Compiled with the help of:
Anjali Purohit, PharmD candidate
School of Pharmacy
The University of North Carolina at Chapel Hill

ALDOCLOR (methyldopa/chlorothiazide)
ALDOMET (methyldopa)
ALDORIL (methyldopa/hydrochlorothiazide)
AMPHOTEC (amphotericin B)
ASACOL (mesalamine)
BIAXIN (clarithromycin)
CEFZIL (cefprozil)
CIPRO (ciprofloxacin)
CYTOTEC (misoprostol)
DIFLUCAN (fluconazole)
ELDEPRYL (selegiline HCl)
HELIDAC (bismuth subsalicylate/metronidazole/tetracycline HCl)
MEGACE (megestrol acetate)
MEVACOR (lovastatin)
MEZLIN (mezlocillin sodium)
NAVELBINE (vinorelbine tartrate)
NEUTREXIN (trimetrexate gluronate)
NYDRAZID (isoniazid)
ORAP (pimozide)
ORUDIS (ketoprofen)
ORUVAIL (ketoprofen)
OVRAL (norgestrel/ethinyl estradiol)
OXISTAT (oxiconazole nitrate)
PRELAY (troglitazone)
PROCARDIA (nifedipine)
PROCARDIA XL (nifedipine)
PROSTIN E2 (dinoprostone)
QUESTRAN (cholestyramine)
REZULIN (troglitazone)
SELDANE (terfenadine)
SELDANE-D (terfenadine/pseudophedrine HCl)
SERZONE (nefazodone HCl)
SPORANOX (itraconazole)
TAXOL (paclitaxel)
TIMOPTIC (timolol maleate)
TORECAN (thiethylperazine maleate)
TRASYLOL (aprotinin)
VIRA-A (vidarabine)
YUTOPAR (ritodrine HCl)
ZOCOR (simvastatin)

ADVERSE REACTIONS:

Hypersensitivity: Eosinophilia added.

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PRECAUTIONS:

Pediatric Use (new subsection): "There are no well-controlled clinical trials in pediatric patients. Information on dosing in pediatric patients is supported by evidence from published literature regarding the treatment of hypertension in pediatric patients. (See DOSAGE AND ADMINISTRATION.)"

ADVERSE REACTIONS:

Hypersensitivity: Eosinophilia added.

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CLINICAL PHARMACOLOGY:

Pharmacokinetics: In Table "Predicted Pharmacokinetic Parameters of Amphotericin B after Administration of Multiple Doses of Amphotec" deletion of the predicted pharmacokinetic parameters for the 5 and 6 mg/kg/day dosing regimens.

DESCRIPTION OF CLINICAL STUDIES:

Renal Function: Patients with normal renal function at baseline (new subsection):

From previous renal subsection deletion of "In a randomized, double blind study of Amphotec (4 mg/kg/day) and amphotericin B deoxycholate (0.8 mg/kg/day) as empiric treatment in febrile neutropenic patients, it was demonstrated that, in patients with normal baseline renal function, the incidence of nephrotoxicity was significantly lower with Amphotec than with amphotericin B deoxycholate."

Addition of

"In a randomized, double-blind, multicenter study, 213 febrile neutropenic patients were given empirically either 4 mg/kg/day of Amphotec or 0.8 mg/kg/day of amphotericin B deoxycholate for a maximum of 14 days. This study was primarily designed to compare the safety profiles of these two treatments. NOTE: Amphotec is NOT approved for empirical treatment in febrile neutropenic patients.

"In the above study, patients had largely normal renal function at baseline; median serum creatinine levels were 0.8 mg/dL for both treatment groups. The mean change in serum creatinine was evaluated for patients with baseline creatinine < or = 1.5 mg/dL. As shown in the graph, patients in both treatment groups showed an increase in serum creatinine while on study, however Amphotec patients experienced significantly less creatinine increase at each time point."

Addition of graph "Changes in Mean Serum Creatinine Over Time in Patients with Febrile Neutropenia, and Baseline Serum Creatinine < or = 1.5 mg/dL" - [see label/package insert.]

Hypokalemia (new subsection): "In the same empiric study, significantly more amphotericin B deoxycholate patients had at least one laboratory result of serum potassium < 3.0 mEq/L at least one time in the study compared with Amphotec patients (23% vs. 7%), although concomitant supplemental potassium was allowed in the study design. Both groups received approximately equal amounts of potassium supplementation."

Hypomagnesemia (new subsection): "In the same empiric study, there was no overall trend for decreasing serum magnesium in either group."

WARNINGS:

Second sentence - "Anaphylactoid reactions require immediate treatment" revised to read "Immediate treatment of anaphylaxis or anaphylactoid reactions is required."

PRECAUTIONS:

General: Second and third sentences revised (new text in italics) - "Acute infusion-related reactions including fever, chills, hypoxia, hypotension, nausea, or tachypnea ["usually" deleted] may occur 1 to 3 hours after starting intravenous infusion. These reactions are usually more severe or more frequent ["after" deleted] with the initial doses of Amphotec and usually diminish with subsequent doses."

Drug Interactions: Cyclosporine and Tacrolimus: Current text deleted and replaced with "In the same randomized, double-blind, empiric trial to compare Amphotec and amphotericin B deoxycholate, patients with normal baseline serum creatinine were prospectively enrolled into four strata: adults receiving cyclosporine or tacrolimus (n=89); or pediatric patients (< 16 years old) receiving cyclosporine or tacrolimus (n=15); adults not receiving cyclosporine or tacrolimus (n=75); or pediatric patients not receiving cyclosporine or tacrolimus (n=34). Patients were assessed for renal toxicity defined as either a doubling or an increase of 1.0 mg/dL or more from baseline serum creatinine, or > 50% decrease from baseline calculated creatinine clearance. Adults and pediatric patients receiving cyclosporine or tacrolimus in addition to Amphotec had a significantly lower rate of renal toxicity (31%, 16/51), compared to the amphotericin B deoxycholate patients receiving cyclosporine or tacrolimus (68%, 34/50). In the adults and pediatric patients not receiving cyclosporine or tacrolimus, only 8% (4/51) of the Amphotec patients experienced renal toxicity compared to 35% (17/49) of the amphotericin B deoxycholate patients."

