Compiled by:
Ruby M. Singh, PharmD
Resident of Drug Information Practice
University of Maryland Drug Information Service
Baltimore, MD

ADENOSCAN (adenosine)	BECLOVENT (beclomethasone dipropionate)	BREVITAL (methohexital Na)	CALCIJEX (calcitriol)	CASODEX (bicalutamide)
CLEOCIN (clindamycin HCl)	CORDARONE (amiodarone HCl)	CYLERT (pemoline)	DIZAC (diazepam)	DYNABAC (dirithromycin)
EPIVIR (lamivudine)	ESTRADERM (estradiol)	NULYTELY (PEG 3350/ NaCl/NaHCO3/KCl)	NUTROPIN (somatropin)	NUTROPIN AQ (somatropin)
POSICOR (mibefradil dihydrochloride)	REZULIN (troglitazone)	ROCEPHIN (ceftriaxone Na)	RYTHMOL (propafenone HCl)	TIMENTIN (ticarcillin/clavulanate)
ULTANE (sevoflurane)	WELLBUTRIN SR (bupropion HCl)

WARNINGS:

Fatal Cardiac Arrest, Life Threatening Ventricular Arrhythmias, and Myocardial Infarctions: Subsection revised (new text in italics) -

"Fatal cardiac arrest, sustained ventricular tachycardia (requiring resuscitation), and non-fatal myocardial infarction have been reported coincident with Adenoscan infusion. Patients with unstable angina may be at greater risk. Appropriate resuscitative measures should be available."

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BOXED WARNING:

Previous text - "This drug should be administered by persons qualified in the use of intravenous anesthetics. Cardiac life support equipment must be immediately available during use of methohexital."

deleted and replaced with -

"Brevital should be used only in hospital or ambulatory care settings that provide for continuous monitoring of respiratory (i.e., pulse oximetry) and cardiac function. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation and personnel trained in their use and skilled in airway management should be assured. For deeply sedated patients, a designated individual, other than the practitioner performing the procedure, should be present to continuously monitor the patients. (See WARNINGS)."

INDICATIONS AND USAGE:

First sentence revised (new text in italics) -

"Brevital Sodium can be used in adults as follows:"

Statement #4 revised (new text in italics) -

"4. As intravenous anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli (see ["PRECAUTIONS" deleted] WARNINGS)."

WARNINGS:

Second paragraph -

"As with all potent anesthetic agents and adjuncts, this drug should be administered only by those trained in the administration of general anesthesia, the maintenance of a patent airway and ventilation, and the management of cardiovascular depression encountered during anesthesia and surgery."

deleted and replaced with -

"As with all potent anesthetic agents and adjuncts, Brevital should be used only in hospital or ambulatory care settings that provide for continuous monitoring of respiratory (i.e., pulse oximetry) and cardiac function. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation and personnel trained in their use and skilled in airway management should be assured. For deeply sedated patients, a designated individual, other than the practitioner performing the precedure, should be present to continuously monitor the patients.

"Maintenance of a patent airway and adequacy of ventilation must be ensured during induction and maintenance of anesthesia with methohexital sodium solution. Laryngospasm is common during induction with all barbiturates and may be due to a combination of secretions and accentuated reflexes following induction or may result from painful stimuli during light anesthesia. Transient apnea/hypoventilation may be noted during induction, which may impair pulmonary ventilation; the duration of apena may be longer than that produced by other barbiturate anesthetics. Cardiorespiratory arrest may occur. [NOTE: This paragraph moved from PRECAUTIONS, General."

"This prescribing information describes intravenous use of methohexital sodium in adults. Although the published literature discusses intravenous administration in pediatric patients, the safety and effectiveness of intravenous administration of methohexital sodium in pediatric patients have not been established in well-controlled, prospective studies (see Pediatric Use).

"Seizures may be elicited in subjects with a previous history of convulsive activity, especially psychomotor seizure disorders ¹."

Fourth paragraph deleted -

"Psychomotor seizures may be elicited in susceptible individuals¹."

PRECAUTIONS:

General: First paragraph deleted and moved to WARNINGS (see above.)

Drug Interactions: New first sentence added -

"Prior chronic administration of barbiturates or phenytoin (e.g. for seizure disorder) appears to reduce the effectiveness of Brevital Sodium ²."

{NOTE: References #2 & #3 renumbered to #3 & #4 from this point on.]

Pediatric Use (Subsection previously titled "Usage in Children"):

Previous text - "Safety and effectiveness in children have not been established."

deleted and replaced with -

"Studies using methohexital sodium intravenously in pediatric patients have been reported in the published literature. this literature is not adequate to establish the safety and effectiveness of intravenous administration of methohexital sodium in pediatric patients. Due to a variety of limitations such as study design, biopharmaceutic issues, and the wide range of effects observed with similar doses of intravenous methohexital, additional studies of intravenous methohexital in pediatric patients are necessary before this route can be recommended in pediatric patients (see Warnings)."

ADVERSE REACTIONS:

Cardiovascular: "tachycardia" added.

DOSAGE AND ADMINISTRATION:

First paragraph revised and moved to become the second paragraph. -

"Preanesthetic medication is generally advisable. Brevital Sodium may be used with any of the recognized preanesthetic medications [", but the phenothiazines are less satisfactory than the combination of an opiate and a belladonna derivative" deleted]."

Second paragraph revised (new text in italics) and moved up to become the first paragraph. -

"Facilities for assisting ["respiration" deleted] ventilation and administering oxygen are necessary adjuncts for intravenous administration of anesthesia. Since cardiorespiratory arrest may occur, patients should be observed carefully during and after use of Brevital Sodium. Age and size appropriate resuscitative equipment (i.e. intubation and cardioversion equipment, oxygen, suction, and a secure intravenous line) and personnel qualified in its use must be immediately available."

Dilution Instructions: Table revised. See new labeling/package insert.

References:

New second reference - "2. Audenaert SM, et al: A prospective study of rectal methohexital: Efficacy and side effects in 648 cases. Anesth Analg 1995;81:957-961."

