ACCOLATE (zafirlukast)	ARICEPT (donepezil HCl)	AVAPRO HCT (irbesartan/ hydrochlorothiazide)	BLEPHAMIDE (sulfacetamide Na/ prednisolone acetate)
CLOZARIL (clozapine)	COZAAR (losartan potassium)	DDAVP (desmopressin acetate)	DEPO-PROVERA (medroxyprogesterone acetate)
FORTOVASE (saquinavir)	GEMZAR (gemcitabine HCl)	HEPARIN Na	HIVID (zalcitabine)
HYZAAR (losartan potassium/ hydrochlorothiazide)	LAMICTAL (lamotrigine)	LIPITOR (atorvastatin calcium)	MARPLAN (isocarboxazid)
MEVACOR (lovastatin)	MODURETIC (amiloride HCl/ hydrochlorothiazide)	OVCON (norethindrone/ ethinyl estradiol)	PEPCID (famotidine)
PRAVACHOL (pravastatin Na)	PROPULSID (cisapride)	PROVERA (medroxyprogesterone acetate)	TRANDATE (labetalol HCl)
TRASYLOL (aprotinin)	TRUSOPT (dorzolamide HCl)	ULTANE (sevoflurane)	ULTRAM (tramadol HCl)
VENTOLIN (albuterol)	VIAGRA (sildenafil citrate)

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PRECAUTIONS:

Eosinophilic Conditions: Existing text-

"The reduction of the oral steroid dose, in some patients on Accolate Therapy, has been followed in rare cases by the occurrence of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy sometimes presenting as Churg Strauss Syndrome, a systemic eosinophilic vasculitis. Although a causal relationship with Accolate has not been established, caution is required when oral steroid reduction is being considered (See ADVERSE REACTIONS)."

deleted and replaced with -

"In rare cases, patients on Accolate therapy may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic steroid therapy. These events usually, but not always, have been associated with the reduction of oral steroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between Accolate and these underlying conditions has not been established. (See ADVERSE REACTIONS)."

ADVERSE REACTIONS:

Sixth paragraph -

"The reduction of the oral steroid dose, in some patients on Accolate Therapy, has been followed in rare cases by the occurrence of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy sometimes presenting as Churg Strauss Syndrome, a systemic eosinophilic vascultitis. A causal relationship with Accolate has not been established.(See PRECAUTIONS - Eosinophilic Conditions)."

deleted and replaced with -

"In rare cases, patients on Accolate therapy may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic steroid therapy. These events usually, but not always, have been associated with the reduction of oral steroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between Accolate and these underlying conditions has not been established (See PRECAUTIONS- Eosinophilic Conditions)."

ADVERSE REACTIONS:

Postintroduction Reports (new subsection):

"Voluntary reports of adverse events temporally associated with Aricept that have been received since market introduction that are not listed above, and that there is inadequate data to determine the causal relationship with the drug include the following: abdominal pain, agitation, cholecystitis, confusion, convulsions, hallucinations, hemolytic anemia, pancreatitis, and rash."

DESCRIPTION:

Sixth paragraph, first sentence revised (new text in italics) -

"Avapro HCT is available for oral administration in tablets containing 150 mg or 300 mg of irbesartan ["and" deleted] combined with 12.5 mg of hydrochlorothiazide"

CLINICAL PHARMACOLOGY:

Clinical Studies: Irbesartan-Hydrochlorothiazide: Second paragraph, third sentence revised (new text in italics) -

"Once-daily dosing with 150 mg irbesartan and 12.5 mg of hydrochlorothiazide, 300 mg irbesartan and 12.5 mg of hydrochlorothiazide, or irbesartan 300 mg and hydrochlorothiazide 25 mg produced mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of about ["13/7 and 13/11 mmHg" deleted] 13-15/7-9, 14/9-12, and 19-21/11-12 mmHg, respectively."

