[U.S. Food and Drug Administration]

MedWatch

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

(Posted: March 2, 1998, Daypro added: March 11, 1998 )

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.

Compiled with the help of:
Robert D. Warhurst, 1998 Pharm. D. Candidate
McWhorter School of Pharmacy
Samford University
Birmingham, AL

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Quick Reference:

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

ACCOLATE
(zafirlukast)
ANAFRANIL
(clomipramine HCl)
A.P.L.
(chorionic gonadotropin)
BREVITAL
(methohexital Na)
CEPTAZ
(ceftazidime)
CALAN
(verapamil HCl)
CLARITIN
(loratidine)
COVERA-HS
(verapamil HCl)
DAYPRO
(oxaprozin)
50% DEXTROSE
D.H.E. 45
(dihydroergotamine mesylate)
FASTIN
(phentermine HCl)
FORTAZ
(ceftazidime)
FRAGMIN
(dalteparin Na)
INVIRASE
(saquinavir mesylate)
ISOPTIN SR
(verapamil HCl)
LOESTRIN 21/FE
(norethindrone acetate/ethinyl
estradiol)
LOVENOX
(enoxaparin Na)
MAXIPIME
(cefepime HCl)
MIACALCIN
(calcitonin salmon)
NAVELBINE
(vinorelbine tartrate)
NORMIFLO
(ardeparin Na)
ORGARAN
(danaparoid Na)
PARAPLATIN
(carboplatin)
PHOTOFRIN
(porfimer Na)
MICRO-K
(potassium Cl)
PLENDIL
(felodipine)

PREMPRO
(conjugated estrogens/
medroxyprogesterone acetate)
SEROSTIM
(somatropin)
TAXOTERE
(docetaxel)
TIAZAC
(diltiazem HCl)

TILADE
(nedocromil Na)
UNIRETIC
(moexipril HCl/
hydrochlorothiazide)
VANCOCIN
(vancomyin HCl)

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ACCOLATE (zafirlukast) Tablets
[January 23, 1998: Zeneca]

PRECAUTIONS:
Drug Interactions: Fourth paragraph revised (new text in italics) -

"Co-administration of zafirlukast (80 mg/day) at steady state with a single dose of a liquid theophylline preparation (6 mg/kg) in 13 asthmatic patients resulted in decreased mean plasma levels of zafirlukast by approximately 30%, but no effect on plasma theophylline levels was observed. Rare cases of patients experiencing increased theophylline levels with or without clinical signs or symptoms of theophylline toxicity after the addition of Accolate to an existing theophylline regimen have been reported. The mechanism of the interaction between Accolate and theophylline in these patients is unknown (see ADVERSE REACTIONS)."

ADVERSE REACTIONS:
New last paragraph added -

"Rare cases of patients experiencing increased theophylline levels with or without clinical signs or symptoms of theophylline toxicity after the addition of Accolate to an existing theophylline regimen have been reported. The mechanism of the interaction between Accolate and theophylline in these patients is unknown and not predicted by available in vitro metabolism data and the results of a clinical drug interaction study (see CLINICAL PHARMACOLOGY, Drug Interactions)."

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ANAFRANIL (clomipramine HCl) Capsules
[January 15, 1998: Novartis]

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

"In a controlled clinical trial in children and adolescents (10-17 years of age), 46 outpatients received Anafranil for up to 8 weeks. In addition, 150 adolescent patients have received Anafranil in open-label protocols for periods of several months to several years. Of the 196 adolescents studied, 50 were 13 years of age or less and 146 were 14-17 years of age. ["While" deleted] The adverse reaction profile in this age group (see ADVERSE REACTIONS) is similar to that observed in adults [", it is unknown what, if any, effects long-term treatment with Anafranil may have on the growth and development of children." deleted].

"The risks, if any, that may be associated with Anafranil's extended use in children and adolescents with OCD have not be systemically assessed. The evidence supporting the conclusion that Anafranil is safe for use in children and adolescents is derived from relatively short term clinical studies and from extrapolation of experience gained with adults patients. In particular, there are no studies that directly evaluate the effects of long term Anafranil use on the growth, development, and maturation of children and adolescents. Although there is no evidence to suggest that Anafranil adversely affects growth, development or maturation, the absence of such findings is not adequate to rule out a potential for such effects in chronic use.

"The safety and effectiveness in pediatric patients below the age of 10 have not been established. Therefore, specific recommendations cannot be made for the use of Anafranil in pediatric patients under the age of 10."

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A.P.L. (chorionic gonadotropin) Injection
[January 23, 1998 : Wyeth-Ayerst]

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

"Safety and effectiveness in pediatric patients ["below the age of 4" deleted] have not been established except as stated for cryptorchidism not due to anatomic obstruction. See 'INDICATIONS and USAGE' and 'DOSAGE and ADMINISTRATION'."

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BREVITAL SODIUM (methohexital sodium) Injection
[January 30, 1998: Lilly]

[Other labeling changes not reflected in the 1998 PDR: Dec97]

HEADING OF LABEL:
"For Intravenous Use" deleted and replaced with either

"For Intravenous Use in Adults, rectal and intramuscular only in pediatric patients"

or

"see Dosage & Administration section for route of administration"

DESCRIPTION:
Last paragraph revised (new text in italics) -

"Methohexital sodium is administered by direct intravenous injection, ["or" deleted] continuous intravenous drip, intramuscular or rectal routes (see PRECAUTIONS - Pediatric Use). Reconstituting instructions vary depending upon the route of administration (see DOSAGE AND ADMINISTRATION)."

CLINICAL PHARMACOLOGY:
New text added as the second to last paragraph in the section -

"Following intramuscular administration to pediatric patients, the onset of sleep occurs in 2 to 10 minutes. A plasma concentration of 3 ug/mL was achieved 15 minutes after an intramuscular dose of a 5 % solution of 10 mg/kg to pediatric patients. Following rectal administration to pediatric patients, the onset of sleep occurs in 5 to 15 minutes. Plasma methohexital concentrations achieved following rectal administration tend to increase both with dose and with the use of more dilute solution concentrations when using the same dose. A 25 mg/kg dose of a 1% methohexital solution yielded plasma concentrations of 6.9 to 7.9 ug/mL 15 minutes after dosing. The absolute bioavailability of rectal methohexital sodium is 17%."

