CALCIJEX (calcitriol) - CEFTIN (cefuroxime) - CLOZARIL (clozapine) - DIDRONEL (etidronate disodium) - DILACOR XR (diltiazem HCl) - DIOVAN (valsartan) - DOPAMINE - INOTROPIN (dopamine HCl) - LACRISERT (hydroxypropyl cellulose) - NEORAL (cyclosporine) - OVCON-50 (norethindrone/ethinyl estradiol) - PAREMYD (hydroxyamphetamine hydrobromide/tropicamide) - PREVACID (lansoprazole) - PRIMAXIN (imipenem/cilastatin) - SODIUM CHROMATE Cr 51 - VASERETIC (enalapril maleate/hydrochlorothiazide) - VASOTEC (enalapril maleate) - VENTOLIN (albuterol sulfate) - ZOLADEX (goserelin acetate)

PRECAUTIONS:

3. Essential Laboratory Tests: Second paragraph revised (new text in italics) -

"Adynamic bone disease may develop if PTH levels are suppressed to abnormal levels. If biopsy is not being done for other (diagnostic) reasons, PTH levels may be used to indicate the rate of bone turnover. If PTH levels fall below ["20 pmol/L or 200mg/mL" deleted] recommended target range (1.5 to 3 times the upper limit of normal), in patients treated with Calcijex, the Calcijex dose should be reduced or therapy discontinued. Discontinuation of Calcijex therapy may result in rebound effect, therefore, appropriate titration downward to a maintenance dose is recomended."

DOSAGE AND ADMINISTRATION:

Table revised as follows (new text in italics) -

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

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ADVERSE REACTIONS:

Postmarketing Experience With Ceftin Products: Hematologic (new subsection): "Hemolytic anemia, leukopenia, pancytopenia, and thrombocytopenia."

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PRECAUTIONS:

Pulmonary Embolism (new subsection): "The possibility of pulmonary embolism should be considered in patients receiving Clozaril (clozapine) who present with deep vein thrombosis, acute dyspnea, chest pain or with other respiratory signs and symptoms. As of December 31, 1993 there were 18 cases of fatal pulmonary embolism in association with Clozaril (clozapine) therapy in users 10-54 years of age. Based upon the extent of use observed in the Clozaril National Registry, the mortality rate associated with pulmonary embolus was 1 death per 3450 person-years of use. This rate was about 27.5 times higher than that in the general population of a similar age and gender (95% Confidence Interval; 17.1, 42.2). Deep vein thrombosis has also been observed in association with Clozaril (clozapine) therapy. Whether pulmonary embolus can be attributed to Clozaril (clozapine) or some characteristic(s) of its users is not clear, but the occurrence of deep vein thrombosis or respiratory symptomatology should suggest its presence."

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PRECAUTIONS:

Drug Interactions (new subsection): "There have been isolated reports of patients experiencing increases in their prothrombin times when etidronate was added to warfarin therapy. The majority of these reports concerned variable elevations in prothrombin times without clinically significant sequelae. Although the relevance of these reports and any mechanism of coagulation alterations is unclear, patients on warfarin should have their prothrombin time monitored." [Change appears in 1997 PDR.]

ADVERSE REACTIONS:

Worldwide Postmarketing Experience: Paragraph added to end of subsection - "In osteoporosis clinical trials, headache, gastritis, leg cramps, and arthralgia occurred at a significantly greater incidence in patients who received etidronate as compared with those who received placebo."

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PRECAUTIONS:

Pharmacokinetics and Metabolism: Deletion of fourth paragraph which read -

"Neither the absolute bioavailability of Dilacor XR capsules nor its relative bioavailability compared to immediate release products has been definitively determined. No information is currently available as to the relative bioavailability of Dilacor XR capsules compared to other approved controlled-release diltiazem products."

Addition of new fourth paragraph - "The absolute bioavailability of diltiazem from a single dose of Dilacor XR (compared to intravenous administration) is 41% (+ or - 14). This value was shown to be similar to the 40% systemic availability reported following administration of an immediate release diltiazem HCl formulation."

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CLINICAL PHARMACOLOGY:

Special Populations: Renal Insufficiency: At the end of third sentence deletion of "or patients undergoing dialysis, and it is not known whether valsartan is removed by hemodialysis."

Addition of sentence - "Valsartan is not removed from the plasma by hemodialysis."

OVERDOSAGE:

Deletion of sentence - "It is not known whether valsartan or its active metabolite can be removed by hemodialysis."

Addition of sentence - "Valsartan is not removed from the plasma by hemodialysis."

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PRECAUTIONS:

Carcinogenesis, Mutagenesis, Impairment of Fertility: Deletion of previous text and replacing with -

"Long term animal studies have not been performed to evaluate the carcinogenic potential of dopamine HCl.