DOSAGE AND ADMINISTRATION:

Table revised as follows (new text in italics) -

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

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CLINICAL PHARMACOLOGY:

Special Populations: Hepatic Insufficiency: Subsection revised (new text in italics) -

"No clinically significant difference in the pharmacokinetics of either enantiomer of bicalutamide was noted in patients with mild to moderate hepatic disease as compared to healthy controls. ["Patients with severe liver disease have significantly longer half-life values for the R-enantiomer." deleted] However, the half-life of the R-enantiomer was increased approximately 76% (5.9 and 10.4 days for normal and impaired patients, respectively) in patients with severe liver disease (n=4)."

Women, Pediatrics: Subsection revised -

"["Because of the mechanism of action and the indication," deleted] Bicalutamide has not been studied in women or pediatric subjects."

Table 1, which presents the pharmacokinetics of the active enantiomer of Casodex in normal males and patients with prostate cancer, revised (standard deviation now included, with coefficient of variation and 95% confidence interval data deleted). [See Table 1 in new labeling/package insert.]

Clinical Studies: Subsection markedly changed to reflect updated analysis of clinical study (see new labeling/package insert.]

CONTRAINDICATIONS:

Last two sentences in section moved up and revised to become the first three sentences in the second paragraph (new text in italics) -

"Casodex is not indicated in women. Further, Casodex is contraindicated in women who are or may become pregnant. 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 hazard to the fetus."

WARNINGS:

Section deleted and text moved to PRECAUTIONS, General as point #2.

PRECAUTIONS:

General: New point #2 (moved from WARNINGS) -

"2. In clinical trials with Casodex as a single agent for prostate cancer, gynecomastia and breast pain have been reported in up to 38% and 39% of patients, respectively."

Nursing Mothers: New first sentence -

"Casodex is not indicated for use in women."

ADVERSE REACTIONS:

First paragraph revised (new text in italics) -

"In patients with advanced prostate cancer treated with Casodex in combination with an LHRH analogue, the most frequent adverse experience was hot flashes ["(53%)" deleted] (49%)."

Second paragraph deleted -

"Diarrhea was the adverse event most frequently leading to treatment withdrawal: 6% of the patients treated with flutamide - LHRH analogue and 0.5% of the patients treated with Casodex-LHRH analogue."

Table 2 titled "Incidence of Adverse Events" revised to reflect updated study results. [See new labeling/package insert.]

Paragraph immediately prior to "Body as a Whole" revised -

"Other ["less frequent" deleted] (greater than or equal to 2%, but less than 5%) adverse experiences reported in the Casodex-LHRH analogue treatment group are listed below by body system and are in order of decreasing frequency within each body system regardless of causality. ["Some of these are commonly reported in elderly patients." deleted]

Body as a Whole: "Edema" moved to Metabolic and Nutritional, "Hernia; Cyst" added.

Cardiovascular: "Myocardial infarct; Heart arrest; Coronary artery disorder; Syncope" added.

Digestive: "Anorexia; Dyspepsia" deleted. "Dysphagia; Gastrointestinal disorder; Periodontal abscess; Gastrointestinal carcinoma" added.

Endocrine: Subsection deleted - "Breast pain; Diabetes Mellitus"

Metabolic and Nutritional: "Alkaline phosphatase increased; Weight gain" deleted. "Edema" moved from Body as a Whole. "Bun increased" and "Hypercholesteremia" added.

Musculoskeletal: "Myasthenia; Arthritis" and "Pathological fracture" deleted.

Nervous: "Anxiety; Depression" deleted.

Respiratory: "Cough increased; Pharyngitis; Bronchitis; Pneumonia; Rhinitis" deleted. "Asthma; Epistaxis; Sinusitis" added.

Skin and Appendages: "Injection site reaction" deleted. "Herpes zoster; Skin carcinoma; Skin disorder" added.

Special Senses (new subsection): "Cataract specified."

Urogenital: "Urinary frequency; Urination impaired" and "Urinary retention" deleted. "Hydronephrosis; Urinary tract disorder" added.

Abnormal Laboratory Test Values: Last two sentences deleted -

"Increased liver enzyme tests and decreases in hemoglobulin were reported less frequently with Casodex-LHRH analogue therapy. Other changes were reported with similar incidences in both treatment groups."

OVERDOSAGE:

First paragraph deleted -

"In animal studies, Casodex demonstrated a low acute toxicity. Doses greater than 2000 mg/kg would be necessary to produce significant mortality in mice and rats."

DOSAGE AND ADMINISTRATION:

Dosage Adjustment in Hepatic Impairment (new subsection): " No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. Although there is a 76% (5.9 and 10.4 days for normal and impaired patients, respectively) increase in the half-life of the active enantiomer of bicalutamide in patients with severe liver impairment (n=4), no dosage adjustment is necessary (see CLINICAL PHARMACOLOGY, Special Populations, Hepatic Impairment and PRECAUTIONS sections)."

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[Other labeling changes not reflected in the 1998 PDR: Jul97]

PRECAUTIONS:

Carcinogenesis, Mutagenesis, Impairment of Fertility: Subsection revised (new text in italics)-

"Long term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential. Genotoxicity tests perfomed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative.

"Fertility studies in rats treated orally with up to 300 mg/kg/day ["(31 times the human exposure based on mg/m²)" deleted] (approximately 1.6 [for HCl] 1.1 [ for Phosphate] times the highest recommended adult human dose based on mg/m²) revealed no effects on fertility or mating ability."

Pregnancy: Teratogenic effects: Pregnancy category B: First paragraph deleted and replaced with -

"Reproduction studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (3.2 and 1.6 [for HCl] 2.1 and 1.1 [for Phosphate] times the highest recommended adult human dose based on mg/m², respectively) or subcutaneous doses of clindamycin up to 250 mg/kg/day (1.3 and 0.7 [for HCl] 0.9 and 0.5 [for Phosphate] times the highest recommended adult human dose based on mg/m², respectively) revealed no evidence of teratogenicity."

OVERDOSAGE (new section):

"Significant mortality was observed in mice at an intravenous dose of 855 mg/kg and in rats at oral or subcutaneous dose of approximately 2618 mg/kg. In the mice, convulsions and depression were observed.

"Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum."

