Summary Of Safety-Related Drug Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
October 2001

(Posted: 11/29/2001)

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[Other safety related information not appearing in the 2001 PDR: http://www.fda.gov/medwatch/safety/2001/safety01.htm#accuta]

Labeling provides for revisions to labeling to reflect the System to Manage Accutane Related Teratogenicity (S.M.A.R.T.) Program, an enhanced risk management program to help prevent fetal exposure to Accutane. In addition, this application specifies several evaluation metrics including those related to 1) female participation in the Accutane Survey conducted by the Slone Epidemiology Unit of Boston University, and 2) prescriber and pharmacist compliance with the use of Accutane qualifying stickers.

To accommodate these changes the labeling has been extensively revised. Contact the company for a copy of the new labeling/package insert

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Clinical experience with ANSAID suggests that elderly patients may have a higher incidence of gastrointestinal complaints than younger patients, including abdominal ulceration, bleeding, flatulence, bloating and abdominal pain. To minimize the potential risk for gastrointestinal events, the lowest effective dose should be used for the shortest possible duration (see WARNINGS, Gastrointestinal Effects). Likewise, elderly patients are at greater risk of developing renal decompensation (see PRECAUTIONS, Renal Effects).

The pharmacokinetics of flurbiprofen do not seem to differ in elderly patients from those in younger individuals (see CLINICAL PHARMACOLOGY, Special Populations). The rate of absorption of NSAID was reduced in elderly patients who also received antacids, although the extent of absorption was not affected (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions)

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Mechanism of Action:

Twenty-five children in an unblinded, multicenter trial with supraventricular (SVT) and/or ventricular (VT) tachyarrhythmias, aged between 3 days and 12 years (mostly neonates and infants), received an ascending titration regimen with daily doses of 30, 90 and 210 mg/m ² with dosing every 8 hours for a total of 9 doses. During steady state, the respective average increases above baseline of the QTc interval, in msec (%), were 2(+1%), 14(+4%) and 29(+7%) msec at the 3 dose levels. The respective mean maximum increases above baseline of the QTc interval, in msec (%), were 23(+6%), 36(+9%) and 55(+14%) msec at the 3 dose levels. The steady-state percent increases in the RR interval were 3, 9 and 12%. The smallest children (BSA<0.33m 2 ) showed a tendency for larger Class III effects (D QTc) and an increased frequency of prolongations of the QTc interval as compared with the larger children (BSA ³ 0.33m ² ). The beta-blocking effects also tended to be greater in the smaller children (BSA<0.33.m ² ). Both the Class III and beta-blocking effects of sotalol were linearly related with the plasma concentrations.

The combined analysis of two unblinded, multicenter trials (a single dose and a multiple dose study) with 59 children, aged between 3 days and 12 years, showed the pharmacokinetics of sotalol to be first order. A daily dose of 30 mg/m ² of sotalol was administered in the single dose study and daily doses of 30, 90 and 210 mg/m ² were administered q 8h in the multi-dose study. After rapid absorption with peak levels occurring on average between 2 - 3 hours following administration, sotalol was eliminated with a mean half-life of 9.5 hours. Steady-state was reached after 1 - 2 days. The average peak to trough concentration ratio was 2. BSA was the most important covariate and more relevant than age for the pharmacokinetics of sotalol. The smallest children (BSA<0.33m ² ) exhibited a greater drug exposure (+59%) than the larger children who showed a uniform drug concentration profile. The intersubject variation for oral clearance was 22%.

However, the Class III electrophysiologic and beta-blocking effects, the pharmacokinetics, and the relationship between the effects (QTc interval and resting heart rate) and drug concentrations have been evaluated in children aged between 3 days and 12 year old. (See Clinical Pharmacology section.)

In an unblinded multicenter trial or 25 patients with SVT and/or VT receiving daily doses of 30, 90 and 210 mg/m ² with dosing every 8 hours for a total of 9 doses, no torsade de pointes or other serious new arrhythmias were observed. One (1) patient, receiving 30 mg/m² daily, was discontinued because of increased frequency of sinus pauses/bradycardia. Additional cardiovascular AEs were seen at the 90 and 210 mg/m ² daily dose levels. They included QT prolongations (2 patients), sinus pauses/bradycardia (1 patient), increased severity of atrial flutter and reported chest pain (1 patient). Values for QTc ³ 525 msec were seen in 2 patients at the 210 mg/m ² daily dose level. Serious adverse events including death, torsade de pointe, other proarrhythmias, high-degree A-V blocks and bradycardia have been reported in infants and/or children.

