AGGRASTAT (tirofiban HCl)	CARDIOQUIN (quinidine polygalacturonate)	CRIXIVAN (indinavir sulfate)	CUTIVATE (fluticasone propionate)
DIOVAN HCT (valsartan/ hydrochlorothiazide)	DIPENTUM (olsalazine Na)	DOPAMINE HCl	DOXIL (doxorubicin HCl liposome)
ETHYOL (amifostine)	FOSAMAX (alendronate Na)	HELIDAC (bismuth subsalicylate/ metronidazole/ tetracycline HCl)	ISMO (isosorbide mononitrate)
ISORDIL (isosorbide dinitrate)	LOTREL (amlodipine besylate/ benazepril)	NORPLANT (levonorgestrel implants)	NORVIR (ritonavir)
PHENDIMETRAZINE TARTRATE	PREMARIN (conjugated estrogens)	PREVEN (levonorgestrel/ ethinyl estradiol)	PROVENTIL-HFA (albuterol sulfate)
PROZAC (fluoxetine)	QUINIDINE GLUCONATE	REZULIN (troglitazone)	VERELAN (verapamil HCl)
VIAGRA (sildenafil citrate)

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ADVERSE REACTIONS:

Allergic Reactions/Readministration: First sentence revised (new text in italics) -

"No patients in the clinical database developed anaphylaxis and/or hives requiring discontinuation of the infusion of tirofiban (see also Post-Marketing Experience, Hypersensitivity)."

Post-Marketing Experience (new subsection):

"The following additional adverse reactions have been reported in post-marketing experience: Body as a Whole: Decreased platelet counts (see Laboratory Findings above) associated with chills and low-grade fever; Hypersensitivity: Rash and/or hives."

HOW SUPPLIED:

Second paragraph, first sentence deleted -

"Store tablets at controlled room temperature (15-30 degrees Celsius; 59-86 degrees Fahrenheit)."

Replaced with the following -

"Store at 25^oC (77^oF); excursions permitted to 15-30 degrees Celsius (59-86 degrees Fahrenheit) [See USP Controlled Room Temperature.]"

CLINICAL PHARMACOLOGY:

Drug Interactions: Drugs Requiring Dose Modification: Delavirdine (new subsection):

"Preliminary data (n=14) indicate that delavirdine inhibits the metabolism of indinavir such that coadministration of a 400 mg single dose of indinavir with delavirdine (400 mg three times a day) resulted in indinavir AUC values slightly less than those observed following administration of an 800 mg dose of indinavir alone. Also, coadministration of a 600 mg dose of indinavir with delavirdine (400 mg three times a day) resulted in indinavir AUC values approximately 40% greater than those observed following administration of an 800 mg dose of indinavir alone. Indinavir had no effect on delavirdine pharmacokinetics (see DOSAGE AND ADMINSITRATION, Concomitant Therapy, Delavirdine)."

Efavirenz (new subsection):

"When indinavir (800 mg every 8 hours) was given with efavirenz (200 mg once daily) for two weeks, the indinavir AUC and C_max were decreased by approximately 31% and 16%, respectively, as a result of enzyme induction. (See DOSAGE AND ADMINISTRATION, Concomitant Therapy, Efavirenz.)"

Itraconazole (new subsection):

In a multiple-dose study, administration in the fasted state of itraconazole capsules 200 mg twice daily with indinavir 600 mg every 8 hours resulted in an indinavir AUC similar to that observed during adminsitration of indinavir 800 mg every 8 hours alone for one weeek ( see DOSAGE AND ADMINISTRATION, Concomitant Therapy, Itraconazole)."

Ketoconazole: Existing text deleted and replaced with -

"In a single-dose study, administartion of a 400-mg dose of ketoconazole with a 400-mg dose of indinavir resulted in a 68% +/- 48% increase in indinavir AUC compared to a 400-mg dose of indinavir alone. In a multiple-dose study, adminsitration of ketoconazole 400 mg once daily with indinavir 600 mg every 8 hours resulted in an 18% +/- 17% decrease in indinavir AUC compared to an 800-mg dose of indinavir alone every 8 hours (see DOSAGE AND ADMINISTRATION, Concomitant Therapy, Ketoconazole)."

Drug Interactions: Drugs Not Requiring Dose Modification: Methadone (new subsection):

"Administration of indinavir (800 mg every 8 hours) with methadone (20 mg to 60 mg daily) for one week resulted in no change in methadone AUC and little or no change in indinavir AUC."

WARNINGS:

Drug Interactions (new subsection) -

"The risk of myopathy including rhabdomyolysis may be increased when protease inhibitors, including Crixivan, are used in combination with HMG-CoA reductase inhibitors that are metabolized by the CYP3A4 pathway (e.g., atorvastatin, cerivastatin, lovastatin, or simvastatin)."

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 second to 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 these conditions are not known at this time."

