath; or troubled breathing after taking this medicine.

Encephalopathic syndrome (brain problem) may occur in patients taking this medicine together with haloperidol (Haldol®). Check with your doctor right away if you have the following symptoms while taking this medicine: a fever, confusion, drowsiness, difficulty with speaking, uncontrolled body movements, and unusual tiredness or weakness.

This medicine may cause some people to become dizzy, drowsy, or less alert than they are normally. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or are not alert.

Use extra care in hot weather and during activities that cause you to sweat heavily, such as hot baths, saunas, or exercising. If you have an infection or illness that causes heavy sweating, vomiting, diarrhea, shakiness, or muscle weakness, check with your doctor right away. The loss of too much water and salt from your body could lead to serious side effects from this medicine.

Do not go on a diet to lose weight and do not make a major change in your diet without first checking with your doctor. Improper dieting could cause the loss of too much water and salt from your body and could lead to serious side effects from this medicine.

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.

Eskalith-CR 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

Confusion, poor memory, or lack of awareness

fainting

fast or slow heartbeat

frequent urination

increased thirst

irregular pulse

stiffness of the arms or legs

troubled breathing (especially during hard work or exercise)

unusual tiredness or weakness

weight gain

Rare

Blue color and pain in the fingers and toes

coldness of the arms and legs

dizziness

eye pain

headache

noise in the ears

vision problems

Incidence not known

Dry, rough skin

fast, irregular, pounding, or racing heartbeat or pulse

hair loss

hoarseness

lightheadedness

mental depression

sensitivity to cold

shortness of breath

swelling of the feet or lower legs

swelling of the neck

unusual excitement

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

Symptoms of overdose

Blurred vision

clumsiness or unsteadiness

convulsions (seizures)

diarrhea

drowsiness

increase in the amount of urine

lack of coordination

loss of appetite

muscle weakness

nausea or vomiting

ringing in the ears

slurred speech

trembling (severe)

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:

Less common

Acne or skin rash

bloated feeling or pressure in the stomach

muscle twitching (slight)

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: Eskalith-CR side effects (in more detail)

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

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

More Eskalith-CR resources

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

Lithium Professional Patient Advice (Wolters Kluwer)

Lithium Prescribing Information (FDA)

Eskalith Prescribing Information (FDA)

Eskalith Concise Consumer Information (Cerner Multum)

Eskalith MedFacts Consumer Leaflet (Wolters Kluwer)

Lithium Salts Monograph (AHFS DI)

Lithobid Prescribing Information (FDA)

Lithobid Controlled-Release and Extended-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Eskalith-CR with other medications

Bipolar Disorder
Cluster Headaches
Mania
Schizoaffective Disorder

Thursday, March 8, 2012

Talwin NX

Generic Name: naloxone and pentazocine (oral) (nal OX one and pen TAZ oh seen)

Brand Names: Talwin NX

What is naloxone and pentazocine?

Pentazocine is in a group of drugs called narcotic pain relievers.

Naloxone is an special narcotic drug that reverses the effects of other narcotic medicines.

The combination of naloxone and pentazocine is used to treat moderate-to-severe pain. Naloxone is included in this combination to prevent the misuse of the narcotic ingredient.

Naloxone and pentazocine may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about naloxone and pentazocine?

Never crush a naloxone and pentazocine tablet to mix into a liquid for injecting the drug into your vein. This practice has resulted in death with the misuse of pentazocine and similar prescription drugs.

Pentazocine may be habit-forming and should be used only by the person it was prescribed for. Naloxone and pentazocine should never be given to another person, especially someone who has a history of drug abuse or addiction. Keep the medication in a secure place where others cannot get to it. Do not drink alcohol while you are taking naloxone and pentazocine. Alcohol can increase some of the side effects of narcotic pain medicine. Never take more than your prescribed dose of naloxone and pentazocine. Tell your doctor if the medicine seems to stop working as well in relieving your pain. Naloxone and pentazocine can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Do not stop using naloxone and pentazocine suddenly after long-term use, or you could have unpleasant withdrawal symptoms. Talk to your doctor about how to avoid withdrawal symptoms when stopping the medication.

What should I discuss with my health care provider before taking naloxone and pentazocine?

Before using naloxone, tell your doctor if you are using any other narcotic pain medicines. The pain-relieving effects of any narcotic medications you use will be reversed if you use them while you are taking naloxone and pentazocine.

Do not use this medication if you have ever had an allergic reaction to naloxone (Narcan) or pentazocine. Pentazocine may be habit-forming and should be used only by the person it was prescribed for. Naloxone and pentazocine should never be given to another person, especially someone who has a history of drug abuse or addiction. Keep the medication in a secure place where others cannot get to it.

Before using naloxone and pentazocine, tell your doctor if you are allergic to any drugs, or if you have:

asthma, COPD, sleep apnea, or other breathing disorders;

liver or kidney disease;

heart disease or history of heart attack;

brain tumor or head injury;

epilepsy or other seizure disorder;

low blood pressure;

gallbladder disease;

mental illness;

a history of drug or alcohol addiction; or

if you have recently received other narcotic pain medicine or methadone.

