ALPHAGAN (brimonidine tartrate)	AMBIEN (zolpidem tartrate)	CALCIJEX (calcitriol)	CARNITOR (levocarnitine)
CELEBREX (celecoxib)	CHIROCAINE (levobupivacaine)	DEMEROL (meperidine HCl)	DIABETA (glyburide)
ERGAMISOL (levamisole HCl)	FLOXIN (ofloxacin)	LIPITOR (atorvastatin calcium)	NASONEX (mometasone furoate)
NIMOTOP (nimodipine)	NUTROPIN (somatropin)	OPTIPRANOLOL (metipranolol)	TAXOL (paclitaxel)
TAXOTERE (docetaxel)	ZOLOFT (sertraline HCl)

Return to Quick Reference

PRECAUTIONS:

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

"Safety and effectiveness in pediatric patients have not been established. Agitation , apnea, bradycardia, convulsions, cyanosis, depression, dyspnea, emotional instability, hypotension, hypothermia, hypotonia, hypoventilation, irritability, lethargy, somnolence, and stupor have been reported in pediatric patients.

Geriatric Use: new subsection -

"No overall differences in safety or effectiveness have been observed between elderly and other adult patients."

CLINICAL PHARMACOLOGY:

Pharmacodynamics: Second paragraph, second sentence revised (new text in italics) -

"In contrast to the benzodiazepines, which nonselectively bind to and activate all ["three" deleted] omega receptor subtypes, zolpidem in vitro binds the (w₁) receptor preferentially with a high affinity ratio of the alpha1/alpha5 subunits."

Controlled trials supporting safety and efficacy:

Chronic insomnia: New paragraph -

"Zolpidem was evaluated in two controlled studies for the treatment of patients with chronic insomnia (most closely resembling primary insomnia, as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM IV)."

Next-day residual effects: Previous text from this subsection replaced with the following -

"Next-day residual effects of Ambien were evaluated in seven studies involving normal volunteers. In three studies in adults (including one study in a phase advance model of transient insomnia) and in one study in elderly subjects, a small but statistically significant decrease in performance was observed in the Digit Symbol Substitution Test (DSST) when compared to placebo. Studies of Ambien in non-elderly patients with insomnia did not detect evidence of next-day residual effects using the DSST, the Multiple Sleep Latency Test (MLST), and patient ratings of alertness."

INDICATION AND USAGE:

Previous text from this section replaced with the following -

"Ambien (zolpidem tartrate) is indicated for the short-term treatment of insomnia. Ambien has been shown to decrease sleep latency and increase the duration of sleep for up to 35 days in controlled clinical studies (see Clinical Pharmacology, Clinical trials supporting safety and efficacy). Hypnotics should generally be limited to 7 to 10 days of use, and reevaluation of the patient is recommended if they are to be taken for more than 2 to 3 weeks. Ambien should not be prescribed in quantities exceeding 1-month supply (see Warnings)."

PRECAUTION:

General: Use in patients with concomitant illness: Third and fourth sentences revised (new text in italics) -

"Although studies did not reveal respiratory depressant effects at hypnotic doses of Ambien in normals or in patients with mild to moderate chronic obstructive pulmonary disease (COPD), a reduction in the Total Arousal Index together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90% was observed in patients with mild to moderate sleep apnea when treated with Ambien 10-mg when compared to placebo. Therefore precautions should be observed if Ambien is prescribed to patients with compromised respiratory function, since sedative/hypnotics have the capacity to depress respiratory drive."

Drug Interactions: CNS-active drugs: new paragraph added -

"A single-dose interaction study with zolpidem 10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interaction. When multiple doses of zolpidem and fluoxetine at steady-state concentrations were evaluated in healthy females, the only significant change was a 17% increase in the zolpidem half-life. There was no evidence of an additive effect in psychomotor performance. Following five consecutive nightly doses of zolpidem 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses in healthy female volunteers), zolpidem C_max was significantly higher (43%) and T_max was significantly decreased (53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem."

