ADENOCARD (adenosine) - ANDRODERM (testosterone) - AREDIA (pamidronate disodium) - AVENTYL (nortriptyline HCl) - CAPOTEN (captopril) - CAPOZIDE (captopril/hydrochlorothiazide) - COZAAR (losartan potassium) - DESOGEN (desogestrel/ethinyl estradiol) - DIFLUCAN (fluconazole) - ENKAID (encainide HCl) - FAMVIR (famciclovir) - HYZAAR (losartan/hydrochlorothiazide) - MONOPRIL (fosinopril) - MONOPRIL-HCT (fosinopril/hydrochlorothiazide) - NIZORAL (ketoconazole) - PAMELOR (nortriptyline HCl) - PARLODEL (bromocriptine mesylate) - SEREVENT (salmeterol xinafoate) - VASERETIC (enalapril maleate/hydrochlorothiazide) - VASOTEC (enalapril maleate)- VASOTEC I.V. (enalaprilat)

ADENOCARD (adenosine)
[July 29, 1996: Medco]

CLINICAL PHARMACOLOGY:

As Adenocard requires no hepatic or renal function for its activation or inactivation, hepatic and renal failure would not be expected to alter its effectiveness or tolerability.

CONTRAINDICATIONS:

Notation regarding sinus node changed to sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (as before, except in patients with a functioning artificial pacemaker).

WARNINGS:

Heart Block: Notation regarding ventricular fibrillation following Adenocard changed to include association with concomitant use of digoxin and verapamil (though less frequent than with concomitant use of digoxin). Adenocard should be used with caution in patients receiving digoxin or digoxin and verapamil in combination.

Bronchoconstriction (New subsection):

Adenocard (adenosine) is a respiratory stimulant (probably through activation of carotid body chemoreceptors) and intravenous administration in man has been shown to increase minute ventilation (Ve) and reduce arterial PCO2 causing respiratory alkalosis. Adenosine administered by inhalation has been reported to cause bronchoconstriction in asthmatic patients, presumably due to mast cell degranulation and histamine release. These effects have not been observed in normal subjects. Adenocard has been administered to a limited number of patients with asthma and mild to moderate exacerbation of their symptoms has been reported. Respiratory compromise has occurred during adenosine infusion in patients with obstructive pulmonary disease. Adenocard should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis, etc.) and should be avoided in patients with bronchoconstriction or bronchospasm (e.g., asthma). Adenocard should be discontinued in any patient who develops severe respiratory difficulties.

PRECAUTIONS:

Asthma: Previous subsection has been removed.

Drug Interactions: Rare association of ventricular fibrillation with combined digoxin, verapamil and Adenocard use noted (see WARNINGS). Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, Adenocard should be used with caution in the presence of these agents.

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ANDRODERM (testosterone)
[July 10, 1996: Theratech]

PRECAUTIONS:

Information for Patients: Advisement added that patients should not apply Androderm over bony prominences or parts of the body that could be subject to prolonged pressure during sleep or sitting, as applications to these sites have been associated with burn-like blister reactions.

ADVERSE REACTIONS:

Revised to indicate that fourteen patients (12% of those in clinical studies) had burn-like blister reactions involving bullae, epidermal necrosis or development of ulcerated lesions. The majority were associated with application over areas outlined in PRECAUTIONS, Information for Patients, with the more severe lesions healing over several weeks with scarring in some cases; such lesions should be treated as burns.

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ADVERSE REACTIONS:

Revised to indicate that of toxicities commonly associated with chemotherapy, viral infection, herpes zoster and anorexia all occurred more frequently in the Aredia arm of the study.

PRECAUTIONS:

Drugs metabolized by P450IID6: A subset (3%-10%) of the population has reduced activity of drug metabolizing enzymes such as the cytochrome P450 isoenzyme P450IID6. Referred to as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants, these individuals may have higher than expected plasma concentrations of tricyclic antidepressants when given usual doses. In addition, certain drugs metabolized by this isoenzyme, including many antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, and others) may inhibit its activity. As a result, normal metabolizers may be made to resemble poor metabolizers with respect to concomitant therapy with other drugs metabolized by this enzyme system, thus leading to drug interactions. Concomitant use of tricyclic antidepressants with other drugs metabolized by cytochrome P450IID6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Therefore, co-administration of tricyclic antidepressants with other drugs including other antidepressants, phenothiazines, carbamazepine and Type 1c antiarrhythmics (e.g., propafenone, flecainide, and encainide), or with drugs that inhibit this enzyme (e.g., quinidine), should be approached with caution.

OVERDOSAGE:

Section completely revised [see complete section in package insert].

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CAPOTEN (captopril)
[July 31, 1996: Bristol-Myers Squibb]

INDICATIONS AND USAGE:

In black patients, ACE inhibitors have a lesser effect on blood pressure and (for which adequate data are available) cause a higher rate of angioedema (see WARNINGS: Angioedema)

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INDICATIONS AND USAGE:

ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients (see WARNINGS: Angioedema).

PRECAUTIONS:

Drug Interactions, Hydrochlorothiazide (New subsection): Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired up to 85% and 43%, respectively, in the presence of these resins.

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COZAAR (losartan potassium)
and
HYZAAR (losartan/hydrochlorothiazide)
[July 18, 1996: Merck]

PRECAUTIONS:

Impaired Renal Function: Revised to indicate that changes in renal function have been reported in susceptible individuals, with these changes reversible upon discontinuation of therapy in some patients.

