SUMMARY OF SAFETY-RELATED DRUG LABELING CHANGES APPROVED BY FDA
February 1998

(Posted: 3/31/98)

Note: The following summaries include only those safety-related sections that have been modified, and therefore do not contain all the information needed for safe and effective prescribing. Contact the manufacturer for the complete labeling/package insert.

NB: Comparison made to 1998 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.

Quick Reference:

(Click on name of the product to go directly to the summary.)

ACCUPRIL (quinapril HCl)	ADRIAMYCIN RDF & PFS (doxorubicin HCl)	AMOXIL (amoxicillin)	ARIMIDEX (anastrozole)	AUGMENTIN (amoxicillin/ clavulanate potassium)
BUMEX (bumetanide)	CECLOR (cefaclor)	CELLCEPT (mycophenolate mofetil)	COZAAR (losartan potassium)	CRIXIVAN (indinavir sulfate)
DEMADEX (torsemide)	DROXIA (hydroxyurea)	EMLA (lidocaine/ prilocaine)	FURADANTIN (nitrofurantoin)	GLUCOPHAGE (metformin HCl)
GLUCOTROL XL (glipizide)	HISMANAL (astemizole)	HUMALOG (insulin lispro [rDNA origin])	HUMULIN (human insulin [rDNA origin])	IMITREX (sumatriptan succinate)
IONAMIN (phentermine resin)	LIPITOR (atorvastatin Ca)	MACROBID (nitrofurantoin monohydrate macrocrystals)	MACRODANTIN (nitrofurantoin macrocrystals)	MAXAIR (pirbuterol acetate)
MIRAPEX (pramipexole dihydrochloride)	NOROXIN (norfloxacin)	NORPACE & NORPACE CR (disopyramide phosphate)	NORVIR (ritonavir)	PRECOSE (acarbose)
RENOVA (tretinoin)	RESCRIPTOR (delavirdine mesylate)	RETROVIR (zidovudine)	RITALIN & RITALIN SR (methylphenidate HCl)	SALAGEN (pilocarpine HCl)
SEREVENT (salmeterol xinafoate)	SUPRAX (cefixime)	TENUATE and TENUATE DOSPAN (diethylpropion HCl)	VERMOX (mebendazole)	VOLTAREN (diclofenac Na)
ZERIT (stavudine)

ADVERSE REACTIONS:

Hypertension and/or Heart Failure: Respiratory (new subsection): "eosinophilic pneumonitis".

CLINICAL PHARMACOLOGY:

Third paragraph, last sentence -

"The literature contains no information regarding gender related differences in the pharmacokinetics of doxorubicin and doxorubicinol."

deleted and replaced with -

"A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in the men compared to the women (113 versus 44 L/hr). However, the terminal half-life of doxorubicin was longer in men compared to the women (54 versus 35 hrs)."

PRECAUTIONS:

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

"Paclitaxel: Two published studies report that initial administration of paclitaxel infused over 24 hours followed by doxorubicin administered over 48 hours resulted in a significant decrease in doxorubicin clearance with more profound neutropenic and stomatitis episodes than the reverse sequence of administration.

"Progesterone: In a published study, progesterone was given intravenously to patients with advanced malignancies (ECOG PS < 2) at high doses (up to 10 g over 24 hours) concomitantly with a fixed doxorubicin dose (60 mg/m²) via bolus. Enhanced doxorubicin-induced neutropenia and thrombocytopenia were observed.

"Verapamil: A study of the effects of verapamil on the acute toxicity of doxorubicin in mice revealed higher initial peak concentrations of doxorubicin in the heart with a higher incidence and severity of degenerative changes in cardiac tissue resulting in a shorter survival.

"Cyclosporine: The addition of cyclosporine to doxorubicin may result in increases in AUC for both doxorubicin and doxorubicinol possibly due to a decrease in clearance of parent drug and a decrease in metabolism of doxorubicinol. Literature reports suggest that adding cyclosporine to doxorubicin results in more profound and prolonged hematologic toxicity than doxorubicin alone. Coma and/or seizures have also been described.

"Literature ["contain the following drug interactions with doxorubicin in humans: cyclosporine (Sandimmune) may induce coma and/or seizures," deleted] reports have also described the following drug interactions: phenobarbital increases the elimination of doxorubicin, phenytoin levels may be decreased by doxorubicin, streptozocin (Zanosar) may inhibit ["the" deleted] hepatic metabolism of doxorubicin, and administration of live vaccines to immunosuppressed patients, including those undergoing cytotoxic chemotherapy, may be hazardous. ["Information on other potential drug interactions may be found in the literature." deleted]"

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CLINICAL PHARMACOLOGY:

Clinical Studies: Second paragraph, sixth sentence revised (new text in italics) -

"In Trial 0004, ["60%" deleted] 62% of patients had measurable disease compared to ["80%" deleted] 79% in Trial 0005."

Numbers in the Trial 0004 and Trial 0005 tables updated, "Median Time to Death (months)" and "2 Year Survival Probability (%)" added, and "Time to Progression (days)" revised to "Median Time to Progression (months)".