Drugs that affect drug metabolism via cytochrome P450: (new subsection):

"Drugs that effect drug metabolism via cytochrome P450: A randomized, double-blind cross-over interaction study in ten healthy volunteers between itraconazole (200 mg once daily for 4 days) and a single dose of zolpidem (10 mg) given 5 hours after the last dose of itraconazole resulted in a 34% increase in AUC_{zero to infinity} of zolpidem. There were no significant pharmacodynamic effects of zolpidem on subjective drowsiness, postural sway, or psychomotor performance. A randomized placebo-controlled, crossover interaction study in eight healthy female volunteers between 5 consecutive daily doses of rifampin (600 mg) and a single dose of zolpidem (20 mg) given 17 hours after the last dose of rifampin showed significant reductions of the AUC (-73%), C_max (-58%), and t_1/2 (-36%) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem."

Drug/Laboratory test interactions: new sentence added -

"In addition, clinical data indicate that zolpidem does not cross-react with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screens."

ADVERSE REACTIONS:

Associated with discontinuation of treatment: new paragraph added -

"Data from a clinical study in which SSRI-treated patients were given zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n=97) was discontinued after an attempted suicide."

Return to Quick Reference

PRECAUTIONS:

5. Carcinogenesis, Mutagenesis, Impairment of Fertility: Second and third sentences deleted -

"There was no evidence of mutagenicity as studied by the Ames Method. No significant effects of calcitriol on fertility were reported using oral calcitriol." Replaced with -

"Calcitriol was not mutagenic in vitro in the Ames Test nor was oral calcitriol genotoxic in vivo in the Mouse Micronucleus Test. No significant effects on fertility and/or general reproductive performances were observed in a Segment I study in rats using oral calcitriol at doses of up to 0.3 mcg/kg."

6. Pregnancy:Extensive revision to subsection. Approved text as follows:
Teratogenic Effects: Pregnancy Category C: Calcitriol has been found to be teratogenic in rabbits when given orally at doses of 0.08 and 0.3 mcg/kg. All 15 fetuses in 3 litters at these doses showed external and skeletal abnormalities. However, none of the other 23 litters (156 fetuses) showed external and skeletal abnormalities compared with controls. Teratogenicity studies in rats at doses up to 0.45 mcg/kg orally showed no evidence of teratogenic potential. There are no adequate and well-controlled studies in pregnant women. Calcijex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: In the rabbit, oral dosages of 0.3 mcg/kg/day administered on days 7 to 18 of gestation resulted in 19% maternal mortality, a decrease in mean fetal body weight and a reduced number of newborn surviving to 24 hours. A study of the effects on orally administered calcitriol on peri- and postnatal development in rats resulted in hypercalcemia in the offspring of dams given calcitriol at doses of 0.08 or 0.3 mcg/kg/day, hypercalcemia and hypophosphatemia in dams given calcitriol at a dose of 0.08 or 0.3 mcg/kg/day and increased serum urea nitrogen in dams given calcitriol at a dose of 0.3 mcg/kg/day. In another study in rats, maternal weight gain was slightly reduced at an oral dose of 0.3 mcg/kg/day administered on days 7 to 15 of gestation.
The offspring of a woman administered oral calcitriol at 17 to 36 mcg/day during pregnancy manifested mild hypercalcemia in the first 2 days of life which returned to normal at day 3."

[Other information regarding these changes: Letter, Q's & A's]

Return to Quick Reference

CLINICAL PHARMACOLOGY:

Pharmacokinetics: Absorption

Second sentence deleted -

"Doses of up to 150 mg administered epidurally for surgery (other than cesarean section) resulted in mean C_max values up to 0.79 microgram/mL."

Last sentence revised -

"Peak levels in blood were reached approximately 30 minutes after epidural administration, and doses [". In elective cesarean section doses" deleted] up to 150 mg resulted in mean C_max levels of up to 1.2 microgram/mL."