If you have any of these conditions, you may need a dose adjustment or special tests to safely take naloxone and pentazocine.

FDA pregnancy category C. This medication may be harmful to an unborn baby, and could cause addiction or withdrawal symptoms in a newborn. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether naloxone and pentazocine passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take naloxone and pentazocine?

Take this medication exactly as it was prescribed for you. Never take naloxone and pentazocine in larger amounts, or use it for longer than recommended by your doctor. Follow the directions on your prescription label. Tell your doctor if the medicine seems to stop working as well in relieving your pain.

Do not stop using naloxone and pentazocine suddenly after long-term use, or you could have unpleasant withdrawal symptoms. Talk to your doctor about how to avoid withdrawal symptoms when stopping the medication. Store naloxone and pentazocine at room temperature away from moisture and heat.

Keep track of how many tablets have been used from each new bottle of this medicine. Pentazocine is a drug of abuse and you should be aware if any person in the household is using this medicine improperly or without a prescription.

What happens if I miss a dose?

Since this medication is sometimes used as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and wait until your next regularly scheduled dose. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include extreme drowsiness, weak pulse, shallow breathing, or fainting.

What should I avoid while taking naloxone and pentazocine?

Do not take naloxone and pentazocine with other narcotic pain medications, sedatives, tranquilizers, muscle relaxers, or other medicines that can make you sleepy or slow your breathing. Dangerous side effects may result. Do not drink alcohol while you are taking naloxone and pentazocine. Alcohol can increase some of the side effects of narcotic pain medicine. Naloxone and pentazocine can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Naloxone and pentazocine side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using naloxone and pentazocine and call your doctor at once if you have any of these serious side effects:

confusion, hallucinations;

fast heart rate;

weak or shallow breathing;

chest pain;

seizure (convulsions);

cold, clammy skin;

tremors;

confusion, unusual thoughts or behavior;

severe anxiety or restlessness; or

feeling like you might pass out.

Less serious side effects may include:

dizziness, drowsiness;

headache, weakness;

sleep problems (insomnia), strange dreams;

diarrhea, constipation;

nausea, vomiting, loss of appetite;

warmth, redness, or tingly feeling under your skin;

sweating;

blurred vision; or

ringing in your ears.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect naloxone and pentazocine?

Before you take naloxone and pentazocine, tell your doctor if you are now using or have recently used other narcotic medications such as:

fentanyl (Actiq, Duragesic);

hydrocodone (Lortab, Vicodin);

hydromorphone (Dilaudid, Palladone);

levorphanol (Levo-Droman);

meperidine (Demerol);

methadone (Diskets, Methadose, Dolophine);

morphine (Duramorph, Kadian, MS Contin, Oramorph, and others);

nalbuphine (Nubain);

oxycodone (Oxycontin);

oxymorphone (Numorphan, Opana); or

pentazocine (Talwin Lactate).

This list is not complete and there may be other drugs that can interact with naloxone and pentazocine. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Talwin NX resources

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

Talwin NX Advanced Consumer (Micromedex) - Includes Dosage Information

Talwin Nx MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Talwin NX with other medications

Pain

Where can I get more information?

Your pharmacist can provide more information about naloxone and pentazocine.

See also: Talwin NX side effects (in more detail)

Wednesday, March 7, 2012

Triaminic Cold/Cough Orally Disintegrating Strips

Pronunciation: DEX-troe-meth-OR-fan/FEN-il-EF-rin
Generic Name: Dextromethorphan/Phenylephrine
Brand Name: Examples include Triaminic Cold/Cough and Triaminic Decongestant/Cough Infant

Triaminic Cold/Cough Orally Disintegrating Strips are used for:

Relieving congestion and cough due to colds, flu, or hay fever. It may also be used for other conditions as determined by your doctor.

Triaminic Cold/Cough Orally Disintegrating Strips are a decongestant and cough suppressant combination. It works by constricting blood vessels and reducing swelling in the nasal passages, which helps you to breathe more easily. The cough suppressant works in the brain to help decrease the cough reflex.

Do NOT use Triaminic Cold/Cough Orally Disintegrating Strips if:

you are allergic to any ingredient in Triaminic Cold/Cough Orally Disintegrating Strips

you have severe high blood pressure, severe heart blood vessel disease, rapid heartbeat, or other severe heart problems

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

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

Before using Triaminic Cold/Cough Orally Disintegrating Strips:

Some medical conditions may interact with Triaminic Cold/Cough Orally Disintegrating Strips. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

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

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

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

if you have a history of glaucoma, an enlarged prostate gland or other prostate problems, heart problems, diabetes, high blood pressure, blood vessel problems, adrenal gland problems, an overactive thyroid, seizures, or stroke

if you have a history of chronic cough, chronic obstructive pulmonary disease (COPD), or other lung problems (eg, asthma, chronic bronchitis, emphysema), or if your cough produces large amounts of mucus

Some MEDICINES MAY INTERACT with Triaminic Cold/Cough Orally Disintegrating Strips. Tell your health care provider if you are taking any other medicines, especially any of the following:

Beta-blockers (eg, propranolol), catechol-O-methyltransferase (COMT) inhibitors (eg, tolcapone), furazolidone, indomethacin, MAOIs (eg, phenelzine), or tricyclic antidepressants (eg, amitriptyline) because the risk of Triaminic Cold/Cough Orally Disintegrating Strips's side effects may be increased

Digoxin or droxidopa because the risk of irregular heartbeat or heart attack may be increased

Bromocriptine because the risk of its side effects may be increased by Triaminic Cold/Cough Orally Disintegrating Strips

Guanadrel, guanethidine, mecamylamine, methyldopa, or reserpine because their effectiveness may be decreased by Triaminic Cold/Cough Orally Disintegrating Strips

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

How to use Triaminic Cold/Cough Orally Disintegrating Strips:

Use Triaminic Cold/Cough Orally Disintegrating Strips as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Take Triaminic Cold/Cough Orally Disintegrating Strips by mouth with or without food.

Do not remove the strip from the pouch until you are ready to take Triaminic Cold/Cough Orally Disintegrating Strips. Be sure that your hands are dry when you touch the strip.

Remove the strip from the pouch and place it onto the tongue. The strip dissolves quickly and can be swallowed with saliva. It may be taken with or without water.

Use the strip right away after you open the pouch. Do not store it for future use.

If you miss a dose of Triaminic Cold/Cough Orally Disintegrating Strips and you are taking it regularly, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Triaminic Cold/Cough Orally Disintegrating Strips.

Important safety information:

Triaminic Cold/Cough Orally Disintegrating Strips may cause dizziness or drowsiness. These effects may be worse if you take it with alcohol or certain medicines. Use Triaminic Cold/Cough Orally Disintegrating Strips with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.

Do not take appetite suppressants while you are taking Triaminic Cold/Cough Orally Disintegrating Strips without checking with your doctor.

If you have trouble sleeping, ask your pharmacist or doctor about the best time to take Triaminic Cold/Cough Orally Disintegrating Strips.

Triaminic Cold/Cough Orally Disintegrating Strips has dextromethorphan and phenylephrine in it. Before you start any new prescription or nonprescription medicine, read the ingredients to see if it has dextromethorphan or phenylephrine in it too. If it does or if you are not sure, check with your doctor or pharmacist.

Do NOT take more than the recommended dose or take Triaminic Cold/Cough Orally Disintegrating Strips for longer than prescribed without checking with your doctor.

Do not use Triaminic Cold/Cough Orally Disintegrating Strips for a cough with a lot of mucous. Do not use it for a long-term cough (eg, caused by asthma, emphysema, smoking). However, you may use it for these conditions if your doctor tells you to.

If your symptoms do not improve within 5 to 7 days, if they become worse, or if they occur with fever, rash, or persistent headache, check with your doctor.

Triaminic Cold/Cough Orally Disintegrating Strips may interfere with certain lab test results. Make sure that all of your doctors and lab personnel know that you are taking Triaminic Cold/Cough Orally Disintegrating Strips.

Tell your doctor or dentist that you take Triaminic Cold/Cough Orally Disintegrating Strips before you receive any medical or dental care, emergency care, or surgery.

Use Triaminic Cold/Cough Orally Disintegrating Strips with caution in the ELDERLY; they may be more sensitive to its effects.

Caution is advised when using Triaminic Cold/Cough Orally Disintegrating Strips in CHILDREN; they may be more sensitive to its effects.

Different brands of Triaminic Cold/Cough Orally Disintegrating Strips may have different dosing instructions for CHILDREN. Follow the dosing instructions on the package labeling. If your doctor has given you instructions, follow those. If you are unsure of the dose to give a child, check with your doctor or pharmacist.

PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Triaminic Cold/Cough Orally Disintegrating Strips while you are pregnant. It is not known if Triaminic Cold/Cough Orally Disintegrating Strips are found in breast milk. Do not breast-feed while taking Triaminic Cold/Cough Orally Disintegrating Strips.

Possible side effects of Triaminic Cold/Cough Orally Disintegrating Strips:

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

Dizziness; excitability; headache; nausea; nervousness or anxiety; trouble sleeping; weakness.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); difficulty urinating; fast or irregular heartbeat; hallucinations; seizures; severe dizziness, lightheadedness, or headache; severe or persistent nervousness, restlessness, or trouble sleeping; tremor.

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

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include blurred vision; confusion; hallucinations; seizures; severe dizziness, lightheadedness, or headache; severe drowsiness; unusually fast, slow, or irregular heartbeat; vomiting.

Proper storage of Triaminic Cold/Cough Orally Disintegrating Strips:

Store Triaminic Cold/Cough Orally Disintegrating Strips at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Triaminic Cold/Cough Orally Disintegrating Strips out of the reach of children and away from pets.

General information:

If you have any questions about Triaminic Cold/Cough Orally Disintegrating Strips, please talk with your doctor, pharmacist, or other health care provider.

Triaminic Cold/Cough Orally Disintegrating Strips are to be used only by the patient for whom it is prescribed. Do not share it with other people.