ANIMAL TOXICOLOGY (new name for section - previously called TOXICOLOGY):

Section revised (new text in italics) - "One year oral toxicity studies in Spartan Sprague-Dawley rats and beagle dogs at dose levels ["of 30, 100 and" deleted] up to 300 mg/kg/day ["(3 grams/day per dog)" deleted] (approximately 1.6 and 5.4 [for HCl] 1.1 and 3.6 [for Phosphate] times the highest recommended adult human dose based on mg/m², respectively) have shown ["Cleocin HCl" deleted] clindamycin to be well tolerated. No appreciable difference in pathological findings has been ["obtained in" deleted] observed between groups of animals treated with clindamycin and comparable control groups. Rats receiving clindamycin hydrochloride at 600 mg/kg/day (approximately 3.2 [for HCl] 2.1 [for Phosphate] times the highest recommended adult human dose based on mg/m²) for 6 months tolerated the drug well; however, dogs dosed at this level (approximately 10.8 [for HCl] 7.2 [for Phosphate] times the highest recommended adult human dose based on mg/m²) vomited, would not eat, and lost weight."

PRECAUTIONS:

Surgery (new subsection) - "Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics."

Drug Interactions: Potential drug class interactions with Cordarone: New subsection -

"Volatile Anesthetic Agents: (see PRECAUTIONS - Surgery)."

ADVERSE REACTIONS:

New sentence added at end of section -

"In postmarketing surveillance, toxic epidermal necrolysis also has been reported with amiodarone therapy."

DOSAGE AND ADMINISTRATION:

Seventh paragraph revised (new text in italics) - "Cordarone I.V. infusions exceeding 2 hours must be administered in glass or polyolefin bottles containing D₅W. Use of evacuated glass containers for admixing Cordarone I.V. is not recommended as incompatibility with a buffer in the container may cause precipitation."

[Other information on these changes: December 1996 (Letter) - Abbott]

INDICATIONS AND USAGE:

Text deleted and replaced with -

"Cylert (pemoline) is indicated in Attention Deficit Hyperactivity Disorder (ADHD). Because of its association with life threatening hepatic failure, Cylert should not ordinarily be considered as first line therapy for ADHD (see WARNINGS).

"Cylert (pemoline) therapy should be part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate to severe distractability, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted."

WARNINGS:

Boxed Warning added before section text - "Because of its association with life threatening hepatic failure, Cylert should not ordinarily be considered as first line drug therapy for ADHD (see INDICATIONS AND USAGE).

"Since Cylert's marketing in 1975, 13 cases of acute hepatic failure have been reported to the FDA. While the absolute number of reported cases is not large, the rate of reporting ranges from 4 to 17 times the rate expected in the general population . This estimate may be conservative because of the under reporting and because the long latency between initiation of Cylert treatment and the occurrence of hepatic failure may limit the association. If only a portion of actual cases were recognized and reported, the risk could be substantially higher.

"Of the 13 cases reported as of May 1996, 11 resulted in death or liver transplantation, usually within four weeks of the onset of signs and symptoms of liver failure. The earliest onset of hepatic abnormalities occurred six months after initiation of Cylert. Although some reports described dark urine and nonspecific prodromal symptoms (e.g., anorexia, malaise, and gastrointestinal symptoms), in other reports it was not clear if any prodromal symptoms preceded the onset of jaundice. It is also not clear if the recommended baseline and periodic liver function testing are predictive of these instances of acute liver failure. Cylert should be discontinued if clinically significant hepatic dysfunction is observed durng its use (see PRECAUTIONS)."

PRECAUTIONS:

Laboratory Tests: Text deleted and replace with -

"Since Cylert's market introduction, there have been reports of elevated liver enzymes associated with its use. Many of these patients had this increase detected several months after starting Cylert. Most patients were asymptomatic, with the increase in liver enzymes returning to normal after Cylert was discontinued. Liver function tests should be performed prior to and periodically during therapy with Cylert. Treatment with Cylert should be initiated only in individuals without liver disease and with normal baseline liver function tests.

"The relationship, if any, between reversible elevations in liver function tests and the occurrence of life threatening hepatic failure in patients on long-term therapy with Cylert is not known. Liver function testing may not predict the onset of acute liver failure. Nonetheless, Cylert should be discontinued if clinically significant liver function test abnormalities are revealed at any time during therapy with this drug (see WARNINGS).

ADVERSE REACTIONS:

Hepatic: Text deleted and replaced with - "There have been reports of hepatic dysfunction, ranging from asymptomatic reversible increases in liver enzymes to hepatitis, jaundice and life-threatening hepatic failure, in patients taking Cylert (See PRECAUTIONS and WARNINGS).

DESCRIPTION:

New bolded paragraph added at end of section -

"Strict aseptic technique must always be maintained during handling. Dizac (diazepam injectable emulsion) is a single-use parenteral product, contains no antimicrobial preservatives, and can support rapid growth of microorganisms. Always discard unused portion (see DOSAGE AND ADMINISTRATION, Handling Procedures). There have been reports in which failure to use aseptic technique when handling other parenteral products [containing the same vehicle] was associated with microbial contamination of the product and with fever, infection/sepsis, other life threatening illnesses, and/or death. Do not use if contamination is suspected." [N.B. This paragraph appears in the 1998 PDR].

WARNINGS:

New bolded paragraph added at end of section -

"Strict aseptic technique must always be maintained during handling. Dizac (diazepam injectable emulsion) is a single-use parenteral product, contains no antimicrobial preservatives, and can support rapid growth of microorganisms. Always discard unused portion (see DOSAGE AND ADMINISTRATION, Handling Procedures). There have been reports in which failure to use aseptic technique when handling other parenteral products [containing the same vehicle] was associated with microbial contamination of the product and with fever, infection/sepsis, other life threatening illnesses, and/or death. Do not use if contamination is suspected."

DOSAGE AND ADMINISTRATION:

Intravenous Use: Addition of the following three paragraphs as paragraphs four through six -

"Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Dizac (diazepam injectable emulsion) must not be administered through filters with a pore size less than 5 microns because this could restrict the flow of Dizac and/or cause the breakdown of the emulsion. Do not use if there is evidence of separation of the phases of the emulsion.