INDICATIONS AND USAGE:
New text added as the last paragraph in the section -

"Brevital Sodium can be used in pediatric patients older than 1 month as follows:

  1. For rectal or intramuscular induction of anesthesia prior to the use of other general anesthetic agents.
  2. For rectal or intramuscular induction of anesthesia and as an adjunct to subpotent inhalational anesthetic agents for short surgical procedures.
  3. As rectal or intramuscular anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli."

WARNINGS:
Fourth paragraph revised (new text in italics) -

"This prescribing information describes intravenous use of methohexital sodium in adults. It also discusses the intramuscular and rectal administration in pediatric patients older than one month. Although the published literature discusses intravenous administration in pediatric patients, the safety and effectiveness of intravenous administration of methohexital sodium in pediatric patients have not been established in well-controlled, prospective studies (see Pediatric Use)." Fifth paragraph revised (new text in italics) -

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

PRECAUTIONS:
General: First sentence revised (new text in italics) -

"["Intravenous" deleted] All routes of administration of Brevital Sodium are often associated with hiccups, coughing, and/or muscle twitching, which may also impair pulmonary ventilation."

Pediatric Use: Text added as the first three sentences in the subsection -

"The safety and effectiveness of methohexital sodium in pediatric patients below the age of 1 month have not been established. Seizures may be elicited in subjects with a previous history of convulsive activity, especially partial seizure disorders1. Apnea has been reported following dosing with methohexital regardless of the route of administration used."

DOSAGE AND ADMINISTRATION:
New tables added -

For intramuscular administration, contents of the vial should be diluted as follows:

 

FOR INTRAMUSCULAR ADMINISTRATION

Strength (Vial No.)

Amount of Diluent to Be Added
to the Contents of the Vial

Concentration After Dilution

500 mg vial (660) 10 mL 5% Solution (50 mg/mL)
2.5 g vial (663)
(larger vial needed)
50 mL 5% Solution (50 mg/mL)

 

For rectal administration, content of the vial should be diluted as follows:

 

FOR RECTAL ADMINISTRATION

Strength (Vial No.) Amount of Diluent to Be Added
to the Contents of the Vial
Concentration After Dilution
500 mg vial (66) 50 mL 1% Solution (10 mg/mL)
2.5 g vial (663)
(larger vial needed)
250 mL 1% Solution (10 mg/mL)

Pediatric Patients (new subsection): "Brevital Sodium is administered intramuscularly in a 5% concentration and rectally as a 1% solution.

"Induction of anesthesia: For the induction of anesthesia by the intramuscular route of administration, the usual dose ranges from 6.6 to 10 mg/kg of the 5% concentration. For rectal administration, the usual dose for induction is 25 mg/kg using the 1% solution."

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CALAN (verapamil HCl) Tablets
[January 13, 1998: Searle]

PRECAUTIONS:
Drug Interactions: New subsection added -

"Alcohol: Verapamil may increase blood alcohol concentrations and prolong its effects."

Lithium: Subsection revised (new text in italics) -

"Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy ["with either no change or an increase in serum lithium levels. However, the addition of verapamil has also resulted in the lowering of serum lithium levels in patients receiving chronic stable oral lithium." deleted]; lithium levels have been observed sometimes to increase, sometimes to decrease, and sometimes to be unchanged. Patients receiving both drugs must be monitored carefully."

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

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

ADVERSE REACTIONS:

Special Senses: "tinnitus" added.

OVERDOSAGE:
Second paragraph revised (new text in italics) -

"Treatment of overdosage should be supportive. Beta-adrenergic simulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel and have been used effectively in treatment of deliberate overdosage with verapamil. In a few reported cases, overdose with calcium channel blockers has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. Verapamil cannot be removed by hemodialysis. Clinically significant hypotensive reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including cardiopulmonary resuscitation."

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CEPTAZ (ceftazidime: L-arginine formulation) Injection
and
FORTAZ (ceftazidime & ceftazidime Na) Injections
[January 26, 1998: Glaxo Wellcome]

PRECAUTIONS:
General: New third paragraph added -

"Inducible type I beta-lactamase resistance has been noted with some organisms (e.g., Enterobacter spp., Pseudomonas spp., and Serratia spp.). As with other extended-spectrum beta-lactam antibiotics, resistance can develop during therapy, leading to clinical failure in some cases. When treating infections caused by these organisms, periodic susceptibility testing should be performed when clinically appropriate. If patients fail to respond to monotherapy, an aminoglycoside or similar agent should be considered."

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CLARITIN (loratadine) Tablets, Syrup, and Rapidly-Disintegrating Tablets
[January 27, 1998: Schering]

CLINICAL PHARMACOLOGY
Clinical Trials: New paragraph added -

"In a single-rising dose study in which doses up to 160 mg (16 times the clinical dose) were studied, loratadine did not cause any clinically significant changes on the QTc interval in the ECGs."

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COVERA-HS (verapamil HCl) Extended- Release Tablets
[January 13, 1998: Searle]

PRECAUTIONS:
Drug Interactions: Lithium: Subsection revised -

"Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy ["with either no change or an increase in serum lithium levels. However, the addition of verapamil has also resulted in the lowering of serum lithium levels in patients receiving chronic stable oral lithium." deleted]; lithium levels have been observed sometimes to increase, sometimes to decrease, and sometimes to be unchanged. Patients receiving both drugs must be monitored carefully."

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

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

ADVERSE REACTIONS:

Special Senses: "tinnitus" added.