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

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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

More Triaminic Cold/Cough resources

Triaminic Cold/Cough Use in Pregnancy & Breastfeeding
Triaminic Cold/Cough Drug Interactions
0 Reviews for Triaminic Cold/Cough - Add your own review/rating

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Cough and Nasal Congestion

Tuesday, March 6, 2012

Calcitriol Injection

Dosage Form: injection
Calcitriol Injection, 1 mcg/mL

Rx Only

DESCRIPTION

Calcitriol Injection is synthetically manufactured calcitriol and is available as a sterile, isotonic, clear, colorless to yellow, aqueous solution for intravenous injection. Calcitriol is available in 1 mL ampules. Each 1 mL contains: Calcitriol 1 mcg; Polysorbate 20, 4 mg; Sodium Chloride 1.5 mg; Sodium Ascorbate 10 mg added; Dibasic Sodium Phosphate, Anhydrous 7.6 mg; Monobasic Sodium Phosphate, Monohydrate 1.8 mg; Edetate Disodium, Dihydrate 1.1 mg added; Water for Injection q.s. pH range 6.7-7.7.

Calcitriol is a crystalline compound which occurs naturally in humans. It is soluble in organic solvents but relatively insoluble in water. Calcitriol is chemically designated (5Z,7E)-9,10-secocholesta-5,7,10(19)-triene-1α,3β,25-triol and has the following structural formula:

Molecular Formula: C27H44O3

The other names frequently used for calcitriol are 1α,25-dihydroxycholecalciferol, 1α,25-dihydroxyvitamin D3, 1,25-DHCC, 1,25(OH)2D3 and 1,25-diOHC.

CLINICAL PHARMACOLOGY

Calcitriol is the active form of vitamin D3 (cholecalciferol). The natural or endogenous supply of vitamin D in man mainly depends on ultraviolet light for conversion of 7-dehydrocholesterol to vitamin D3 in the skin. Vitamin D3 must be metabolically activated in the liver and the kidney before it is fully active on its target tissues. The initial transformation is catalyzed by a vitamin D3-25-hydroxylase enzyme present in the liver, and the product of this reaction is 25-(OH)D3 (calcifediol). The latter undergoes hydroxylation in the mitochondria of kidney tissue, and this reaction is activated by the renal 25-hydroxyvitamin D3-1-α-hydroxylase to produce 1,25-(OH)2D3 (calcitriol), the active form of vitamin D3.

The known sites of action of calcitriol are intestine, bone, kidney and parathyroid gland. Calcitriol is the most active known form of vitamin D3 in stimulating intestinal calcium transport. In acutely uremic rats, calcitriol has been shown to stimulate intestinal calcium absorption. In bone, calcitriol, in conjunction with parathyroid hormone, stimulates resorption of calcium; and in the kidney, calcitriol increases the tubular reabsorption of calcium. In-vitro and in-vivo studies have shown that calcitriol directly suppresses secretion and synthesis of PTH. A vitamin D-resistant state may exist in uremic patients because of the failure of the kidney to adequately convert precursors to the active compound, calcitriol.

Calcitriol when administered by bolus injection is rapidly available in the blood stream. Vitamin D metabolites are known to be transported in blood, bound to specific plasma proteins. The pharmacologic activity of an administered dose of calcitriol is about 3 to 5 days. Two metabolic pathways for calcitriol have been identified, conversion to 1,24,25-(OH)3D3 and to calcitroic acid.

INDICATIONS AND USAGE

Calcitriol Injection is indicated in the management of hypocalcemia in patients undergoing chronic renal dialysis. It has been shown to significantly reduce elevated parathyroid hormone levels. Reduction of PTH has been shown to result in an improvement in renal osteodystrophy.

CONTRAINDICATIONS

Calcitriol Injection should not be given to patients with hypercalcemia or evidence of vitamin D toxicity.

WARNINGS

Since calcitriol is the most potent metabolite of vitamin D available, vitamin D and its derivatives should be withheld during treatment.

A non-aluminum phosphate-binding compound should be used to control serum phosphorus levels in patients undergoing dialysis.

Overdosage of any form of vitamin D is dangerous (see also OVERDOSAGE). Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention. Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis and other soft-tissue calcification. The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition.

PRECAUTIONS

1. General

Excessive dosage of Calcitriol Injection induces hypercalcemia and in some instances hypercalciuria; therefore, early in treatment during dosage adjustment, serum calcium and phosphorus should be determined at least twice weekly. Should hypercalcemia develop, the drug should be discontinued immediately.

Calcitriol Injection should be given cautiously to patients on digitalis, because hypercalcemia in such patients may precipitate cardiac arrhythmias.

2. Information for Patients

The patient and his or her parents should be informed about adherence to instructions about diet and calcium supplementation and avoidance of the use of unapproved non-prescription drugs, including magnesium-containing antacids. Patients should also be carefully informed about the symptoms of hypercalcemia (see ADVERSE REACTIONS).

3. Essential Laboratory Tests

Serum calcium, phosphorus, magnesium and alkaline phosphatase and 24-hour urinary calcium and phosphorus should be determined periodically. During the initial phase of the medication, serum calcium and phosphorus should be determined more frequently (twice weekly).