Children: As in adults the following precautionary measures should be considered when initiating sotalol treatment in children: initiation of treatment in the hospital after appropriate clinical assessment; individualized regimen as appropriate; gradual increase of doses if required; careful assessment of therapeutic response and tolerability; and frequent monitoring of the QTc interval and heart rate.

For children aged about 2 years and greater, with normal renal function, doses normalized for body surface area are appropriate for both initial and incremental dosing. Since the Class III potency in children (See Clinical Pharmacology) is not very different from that in adults, reaching plasma concentrations that occur within the adult dose range is an appropriate guide. From pediatric pharmacokinetic data the following is recommended. For initiation of treatment, 30 mg/m ² three times a day (90 mg/m ² total daily dose) is approximately equivalent to the initial 160 mg total daily dose for adults. Subsequent titration to a maximum of 60 mg/m² (approximately equivalent to the 360 mg total daily dose for adults) can then occur. Titration should be guided by clinical response, heart rate and QTc, with increased dosing being preferably carried out in-hospital. At least 36 hours should be allowed between dose increments to attain steady state plasma concentrations of sotalol with age-adjusted normal renal function.

Replaced with -

Healthy geriatric volunteers (>65 years of age) who received a single 1-g dose of

cefprozil had 35%-60% higher AUC and 40% lower renal clearance values compared with healthy adult volunteers 20-40 years of age. [Moved from PREACUTIONS: Geriatric Use subsection] The average AUC in young and elderly female subjects was approximately 15-20% higher than in young and elderly male subjects.

Replaced with -

Labeling provides for the use of Celebrex capsules for the management of acute pain in adults and the treatment of primary dysmenorrhea. Contact the company for a copy of the new labeling/package insert.

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[Other labeling changes not in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/aug01.htm#cozaar ]

[Other labeling changes not in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/mar01.htm#cyklok ]

PRECAUTIONS:

Geriatric Use: Clinical studies of Dantrium Intravenous did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience had not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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Labeling provides for the use of Derma-Smoothe/FS in pediatric patients 2 years and older for the treatment of atopic dermatitis. Contact the company for a copy of the new labeling/package insert.

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DIPROLENE AF Cream is a high-potency corticosteroid indicated for relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 13 years and older.

Use of DIPROLENE AF Cream in pediatric patients 12 years of age and younger is not recommended. (See CLINICAL PHARMACOLOGY and ADVERSE REACTIONS Sections.) In an open label study, 19 of 60 (32%) evaluable pediatric patients (aged 3 months – 12 years old) using DIPROLENE AF Cream for treatment of atopic dermatitis demonstrated HPA axis suppression. The proportion of patients with adrenal suppression in this study was progressively greater, the younger the age group. (See CLINICAL PHARMACOLOGY-Pharmacokinetics.)

Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing’s syndrome than mature patients because of a larger skin surface area to body weight ratio. The study described above supports this premise, as adrenal suppression in 9-12 year olds, 6- 8 year olds, 2-5 year olds, and 3 months – 1 year old was 17%, 32%, 38%, and 50%, respectively.

Labeling revisions provide results of pediatric safety studies conducted with DIPROSONE (betamethasone dipropionate) Products, in patients with atopic dermatitis, 12 years of age and younger.

DIPROSONE Ointment was applied twice daily for 2 to 3 weeks over a mean body surface area of 58% (range 35% to 99%). In 15 of 53 (28%) evaluable patients, adrenal suppression was indicated by either a pre-stimulated cortisol concentration £ 5 mcg/dL pre-stimulation cortisol, or a cosyntropin post-stimulation cortisol £ 18 mcg/dL and an increase of < 7 mcg/dL from the baseline cortisol. Follow-up testing 2 weeks after study completion available for 2 of the 15 patients demonstrated a normally responsive HPA axis.

DIPROSONE Ointment is a high-potency corticosteroid indicated for relief of the inflammatory and pruritic manifestations of corticosteroid-responsive-dermatoses in patients 13 years and older.

5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a patient being treated in the diaper area, as these garments may constitute occlusive dressing. (see DOSAGE AND ADMINISTRATION).

5. Other corticosteroid-containing products should not be used with DIPROSONE Cream without first talking to your physician.