DOSAGE AND ADMINISTRATION:

Dose Titration by Clinical Effect: First paragraph -

"A patient whose blood pressure is inadequately controlled with irbesartan monotherapy (see above) or hydrochlorothiazide may be switched to Avapro HCT (irbesartan 150 mg/ hydrochlorothiazide 12.5 mg) once daily. The combination of irbesartan 150 mg/hydrochlorothiazide 12.5 mg may produce antihypertensive effects somewhat greater than those of either irbesartan 300 mg alone or hydrochlorothiazide 25 mg alone. If blood pressure remains uncontrolled after about 2-4 weeks of therapy, the dose may be increased to two tablets once daily."

deleted and replaced with -

"A patient whose blood pressure is inadequately controlled by irbesartan or hydrochlorothiazide alone may be switched to once daily Avapro HCT. Recommended doses of Avapro HCT, in order of increasing mean effect are (irbesartan/hydrochlorothiazide) 150/12.5 mg, 300/12.5 mg, and 300/25 mg (two 150/12.5 mg tablets). The largest incremental effect will likely be in the transition from monotherapy to 150/12.5 mg (See CLINICAL PHARMACOLOGY; Clinical Studies). It takes 2 - 4 weeks for the blood pressure to stabilize after a change in the dose of Avapro HCT."

CLINICAL PHARMACOLOGY:

Existing second paragraph moved to new "Microbiology" subsection as the third paragraph and revised -

Microbiology (new subsection):

"Sulfacetamide sodium exerts a bacteriostatic effect against susceptible bacteria by restricting the synthesis of folic acid required for growth through competition with p-aminobenzoic acid.

"Some strains of bacteria may be resistant to sulfacetamide or resistant strains may emerge in vivo.

[Note: The following paragraph was moved from the "CLINICAL PHARMACOLOGY" and revised (new text in italics)] -

"The anti-infective component in ["Blephamide" deleted] these products is included to provide action against specific organisms susceptible to it. Sulfacetamide sodium is ["considered" deleted] active in vitro against susceptible strains of the following microorganisms: Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus (viridans group), ["Pseudomonas species" deleted] Haemophilus influenzae, Klebsiella species, and Enterobactor species. This product does not provide adequate coverage against: Neisseria species, Pseudomonas species, Serratia marcescens. (see INDICATIONS AND USAGE).

INDICATIONS AND USAGE:

Section revised (new text in italics) -

"A steroid/anti-infective combination is indicated for steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where superficial bacterial infection or a risk of bacterial ocular infection exists.

"Ocular corticosteroids are indicated in inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe where the inherent risk of corticosteroid use in certain infective conjunctivitides is accepted to obtain diminution in edema and inflammation. They are also indicated in chronic anterior uveitis and corneal injury from chemical, radiation or thermal burns or penetration of foreign bodies.

"The use of a combination drug with an anti-infective component is indicated where the risk of superficial ocular infection is high or where there is an expectation that potentially dangerous numbers of bacteria will be present in the eye.

"The particular anti-["infective" deleted] bacterial drug in this product is active against the following common bacterial eye pathogens: Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus (viridans group), ["Pseudomonas species" deleted] Haemophilus influenzae, Klebsiella species, and Enterobactor species. This product does not provide adequate coverage against: Neisseria species, Pseudomonas species, ["and" deleted] Serratia marcescens.

"A significant percentage of staphylococcal isolates are completely resistant to sulfa drugs."

PRECAUTIONS:

Information For Patients: Section revised (new in italics) -

"If inflammation or pain persists longer than 48 hours or becomes aggravated, the patient should be advised to discontinue use of the medication and consult a physician (see WARNINGS).

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

"This product is sterile when packaged. To prevent contamination, care should be taken to avoid touching the applicator tip to eyelids or to any other surface. The use of this bottle by more than one person may spread infection. Keep bottle tightly closed when not in use. Protect from light. Sulfonamide solutions darken on prolonged standing and exposure to heat and light. Do not use if solution has darkened. Yellowing does not affect activity. Keep out of the reach of children."