Adynamic bone disease may develop if PTH levels are suppressed to abnormal levels. If biopsy is not being done for other (diagnostic) reasons, PTH levels may be used to indicate the rate of bone turnover. If PTH levels fall below recommended target range (1.5 to 3 times the upper limit of normal), in patients treated with Calcitriol Injection, the Calcitriol Injection dose should be reduced or therapy discontinued. Discontinuation of Calcitriol Injection therapy may result in rebound effect, therefore, appropriate titration downward to a maintenance dose is recommended.

4. Drug Interactions

Magnesium-containing antacid and Calcitriol Injection should not be used concomitantly, because such use may lead to the development of hypermagnesemia.

5. Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of Calcitriol Injection. Calcitriol was not mutagenic in vitro in the Ames test nor was oral calcitriol genotoxic in vivo in the Mouse Micronucleus Test. No significant effects on fertility and/or general reproductive performances were observed in a Segment I study in rats using oral calcitriol at doses of up to 0.3 mcg/kg.

6. Pregnancy

Teratogenic Effects

Pregnancy Category C:

Calcitriol has been found to be teratogenic in rabbits when given orally at doses of 0.08 and 0.3 mcg/kg. All 15 fetuses in 3 litters at these doses showed external and skeletal abnormalities. However, none of the other 23 litters (156 fetuses) showed external and skeletal abnormalities compared with controls. Teratogenicity studies in rats at doses up to 0.45 mcg/kg orally showed no evidence of teratogenic potential. There are no adequate and well-controlled studies in pregnant women. Calcitriol Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: In the rabbit, oral dosages of 0.3 mcg/kg/day administered on days 7 to 18 of gestation resulted in 19% maternal mortality, a decrease in mean fetal body weight and a reduced number of newborns surviving to 24 hours. A study of the effects on orally administered calcitriol on peri- and postnatal development in rats resulted in hypercalcemia in the offspring of dams given calcitriol at doses of 0.08 or 0.3 mcg/kg/day, hypercalcemia and hypophosphatemia in dams given calcitriol at a dose of 0.08 or 0.3 mcg/kg/day and increased serum urea nitrogen in dams given calcitriol at a dose of 0.3 mcg/kg/day. In another study in rats, maternal weight gain was slightly reduced at an oral dose of 0.3 mcg/kg/day administered on days 7 to 15 of gestation.

The offspring of a woman administered oral calcitriol at 17 to 36 mcg/day during pregnancy manifested mild hypercalcemia in the first 2 days of life which returned to normal at day 3.

7. Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from calcitriol, 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.

8. Pediatric Use

The safety and effectiveness of Calcitriol Injection were examined in a 12-week randomized, double-blind, placebo-controlled study of 35 pediatric patients, aged 13-18 years, with end-stage renal disease on hemodialysis. Sixty-six percent of the patients were male, 57% were African-American, and nearly all had received some form of vitamin D therapy prior to the study. The initial dose of Calcitriol Injection was 0.5 mcg, 1 mcg, or 1.5 mcg, 3 times per week, based on baseline iPTH level of less than 500 pg/mL, 500-1000 pg/mL, or greater than 1000 pg/mL, respectively. The dose of Calcitriol Injection was adjusted in 0.25 mcg increments based on the levels of serum iPTH, calcium, and Ca x P. The mean baseline levels of iPTH were 769 pg/mL for the 16 Calcitriol Injection-treated patients and 897 pg/mL for the 19 placebo-treated subjects. The mean weekly dose of Calcitriol Injection ranged from 1 mcg to 1.4 mcg. In the primary efficacy analysis, 7 of 16 (44%) subjects in the Calcitriol Injection group had 2 consecutive 30% decreases from baseline iPTH compared with 3 of 19 (16%) patients in the placebo group (95% CI for the difference between groups -6%, 62%). One Calcitriol Injection-treated patient experienced transient hypercalcemia (>11 mg/dL), while 6 of 16 (38%) Calcitriol Injection-treated patients vs. 2 of 19 (11%) placebo-treated patients experienced Ca x P >75.

9. Geriatric Use

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

ADVERSE REACTIONS

Adverse effects of Calcitriol Injection are, in general, similar to those encountered with excessive vitamin D intake. The early and late signs and symptoms of vitamin D intoxication associated with hypercalcemia include:

EarlyWeakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain and metallic taste.

LatePolyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated SGOT and SGPT, ectopic calcification, hypertension, cardiac arrhythmias and, rarely, overt psychosis.

Occasional mild pain on injection has been observed.

Post-Marketing Experience Rare cases of hypersensitivity reactions have been reported, including anaphylaxis.

OVERDOSAGE

Administration of Calcitriol Injection to patients in excess of their requirements can cause hypercalcemia, hypercalciuria and hyperphosphatemia. High intake of calcium and phosphate concomitant with calcitriol injection may lead to similar abnormalities.

1. Treatment of Hypercalcemia and Overdosage in Patients on Hemodialysis

General treatment of hypercalcemia (greater than 1 mg/dL above the upper limit of normal range) consists of immediate discontinuation of Calcitriol Injection therapy, institution of a low calcium diet and withdrawal of calcium supplements. Serum calcium levels should be determined daily until normocalcemia ensues. Hypercalcemia usually resolves in two to seven days. When serum calcium levels have returned to within normal limits, Calcitriol Injection therapy may be reinstituted at a dose 0.5 mcg less than prior therapy. Serum calcium levels should be obtained at least twice weekly after all dosage changes.