Pharmacodynamics: Last paragraph deleted -

"In another study, 22 healthy subjects received an intravenous infusion of bupivacaine to establish the individual maximum tolerated dose based upon CNS symptoms. Subjects were then randomized to receive either Chirocaine or bupivacaine to the previously defined doses (30 to 122 mg). With the second infusion to these doses, 10 of 11 bupivacaine subjects experienced CNS symptoms compared with 6 of 11 Chirocaine subjects. The primary endpoints which were QT dispersion and QRS duration, were not different between treatments."

CLINICAL TRIALS:

Post-Operative Pain Management: Second and third sentences revised (new text in italics) -

" The dose ranging study evaluated Chirocaine ["in concentrations of 0.0625%, 0.125%, and 0.25% Chirocaine" deleted] in patients undergoing orthopedic surgery; the highest concentration, 0.25%, was significantly more effective than lower concentrations. The Chirocaine combination studies in post-operative pain management tested 0.125% Chirocaine in combination with 4 microgram/mL fentanyl and 0.125% Cirocaine in combination with clonidine 50 microgram/hour in ["patients undergoing major" deleted] orthopedic surgery."

ADVERSE REACTIONS:

First paragraph, fourth sentence revised -

"The reference drug was primarily bupivacaine. ["and, on one occaision, lidocaine was also used as a reference." deleted]"

DOSAGE AND ADMINISTRATION:

Chirocaine Compatibility and Admixtures First sentence revised -

"Studies have shown that Chirocaine is compatible with 0.9% Sodium Chloride Injection USP and with saline solutions containing ["morphine" deleted] fentanyl and clonidine."

Dilution Stability

First sentence revised -

"Chirocaine diluted ["to 0.625 - 2.5 mg levobupivacaine per ml" deleted] in 0.9% Sodium Chloride Injection is physically and chemically stable when stored in PVC (polyvinyl chloride) bags at ambient room temperature for up to 24 hours."

Dosage Recommendations: From the Chart, superscripts denoting footnotes revised for "Post-operative pain (epidural infusion" and the "% Concentration" column (new text in italics) -

"0.125^b -0.25^c"

footnotes revised (new text in italics) -

" ^b 0.125% is to be used only as adjunct therapy in combination with fentanyl or clonidine.
^c Dilutions of Chirocaine standard solutions should be made with preservative free 0.9% saline according to standard hospital procedures for sterility."

CLINICAL PHARMACOLOGY:

New second paragraph -

"In clinical studies reported in the literature, changes in several pharmacokinetic parameters with increasing age have been observed. The initial volume of distribution and steady-state volume of distribution may be higher in elderly patients than in younger patients. The free fraction of meperidine in plasma may be higher in patients over 45 years of age than in younger patients."

PRECAUTIONS

Special Risk Patients: "Meperidine should be given with caution and the initial dose should be reduced in certain patients such as ["the elderly or" deleted] debliltated, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, and prostatic hypertrophy or urethral stricture."

Geriatric Use: (new subsection):

"Clinical studies of Demerol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be low, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

"Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be started on low doses of Demerol and observed closely.

"This drug is known to be excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

"Clinical studies indicate that differences in in various pharmacokinetic parameters may exist between elderly."

DOSAGE AND ADMINISTRATION

Under subsections for "Relief of Pain: Adults, For Preoperative Medicaton and For Support of Anesthesia", the following sentence added:

"Elderly patients should usually be given meperidine at the lower end of the dose range and observed closely."

PRECAUTIONS:

Geriatric Use:New subsection -

"In US clinical studies of glyburide, 1406 of 2897 patients were greater than or equal to 60 years and 515 patients were greater than or equal to 70 years. Differences in safety and efficacy were not determined between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

"Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS). The initial and maintenance dosing should be conservative to avoid hypoglycemic reactions. "In three published studies of 20 to 51 subjects each, mixed results were seen in comparing the pharmacokinetics of glyburide in elderly versus younger subjects. However, observed pharmacodynamic differences indicate the necessity for dosage titration to a specified therapeutic response. "This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. "In elderly, debilitated, or malnourished patients, or in patients with renal or hepatic insufficiency, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. (See PRECAUTION, General: and DOSAGE AND ADMINISTRATION)."

