AGGRASTAT (tirofiban HCl)	AMBISOME (amphotericin B)	BREVICON/NORINYL/ TRI-NORINYL (norethindrone/ ethinyl estradiol & norethindrone/mestranol)
CARDIOLITE/MIRALUMA (Technetium Tc99m Sestamibi)	COMBIVIR (lamivudine/zidovudine)	COZAAR & HYZAAR (losartan potassium & lorsartan potassium/hydrochlorothiazide)
EMLA (2.5% lidocaine/2.5% prilocaine)	HYDREA (hydroxyurea)	INOCOR (amrinone lactate)
LAMISIL (terbinafine HCl)	MONOKET (isosorbide mononitrate)	PRAVACHOL (pravastatin)
PREMPRO/PREMPHASE (conjugated estrogen/medroxyprogesterone)	SULAR (nisoldipine)	VIAGRA (sildenafil citrate)

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ADVERSE REACTIONS:

Post-Marketing Experience Subsection revised (new text in italics) -

"The following additional adverse reactions have been reported in post-marketing experience: Bleeding: intracranial bleeding, retroperitoneal bleeding, and hemopericardium; Body as a Whole: ["Decreased" deleted] Acute decreases in platelet counts (see Laboratory Findings above) which may be associated with chills and low-grade fever; Hypersensitivity: Rash and/or hives. "

DOSAGE AND ADMINISTRATION:

Directions for Use Last paragraph, last sentence added:

"Aggrastat should not be administered in the same intravenous line as diazepam."

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WARNINGS:

Thromboembolic Disorders and Other Vascular Problems: d. Dose related risks of vascular disease from oral contraceptives sentence added after second paragraph -

"Products containing 50 mcg estrogen should be used only when medically indicated."

PRECAUTIONS:

Geriatric Use: (new subsection):

"Of 3068 patients in clinical studies of Cardiolite (kit for the preparation of Technetium Tc99m Sestamibi for Injection) 693 patients were 65 or older and 121 were 75 or older.

"Of 673 patients in clinical studies of Miraluma (kit for the preparation of Technetium Tc99m Sestamibi for Injection) 138 patients were 65 or older and 30 were 75 or older.

"Based on the evaluation of the frequency of adverse events and review of vital signs data, no overall differences in safety were observed between these subjects and younger subjects. Although reported clinical experience has not identified differences in response between elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out."

INDICATIONS AND USAGE:

First sentence revised (new text in italics) -

" COMBIVIR in combination with other antiretroviral agents is indicated for the treatment of HIV infection."

PRECAUTIONS:

General: subsection deleted -

"Reduction of doses of lamivudine is recommended for patients with low body weight (less than 50 kg or 110 lb); therefore patients with low body weight should not receive Combivir."

DOSAGE AND ADMINISTRATION:

Dose Adjustment: text revised as follows -

"Because it is a fixed-dose combination, Combivir should not be prescribed for patients requiring dosage adjustment such as those with reduced renal function (creatinine clearance less than or equal to 50 mL/min), ["those with low body weight (less than 50 kg or 110 lb)" deleted] or those experiencing dose-limiting adverse events."

ADVERSE REACTIONS:

Post-Marketing Experience
Hypersensitivity (Cozaar): The following sentence added -

"Anaphylactic reactions have been reported."

Hypersensitivity (Hyzaar): Text revised (new text in italics) and moved from subsection - Hydrochlorothiazide; Body as a Whole; Hypersensitivity -

"Anaphylactic reactions have been reported."

Last sentence in subsection revised (Cozaar and Hyzaar), (new text in italics) -

"Hyperkalemia ["has" deleted] and hyponatremia have been reported."

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WARNINGS:

Carcinogenisis and Mutagenisis: (new subsection):

"Hydroxyurea is genotoxic in a wide range of test systems and is thus presumed to be a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patients' underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxyurea.

Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However, intraperitoneal administration of 125-250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m² basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumerogenic phenotype. "

Pregnancy: new second paragraph -

"Hydrea (hydroxyurea capsules, USP) can cause fetal harm when administered to a pregnant woman. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m² basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m² basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of greater than or equal to 375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m² basis) to rats caused growth retardation and impaired learning ability. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant."

PRECAUTIONS:

Carcinogenesis, Mutagenesis, and Impairment of Fertility: (new subsection):

"See WARNINGS for carcinogenesis and Mutagenesis Information.
Impairment of fertility: Hydroxyurea administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m² basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females."

Pregnancy: (new subsection):

"Pregnancy Category D. (See WARNINGS.)"

Drug Interactions: new first sentence -

"Prospective studies on the potential for hydroxyurea to interact with other drugs have not been performed."

ADVERSE REACTIONS:

First paragraph, new third sentence -

"Skin cancer has been reported."

INDICATIONS AND USAGE:

Following text deleted -

"Inocor lactate injection is indicated for the short-term management of congestive heart failure. Because of limited experience and potential for serious adverse effects (see ADVERSE REACTIONS), Inocor should be used only in patients who can be closely monitored and who have not responded adequately to digitalis, diuretics, and/or vasodilators. Although most patients have been studied hemodynamically for periods only up to 24 hours, some patients were studied for longer periods and demonstrated consistent hemodynamic and clinical effects. The duration of therapy should depend on patient responsiveness."

Replaced with -

"Inocor is indicated for the short-term management of congestive heart failure. Because of limited experience and potential for serious adverse effects (see ADVERSE REACTIONS), Inocor should be used only in patients who can be closely monitored and who have not responded adequately to digitalis, diuretics, and/or vasodilators. Experience with intravenous amrinone 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 amrinone 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 (including amrinone), 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."

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PRECAUTIONS:

Geriatric Use: (new subsection) -

"Clinical studies of Monoket 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, dose selection for an elderly patient should be cautious, 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 other drug therapy."

CLINICAL PHARMACOLOGY:

Third paragraph, fourth and fifth sentences deleted -

"Though frequently found in association with low HDL, elevated plasma triglycerides (TG) has not been established as an independent risk factor for coronary heart disease. The independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined"

Replaced with -

"Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, IDL and remnants, can also promote atherosclerosis. Elevated plasma TG are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined."

Clinical Studies subheading added: "Primary Hypercholesteremia (Fredrickson Type IIa and IIb)

Second paragraph, second sentence deleted -

"Once daily administration in the evening appears to be marginally more effective than once daily administration in the morning, perhaps because hepatic cholesterol is synthesized mainly at night."

Hypertriglyceridemia (Fredrickson Type IV)

The response to pravastatin in patients with Type IV hyperlipidemia (baseline TG greater than 200 mg/dL and LDL-C less than 160 mg/dL) was evaluated in a subset of 429 patients from the Cholesterol and Recurrent Events (CARE) study. For pravastatin-treated subjects, the median (min, max) baseline triglyceride level was 246.0 (200.5, 349.5)mg/dL.

Patients with Fredrickson Type IV Hyperlipidemia Median (25th , 75th percentile) Percent Change From Baseline
	Pravastatin 40 mg (N=429)	Placebo (N=430)
Triglycerides	-21.1 (-34.8, 1.3)	-6.3 (-23.1, 18.3)
Total -C	-22.1 (-27.1, -14.8)	0.2 (-6.9, 6.8)
LDL-C	-31.7 (-39.6, -21.5)	0.7 (-9.0, 10.0)
HDL-C	7.4 (-1.2, 17.7)	2.8 (-5.7, 11.7)
Non-HDL-C	-27.2 (-34.0, -18.5	-0.8 (-8.2, 7.0)

Dysbetalipoproteinemia (Fredrickson Type III)

The response to pravastatin in two double-blind crossover studies of 46 patients with genotype E2/E2 and Fredrickson Type III dysbetalipoproteinemia is shown in the table below.