DOSAGE AND ADMINISTRATION:

Existing text deleted and replaced with -

"SHAKE WELL BEFORE USING. Two drops should be instilled into the conjunctival sac every four hours during the day and at bedtime.

"Not more than 20 milliliters should be prescribed initially, and the prescription should not be refilled without further evaluation as outlined in PRECAUTIONS above.

"Blephamide dosage may be reduced, but care should be taken not to discontinue therapy prematurely. In chronic conditions, withdrawal of treatment should be carried out by gradually decreasing the frequency of application.

"If signs and symptoms fail to improve after two days, patients should be re-evaluated (see PRECAUTIONS)."

HOW SUPPLIED:

Storage (new subsection): -

"Store Blephamide at 8^o-24^oC (46^o-75^oF) in an upright position.

"PROTECT FROM LIGHT.

"Sulfonamide solutions darken on prolonged standing and exposure to heat and light. Do not use if solution has darkened. Yellowing does not affect activity.

"KEEP OUT OF REACH OF CHILDREN."

CONTRAINDICATIONS:

First paragraph, first sentence revised (new text in italics) -

"Clozaril (clozapine) is contraindicated in patients with a previous hypersensitivity to clozapine or any other component of this drug, in patients with myeloproliferative disorders, uncontrolled epilepsy, or a history of Clozaril (clozapine) induced agranulocytosis or severe granulocytopenia."

WARNINGS:

Boxed Warning: Agranulocytosis: Sixth and seventh sentences revised (new text in italics) -

"In the US, under a weekly WBC monitoring system with Clozaril (clozapine), there have been ["317" deleted] 585 cases of agranulocytosis as of ["January 1, 1994" deleted] August 21, 1997; ["11" deleted] 19 were fatal. during this period ["68,000" deleted] 150,409 patients received Clozaril (clozapine)."

PRECAUTIONS:

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

"["Elevated serum levels of clozapine have been observed when Clozaril (clozapine) is administered with selective serotonin reuptake inhibitor (SSRI's), e.g. fluoxetine and fluvoxamine." deleted] In a study of schizophrenic patients who received clozapine under steady state conditions, fluvoxamine or paroxetine was added in 16 and 14 patients, respectively. After 14 days of co-administration , mean trough concentrations of clozapine and its metabolites, N-desmethylclozapine and clozapine N-oxide, were elevated with fluvoxamine by about three-fold compared to baseline concentrations. Paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline. Therefore, such combined treatment should be approached with caution and patients should be monitored closely when Clozaril (clozapine) is combined with ["an SSRI" deleted] these drugs, particularly with fluvoxamine. A reduced Clozaril (clozapine) dose should be considered."

CLINICAL PHARMACOLOGY:

Pharmacodynamics and Clinical Effects: Sixth paragraph, last sentence -

"Black patients, however, had notably smaller responses to losartan monotherapy."

deleted and replaced with -

"Cozaar was effective in reducing blood pressure regardless of race, although the effect was somewhat less in black patients (usually a low-renin population.)"

The information concerning cough relocated to the "ADVERSE REACTIONS" section.

INDICATIONS AND USAGE:

Second paragraph deleted -

"In considering the use of monotherapy with Cozaar, it should be noted that in controlled trials Cozaar had an effect on blood pressure that was notably less in black patients than in non-blacks, a finding similar to the small effect of angiotensin converting enzyme inhibitors in blacks."

PRECAUTIONS:

General: Impaired Hepatic Function (new subsection heading): -

Existing first paragraph moved into this subsection.

General: Drug Interactions: Text added to end of subsection -

"As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium."

ADVERSE REACTIONS:

Information on cough that was formerly under "CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects" relocated to just above the "Post-Marketing Experience" subsection, with the addition of the following paragraph -

"Cases of cough, including positive re-challenges, have been reported with the use of losartan in post-marketing experience."

Post-Marketing Experience: Respiratory: "Dry cough (see above)" added.

Laboratory Test Findings: Creatinine, Blood Urea Nitrogen:

Next to last sentence deleted -

"No patient discontinued taking Cozaar alone due to increased BUN or serum creatinine."