Delavirdine (new subsection):

"Due to an increase in indinavir plasma concentrations (preliminary results), a dosage reduction of indinavir should be considered when Crixivan and delavirdine are coadministered. (See DOSAGE AND ADMINISTRATION, Concomitant Therapy, Delavirdine; CLINICAL PHARMACOLOGY, Drug Interactions, Drugs Requiring Dose Modification, Delavirdine.)"

Efavirenz (new subsection):

"Due to a decrease in the plasma concentrations of indinavir, a dosage increase of indinavir is recommended when Crixivan and efavirenz are coadministered. No adjustment of the dose of efavirenz is necessary when given with indinavir. (See DOSAGE AND ADMINISTRATION, Concomitant Therapy, Efavirenz; CLINICAL PHARMACOLOGY, Drug Interactions, Drugs Requiring Dose Modification, Efavirenz.)"

Itraconazole (new subsection):

"Itraconazole is an inhibitor of P-450 3A4 that increases plasma concentrations of indinavir. Therefore, a dosage reduction of indinavir is recommended when Crixivan and itraconazole are coadministered. (See DOSAGE AND ADMINISTRATION, Concomitant Therapy, Itraconazole; CLINICAL PHARMACOLOGY, Drug Interactions, Drugs Requiring Dose Modification, Itraconazole.)"

Ketoconazole (new subsection):

"Ketoconazole is an inhibitor of P-450 3A4 that increases plasma concentrations of indinavir. Therefore, a dosage reduction of indinavir is recommended when Crixivan and ketoconazole are coadministered. (See DOSAGE AND ADMINISTRATION, Concomitant Therapy, Ketoconazole; CLINICAL PHARMACOLOGY, Drug Interactions, Drugs Requiring Dose Modification, Ketoconazole.)"

ADVERSE REACTIONS:

Post-Marketing Experience: Body As A Whole: "(see PRECAUTIONS, Fat Redistribution)" added

Digestive System: "pancreatitis; jaundice; abdominal distention, dyspepsia" added

Hypersensitivity: "urticaria" added

Musculoskeletal System (new subsection): "arthralgia"

Nervous System/Psychiatric (new subsection): "oral paresthesia, depression"

Skin and Skin Appendage: "ingrown toenails and/or paronychia; pruritus" added

Urogenital System: "sometimes with indinavir crystal deposits; in some patinets, the interstitial nephritis did not resolve following discontinuation of Crixivan;" and "dysuria" added

Laboratory Abnormalities: "increased serum cholesterol" added

OVERDOSAGE:

Existing text -

"Single oral or intraperitoneal doses of indinavir up to 20 times the related human dose in rats and 10 times the related human dose in mice caused no lethality."

deleted and replaced with -

"There have been more than 60 reports of acute or chronic human overdosage (up to 23 times the recommended total daily dose of 2400 mg) with Crixivan. The most commonly reported symptoms were reanl (e.g., nephrolithiasis, flank pain, hematuria) and gastrointestinal (e.g., nausea, vomiting, diarrhea).

"It is not known whether Crixivan is dialyzable by peritoneal or hemodialysis."

DOSAGE AND ADMINISTRATION:

Concomitant Therapy: "(See CLINICAL PHARMACOLOGY, Drug Interactions, and/or PRECAUTIONS, Drug Interactions.)" added after subsection name

Delavirdine (new subsection): "Dose reduction of Crixivan to 600 mg every 8 hours should be considered when administering delavirdine 400 mg three times a day."

Efavirenz (new subsection): "Dose increase of Crixivan to 1000 mg every 8 hours is recommended with administering efavirenz concurrently (consult the manufacturer's product circular for efavirenz)."

Itraconazole (new subsection): "Dose reduction of Crixivan to 600 mg every 8 hours is recommended when administering itraconazole 200 mg twice daily concurrently."

Ketoconazole: subsection revised (new text in italics) -

"Dose reduction of Crixivan to 600 mg every 8 hours ["should be considered" deleted] is recommended when administering ketoconazole concurrently."

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ADVERSE REACTIONS:

Valsartan: Post-Marketing Experience (new subsection): -

"The following additional adverse reactions have been reported in post-marketing experience:
Hypersensitivity: There are rare reports of angioedema.
Digestive: Elevated liver enzymes and very rare reports of hepatitis."

ADVERSE REACTIONS:

Postmarketing Reports (new subsection) -

"The following events have been identified during post-approval use of products which contain (or are metabolized to) mesalamine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to mesalamine:

"Gastrointestinal: Reports of hepatotoxicity, including elevated liver function test (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. One case of Kawasaki-like syndrome, which included hepatic function changes, was also reported."

PRECAUTIONS:

Weaning: Subsection revised (new text in italics) -

"When discontinuing the infusion, it may be necessary to gradually decrease the dose of dopamine HCl while expanding blood volume with IV fluids.["since" deleted] Sudden cessation may result in marked hypotension."