Patients With Fredrickson Type III Dysbetalipoproteinemia Median (min, max) Percent Change From Baseline
	Median (min, max) at Baseline (mg/dL)	Median % Change (min., max) Pravastatin 40 mg (N=20)
Study 1
Total -C	386.5 (245.0, 672.0)	-32.7 (-58.5, 4.6)
Triglycerides	443.0 (275.0, 1299.0)	-23.7 (-68.5, 44.7)
VLDL-C*	206.5 (110.0, 379.0)	-43.8 (-73.1, -14.3)
LDL-C*	117.5 (80.0, 170.0)	-40.8 (-63.7, 4.6)
HDL-C	30.0 (18.0, 88.0)	6.4 (-45.0, 105.6)
Non-HDL-C	344.5 (215.0, 646.0)	-36.7 (-66.3, 5.8)
	Median (min, max) at Baseline (mg/dL)	Median % Change (min, max) Pravastatin 40 mg (N=26)
Study 2
Total-C	340.3 (230.1, 448.6)	-31.4 (-54.5, -13.0)
Triglycerides	343.2 (212.6, 845.9)	-11.9 (-56.5, 44.8)
VLDL-C	145.0 (71.5, 309.4)	-35.7 (-74.7, 19.1)
LDL-C	128.6 (63.8, 177.9)	-30.3 (-52.2, 13.5)
HDL-C	38.7 (27.1, 58.0)	5.0 (-17.7, 66.7)
Non-HDL-C	295.8 (195.3, 421.5)	-35.5 (-81.0, -13.5)
*N=14

INDICATIONS AND USAGE:

Hyperlipidemia: " Hypercholesterolemia and Mixed Dyslipidemia deleted.
Second and third paragraphs added -

"Pravachol is indicated as adjunctive therapy to diet for the treatment of patients with elevated serum triglyceride levels (Fredrickson Type IV).

Pravachol is indicated for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet."

Last paragraph, last sentence deleted -

"The efficacy of pravastatin has not been evaluated in patients with combined elevated Total-C and hypertriglyceridemia [greater than 500 mg/dL (greater than 5.7 mmol/L)] or in patients with elevated intermediate density lipoproteins as their primary lipid abnormality."

DOSAGE AND ADMINISTRATION:

Second paragraph revised (new text in italics) -

"The recommended starting dose is ["10 or 20 mg once daily at bedtime." Deleted] 10, 20 or 40 mg once daily. Pravacol can be administered as a single dose at any time of the day, with or without food. In ["primary hypercholesterolemic" deleted] patients with a history of significant renal or hepatic dysfunction [",and in the elderly," deleted] a starting dose of 10 mg daily ["at bedtime" deleted] is recommended. ["Pravacol (pravastatin sodium) may be taken without regard to meals." Deleted]"

Third paragraph, second and third sentences deleted -

"The recommended dosage range is generally 10 to 40 mg administered once a day at bedtime. In the elderly, maximum reductions in LDL-cholesterol may be achieved with daily doses of 20 mg or less."

REFERENCES:

Number 7. Deleted -

"Frederickson classification: Type IIa-elevation of LDL;Type IIb-elevation of LDL and VLDL. Type III (familial dysbetalipoproteinemia)-elevation of IDL. Frederickson,DS, Fat transport in lipoproteins-an integrated approach to mechanism and disorders, N Engl J Med 276:34, 1967."

Replaced with -

"Frederickson DS, et. al. Fat transport in lipoproteins - an integrated approach to mechanisms and disorders. N Engl J Med 1967;276:34-42, 94-102, 148-156, 215-224, 273-281."