Pediatric Use DIPROSONE Ointment is not recommended in pediatric patients 12 years of age and younger. (See CLINICAL PHARMACOLOGY and ADVERSE REACTIONS Sections.)

Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing's syndrome than mature patients because of a larger skin surface area to body weight ratio. The study described above supports this premise as adrenal suppression in 9-12 year olds, 6-8 year olds, 2-5 year olds, and 3 months – 1 year old was 17%, 27%, 29%, and 36%, respectively.

DIPROSONE Cream was applied twice daily for 2 to 3 weeks over a mean body surface area of 40% (range 35% to 90%). In 10 of 43 (23%) evaluable patients, adrenal suppression was indicated by either a £ 5 mcg/dL pre-stimulation cortisol, or a cosyntropin post-stimulation cortisol £ 18 mcg/dL and/or an increase of < 7 mcg/dL from the baseline cortisol. Studies performed with DIPROSONE Cream indicate that it is in the medium range of potency as compared with other topical corticosteroids.

DIPROSONE Cream is a medium-potency corticosteroid indicated for relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 13 years and older.

5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a patient being treated in the diaper area, as these garments may constitute occlusive dressing. (see DOSAGE AND ADMINISTRATION).

5. Other corticosteroid-containing products should not be used with DIPROSONE Cream without first talking to your physician.

Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing's syndrome than mature patients because of a larger skin surface area to body weight ratio. The study described above supports this premise, as suppression in 9-12 year olds, 6-8 year olds, and 2-5 year olds was 14%, 23%, and 30%, respectively.

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DIPROSONE Lotion is a medium-potency corticosteroid indicated for relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 13 years and older.

5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a patient being treated in the diaper area, as these garments may constitute occlusive dressing. (see DOSAGE AND ADMINISTRATION).

5. Other corticosteroid-containing products should not be used with DIPROSONE Cream without first talking to your physician.

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

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CLINICAL PHARMACOLOGY, Microbiology subsection was extensively revised in order to modify the list of microorganisms that showed in vitro activity. Contact the company for a copy of the new labeling/package insert.

[Not in 2000 PDR]

Convulsions have been reported in patients receiving lomefloxacin.

Meprobamate Tablets

[October 18, 2001: Eon]

PRECAUTIONS

Geriatric Use:

Clinical studies of meprobamate 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, dose selection for an elderly patient should be cautious, 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.

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[Other labeling changes not in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/apr01.htm#mevaco ]

[Changes not appearing in 2000 PDR]

The first paragraph revised and a new second paragraph added:

MYAMBUTOL may produce decreases in visual acuity which appear to be due to optic neuritis. This effect may be related to dose and duration of treatment. The effects are This effect is generally reversible when administration of the drug is discontinued promptly. In rare cases recovery may be delayed for up to one year or more. and effect may possibly be irreversible in these cases Irreversible blindness has been reported.

Last sentence in the seventh paragraph revised concerning visual acuity:

Patients have then Some patients have received MYAMBUTOL ethambutol hydrochloride again after such recovery without recurrence of loss of visual acuity.

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Labeling provides for revised labeling text based on the results of a Phase 4 study conducted by the Southwest Oncology Group (SWOG 9308).

Labeling revisions, linked to the data from the trial, are extensive. These include new information from SWOG 9308 in the CLINICAL TRIALS sections, the ADVERSE REACTIONS sections, the DOSAGE AND ADMINISTRATION section. Contact the company for a copy of the new labeling/package insert.

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The concurrent administration of a MAO inhibitor and bupropion hydrochloride (Wellbutrin, Wellbutrin SR, Zyban, GlaxoSmithKline) is contraindicated.

Rare instances of hepatitis, skin rash and alopecia have been reported.

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New last paragraph -

and DOSAGE AND

ADMINISTRATION sections -

First paragraph, fourth sentence revised:

The drug should be discontinued in the presence of agranulocytosis, aplastic anemia (pancytopenia), ANCA-positive vasculitis, hepatitis, interstitial pneumonitis, fever or exfoliative dermatitis.

Anticoagulants (oral): The activity of anticoagulants may be potentiated by anti-vitamin-K activity attributed to propylthiouracil.

Theophylline: Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed.

Under "Major adverse reactions..."

Under "Minor adverse reactions..." the following was added -

taste perversion.