Geriatric Use: (new subsection) -

"Clinical studies of dopamine 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 dosing range, reflecting the frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

DOSAGE AND ADMINISTRATION:

Rate of Administration: Sentence added at end of subsection:

"When discontinuing the infusion, it may be necessary to gradually decrease the dose of dopamine HCl while expanding the blood volume with IV fluids to prevent the development of marked hypotension."

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[Other labeling changes not appearing in the 1999 PDR: Mar99, May98]

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CLINICAL PHARMACOLOGY:

Helicobacter: Helicobacter pylori: Subsection revised (new text in italics) -

"Metronidazole resistance has been increasing in the U.S. and mostly occurs in patients previously treated with metronidazole. Some H. pylori strains isolated from patients treated with bismuth, metronidazole, and tetracycline demonstrate an increase in metronidazole MICs, indicating decreasing susceptibility ["and increasing resistance" deleted].

"In the ["clinical" deleted] Graham and Cutler studies, pretreatment and emerging resistance were not assessed for bismuth subsalicylate, metronidazole, or tetracycline, because susceptibility testing was not performed. No adequate data were collected during the clinical studies to indicate that bismuth subsalicyclate can either decrease or increase metronidazole resistance. (See CLINICAL STUDIES.)

Pretreatment Resistance (new subsection):

"Of the 49 patients enrolled in the P&GP study for whom pretreatment metronidazole susceptibility was determined by agar diltuion, 22% (11/49) were classified as resistant."

Metronidazole Susceptibility Test Results and Clinical/Bacteriologic Outcome (new subsection):

"In the P&GP clinical study, 42.1% (24/57) of the patients in the intent-to-treat population who received Helidac Therapy did not have pretreatment metronidazole-susceptibility determined due to non-viability of the isolates or negative cultures. Of the patients receiving Helidac Therapy with pretreatment metronidazole susceptible MICs (< /= 8 ug/mL), 88.5% (23/26) were eradicated of H. pylori and 11.5% (3/26) failed therapy. Of the three patients who failed therapy, one had a post-treatment H. pylori isolate with a metronidazole susceptible MIC. The other two patients who failed therapy had post-treatment H. pylori isolates with metronidazole resistant MICs (>/= 32ug/mL). Of the seven patients who had metronidazole-resistant isolates pretreatment, three were eradicated, one had a post-treatment isolate with a metronidazole susceptible MIC, one had a post-treatment ioslate with a metronidazole resistant MIC, one had a negative culture, and one had no post-treatment susceptibility results."

Next paragraph revised -

"It is recommended that all patients not eradicated of H. pylori following bismuth subsalicylate, metronidazole, and tetracycline treatment be considered to have H. pylori resistant to metronidazole. ["Patients who fail therapy should not be retreated with a regiment containing metronidazole." deleted]

The subsection "In Vitro Activity of Bismuth Subsalicylate, Metronidazole and Tetracycline Hydrochloride Against Helicobacter pylori" deleted and replaced with -

Susceptibility Tests for Helicobacter pylori (new subsection):

"The reference methodology for susceptibility testing of H. pylori is agar dilution MICs. One to three microliters of an inoculum equivalent to a No. 2 McFarland standard ( 1 x 10⁷ to 1 x 10⁸ CFU/mL for H. pylori) are inoculated directly onto freshly perpared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (> 2-weeks old). The agar dilution plates are incubated at 35^oC in a microaerobic environment produced by a gas generating system suitable for Campylobacter species. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism.

"Results obtained from the P&GP study were determined using agar dilution methodology for metronidazole and bismuth subsalicylate. Tetracycline hydrochloride susceptibility was determined using the E-Test.

"Breakpoints for bismuth subsalicylate, metronidazole, and tetracycline hydrochloride have not been standardized. For the purposes of this study, the following breakpoints were used:

Classification	Metronidazole* (ug/mL)	Tetracycline HCl* (ug/mL)	Bismuth Subsalicylate** (ug/mL)
Resistant	>/= 32	>/= 16	>/= 256
Intermediate	16	8	128
Susceptible	</= 8	</= 4	</= 64
* Based on NCCCLS recommendations for anaerobes ** Based on empirical judgement

"Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard metronidazole powders should provide the following MIC values:

Microorganism	Antimicrobial Agent	MIC (ug/mL)a
H. pylori ATCC 43504	Metronidazole	64 to 256 ug/mL
a these are quality control ranges for the agar dilution methodology and they should not be used to control test results obatined using alernative methods

INDICATIONS AND USAGE:

Section deleted and replaced with -

"The components of the Helidac Therapy (bismuth subsalicylate, metronidazole, and tetracycline hydrochloride), in combination with an H₂ antagonist, are indicated for the eradication of H. pylori for treatment of patients with H. pylori infection and duodenal ulcer disease (active or a history of duodenal ulcer). Appropriate doses of H₂ antagonists for the treatment of active duodenal ulcers should be prescribed in all patients. The eradication of H. pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence in patients with active duodenal ulcer disease. (See CLINICAL STUDIES and DOSAGE AND ADMINISTRATION.)