[Note: The following changes appear in the 1998 PDR.]

PRECAUTIONS:

Carcinogenicity, Mutagenicity, Impairment of Fertility: Subsection deleted and replaced with -

"Studies with DDAVP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility."

Pregnancy Category B: First paragraph revised (new text in italics) -

"["Reproduction studies performed in rats and rabbits by the subcutaneous route at doses up to 10 ug/kg/day have revealed no evidence of harm to the fetus due to desmopressin acetate. This dose is equivalent to 10 times (for Factor VIII stimulation) or 38 times (for diabetes insipidus) the systemic human dose based on mg/M² surface area. There are no adequate and well-controlled studies in pregnant women." deleted]

"Fertility studies have not been done. Teratology studies in rats and rabbits at doses from 0.05 to 10 ug/kg/day (approximately 0.1 times the maximum systemic human exposure in rats and up to 38 times the maximum systemic human exposure in rabbits based on surface area, mg/m²) revealed no harm to the fetus due to DDAVP. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed."

Second paragraph, third sentence revised (new text in italics) -

"A fifteen year, Swedish epidemiologic study of the use of desmopressin acetate in pregnant women with diabetes insipidus found the rate of birth defects to be no greater than that in the general population; however the statistical power of this study is low.

PRECAUTIONS:

1. Physical Examination: Existing text -

"The pretreatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear."

deleted and replaced with -

"It is good medical practice for all women to have annual history and physical examinations, including women using Depo-Provera Contraceptive Injection. The physical examination, however, may be deferred until after initiation of Depo-Provera if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology and laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care."

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BOXED WARNING:

Second paragraph, first sentence -

"Rare occurrences of potentially fatal lactic acidosis in the absence of hypoxia and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues, including zidovudine and Hivid."

deleted and replaced with -

"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 zalcitabine (see WARNINGS)"

WARNINGS:

3. Lactic Acidosis/Severe Hepatomegaly With Steatosis and Hepatic Toxicity (subsection formerly named "Hepatic Toxicity"): Subsection revised (new text in italics) -

"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 zalcitabine. A majority of these cases have been in women. Caution should be exercised when administering Hivid to any patient, and particularly to those with known risk factors for liver disease. ["Rare occurrences of potentially fatal lactic acidosis in the absence of hypoxemia and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues, including zidovudine and Hivid." deleted]

"In addition, rare cases of hepatic failure and death considered possibly related to underlying hepatitis B and Hivid have been reported. Treatment with Hivid in patients with preexisting liver disease, liver enzyme abnormalities, a history of ethanol abuse or hepatitis should be approached with caution. Treatment with Hivid should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity. ["Hivid should be interrupted or discontinued in the setting of deterioration of liver function tests, hepatic steatosis, progressive hepatomegaly or unexplained lactic acidosis." deleted] In clinical trials, drug interruption was recommended if liver function tests exceeded > 5 times the upper limit of normal."

CLINICAL PHARMACOLOGY:

Pharmacokinetics: Drug Interactions: Losartan Potassium: Text added as new second to last sentence in subsection -

"Conversion of losartan to its active metabolite after intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4."

PRECAUTIONS:

Information for Patients: Potassium Supplements: Text added to end of subsection -

"(see PRECAUTIONS, Drug Interactions, Losartan Potassium)"

Drug Interactions: Lorsartan Potassium: New text added before the existing last sentence -

"In humans, ketoconazole, an inhibitor of P450 3A4, did not affect the conversion of losartan to the active metabolite after intravenous administration of losartan. Inhibitors of cytochrome P450 2C9 have not been studied clinically."

Existing last sentence revised (new text in italics) -

"The pharmacodynamic consequences of concomitant use of losartan and ["these" deleted] inhibitors of P450 2C9 have not been examined."

Text added as new last paragraph -

"As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium (see PRECAUTIONS, Information for Patients, Potassium Supplements)."