"Strict aseptic technique must always be maintained during handling. Dizac (diazepam injectable emulsion) is a single-use parenteral product, contains no antimicrobial preservatives, and can support rapid growth of microorganisms. Always discard unused portion (see DOSAGE AND ADMINISTRATION, Handling Procedures). There have been reports in which failure to use aseptic technique when handling other parenteral products [containing the same vehicle] was associated with microbial contamination of the product and with fever, infection/sepsis, other life threatening illnesses, and/or death. Do not use if contamination is suspected.

"ASEPTIC GUIDELINES FOR PARENTERAL USE OF DIZAC
Dizac (diazepam injectable emulsion) should be prepared for use just prior to initiation of each individual treatment procedure. Dizac should be drawn into sterile syringes immediately after ampules are opened. The syringe(s) should be labeled with appropriate information including the date and time the ampule was opened. Administration should commence promptly and be completed within 6 hours after the ampules have been opened. Dizac should be prepared for single patient use only. Any unused portion of Dizac reservoirs, dedicated administration tubing and/or solutions containing Dizac must be discarded after the end of parenteral treatment or at 6 hours, whichever occurs sooner. The I.V. line should be flushed every 6 hours and at the end of treatment procedure to remove residual Dizac."

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[Other information regarding these changes: September 8, 1997 (Letter) - Glaxo Wellcome]

BLACK BOX WARNING:

(Addition of black box warning before "Description" section)

"Warning: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including lamivudine (see WARNINGS)."

INDICATIONS AND USAGE:

First sentence revised (new text in italics) -

"Epivir in combination with Retrovir is indicated for the treatment of HIV infection ["when therapy is warranted" deleted] (see Description of Clinical Studies)."

Description of Clinical Studies: Clinical Study: Second sentence revised (new text in italics) -

"A total of 1,816 HIV-infected adults with 25 to 250 (median = 122 cells/mm³) CD4 cells/mm³ at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive."

WARNINGS:

Lactic Acidosis/Severe Hepatomegaly with Steatosis (new subsection): "Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including lamivudine. A majority of these cases have been in women. Caution should be exercised when administering Epivir to any patient, and particularly to those with known risk factors for liver disease. Treatment with Epivir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity."

PRECAUTIONS:

Patients with HIV and Hepatitis B Virus Coinfection: New subsection (which appears in the 1998 PDR) revised (new text in italics) -

"In clinical trials and postmarketing experience, some patients with HIV infection who have chronic liver disease due to hepatitis B virus infection experienced clinical or laboratory evidence of recurrent hepatitis upon discontinuation of ["Epivir" deleted] lamivudine. Consequences may be more severe in patients with decompensated liver disease."

Carcinogenesis, Mutagenesis, and Impairment of Fertility: First sentence -

"Long term carcinogenicity studies of lamivudine in animals have not yet been completed."

deleted and replaced with -

"Lamivudine long-term carcinogenicity studies in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) those observed in humans at the recommended therapeutic dose."

Nursing mothers: New first sentence - "The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV infection."

Last sentence in subsection -

"This instruction is consistent with the Centers for Disease Control recommendation that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV infection."

deleted and replaced with -

"Mothers should be instructed not to breastfeed if they are receiving Epivir."

ADVERSE REACTIONS:

Deletion of table titled "Table 4: Frequencies of Selected Laboratory Abnormalities Among Adults in Four Controlled Clinical Trials (A3001, A3002, B3001, B3002)"

and replaced with new table titled "Table 4: Frequencies of Selected Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Studies (A3001, A3002, B3001, B3002) and a Clinical Endpoint Study (NUCB3007)". [Please refer to package insert for actual table.]

Observed During Clinical Practice: Last sentence of subsection -

"Endocrine and Metabolic: Hyperglycemia; General: Weakness; Nervous: Peripheral neuropathy; Skin: Alopecia, maculopapular rash, pruritis, urticaria."

Revised to (new adverse effects in italics) -

"Alopecia, anaphylaxis, hyperglycemia, lactic acidosis and hepatic steatosis (see WARNINGS), peripheral neuropathy, pruritis, ["maculopapular" deleted] rash, urticaria, and weakness."

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[N.B. The following changes appear in the 1998 PDR.]

PRECAUTIONS:

General: 4. Hypercoagulability: Last two sentences in subsection deleted -

"Women on estrogen replacement therapy have not been reported to have an increased risk of thrombophlebitis and/or thromboembolic disease. However, there is insufficient information regarding women who have had previous thromboembolic disease."

Pediatric Use (new subsection):

"The safety and effectiveness in pediatric patients have not been established."

WARNINGS:

Section revised (new text in italics) -

"No additional ingredients, e.g. flavorings, should be added to the solution. NuLytely should be used with caution in patients with severe ulcerative colitis. Use of NuLytely in children younger than 2 years of age should be carefully monitored for occurrence of possible hypoglycemia, as this solution has no caloric substrate. Dehydration has been reported in 1 child and hypokalemia has been reported in 3 children."

PRECAUTIONS:

Information for patients: Addition of new second paragraph -

"Use of NuLytely in children younger than 2 years of age should be carefully monitored for occurrence of possible hypoglycemia, as this solution has no caloric substrate. Dehydration has been reported in 1 child and hypokalemia has been reported in 3 children."

Third paragraph revised (new text in italics) -

"Adults drink 240 mL (8 oz.) every 10 minutes. Pediatric patients (aged 6 months or greater) drink 25mL/kg/hour. Rapid drinking...."

ADVERSE REACTIONS:

Last sentence revised (new text in italics) -

"Isolated cases of urticaria, rhinorrhea, ["and" deleted] dermatitis and (rarely) anaphylactic reaction have been reported ["with a related drug (GoLytely)" deleted] which may represent allergic reactions."