[Other labeling changes not in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/may01.htm#proton , http://www.fda.gov/medwatch/SAFETY/2001/jun01.htm#proton]

[Other safety related labeling changes: http://www.fda.gov/medwatch/SAFETY/2001/jul01.htm#proton2 ]

[Other labeling changes not in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/mar01.htm#rebetr, http://www.fda.gov/medwatch/SAFETY/2001/feb01.htm#rebetr ]

BOXED WARNING:

ADVERSE REACTIONS:

Third paragraph, second, third and fourth sentences.

However, as with all NSAIDs, patients with impaired renal function should be monitored more closely than patients with normal renal function (see CLINICAL PHARMACOLOGY, Renal Insufficiency). In patients with severe renal impairment (creatinine clearance £ 30 mL/min.), laboratory tests should be performed at baseline and within weeks of starting therapy. Further tests should be carried out as necessary; if the impairment worsens, discontinuation of therapy may be warranted.

Incidence <1%- Probably Causally Related†

Gastrointestinal: hepatic failure

Dermatologic: erythema multiforme, Stevens-Johnson Syndrome [Moved from "Incidence <1%- Causal relationship Unknown"]

Respiratory: idiopathic interstitial pneumonitis

Genitourinary: renal failure

Hematologic/Lymphatic: Thrombocytopenia [Moved from "Incidence <1%- Causal relationship Unknown"]

† Adverse reactions reported only in worldwide postmarketing experience or in the literature, not seen in clinical trials, are considered rarer and are italicized.

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[Other labeling changes not in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/mar01.htm#retrov ]

Geriatric Use: Clinical studies of RETROVIR 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, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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In addition, the following adverse events have been identified during post-approval use of products which contain (or are metabolized to) mesalamine in clinical practice: nephrotoxicity, pancreatitis, fibrosing alveolitis and elevated liver enzymes. Cases of pancreatitis and fibrosing alveolitis have been reported as manifestations of inflammatory bowel disease as well. Published case reports and/or spontaneous post marketing surveillance have described rare instances of aplastic anemia, agranulocytosis, thrombocytopenia, or eosinophilia. Anemia, leukocytosis, and thrombocytosis can be part of the clinical presentation of inflammatory bowel disease.

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The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV infection. Studies in rats have demonstrated that efavirenz is secreted in milk. Mothers should be instructed not to breast-feed if they are receiving SUSTIVA."

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Although it is not known if efavirenz is secreted in human milk, efavirenz is secreted into the milk of lactating rats. Because of the potential for HIV transmission and the potential for serious adverse effects in nursing infants, mothers should be instructed not to breast-feed if they are receiving SUSTIVA.

ALERT: Find out about medicines that should NOT be taken with SUSTIVA. This statement is also included on the product's bottle labels.

Concomitant use of SUSTIVA and St. John’s Wort (hypericum perforatum) or St. John’s Wort containing products is not recommended. Coadministration of non-nucleoside reverse transcriptase inhibitors (NNRTI), including SUSTIVA, with St. John’s Wort is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels and lead to loss of virologic response and possible resistance to SUSTIVA or to the class of NNRTIs.

A statement to patients and healthcare providers is included on the product's bottle labels: ALERT: Find out about medicines that should NOT be taken with SUSTIVA. A Patient Package Insert (PPI) for SUSTIVA is available for patient information.

SUSTIVA may interact with some drugs, therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John’s Wort.

ALERT: Find out about medicines that should NOT be taken with SUSTIVA.

Please also read the section "MEDICINES YOU SHOULD NOT TAKE WITH SUSTIVA."

Taking SUSTIVA with St. John’s Wort (hypericum perforatum) or St. John’s Wort containing products is not recommended. Talk with your doctor if you are taking or are planning to take St. John’s Wort. Taking St. John’s Wort may decrease SUSTIVA levels and lead to increased viral load and possible resistance or cross-resistance to other antiretroviral drugs.

Figure 3

Table 4

Serious psychiatric adverse experiences have been reported in patients treated with SUSTIVA. In controlled trials of 1,008 patients treated with regimens containing SUSTIVA and 635 patients treated with control regimens, the frequency of specific serious psychiatric events among patients who received SUSTIVA or control regimens, respectively, were: severe depression (0.9%, 0.5%), suicidal ideation/attempts (0.5%, 0.3%), aggressive behavior (0.3%, 0.3%), paranoid reactions (0.2%, 0.2%) and manic reactions (0.1%, 0%). Patients with a prior history of psychiatric disorders appear to be at greater risk for these serious psychiatric adverse experiences, with the frequency of each of the above events approximating 1%.