	ARIMIDEX 1 mg	ARIMIDEX 10 mg	Megestrol Acetate 160 mg
Trial 0004 (N. America)	(n=128)	(n=130)	(n=128)
Median Follow-up (months)	31.3	30.9	32.9
Median Time to Death (months)	29.6	25.7	26.7
2 Year Survival Probability (%)	62.0	58.0	53.1
Median Time to Progression (months)	5.7	5.3	5.1
Objective Response (all patients) (%)	12.5	10.0	10.2
Stable Disease for >24 weeks (%)	35.2	29.2	32.8
Progression (%)	86.7	85.4	90.6

 

 

	ARIMIDEX 1 mg	ARIMIDEX 10 mg	Megestrol Acetate 160 mg
Trial 0005 (Europe, Australia, S. Africa)	(n=135)	(n=118)	(n=125)
Median Follow-up (months)	31.0	30.9	31.5
Median Time to Death (months)	24.3	24.8	19.8
2 Year Survival Probability (%)	50.5	50.9	39.1
Median Time to Progression (months)	4.4	5.3	3.9
Objective Response (all patients) (%)	12.6	15.3	14.4
Stable Disease for >24 weeks (%)	24.4	25.4	23.2
Progression (%)	91.9	89.8	92.0

* Surviving Patients

Fourth paragraph, first and second sentences revised (new text in italics) -

"["Approximately" deleted] More than 1/3 of the patients in each treatment group in both studies had either an objective response or stabilization of their disease for greater than 24 weeks. Among the 263 patients who received Arimidex 1 mg, there were ["6" deleted] 11 complete responders and ["21" deleted] 22 partial responders.

Fourth paragraph, last sentence -

"In patients who had an objective response, over 60% of the patients responded for greater than 6 months, and over 15% responded for greater than 12 months."

deleted and replaced with -

"In patients who had an objective response, more than 80% were still responding at 6 months from randomization and more than 45% were still responding at 12 months from randomization."

Fifth paragraph beginning "To compare the three treatments, ..." deleted and replaced with -

"When data from the two controlled trials are pooled, the objective response rates and median times to progression and death were similar for patients randomized to Arimidex 1 mg and megestrol acetate. There is, in this data, no indication that Arimidex 10 mg is superior to Arimidex 1 mg.

	ARIMIDEX 1 mg	ARIMIDEX 10 mg	Megestrol Acetate 160 mg
Trials 0004 & 0005 (Pooled Data)	(n=263)	(n=248)	(n=253)
Median Time to Death (months)	26.7	25.5	22.5
2 Year Survival Probability (%)	56.1	54.6	46.3
Median Time to Progression (months)	4.8	5.3	4.6
Objective Response (all patients) (%)	12.5	12.5	12.3

Last paragraph revised (new text in italics)-

"["There were no differences in response seen between women over or under 65." deleted] Objective response rates and median times to progression and death for Arimidex 1 mg were similar to megestrol acetate for women over or under 65. There were too few non-white patients studied to draw conclusions about racial differences in response ["rates" deleted]."

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

ADVERSE REACTIONS:

Gastrointestinal: "pseudomembranous colitis" changed to "hemorrhagic/pseudomembranous colitis"

Liver: Second sentence revised (new text in italics) -

"Hepatic dysfunction, including increases in serum transaminases (AST and/or ALT), serum bilirubin and/or alkaline phosphatase has been infrequently reported with Augmentin and, when reported, has been reported more commonly in elderly and/or males, and /or in patients on prolonged treatment."

Hemic and Lymphatic Systems: Text added as new last sentence in subsection -

"There have been rare reports of increased prothrombin time in patients receiving Augmentin and anticoagulant therapy concomitantly."

Central Nervous System: "convulsions" added.

CLINICAL PHARMACOLOGY:

Pediatric Pharmacology (new subsection): "Elimination of Bumex appears to be considerably slower in neonatal patients compared with adults, possibly because of immature renal and hepatobiliary function in this population. Small pharmacokinetic studies of intravenous Bumex in preterm and fullterm neonates with respiratory disorders have reported an apparent half-life of approximately 6 hours, with a range up to 15 hours and a serum clearance ranging from 0.2 to 1.1 mL/min/kg. In a population of neonates receiving Bumex for volume overload, mean serum clearance rates were 2.17 mL/min/kg in patients less than 2 months of age and 3.8 mL/min/kg in patients aged 2 to 6 months. Mean serum half-life of bumetanide was 2.5 hours and 1.5 hours in patients aged less than 2 months and those aged 2 to 6 months, respectively. Mean volume of distribution in neonates has been reported to range from 0.26 L/kg to 0.38 L/kg.

"In preterm and neonates, mean serum concentrations following a single 0.05 mg/kg dose ranged from 126 mcg/L at 1 hour to 57 mcg/L at 8 hours. In another study, mean serum concentrations following a single 0.05 mg/kg dose were 338 ng/mL at 30 minutes and 176 ng/mL after 4 hours. A single dose of 0.1 mg/kg produced mean serum levels of 314 ng/mL at 1 hour, and 195 ng/mL at 6 hours.

"The degree of protein binding of bumetanide in cord sera from healthy neonates was approximately 97%, suggesting the potential for bilirubin displacement. A study using pooled sera from critically ill neonates found that bumetanide at concentrations of 0.5 to 50 ug/mL, but not 0.25 ug/mL, caused a linear increase in unbound bilirubin concentrations.

"In 36 infants aged 4 to 6 months, Bumex doses ranging from 0.005 mg/kg to 0.1 mg/kg were studied for pharmacodynamic effect. Urine flow rates increased an average of six-fold, peaking at one hour in most patients, and returning to or falling below baseline by 6 hours. Maximal increases in electrolyte excretion were seen within 2 hours, which correlated with an increased rate of bumetanide excretion during this time period. Pharmacologic response was best correlated with bumetanide excretion rate, and was not necessarily dose-related in these patients."

PRECAUTIONS:

Pediatric Use: Subsection revised (new text in italics) -

Safety and effectiveness in ["children" deleted] pediatric patients below the age of 18 have not been established.