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WARNINGS:

Thromboembolic Disorders and Other Vascular Problems: Desogestrel has minimal androgenic activity, with some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestogen has minimal androgenic activity than when activity is greater (Br Med J 1996;312:88-90). Studies of venous thromboembolism and third generation oral contraceptives, including those containing desogestrel, reported relative risks (RRs) between 1.5 and 2.4 when compared to certain second generation oral contraceptives (Lancet 1995;346:1589-93; Lancet 1995;346:1582-88; Br Med J 1996;312:83-88); an RR of 2 translates into an additional 1-2 cases of non-fatal venous thromboembolism in 10,000 women-years of use. The risk of venous thromboembolic disease associated with oral contraceptives does not increase with length of use and disappears after pill useis stopped.

PATIENT LABELING:

Risks of Taking Oral Contraceptives: Risk of developing blood clots: These risks may be greater with desogestrel-containing oral contraceptives such as DesogenR than with certain other low-dose pills.

DIFLUCAN (fluconazole)
[July 23, 1996: Pfizer]

PRECAUTIONS:

Drug Interactions, Terfenadine: Revised to indicate that the concurrent use of fluconazole with drugs metabolized by the cytochrome P450 system (i.e., terfenadine, cisapride and astemizole) may be associated with elevations in serum levels of these other drugs. Given the lack of definitive information at higher doses of fluconazole, co-administration of Diflucan and such agents should be carefully monitored.

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ENKAID (encainide HCl)
[July 15, 1996: Bristol-Myers Squibb]

WARNINGS:

Enkaid was included in the National Heart Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a study of patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction (> six days and

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FAMVIR (famciclovir)
[July 29, 1996: SmithKline Beecham]

PRECAUTIONS:

Impairment of Fertility: Revised to include results of two placebo-controlled studies that showed no evidence of significant effects on sperm count, motility or morphology during treatment or 8-week follow-up.

ADVERSE REACTIONS:

During clinical practice, confusion (including delirium, disorientation, confusional state) has been infrequently reported, with most reports in the elderly.

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MONOPRIL (fosinopril)
and
MONOPRIL-HCT (fosinopril/hydrochlorothiazide)
[July 24, 1996: Bristol-Myers Squibb]

INDICATIONS AND USAGE:

In black patients, ACE inhibitors have a lesser effect on blood pressure and (those ACE inhibitors for which adequate data are available) cause a higher rate of angioedema (see WARNINGS: Angioedema).

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NIZORAL (ketoconazole)
[July 8, 1996: Janssen]

BOXED WARNING:

Revised to denote that coadministration of cisapride with ketoconazole is contraindicated, as serious cardiovascular adverse events that include ventricular tachycardia, ventricular fibrillation and torsades de pointes have occurred in patients concomitantly taking cisapride and ketoconazole (see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS sections).

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PARLODEL (bromocriptine mesylate)
[July 3, 1996: Sandoz]

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SEREVENT (salmeterol xinafoate)
[July 9, 1996: Glaxo Wellcome]

ADVERSE REACTIONS:

Postmarketing Experience: Revised to indicate that hypertension and arrhythmias have been reported.

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WARNINGS:

Pregnancy, Enalapril-Hydrochlorothiazide; Enalapril Maleate, Fetal/Neonatal Morbidity and Mortality: These subsections were revised to present data from rodent (rats and mice) studies in terms of maximum recommended human daily dose (MRHDD) on a body surface area (mg/m2) basis, rather than the previously utilized mg/kg/day [see complete subsections in package insert].

Hydrochlorothiazide: Subsection revised to include results of studies in pregnant mice and rats that provided no evidence of harm to the fetus [see complete subsection in package insert].

PRECAUTIONS:

Carcinogenesis, Mutagenesis, Impairment of Fertility; Enalapril Maleate; Hydrochlorothiazide: These subsections likewise revised to present rodent data on a body surface area (mg/m2) basis, rather than the previously utilized mg/kg/day [see complete subsections in package insert].

Nursing Mothers: Subsection revised by deletion of "trace amounts" with respect to enalapril and enalaprilat.

OVERDOSAGE:

Enalapril Maleate and Hydrochlorothiazide: Subsections revised by deleting statements regarding oral LD50 of enalapril and hydrochlorothiazide in mice and rats and adding statements regarding lethality of enalapril and hydrochlorothiazide:

Enalapril: Single oral doses above 1,000 mg/kg (mice) and 1,775 mg/kg (rats) were associated with lethality.

Hydrochlorothiazide: Lethality was not observed after administration of an oral dose of 10 g/kg to mice and rats.

INDICATIONS AND USAGE:

Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema (see WARNINGS, Angioedema).

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WARNINGS:

Fetal/Neonatal Morbidity and Mortality: Subsection revised as per Vaseretic (see above).

PRECAUTIONS:

Carcinogenesis, Mutagenesis, Impairment of Fertility: Subsection revised as per Vaseretic (see above).

Nursing Mothers: Statement regarding detection of enalapril and enalaprilat in human breast milk revised by deletion of "trace amounts", and statement regarding use revised to indicate that because of the potential for serious adverse reactions in nursing infants from enalapril, a decision should be made whether to discontinue nursing or to discontinue Vasotec/Vasotec I.V., taking into account the importance of the drug to the mother.

INDICATIONS AND USAGE:

Revised with notation that ACE inhibitors have a lesser effect on blood pressure in black patients, and that black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks (see WARNINGS: Angioedema).

OVERDOSAGE:

Vasotec: Section revised as per Enalapril subsection in Vaseretic revised labeling (see above)

Vasotec I.V.: Section revised with deletion of statement regarding the intravenous LD50 of enalaprilat in female mice and addition of statements that a single intravenous dose of 4,167 mg/kg of enalaprilat was associated with lethality in female mice, with no lethality after an intravenous dose of 3,472 mg/kg.

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