OVERDOSAGE:
Second paragraph revised (new text in italics) -

"Treatment of overdosage should be supportive. Beta-adrenergic simulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel and have been used effectively in treatment of deliberate overdosage with verapamil. In a few reported cases, overdose with calcium channel blockers has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. Verapamil cannot be removed by hemodialysis. Clinically significant hypotensive reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including cardiopulmonary resuscitation."

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DAYPRO (oxaprozin) Caplets
[January 6, 1998: Searle]

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

ADVERSE REACTIONS:
Hematologic system: "agranulocytosis, pancytopenia" added

Urogenital: "nephrotic syndrome" added

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50% DEXTROSE Injection (in Abboject Syringe)
[January 27, 1998: Abbott]

INDICATIONS AND USAGE:
First paragraph revised (new text in italics) -

"50% Dextrose Injection [",USP" deleted] is indicated in the treatment of ["acute or severe episodes of drug-induced (insulin or oral hypoglycemic) hypoglycemia." deleted] insulin hypoglycemia (hyperinsulinemia or insulin shock) to restore blood glucose levels."

WARNINGS:
New fourth paragraph added -

"Additives may be incompatible. Consult with pharmacist if available. When introducing additives, use aseptic technique, mix thoroughly and do not store."

PRECAUTIONS:
Second paragraph deleted -

"In treating hypoglycemia, blood glucose determination should be performed as necessary to verify the results of therapy."

"Electrolyte deficits, particularly in serum potassium and phosphate, may occur during prolonged use of concentrated dextrose solutions. Blood electrolyte monitoring is essential and fluid and electrolyte imbalances should be corrected. Essential vitamins and minerals also should be provided as needed.

"To minimize hyperglycemia and consequent glycosuria, it is desirable to monitor blood and urine glucose and if necessary, add insulin.

"When a concentrated dextrose infusion is abruptly withdrawn, it is advisable to follow with the administration of 5% or 10% dextrose injection to avoid rebound hypoglycemia."

Carcinogenesis, Mutagenesis, Impairment of Fertility: (new subsection) -

"Studies with solutions in polypropylene syringes have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility."

Nursing Mothers (new subsection): "It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when 50% Dextrose Injection, USP is administered to a nursing mother."

DOSAGE AND ADMINISTRATION:
For Central Venous Administration (new subsection): "For total parenteral nutrition 50% Dextrose Injection, USP is administered by slow intravenous infusion (a) after admixture with amino acid solutions via an indwelling catheter with the tip positioned in a large central vein, perferably the superior vena cava, or (b) after dilution with sterile water for injection. Dosage should be adjusted to meet individual patient requirements.

"Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation.

"The maximum rate of dextrose administration which does not result in glycosuria is the same as cited above."

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D.H.E. 45 (dihydroergotamine mesylate) Injection
[January 29, 1998: Novartis]

Entire labeling extensively revised. Contact the company for a copy of the new labeling/package insert.

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FASTIN (phentermine HCl) Capsules
[January 16, 1998: SmithKline Beecham]

[Other labeling changes not reflected in the 1998 PDR: oct97]

PRECAUTIONS:
Pediatric use: Subsection revised (new text in italics) -

"Safety and effectiveness in ["children" deleted] pediatric patients have not been established.

DOSAGE AND ADMINISTRATION:
Exogenous Obesity: Last paragraph revised (new text in italics) -

"Fastin is not recommended for use in ["children under 12 years of age" deleted] patients 16 years of age and under.

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FRAGMIN (dalteparin Na) Injection
[January 30, 1998: Pharmacia & Upjohn]

[Other information regarding these changes:
December 15, 1997 ( Talk Paper) - FDA, ( Public Health Advisory) - FDA, May 6, 1998: (Questions and Answers) - FDA]

BOXED WARNING (new section):
"Spinal/Epidural Hematomas: When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.

"The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as non steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.

"Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurologic compromise is noted, urgent treatment is necessary.

"The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis (see also WARNINGS, Hemorrhage and PRECAUTIONS, Drug Interactions)."

WARNINGS:
Hemorrhage: New paragraph added at end of subsection -

"Spinal or epidural hematomas can occur with the associated use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture, which can result in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative indwelling epidural catheters or concomitant use of additional drugs affecting hemostasis such as NSAIDs (see BOXED WARNING)."

Thrombocytopenia: First paragraph revised (new text in italics) -

"In clinical trials, thrombocytopenia with platelet counts of < 50,000/mm3 and < 100,000/mm3 occurred in < 1% and < 1%, respectively, of patients undergoing abdominal surgery. In clinical practice, rare cases of thrombocytopenia with thrombosis have also been observed."

Miscellaneous (new subsection): "The multiple-dose vial of Fragmin contains benzyl alcohol as a preservative. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. Because benzyl alcohol may cross the placenta, Fragmin preserved with benzyl alcohol should not be used in pregnant women. (See PRECAUTIONS, Pregnancy Category B., Nonteratogenic Effects.)"

PRECAUTIONS:
Laboratory Tests: New paragraph added to end of subsection -

"When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of Fragmin activity and, therefore, unsuitable for monitoring."

Pregnancy: Pregnancy Category B:

Nonteratogenic Effects (new subsection): "Cases of "Gasping Syndrome" have occurred when large amounts of benzyyl alcohol have been administered (99 - 404 mg/kg/day). The 9.5 ml multi-dose vial of Fragmin contains 14 mg/mL of benzyl alcohol."

ADVERSE REACTIONS:
Thrombocytopenia: "(See WARNINGS)" added at end of subsection.

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INVIRASE (saquinavir mesylate) Capsules
[January 16, 1998: Roche]

CLINICAL PHARMACOLOGY:
Pharmacokinetics: Absorption and Bioavailability in Adults: First sentence -

"n=29" has been changed to "n=30"

Drug Interactions:
Nelfinavir (new subsection): "In 14 HIV-positive patients, coadministration of nelfinavir (750 mg) with saquinavir (given as Fortovase, 1200 mg) resulted in an 18% (95% CI 5-33%) increase in nelfinavir plasma AUC and a 392% (95% CI 271-553%) increase in saquinavir plasma AUC (see PRECAUTIONS: Drug Interactions)."