"It is recommended that all patients not eradicated of H. pylori following Helidac Terapy plus an H₂ antagonist, should be considered to have H. pylori resistant to metronidazole. (See MICROBIOLOGY subsection.)"

CLINICAL STUDIES:

Eradication of H. pylori in Patients with Active Duodenal Ulcer Disease: New subsection title added prior to first paragraph in section.

Title of first table in section revised (new text in italics) -

"Helicobacter pylori Eradication Rates in Patients with Active Duodenal Ulcer Disease"

Eradication of H. pylori in Patients with a History of duodenal Ulcer Disease (new subsection) -

"A controlled, multicenter trial conducted by P&GP in the U.S. compared the rates or eractication of H. pylori following 14 days of treatment with Helidac Therapy (bismuth subsalicylate, metronidazole, and tetracycline hydrochloride) or control (bismuth subsalicyclate, metronidazole placebo, and tretracylcine placebo) in 103 patients infected with H. pylori who had a history of duodenal ulcer disease. No H₂-receptor antagonist was used. The primary efficacy measurement was H. pylori eradication assessed by rapid urease testing, histology, and culture at least 4 weeks after the last dose. Helidac Therapy was effective in eradicating H. pylori . The eradication rates are noted in the table below:

H. pylori Eradication Rates in Patients with a History of Duodenal Ulcer Disese

Population	Evaluable Population*		Intent-To-Treat Population**
Therapy	Helidac Therapy	Control	Helidac Therapy	Control
Eradication Rate (Number of Patients)	71% (40/56)	7% (2/30)	72% (41/57)	6% (2/32)
95% confidence interval	60, 83	0a, 16	60, 84	0a, 15
a the lower limit for this calculation was -2.2 but was truncated to 0 for reporting purposes. * Evaluable patients were defined as having a history of a confirmed duodenal ulcer prior to treatment and having taken >/= 70% of each component of Helidac therapy (bismuth subsalicylate, metronidazole, tetracycline hydrochloride) during the 14-day dosing period. Eradication was defined as no evidence of H. pylori infection by two or three diagnostic test (culture, histology, and rapid urease test) from at least 4 weeks to 6 weeks post-treatment. Excluded from the evaluable population were patients who were non-compliant with medication, patients who were not infected with H. pylori at baseline, and patients without ulcer documentation. Three patients in the Helidac Therapy group and one patient in the Control group were included as eradication failures because they withdrew from the study due to treatment-related adverse events. ** Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were included as failures of therapy. Eradication was defined as no evidence of H. pylori infection by culture, histoloty, or rapid urease test.

"Compliance with the triple therapy regimen was also evaluated in the clinical study. In the intent-to-treat population, 93% of the Helidac Therapy group took at least 75% of their medication."

ADVERSE REACTIONS:

Table and first paragraph under table revised (new text in italics) -

"Incidence of Adverse Reactions Reported in Clinical Trials (>/=1%)**

	BSS/MTZ/TCN** (N=266)
Adverse Reactions	% Patients
Nausea	["10.2" deleted] 12
Diarrhea	["5.1"deleted] 6.8
Abdominal Pain	["3.0" deleted] 6.8
Melena	["2.5" deleted] 3
Upper Respiratory Infection	["1.0" deleted] 2.3
Constipation	["1.0" deleted] 1.9
Anorexia	1.5
Asthenia	["1.0" deleted] 1.5
Vomiting	1.5
Discolored Tongue	1.5
Headache	1.5
Dyspepsia	1.5
Stool Abnormality	1.1
Duodenal Ulcer	1.1
Sinusitis	1.1
Taste Perversion	1.1
Flatulence	1.1
GI Hemorrhage	1.1
Pain	["1.0 deleted"] 1.1
Insomnia	["1.0 deleted"] 1.1
Anal Discomfort	["1.5 deleted"] 1.1
Paresthesia	["1.5" deleted"] 1.1

* includes reactions reported at >/= 1% in patients taking BSS/MTZ/TCN in Graham, Cutler, and P&GP studies
** in the Graham and Cutler studies (N=197),most patients were on concomitant acid suppression therapy.

"The additional adverse reactions (<1%) reported in clinical trials when all three components of this therapy were given concomitantly are listed below and divided by body system:

"Gastrointestinal: dry mouth, ["dyspepsia" moved to table] dysphagia, ["flatulence & GI hemorrhage" moved to table] eructation, GI monila, glossitis, intestinal obstruction, rectal hemorrhage, stomatis
Skin: acne, ecchymosis, photosensitivity reaction (see WARNINGS), pruritus, rash
Cardiovascular: cerebral ischemia, chest pain, hypertension, myocardial infarction
CNS: nervousness, somnolence
Musculoskeletal: arthritis, rheumatoid arthritis, tendonitis
Metabolic: SGOT increase, SGPT increase
Urogenital: urinary tract infection
Other: conjuctivitis, flu syndrome, infection, malaise, neoplasm, rhinitis, syncope, tooth disorder"

REFERENCES:

New reference added and others renumbered -

"1. National Committee for Clinical Laboratory Standards. Summary Minutes, Subcommittee on Antimicrobial Susceptibility Testing, Tampa, FL. January, 1997."