ADVERSE REACTIONS:

Fourth paragraph, new last sentence -

"Isolated cases of Stevens-Johnson syndrome have also been reported."

CLINICAL PHARMACOLOGY:

Eighth paragraph deleted -

"Following the administration of oral doses of ofloxacin to healthy elderly volunteers (64-74 years of age) with normal renal function, the apparent half-life of ofloxacin was 7 to 8 hours, as compared to approximately 6 hours in younger adults. Drug absorption, however, appears to be unaffected by age."

Replaced with -

"Following oral administration to healthy elderly subjects (65-81 years of age), maximum plasma concentrations are usually achieved one to two hours after single and multiple twice-daily doses, indicating that the rate of oral absorption is unaffected by age or gender. Mean peak plasma concentrations in elderly subjects were 9-21% higher than those observed in younger subjects. Gender differences in the pharmacokinetic properties of elderly subjects have been observed. Peak plasma concentrations were 114% and 54% higher in elderly females compared to elderly males following single and multiple twice daily doses. [This interpretation was based on study results collected from two separate studies] Plasma concentrations increase dose-dependently with the increase in doses after single oral dose and at steady state. No differences were observed in the volume of distribution values between elderly and younger subjects. As in younger subjects, elimination is mainly by renal excretion as unchanged drug in elderly subjects, although less drug is recovered from renal excretion in elderly subjects. Consistent with younger subjects, less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites in the elderly. A longer plasma half-life of approximately 6.4 to 7.4 hours was observed in elderly subjects, compared with 4 to 5 hours for young subjects. Slower elimination of ofloxacin is observed in elderly subjects as compared with younger subjects which maybe attributable to the reduced renal function and renal clearance observed in the elderly subjects. Because ofloxacin is known to be substantially excreted by the kidney, and elderly patients are more likely to have decreased renal function, dosage adjustment is necessary for elderly patients with impaired renal function as recommended for all patients (See PRECAUTIONS: General and DOSAGE AND ADMINISTRATION.)"

MICROBIOLOGY:

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

WARNINGS:

Third paragraph, fifth sentence added -

"Insomnia may be more common with ofloxacin than some other products in the quinolone class."

PRECAUTIONS:

Information for Patients: Second bullet revised (new text in italics) - (tablet only)

" - that mineral supplements, vitamins with iron or minerals, calcium- , aluminum- or magnesium-based antacids, sucralfate or Videx, (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution should not be taken within the two-hour period before or within the two-hour period after taking ofloxacin (See Drug Interactions);"

Drug Interactions: First Paragraph revised (new text in italics) - (tablet only)

"Antacids, Sucralfate, Metal Cations, Multivitamins: Quinolones form chelates with alkaline earth and transition metal cations. Administration of quinolones with antacids containing calcium, magnesium, or aluminum, with sucralfate, with divalent or trivalent cations such as iron, or with multivitamins containing zinc or with Videx, (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution may substantially interfere with the absorption of quinolones resulting in systemic levels considerably lower than desired. These agents should not be taken within the two-hour period before or within the two-hour period after ofloxacin administration. (See DOSAGE AND ADMINISTRATION.)"

(I.V. only)

"Antacids, Sucralfate, Metal Cations, Multivitamins: There are no data concerning an interaction of Intravenous quinolones with oral antacids, sucralfate, multivitamins, Videx, (Didanosine), or metal cations. However, no quinolone should be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line. (See DOSAGE AND ADMINISTRATION.)"

