ADENOCARD (adenosine)	ALDACTAZIDE (spironolactone/ hydrochlorothiazide)	AVALIDE (irbesartan/ hydrochlorothiazide)	BACTROBAN (mupirocin)
BRETYLIUM TOSYLATE	CAPOTEN (captopril)	DIPRIVAN (propofol)	DOBUTAMINE HCl
GABITRIL (tiagabine HCl)	LOVENOX (enoxaparin Na)	MIOSTAT (carbachol)	NITROGLYCERIN
NORVIR (ritonavir)	OVIDE (malathion)	TESLASCAN (mangafodipir trisodium)	TOBRADEX (tobramycin/ dexamethasone)
VEPESID (etoposide)	XELODA (capecitabine)

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WARNINGS:

Heart Block: Subsection revised (new text in italics) -

"Adenocard (adenosine) exerts its effect by decreasing conduction through the A-V node and may produce a short lasting first-, second- or third-degree heart block. ["In extreme cases, transient asystole may result (one case has been reported in a patient with atrial flutter who was receiving carbamazepine)" deleted] Appropriate therapy should be instituted as needed. Patients who develop high-level block on one dose of Adenocard should not be given additional doses. Because of the very short half-life of adenosine, these effects are generally self-limiting.

"Transient or prolonged episodes of asystole have been reported with fatal outcomes in some cases. Rarely, ventricular fibrillation has been reported following Adenocard administration, including both resuscitated and fatal events. In most instances, these cases were associated with the concomitant use of digoxin and, less frequently with digoxin and verapamil. Although no causal relationship or drug-drug interaction has been established, Adenocard should be used with caution in patients receiving digoxin or digoxin and verapamil in combination. Appropriate resuscitative measures should be available."

PRECAUTIONS:

Carcinogenesis, Mutagenesis, Impairment of Fertility: Last sentence -

"In rats and mice, adenosine administered intraperitoneally once a day for five days at 50, 100, and 150 mg/kg [10-30 (rats) and 5-15 (mice) times human dosage on a mg/M² basis] caused decreased spermatogenesis and increased numbers of abnormal sperm, a reflection of the ability of adenosine to produce chromosomal damage."

deleted and replaced with -

"Fertility studies in animals have not been conducted with adenosine."

Pediatric Use: Subsection revised (new text in italics) -

"No controlled studies have been conducted in pediatric patients to establish the safety and efficacy of Adenocard for the conversion of paroxysmal supraventricular tachycardia (PSVT). However, intravenous adenosine has been used for the treatment of PSVT in neonates, infants, children and adolescents (see DOSAGE AND ADMINISTRATION)."

Geriatric Use (new subsection) -

"Clinical studies of Adenocard 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 elderly and younger patients. In general, Adenocard in geriatric patients should be used with caution since this population may have a diminished cardiac function, nodal dysfunction, concomitant diseases or drug therapy that may alter hemodynamic function and produce severe bradycardia or AV block."

DOSAGE AND ADMINISTRATION:

Adult Patients (new subsection): Existing text moved into subsection.

Pediatric Patients (new subsection):

"The dosages used in neonates, infants, children and adolescents were equivalent to those administered to adults on a weight basis.

"Pediatric Patients with a Body Weight < 50 kg:
Initial dose: Give 0.05 to 0.1 mg/kg as a rapid IV bolus either centrally or peripherally. A saline flush should follow.

"Repeat Administration: If conversion of PSVT does not occur within 1-2 minutes, additional bolus injections of adenosine can be administered at incrementally higher doses, increasing the amount given by 0.05 to 0.1 mg/kg. Follow each bolus with a saline flush. This process should continue until sinus rhythm is established or a maximum single dose of 0.3 mg/kg is used.

"Pediatric Patients with a Body Weight > or = 50 kg:
Administer the adult dose."

ADVERSE REACTIONS:

Spironolactone: Renal (new subsection): "Renal dysfunction (including renal failure)"

ADVERSE REACTIONS:

Post-Marketing Experience (new subsection): "The following adverse reactions have been reported in post-marketing experience: Rare cases of urticaria and angioedema (involving swelling of the face, lips, pharynx, and/or tongue) have been reported with irbesartan."