Ritonavir: Previous text - "Ritonavir extensively inhibits the metabolism of saquinavir resulting in greatly increased saquinavir plasma concentrations. Coadministration of ritonavir 400 or 600 mg bid regimens produced greater than twentyfold increases in steady-state dose-normalized saquinavir concentrations in healthy subjects. The appropriate doses for this combination, with respect to activity and safety, have not been established. "

deleted and replaced with -

"Following approximately 4 weeks of a combination regimen of saquinavir (400 or 600 mg bid) and ritonavir (400 or 600 mg bid) in HIV-positive patients, saquinavir AUC and Cmax values increased at least 17-fold (95% CI 9 - 31-fold) and 14-fold, respectively (see PRECAUTIONS: Drug Interactions).

Delavirdine (new subsection): "In 13 healthy volunteers, coadministration of saquinavir (600 mg tid) with delavirdine (400 mg tid) resulted in a 5-fold increase in saquinavir AUC. In 7 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)."

Nevirapine (new subsection): "In 23 HIV-positive patients, coadministration of saquinavir (600 mg tid) with nevirapine (200 mg bid) resulted in an 24% (95% CI 1-42%) and 28% (95% CI 1-47%) decrease in saquinavir plasma AUC and Cmax respectively (see PRECAUTIONS: Drug Interactions)."

INDICATIONS AND USAGE:
First sentence revised (new text in italics) -

"Invirase in combination with ["nucleoside analogues" deleted] other antiretroviral agents is indicated for the treatment of HIV infection ["when therapy is warranted" deleted].

CONTRAINDICATIONS:
New text added as last paragraph -

"Invirase should not be administered concurrently with terfenadine, cisapride, astemizole, triazolam, midazolam or ergot derivatives. Inhibition of CYP3A4 by saquinavir could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions."

WARNING (new section):
"New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established."

PRECAUTIONS:
General: Third paragraph, text added as last sentence -

"Although a causal relationship has not been established, exacerbation of chronic liver dysfunction, including portal hypertension, has been reported in patients with underlying hepatitis B or C, cirrhosis or other underlying liver abnormalities."

Drug Interactions: Anti-HIV Compounds (new subsection):

"Nelfinavir : Coadministration of nelfinavir with saquinavir (given as Fortovase, 1200 mg) resulted in an 18% increase in nelfinavir plasma AUC and a 4-fold increase in saquinavir plasma AUC. If used in combination with saquinavir hard-gelatin capsules at the recommended dose of 600 mg tid, no dose adjustments are needed. Currently, there are no safety and efficacy data available from the use of this combination

"Ritonavir: Following approximately 4 weeks of a combination regimen of saquinair (400 or 600 mg bid) and ritonavir (400 or 600 mg bid) in HIV-positive patients, saquinavir AUC values were at least 17-fold greater than historical AUC values from patients who received saquinaivr 600 mg tid without ritonavir. When used in combination therapy for up to 24 weeks, doses greater than 400 mg bid of either ritonavir or saquinavir were associated with an increase in adverse events.

"Delavirdine: Saquinavir AUC increased 5-fold when delavirdine (400 mg tid) and saquinavir (600 mg tid) were administered in combination. Currently, there are limited safety and no efficacy data available from the use of this combination. In a small, preliminary study, hepatocellular enzyme elevations occurred in 15% of subjects during the first several weeks of the delavirdine and saquinavir combination (6% Grade 3 or 4). Hepatocellular enzymes (ALT/AST) should be monitored frequently if this combination is prescribed."

"Nevirapine: Coadministration of nevirapine with Invirase resulted in a 24% decrease in saquinavir plasma AUC. Currently, there are no safety and efficacy data available from the use of this combination"

ADVERSE REACTIONS:
To the fifth paragraph, which begins "Rare occurrences of the following serious adverse experiences have been reported during clinical trials of Invirase and were considered at least possibly related to use of study drugs: ...",

"bullous skin eruption and polyarthritis" and "portal hypertension" were added.

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ISOPTIN SR (verapamil HCl) Sustained Release Tablets
[January 13, 1998: Knoll]

CLINICAL PHARMACOLOGY:
Pharmacokinetics and Metabolism: New paragraph added at end of subsection -

"In ten healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg) resulted in a 17% increase in mean peak ethanol concentrations (106.45 +/- 21.40 to 124.23 +/- 24.74 mg.hr/dL) compared to placebo. The area under the blood ethanol concentration versus time curve (AUC over 12 hours) increased by 30% (365.67 +/- 93.52 to 475.07 +/- 97.24 mg.hr/dL) Verapamil AUCs were positively correlated (r=0.71) to increased ethanol blood AUC values (See PRECAUTIONS: Drug Interactions.)."

PRECAUTIONS:
Drug Interactions: Other:

Alcohol (new subsection): "Verapamil has been found to inhibit ethanol elimination significantly resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol. (See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism)."

ADVERSE REACTIONS:

Special senses: "tinnitus" added.

OVERDOSAGE:
Section revised (new text in italics) -

"Overdose with verapamil may lead to pronounced hypotension, bradycardia, and conduction system abnormalities (e.g., junctional rhythm with AV dissociation and high degree AV block, including asystole). Other symptoms secondary to hypoperfusion (e.g., metabolic acidosis, hyperglycemia, hyperkalemia, renal dysfunction, and convulsions) may be evident.

"Treat all verapamil overdoses as serious and maintain observation for at least 48 hours (especially Isoptin SR), preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained release formulation. Verapmil is known to decrease gastrointestinal transit time.

"In overdose, tablets of Isoptin SR have occasionally been reported to form concretions within the stomach or intestines. These concretions have not been visible on plain radiographs of the abdomen, and no medical means of gastrointestinal emptying is of proven efficacy in removing them. Endoscopy might reasonably be considered in cases of massive overdose when symptoms are unusually prolonged.