CLINICAL PHARMACOLOGY:

Clinical Studies:
Information Regarding Lipid Effects: New sentence following footnote to "Table 3. MEAN PERCENT CHANGE FROM BASELINE LIPID PROFILE VALUES AFTER ONE YEAR OF TREATMENT"
"For information regarding cardiovascular effects in the general population, as well as in women with documented coronary heart disease, see PRECAUTIONS, General Cardiovascular Risk"

PRECAUTIONS:

General:
Based on experience with estrogens and/or progestins: "1. Cardiovascular Risk.

Paragraphs reordered. Fifth paragraph deleted -

"While the effects of added progestins on the risk of breast cancer are also unknown, available epidemiologic evidence suggests that progestins do not reduce, and may enhance, the moderately increased breast cancer risk that has been reported with prolonged estrogen replacement therapy (see WARNINGS).

Sixth paragraph first and second sentences deleted -

The safety data regarding Prempro and Premphase were obtained primarily from clinical trials and epidemiologic studies of postmenopausal Caucasian women, who were at generally low risk for cardiovascular disease and higher than average risk for osteoporosis. The safety profile of Prempro and Premphase derived from these study populations cannot necessarily be extrapolated to other populations of diverse and/or demographic composition."

Third sentence revised (new text in italics) -

"When considering prescribing an estrogen/progestin regimen, such as Prempro or Premphase, physicians are advised to weight the potential benefits and risks of therapy as applicable to each individual patient."

Two new subheadings added:
Studies in the General Population: Second paragraph, last sentence deleted -

"Thus, ongoing and future large-scale randomized trials may fail to confirm this apparent benefit."

Replaced with -

"Ongoing large-scale trials are intended to further explore this relationship."

Studies in Women with Documented Coronary Heart Disease: New first paragraph -

In the Heart and Estrogen/progestin Replacement Study (HERS), 2763 postmenopausal women with documented coronary heart disease (CHD) who were taking their usual cardiac medications were randomized to Prempro 0.625 mg/2.5 mg or placebo. Documented CHD was defined as the presence of one or more of the following: previous myocardial infarction, previous percutaneous mechanical revascularization, previous coronary artery bypass graft surgery, or angiographic evidence of greater than 50 % occlusion of one or more major coronary arteries. During an average follow-up of 4.1 years, treatment with Prempro did not reduce the overall rate of recurrent coronary heart disease events, defined as CHD death or nonfatal myocardial infarctions, in this predominantly elderly population (average age 66.7 years) with established coronary disease. There were more CHD events in the hormone group than in the placebo group in year 1 and fewer events in years 3 through 5."

Based on experience with estrogens:
2. Hypercoagulability. First sentence revised (new text in italics) -

"Some epidemiological studies have shown that women taking estrogen replacement therapy have hypercoagulability primarily related to decreased antithrombin activity."

INFORMATION FOR THE PATIENT:

Risks of Estrogens and/or Progestins: new subsection (following the Abnormal blood clotting subsection):

" Heart Disease. A recent 4-year study suggests that women with a history of coronary heart disease may have an increased risk of serious cardiac events during the first year of treatment with estrogen/progestin therapy. Therefore, if you have had a heart attack, or you have been told you have blocked coronary arteries (arteries to your heart) or have any heart problem, you should consult your physician regarding the potential benefits and risks of estrogen/progestin therapy. "

PRECAUTIONS:

Drug Interactions: new second paragraph -

"Coadministration of phenytoin with 40 mg Sular tablets in epileptic patients lowered the nisoldipine plasma concentrations to undetectable levels. Coadministration of Sular with phenytoin or any known CYP3A4 inducer should be avoided and alternative antihypertensive therapy should be considered."

ADVERSE REACTIONS:

Last paragraph, last sentence added -

"Gynecomastia has been associated with the use of calcium channel blockers. "

CLINICAL PHARMACOLOGY:

Pharmacodynamics: Effects of Viagra on Vision: Last sentence revised -

"An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of Viagra on visual acuity, ["electroretinograms," deleted] intraocular pressure, or pupillometry."