Pediatric Use: First sentence revised (new text in italics) - "["Seventy" deleted] Ninety-seven pediatric patients with systemic fungal infections have been treated with Amphotec, at daily doses (mg/kg) similar to those ["in" deleted] given to adults."

Addition of paragraph at end of subsection - "In the same empiric, multicenter trial, pediatric patients (< 16 years) treated with Amphotec had significantly less renal toxicity than amphotericin B deoxycholate patients. Only 12% (3/25) of pediatric patients treated with amphotec developed nephrotoxicity compared to 52% (11/21) of pediatric patients receiving amphotericin B deoxycholate. Renal toxicity defined as either a doubling or an increase of 1.0 mg/dL or more from baseline serum creatinine, or > 50% decrease from baseline calculated creatinine clearance."

Geriatric Use: First sentence revised (new text in italics) - "Sixty-["one" deleted] eight patients at least 65 years of age have been treated with Amphotec."

ADVERSE REACTIONS:

First paragraph, second sentence revised (new text in italics) - "Additionally, comparative adverse event data from ["110" deleted] 150 Amphotec (4 or 6 mg/kg/day) and ["109" deleted] 146 amphotericin B deoxycholate (0.8 or 1mg/kg/day) patients in prospectively randomized double-blinded studies of empiric treatment of febrile and neutropenic patients or treatment of aspergillosis are also provided.

Infusion-Related Adverse Events: First sentence revised (new text in italics) - "["Acute" deleted] Infusion-related adverse events (1 to 3 hours after starting intravenous infusion) occurred most frequently in association with the first infusion of Amphotec."

Revision of table "Summary of Probably and Possibly Related Adverse Events Reported by > or = 5% of Amphotec Patients" [See label/package insert.]

In the paragraph "Additionally, the following adverse events also occurred in 5% or more of Amphotec patients; however, the causal relationship of these adverse events is uncertain:"

General: "abdomen enlarged" moved up from 1% to less than 5%; "injection site inflammation" added; "chills and fever" deleted.

Cardiovascular system: "cardiovascular disorder" added; "hemorrhage" and "postural hypotension" moved up from 1% to less than 5%.

Digestive system: "diarrhea" and "dry mouth" added; "hematemesis" and "jaundice" moved up from 1% to less than 5%.

Hemic and lymphatic system: "prothrombin decreased" added; "prothrombin time increased" deleted.

Metabolic and nutritional disorders (new category replacing "Altered laboratory data"): "generalized edema" and "weight gain" added; "hypocalcemia" moved from table and added.

Nervous system: "dizziness", "somnolence" and "tremor" moved up from 1% to less than 5%; "insomnia" added.

Respiratory system: "asthma" moved up from 1% to less than 5%; "rhinitis" added.

Skin and appendages: "sweating" added.

In the paragraph "The following adverse events occurred in 1% to less than 5% of Amphotec patients. The causal relationship of these adverse events and Amphotec is uncertain:"

General: "accidental injury", "death", "hypothermia", "immune system disorder" and "neck pain" added; "asthenia" moved down from 5% or more.

Cardiovascular system: "vasodilatation" and "venoocclusive liver disease" added; "arrhythmia" moved down from 5% or more.

Digestive system: "bloody diarrhea", "constipation", "dyspepsia", "fecal incontinence", "gamma glutamyl transpeptidase increased", "gingivitis", "glossitis", "hepatic failure", "mouth ulceration", "oral moniliasis" and "rectal disorder" added; "melena" moved down from 5% or more

Hemic and lymphatic system: "ecchymosis", "fibrinogen increased", "petechia", and "thromoplastin decreased" added.

Metabolic and nutritional disorders (new category replacing "Altered laboratory data"): "dehydration", "hyperlipemia", "hypernatremia", "hypoproteinemia, and "weight loss" added; "hyperglycemia acidosis" changed to "acidosis."

Nervous system: "nervousness", "psychosis", and "speech disorder" added; "depression" moved down from 5% or more.

Respiratory system: "pharyngitis", "pleural effusion", and "sinusitis" added; "hemoptysis" moved down from 5% or more.

Skin and appendages: "acne", "alopecia", "petechial rash", "skin discoloration", "skin nodule", "skin ulcer", "urticaria", and "vesiculobullous rash" added.

Special senses: "amblyopia", "deafness", and "ear disorder" added.

Urogenital system: "albuminuria", "dysuria", "glycosuria", "oliguria", "urinary incontinence", "urinary retention", and "urinary tract disorder" added; "kidney failure" moved down from 5% or more; "kidney function abnormal" deleted.

DOSAGE AND ADMINISTRATION:

First sentence revised (new text in italics) - "The recommended dose for adults and ["children," deleted] pediatric patients is ["therapy may begin at a daily dose of" deleted] 3 - 4 mg/kg as required, once a day.

Second sentence deleted - "The dose may be increased to 6 mg/kg/day if there is no improvement or if there is evidence of progression of the fungal infection."

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CLINICAL PHARMACOLOGY:

Pharmacokinetics: Paragraph added to end of subsection - "For information on ranitidine bismuth citrate, refer to the CLINICAL PHARMACOLOGY section of the Tritec package insert."

Microbiology: NOTE: Second paragraph revised (new text in italics) -

"Clarithromycin has been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections when combined with omeprazole or ranitidine bismuth citrate as described in the INDICATIONS AND USAGE section."

Helicobacter: Helicobacter pylori: New second paragraph -

"Emerging clarithromycin resistance was not assessed for the ranitidine bismuth citrate plus clarithromycin regimen because there were no patients that had H. pylori isolates with both pre-treatment and post-treatment susceptibility tests. No adequate data were collected during clinical trials or in vitro studies to indicate that ranitidine bismuth citrate can either decrease or increase emerging clarithromycin resistance."

INDICATIONS AND USAGE:

Adults: Seventh paragraph, first sentence revised (new text in italics) -

"Biaxin (clarithromycin) Filmtab tablets in combination with Prilosec (omeprazole) capsules or Tritec (ranitidine bismuth citrate) tablets is indicated for the treatment of patients with an active duodenal ulcer associated with H. pylori infection."

CONTRAINDICATIONS:

Paragraph added to end of section - "For information on ranitidine bismuth citrate, refer to the CONTRAINDICATIONS section of the Tritec package insert."