In vitro studies using pooled sera from critically ill neonates have shown Bumex to be a potent displacer of bilirubin ( see CLINICAL PHARMACOLOGY: Pediatric Pharmacology). The administration of Bumex could present a particular concern if given to critically ill or jaundiced neonates at risk for kernicterus."

WARNINGS:

First paragraph deleted and replaced with the following two paragraphs -

"Before therapy with Ceclor is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cefaclor, cephalosporins, penicillins, or other drugs. If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross-hypersensitivity among B-lactam antibiotics has been clearly documented and may occur in up to 10% of patinets with a history of penicillin allergy.

"If an allergic reaction to Ceclor occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated."

Previous third paragraph, now the fourth paragraph, revised (new text italics) -

"Pseudomembranous colitis has been reported with ["virtually" deleted] nearly all ["broad-spectrum antibiotics (including macrolides, semi-synthetic penicillins, and cephalosporins);" deleted] antibacterial agents, including cefaclor, and has ranged in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who ["develop" deleted] present with diarrhea ["in association with the use of antibiotics" deleted] subsequent to the administration of antibacterial agents. ["Such colitis may range in severity from mild to life threatening." deleted].

Last paragraph -

"Mild cases of pseudomembranus colitis usually respond to drug discontinuation alone. In moderate to severe cases, management should include sigmoidoscopy, appropriate bacteriologic studies, and fluid, electrolyte, and protein supplementation. When the colitis does not improve after the drug has been discontinued, or when it is severe, oral vancomycin is the drug of choice for antibiotic-associated pseudomembraneous colitis produced by C. difficile. Other causes of colitis should be ruled out."

deleted and replaced with -

"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 effective against C. difficile."

PRECAUTIONS:

General: First paragraph deleted -

"If an allergic reaction to Ceclor occurs, the drug should be discontinued, and, if necessary, the patient should be treated with appropriate agents, eg, pressor amines, antihistamines, or corticosteroids."

Sixth paragraph deleted -

"As a result of administration of Ceclor, a false-positive reaction for glucose in the urine may occur. This has been observed with Benedict's and Fehling's solutions and also with Clinitest tablets." [Note: This paragraph was revised and moved to the new Drug/Laboratory Tests subsection - see below.]

Last paragraph revised (new text in italics) -

"["Broad-spectrum" deleted] Antibiotics, including cephalosporins, should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis."

Drug/Laboratory Test Interactions (new subsection): "Patients receiving Ceclor may show a false-positive reaction for glucose in the urine with tests that use Benedict's and Fehling's solutions and also with Clinitest tablets.

"There have been reports of increased anticoagulant effect when Ceclor and oral anticoagulants were administered concomitantly."

Carcinogenesis, Mutagenesis, Impairment of Fertility (new subsection): "Studies have not been performed to determine potential for carcinogenicity, mutagenicity, or impairment of fertility."

Pregnancy: Teratogenic Effects: Pregnancy Category B: Subsection name changed from "Pregnancy: Pregnancy Category B:"

Labor and Delivery (new subsection): "The effect of Ceclor on labor and delivery is unknown."

ADVERSE REACTIONS:

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

"["Symptoms" deleted] Onset of pseudomembranous colitis symptoms may ["appear either" deleted] occur during or after antibiotic treatment (see WARNINGS)."

Cephalosporin-class Adverse Reactions (new subsection): "In addition to the adverse reactions listed above that have been observed in patients treated with cefaclor, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics: fever, abdominal pain, superinfection, renal dysfunction, toxic nephropathy, hemorrhage, false positive test for urinary glucose, elevated bilirubin, elevated LDH, and pancytopenia.

"Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated (see DOSAGE AND ADMINISTRATION and OVERDOSAGE sections)."

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CLINICAL PHARMACOLOGY:

Pharmacokinetics: Drug Interactions: New sentence added before the last sentence -

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

PRECAUTIONS:

Drug Interactions: New text added before the 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."

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."

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The following specific changes are included in the new labeling.

CLINICAL PHARMACOLOGY:

Drug Interactions: Drugs Requiring Dose Modification: Rifabutin: Existing text -

Administration of indinavir (800 mg every 8 hours) with rifabutin (300 mg once daily) for 10 days resulted in a 32% +/- 19% decrease in indinavir AUC and a 204% +/- 142% increase in rifabutin AUC (see DOSAGE AND ADMINISTRATION, Concomitant Therapy, Rifabutin)."

deleted and replaced with

"The coadministration of indinavir 800 mg every 8 hours with rifabutin either 300 mg once daily or 150 mg once daily was evaluated in two separate clinical studies. The results of these studies showed a decrease in indinavir AUC (32% +/- 19% and 31% +/- 15%, respectively) vs. indinavir 800 mg every 8 hours alone and an increase in rifabutin AUC (204% +/- 142% and 60% +/- 47%, respectively) vs. rifabutin once daily alone. (See DOSAGE AND ADMINISTRATION, Concomitant Therapy, Rifabutin)."

PRECAUTIONS:

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

"["Due to an increase in the plasma concentrations of rifabutin, a dosage reduction of rifabutin is necessary when it is coadministered with Crixivan." deleted] When rifabutin and Crixivan are coadministered, there is an increase in the plasma concentrations of rifabutin and a decrease in the plasma concentrations of indinavir. A dosage reduction of rifabutin and a dosage increase of Crixivan are necessary when rifabutin is coadministered with Crixivan. The suggested dose adjustments are expected to result in rifabutin concentrations at least 50% higher than typically observed when rifabutin is administered alone at its usual dose (300 mg/day) and indinavir concentrations which may be slightly less than typically observed when indinavir is administered alone at its usual dose (800 mg every 8 hours). (See DOSAGE AND ADMINISTRATION, Concomitant Therapy, Rifabutin; CLINICAL PHARMACOLOGY, Drug Interactions, Drugs Requiring Dose Modification, Rifabutin.)"