Persistent or markedly elevated serum calcium levels may be corrected by dialysis against a calcium-free dialysate.

2. Treatment of Accidental Overdosage of Calcitriol Injection The treatment of acute accidental overdosage of Calcitriol Injection should consist of general supportive measures. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and low calcium diet are also indicated in accidental overdosage. Due to the relatively short duration of the pharmacological action of calcitriol, further measures are probably unnecessary. Should, however, persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives which may be considered, depending on the patients’ underlying condition. These include the use of drugs such as phosphates and corticosteroids as well as measures to induce an appropriate forced diuresis. The use of peritoneal dialysis against a calcium-free dialysate has also been reported.

DOSAGE AND ADMINISTRATION

The optimal dose Calcitriol Injection must be carefully determined for each patient.

The effectiveness of Calcitriol Injection therapy is predicated on the assumption that each patient is receiving an adequate and appropriate daily intake of calcium. The RDA for calcium in adults is 800 mg. To ensure that each patient receives an adequate daily intake of calcium, the physician should either prescribe a calcium supplement or instruct the patient in proper dietary measures.

The recommended initial dose of Calcitriol Injection, depending on the severity of the hypocalcemia and/or secondary hyperparathyroidism, is 1 mcg (0.02 mcg/kg) to 2 mcg administered three times weekly, approximately every other day. Doses as small as 0.5 mcg and as large as 4 mcg three times weekly have been used as an initial dose. If a satisfactory response is not observed, the dose may be increased by 0.5 to 1 mcg at two to four week intervals. During this titration period, serum calcium and phosphorus levels should be obtained at least twice weekly. If hypercalcemia or a serum calcium times phosphate product greater than 70 is noted, the drug should be immediately discontinued until these parameters are appropriate. Then, the Calcitriol Injection dose should be reinitiated at a lower dose. Doses may need to be reduced as the PTH levels decrease in response to the therapy. Thus, incremental dosing must be individualized and commensurate with PTH, serum calcium and phosphorus levels.

The following is a suggested approach in dose titration:

PTH Levels	Calcitriol Dose
the same or increasing	increase
decreasing by <30%	increase
decreasing by >30%, <60%	maintain
decreasing by >60%	decrease
one and one-half to three times the upper limit of normal	maintain

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Discard unused portion

WARNING: PROTECT FROM LIGHT. RETAIN IN CARTON UNTIL TIME OF USE.

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) (See USP Controlled Room Temperature).

HOW SUPPLIED

Calcitriol Injection NDC 0517-0132-25 1 mcg/mL 1 mL ampules Boxed in 25

AMERICAN REGENT, INC.

SHIRLEY, NY 11967

IN0132

Rev. 6/08

MG #15726

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL – 1 mL Carton

Calcitriol Injection

1 mcg/mL

NDC 0517-0132-25

25 x 1 mL Ampules

FOR INTRAVENOUS USE

Rx Only

Each mL contains: Calcitriol 1 mcg; Polysorbate 20, 4 mg; Sodium Chloride 1.5 mg; Sodium Ascorbate 10 mg added; Dibasic Sodium Phosphate, Anhydrous 7.6 mg; Monobasic Sodium Phosphate, Monohydrate 1.8 mg; Edetate Disodium, Dihydrate 1.1 mg added; Water for Injection q.s. pH range 6.7 to 7.7. Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) (See USP Controlled RoomTemperature).

WARNING: Protect from light. Retain ampules in carton until time of use.

Directions for Use: See Package Insert.

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Rev. 11/05

CALCITRIOL
calcitriol injection, solution

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	NDC Product Code (Source)	0517-0132
Route of Administration	INTRAVENOUS	DEA Schedule

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
CALCITRIOL (CALCITRIOL)	CALCITRIOL	1 ug in 1 mL

Inactive Ingredients
Ingredient Name	Strength
POLYSORBATE 20	4 mg in 1 mL
SODIUM CHLORIDE	1.5 mg in 1 mL
SODIUM ASCORBATE	10 mg in 1 mL
SODIUM PHOSPHATE, DIBASIC ANHYDROUS	7.6 mg in 1 mL
SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE	1.8 mg in 1 mL
EDETATE DISODIUM	1.1 mg in 1 mL
WATER

Product Characteristics
Color		Score
Shape		Size
Flavor		Imprint Code
Contains

Packaging
#	NDC	Package Description	Multilevel Packaging
1	0517-0132-25	25 AMPULE In 1 CARTON	contains a AMPULE
1		1 mL In 1 AMPULE	This package is contained within the CARTON (0517-0132-25)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA075746	03/14/2005

Labeler - American Regent, Inc. (622781813)

Revised: 09/2011American Regent, Inc.