WARNINGS:

Paragraph added to end of section - "For information on ranitidine bismuth citrate, refer to the WARNINGS section of the Tritec package insert."

PRECAUTIONS:

General: New second and third paragraphs added -

"Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with creatinine clearance less than 25 mL/min. (See DOSAGE AND ADMINISTRATION.)

"Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of acute porphyria."

Paragraph added to end of subsection - "For information on ranitidine bismuth citrate, refer to the PRECAUTIONS section of the Tritec package insert."

Drug Interactions: New fifth paragraph added -

"Co-administration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14-hydroxy-clarithromycin plasma concentrations (31%). These effects are clinically insignificant."

DOSAGE AND ADMINISTRATION:

Title of table revised (new text in italics) -

"Active Duodenal Ulcer Associated with H. Pylori Infection
(28 day therapy) Clarithromycin + Omeprazole"

New table and text added to end of subsection -

Active Duodenal Ulcer Associated with H. Pylori Infection (28 day therapy) Clarithromycin + ranitidine Bismuth Citrate
Days 1 to 14	Days 15 to 28
Clarithromycin 500 mg tablet t.i.d plus ranitidine Bismuth Citrate 400 mg tablet b.i.d.	ranitidine Bismuth Citrate 400 mg tablet b.i.d.

"Biaxin and ranitidine bismuth citrate combination therapy is not recommended in patients with creatinine clearance less than 25 mL/min.

"For information on ranitidine bismuth citrate, refer to the DOSAGE AND ADMINISTRATION section of the Tritec package insert."

CLINICAL STUDIES:

Duodenal Ulcer Associated with H. pylori Infection: Clarithromycin + Omeprazole Therapy (new subsection): Existing text moved into subsection.

Duodenal Ulcer Healing: Title of table revised (new text in italics) -

"End-of-Treatment Ulcer Healing Rates
Percent of Patients Healed (n/N)"

Eradication of H. pylori Associated with Duodenal Ulcer: Title of table revised (new text in italics) -

"H. pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks
Percent of Patients Cured (n/N)"

Clarithromycin + Ranitidine Bismuth Citrate Therapy (new subsection): "Biaxin alone and in combination with ranitidine bismuth citrate was evaluated in two U.S. double-blind, randomized, multicenter, placebo-controlled trials. Four hundred and nine (409) patients were enrolled and 265 had H. pylori infection and active duodenal ulcer prestudy. Clarithromycin 500 mg t.i.d. for the first 2 weeks plus ranitidine bismuth citrate 400 mg b.i.d. for 4 weeks was found to have a significantly higher H. pylori eradication rate when compared to clarithromycin 500 mg t.i.d. for 2 weeks, ranitidine bismuth citrate 400 mg b.i.d. for 4 weeks, or placebo.

"Duodenal Ulcer Healing at 4 weeks (End of Treatment): Ulcer healing rates for the two U.S. double-blind, randomized, multicenter, placebo-controlled trials are represented in the table below.

End-of-Treatment Ulcer Healing Rates* Percent of Patients Healed + [95% Confidence Interval] (number of patients)
Study	Clarithromycin + Ranitidine Bismuth Citrate	Ranitidine Bismuth Citrate	Clarithromycin	Placebo
Study 305     Study 306	75% [53%-90%] (n = 24) 71%^ [51%-87%] (n = 28)	73% [54%-88%] (n = 30) 79% [58%-93%] (n = 24)	70% [50%-86%] (n = 27) 53% [34%-72%] (n = 30)	56% [30%-80%] (n = 16) 21% [5%-51%] (n = 14)
* This analysis excludes dropouts and patients with major protocol violations. + Ranitidine bismuth citrate alone has not been proven to be superior to ranitidine for duodenal ulcer healing. ^ P < 0.05 for clarithromycin + ranitidine bismuth citrate versus placebo

 

"Eradication of H. pylori Associated with Active Duodenal Ulcer:

The combination of clarithromycin and ranitidine bismuth citrate was effective in eradicating H. pylori.

 

 

H. pylori Eradication Rates* Percent of Patients Cured [95% Confidence Interval] (number of patients)
Study	Clarithromycin + Ranitidine Bismuth Citrate	Ranitidine Bismuth Citrate	Clarithromycin	Placebo
Study 305       Study 306	84% [60%-97%] (n = 19)   73% ^ [50%-89%] (n = 22)	0% [0%-14%] (n = 25)   0% [0%-15%] (n = 22)	25% [10%-47%] (n = 24)   25% [10%-47%] (n = 24)	0% [0%-21%] (n = 16)   0% [0%-23%] (n = 14)
* H. pylori eradication was defined as no positive test (CLOtestTM, culture, histology) at 4 weeks following the end of treatment. Patients must have had two tests performed and these must have been negative to be considered eradicated of H. pylori. The following patients were excluded: patients not infected with H. pylori prestudy, dropouts, patients with major protocol violations, patients with missing H. pylori tests, and patients that were not assessed for H. pylori eradication 4 weeks after the end of treatment becauses they were found to have an unhealed ulcer and were H. pylori negative at the end of treatment. ^ P < 0.001 for clarithromycin + ranitidine bismuth citrate versus all other treatment groups.

 

"The relationship between H. pylori eradication and duodenal ulcer recurrence was assessed in a combined analysis of six U.S. randomized, double-blind, multicenter, placebo-controlled trials using ranitidine bismuth citrate with or without antibiotics. The results from approximately 65-U.S. patients showed that the risk of ulcer recurrence within 6 months of completing treatment was two times less likely in patients whose H. pylori infection was eradicated compared to patients in whom H. pylori infection was not eradicated.

"Safety: Placebo-controlled trials in patients with active duodenal ulcer in the United States included 240 patients given clarithromycin alone or in combination with ranitidine bismuth citrate, 903 patients given ranitidine bismuth citrate alone, and 469 patients given placebo.

"Incidence of Drug-Related Adverse Reactions in Placebo-Controlled Clinical Trials: The following table lists drug-related adverse reactions that occurred at a frequency of > or = 1% among patients treated with ranitidine bismuth citrate who participated in U.S. placebo-controlled trials.