DOSAGE AND ADMINISTRATION:

Second paragraph revised (new text in italics) -

"Hydrochlorothiazide is effective in doses of 12.5 to ["100 mg" deleted] 50 mg once daily and can be given at doses of 12.5 to 25 mg as Hyzaar."

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PRECAUTIONS:

Drug Interactions: Other Concomitant Therapy: Subsection deleted.

ADVERSE REACTIONS:

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

"Adverse events associated with Lipitor that have been received since market introduction, that are not listed above, and that may have no causal relationship to drug include the following: anaphylaxis, angioneurotic edema and rhabomyolysis."

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PRECAUTIONS:

Drug Interactions: Other Concomitant Therapy: Entire subsection deleted.

DOSAGE AND ADMINISTRATION:

Section revised (new text in italics) -

"Moduretic should be administered with food.

"The usual starting dosage is 1 tablet per day. The dosage may be increased to 2 tablets a day, if necessary. More than 2 tablets of MODURETIC daily usually are not needed and there is no controlled experience with such doses. Hydrochlorothiazide can be given at doses of 12.5 to 50 mg per day when used alone. Patients usually do not require doses of hydrochlorthiazide in excess of 50 mg daily when combined with other antihypertensive agents.

"The daily dose is usually given as a single dose but may be given in divided doses. Once an initial diuresis has been achieved, dosage adjustment may be necessary. Maintenance therapy may be on an intermittent basis."

PRECAUTIONS:

Pediatric Use (new subsection):

"Safety and efficacy of Ovcon 35 and Ovcon 50 have been established in women of reproductive age. Safety and efficacy are expected to be the same in postpubertal adolescents under the age of 16 years and in users ages 16 years and older. Use of this product before menarche is not indicated."

CLINICAL PHARMACOLOGY IN ADULT PATIENTS:

New name for section formerly titled "CLINICAL PHARMACOLOGY"

CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS (new section):

Pharmacokinetics:

"Table 6 presents pharmacokinetic data from published studies of small numbers of pediatric patients given famotidine intravenously. Areas under the curve (AUCs) are normalized to a dose of 0.5 mg/kg I.V. for pediatric patients and compared with an extrapolated 40 mg intravenous dose in adults (extrapolation based on results obtained with a 20 mg I.V. adult dose).

TABLE 6
"Pharmacokinetic Parameters^a of Intravenous Famotidine

Age (N= number of patients)	Area under the curve (AUC) (ng-hr/mL)	Total Clearance (Cl) (L/hr/kg)	Volume of Distribution (Vd) (L/kg)		Elimination Half-life (T1/2 ) (hours)
1-11 yrs (N=20)	1089 " 834	0.54 " 0.34	2.07 " 1.49		3.38 " 2.60
11-15 yrs (N=6)	1140 " 320	0.48 " 0.14	1.5 " 0.4		2.3 " 0.4
Adult (N=16)	1726b	0.39 " 0.14	1.3 " 0.2	2.83 " 0.99

^aValues are presented as means"SD unless indicated otherwise.
^bMean value only.

"Values of pharmacokinetic parameters for pediatric patients, ages 1-15 years are comparable to those obtained for adults.

"Bioavailability studies of 8 pediatric patients (11-15 years of age) showed a mean oral bioavailability of 0.5 compared to adult values of 0.42 to 0.49. Oral doses of 0.5 mg/kg achieved an AUC of 580 " 60 ng-hr/mL in pediatric patients 11-15 years of age compared to 482 " 181 ng-hr/mL in adults treated with 40 mg orally."

Pharmacodynamics:

"Pharmacodynamics of famotidine were evaluated in 5 pediatric patients 2-13 years of age using the sigmoid E_max model. These data suggest that the relationship between serum concentration of famotidine and gastric acid suppression is similar to that observed in one study of adults (Table 7).