More Calcitriol Injection resources

Calcitriol Injection Use in Pregnancy & Breastfeeding
Drug Images
Calcitriol Injection Drug Interactions
Calcitriol Injection Support Group
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Hypocalcemia
Hypoparathyroidism
Renal Osteodystrophy
Rickets
Secondary Hyperparathyroidism

Monday, March 5, 2012

Stimate nasal

Generic Name: desmopressin (nasal) (DEZ mo press in)

Brand Names: DDAVP Nasal, DDAVP Rhinal Tube, Stimate

What is Stimate (desmopressin (nasal))?

Desmopressin is a man-made form of a hormone that occurs naturally in the pituitary gland. This hormone is important for many functions including blood flow, blood pressure, kidney function, and regulating how the body uses water.

Desmopressin nasal is used to treat central cranial diabetes insipidus, and increased thirst and urination caused by head surgery or head trauma.

Desmopressin nasal is also used to treat hemophilia A or von Willebrand's disease Type I.

Desmopressin nasal may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Stimate (desmopressin (nasal))?

It is very important to reduce your intake of water and other fluids while you are using desmopressin. Drinking too much water can cause your body to lose sodium, which may lead to a serious, life-threatening electrolyte imbalance.

Fluid restriction is especially important in children and older adults using desmopressin nasal. Follow your doctor's instructions about the type and amount of liquids you should drink.

You should not use this medication if you have severe kidney disease or if you have ever had hyponatremia (low sodium levels in your body).

Before using desmopressin nasal, tell your doctor if you have heart disease, coronary artery disease, congestive heart failure, kidney disease, cystic fibrosis, high or low blood pressure, an electrolyte imbalance, or a psychological disorder that causes extreme or unusual thirst.

Desmopressin nasal may be less effective if you have any swelling or scarring inside your nose, or any nasal or sinus problems (such as deviated septum).

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

To be sure desmopressin nasal is helping your condition, your blood will need to be tested often. This will help your doctor determine how long to treat you with this medication. Do not miss any scheduled appointments.

What should I discuss with my healthcare provider before using Stimate (desmopressin (nasal))?

You should not use this medication if you are allergic to desmopressin, or if you have:

severe kidney disease; or

if you have ever had hyponatremia (low sodium levels in your body).

Before using desmopressin nasal, tell your doctor if you are allergic to any medications, or if you have:

heart disease, coronary artery disease;

congestive heart failure;

kidney disease;

cystic fibrosis;

high or low blood pressure;

an electrolyte imbalance; or

a psychologic disorder that causes extreme or unusual thirst.

If you have any of these conditions, you may need a dose adjustment or special tests to safely use desmopressin.

Desmopressin nasal may be less effective if you have any swelling or scarring inside your nose, or any nasal or sinus problems (such as deviated septum).

FDA pregnancy category B. This medication is not expected to harm an unborn baby. Do not use desmopressin nasal without telling your doctor if you are pregnant. It is not known whether desmopressin nasal passes into breast milk, or if it could harm a nursing baby. Do not use desmopressin nasal without telling your doctor if you are breast-feeding a baby.

How should I use Stimate (desmopressin (nasal))?

Use this medication exactly as prescribed by your doctor. Do not use it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

Fluid restriction is especially important in children and older adults using desmopressin nasal. Follow your doctor's instructions about the type and amount of liquids you should drink.

Before using desmopressin nasal spray for the first time, prime the spray pump by pressing down on the pump 4 times.

To be sure this medication is helping your condition, your blood will need to be tested often. This will help your doctor determine how long to treat you with desmopressin nasal. Do not miss any scheduled appointments.

Keep track of how many sprays have been used from each bottle of desmopressin nasal spray. Stimate nasal spray contains enough desmopressin for the priming spray plus 25 full sprays. DDAVP nasal spray contains enough desmopressin for the priming spray plus 50 sprays. Your patient instructions may include a check-off chart to help you keep an accurate record or sprays you use. If you are treating hemophilia or von Willebrand's disease, call your doctor if your bleeding is not controlled during treatment with desmopressin nasal.

The desmopressin nasal spray bottle should be thrown away after the specified number of sprays have been used, even if there is medicine leftover in the bottle. Do not try to pour solution from one bottle to another.

Store DDAVP nasal spray at room temperature away from moisture and heat. Keep the bottle in an upright position when not in use. Store Stimate nasal spray or DDAVP Rhinal Tube in the refrigerator. Do not freeze. If refrigeration is not available, you may keep the closed bottles at room temperature for up to 3 weeks.

What happens if I miss a dose?

Use the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to use the medicine and skip the missed dose. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include headache, confusion, drowsiness, rapid weight gain, or urination problems.

What should I avoid while using Stimate (desmopressin (nasal))?

Follow your doctor's instructions about any restrictions on food, beverages, or activity while you are using desmopressin.

Stimate (desmopressin (nasal)) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using desmopressin nasal and call your doctor at once if you have any of these serious side effects:

nausea, vomiting, weakness, loss of appetite, headache, feeling restless or irritable, confusion, hallucinations, muscle pain or weakness, and/or seizure;

feeling like you might pass out;

swelling;

chest pain, fast or pounding heart rate;

vaginal pain;

nosebleed; or

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

Less serious side effects may include:

runny or stuffy nose;

sore throat, cough, or other cold symptoms;

eye redness or watering;

eye itching or increased sensitivity to light;

headache, weakness;

feeling dizzy or agitated;

nausea, vomiting, stomach pain;

hot or cold feeling; or

warmth, redness, or tingly feeling in your face.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Stimate (desmopressin (nasal))?