"Dopamine HCl at doses approaching maximal solubility showed no clear genotoxic potential in the Ames test. Although there was a reproducible dose-dependent increase in the number of revertant colonies with strains TA100 and TA98, both with and without metabolic activation, the small increase was considered inconclusive evidence of mutagenicity. In the L5178Y TK+/- mouse lymphoma assay, dopamine HCl at the highest concentrations used of 750 ug/mL without metabolic activation, and 3000 ug/mL with activation, was toxic and associated with increases in mutant frequencies when compared to untreated and solvent controls; at the lower concentrations no increases over controls were noted.

"No clear evidence of clastogenic potential was reported in the in vivo mouse or male rat bone marrow micronucleus test when the animals were treated intravenously with up to 224 mg/kg and 30 mg/kg of dopamine HCl, respectively."

Pregnancy: Pregnancy Category C: Deletion of previous text and replacing with -

"Teratogenic Effects: Teratogenicity studies in rats and rabbits at dopamine HCl dosages up to 6 mg/kg/day intravenously during organogenesis produced no detectable teratogenic or embryotoxic effects, although maternal toxicity consisting of mortalities, decreased body weight gain, and pharmacotoxic signs were observed in rats. In a published study, dopamine HCl administered at 10 mg/kg subcutaneously for 30 days, markedly prolonged metestrus and increased mean pituitary and ovary weights in female rats. Similar administration to pregnant rats throughout gestation or for 5 days starting on gestation day 10 or 15 resulted in decreased body weight gains, increased mortalities and slight increases in cataract formation among the offspring. There are no adequate and well-controlled studies in pregnant women, and it is not known if dopamine HCl crosses the placental barrier. Dopamine HCl should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."

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PRECAUTIONS:

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

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PHYSICIAN'S INSERT

INDICATIONS AND USAGE:

First paragraph revised to read (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 Ovcon-50, 28-day, which contain 50 mcg of estrogen, should not be used unless medically indicated."

WARNINGS:

1. Thromboembolic Disorders and Other Vascular Problems: d. Dose-related risk of vascular disease from oral contraceptives: Sentence added at end of subsection -

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

PATIENT PACKAGE INSERT

INTRODUCTION:

New first paragraph added - "You should not use Ovcon 50 (norethindrone and ethinyl estradiol tablets, USP) , 28-Day, which contains higher doses of estrogen than other oral contraceptives, unless specifically recommended by your health care provider."

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ADVERSE REACTIONS:

Second paragraph added to section - "Rare but serious cardiovascular events, including death due to myocardial infarction, ventricular fibrillation and significant hypotensive episodes have occurred shortly following Paremyd instillation."

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PRECAUTIONS:

Pediatric Use: Section revised (new text in italics) - "Safety and effectiveness in ("children" deleted) pediatric patients have not been established."

ADVERSE REACTIONS:

Header "Incidence in Clinical Trials" deleted.

Deletion of fifth paragraph - "In short-term and long-term studies, the following adverse events were reported in < 1% of the lansoprazole-treated patients."

New fifth paragraph added - "Additional adverse experience occurring in < 1% of patients or subjects in domestic and/or international trials, or occurring since the drug was marketed, are shown below within each body system.

Hematologic and Lymphatic System*: Subsection revised (new text in italics) - "agranulocyctosis, anemia, aplastic anemia, hemolysis, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thromobocytopenia, and thrombotic thrombocytopenic purpura;"

"* The majority of hematologic cases received were foreign-sourced and their relationship to lansoprazole was unclear."

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ADVERSE REACTIONS:

Systemic Adverse Reactions: Gastrointestinal: and/or tongue added after "staining of the teeth"

Body as a Whole: drug fever added.

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PRECAUTIONS:

New paragraph added - "Nuclear medicine procedures involving withdrawal and reinjection of blood have the potential for transmission of blood borne pathogens. Procedures should be implemented to avoid administration errors and viral contamination of personnel during blood product labeling. A system of checks similar to the ones used for administering blood transfusions should be routine."

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ADVERSE REACTIONS:

Enalapril Maleate: Cardiovascular: "Raynaud's phenomenon" added.

Nervous System/Psychiatric: "dream abnormality" added.

Miscellaneous: The first sentence has been revised (new text in italics) -

"A symptom complex has been reported which may include some or all of the following: a positive ANA, ..."

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ADVERSE REACTIONS:

[Enalapril Maleate subsection - for I.V.] Cardiovascular: "Raynaud's phenomenon" added.

Nervous/Psychiatric: "dream abnormality" added.

Miscellaneous: The first sentence has been revised (new text in italics) -

"A symptom complex has been reported which may include some or all of the following: a positive ANA, ..."