WARNINGS:

Text added as new first paragraph -

"Amplification of the vasodilatory effects of Ismo 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."

WARNINGS:

Text added as new first paragraph -

"Amplification of the vasodilatory effects of Isordil 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."

ADVERSE REACTIONS:

[Note: The following changes appear in the 1999 PDR]

Paragraph following Urogenital subsection revised (new text in italics) -

"Other infrequently reported events were seen in clinical trials (causal relationship unlikely) or in postmarketing experience. These included chest pain, ventricular extrasystole, gout, neuritis, tinnitus, and alopecia"

Paragraph prior to "Clinical Laboratory Test Findings" subsection revised (new text in italics) -

"Monotherapies of benzepril and amlodipine have been evaluated for safety in clinical trials in over 6,000 and 11,000 patinets, respectively. The observed aadverrse reactions to the monotherapies in these trials were similar to those seen in trials of Lotrel. In postmarketing experience with benazepril, there have been rare reports of Stevens-Johnson syndrome, ["pancreatitis, hemolytic anemia, pemphigus" moved from Digestive, Hematologic, Dermatologic subsections respectively] pancreatitis, hemolytic anemia, pemphigus, and thrombocytopenia. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis) severe enough to require hospitalization have been reported in association with use of amlodipine. Other potentially important adverse experiences attributed to other ACE inhibitors and calcium channel blockers include: eosinophilic pneumonitis (ACE inhibitors) ["gynecomastia" moved from Body as a Whole subsection] and gynecomastia (CCB's).

WARNINGS:

A. Warnings Based on Experience with the NORPLANT SYSTEM

1. Insertion and Removal Complications (new subsection)-

"A surgical incision is required to insert Norplant System capsules. Complications related to insertion such as pain, edema, and bruising may occur. There also have been reports of infection (including cellulitis and abscess formation), blistering, ulcerations, sloughing, excessive scarring, phlebitis, and hyperpigmentation at the insertion site. There have also been reports of arm pain, numbness, and tingling following the insertion and removal procedures. There also have been reports of nerve injury, most commonly associated with deep placement and removal. Expulsion of capsules has been reported more frequently when placement of the capsules was shallow or too close to the incision or when infection was present. There have been reports of capsule displacement (i.e., movement), most of which involved minor changes in the positioning of the capsules. However, infrequent reports (less than 1%) of significant displacement (a few to several inches) have been received. Some of these reports have been associated with pain and difficult removal. Removal is also a surgical procedure and may take longer, be more difficult, and/or cause more pain than insertion and may be associated with difficulty locating capsules. These complications may lead to the need for additional incisions and/or office visits. See also 'PRECAUTIONS' and 'ADVERSE REACTIONS'."

2. Bleeding Irregularities

Last sentence revised (new text in italics) -

"In rare instances, ["blood loss did result" deleted] patients experienced heavy bleeding that resulted in hemoglobin values consistent with anemia."

PRECAUTIONS:

General: 2.Insertion and Removal (new name for combination of former subsections 8.Insertion and Removal, 9.Infections, 10.Capsule Expulsion and Displacement, 11. Provisions for Removal):

"To be sure that the woman is not pregnant at the time of capsule placement and to assure contraceptive effectiveness during the first cycle of use, it is advisable that insertion be done during the first 7 days of the menstrual cycle or immediately following an abortion. However, Norplant System capsules may be inserted at any time during the cycle provided pregnancy has been excluded and a nonhormonal contraceptive method is used for at least 7 days following insertion. Insertion is not recommended before 6 weeks post-partum in breast-feeding women.

"Insertion and removal instructions must be followed closely. It is strongly advised that all health-care professionals who insert and remove Norplant System capsules be instructed in the procedures before they attempt them. Proper insertion just under the skin will facilitate removal.

"If infection develops after insertion, suitable treatment should be instituted. If infection persists, capsules should be removed.

"In the case of capsule expulsion, the expelled capsule must be replaced using a new sterile capsule, as contraceptive efficacy may be in inadequate with fewer than 6 capsules. If infection is present, it should be treated and cured before capsule replacement.

"Removal should be done upon patient request, for medical indications, or at the end of 5 years of use, by personnel instructed in the removal technique. If the capsules were placed deeply, they may be harder to remove. The use of general anesthesia during removal should generally be avoided.