Serious psychiatric adverse experiences have been reported in patients treated with SUSTIVA. In controlled trials of 1008 patients treated with regimens containing SUSTIVA for an average of 1.6 years and 635 patients treated with control regimens for an average of 1.3 years, the frequency of specific serious psychiatric events among patients who received SUSTIVA or control regimens, respectively, were: severe depression (1.6%, 0.6%), suicidal ideation (0.6%, 0.3%), non-fatal suicide attempts (0.4%, 0%), aggressive behavior (0.4%, 0.3%), paranoid reactions (0.4%, 0.3%) and manic reactions (0.1%, 0%). Patients with a history of psychiatric disorders appear to be at greater risk of these serious psychiatric adverse experiences, with the frequency of each of the above events ranging from 0.3% for manic reactions to 2.0% for both severe depression and suicidal ideation.

Serious psychiatric adverse experiences have been reported in patients treated with SUSTIVA. In controlled trials the frequency of specific serious psychiatric symptoms among patients who received SUSTIVA or control regimens, respectively, were: severe depression (0.9%, 0.5%), suicidal ideation or attempts (0.5%, 0.3%), aggressive behavior (0.3%, 0.3%), paranoid reactions (0.2%, 0.2%) and manic reactions (0.1%, 0%) (see WARNINGS; Psychiatric Symptoms). Additional psychiatric symptoms observed at a frequency of >2% among patients treated with SUSTIVA or control regimens, respectively, in controlled clinical trials were depression (10.0%, 8.2%), anxiety (8.2%, 5.5%), and nervousness (5.9%, 1.9%).

Serious psychiatric adverse experiences have been reported in patients treated withmSUSTIVA. In controlled trials the frequency of specific serious psychiatric symptoms among patients who received SUSTIVA or control regimens, respectively, were: severe depression (1.6%, 0.6%), suicidal ideation (0.6%, 0.3%), non-fatal suicide attempts (0.4%, 0%), aggressive behavior (0.4%, 0.3%), paranoid reactions (0.4%, 0.3%) and manic reactions (0.1%, 0%) (see WARNINGS; Psychiatric Symptoms). Additional psychiatric symptoms observed at a frequency of >2% among patients treated with SUSTIVA or control regimens, respectively, in controlled clinical trials were depression (15.8%, 13.1%), anxiety (11.1%, 7.6%), and nervousness (6.3%, 2.0%).

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PRECAUTIONS

Geriatric Use

Labeling provides for the use of Tazorac (tazarotene) Cream, 0.1%, for acne vulgaris.

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

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[Other labeling changes not in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/aug01.htm#tequin ]

Susceptibility Tests

For testing Haemophilus influenzae and Haemophilus parainfluenzae ^a :

Although not seen in clinical trials of TEQUIN Ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones.

As with other quinolones, Disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with TEQUIN (as with other quinolones), usually in diabetic patients. receiving concomitant treatment with oral hypoglycemic agents (e.g., glyburide) with or without insulin. In these patients, The careful monitoring of blood glucose is recommended when TEQUIN is administered to patients with diabetes. If a hypoglycemic reaction occurs in or signs and symptoms of hyperglycemia occur in any patient being treated with TEQUIN, appropriate therapy should be initiated immediately and TEQUIN should be discontinued. (See CLINICAL PHARMACOLOGY, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS.)

Patients should be advised:

• that disturbances of blood glucose, including including symptomatic hyper- and hypoglycemia, have been reported with TEQUIN (as with other quinolones), usually in diabetic patients. If a hypoglycemic reaction or symptoms of hyperglycemia occur, patients should initiate appropriate therapy immediately, discontinue TEQUIN, and contact a physician (see PRECAUTIONS: General and Drug Interactions ).

Compatible intravenous solutions: Because a hypotonic solution results, Water for Injection should not be used as a diluent when preparing a 2 mg/mL solution from the concentrated solution of gatifloxacin (10 mg/mL) (see PRECAUTIONS).

If you have diabetes, it is important to let your healthcare provider know if you are on oral hypoglycemic agents with or without insulin that you have this condition and what mediations you are taking for it.

 

What are the possible side effects of TEQUIN?