Drug-Related Adverse Reactions During Treatment
Adverse Reactions	Tritec Tablets 800 mg + Clarithromycin 1,500 mg < (n = 120)	Clarithromycin 1,500 mg (n = 120)	Tritec Tablets 800 mg (n = 903)	Placebo (N = 469)
Gastrointestinal Diarrhea Nausea & vomiting Constipation Neurological Headache Dizziness Miscellaneous Disturbance of taste Sleep disorder Chest symptoms Skin Pruritus Urogenital Gynecological problems	... 8% 3% 0% ... 5% 0% ... 10% 2% 2% ... 3% ... 3% (n = 34)	... 5% 2% 0% ... < 1% 2% ... 11% < 1% 0% ... 0% ... 6% (n = 32)	... 2% < 1% 1% ... 1% < 1% ... < 1% < 1% 0% ... < 1% ... < 1% (n = 267)	... 1% 1% < 1% ... < 1% < 1% ... < 1% < 1% < 1% ... 0% ... 0% (n = 159)
* Total daily dose

 

"For information on ranitidine bismuth citrate, refer to the ADVERSE REACTIONS section of the Tritec package insert."

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CLINICAL PHARMACOLOGY:

New paragraph and table added to end of section - "Comparative pharmacokinetic parameters of cefprozil are observed between pediatric patients (6 months-12 years) and adults following oral administration of selected matched doses. The maximum concentrations are achieved at 1-2 hours after dosing. The plasma elimination half-life is approximately 1.5 hours. In general, the observed plasma concentrations of cefprozil in pediatric patients at the 7.5, 15, and 30 mg/kg doses are similar to those observed within the same time frame in normal adult subjects at the 250, 500, and 1000 mg doses, respectively. The comparative plasma concentrations of cefprozil in pediatric patients and adult subjects at the equivalent dose level are presented in the table below. "

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CONTRAINDICATIONS AND WARNINGS BOX:

Addition of new third sentence - "["Anecdotal" deleted] Reports, primarily from Brazil, of congenital anomalies and reports of fetal death subsequent to misuse of misoprostol alone as an abortifacient have been received." [Note: Change appears in 1997 PDR. The deletions and additions (in italics) reflect additional revisions.]

PRECAUTIONS:

Nonteratogenic effects: Addition of new fifth sentence - "["Anecdotal" deleted] Reports, primarily from Brazil, of congenital anomalies and reports of fetal death subsequent to misuse of misoprostol alone as an abortifacient have been received." [Note: Change appears in 1997 PDR. The deletions and additions (in italics) reflect additional revisions.]

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PRECAUTIONS:

Drug Interactions: Terfenadine: Sentence added to end of subsection - "The coadministration of fluconazole at doses lower than 400mg/day with terfenadine should be carefully monitored."

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CLINICAL PHARMACOLOGY:

Fifth paragraph, new second sentence added - "Although rare, a few reports of hypertensive reactions have occurred in patients receiving Eldepryl at recommended dose, with tyramine-containing foods."

Fifth paragraph, former second sentence revised (new text in italics) - "["However" deleted] In addition, one case of hypertensive crisis has been reported in a patient taking the recommended dose of selegiline and a sympathomimetic medication, ephedrine."

Sixth paragraph revised (new text in italics) - "In short, attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet and concomitant drug use although, as noted above, ["a case" deleted] a few cases of hypertensive reactions have been reported at the recommended dose. (See WARNINGS and PRECAUTIONS.)"

WARNINGS:

Second paragraph, new second sentence added - "Rare cases of hypertensive reactions associated with ingestion of tyramine- containing foods have been reported in patients taking the recommended daily dose of selegiline."

PRECAUTIONS:

Information for Patients: Second paragraph, third sentence deleted - "While hypertensive reactions with selegiline associated with dietary influences have not been reported, documented experience is limited."

Addition of new third sentence - "Rare hypertensive reactions with selegiline at recommended doses associated with dietary influences have been reported."

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WARNINGS:

Metronidazole: Pregnancy: Teratogenic Effects (new subsection): "Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. No fetotoxicity was observed when metronidazole was administered orally to pregnant mice at 20 mg/kg/day approximately one and a half times the most frequently recommended human dose (750 mg/kg/day) based on mg/kg body weight; however, in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed. The relationship of these findings to the drug is unknown."

PRECAUTIONS:

General: Metronidazole: Second sentence revised (new text in italics) - "Metronidazole is a nitroimidazole and should be used with ["care" deleted] caution in patients with evidence of, or history of, blood dyscrasia."

Carcinogenesis, Mutagenesis, Impairment of Fertility: First paragraph, fourth sentence revised (new text in italics) - "At very high dose levels, (approximately 500 mg/kg/day, which is approximately ["two" deleted] 33 times the most frequently recommended ["maximum" deleted] human dose for a 50 kg adult based on ["mg/m²)" deleted] mg/kg body weight), there was a statistically significant increase in the incidence of malignant liver tumors in male mice."

Last paragraph, new sentence added to end - "Fertility studies have been performed in mice at doses up to six times the maximum recommended human dose based on mg/m² and have revealed no evidence of impaired fertility."

Teratogenic Effects. Pregnancy Category D: Subsection revised (new text in italics) - "Category D is based on the pregnancy category for tetracycline hydrochloride. (See CONTRAINDICATIONS and WARNINGS, Tetracycline and Metronidazole subsections.)"

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PRECAUTIONS: Drug Interactions: Text deleted - "Pharmacokinetic studies show that there are no alterations in pharmacokinetic parameters when megestrol acetate is administered with zidovudine or with rifabutin."

New text added - "Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. The effects of zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied."

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INDICATIONS AND USAGE:

Third footnote added to the National Cholesterol Education Program (NCEP) Treatment Guidelines summarized in section - "In CHD patients with LDL-C levels 100-129 mg/dL, the physician should exercise clinical judgement in deciding whether to initiate drug treatment."

New fifth paragraph - "At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL-C is > or = 130 mg/dL (see NCEP Guidelines, above)."

CONTRAINDICATIONS:

Pregnancy and lactation: Subsection revised (new text in italics) - "Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase such as Mevacor to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, Mevacor ["may cause fetal harm when administered to a pregnant woman. Therefore, lovastatin" deleted] is contraindicated during pregnancy and in nursing mothers. Mevacor ["Lovastatin" deleted] should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, Mevacor ["lovastatin" deleted] should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy)."