"Treatment of overdosage should be supportive. Beta adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel, and have been used effectively in treatment of deliberate overdosage with verapamil. Continued treatment with large doses of calcium may produce a response. In a few reported cases, overdose with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. Verapamil cannot be removed by hemodialysis. Clinically significant hypotensive reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including cardiopulmonary resuscitation."

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LOESTRIN FE (norethindrone acetate/ethinyl estradiol + ferrous fumarate) Tablets
and
LOESTRIN 21 (norethindrone acetate/ethinyl estradiol ) Tablets
[January 16, 1998: Parke-Davis]

DETAILED PATIENT PACKAGE INSERT:
Effectiveness of Oral Contraceptives: Second paragraph revised (new text in italics) -

"In comparison, typical failure rates for other methods of birth control during the first year of use are as follows:

Implant: <1%

["Vaginal sponge: 18 to 30%" deleted]

Cervical Cap: 18 to 36%

Injection: <1%

Condom alone (male): 12%

IUD: ["6%" deleted] 1 to 2%

Condom alone (female): 21%

Diaphragm with spermicides: 18%

Periodic abstinence: 20%

Spermicides alone: 21%

No method: ["89%" deleted] 85 %

DETAILED PATIENT PACKAGE INSERT &
BRIEF SUMMARY PATIENT PACKAGE INSERT:
How to Take The Pill: Section revised to reflect the most recent oral contraceptive labeling draft guidance. See new labeling/package insert.

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LOVENOX (enoxaparin Na) Injection
[January 30, 1998: Rhone-Poulenc Rorer]

[Other information regarding these changes:
December 15, 1997 ( Talk Paper) - FDA, ( Public Health Advisory) - FDA, May 6, 1998: (Questions and Answers) - FDA]

Labeling extensively revised to incorporate information on a new indication - use during and following hospitalization for the prevention of deep vein thrombosis, which may lead to pulmonary embolism, in patients undergoing hip replacement surgery. Contact the company for a copy of the new labeling/package insert.

Some of these changes related to new safety information are summarized below.

BOXED WARNING (new section):
Spinal/Epidural Hematomas: "When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.

"The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as non steroidal anti-inflammatory drugs (NSAIDS), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.

"Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurologic compromise is noted, urgent treatment is necessary.

"The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis (see also WARNINGS, Hemorrhage and PRECAUTIONS, Drug Interactions)."

WARNINGS:
Hemorrhage: New paragraph added as the second one in the subsection -

"Cases of epidural or spinal hematomas have been reported with the associated use of enoxaprin and spinal/epidural anesthesia or spinal puncture resulting in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative indwelling epidural catheters or by the concomitant use of additional drugs affecting hemostasis such as NSAIDs (see BOXED WARNING; ADVERSE REACTIONS, Ongoing Safety Surveillance; and PRECAUTIONS, Drug Interactions)."

Neuraxial Anesthesia and Post-operative Indwelling Epidural Catheter Use: Spinal/Epidural Anesthesia: Subsection deleted.

Thrombocytopenia: First paragraph revised and split into 3 paragraphs (new text in italics) -

"Thrombocytopenia can occur with the administration of Lovenox.

"Hip and Knee Replacement surgery: During clinical trials in patients following hip and knee replacement surgery, moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at a rate of ["1.8%" deleted] 1.5% in patients given Lovenox, ["1.7%" deleted] 2.0% in patients given heparin, and ["1.7%" deleted] 0.6% in patients given placebo.

"Platelet counts less than 50,000/mm3 occurred at a rate of ["0.1%" deleted] 0.05% in patients given Lovenox, ["0.4%" deleted] 0.5% in patients given heparin, and 0% in patients given placebo in the same trials.

New text added as fourth and fifth paragraphs -

"Abdominal surgery: During clinical trials in patients following abdominal surgery, moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at a rate of 2% in patients given Lovenox, and 1.5% in patients given heparin.

"Platelet counts less than 50,000/mm3 occurred at a rate of 0.08% in patients given Lovenox and in 0.3% of patients given heparin in the same trials."

PRECAUTIONS:
Laboratory Tests: Text added to subsection -

"When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of Lovenox activity and, therefore, unsuitable for monitoring."

for monitoring."

ADVERSE REACTIONS:
Ongoing Safety Surveillance: First paragraph -

"There have been rare reports of neuraxial hematoma formation with concurrent use of enoxaparin and spinal/epidural anesthesia, and post-operative indwelling catheters. These events resulted in varying degrees of neurologic injuries including long-term or permanent paralysis."

deleted and replaced with

"Since 1993, there have been more than 30 reports of epidural or spinal hematoma formation with concurrent use of enoxaparin and spinal/epidural anesthesia or spinal puncture. The majority of patients had a post-operative indwelling epidural catheter placed for analgesia or received additional drugs affecting hemostasis such as NSAIDs. Many of the epidural or spinal hematomas caused neurologic injury, including long-term or permanent paralysis. Because these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made."

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

"All patients should be screened prior to prophylactic administration of Lovenox to rule out a bleeding disorder. ["There is usually no need for daily monitoring of coagulation parameters in patients with normal pre-surgical values." deleted] Since coagulation parameters are unsuitable for monitoring Lovenox activity, routine monitoring of coagulation parameters is not required (see PRECAUTIONS, Laboratory Tests).

Second paragraph deleted -

"When patients receive Lovenox Injection for prevention of deep vein thrombosis, such prophylaxis should be continued throughout the post-operative period."