Geriatrics: (new subsection):

"In phase 2/3 clinical trials with ofloxacin, 688 patients (14.2%) were greater than or equal to 65 years of age. Of these, 436 patients (9.0%) were between the ages of 65 and 74 and 252 patients (5.2%) were 75 years or older.¹ There was no apparent difference in the frequency or severity of adverse reactions in elderly adults compared with younger adults.² The pharmacokinetic properties of ofloxacin in elderly subjects are similar to those in younger subjects. Drug absorption appears to be unaffected by age. Dosage adjustment is necessary for elderly patients with impaired renal function (creatinine clearance rate less than or equal to 50 mL/min) due to reduced clearance of ofloxacin. In comparative studies, the frequency and severity of most drug-related nervous system events in patients greater to or equal than 65 years of age were comparable for ofloxacin and control drugs. The only differences identified were an increase in reports of insomnia (3.9% vs 1.5%) and headache (4.7% vs 1.8%) with ofloxacin. It is important to note that these geriatric safety data are extracted from 44 comparative studies where the adverse reaction information from 20 different controls (other antibiotics or placebo) were pooled for comparison with ofloxacin. The clinical significance of such a comparison is not clear. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)³"

^"1 Ofloxacin Integrated Summary of Efficacy and Safety in Geriatric Subjects: Page 15, Table 6.
² Ofloxacin Integrated Summary of Efficacy and Safety in Geriatric Subjects: Pages 32 and 33.
³ Ofloxacin Integrated Summary of Efficacy and Safety in Geriatric Subjects: Pages 26-29."

DOSAGE AND ADMINISTRATION:

Fourth paragraph, second sentence - (I.V. only)

"These recommendations apply to patients with ["mild to moderate infection and" deleted] normal renal function (i.e., creatinine clearance greater than 50 mL/min)."

Patients with normal renal function: Paragraph revised (new text in italics)- (tablet only)

"Antacids containing calcium, magnesium, or aluminum: sucralfate; divalent or trivalent cations such as iron; or multivitamins containing zinc; or Videx, (Didanosine), chewable/buffered tablets or the oral solution should not be taken within the two-hour period before or within the two-hour period after taking ofloxacin. (See PRECAUTIONS.)"

[Other labeling changes not appearing in the 1999 PDR: Jul98]

Return to Quick Reference

[Other changes not appearing in 1999 PDR: Nov98]

Return to Quick Reference

CLINICAL PHARMACOLOGY:

Pharmacokinetics and Metabolism: (new subsection):

"In a single parallel-group study involving 24 elderly subjects (aged 59-79) and 24 younger subjects (aged 22-40), the observed AUC and C_max of nimodipine was approximately 2-fold higher in the elderly population compared to the younger study subjects following oral administration (given as a single dose of 30 mg and dosed to steady-state with 30 mg t.i.d. for 6 days). The clinical response to these age-related pharmacokinetic differences, however, was not considered significant. (See PRECAUTIONS: Geriatric Use.)"

PRECAUTIONS:

Geriatric Use:(new subsection):

"Clinical studies of nimodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dosing for elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy."

[Other labeling changes not found in 1999 PDR: Nov99]

CLINICAL PHARMACOLOGY:

General: E. Mineral Metabolism - last sentence added -

"GH therapy results in increases in serum alkaline phospahtase."

Efficacy Studies: Adult Growth Hormone Deficiency (GHD) next to last paragraph added -

"In the childhood-onset study, 55% of the patients had decreased spine bone mineral density (BMD) (z-score less than -1) at baseline. The administration of Nutropin (n=16) (0.025 mg/kg/day) for two years resulted in increased spine BMD from baseline when compared to placebo (n=13) (4.6% vs. 1.0%, respectively, p less than 0.03); a transient decrease in spine BMD was seen at six months in the Nutropin-treated patients. Thirty-five percent of subjects treated with this dose had supraphysiological levels of IGF-1 at some point during the study, which may carry unknown risks. No significant improvement in total body BMD was found when compared to placebo. A lower GH dose (0.0125 mg/kg/day) did not show significant increments in either of these bone parameters when compared to placebo. No statistically significant effects on BMD were seen in the adult-onset study where patients received GH (0.0125 mg/kg/day) for one year."

PRECAUTIONS:

Geriatric Use: new subsection -

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

[Other labeling changes not appearing in 1999 PDR: Oct99]

PRECAUTIONS:

Information for Patients: (See Patient Information Leaflet.)

Patient information leaflet provided. Contact the company for a copy of the new labeling.

Return to Quick Reference

Return to Quick Reference