PRECAUTIONS:

General: First paragraph deleted - "Before instituting therapy with Mevacor, an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in obese patients, and to treat other underlying medical problems (see INDICATIONS AND USAGE)."

Information for Patients: Subsection revised (new text in italics) - "Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. (see WARNINGS, Skeletal Muscle)."

PREGNANCY:

Pregnancy Category X: Subsection revised (new text in italics)-

"Safety in pregnant women has not been established.

"Lovastatin has been shown to produce skeletal malformations at plasma levels 40 times the human exposure (for mouse fetus) and 80 times the human exposure (for rat fetus) based on
mg/m² surface area (doses were 800 mg/kg/day). No drug-induced changes were seen in either species at multiples of 8 times (rat) or 4 times (mouse) based on surface area. No evidence of malformations was noted in rabbits at exposures up to 3 times the human exposure (dose of 15 mg/kg/day, highest tolerated dose).

"Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. ["There has been one report of severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took lovastatin with dextroamphetamine sulfate during the first trimester of pregnancy." deleted] In a review ⁺of approximately 100 prospectively followed pregnancies in women exposed to Mevacor or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a 3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with Mevacor during pregnancy (see CONTRAINDICATIONS) treatment should be immediately discontinued as soon as pregnancy is recognized. Mevacor should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. ["If the woman becomes pregnant while taking Mevacor, it should be discontinued and the patient advised again as to the potential hazards to the fetus." deleted]

"+ Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P. Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy. Reproductive Toxicology. 10(6):439-446, 1996."

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WARNINGS: Text deleted and replaced with - "Before therapy with mezlocillin is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to mezlin, other penicillins, cephalosporins, or other drugs. If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Mezlin occurs, discontinue the drug. Serious acute hypersensitivity may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.

"Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Mezlin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

"Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of 'antibiotic-associated colitis'.

"After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis."

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ADVERSE REACTIONS: Observed During Clinical Practice: Subsection revised (new text in italics):

"In addition to the adverse experiences reported during clinical trials, the following adverse events have been ["reported in patients receiving marketed" deleted] identified during postapproval use of Navelbine in clinical practice. [For these events the frequency and causality for Navelbine has not been established." deleted] 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 either their seriousness, frequency of reporting, causal connection to Navelbine, or a combination of these factors.

"Body As A Whole: Systemic allergic reactions reported as anaphylaxis, pruritis, urticaria, and angioedema; flushing; and radiation recall events such as dermatitis and esophagitis (see PRECAUTIONS) have been reported.

. "Hematologic: Thromboembolic events including pulmonary embolus and deep venous thrombosis, have been reported primarily in seriously ill and debilitated patients with known predisposing risk factors for these events.

"Neurologic: Peripheral neurotoxicities such as, but not limited to, muscle weakness and disturbance of gait, have been observed in patients with and without prior symptoms. There may be increased potential for neurotoxicity in patients with pre-existing neuropathy, regardless of etiology, who receive Navelbine.

"Skin: Injection site reactions, including localized rash and urticaria, blister formation, and skin sloughing have been observed in clinical practice. Some of these reactions may be delayed in appearance.

"Gastrointestinal: Dysphagia and mucositis have been reported.

"Cardiovascular: Hypertension, hypotension, vasodilation, and tachycardia have been reported.

"Pulmonary: Pneumonia has been reported.

"Musculoskeletal: Headache has been reported, with and without other musculoskeletal aches and pains.

"Other: Pain in tumor-containing tissue and back pain have been reported. Electrolyte abnormalities, including hyponatremia, have been reported in seriously ill and debilitated patients.

"Combination Use: Patients with prior exposure to paclitaxel and who have demonstrated neuropathy should be monitored closely for new or worsening neuropathy. Patients who have experienced neuropathy with previous drug regimens should be monitored for symptoms of neuropathy while receiving Navelbine. Navelbine may result in radiosensitizing effects with prior or concomitant radiation therapy (see PRECAUTIONS)."

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DOSAGE AND ADMINISTRATION: New paragraph and table added prior to Dosage Modification subsection -

"Neutrexin and leucovorin may alternatively be dosed on a mg/kg basis, depending on the patient's body weight, using the conversion factors shown in the table below:"

Body Weight (kg)	Neutrexin Dose (mg/kg/day)	Leucovorin Dose (mg/kg/qid)
< 50	1.5	0.6
50-80	1.2	0.5
> 80	1.0	0.5

RECONSTITUTION AND DILUTION:

First paragraph, third sentence revised - "Do not use if cloudiness or precipitate is observed [", but even if the solution appears clear, it should be filtered (0.22um) prior to dilution" deleted]."

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CONTRAINDICATIONS:

#3 revised (new text in italics) -

"Because Orap prolongs the QT interval of the electrocardiogram it is contraindicated in patients with congenital long QT syndrome, patients with a history of cardiac arrhythmias, or patients taking other drugs which prolong the QT interval of the electrocardiogram (see Precautions - DRUG INTERACTIONS)."

#6 (new contraindication) -

"Ventricular arrhythmias have been rarely associated with the use of macrolide antibiotics in patients with prolonged QT intervals, as might be produced by Orap. Specifically, two sudden deaths have been reported when clarithromycin was added to ongoing pimozide therapy. [Note: These preceding two sentences appear in the 1997 PDR.] Furthermore, some evidence suggests that pimozide is metabolized partly by the enzyme system P450 3A (CYP 3A). Macrolide antibiotics are inhibitors of CYP 3A, and thus could potentially impede pimozide metabolism. For these reasons, Orap is contraindicated in patients receiving the macrolide antibiotics clarithromycin, erythromycin, azithromycin, and dirithromycin." [Note: The preceding sentence atarting with "Orap.." appears in the 1997 PDR.]

"Because azole antifungal agents are also inhibitors of the CYP 3A enzymes and thus may likewise impair pimozide metabolism, Orap is contraindicated in patients receiving the azole antifungal agents intraconazole and ketoconazole."

PRECAUTIONS:

Drug Interactions: New second sentence added -

"Also, the use of macrolide antibiotics in patients with prolonged QT intervals has been rarely associated with ventricular arrhythmias." [Note: This sentence appears in the 1997 PDR.]