Adult Dosage: Hip or Knee Replacement Surgery: Subsection revised (new text in italics) -

"In patients undergoing hip or knee replacement surgery, the recommended dose of Lovenox Injection is 30 mg every 12 hours administered by s.c. injection. Provided that hemostasis has been established, the initial dose should be given 12-24 hours post-operatively. Up to 14 days administration (average duration 7 to 10 days) of Lovenox 30 mg every 12 hours has been well tolerated in controlled clinical trials. ["The average duration of administration is 7 to 10 days." deleted] For hip replacement surgery, a dose of 40 mg once daily s.c., given initially 12 (+/-3) hours prior to surgery, may be considered. Following the initial phase of thromboprophylaxis in hip replacement surgery patients (Lovenox 30 mg every 12 hours or 40 mg once daily), continued prophylaxis with Lovenox Injection 40 mg once daily administered by s.c. injection for 3 weeks is recommended."

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MAXIPIME (cefepime HCl) Injection
[January 30, 1998: Bristol Myers Squibb]

The patient package insert has been revised to incorporate information on a new indication - use in combination with metronidazole for the treatment of complicated intra-abdominal infections.
Contact the company for a copy of the patient package insert.
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MIACALCIN (calcitonin-salmon) Nasal Spray
[January 12, 1998: Novartis]

The patient package insert has been revised to include changes in format; addition of nasal bleeding, crusting and back/joint pain as adverse reactions; specific recommendations regarding required supplemental vitamins A and D; and correction of the mechanism of action to state that Miacalcin "works to stop bone loss and helps your bones become stronger".
Contact the company for a copy of the patient package insert.

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MICRO-K & MICRO-K 10 (potassium Cl) Extencaps
[January 30, 1998: Wyeth-Ayerst]

CLINICAL PHARMACOLOGY (section name changed from ACTIONS):
Section revised (new text in italics) -

"Potassium ion is the principal intracelluar cation of most body tissues. Potassium ions participate in a number of essential physiological processes, including the maintenance of intracellular tonicity, the transmission of nerve impulses, the contraction of cardiac, skeletal, and smooth muscle, and the maintenance of normal renal function.

"The intracellular concentration of potassium is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.

"Potassium is a normal dietary constituent and under steady-state conditions the amount of potassium absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of potassium is 50 to 100 mEq per day.

"Potassium depletion ["may" deleted] will occur whenever the rate of potassium loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of potassium intake. Such depletion usually develops slowly as a consequence of therapy with ["oral" deleted] diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, ["severe diarrhea" deleted] or inadequate replacement of potassium in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Potassium depletion due to these causes is usually accompanied by a concomitant ["deficiency of" deleted] loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Potassium depletion may produce weakness, fatigue, disturbances of cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.

"If potassium depletion associated with metabolic alkalosis ["is" deleted] cannot be managed by correcting the fundamental cause of the deficiency, ["whenever possible and administering supplemental potassium chloride," deleted] e.g., where the patient requires long-term diuretic therapy, supplemental potassium in the form of high potassium food or potassium chloride ["solution, capsules, or tablets" deleted] may be able to restore normal potassium levels.

"In rare circumstances (e.g., patients with renal tubular acidosis) potassium depletion may be associated with metabolic acidosis and hyperchloremia. In such patients potassium replacement should be accomplished with potassium salts other than the chloride, such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate."

INDICATIONS AND USAGE (section name changed from INDICATIONS):
Section revised (new text in italics) -

"Because of reports of intestinal and gastric ulceration and bleeding with ["slow" deleted] controlled-release potassium chloride preparations, these drugs should be reserved for those patients who cannot tolerate or refuse to take liquid or effervescent potassium preparations or for patients in whom there is a problem of compliance with these preparations.

"

  1. For ["therapeutic use in" deleted] the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.

    "

  2. For the prevention of ["potassium depletion when the dietary intake of potassium is inadequate in the following conditions: patients receiving digitalis and diuretics for congestive heart failure" deleted] hypokalemia in patients who would be at particular risk if hypokalemia were to develop, e.g., digitalized patients or patients with significant cardiac arrhythmias, hepatic cirrhosis with ascites, states of aldosterone excess with normal renal function, potassium-losing nephropathy, and certain diarrheal states.

    "["3. " deleted] The use of potassium salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum potassium should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with potassium salts may be indicated."

WARNINGS:
Hyperkalemia: "(see OVERDOSAGE)" added to subsection name.

Interaction with Potassium-Sparing Diuretics: Subsection revised (new text in italics) -

"Hypokalemia should not be treated by the concomitant administration of potassium salts and a potassium-sparing diuretic (e.g., spironolactone, triamterene, or amiloride), since the simultaneous administration of these agents can produce severe hyperkalemia."

Gastrointestinal Lesions: Text deleted and replaced with -

"Solid oral dosage forms of potassium chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric coated preparations of potassium chloride are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained-release was matrix formulations (less than one per 100,000 patient years).

"Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric coated products is not available. Micro-K Extencaps and Micro-K 10 Extencaps are microencapsulated capsules formulated to provide a controlled rate of release of microencapsulated potassium chloride and thus to minimize the possibility of a high local concentration of potassium near the gastrointestinal wall.

"Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after one week of solid oral potassium chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (i.e., 96 mEq per day in divided doses of potassium chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (hemoccult testing). The relevance of these findings to the usual conditions (i.e., non-fasting, no anticholinergic agent, small doses) under which controlled-release potassium chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving was matrix formulations. Micro-K Extencaps and Micro-K 10 Extencaps should be discontinued immediately and the possibility of ulceration, obstruction or perforation considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occur."

Metabolic Acidosis: Subsection revised (new text in italics) -

"Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing potassium salt such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate."

ADVERSE REACTIONS:
Third paragraph, first sentence revised (new text in italics) -

"The most common adverse reactions to the oral potassium salts are nausea, vomiting, flatulence, abdominal discomfort, and diarrhea."

New paragraph added at end of section -

"Skin rash has been reported rarely with potassium preparations."

OVERDOSAGE:
First paragraph, last two sentences revised (new text in italics) -

"It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum potassium concentration (6.5 - 8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of ST segment, and prolongation of the QT interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9 - 12 mEq/L).