Carcinogenesis, Mutagenesis, Impairment of Fertility: First sentence -

"Long-term carcinogenicity studies of indinavir in rats and mice are in progress."

deleted and replaced with -

"Carcinogenicity studies were conducted in mice and rats. In mice, no increased incidence of any tumor type was observed. The highest dose tested in rats was 640 mg/kg/day; at this dose a statistically increased incidence of thyroid adenomas was seen only in male rats. At that dose, daily systemic exposure in rats was approximately 1.3 times higher than daily systemic exposure in humans."

Pregnancy: Pregnancy Category C: Existing text deleted and replaced with -

"Developmental toxicity studies were performed in rabbits (at doses up to 240 mg/kg/day), dogs (at doses up to 80 mg/kg/day), and rats (at doses up to 640 mg/kg/day). The highest doses in these studies produced systemic exposures in these species comparable to or slightly greater than human exposure. No treatment-related external, visceral, or skeletal changes were observed in rabbits or dogs. No treatment-related external or visceral changes were observed in rats. Treatment-related increases over controls in the incidence of supernumerary ribs (at exposures at or below those in humans) and of cervical ribs (at exposures comparable to or slightly greater than those in humans) were seen in rats. In all three species, no treatment-related effects on embryonic/fetal survival or fetal weights were observed.

"In rabbits, at a maternal dose of 240 mg/kg/day, no drug was detected in fetal plasma 1 hour after dosing. Fetal plasma drug levels 2 hours after dosing were approximately 3% of maternal plasma drug levels. In dogs, at a maternal dose of 80 mg/kg/day, fetal plasma drug levels were approximately 50% of maternal plasma drug levels both 1 and 2 hours after dosing. In rats, at maternal doses of 40 and 640 mg/kg/day, fetal drug levels were approximately 10 to 15% and 10 to 20% of maternal plasma drug levels 1 and 2 hours after dosing, respectively.

"Indinavir was administered to Rhesus monkeys during the third trimester of pregnancy (at dose up to 160 mg/kg b.i.d.) and to neonatal Rhesus monkeys (at dose up to 160 mg/kg b.i.d.). When administered to neonates, Indinavir caused an exacerbation of the transient physiologic hyperbilirubinemia seen in this species after birth; serum bilirubin values were approximately fourfold above controls at 160 mg/kg b.i.d. [6]. A similar exacerbation did not occur in neonates after in utero exposure to indinavir during the third trimester of pregnancy. In Rhesus monkeys, fetal plasma drug levels were approximately 1 to 2 % of maternal plasma drug levels approximately 1 hour after maternal dosing at 40, 80, or 160 mg/kg b.i.d.

"Hyperbilirubinemia has occurred during treatment with Crixivan (see PRECAUTIONS and ADVERSE REACTIONS). It is unknown whether Crixivan administered to the mother in the perinatal period will exacerbate physiologic hyperbilirubinemia in neonates.

"There are no adequate and well-controlled studies in pregnant women. Crixivan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus." [Note: This paragraph appears in previous labeling.]

Nonteratogenic Effects: Subsection deleted and text moved up to become the next to last paragraph in the PRECAUTIONS, Pregnancy, Pregnancy Category C subsection.

DOSAGE AND ADMINISTRATION:

Concomitant Therapy: Rifabutin: Subsection revised (new text in italics) -

"Dose reduction of rifabutin to half the standard dose ["is recommended" deleted] (consult the manufacturer's product circular for rifabutin) and a dose increase of Crixivan to 1000 mg every 8 hours are recommended when rifabutin and Crixivan are coadministered (See PRECAUTIONS, Drug Interactions)."

DOSAGE AND ADMINISTRATION:

New text added as the third paragraph in the section -

"If Demadex (torsemide) is administered as a continuous infusion, stability has been demonstrated through 24 hours at room temperature in plastic containers for the following fluids and concentrations:

"200 mg Demadex (torsemide) (10 mg/mL) added to:

250 mL Dextrose 5% in water
250 mL 0.9% Sodium Chloride
500 mL 0.45% Sodium Chloride

"50 mg Demadex (torsemide) (10mg/mL) added to:

500 mL Dextrose 5% in water
250 mL 0.9% Sodium Chloride
500 mL 0.45% Sodium Chloride"

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In addition, the following safety related changes were made -

WARNINGS:

Methemoglobinemia: Fourth paragraph beginning "A methemoglobinemia value of 28%..." deleted and replaced with the following two paragraphs -

"There have been reports of significant methemoglobinemia (20-30%) in infants and children following excessive applications of EMLA Cream. These cases involved the use of large doses, larger than recommended areas of application, or infants under the age of 3 months who did not have fully mature enzyme systems. Most patients recovered spontaneously after removal of the cream. Treatment with IV methylene blue may be effective if required.

"Physicians are cautioned to make sure that parents or other caregivers understand the need for careful application of EMLA, to ensure that the doses and areas of application recommended in Table 2 are not exceeded (especially in children under the age of 3 months), and to limit the period of application to the minimum required to achieve the desired anesthesia."