ADVERSE REACTIONS:

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

"The following experiences were described in spontaneous postmarketing reports. These reports do not provide sufficient information to establish a clear causal relationship with the use of Orap.
Gastrointestinal: Gingival hyperplasia in one patient.
Hematologic: Hemolytic anemia
Metabolic/Nutritional: Hyponatremia
Other: Seizure ["has been reported in one patient" deleted]." [Note: These changes appear in the 1997 PDR.]

ADVERSE REACTIONS:

Fourth paragraph, 3rd sentence revised (new text in italics) -

"Rare adverse reactions (incidence less than 1%) were collected from one or more of the following sources: foreign reports to manufacturers and regulatory agencies, publications, ["and" deleted] U.S. clinical trials, and/or U.S. postmarketing spontaneous reports."

Incidence less than 1% (probable cause relationship): Digestive: addition of "hepatic dysfunction, hepatitis, cholestatic hepatitis, jaundice".

Metabolic and Nutritional: deletion of "hepatic dysfunction".

Skin and Appendages: addition of "toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome."

Incidence less than 1% (causal relationship unknown): Digestive: deletion of "jaundice".

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INDICATIONS AND USAGE:

First paragraph revised (new text in italics) - "Oral contraceptives are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception. Oral contraceptive products such as Ovral or Ovral-28, which contain 50 mcg of estrogen, should not be used unless medically indicated."

WARNINGS:

Thromboembolic Disorders and Other Vascular Problems: d. Dose-related risk of vascular disease from oral contraceptives: New sentence added to end of subsection - "Products containing 50 mcg estrogen should be used only when medically indicated."

DETAILED PATIENT LABELING:

Introduction: New first sentence - "You should not use Ovral or Ovral-28, which contain higher doses of estrogen than other oral contraceptives, unless specifically recommended by your health-care provider."

Effectiveness of oral contraceptives: Deletion of "Vaginal sponge: 18% to 28%"

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ADVERSE REACTIONS:

Paragraph added to end of section - "In post-marketing experience, there have been rare reports of exfoliative dermatitis caused by nifedipine. There have been rare reports of exfoliative or bullous skin adverse events (such as erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis) and photosensitivity reactions."

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PRECAUTIONS:

6. Pediatric Use (new subsection): "Safety and effectiveness in pediatric patients have not been established."

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ADVERSE REACTIONS:

Drug Interactions: HMG-CoA Reductase Inhibitors (new subsection): This subsection cautions the physician about the occurrence of rhabdomyolysis when these agents are given alone, for certain drugs in this class, or when given in combination with inhibitors of the
IIIA₄ isozyme such as nefazodone.

Postintroduction Clinical Experience: Addition of a statement describing rare reports of rhabdomyolysis in patients receiving the combination of Serzone and lovastatin or simvastatin.

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WARNINGS:

Paragraph added to beginning of section - "Sporanox (itraconazole) Capsules and Sporanox Oral Solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. Additionally, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis."

PRECAUTIONS:

Information for Patients: New first paragraph - "Patients should be aware that Sporanox (itraconazole) Capsules is a different preparation than Sporanox Oral Solution, and these should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. Additionally, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis."

Pediatric use: First paragraph revised (new text in italics) - "The efficacy and safety of Sporanox have not been established in pediatric patients. No pharmacokinetic data on capsules are available in children. A small number of patients age 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections and no serious unexpected adverse effects have been reported. Sporanox Oral Solution (5mg/kg/day) has been administered to pediatric patients (n=26, age 0.5-12 years) for two weeks and no serious unexpected adverse events were reported."

ADVERSE REACTIONS:

Last sentence of section revised (new text in italics) - "Although the causal association with Sporanox is uncertain, rare alopecia, hypertriglyceridemia, neutropenia and isolated cases of neuropathy have also been reported."

DOSAGE AND ADMINISTRATION:

Paragraph added to end of section - "Sporanox (itraconazole) Capsules and Sporanox Oral Solution should not be used interchangeably. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis."

N.B.: Where the label refers to the Capsules (e.g., WARNING box, CONTRAINDICATIONS, OVERDOSAGE, reference to the Oral Solution was added.

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CLINICAL PHARMACOLOGY:

Pharmacokinetics (new subsection): "In a study of plasma drug concentration in six subjects, the systemic exposure of timolol was determined following twice daily administration of Timoptic 0.5%. The mean peak plasma concentration following morning dosing was 0.46 ng/mL and following afternoon dosing was 0.35 ng/mL."

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CONTRAINDICATIONS:

Second paragraph revised (new text in italics) - "Use of Torecan (thiethylperazine) is contraindicated in patients who have demonstrated a hypersensitivity reaction (e.g., blood dyscrasias, jaundice) to phenothiazines.

WARNINGS:

Second paragraph revised (new text in italics) - "Phenothiazines are capable of potentiating CNS depressants (e.g., barbiturates, anesthetics, opiates, alcohol, etc.) as well as atropine and phosphorous insecticides."

PRECAUTIONS:

Pediatric Use: Subsection revised (new text in italics) - "["The" deleted] Safety and ["efficacy" deleted] effectiveness in pediatric patients have not been established. ["of Torecan (thiethylperazine) in children under 12 years of age has not been established" deleted]"

DRUG ABUSE AND DEPENDENCE (new section): "Torecan (thiethylperazine) is not a controlled substance."

OVERDOSAGE (new section):

"Manifestations of acute overdosage of Torecan (thiethylperazine) can be expected to reflect the CNS effects of the drug and include extrapyramidal symptoms (E.P.S.), confusion and convulsions with reduced or absent reflexes, respiratory depression and hypotension. If the patient is conscious, vomiting should be induced mechanically or with emetics. Gastric lavage should be employed utilizing concurrently a cuffed endotracheal tube if the patient is unconscious to prevent aspiration and pulmonary complications. Maintenance of adequate pulmonary ventilation is essential. The use of pressor agents intravenously may be necessary to combat hypotension. The administration of epinephrine should be avoided since phenothiazine may induce a reversed epinephrine effect. The most suitable vasoconstrictive agents are norepinephrine and phenylephrine. Fluids should be administered intravenously to encourage diuresis. The value of dialysis has not been determined. If excitation occurs, barbiturates should not be used. It should be borne in mind that multiple agents may have been ingested."