DOSAGE AND ADMINISTRATION:
Section revised (new text in italics) -

"The usual dietary intake of potassium by the average adult is ["40 to 80 mEq" deleted] 50 to 100 mEq per day. Potassium depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of potassium from the total body store.

"Dosage must be adjusted to the individual needs of each patients. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40 to 100 mEq per day or more are used for the treatment of potassium depletion. [Table with doses for prevention and for treatment was deleted.] ["If more than 2 Extencaps are prescribed per day, the total daily dosage should be divided into two or more separate doses." deleted] Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.

"Because of the potential for gastric irritation (see WARNINGS), Micro-K Extencaps should be taken with meals and with a full glass of water or other liquid.

"["Those" deleted] Patients who have difficulty swallowing capsules may ["be advised to" deleted] sprinkle the contents of the capsule onto a spoonful of soft food. The soft food, such as applesauce or pudding should be swallowed immediately without chewing and followed with a glass of cool water or juice to ensure complete swallowing of the microcapsules. The food used should not be hot and should be soft enough to be swallowed without chewing. Any microcapsule/food mixture should be used immediately and not stored for future use."

Animal Toxicology: Subsection deleted.

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NAVELBINE (vinorelbine tartrate) Injection
[January 6, 1998: Glaxo Wellcome]

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

"Pain in tumor-containing tissue, ["and" deleted] back pain, and abdominal pain have been reported. Electrolyte abnormalities, including hyponatremia with or without the syndrome of inappropriate ADH secretion have been reported in seriously ill and debilitated patients."

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NORMIFLO (ardeparin Na) Injection
[January 30, 1998: Wyeth-Ayerst]

[Other information regarding these changes:
December 15, 1997 ( Talk Paper) - FDA, ( Public Health Advisory) - FDA, May 6, 1998: (Questions and Answers) - FDA]

BOXED WARNING (new section):

"Spinal/Epidural Hematomas: When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.

"The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as non steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anti-coagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.

"Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurologic compromise is noted, urgent treatment is necessary.

"The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis (see also WARNINGS, Hemorrhage and PRECAUTIONS, Drug Interactions)."

WARNINGS:
Hemorrhage: New paragraph added at the end of subsection-

"Spinal or epidural hemotomas can occur with the associated use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture which can result in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative indwelling epidural catheters or concomitant use of additional drugs affecting hemostasis such as NSAIDs (see boxed WARNING)."

PRECAUTIONS:
Laboratory Tests: New paragraph added at the end of the subsection -

"When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time [PT] and Activated Partial Thromboplastin Time [APTT] are relatively insensitive measures of Normiflo activity and, therefore, unsuitable for monitoring."

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ORGARAN (danaparoid Na) Injection
[January 30, 1998: Organon]

[Other information regarding these changes:
December 15, 1997: ( Talk Paper) - FDA, ( Public Health Advisory) - FDA, May 6, 1998: (Questions and Answers) - FDA]

BOXED WARNING (new section):

"Spinal/Epidural Hematomas: When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.

"The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as non steroidal anti-inflammatory drugs (NSAIDS), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.

"Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurologic compromise is noted, urgent treatment is necessary.

"The physician should consider the potential benefit versus risk before intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis (see also WARNINGS, Hemorrhage and PRECAUTIONS, Drug Interactions)."

WARNINGS:
Hemorrhage: New paragraph added at end of subsection -

"Spinal or epidural hematomas can occur with the associated use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture which can result in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative indwelling epidural catheters or concomitant use of additional drugs affecting hemostasis such as NSAIDs (see BOXED WARNING)."

PRECAUTIONS:
Laboratory Tests: First paragraph -

"Orgaran (danaparoid sodium) Injection has only a small effect on factor IIa (thrombin) activity, therefore, routine coagulation tests (e.g., Prothrombin Time [PT], Activated Partial Thromboplastin Time [APTT], Kaolin Cephalin Clotting Time [KCCT], Whole Blood Clotting Time [WBCT], and Thrombin Time [TT] are unsuitable for monitoring Orgaran activity at recommended doses."

deleted and replaced with -

"When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of Orgaran activity and, therefore, unsuitable for monitoring."

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PARAPLATIN (carboplatin) Injection
[January 6, 1998: Bristol-Myers Squibb]

[Note: The following change appears in the 1998 PDR.]

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

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PHOTOFRIN (porfimer Na) Injection
[January 9, 1998: QLT Phototherapeutics]

The labeling has been revised to incorporate a new indication -use in the treatment of microinvasive endobronchial nonsmall cell lung cancer in patients for whom surgery and radiotherapy are not indicated.
Contact the company for a copy of the labeling/package insert.
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PLENDIL (felodipine) Extended-Release Tablets
[January 13, 1998: Astra Merck]

CLINICAL PHARMACOLOGY:
Pharmacokinetics and Metabolism: Last paragraph revised (new text in italics) -

"The bioavailability of Plendil is ["not" deleted] influenced by the presence of food ["in the gastrointestinal tract" deleted]. ["In a study of six patients, the bioavailability of felodipine was increased more than two-fold when taken with doubly concentrated grapefruit juice, compared to when taken with water or orange juice." deleted] When administered either with a high fat or carbohydrate diet, Cmax is increased by approximately 60 percent. AUC is unchanged. When Plendil was administered after a light meal (orange juice, toast and cereal), however, there is no effect on felodipine's pharmacokinetics. The bioavailability of felodipine was increased approximately 2-fold when taken with grapefruit juice. Orange juice does not appear to modify the kinetics of Plendil. A similar finding has been seen with other dihydropyridine calcium antagonists, but to a lesser extent than that seen with felodipine."

DOSAGE AND ADMINISTRATION:
Second paragraph, new first sentence added -

"Plendil should regularly be taken either without food or with a light meal (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism)."