TABLE 7
"Pharmacodynamics of famotidine using the sigmoid E_max model

	EC50(ng/ml)*
Pediatric Patients	26 " 13
Data from one study
a) healthy adult subjects	26.5 " 10.3
b) adult patients with upper GI bleeding	18.7 " 10.8

^*Serum concentration of famotidine associated with 50% maximum gastric acid reduction. Values are presented as means " SD.

"Four published studies (Table 8) examined the effect of famotidine on gastric pH and duration of acid suppression in pediatric patients. While each study had a different design, acid suppression data over time are summarized as follows:

TABLE 8

Dosage	Route	Effecta	Number of Patients
0.3 mg/kg single dose	I.V.	gastric pH >3.5 for 8.7" 4.7b hours	6
0.4-0.8 mg/kg	I.V.	gastric pH >4 for 6-9 hours	18
0.5 mg/kg, single dose	I.V.	a > 2 pH unit increase above baseline gastric pH for > 8 hours	9
0.5 mg/kg b.i.d	I.V.	gastric pH >5 for 13.5" 1.8b hours	4
0.5 mg/kg b.i.d	oral	gastric pH >5 for 5.0" 1.1b hours	4

^avalues reported in published literature
^bMeans"SD"

PRECAUTIONS:

Pediatric Patients: (New name for section formerly titled "Pediatric Use")

Existing text -

"Safety and effectiveness in children have not been established."

deleted and replaced with -

"Use of Pepcid in pediatric patients 1-16 years of age is supported by evidence from adequate and well-controlled studies of Pepcid in adults, and by the following studies in pediatric patients: In published studies in small numbers of pediatric patients 1-15 years of age, clearance of famotidine was similar to that seen in adults. In pediatric patients 11-15 years of age, oral doses of 0.5 mg/kg were associated with a mean area under the curve (AUC) similar to that seen in adults treated orally with 40 mg. Similarly, in pediatric patients 1-15 years of age, intravenous doses of 0.5 mg/kg were associated with a mean AUC similar to that seen in adults treated intravenously with 40 mg. Limited published studies also suggest that the relationship between serum concentration and acid suppression is similar in pediatric patients 1-15 years of age as compared with adults. These studies suggest a starting dose for pediatric patients 1-16 years of age as follows:

"Peptic Ulcer - 0.5 mg/kg/day p.o. at bedtime or divided b.i.d up to 40 mg/day.

"Gastroesophageal Reflux Disease with or without esophagitis including erosions and ulcerations - 1.0 mg/kg/day p.o. divided b.i.d up to 40 mg b.i.d.

"While published uncontrolled studies suggest effectiveness of famotidine in the treatment gastroesophegeal reflux disease and peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or pH determination (gastric or esophageal) and endoscopy. Published uncontrolled clinical studies in pediatric patients have employed doses up to 1 mg/kg/day for peptic ulcer and 2 mg/kg/day for GERD with or without esophagitis including erosions and ulcerations.

"No pharmacokinetic or pharmacodynamic data are available on pediatric patients under 1 year of age."

DOSAGE AND ADMINISTRATION:

Dosage for Pediatric Patients (new subsection):

"See PRECAUTIONS, Pediatric Patients.

"The studies described in PRECAUTIONS, Pediatric Patients suggest the following starting doses in pediatric patients 1-16 years of age:

"Peptic ulcer - 0.5 mg/kg/day p.o. at bedtime or divided b.i.d up to 40 mg/day.

"Gastroesophageal Reflux Disease with or without esophagitis including erosions and ulcerations - 1.0 mg/kg/day p.o. divided b.i.d up to 40 mg b.i.d.

"While published uncontrolled studies suggest effectiveness of famotidine in the treatment of gastroesophageal reflux disease and peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or pH determination (gastric or esophageal) and endoscopy. [Note: The following sentence appears only in the oral dosage form labeling.] Published uncontrolled clinical trials in pediatric patients have employed doses up to 1 mg/kg/day for peptic ulcer and 2 mg/kg/day for GERD with or without esophagitis including erosions and ulcerations. [Note: The following sentence appears only in the parenteral dosage form labeling.] Published uncontrolled clinical trials in pediatric patients have demostrate gastric acid suppression with doses up to 0.5 mg/kg intravenously every 12 hours.