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CLINICAL PHARMACOLOGY:

New paragraph added to the end of section - "Published reports of trials in asthmatic children aged 3 years or older have demonstrated significant improvements in either FEV₁ or PEFR within 2 to 20 minutes following single doses of albuterol inhalation solution. An increase of 15% or more in baseline FEV₁ has been observed in children aged 5 to 11 years up to 6 hours after treatment with doses of 0.10 mg/kg or higher of albuterol inhalation solution. Single doses of 3, 4, or 10 mg resulted in improvement in baseline PEFR that was comparable in extent and duration to a 2-mg dose, but doses above 3 mg were associated with heart rate increases of more than 10%."

INDICATIONS AND USAGE:

Section revised (new text in italics): "Ventolin (Ventolin Nebules) Inhalation Solution is indicated for the relief of bronchospasm in patients 2 years of age and older with reversible obstructive airway disease and acute attacks of bronchospasm."

PRECAUTIONS:

General: New paragraph added to the end of the subsection - "Repeated dosing with 0.15 mg/kg of albuterol inhalation solution in children aged 5 to 17 years who were initially normokalemic has been associated with an asymptomatic decline of 20% to 25% in serum potassium levels."

Pediatric Use: Deletion of previous text - "Safety and effectiveness in children below 12 years of age have not been established."

Addition of new text - "The safety and effectiveness of Ventolin (Ventolin Nebules) Inhalation Solution have been established in children 2 years of age or older. Use of Ventolin (Ventolin Nebules) Inhalation Solution in these age groups is supported by evidence from adequate and well-controlled studies of Ventolin Inhalation solution in adults; the likelihood that the disease course, pathophysiology, and the drug's effect in pediatric and adult patients are substantially similar; and published reports of trials in pediatric patients 3 years of age or older. The recommended dose for the pediatric population is based upon three published dose comparison studies of efficacy and safety in children aged 5 to 17 years, and on the safety profile in both adults and pediatric patients at doses equal to or higher than the recommended doses. The safety and effectiveness of Ventolin (Ventolin Nebules) Inhalation Solution in children 2 years of age have not been established."

ADVERSE REACTIONS:

Last sentence in section revised to read (new text in italics) - "Rare cases of supraventricular tachycardia, urticaria, angioedema, rash, bronchospasm, and oropharyngeal edema have been reported after the use of inhaled albuterol"

OVERDOSAGE:

New second sentence (Ventolin Nebules)/third sentence (Ventolin) added - "In isolated cases in children 2 to 12 years of age, tachycardia with rates >200 beats/min has been observed."

DOSAGE AND ADMINISTRATION:

For Ventolin Nebules Inhalation Solution-

Adults and Children 2 to 12 Years of Age (new subheading): First sentence of section (new text in italics) -

"The usual dosage for adults and for children ["12 years and older" deleted] weighing at least 15 kg is 2.5 mg of albuterol (one Nebule) administered three to four times daily by nebulization."

New second sentence added - "Children weighing < 15 kg who required < 2.5 mg/dose (i.e., less than a full Nebule) should use Ventolin (albuterol sulfate, USP) Inhalation Solution, 0.5% instead of Ventolin Nebules Inhalation Solution."

For Ventolin Inhalation Solution

Children 2 to 12 Years of Age (new subsection): "For children 2 to 12 years of age, initial dosing should be based upon body weight (0.1 to 0.15 mg/kg/dose), with subsequent dosing titrated to achieve the desired clinical response. Dosing should not exceed 2.5 mg three to four times daily by nebulization. The following table outlines approximate dosing according to body weight.

Approximate Weight (kg)	Approximate Weight (lb)	Dose (mg)	Volume of Inhalation Solution
10-15	22-33	1.25	0.25 mL
> 15	> 33	2.5	0.5 mL

"The appropriate volume of the 0.5% inhalation solution should be diluted in sterile normal saline solution to a total volume of 3 mL prior to administration via nebulization."

Adults and Children 12 Years and Older (new subsection): Text from previous section moved here.

PATIENT'S INSTRUCTIONS FOR USE:

For Ventolin Inhalation Solution

Instruction #1 revised (new text in italics) - "Draw ("0.5 mL" deleted) the appropriate volume of Ventolin Inhalation Solution into the specially marked dropper that comes with each multidose bottle (Figure 1). For children under 12 years of age, the volume is based upon body weight. Use the dropper volume prescribed by your doctor."

Instruction #3 revised (new text in italics) - "Add ("2.5 mL of" deleted) sterile normal saline solution, as your doctor has directed. A general guideline for the amount of saline to add is : For children using 0.25 mL or 1.25 mg of Ventolin Inhalation Solution, add 2.75 mL of sterile normal saline. For children or adults using 0.5 mL or 2.5 mg of Ventolin Inhalation Solution, add 2.5 mL of sterile normal saline."

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