DOSAGE AND ADMINISTRATION:

Second paragraph revised (new text in italics) -

"Oral Administration: Adults: ["is" deleted] At a rate of 240 mL (8 oz.) every 10 minutes, until the rectal effluent is clear or 4 liters are consumed. Pediatric Patients (aged 6 months or greater): At a rate of 25 mL/kg/hour, until the rectal effluent is clear or 4 liters are consumed. Rapid drinking of each portion is preferred to drinking small amounts continuously. Nasogastric tube administration: Adults: ["is" deleted] At a rate of 20-30 mL per minute (1.2 - 1.8 liters per hour). Pediatric Patients (aged 6 months orgreater): At a rate of 25 mL/kg/hour, until the rectal effluent is clear or 4 liters are consumed.

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NUTROPIN and NUTROPIN AQ (somatropin [rDNA origin] biosynthetic) Injection
[December 15 & 17, 1997: Genentech]

The labeling has been revised to incorporate a new indication - the replacement of endogenous growth hormone in patients with adult growth hormone deficiency.
Contact the company for a copy of the labeling/package insert.

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POSICOR (mibefradil dihydrochloride)
[December 23, 1997: Hoffman-La Roche]

[Other information regarding these changes:
December 1997 ( Letter) - Roche,
December 18, 1997 ( Talk Paper) - FDA,
and December 18, 1997 (Backgrounder) - FDA]

CLINICAL PHARMACOLOGY:

Pharmacodynamics: Electrophysiology: Addition of new last sentence in fifth paragraph -

"However, care should be taken when combining Posicor with beta blockers (see WARNINGS), particularly when the heart rate is already slow."

CONTRAINDICATIONS:

Section revised (new text in italics)-

"Posicor is contraindicated in patients ["with" deleted] who:

1. Have sick sinus syndrome or second- or third-degree AV block, without a pacemaker;
   
2. Have a known sensitivity to mibefradil;
   
3. Are concurrently receiving ["Coadministration of" deleted] terfenadine, astemizole, ["and" deleted] cisapride, lovastatin or simvastatin (see WARNINGS and PRECAUTIONS).

WARNINGS:

Section revised (new text in italics)-

"Supression of Sinoatrial Node Activity: Use of mibefradil has been associated with slowing or complete suppression of sinoatrial node activity. The supervening junctional rhythms have often been slow (as slow as 30 to 40 bpm). Many of the reports have incorrectly identified the adverse event as complete AV block. The reports have been most common in the elderly, mainly in association with the concomitant use of beta-blockers. Care should be taken when combining Posicor with beta-blockers, particularly when pretreatment sinus rate is below 55 bpm, and this combination should be avoided in the elderly when pretreatment sinus rate is below 55 bpm (see PRECAUTIONS). In patients with low heart rates, use of any combination of agents that can slow the sinus node or affect the AV node (eg, beta-blockers, digitalis, and the calcium channel blockers mibefradil, diltiazem, and verapamil) should in general be undertaken only after careful consideration, as such combinations can unmask underlying sick sinus syndrome. Use of Posicor in patients with sick sinus syndrome without a pacemaker is contraindicated (see CONTRAINDICATIONS).

"Electrocardiographic Changes: As described in the CLINICAL PHARMACOLOGY section, mibefradil may cause dose-related changes in the appearance of the electrocardiographic T and U waves. These changes may interfere with measurement of the QTc interval. Some drugs (eg, quinidine, sotalol) are sometimes monitored by following the QTc interval on serial electrocardiograms, in order to reduce the risk of torsades de pointes and other malignant arrhythmias. When mibrefradil is coadministered with these drugs, it may be difficult to utilize serial electrocardiograms for this purpose.

"Interaction Resulting in HMG-CoA Reductase Inhibitor-Induced Rhabdomyolysis: Mibefradil inhibits the action of CYP 450 3A4. When this enzyme is inhibited, plasma concentrations of those drugs that are metabolized by CYP 450 3A4 may become elevated, sometimes by more than an order of magnitude (see PRECAUTIONS).

"Rhabdomyolysis is a known rare adverse effect of all of the HMG CoA reductase inhibitors (the "statin" cholesterol-lowering agents).

"The statins are not identically metabolized:

• Lovastatin and simvastatin are dependent on CYP 450 3A4 for their metabolic clearance. Among patients receiving simvastatin and mibefradil there have been reported cases of rhabdomyolysis. These events appear to reflect an incidence of rhabdomyolysis higher than that seen during treatment with simvastatin alone. Because of the metabolic similarities of lovastatin and simvastatin, coadministration of Posicor with either of these two drugs is contraindicated.

• Atorvastatin and cerivastatin are biotransformed by CYP 450 3A4 to active and inactive metabolites. Also, only small changes in HMG-CoA reductase inhibitor activity have been seen in studies where atorvastatin and cerivastatin were combined with erythromycin (a less potent CYP 450 3A4 inhibitor than mibefradil). Nevertheless, until there is more information on the coadministration of CYP 450 3A4 inhibitors (including mibefradil) with atorvastatin and cerivastatin, coadministration of either of these two drugs with Posicor should generally be avoided.

• Fluvastatin and pravastatin are not significantly metabolized by CYP450 3A4; no clinically important interaction with mibefradil is anticipated. Therefore, no specific dose adjustment of fluvastatin or pravastatin is recommended with coadministration of Posicor.

"Drug Interactions - Cyclosporine/Tacrolimus and HMG-CoA Reductase Inhibitors: The calcineurin immunosuppressants tacrolimus (FK-506) and cyclosporine are metabolized by CYP 450 3A4, so their blood levels rise (in the case of cyclosporine, about twofold) when Posicor is coadministered; dose adjustment may be necessary. Because the immunosuppressants themselves inhibit a drug-transport system that participates in the excretion of HMG-CoA reductase inhibitors, elevated levels of the immunosuppressants can cause additional elevations in the blood levels of any of the HMG CoA reductase inhibitors. Use of Posicor should be avoided in patients also receiving both a calcineurin immunosuppressant and an HMG-CoA reductase inhibitor."

PRECAUTIONS:

General: Subsection revised (new text in italics) -

"Posicor inhibits cytochrome P450 2D6 and 3A4 and can interact with many concomitant drugs, increasing their plasma concentrations (see Drug Interactions and WARNINGS)."