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WARNINGS:

Hypotension: Text added as new third paragraph -

"Patients over 65 years may be at increased risk of developing orthostatic hypotension, especially when the recommended rate of intravenous infusion is exceeded. See DOSAGE AND ADMINISTRATION."

PRECAUTIONS:

Pediatric Use: Subsection revised (new text in italics) -

"["Safety and effectiveness in children have not been established" deleted]. The safety and effectiveness of Bretylium Tosylate have not been established. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use.

"Safety and effectiveness of solutions from flexible plastic containers in ["children" deleted] pediatric patients have not been well established."

Geriatric Use (new subsection) -

"Clinical studies of bretylium tosylate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.

"Intravenous infusion, especially if administered at a rate beyond that recommended in the DOSAGE AND ADMINISTRATION section, may produce an increased risk of orthostatic hypotension in the elderly. See WARNINGS.

"This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patinets with impaired renal function. Beause elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. See CLINICAL PHARMACOLOGY."

DOSAGE AND ADMINISTRATION:

Fourth paragraph, last sentence revised (new text in italics) -

"More rapid infusion may cause nausea and vomiting, and in patients older than 65 years, may increase the risk of developing orthostatic hypotension."

PRECAUTIONS:

Drug Interactions:

Cardiac Glycosides (new subsection): "In a study of young healthy male subjects no evidence of a direct pharmacokinetic captopril-digoxin interaction could be found."

Loop Diuretics (new subsection): "Furosemide administered concurrently with captopril does not alter the pharmacokinetics of captopril in renally impaired hypertensive patients."

Allopurinol (new subsection): "In a study of healthy male volunteers no significant pharmacokinetic interaction occurred when captopril and allopurinol were administered concomitantly for 6 days."

HOW SUPPLIED:

Storage: Subsection revised (new text in italics):

"Do not store above 86^o F (30^o C). Keep bottles tightly closed (protect from moisture)."

PRECAUTIONS:

Geriatric Use: Text added as new first paragraph -

"The effect of age on induction dose requirements for propofol was assessed in an open study involving 211 unpremedicated patients with approximately 30 patients in each decade between the ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age."

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INDICATIONS AND USAGE:

Existing text deleted and replaced with -

"Dobutamine in 5% Dextrose Injection is indicated when parenteral therapy is necessary for inotropic support in the short-term treatment of patients with cardiac decompensation due to depressed contractility resulting either from organic heart disease or from cardiac surgical procedures. Experience with intravenous dobutamine in controlled trials does not extend beyond 48 hours of repeated boluses and/or continuous infusions.

"Whether given orally, continuously intravenously, or intermittently intravenously, neither dobutamine nor any other cyclic-AMP-dependent inotrope has been shown in controlled trials to be safe or effective in the long-term treatment of congestive heart failure. In controlled trials of chronic oral therapy with various such agents, symptoms were not consistently alleviated, and the cyclic-AMP-dependent inotropes were consistently associated with increased risks of hospitalization and death. Patients with NYHA Class IV symptoms appeared to be at particular risk."

WARNINGS:

Cognitive/Neuropsychiatric Adverse Events: Text added as new last paragraph -

"Additionally, there have been postmarketing reports of patients who have experienced cognitive/neuropsychiatric symptoms, some accompanied by EEG abnormalities such as generalized spike and wave activity, that have been reported as nonconvulsant status epilepticus. Some reports describe recovery following reduction of dose or discontinuation of Gabitril."

Note: A new 2 mg tablet strength has also been approved.

ADVERSE REACTIONS:

Ongoing Safety Surveillance: New text added -

"Very rare cases of hyperlipidemia have been reported, with one case of hyperlipidemia, with marked hypertriglyceridemia, reported in a diabetic pregnant woman; causality has not been determined."