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PREMPRO (conjugated estrogens/medroxyprogesterone acetate) Tablets
[January 9, 1998: Wyeth-Ayerst]

The labeling has been revised to incorporate information providing for the continuous combined dosing regimen of 0.625 mg conjugated estrogens/5 mg medroxyprogesterone acetate for use in women with an intact uterus, for the following indications: 1) treatment of moderate to severe vasomotor symptoms associated with the menopause; 2) treatment of vulvar and vaginal atrophy; and 3) prevention of osteoporosis. Contact the company for a copy of the new labeling/package insert.

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SEROSTIM (somatropin (rDNA) origin) Injection
[January 16, 1998: Serono]

PRECAUTIONS:
Pediatric Use: Previous text -

"Safety and effectiveness in pediatric patients with AIDS have not been established."

deleted and replaced with -

"In two small studies, 11 children with HIV associated failure to thrive were treated subcutaneously with human growth hormone. In one study, five children (age range, 6 to 17 years) were treated with 0.04 mg/kg/day for 26 weeks. In a second study, six children age range, 8 to 14 years) were treated with 0.07 mg/kg/day for 4 weeks. Treatment appeared to be well tolerated in both studies. These preliminary data collected on a limited number of patients with HIV associated failure to thrive appear to be consistent with safety observations in growth hormone treated adults with AIDS wasting."

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TAXOTERE (docetaxel) Injection
[January 6, 1998: Rhone-Poulenc Rorer]

ADVERSE REACTIONS:
Ongoing Evaluation:

Cardiovascular: "myocardial infarction" added.

Digestive: "gastrointestinal perforation" and "neutropenic enterocolitis" added.

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TIAZAC (diltiazem HCl) Extended Release Capsules
[January 30, 1998: Biovail]

The labeling has been revised to incorporate information on a new indication - treatment of chronic stable angina. Contact the company for a copy of the new labeling/package insert.

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TILADE (nedocromil Na) Inhalation Aerosol
[January 30, 1998: Rhone-Poulenc Rorer]

DESCRIPTION:
New last paragraph added -

"Each Tilade Inhaler canister must be primed with 3 actuations prior to the first use. If a canister remains unused for more than 7 days, then it should be reprimed with 3 actuations."

DOSAGE AND ADMINISTRATION:
New second paragraph added -

"Each Tilade Inhaler canister must be primed with 3 actuations prior to the first use. If a canister remains unused for more than 7 days, then it should be reprimed with 3 actuations."

PATIENT INFORMATION LEAFLET:
Instructions for Use: New text added as #2 -

"2. To prepare your Tilade Inhaler for use, the inhaler must be primed prior to the first use. To prime, hold the inhaler upright, with the mouthpiece facing away from you. Shake the inhaler, then press firmly downward on the canister. Repeat this procedure again until a total of three (3) sprays are released. Your Tilade Inhaler is now ready for use. Repriming is only necessary when your inhaler remains unused for more than 7 days. To reprime, shake the inhaler and release one spray. Repeat this procedure until a total of three (3) sprays are released."

For Best Results: #2 revised (new text in italics) -

"2. ["Before using the Inhaler for the very first time, or the first time in a while, shake the Inhaler and give it one press in the upright position to be sure it's working properly." deleted] Remember, your Tilade Inhaler must be primed prior to the first use. Repriming is only necessary when the inhaler remains unused for more than 7 days. Do not reprime between more frequent usage. (See Step 2 under INSTRUCTIONS FOR USE). Note: the Valve Cover should not be removed from the Canister (see Step 1 under INSTRUCTIONS FOR USE)."

#6 revised (new text in italics) -

"6. Keep a record of the number of sprays used and discard the canister after 104 sprays. The amount of medication in each spray cannot be assured after 104 sprays. Please note that the canister has been filled with extra suspension to accommodate the initial priming activity."

HOW TO CHECK CONTENTS OF YOUR CANISTER (new subsection): "Shaking the canister will NOT give you a good estimate of how much medication is left. We have included a convenient check-off chart to assist you in keeping track of medication inhalations used. This will help assure that you receive the labeled number of inhalations present. Please note that the canister has been filled with extra suspension to accommodate the initial priming activity.

"Each 16.2 gram inhaler delivers 104 metered inhalations. [See new leaflet for the Tilade Inhaler Check-Off Chart]

"

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UNIRETIC (moexipril HCl/hydrochlorothiazide) Tablets
[January 21, 1998: Schwarz]

PRECAUTIONS:
General: Serum Electrolyte Imbalances: Third paragraph, first sentence revised (new text in italics) -

"The opposite effects of moexipril and hydrochlorothiazide on serum potassium will approximately counterbalance each other in many patients, so that ["no" deleted] little net effect upon serum potassium will be seen."

ADVERSE REACTIONS:
Respiratory: "eosinophilic pneumonitis" added.

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VANCOCIN (vancomycin HCl) Injection
[January 8, 1998: Baxter]

PRECAUTIONS:
The phrase/word "premature neonates and young infants" and "children" are replaced with "pediatric patients" throughout the section.

DOSAGE AND ADMINISTRATION:
Patients with Normal Renal Function: Pediatric Patients (new name - changed from Children): New last sentence added -

"Close monitoring of serum concentrations of vancomycin may be warranted in these patients."

Neonates (new name - changed from Infants and Neonates): Subsection revised (new text in italics) -

"In ["neonates and young infants" deleted] pediatric patients up to the age of 1 month, the total daily intravenous dosage may be lower. In ["both" deleted] neonates ["and infants" deleted] an initial dose of 15 mg/kg is suggested, followed by 10 mg/kg every 12 hours for neonates in the 1st week of life and every 8 hours thereafter up to the age of l month. Each dose should be administered over 60 minutes. In premature infants, vancomycin clearance decreases as postconceptional age decreases. Therefore, longer dosing intervals may be necessary in premature infants. Close monitoring of serum concentrations of vancomycin ["may be warranted" deleted] is recommended in these patients.

Patients with Impaired Renal Function and Elderly Patients: First paragraph, second sentence revised -

"In ["premature infants and" deleted] the elderly, greater dosage reductions than expected may be necessary because of decreased renal function."

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