"Before initiating the removal procedure, all Norplant System capsules should be located via palpation. If all 6 capsules cannot be located by palpation, they may be localized by ultrasound (7 MHz ), X ray, or compression mammography. If all capsules cannot be removed at the first attempt, removal should be attempted later when the site has healed.

"Upon removal, Norplant System capsules should be disposed of in accordance with the Center for Disease Control and Prevention guidelines for the handling of biohazardous waste.

"See also 'WARNINGS', 'ADVERSE REACTIONS' and 'INSTRUCTIONS FOR INSERTION AND REMOVAL - Removal Procedure'."

Drug Interactions: Subsection revised (new text in italics) -

"Reduced efficacy (pregnancy) has been reported for Norplant System users taking phenytoin and carbamazepine. These drugs may increase the metabolism of levonorgestrel through induction of microsomal enzymes. Norplant System users should be warned of the possibility of decreased efficacy with the use of drugs exhibiting enzyme-inducing activity such as those noted above and ["rifampicin" deleted] rifampin. For women receiving long-term therapy with hepatic enzyme inducers, another method of contraception should be considered."

Pediatric Use (new subsection):

"Safety and efficacy of the Norplant System have been established in women of reproductive age. Safety and efficacy are expected to be similar for postpubertal adolescents under 16 and users 16 and older. Use of the product before menarche is not indicated."

ADVERSE REACTIONS:

Second paragraph revised (new text in italics) -

"In addition, removal difficulties affecting subjects (including multiple incisions, capsule fragments remaining, pain, multiple visits, deep placement, lengthy removal procedure, or other) have been reported with a frequency of 6.2%, which is based on 849 removals occurring through 5 years of use. See 'WARNINGS' and 'PRECAUTIONS'"

Fifth paragraph -

"The following adverse reactions have been reported post-marketing with an incidence of less than 1% and are possibly related to Norplant System use:"

Has had the following added to the list:

"Induration", "Bruising", "Abscess, cellulitis", "Excessive scarring", "Hyperpigmentation", and "Nerve injury"

Sixth paragraph -

"The following adverse reactions have been reported post-marketing with an incidence of less than 1%. These events occurred under circumstances where a causal relationship to the Norplant System is unknown. These reactions are listed as information for physicians:"

Has had the following added to the list:

"Blistering, ulcerations and sloughing" and "Phlebitis"

REMOVAL PROCEDURE:

First three sentences of third paragraph revised (new text in italics) -

"Removal of the capsules should be performed very gently and will usually take more time and may be more difficult and/or more painful than insertion. Capsules are sometimes nicked, cut or broken during removal, or may be difficult to locate. The incidence of overall removal difficulties including those that did not result in patient complaints (e.g., damage to the capsules) ["has been" deleted] was 13.2%."

Removal: Second and third bullets revised (new text in italics) -

"- The removal of the implanted capsules will usually take ["a little" deleted] more time and may be more difficult and/or more painful than the insertion. Capsules are sometimes nicked, cut, or broken during removal, or may be difficult to locate."

"- Before initiating removal, all capsules should be located by palpation. If all six capsules cannot be ["palpated" deleted] located by palpation, they may be localized ["via" deleted] by ultrasound (7 MHz), X ray, or compression mammography."

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INDICATIONS AND USAGE:

Section revised (new text in italics) -

"Phendimetrazine tartrate extended-release capsules are indicated in the management of exogenous obesity as a short term adjunct (a few weeks) in a regimen of weight reduction based on caloric restriction in patients with an initial body mass index (BMI) of 30 kg/m² or higher who have not responded to appropriate weight reducing regimen (diet and/or exercise) alone. ["The limited usefulness of agents of this class (see CLINICAL PHARMACOLOGY) should be measured against possible risk factors inherent in their use such as those described below." deleted]

Below is a chart of Body Mass Index (BMI) based on various heights and weights."

"BMI is calculated by taking the patient's weight, in kilograms (kg), divided by the patient's height , in meters (m), squared. Metric conversions are as follows: pounds divided by 2.2 = kg; inches x 0.0254 = meters

"BODY MASS INDEX (BMI), kg/m²

Height (feet, inches)
Weight (pounds)	5'0"	5'3"	5'6"	5'9"	6'0"	6'3"
140	27	25	23	21	19	18
150	29	27	24	22	20	19
160	31	28	26	24	22	20
170	33	30	28	25	23	21
180	35	32	29	27	25	23
190	37	34	31	28	26	24
200	39	36	32	30	27	25
210	41	37	34	31	29	26
220	43	39	36	33	30	28
230	45	41	37	34	31	29
240	47	43	39	36	33	30
250	49	44	40	37	34	31

"Phendimetrazine tartrate is indicated for use as monotherapy only."

CONTRAINDICATIONS:

Second paragraph, first sentence revised (new text in italics)

"Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate and severe hypertension, pulmonary hypertension, hyperthyroidism and glaucoma."