"No pharmacokinetic or pharmacodynamic data are available on pediatric patients under 1 year of age."

Dosage Adjustment for Patients with Severe Renal Insufficiency: Text added as last paragraph in subsection -

[Note: The following paragraph appears only in the parenteral dosage form labeling.]

"Based on the comparison of pharmacokinetic parameters for Pepcid in adults and pediatric patients, dosage adjustment in pediatric patients with severe renal insufficiency should be considered."

INDICATIONS AND USAGE:

Hypercholesterolemia: Footnote added to second table in subsection, which summarizes The National Chloesterol Education Program's Treatment Guidelines: -

"*** 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 paragraph added after second table -

"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 discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they ["may cause fetal harm when administered to pregnant women. Therefore, HMG-CoA reductase inhibitors" deleted] are contraindicated during pregnancy and in nursing mothers. Pravastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this class of drug, therapy should be discontinued immediately and the patient apprised of the potential hazard to the fetus (see PRECAUTIONS: Pregnancy)."

PRECAUTIONS:

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. Pravastatin was not teratogenic in rats at doses up to 1000 mg/kg daily or in rabbits at doses of up to 50 mg/kg daily. These doses resulted in 20x (rabbit) or 240x (rat) the human exposure based on surface area (mg/meter²). ["However, in studies with another HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice. 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] Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In a review ⁷of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, 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 somepoint 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 Pravachol during pregnancy (see CONTRAINDICATIONS), treatment should be immediately discontinued as soon as pregnancy is recognized. Pravachol (pravastatin sodium) should be administered to women of childbearing 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 Pravachol (pravastatin sodium), it should be discontinued and the patient advised again as to the potential hazards to the fetus" deleted]"

REFERENCES: .

New reference added -

"7. 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."

[Other labeling changes not appearing in the 1998 PDR: Jul98]

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CONTRAINDICATIONS:

Text added as new last paragraph -

"Beta-blockers, even those with apparent cardioselectivity, should not be used in patients with a history of obstructive airway disease, including asthma."

WARNINGS:

(Note: The following changes to the WARNINGS section apply to the injection labeling only)

Major Surgery: Text added as new second paragraph - "Several deaths have occurred when Trandate (labetalol HCl) Injection was used during surgery (including when used in cases to control bleeding)."

Rapid Decrease of Blood Pressure: Subsection revised -

"Caution must be observed when reducing severely elevated blood pressure. ["Although such findings have not been reported with IV labetalol HCl." deleted] A number of adverse reactions, including cerebral infarction, optic nerve infarction, angina, and ischemic changes in the electrocardiogram, have been reported with other agents when severely elevated blood pressure was reduced over time courses of several hours to as long as 1 or 2 days. The desired blood pressure lowering should therefore be achieved over as long a period of time as is compatible with the patient's status."

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CLINICAL PHARMACOLOGY:

Clinical Studies: Paragraph added at end of subsection -

"In a one year clinical study, the effect of Trusopt 2% t.i.d. on the corneal endothelium was compared to that of betaxolol ophthalmic solution b.i.d. and timolol maleate ophthalmic solution 0.5% b.i.d. There were no statistically significant differences between groups in corneal endothelial cell counts or in corneal thickness measurements. There was a mean loss of approximately 4% in the endothelial cell counts for each group over the one year period."

PRECAUTIONS:

General: First paragraph deleted -

"Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. The effect of continued administration of Trusopt on the corneal endothelium has not been fully evaluated."

Last paragraph deleted -

"The preservative in Trusopt Ophthalmic Solution, benzalkonium chloride, may be absorbed by soft contact lenses. Trusoft should not be administered while wearing soft contact lenses."

Information for Patients: Text added as last paragraph in subsection -

"Patients should be advised that Trusopt contains benzalkonium chloride which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following TRUSOPT administration."