Many drugs can interact with desmopressin nasal. Below is just a partial list. Tell your doctor if you are using:

carbamazepine (Carbatrol, Tegretol);

chlorpromazine (Thorazine);

lamotrigine (Lamictal);

oxybutynin (Ditropan, Urotrol, Oxytrol);

vasopressin (Pitressin);

a narcotic pain medicine such as fentanyl (Actiq, Duragesic), hydrocodone (Lortab, Vicodin), oxycodone (Oxycontin), and others;

an "SSRI" antidepressant such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil), or sertraline (Zoloft);

a tricyclic antidepressant such as amitriptyline (Elavil, Etrafon), clomipramine (Anafranil), desipramine (Norpramin), doxepin (Sinequan), imipramine (Janimine, Tofranil), and others;

medicine to treat erectile dysfunction, such as sildenafil (Viagra), tadalafil (Cialis), or vardenafil (Levitra);

drugs to treat high blood pressure or a prostate disorder, such as alfuzosin (Uroxatral), doxazosin (Cardura), prazosin (Minipress), terazosin (Hytrin), tamsulosin (Flomax);

a beta-blocker such as atenolol (Tenormin), bisoprolol (Zebeta, Ziac), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal, InnoPran), sotalol (Betapace), or timolol (Blocadren); or

an NSAID (non-steroidal anti-inflammatory drug) such as ibuprofen (Motrin, Advil), naproxen (Aleve, Naprosyn), diclofenac (Cataflam, Voltaren), etodolac (Lodine), indomethacin (Indocin), and others.

This list is not complete and there may be other drugs that can interact with desmopressin nasal. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Stimate resources

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

Compare Stimate with other medications

Hemophilia A
von Willebrand's Disease

Where can I get more information?

Your pharmacist can provide more information about desmopressin nasal.

See also: Stimate side effects (in more detail)

Monday, March 12, 2012

Tikosyn

Tikosyn - Clinical Pharmacology

Mechanism of Action

Electrophysiology

Hemodynamic Effects

Pharmacokinetics, General

Pharmacokinetics in Special Populations

Drug-Drug Interactions

Dose-Response and Concentration Response for Increase in QT Interval

Clinical Studies

Chronic Atrial Fibrillation and/or Atrial Flutter

Safety in Patients with Structural Heart Disease: DIAMOND Studies (The Danish Investigations of Arrhythmia and Mortality on Dofetilide)

Indications and Usage for Tikosyn

Maintenance of Normal Sinus Rhythm (Delay in AF/AFl Recurrence)

Conversion of Atrial Fibrillation/Flutter

Contraindications

Warnings

Ventricular Arrhythmia

Drug-Drug Interactions

Hypokalemia and Potassium-Depleting Diuretics

Use with Drugs that Prolong QT Interval and Antiarrhythmic Agents

Precautions

Renal Impairment

Hepatic Impairment

Cardiac Conduction Disturbances

Information for Patients

Drug/Laboratory Test Interactions

Drug-Drug Interactions

Sunday, March 11, 2012

Eskalith-CR

Commonly used brand name(s)

Uses For Eskalith-CR

Before Using Eskalith-CR

Allergies

Pediatric

Geriatric

Pregnancy

Breast Feeding

Interactions with Medicines

Interactions with Food/Tobacco/Alcohol

Other Medical Problems

Proper Use of lithium

Dosing

Missed Dose

Storage

Precautions While Using Eskalith-CR

Eskalith-CR Side Effects

More Eskalith-CR resources

Compare Eskalith-CR with other medications

Thursday, March 8, 2012

Talwin NX

What is naloxone and pentazocine?

What is the most important information I should know about naloxone and pentazocine?

What should I discuss with my health care provider before taking naloxone and pentazocine?

How should I take naloxone and pentazocine?

What happens if I miss a dose?

What happens if I overdose?

What should I avoid while taking naloxone and pentazocine?

Naloxone and pentazocine side effects

What other drugs will affect naloxone and pentazocine?

More Talwin NX resources

Compare Talwin NX with other medications

Where can I get more information?

Wednesday, March 7, 2012

Triaminic Cold/Cough Orally Disintegrating Strips

Triaminic Cold/Cough Orally Disintegrating Strips are used for:

Do NOT use Triaminic Cold/Cough Orally Disintegrating Strips if:

Before using Triaminic Cold/Cough Orally Disintegrating Strips:

How to use Triaminic Cold/Cough Orally Disintegrating Strips:

Important safety information:

Possible side effects of Triaminic Cold/Cough Orally Disintegrating Strips:

If OVERDOSE is suspected:

General information:

More Triaminic Cold/Cough resources

Compare Triaminic Cold/Cough with other medications

Tuesday, March 6, 2012

Calcitriol Injection

DESCRIPTION

CLINICAL PHARMACOLOGY