PRECAUTIONS:

Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: First paragraph, third sentence revised (new text in italics) -

"The typical application of EMLA Cream for one or two treatments for venipuncture sites (2.5 or 5 g) would be 1/24 or 1/12 of that dose in an adult or about the same mg/kg dose in an infant. "

First paragraph, new last sentence added -

"The typical application of EMLA Anesthetic Disc for one or two treatments for venipuncture sites (1 or 2 g) would be 1/60 or 1/30 of that dose in an adult or about half the same mg/kg dose in an infant. "

Pediatric Use: Third paragraph revised (new text in italics) -

"When using EMLA Cream in young children, especially infants under the age of 3 months, care must be taken to insure that ["application of the cream is limited to the intended site" deleted] the caregiver understands the need to limit the dose and area of application, and to prevent accidental ingestion (see DOSAGE AND ADMINISTRATION and Methemoglobinemia). ["Accidental ingestion may lead to dose related toxicity" deleted]

New fourth paragraph added -

"Due to the risk of methemoglobinuria and the lack of proven efficacy EMLA Cream is not recommended for use prior to circumcision in pediatric patients."

Last paragraph revised (new text in italics) -

"In children above the age of one month of age weighing less than 20 kg, the area and duration of application should be limited. (see TABLE 2 in Individualization of Dose)."

ADVERSE REACTIONS:

Allergic: Text added as last sentence in the subsection -

"Hypersensitivity reactions represent the most frequent spontaneously-reported adverse events in worldwide postmarketing experience with nitrofurantoin formulations."

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

CONTRAINDICATIONS:

#3 revised (new text in italics) -

"3. Glucophage should be temporarily ["withheld" deleted] discontinued in patients undergoing radiologic studies involving ["parenteral" deleted] intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. (See also PRECAUTIONS)."

PRECAUTIONS:

General: Subsection beginning "Radiologic studies..." revised (new text in italics) -

"Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials) - ["Parenteral contrast studies with iodinated materials can lead to acute renal failure" deleted] Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving Glucophage ( see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, Glucophage should be ["withheld for at least 48 hours prior to, and 48 hours subsequent to, the procedure" deleted] discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal."

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INDICATION:

Section revised (new text in italics) -

"Ionamin is indicated as a short-term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity for patients with an initial body mass index > or = 30 kg/m², or > or = 27 kg/m² in the presence of other risk factors (e.g., hypertension, diabetes, hyperlipidemia).

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

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

"

BODY MASS INDEX (BMI), kg/m2 Height (feet, inches)
Weight (pounds)	5'0"	5'3"	5'6"	5'9"	6'0"	6'3"
140	27	25	23	21	19	18
150	29	27	24	22	20	19
160	31	28	26	24	22	20
170	33	30	28	25	23	21
180	35	32	29	27	25	23
190	37	34	31	28	26	24
200	39	36	32	30	27	25
210	41	37	34	31	29	26
220	43	39	36	33	30	28
230	45	41	37	34	31	29
240	47	43	39	36	33	30
250	49	44	40	37	34	31

"The limited usefulness of agents of this class (see ACTIONS) should be measured against possible risk factors inherent in their use such as those described below."

WARNINGS

Addition of three paragraphs to beginning of section -

"Ionamin capsules are indicated only as short-term monotherapy for the management of exogenous obesity. The safety and efficacy of combination therapy with phentermine and any other drug products for weight loss, including selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, fluvoxamine, paroxetine), have not been established. Therefore, coadministration of these drug products for weight loss is not recommended.

"Primary Pulmonary Hypertension (PPH) - a rare, frequently fatal disease of the lungs - has been reported to occur in patients receiving a combination of phentermine with fenfluramine or dexfenfluramine. The possibility of an association between PPH and the use of phentermine alone cannot be ruled out. The initial symptom of PPH is usually dyspnea. Other initial symptoms include: angina pectoris, syncope, or lower extremity edema. Patients should be advised to report immediately any deterioration in exercise tolerance. Treatment should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope, or lower extremity edema.

"Valvular Heart Disease: Serious regurgitant cardiac valvular disease, primarily affecting the mitral, aortic and/or tricuspid valves, has been reported in otherwise healthy persons who had taken a combination of phentermine with fenfluramine or dexfenfluramine for weight loss. The etiology of these valvulopathies has not been established and their course in individuals after the drugs are stopped is not known. "

Pediatric Use: Subsection revised (new text in italics) -

"Ionamin Capsules (phentermine resin) are ["is" deleted] not recommended for use in pediatric patients under ["12" deleted] 16 years of age."

ADVERSE REACTIONS:

Cardiovascular: Subsection revised (new text in italics) -

"Primary pulmonary hypertension (see WARNINGS), palpitation, tachycardia, elevation of blood pressure."

DOSAGE AND ADMINISTRATION: First paragraph, last sentence revised (new text in italics) -

"Ionamin is not recommended for use in pediatric patients under ["12" deleted] 16 years of age."

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WARNINGS:

Liver Dysfunction: Third paragraph, first sentence revised (new text in italics) -

"It is recommended that liver function tests be performed ["before the initiation of treatment, at 6 and " deleted] prior to and at 12 weeks [" after" deleted] following both the initiation of therapy ["or" deleted] and any elevation in dose, and periodically (e.g., semiannually) thereafter."

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ADVERSE REACTIONS:

Early Parkinson's Disease: Adverse-event incidence in controlled clinical studies in early Parkinson's disease: Last paragraph in subsection - "tooth disease" added.

Advanced Parkinson's Disease: Adverse-event incidence in controlled clinical studies in advanced Parkinson's disease: Last paragraph in subsection - "leg cramps" added.

CLINICAL PHARMACOLOGY:

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

"The presence of food and/or dairy products may decrease absorption."

Microbiology: Entire subsection revised - contact the company for a copy of the new labeling/package insert.

PRECAUTIONS:

Information for patients: Second bullet revised (new text in italics) -

" - that norfloxacin should be taken at least one hour before or at least two hours after a meal or ingestion of milk ["ingestion" deleted] and/or other dairy products."