Text added as new third paragraph -

"Use in combination with other anorectic agents is contraindicated"

WARNINGS:

Text added as new first through fifth paragraphs -

"Phendimetrazine tartrate should not be used in combination with other anorectic agents, including prescribed drugs, over-the-counter preparations and herbal products.

"In a case-control epidemiological study, the use of anorectic agents, including phendimetrazine tartrate, was associated with an increased risk of developing pulmonary hypertension, a rare, but often fatal disorder. The use of anorectic agents for longer than three months was associated with a 23-fold increase in the risk of developing pulmonary hypertension. Increased risk of pulmonary hypertension with repeated courses of therapy cannot be excluded.

"The onset or aggravation of exertional dyspnea, or unexplained symptoms of angina pectoris, syncope, or lower extremity edema suggest the possibility of occurrence of pulmonary hypertension. Under these circumstances, phendimetrazine tartrate should be immediately discontinued, and the patient should be evaluated for the possible presence of pulmonary hypertension.

"Valvular heart disease associated with the use of some anorectic agents such as fenfluramine and dexfenfluramine has been reported. Possible contributing factors include use for extended periods of time, higher than recommended dose, and/or use in combination with other anorectic drugs. However, no cases of this valvulopathy have been reported when phendimetrazine tartrate has been used alone.

"The potential risk of possible serious adverse effects such as valvular heart disease and pulmonary hypertension should be assessed carefully against the potential benefit of weight loss. Baseline cardiac evaluation should be considered to detect preexisting valvular heart diseases or pulmonary hypertension prior to initiation of phendimetrazine treatment. Phendimetrazine tartrate is not recommended in patients with known heart murmur or valvular heart disease. Echocardiogram during and after treatment could be useful for detecting any valvular disorders which may occur. To limit unwarranted exposure and risks, treatment with phendimetrazine tartrate should be continued only if the patient has satisfactory weight loss within the first 4 weeks of treatment (i.e.. weight loss of at least 4 pounds, or as determined by the physician and patient)."

Text added as new ninth paragraph -

"Phendimetrazine tartrate is not recommended for patients who used any anorectic agents within the prior year"

PRECAUTIONS:

Drug Interactions (new subsection):

"Efficacy of phendimetrazine tartrate with other anorectic agents has not been studied and the combined use may have the potential for serious cardiac problems."

Pediatric Use: [Title changed from "Usage in Children:"] Subsection revised (new text in italics) -

"Safety and effectiveness in pediatric patients have not been established.["Phendimetrazine tartrate is not recommended for use in children under 12 years of age" deleted]

ADVERSE REACTIONS:

Cardiovascular: New second paragraph -

"Valvular heart disease associated with the use of some anorectic agents such as fenfluramine and dexfenfluramine, both independently and especially when used in combination with other anorectic drugs, have been reported. However, no case of this valvulopathy has been reported when phendimetrazine has been used alone."

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INDICATIONS AND USAGE:

Text added as new last sentence -

"Preven is not recommended as a form of regular contraception"

CONTRAINDICATIONS:

Text deleted -

"Heavy smoking (greater than 15 cigarettes per day) and over the age of 35"

WARNINGS:

Black boxed warning deleted -

"Cigarette smoking increases the risk of serious cardiovascular side effects from COC use. This risk increases with age and heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use COCs should be strongly advised not to smoke."

9. Heavy Smoking in women over the age of 35 (new subsection) -

Daily cyclical combination oral contraceptive use (One pill each day for 21 days of a 28-day cycle) is contraindicated in women who are heavy smokers (greater than 15 cigarettes per day) and are over the age of 35. The risk of Preven in women who are heavy smokers and over the age of 35 is unknown."

DETAILED PATIENT LABELING

WHO SHOULD NOT TAKE EMERGENCY CONTRACEPTIVE PILLS

Text deleted -

"Heavy smoker (greater than 15 cigarettes per day) and over age 35"

RISKS OF EMERGENCY CONTRACEPTIVE PILLS

2. Heart Attacks and Strokes: Second paragraph revised (new text in italics)-

"Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and the use of COCs greatly increase the chances of developing and dying of heart disease. The risk is greater for women over the age of 35 who smoke."

[Other labeling changes not appearing in the 1999 PDR: Sep98]

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[Other labeling changes not appearing in 1999 PDR: Mar98]

INDICATIONS AND USAGE:

First and second paragraphs revised (new text in italics) -

"Depression-- Prozac is indicated for the treatment of depression. The efficacy of Prozac was established in 5- and 6-week trials with depressed outpatients (greater than or equal to 18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of major depressive disorder (see Clinical Trials under Clinical Pharmacology).

"A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning ["(nearly every day for at least 2 weeks; it should include" deleted] ,and includes at least ["4 of the following 8" deleted] 5 of the following 9 symptoms: ["change in appetite, change in sleep," deleted] depressed mood; loss of interest in usual activities; significant change in weight and/or appetite; insomnia or hypersomnia; psychomotor agitation or retardation; ["loss of interest in usual activities or decrease in sexual drive," deleted] increased fatigue; feelings of guilt or worthlessness; slowed thinking or impaired concentration; ["and" deleted] a suicide attempt or suicidal ideation.