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WARNINGS:

Text deleted and replaced with - "Anaphylactic or anaphylactoid reactions are possible when Trasylol is administered. Hypersensitivity reactions are rare in patients with no prior exposure to aprotinin. Hypersensitivity reactions can range from skin eruptions, itching, dyspnea, nausea and tachycardia to fatal anaphylactic shock with circulatory failure. If a hypersensitivity reaction occurs during injection or infusion of Trasylol, administration should be stopped immediately and emergency treatment should be initiated. It should be noted that severe (fatal) hypersensitivity/anaphylactic reactions can also occur in connection with application of the test dose. Even when a second exposure to aprotinin has been tolerated without symptoms, a subsequent administration may result in severe hypersensitivity/anaphylactic reactions.

"Re-exposure to aprotinin: In a retrospective review of 387 European patient records with documented re-exposure to Trasylol, the incidence of hypersensitivity/anaphylactic reactions per re-exposure was 2.7%. Two patients who experienced hypersensitivity/anaphylactic reactions subsequently died, 24 hours and five days after surgery, respectively. The relationship of these two deaths to Trasylol is unclear. This retrospective review also showed that the incidence of a hypersensitivity or anaphylactic reaction following re-exposure is increased when re-exposure occurs within six months of the initial administration (5.0% for re-exposures within six months and 0.9% for re-exposures greater than six months). Other smaller studies have confirmed that in case of re-exposure, the incidence of hypersensitivity/anaphylactic reactions may reach the five percent level.

"Before initiating treatment with Trasylol in a patient with a history of prior exposure, the recommendations below should be followed to manage a potential hypersensitivity or anaphylactic reaction:

1. Have standard emergency treatments for hypersensitivity or anaphylactic reactions readily available in the operating room (e.g., epinephrine, corticosteroids).

2. Administration of the test dose and loading dose should be done only when the conditions for rapid cannulation (if necessary) are present.

3. Delay the addition of Trasylol into the pump prime solution until after the loading dose has been safely administered.

Additionally, administration of H1 and H2 blockers 15 minutes before the test dose may be considered."

PRECAUTIONS:

General: Test Dose ["and Use of H1 Antihistamine" deleted]: Last two sentences deleted - "Particular caution is necessary when administering Trasylol (even test doses) to patients who have received aprotinin in the past because of the risk of anaphylaxis. In re-exposure cases, intravenous administration of an H1-histamine antagonist (antihistamine) is recommended shortly before the loading dose of Trasylol."

New text added to end of subsection - "However, even after the uneventful administration of the initial 1 mL-dose, the therapeutic dose may cause an anaphylactic reaction. If this happens the infusion of aprotinin should immediately be stopped, and standard emergency treatment for anaphylaxis should be applied. Patients who experience any allergic reaction to the test dose of aprotinin should not receive further administration of the drug. (See WARNINGS)"

Allergic Reactions: Text deleted and replaced with - "Patients with a history of allergic reactions to drugs or other agents may be at greater risk of developing a hypersensitivity or anaphylactic reaction upon exposure to Trasylol (see WARNINGS)."

Laboratory Monitoring of Anticoagulation during Cardiopulmonary Bypass: Text deleted and replaced with -

"Trasylol prolongs whole blood clotting times by a different mechanism than heparin. In the presence of aprotinin, prolongation is dependent on the type of whole blood clotting test employed. If an activated clotting time (ACT) is used to determine the effectiveness of heparin anticoagulation, the prolongation of the ACT by aprotinin may lead to an overestimation of the degree of anticoagulation, thereby leading to inadequate anticoagulation. During extended extracorporeal circulation, patients may require additional heparin, even in the presence of ACT levels that appear adequate.

"In patients undergoing CPB with Trasylol therapy, one of the following methods may be employed to maintain adequate anticoagulation:

"ACT - An ACT is not a standardized coagulation test, and different formulations of the assay are affected differently by the presence of aprotinin. The test is further influenced by variable dilution effects and the temperature experienced during cardiopulmonary bypass. It has been observed that kaolin-based ACTs are not increased to the same degree by aprotinin as are diatomaceous earth-based (celite) ACTs. While protocols vary, during bypass a minimal celite ACT of 750 seconds or kaolin-ACT of 480 seconds, independent of the effects of hemodilution and hypothermia, is recommended in the presence of aprotinin. Consult the manufacturer of the ACT test regarding the interpretation of the assay in the presence of Trasylol.

"Fixed Heparin Dosing - A standard loading dose of heparin, administered prior to cannulation of the heart, plus the quantity of heparin added to the prime volume of the CPB circuit, should total at least 350 IU/kg. Addition heparin should be administered in a fixed-dose regiment based on patient weight and duration of CPB.

"Heparin Titration - Protamine titration, a method that is not affected by aprotinin can be used to measure heparin levels. A heparin dose response, assessed by protamine titration, should be performed prior to administration of aprotinin to determine the heparin loading dose. Addition heparin should be administered on the basis of heparin levels measured by protamine titration. Heparin levels during bypass should not be allowed to drop below 2.7 U/mL (2.0 mg/kg) or below the level indicated by heparin dose-response testing performed prior to administration of aprotinin.

"Protamine Administration - In patients treated with Trasylol, the amount of protamine administered to reverse heparin activity should be based on the actual amount of heparin administered, and not on the ACT values."

ADVERSE REACTIONS:

The three paragraphs beginning with "In the pooled analysis...", "In the study of patients..." and "Less frequent adverse events of concern, ..." have been deleted.

Myocardial Infarction (new subsection): "In a pooled analysis of all patients undergoing CABG surgery, there was no significant difference in the incidence of investigator-reported myocardial infarction (MI) in Trasylol treated patients as compared to placebo treated patients. However, because no uniform criteria for the diagnosis of myocardial infarction were utilized by investigators, this issue was addressed prospectively in three later studies (two studies evaluated Regimen A, Regimen B, and pump prime regimen; one study evaluated only Regimen A) in which data were analyzed by a blinded consultant employing an algorithm for possible, probable or definite MI. Utilizing this method, the incidence of definite myocardial infarction was 5.9% in the aprotinin treated patients versus 4.7% in the placebo treated patients. This difference in the incidence rates was not statistically significant. Data from these three studies are summarized below." [See Table "Incidence of Myocardial Infarction by Treatment Group Population: All CABG Patients Valid for Safety Analysis" in labeling/package insert.]