DOSAGE AND ADMINISTRATION:

First sentence revised (new text in italics) -

"Tablets Noroxin should be taken at least one hour before or at least two hours after a meal or ingestion of milk ["ingestion" deleted] and/or other dairy products."

REFERENCES (new section):

"1. National Committee for Clinical Laboratory Standards, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically - 3rd ed., Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, 1993.

"2. National Committee for Clinical Laboratory Standards, Performance standards for anticrobial disk susceptibility tests - 5th ed., Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, 1993."

PRECAUTIONS:

Drug Interactions: New second paragraph added -

"Patients taking disopyramide phosphate and erythromycin concomitantly may develop increased serum concentrations of disopyramide resulting in excessive widening of the QRS complex and/or prolongation of the Q-T interval (see WARNINGS.) Patients taking disopyramide phosphate and hepatic enzyme inhibitors concomitantly should be closely monitored."

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

PRECAUTIONS:

Drug Interactions: Effects on Co-administered Drugs: Saquinavir: Text added at end of subsection -

"Plasma exposures achieved with Invirase (saquinavir mesylate) (400 mg b.i.d.) and ritonavir (400 mg b.i.d.) are similar to those achieved with Fortovase (saquinavir) (400 mg b.i.d.) and ritonavir (400 mg b.i.d.)."

PRECAUTIONS:

Elevated Serum Transaminase Levels: Existing text deleted and replaced with -

"In long-term studies (up to 12 months, and including Precose doses up to 300 mg t.i.d.) conducted in the United States, treatment-emergent elevations of serum transaminases (AST and/or ALT) above the upper limit of normal (ULN), greater than 1.8 times the ULN, and greater than 3 times the ULN occurred in 14%, 6%, and 3% respectively, of Precose-treated patients as compared to 7%, 2%, and 1%, respectively, of placebo-treated patients. Although these differences between treatments were statistically significant, these elevations were asymptomatic, reversible, more common in females, and, in general, were not associated with other evidence of liver dysfunction. In addition, these serum transaminase elevations appeared to be dose related. In US studies including Precose doses up to the maximum approved dose of 100 mg t.i.d., treatment-emergent elevations of AST and/or ALT at any level of severity were similar between Precose-treated patients and placebo-treated patients (p>=0.496).

"In approximately 3 million patient-years of international post-marketing experience with Precose, 62 cases of serum transaminase elevations >500 IU/L (29 of which were associated with jaundice) have been reported. Forty-one of these 62 patients received treatment with 100 mg t.i.d. or greater and 33 of 45 patients for whom weight was reported weighed <60 kg. In the 59 cases where follow-up was recorded, hepatic abnormalities improved or resolved upon discontinuation of Precose in 55 and were unchanged in two. Two patients in Japan died of fulminant hepatitis; the relationship to acarbose is unclear."

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INDICATIONS AND USAGE:

Second bullet revised (new text in italics) -

"Renova should only be used under medical supervision ..."

"(See WARNINGS section.)" deleted at end of third bullet which begins "The effectiveness of Renova in the mitigation of fine wrinkles, ..."

WARNINGS:

Boxed Warning: Box is deleted but the two bullets it contained remain.

First bullet revised (new text in italics) -

"Renova is a dermal irritant, and the results of continued irritation of the skin for greater than 48 weeks in chronic, long term use are not known."

Fourth bullet deleted -

"Safety and effectiveness of Renova in individuals older than 50 years of age have not been established." [Note: This statement remains unchanged in the "PRECAUTIONS: Geriatric Use" sections.]

First non-bulleted paragraph, first three sentences deleted -

"This product should only be used under medical supervision as part of a comprehensive skin care and sun avoidance program. (See INDICATIONS AND USAGE section.) It should only be applied before retiring at night." [Note: The first sentence remains as part of a similar sentence in the "INDICATIONS AND USAGE" section.]

Last sentence revised (new text in italics) -

"Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using Renova and assure that the precautions outlined in the ["Information for Patients subsection" deleted] Patient Package Insert are observed."

PRECAUTIONS:

Information for Patients: Text of subsection deleted and replaced with -

"See Patient Package Insert."

ADVERSE REACTIONS:

First sentence revised -

"(See ["BOXED WARNING," deleted] WARNINGS, and PRECAUTIONS sections.)"

DOSAGE AND ADMINISTRATION:

First non-bulleted paragraph revised (new text in italics) -

"["Renova is not a cosmetic product. It should only be used with care under medical supervision as an adjunct to a comprehensive skin care and sun avoidance program that included the use of sunscreens (minimum SPF of 15) and protective clothing when desired results on fine wrinkles, mottled hyperpigmentation, and tactile roughness of facial skin have not been achieved with a comprehensive skin care and sun avoidance program alone." deleted] Patients require detailed instruction to obtain maximal benefits and to understand all the precautions necessary to use this product with greatest safety. The physician should review the Patient Package Insert. ["(See INDICATIONS AND USAGE section, Information For Patients subsection, and the PATIENT PACKAGE INSERT.)" deleted] [NOTE: The deleted sentence beginning "It should only be used..." remains in the "INDICATIONS AND USAGE" section.]

CLINICAL PHARMACOLOGY:

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

"In ["seven" deleted] 13 healthy volunteers, coadministration of saquinavir (600 mg tid) with delavirdine (400 mg tid) resulted in a five-fold increase in saquinavir AUC. In ["13" deleted] seven healthy volunteers, coadministration of saquinavir (600 mg tid) with delavirdine (400 mg tid) resulted in a 15 +/- 16% decrease in delavirdine AUC (see PRECAUTIONS-Drug Interactions)."