Pregnancy: Fourth sentence in the paragraph deleted -

"There were no treatment-related fetal malformations in developmental toxicity studies with dorzolamide hydrochloride in rats at oral doses up to 10 mg/kg/day (125 times the recommended human ophthalmic dose)."

Geriatric Use: Entire subsection deleted.

ADVERSE REACTIONS:

Controlled clinical trials (new subsection): Existing first paragraph moved into new subsection, with "In clinical studies" deleted from first sentence.

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

"Events occurring in approximately 1-5% of patients were conjunctivitis and lid reactions (see PRECAUTIONS, General), blurred vision, eye redness, tearing, dryness, and photophobia."

Remaining existing text deleted.

Clinical practice (new subsection):

"The following adverse events have occurred at low incidence (<1%) during clinical trials or have been reported during the use of Trusopt in clinical practice where these events were reported voluntarily from a population of unknown size and frequency of occurrence cannot be determined precisely. They have been chosen for inclusion based on factors such as seriousness, frequency of reporting, possible causal connection to Trusopt, or a combination of these factors: signs and symptoms of systemic allergic reactions including angioedema, bronchospasm, pruritis, and urticaria; dizziness; ocular pain; transient myopia; dyspnea; and contact dermatitis."

OVERDOSAGE:

Section revised -

"["Although no human data are available," deleted] Electrolyte imbalance, development of an acidotic state, and possible central nervous system effects may occur. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored.

"["Significant lethality was observed in female rats and mice after single oral doses of dorzolamide hydrochloride 1927 mg/kg and 1320 mg/kg, respectively." deleted]"

WARNINGS:

Section revised (new text in italics) -

"["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." - deleted]

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

"Although data from controlled clinical studies at low flow rates are limited, findings taken from patient and animal studies suggest that there is a potential for renal injury which is presumed due to compound A. Animal and human studies demonstrate that sevoflurane administered for more than 2 MAC- hours and at fresh gas flow rates of < 2 L/minute may be associated with proteinuria and glycosuria."

"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 concentration and fresh gas flow rates to minimize exposure to compound A. To minimize exposure to compound A, sevoflurane exposure should not exceed 2 MAC-hours at flow rates of 1 to < 2 L/min. Fresh gas flow rates < 1L/min are not recommended.

" Because clinical experience in administering sevoflurane to patients with renal insufficiency (creatinine > 1.5 mg/dL) is limited, its safety in these patients has not been established.

"Sevoflurane may be associated with glycosuria and proteinuria when used for 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 = 2 hours at a fresh gas flow rate of < or = 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 = 800 ml/minute. One patient in the active control group developed an elevated serum creatinine, but did not experience proteinuria or glycosuria." deleted] Per study criteria (Hou et al.), one patient in the sevoflurane group developed transient elevations of creatinine, in addition to glycosuria and proteinuria. This patient received sevoflurane at fresh gas flow rates of < 800 ml/minute. Using these same criteria, there were no patients in the active control group who developed treatment emergent elevations in serum creatinine.

["Uncontrolled clinical studies in volunteers evaluated low-flow... particularly at > 2 MAC-hours of exposure." deleted]"

ADVERSE EVENTS:

"Suicidal tendency" moved from "Other adverse experiences, causal relationship unknown, Body as a Whole" subsection to the "Incidence less than 1%, possibly causally related, Body as a Whole" subsection.

DOSAGE AND ADMINISTRATION:

Text added -

"In a clinical trial, fewer discontinuations due to adverse events, especially dizziness and vertigo, were observed when titrating the dose in increments of 50 mg/day every 3 days until an effective dose (not exceeding 400 mg/day) was reached."

DOSAGE AND ADMINISTRATION:

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

"It is recommended to 'test spray' Ventolin Inhalation Aerosol. Do this by spraying four times into the air before using for the first time and when ["in cases where" deleted] the inhaler ["aerosol" deleted] has not been used for a prolonged period of time (i.e., more than 4 weeks)."

The Patient Package Insert was also revised to reflect this change.

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