Cardiac Conduction: Subsection revised (new text in italics) -

"As described under CLINICAL PHARMACOLOGY, Posicor slows sinus and AV node conduction, sometimes resulting in abnormally low heart rates; 0.7% and 1.4% of patients had heart rates below 45 bpm on 50 mg and 100 mg, respectively. Therefore, patients with a pretreatment heart rate below 55 bpm should be followed closely. Treatment with Posicor has rarely been associated with second-degree heart block, 0.2% of patients on doses of 50 mg to 100 mg. One case of third-degree AV block occurred in clinical trials at a 150 mg dose of Posicor. Care should be taken when combining Posicor with beta-blockers, particularly when pretreatment sinus rate is below 55 bpm, and this combination should be avoided in the elderly when pretreatment sinus rate is below 55 bpm (see WARNINGS). ["Therefore, patients with a pretreatment heart rate below 50 bpm should be followed closely. Treatment with Posicor has rarely been associated with second degree AV block, 0.2% of patients on doses of 50 mg to 100 mg. No cases of third degree AV block have been reported at 50 mg to 100 mg, but at higher doses third degree AV block can rarely occur." deleted]

Drug Interactions: Effects of Mibefradil on the Pharmacokinetics of Other Drugs: Drugs Metabolized by Cytochrome P450 3A: HMG-CoA Reductase Inhibitors (new subsection): "See CONTRAINDICATIONS and WARNINGS."

Cyclosporine and Tacrolimus (subsection formerly called "Cyclosporine A): Subsection revised (new text in italics) -

"["Cyclosporine A (Sandimmune), a drug metabolized by CYP 450 3A4, levels increased about twofold under concomitant treatment with 50 mg Posicor for eight days. Therefore, cyclosporine A levels should be monitored and its dose adjusted accordingly" deleted] See WARNINGS."

Other information: First sentence revised (new text in italics) -

"In clinical studies, Posicor has been administered without apparent harm with commonly used drugs including diuretics, ["beta-blockers," deleted] ACE inhibitors, nonsteroidal antiinflammatory drugs, long-acting nitrates, sublingual nitroglycerin, oral hypoglycemics, fibrate lipid-lowering agents, conjugated estrogens, antibiotics and antithrombotics.

The remainder of the subsection beginning with "CYP 450 3A4 mediates the metabolism of ..." deleted.

Geriatric Use (new subsection): "In clinical studies, Posicor was shown to be effective and well-tolerated in elderly patients with hypertension or chronic stable angina pectoris. However, concomitant use of Posicor and beta-blockers should be avoided in the elderly when pretreatment sinus rate is below 55 bpm (see WARNINGS)."

ADVERSE REACTIONS:

Electrocardiographic Changes: First paragraph, new last sentence added -

"Junctional rhythm has been reported in association with sinus node dysfunction and/or sinus arrest and third-degree AV block has been reported (see WARNINGS)."

DOSAGE AND ADMINISTRATION:

Coadministration With Other Antihypertensive and/or Antianginal Drugs: Subsection revised -

"Posicor has been safely administered with diuretics, ACE inhibitors, ["beta-blockers," deleted] long-acting nitrates and sublingual nitroglycerin."

[Other information regarding these changes:
October 28, 1997 (Letter) - Parke-Davis,
November 3, 1997 ( Talk Paper) - FDA,
December 1, 1997 ( Talk Paper) - FDA,
December 1, 1997 ( Letter) - Parke-Davis]

[Other labeling changes not reflected in the 1998 PDR: Aug97 and Nov97]

BOXED WARNING (new section):

"Hepatic: Rare cases of severe idiosyncratic hepatocellular injury have been reported during marketed use (see ADVERSE REACTIONS ["Postintroduction Reports" deleted]). The hepatic injury is usually reversible, but very rare cases of hepatic failure leading to ["including" deleted] death or liver transplant, have been reported. Injury has occurred after both short- and long-term troglitazone treatment.

"During all clinical studies in North America, a total of 48 of 2510 (1.9%) Rezulin-treated patients and 3 of 475 (0.6%) placebo-treated patients had ALT levels greater than 3 times the upper limit of normal. Twenty of the Rezulin-treated and one of the placebo-treated patients were withdrawn from treatment. Two of the 20 Rezulin-treated patients developed reversible jaundice; one of these patients had a liver biopsy which was consistent with an idiosyncratic drug reaction. An additional Rezulin-treated patient had a liver biopsy which was also consistent with an idiosyncratic drug reaction. (See ADVERSE REACTIONS, Laboratory Abnormalities).

"It is recommended that serum transaminase levels be checked ["within the first one to two months and then every three months during" deleted] at the start of therapy, monthly for the first six months of therapy, every two months for the remainder of the first year of troglitazone therapy, and periodically thereafter. Liver function tests also should be obtained for patients at the first symptoms suggestive of hepatic dysfunction, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine. Rezulin therapy should not be initiated if the patient exhibits clinical or laboratory evidence of active liver disease (e.g., ALT > 3 times the upper limit of normal) and should be discontinued if the patient has jaundice or laboratory measurements suggest liver injury (e.g., ALT > 3 times the upper limit of normal)."

CLINICAL PHARMACOLOGY:

Special Populations: Hepatic Insufficiency: Last sentence -

"Nevertheless, Rezulin should be used with caution in patients with hepatic disease."

deleted and new last sentence added -

"However, Rezulin therapy should not be initiated if the patient exhibits clinical or laboratory evidence of active liver disease (e.g., ALT > 3 times the upper limit of normal); see WARNINGS."

Clinical Studies: Monotherapy: New sentence added at end of subsection -

"At 600 mg per day, 58% of patients previously treated with diet in the 12-week study and 47% of patients previously treated with diet in the 26-week study (versus placebo values of 28% and 21% respectively) had a response to Rezulin of > or = 30 mg/dL reduction from baseline in fasting serum glucose."

INDICATIONS AND USAGE:

First sentence revised (new text in italics) -

"Rezulin may be used concomitantly with a sulfonylurea or insulin to improve glycemic control. Rezulin, as monotherapy, is indicated as an adjunct to diet and exercise to lower blood glucose in patients with type II diabetes (See DOSAGE AND ADMINISTRATION).