[Other labeling changes in lasat 12 months: Jun98]

PRECAUTIONS:

Geriatric Use: Existing text deleted and replaced with -

"Safety and efficacy of quinidine in elderly patients has not been systematically studied. Clinical studies of quinidine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. The 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 dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy."

DOSAGE AND ADMINISTRATION:

Treatment of life-threatening ventricular arrhythmias

"Note: Am J Health-Syst Pharm, March 1996: A study suggests that minimization of PVC tubing enhances bioavailability. In this study, 112 inches of tubing resulted in a 30% loss of quinidine; wheras,12 inches (attached to the winged catheter) minimized drug loss to under 3%."

Moved to -

Treatment of symptomatic atrial fibrillation/flutter:

And replaced with -

"Because quinidine may be adsorbed to PVC tubing, tubing length should be minimized. In one study (Am J Health Syst Pharm. 1996; 53:655-8), use of 112 inches of tubing resulted in 30% loss of quinidine, but drug loss was less than 3% when only 12 inches of tubing was used."

HOW SUPPLIED

"Store at controlled room temperature, 59 to 86^oF (15 to 30^oC)."

Deleted and replaced with -

"Store at 25^oC (77^oF); excursions permitted to 15-30^oC (59-86^oF). [see USP Controlled Room Temperature]."

[Other labeling changes not appearing in 1999 PDR: Jul98]

[Other information regarding these changes: June 17, 1999 ( Letter), (Label and Patient Information PDF Version )- Parke-Davis, (Talk Paper)- FDA)]

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[Other labeling changes not appearing in the 1999 PDR: Jul98]

PRECAUTIONS:

Geriatric Use (new subsection):

"Clinical studies of verapamil 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 dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

"Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).

"Verapamil is highly metabolized by the liver, and about 70% of the administered dose is excreted as metabolites in the urine. Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered (see PRECAUTIONS, General). In general, lower initial doses of Verelan may be warranted in the elderly (see DOSAGE AND ADMINISTRATION)."

[Other labeling changes not appearing in the 1999 PDR: Aug98, Nov98]

WARNINGS:

Text added as new last paragraph -

"The concomitant administration of the of the protease inhibitor ritonavir substantially increases serum concentrations of sildenafil (11-fold increase in AUC). If Viagra is prescribed to patients taking ritonavir, caution should be used. Data from subjects exposed to high systemic levels of sildenafil are limited. Visual disturbances occurred more commonly at higher levels of sildenafil exposure. Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to high doses of sildenafil (200-800 mg). To decrease the chance of adverse events in patients taking ritonavir, a decrease in sildenafil dosage is recommended (see Drug Interactions, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION)."

PRECAUTIONS:

Drug Interactions: Effects of Other Drugs on Viagra: in vivo studies:

Second paragraph revised (new text in italics) -

"When a single 100 mg dose of Viagra was administered with erythromycin, a specific CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In addition, in a study performed in healthy male volunteers, coadministration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with Viagra (100 mg single dose) resulted in a 140% increase in sildenafil C_max and a 210% increase in sildenafil AUC. Viagra had no effect on saquinavir pharmacokinetics. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole would be expected to have still greater effects, and population data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) (see DOSAGE AND ADMINISTRATION)."

Text added as new third & fourth paragraphs -

"In another study in healthy male volunteers, coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with Viagra (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil C_max and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates. Viagra had no effect on ritonavir pharmacokinetics (see DOSAGE AND ADMINISTRATION).

"Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels."

Effects of Viagra on Other Drugs: in vivo studies:

Text added as new last paragraph -

"In a study of healthy male volunteers, sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates."

DOSAGE AND ADMINISTRATION:

Second paragraph revised (new text in italics) -

"The following factors are associated with increased plasma levels of sildenafil: age greater than 65 (40% increase in AUC), hepatic impairment (e.g., cirrhosis, 80%), severe renal impairment (creatinine clearance <30 mL/min, 100%), and concomitant use of potent cytochrome P450 3A4 inhibitors ( ketoconazole, itraconazole, erythromycin (182%), saquinavir (210%). Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered in these patients."

New third paragraph -

"Ritonavir greatly increased the systemic level of sildenafil in a study of healthy, non-HIV infected volunteers (11-fold increase in AUC, see Drug Interactions.) Based on these pharmacokinetic data, it is recommended not to exceed a maximum single dose of 25 mg of Viagra in a 48 hour period."

Patient Summary of Information:

Finding the Right Dose for You:

Text added at end of last paragraph -

"If you are taking protease inhibitors, such as for the treatment of HIV, your doctor may recommend a 25 mg dose and may limit you to a maximum single dose of 25 mg of Viagra in a 48 hour period."