Graft Patency (new subsection): "In a recently completed multi-center, multi-national study to determine the effects of Trasylol Regimen A vs. placebo on saphenous vein graft patency in patients undergoing primary CABG surgery, patients were subjected to routine postoperative angiography. Of the 13 study sites, 10 were in the United States and three were non-U.S. centers (Denmark (1), Israel (2)). The results of this study are summarized below." [See Table "Incidence of Graft Closure, Myocardial Infarction and Death by Treatment Group" in labeling/package insert.]

"Although there was a statistically significantly increased risk of graft closure for Trasylol treated patients compared to patients who received placebo (p=0.035), further analysis showed a significant treatment by site interaction for one of the non-U.S. sites vs. the U.S. centers. When the analysis of graft closures was repeated for U.S. centers only, there was no statistically significant difference in graft closure rates in patients who received Trasylol vs. placebo. These results are the same whether analyzed as the proportion of patients who experienced at least one graft closure postoperatively or as the proportion of grafts closed. There were no differences between treatment groups in the incidence of myocardial infarction as evaluated by the blinded consultant (2.9% Trasylol vs. 3.8% placebo) or of death (1.4% Trasylol vs. 1.6% placebo) in this study."

Hypersensitivity and Anaphylaxis: Text added - "Hypersensitivity and anaphylactic reactions during surgery were rarely reported in U.S. controlled clinical studies in patients with no prior exposure to Trasylol (1/1424 patients or < 0.1% on Trasylol vs. 1/861 patients or 0.1% on placebo). In case of re-exposure the incidence of hypersensitivity/anaphylactic reactions has been reported to reach the 5% level."

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CLINICAL PHARMACOLOGY:

Text deleted and replaced with -

"Vira-A is rapidly deaminated to arabinosylhypoxanthine (Ara-Hx), the principal metabolite. Ara-Hx also possesses in vitro antiviral activity but this activity is less than that of Vira-A. Because of the low solubility of Vira-A, trace amounts of both Vira-A and Ara-Hx can be detected in the aqueous humor only if there is an epithelial defect in the cornea. If the cornea is normal, only trace amounts of Ara-Hx can be recovered from the aqueous humor.

"Systemic absorption of Vira-A should not be expected to occur following ocular administration and swallowing lacrimal secretions. In laboratory animals, Vira-A is rapidly deaminated in the gastrointestinal tract to Ara-Hx.

"In contrast to topical idoxuridine, Vira-A demonstrated less cellular toxicity in the regenerating corneal epithelium of the rabbit.

"In controlled and uncontrolled clinical trials, an average of seven and nine days of continuous Vira-A Ophthalmic Ointment, 3%, therapy was required to achieve corneal re-epithelialization. In the controlled trials, 70 of 81 subjects (86%) re-epithelialized at the end of three weeks of therapy. In the uncontrolled trials, 101 of 142 subjects (71%) re-epithelialized at the end of three weeks. Seventy-five percent of the subjects in these uncontrolled trials had either not healed previously or had developed hypersensitivity to topical idoxuridine therapy. [Note: This paragraph was moved from the previous INDICATIONS AND USAGE section.]

"Microbiology: Vidarabine is a purine nucleoside obtained from fermentation cultures of Streptomyces antibioticus. The antiviral mechanism of action has not been established. Vidarabine appears to interfere with the early steps of viral DNA synthesis.

"Vidarabine has been shown to possess antiviral activity against the following viruses in vitro:
Herpes simplex types 1 and 2
Vaccinia
Varicella-Zoster

"Except for Rhabdovirus and Oncornavirus, vidarabine does not display in vitro antiviral activity against other RNA or DNA viruses, including Adenovirus.

"Susceptibility Tests - No universal, standardized, quantitative in vitro procedures have as yet been developed to estimate the susceptibility of viruses to antiviral agents."

PRECAUTIONS:

Pediatric Use (new subsection): "The safety and effectiveness in pediatric patients below the age of 2 years have not been established."

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ADVERSE REACTIONS:

Effects Associated with Intravenous Administration: Infrequent Effects (1-3% of patients): Second paragraph, sentence added to end - "Enlargement of the salivary glands and an increased amylase secretion, with a complete recovery within several days of discontinuation of ritodrine treatment, have been reported."

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INDICATIONS AND USAGE:

Third footnote added to the National Cholesterol Education Program (NCEP) Treatment Guidelines summarized in section - "In CHD patients with LDL-C levels 100-129 mg/dL, the physician should exercise clinical judgement in deciding whether to initiate drug treatment."

New fifth paragraph - "At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL-C is > or = 130 mg/dL (see NCEP Guidelines, above)."

CONTRAINDICATIONS:

Pregnancy and lactation: Subsection revised (new text in italics) - "Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase such as Zocor to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, Zocor ["may cause fetal harm when administered to a pregnant woman. Therefore, simvastatin" deleted] is contraindicated during pregnancy and in nursing mothers. Zocor ["simvastatin" deleted] should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, Zocor ["simvastatin" deleted] should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy)."

PRECAUTIONS:

General: First paragraph deleted - "Before instituting therapy with Zocor, an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in obese patients, and to treat other underlying medical problems (see INDICATIONS AND USAGE)."

Information for Patients: Subsection revised (new text in italics) - "Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. (see WARNINGS, Skeletal Muscle)."

PREGNANCY:

Pregnancy Category X: Subsection revised (new text in italics)-

"Safety in pregnant women has not been established.

"Simvastatin was not teratogenic in rats at doses of 25 mg/kg/day or in rabbits at doses up to 10 mg/kg daily. These doses resulted in 6 times (rat) or 4 times (rabbit) the human exposure based on mg/m² surface area. However, in studies with another structurally- related HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice.

"Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. ["There has been one report of severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took another HMG-CoA reductase inhibitor with dextroamphetamine sulfate during the first trimester of pregnancy." deleted] In a review ⁺of approximately 100 prospectively followed pregnancies in women exposed to Zocor or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a three-to-four-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with Zocor during pregnancy (see CONTRAINDICATIONS), treatment should be immediately discontinued as soon as pregnancy is recognized. Zocor should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. ["If the woman becomes pregnant while taking simvastatin, it should be discontinued and the patient advised again as to the potential hazards to the fetus." deleted]

"+ Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P. Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy. Reproductive Toxicology. 10(6):439-446, 1996."

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