WARNINGS:

Section revised (new text in italics) - "See Boxed Warning." [Previous text moved to BOXED WARNING section - see above]

PRECAUTIONS:

Use in Patients with Heart Failure: Entire subsection moved after "PRECAUTIONS: General" subsection and before "PRECAUTIONS: Information for Patients" subsection.

ADVERSE REACTIONS:

First paragraph deleted -

"In general, Rezulin is well-tolerated. Two patients in the clinical studies developed reversible jaundice with findings on liver biopsy consistent with idiosyncratic drug reaction (see WARNINGS)."

New first paragraph added -

"Two patients in the clinical studies developed reversible jaundice; one of these patients had a liver biopsy which was consistent with an idiosyncratic drug reaction. An additional patient had a liver biopsy which was consistent with an idiosyncratic drug reaction. Symptoms that are associated with hepatic dysfunction have been reported, including: nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine, abnormal liver function tests (including increased ALT, AST, LDH, alkaline phosphatase, bilirubin). Also see WARNINGS."

Postintroduction Reports: Subsection revised (new text in italics) -

"Adverse events associated with Rezulin that have been reported since market introduction, that are not listed above, and for which causal relationship to drug has not been established include the following: ["jaundice, hepatitis, liver transplant, death. Also see WARNINGS." deleted] congestive heart failure, weight gain, edema, fever, abnormal lab tests including increased CPK and creatinine, hyperglycemia, syncope, anemia, and malaise."

DOSAGE AND ADMINISTRATION:

Monotherapy: Subsection revised (new text in italics) -

"Rezulin monotherapy in patients not adequately controlled with diet alone should be initated at 400 or 600 mg once daily. For patients not responding to 400 mg once daily, the Rezulin dose should be increased to 600 mg after 6-8 weeks. For patients not responding adequately to 600 mg after 6-8 weeks, Rezulin should be discontinued alternative therapeutic options should be pursued. See CLINICAL PHARMACOLOGY, Clinical Studies, Monotherapy."

Patients with Hepatic Impairment: Section revised (new text in italics) -

"["Rezulin should be used with caution in patients with hepatic disease" deleted] Rezulin therapy should not be initiated if the patient exhibits clinical or laboratory evidence of active liver disease (e.g., ALT > 3 times the upper limit of normal). See CLINICAL PHARMACOLOGY, ["Pharmacokinetics and Drug Metabolism" deleted] Special Populations, Hepatic Insufficiency and WARNINGS."

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DESCRIPTION:

Sixth and seventh paragraphs deleted from section and moved to "CLINICAL PHARMACOLOGY: Compound A" subsection.

CLINICAL PHARMACOLOGY:

Compound A (new subsection):

"Compound A is produced when sevoflurane interacts with soda lime and Baralyme (See DESCRIPTION). Its concentration in a circle absorber system increases as a function of increasing CO₂ absorbant temperature and composition (Baralyme producing higher levels than soda lime), increased body temperature, and increased minute ventilation, and decreasing fresh gas flow rates. It has been reported that the concentration of Compound A increases significantly with prolonged dehydration of Baralyme. Compound A exposure in patients also has been shown to rise with increased sevoflurane concentrations and duration of anesthesia. In a clinical study in which sevoflurane was administered to patients under low flow conditions for > or = to 2 hours at flow rates of 1 Liter/minute, Compound A levels were measured in an effort to determine the relationship between MAC hours and Compound A levels produced. The relationship between Compound A levels and sevoflurane exposure are shown in Figure 2a.

"Figure 2a: Inspired Compound A AUC (ppm-hr) vs. Sevoflurane (MAC-hr) - (See new labeling.)

"Compound A has been shown to be nephrotoxic in rats after exposures that have varied in duration from one to three hours. No histopathologic change was seen at a concentration of up to 270 ppm for one hour. Sporadic single cell necrosis of proximal tubule cells has been reported at a concentration of 114 ppm after a 3-hour exposure to Compound A in rats. The LC50 reported at 1 hour is 1050-1090 ppm (male-female) and, at 3 hours, 350-490 ppm (male-female). [Note: this paragraph moved from previous DESCRIPTION section.]

"An experiment was performed comparing sevoflurane plus 75 or 100 ppm Compound A with an active control to evaluate the potential nephrotoxicity of Compound A in non-human primates. A single 8-hour exposure of Sevoflurane in the presence of 100 ppm of Compound A produced renal tubular degeneration in cynomolgus monkeys. These changes are consistent with the increased urinary protein, glucose level and enzymic activity noted on days one and three on the clinical pathology evaluation. This nephrotoxicity produced by Compound A may be dose and duration of exposure dependent."

"At a fresh gas flow rate of 1 L/min, mean maximum concentrations of Compound A in the anesthesia circuit in clinical settings are approximately 20 ppm (0.002%) with soda lime and 30 ppm (0.003%) with Baralyme in adult patients; mean maximum concentrations in pediatric patients with soda lime are about half those found in adults. The highest concentration observed in a single patient with Baralyme was 61 ppm (0.0061%) and 32 ppm (0.0032%) with soda lime. ["The concentrations of Compound A measured in the anesthesia circuit when sevoflurane is used clinically are not known to be deleterious to humans." deleted] The levels of Compound A at which toxicity occurs in humans is not known. [Note: This paragraph revised and moved from previous DESCRIPTION section (new text in italics).]"

WARNINGS:

Previous text deleted and replaced with - "Findings taken from volunteer and patient studies confirmed the potential for renal injury associated with sevoflurane. This potential is greatest when sevoflurane is administered for more than 2 MAC-hours and fresh gas flow rates of 1 L/minute to minimize exposure to compound A. Because of the findings in clinical studies, exposure at 1 L/minute flow gas flow rates should not exceed 2 MAC-hours. Fresh gas flow rates <1 L/minute are not recommended.

"Sevoflurane should be used with caution in patients with renal insufficiency (creatinine >1.5 mg/dl).

"While a level of compound A exposure at which clinical nephrotoxicity might be expected to occur has not been established, it is prudent to consider all of the factors leading to compound A exposure in humans, especially duration of exposure, fresh gas flow rate, and concentration of sevoflurane. During sevoflurane anesthesia the clinician should adjust inspired concentrations and fresh gas flow rate to minimize exposure to compound A.