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ADVERSE REACTIONS:

New paragraph added -

"Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten year old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause."

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PRECAUTIONS:

Drug Interactions: Carbamazepine (new subsection with revisions in italics compared to text in 1998 PDR): "Elevated carbamazepine levels have been reported in postmarketing experience when Suprax is administered concomitantly. Drug monitoring may be of assistance in detecting alterations in carbamazepine plasma concentrations."

PRECAUTIONS:

Pregnancy: Teratogenic Effects: Pregnancy Category B: First sentence revised (new text in italics) -

"Reproduction studies have been performed in rats at doses up to ["8" deleted] 1.6 times the human dose (based on mg/m²) and have revealed no evidence of impaired fertility or harm to the fetus due to diethylpropion hydrochloride."

Pediatric Use: Subsection revised (new text in italics) -

"Since safety and effectiveness in ["children" deleted] pediatric patients below the age of 12 have not been established, Tenuate or Tenuate Dospan is not recommended for use in ["children" deleted] pediatric patientsunder 12 years of age."

PRECAUTIONS:

General (new subsection): "Periodic assessment of organ system functions, including hematopoietic and hepatic, is advisable during prolonged therapy."

Carcinogenesis, Mutagenesis, Impairment of Fertility: The former "Carcinogenesis, Mutagenesis" and "Impairment of Fertility" sections were combined together, with addition of information providing equivalence to human dose, based on mg/m².

Pregnancy: Teratogenic Effects. Pregnancy Category C: (Subsection name changed from "Use in Pregnancy: Pregnancy Category C:") -

First sentence revised (new text in italics) -

"Mebendazole has shown embryotoxic and teratogenic activity in pregnant rats at single oral doses as low as 10 mg/kg (approximately equal to the human dose, based on mg/m²)."

Third sentence revised (new text in italics) -

"["In humans," deleted] Although there are no adequate and well-controlled studies in pregnant women, a post-marketing study has been done of a limited number of women who inadvertently had consumed Vermox during the first trimester of pregnancy."

Last sentence deleted -

"During pregnancy, especially during the first trimester, Vermox should be used only if the potential benefit justifies the potential risk to the fetus."

ADVERSE REACTIONS:

Section revised (new text in italics) -

"Gastrointestinal: Transient symptoms of abdominal pain and diarrhea in cases of massive infection and expulsion of worms.

"Hypersensitivity: Rash, urticaria and angioedema have been observed on rare occasions.

"Central Nervous System: Very rare cases of convulsions have been reported.

"Liver: There have been liver function test elevations [AST (SGOT), ALT (SGPT), and GGT] and rare reports of hepatitis when Vermox was taken for prolonged periods and at dosages substantially above those recommended.

"Hematologic: Neutropenia and agranulocytosis. (See WARNINGS)."

OVERDOSAGE:

Last sentence deleted -

"Activated charcoal may be given."

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BOXED WARNING (new section):

"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 stavudine (See WARNINGS)."

CLINICAL PHARMACOLOGY:

Pharmacokinetics in Adults: Text deleted and replaced with -

"The pharmacokinetics of stavudine have been evaluated in HIV-infected adult and pediatric patients (Table 1). Peak plasma concentrations (C_max) and area under the plasma concentration-time curve (AUC) increased in proportion to dose after both single and multiple doses ranging from 0.03 to 4 mg/kg. There was no significant accumulation of stavudine with repeated administration every 6, 8, or 12 hours."

Table 1 "Mean +/- SD Pharmacokinetic Parameters of Stavudine in Adults and Pediatric HIV-Infected Patients" - is a new table - Refer to new labeling/package insert.

[Please note that the numbering of all tables was changed after the addition of the new Table 1.]

Absorption (renamed from "Absorption and Bioavailability"): Text deleted and replaced with -

"Following oral administration, stavudine is rapidly absorbed, with peak plasma concentrations occurring within 1 hour after dosing. The systemic exposure to stavudine is the same following administration as capsules or solution."

Distribution: First paragraph "Following 1-hour intravenous infusions (n=44) ... and did not correlate with body weight." deleted.

Excretion (renamed from "Elimination"): All text in subsection deleted except the following two sentences -

"Renal elimination accounted for about 40% of the overall clearance regardless of the route of administration. The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration."

Special Populations: Renal Insufficiency: Text and previous Table 1 deleted and replaced with -

"Data from two studies indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2). C_max and T_max were not significantly altered by renal insufficiency. The mean +/- SD hemodialysis clearance value of stavudine was 120 +/- 18 mL/min (n=12); the mean +/- SD percentage of the stavudine dose recovered in the dialysate, timed to occur between 2-6 hours post-dose, was 31 +/- 5%. Based on these observations, it is recommended that Zerit (stavudine) dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION)."

Table 2 "Mean +/- SD Pharmacokinetic Parameter Values: Single 40-mg Oral Dose of Zerit" (formerly Table 1) - values in the "9-25 mL/min" column revised and a new column, "Hemodialysis Patients", added - refer to new labeling/package insert.

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

"Stavudine pharmacokinetics were not altered in ["6" deleted] 5 non-HIV infected patients ..."

Geriatric: Subsection revised (new text in italics) -

"Stavudine pharmacokinetics have not been ["specifically investigated" deleted] studied in patients > 65 years of age."

Gender: Subsection revised (new text in italics) -

"The effects of gender on stavudine pharmacokinetics ["have not been studied as a function of gender" deleted] are not known.

Race: Subsection revised (new text in italics) -

"The effects of race on stavudine pharmacokinetics ["differences due to race have not been evaluated" deleted] are not known."