DOSAGE AND ADMINISTRATION:

Third sentence -

"Withdraw the contents into a dry sterile syringe, and replace the needle with an atraumatic cannula prior to intraocular irrigation."

deleted and replaced with -

"Attach the filter supplied with this product to a sterile disposable syringe and then place a 21 gauge beveled needle securely on the end of the filter unit. Withdraw the solution through the filter into the syringe. Discard the needle and filter (see DIRECTIONS FOR USE for more detailed instructions). Replace the needle with an atraumatic cannula prior to intraocular irrigation."

DIRECTIONS FOR USE:

Number 6 revised (new text in italics) -

"6. After Miostat has been completely transferred to the syringe, withdraw the needle from the vial and remove the 21 gauge beveled needle and filter from the syringe."

HOW SUPPLIED:

Text revised (new text in italics) -

["In" deleted] 1.5 mL sterile glass vials and 0.45 uM sterile filters packaged twelve to a carton."

WARNINGS:

Text added as new first paragraph -

"Amplification of the vasodilatory effects of Nitroglycerin by sildenafil can result in severe hypotension. The time course and dose dependence of this interaction have not been studied. Appropriate supportive care has not been studied, but it seems reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central volume expansion."

PRECAUTIONS:

Fat Redistribution (new subsection):

"Redistribution /accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and 'cushingoid appearance' have been observed in patients receiving protease inhibitors. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established."

Information For Patients: Text added as new last paragraph -

"Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving protease inhibitors and that the cause and long-term health effects of those conditions are not known at this time."

Drug Interactions: Table 3 - "Predicted Effects on Drugs Co-Administered with Ritonavir" -

"Pravastatin" deleted under "Hypolipidemics"

ADVERSE REACTIONS:

Body as a Whole: Subsection revised (new text in italics) -

"Abdomen enlarged, accidental injury, allergic reaction, back pain, cachexia, chest pain, chills, facial edema, facial pain, flu syndrome, hormone level altered, hypothermia, kidney pain, neck pain, neck rigidity, pain (unspecified), redistribution/accumulation of body fat (see PRECAUTIONS, Fat Redistribution), substernal chest pain, and photosensitivity reaction."

HOW SUPPLIED:

(Capsules) Recommended Storage: Text added at end of subsection -

"Use by product expiration date."

Labeling extensively revised. Contact the company for a copy of the labeling/package insert.

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CLINICAL PHARMACOLOGY:

Clinical Trials: Table 3 revised as follows:

TABLE 3 COMPARISON OF PROPORTION OF CORRECTLY CHARACTERIZED LESIONS WITH HISTOPATHOLOGIC CONFIRMATION (N = 105 LESIONS)
	Detected by Imaging		Not Detected by Imaging
	Correctly Characterized	Not Correctly Characterized
Paired Teslascan MRI	["51 (49%)" deleted] 49 (47%)	["32 (27%)" deleted] 34 (32%)	["22 (32%)" deleted] 22 (21%)
Unenhanced MRI	["28 (30%)"deleted] 28 (27%)	48 (46%)	["29 (33%)" deleted] 29 (28%)
CECT	["28 (21%)" deleted] 34 (32%)	["34 (28%)" deleted] 35 (33%)	["35 (34%)" deleted] 36 (34%)
*Of the 105 histopathologically confirmed lesions, ["83 (78%) detected" deleted] 83 (79%) lesions were detected by paired Teslascan MRI. ["Of these 83, 51 (62%) were correctly characterized by the paired Teslascan MRI and 28 (39%) by the unenhanced MRI or CECT (statistically significant)." deleted] Of the lesions detected by the respective image sets, 59% (49/83) were correctly characterized by the paired Teslascan MRI, 37% (28/76) by unenhanced MRI, and 49% (34/69) by CECT (statistically significant).

WARNINGS:

Second paragraph, second sentence -

"children" replaced with "pediatric patients"

PRECAUTIONS:

General: Text added as new last paragraph -

"Ophthalmic ointment may retard corneal wound healing."

Information for Patients: Text added as new last sentence -

"Contact lenses should not be worn during the use of this product."

Pediatric Use: Subsection revised (new text in italics) -

"Safety and effectiveness in pediatric patients below the age of 2 years have not been established."

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