"Sevoflurane may be associated with glycosuria and proteinuria when used in long procedures at low flow rates. The safety of low flow sevoflurane on renal function was evaluated in patients with normal preoperative renal function. One study compared sevoflurane (N=98) to an active control (N=90) administered for > or = to 2 hours at a fresh gas flow rate of < or = to 1 Liter/minute. There were no statistically significant differences between BUN and creatinine compared to the active control for up to 72 hours post anesthesia. However, 5 patients in the sevoflurane group developed elevations of creatinine, in addition to glycosuria and proteinuria. These patients received sevoflurane at fresh gas flow rates of < or = to 800 ml/minute. One patient in the active control group developed an elevated serum creatinine, but did not experience proteinuria or glycosuria.

"Uncontrolled clinical studies in volunteers evaluated low-flow (1 Liter/minute) sevoflurane at 5, 8 and 10 MAC-hours of anesthesia. Although BUN and serum creatinine were normal, proteinuria and glycosuria were reported in all treatment groups. There was a trend toward a greater degree of abnormality in patients who had the longest exposure time (5>8>10 MAC hours). Subjects in the highest exposure group manifested more significant and prolonged proteinuria and glycosuria than those in the intermediate and lowest exposure groups. In some cases these abnormalities had not resolved or had worsened by post anesthesia day 5. Compound A levels measured in these volunteer studies exceeded those seen in the clinical patient studies. The volunteer studies demonstrate the potential risks associated with extended exposure tosevoflurane under low flow conditions, particularly at >2 MAC-hours of exposure."

PRECAUTIONS:

Hepatic Function (Subsection renamed from "Renal or Hepatic Function"): Deletion of last two paragraphs beginning "Based on the incidence and magnitude....." and "Serum fluoride levels increased with ......".

Carcinogenesis, Mutagenesis, Impairment of Fertility: Subsection revised (new text in italics) -

"Studies on carcinogenesis have not been performed for either sevoflurane or Compound A. No mutagenic effect of sevoflurane was noted in the Ames test, mouse micronucleus test, mouse lymphoma mutagenicity assay, human lymphocyte culture assay, mammalian cell transformation assay, ³²P DNA adduct assay, and no chromosomal aberrations were induced in cultured mammalian cells.

"Similarly, no mutagenic effect of Compound A was noted in the Ames test, the Chinese hamster chromosomal aberration assay and the in vivo mouse micronucleus assay. However, positive responses were observed in the human lymphocyte chromosome aberration assay."

DOSAGE AND ADMINISTRATION:

Text added to end of section - "Limitations: 1. Sevoflurane exposure should not exceed 2 MAC-h at flow rates of 1 L/minute.
2. Fresh gas flow rates <1 L/minute are not recommended.
3. Use with caution in patients with renal insufficiency."

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CLINICAL PHARMACOLOGY:

Hepatic: Previous text -

"The effect of hepatic impairment on the pharmacokinetics of buporpion has not been studied. The formation of the major metabolites of bupropion may be affected by reduced hepatic function."

deleted and new text added -

"The disposition of bupropion following a single 200-mg oral dose was compared in eight healthy volunteers and eight weight- and age-matched volunteers with alcoholic liver disease. The half-life of the morpholinol metabolite was significantly prolonged in subjects with alcoholic liver disease (32 hours (+/- 41%] versus 21 hours [+/- 23%]. The differences in half-life for bupropion and the other metabolites in the two patient groups were minimal."

CONTRAINDICATIONS:

New second paragraph - "Wellbutrin SR is contraindicated in patients treated with Zyban (buproprion hydrochloride) Sustained-Release Tablets, or any other medications that contain buproprion because the incidence of seizure is dose dependent."

WARNINGS:

New first paragraph added -

"Patients should be made aware that Wellbutrin SR contains the same active ingredient found in Zyban, used as an aid to smoking cessation treatment, and Wellbutrin SR should not be used in combination with Zyban, or any other medications that contain bupropion."

Seizures: Fifth paragraph -

"Predisposing factors that may increase the risk of seizure with bupropion use include history of head trauma or prior seizure, CNS tumor, and concomitant medications that lower seizure threshold."

deleted and replaced with -

"The risk of seizure is also related to patient factors, clinical situations, and concomitant medications, which must be considered in selection of patients for therapy with Wellbutrin SR.

• Patient factors: Predisposing factors that may increase the risk of seizure with bupropion use include history of head trauma or prior seizure, central nervous system (CNS) tumor, and concomitant medications that lower seizure threshold.
  
• Clinical situations: Circumstances associated with an increased seizure risk include, among others, excessive use of alcohol; abrupt withdrawal from alcohol or other sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and diabetes treated with oral hypoglycemics or insulin.
  
• Concomitant medications: Many medications (e.g., antipsychotics, antidepressants, theophylline, systemic steroids) and treatment regimens (e.g., abrupt discontinuation of benzodiapines) are known to lower seizure threshold."

Potential for Hepatotoxicity: Last sentence deleted -

"Although scattered abnormalities in liver function tests were detected in patients participating in clinical trials, there is no clinical evidence that bupropion acts as a hepatoxin in humans."

PRECAUTIONS:

Allergic Reactions (new subsection): "Anaphylactoid reactions characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion."

Information for Patients: New first paragraph added -

"Patients should be made aware that Wellbutrin SR contains the same active ingredient found in Zyban, used as an aid to smoking cessation treatment, and Wellbutrin SR should not be used in combination with Zyban, or any other medications that contain bupropion hydrochloride."

Pregnancy: Teratogenic Effects: Pregnancy Category B: Paragraph added to end of subsection -

"To monitor fetal outcomes of pregnant women exposed to Wellbutrin, Glaxo Wellcome Inc. maintains a Bupropion Pregnancy Registry. Health care providers are encouraged to register patients by calling (800) 722-9292, ext. 39441." [NOTE: This change DOES NOT appear in the 1998 PDR.]

ADVERSE REACTIONS:

Extensive revisions to incorporate events noted in smoking cessation trials and other adverse events seen in postmarketing experience. (see 1998 PDR).

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