INDICATIONS AND USAGE:

Second paragraph deleted -

"The duration of clinical benefit from antiretroviral therapy may be limited. Alteration in antiretroviral therapy should be considered if disease progression occurs while receiving Zerit."

WARNINGS:

Text deleted (second paragraph moved to ADVERSE REACTIONS: Adults - see below) and replaced with -

"Lactic Acidosis/Severe Hepatomegaly with Steatosis: 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 stavudine. A majority of these cases have been in women. Caution should be exercised when administering Zerit to any patient, and particularly to those with known risk factors for liver disease. Treatment with Zerit should be discontinued in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

"Peripheral Neuropathy: Zerit therapy can be associated with severe peripheral neuropathy, which is dose-related and occurs more frequently in patients with advanced HIV infection or who have previously experienced peripheral neuropathy (See Table 4)."

PRECAUTIONS:

Information for Patients: Text of first paragraph moved to become the second & third sentences in the new third paragraph beginning "The duration of clinical benefit ...".

Fourth paragraph deleted and replaced with -

"The duration of clinical benefit from antiretroviral therapy may be limited. Patients should be informed that Zerit is not a cure for HIV infection, and that they may continue to acquire illnesses associated with HIV infection, including opportunistic infections. Patients should be advised to remain under the care of a physician when using Zerit. They should be advised that Zerit therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be informed that long-term effects of Zerit are unknown at this time."

Last paragraph revised (new text in italics) -

"Patients should be informed that the Centers for Disease Control and Prevention

Laboratory Tests: Subsection deleted.

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

"Long-term carcinogenicity studies of stavudine in animals have not been completed."

New first paragraph -

"In 2-year carcinogenicity studies in mice and rats, stavudine was noncarcinogenic at doses which produced exposures (AUC) 39 and 168 times, respectively, human exposure at the recommended clinical dose. Benign and malignant liver tumors in mice and rats and malignant urinary bladder tumors in male rats occurred at levels of exposure 250 (mice) and 732 (rats) times human exposure, at the recommended clinical dose."

Pediatric Use: First two paragraphs revised (new text in italics) -

"Use of stavudine in pediatric patients is supported by evidence from adequate and well-controlled studies of stavudine in adults with additional safety data in 115 pediatric patients ["and pharmacokinetic data in 25 of these patients" deleted].

"Stavudine pharmacokinetics have been evaluated in 25 HIV-infected pediatric patients ranging in age from 5 weeks to 15 years and in weight from 2 to 43 kg after IV ["and" deleted] or oral administration of ["0.125, 0.5, 1, and 2 mg/kg as" deleted] single doses and ["as" deleted] BID regimens (see Table 1)."

The three paragraphs beginning "Following intravenous infusions...", "The terminal elimination half-life..", and "The clearance of stavudine..." deleted.

ADVERSE REACTIONS:

First sentence deleted -

"The major clinical toxicity of Zerit is peripheral neuropathy (see WARNINGS section)."

Adults: First two sentences -

"Peripheral neuropathy is dose related (see Table 3). Modest elevation of hepatic transaminases was also observed commonly in controlled trials."

deleted and replaced with -

" Zerit therapy can be associated with severe peripheral neuropathy, which is dose-related and occurs more frequently in patients with advanced HIV infection or who have previously experienced peripheral neuropathy (See Table 4).

"Patients should be monitored for the development of neuropathy that is usually characterized by numbness, tingling, or pain in the feet or hands. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. In some cases, symptoms may worsen temporarily following discontinuation of therapy. If symptoms resolve completely, resumption of treatment may be considered at a reduced dose (see DOSAGE AND ADMINISTRATION)." [Note: This paragraph moved from previous WARNINGS section.]

Observed During Clinical Practice (new subsection): "The following events have been identified during post-approval use of Zerit. 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 their seriousness, frequency of reporting, causal connection to Zerit, or a combination of these factors.

"Lactic acidosis and hepatic steatosis (see WARNINGS), hepatitis and liver failure."

OVERDOSAGE:

Section revised (new text in italics) -

"Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity. Stavudine can be removed by hemodialysis; the mean +/- SD hemodialysis clearance of stavudine is 120 +/- 18 mL/min. ["It is not known" deleted] Whether stavudine is eliminated by peritoneal dialysis ["or hemodialysis" deleted] has not been studied."

DOSAGE AND ADMINISTRATION:

Pediatrics: First sentence revised (new text in italics) -

"The recommended starting dose for pediatric patients weighing less than 30 kg is ["2 mg/kg/day" deleted] 1 mg/kg/dose, given every 12 hours."

Dosage Adjustment: Last sentence deleted -

"Clinically significant elevations of hepatic transaminases should be managed in the same fashion."

Renal Impairment: First paragraph revised (new text in italics) -

"Zerit may be administered to adult patients with impaired renal function with adjustment in dose as shown in Table 7. ["The following schedule is recommended:" deleted]"

Table 7 "Recommended Dosage Adjustment for Renal Impairment" (new name, formerly Table 6).

Last paragraph -

"There are insufficient data to recommend a dose for patients with creatinine clearance <10 mL/min or for patients undergoing dialysis."

deleted and replaced with -

"Since urinary excretion is also a major route of elimination of stavudine in pediatric patients, the clearance of stavudine may be altered in children with renal impairment. Although there are insufficient data to recommend a specific dose adjustment of Zerit in this patient population, a reduction in the dose and/or an increase in the interval between doses should be considered."

Hemodialysis Patients (new subsection) - "The recommended dose is 20 mg every 24 hours (> or = 60 kg) or 15 mg every 24 hours (< 60 kg), administered after the completion of hemodialysis and at the same time of day on non-dialysis days."