If you have diabetes, you should know that Disturbances of blood sugar, including high blood sugar (hyperglycemia) and low blood sugar (hypoglycemia), have been reported in patients treated concomitantly with TEQUIN (as with other quinolone antibiotics), and oral antdiabetic drugs with or without insulin usually in diabetic patients. If you develop symptoms of low blood sugar while on TEQUIN, you should take immediate measures to increase your blood sugar, stop taking TEQUIN, and contact your healthcare professional at once. If you develop high blood sugar while on TEQUIN, you should stop taking TEQUIN, and contact your healthcare professional at once. If you have diabetes or suspect that you may have diabetes, discuss how to detect changes in your blood sugar with your healthcare professional.

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TONOCARD (tocainide HCl) Tablets

[October 24, 2001: AstraZeneca]

PRECAUTIONS:

Nursing Mothers

It is not known whether tocainide is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from TONOCARD, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Tocainide is secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from TONOCARD, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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TRILAFON (perphenazine) Tablets & Injection

[October 18, 2001: Schering]

WARNINGS

Older patients are at increased risk for development of tardive dyskinesia.

Given these considerations, especially in the elderly, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

PRECAUTIONS

Drug Interactions: Metabolism of a number of medications, including antipsychotics, antidepressants, $ - blockers, and antiarrhythmics, occurs through the cytochrome P450 2D6 isoenzyme (debrisoquine hydroxylase). Approximately 10% of the Caucasian population has reduced activity of this enzyme, so-called iopoorle metabolizers. Among other populations the prevalence is not known. Poor metabolizers demonstrate higher plasma concentrations of antipsychotic drugs at usual doses, which may correlate with emergence of side effects. In one study of 45 elderly patients suffering from dementia treated with perphenazine, the 5 patients who were prospectively identified as poor P450 2D6 metabolizers had reported significantly greater side effects during the first 10 days of treatment than the 40 extensive metabolizers, following which the groups tended to converge. Prospective phenotyping of elderly patients prior to antipsychotic treatment may identify those at risk for adverse events.

The concomitant administration of other drugs that inhibit the activity of P450 2D6 may acutely increase plasma concentrations of antipsychotics. Among these are tricyclic antidepressants and selective serotonin reuptake inhibitors, e.g.fluoxetine, sertraline and paroxetine. When prescribing these drugs to patients already receiving antipsychotic therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the antipsychotic or the other drug may be required.

Geriatric Use: Clinical studies of TRILAFON products did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic function, concomitant disease or other drug therapy.

Geriatric patients are particularly sensitive to the side effects of antipsychotics, including TRILAFON. These side effects include extrapyramidal symptoms (tardive dyskinesia, antipsychotic-induced parkinsonism, akathisia), anticholinergic effects, sedation and orthostatic hypotension (See WARNINGS). Elderly patients taking psychotropic drugs may be at increased risk for falling and consequent hip fractures. Elderly patients should be started on lower doses and observed closely.

DOSAGE AND ADMINISTRATION

Elderly patients: With increasing age, plasma concentrations of perphenazine per daily ingested dose increase. Geriatric dosages of perphenazine preparations have not been established, but initiation of lower dosages is recommended. Optimal clinical effect or benefit may require lower doses for a longer duration. Dosing of perphenazine may occur before bedtime, if required.

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ZERIT (stavidine) Capsules & Pediatric Oral Solution

[October 16, 2001: Bristol-Myers Squibb]

Labeling changes described in January 5, 2001 Safety Letter:

http://www.fda.gov/medwatch/safety/2001/safety01.htm#zerit

WARNING

LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING STAVUDINE AND OTHER ANTIRETROVIRALS. FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION OF STAVUDINE AND DIDANOSINE WITH OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF STAVUDINE AND DIDANOSINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS: PREGNANCY).

FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WHEN ZERIT WAS PART OF A COMBINATION REGIMEN THAT INCLUDED DIDANOSINE, WITH OR WITHOUT HYDROXYUREA, IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION (SEE WARNINGS).

WARNINGS

Lactic Acidosis/Severe

Hepatomegaly with Steatosis/Hepatic failure:

Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk (see PRECAUTIONS: Pregnancy)

PRECAUTIONS: Pregnancy

Second and third paragraphs added:

There are no adequate and well-controlled studies of stavudine in pregnant women. Stavudine should be used during pregnancy only if the potential benefit justifies the potential risk.

Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic Acidosis/Severe Hepatomegaly with Steatosis/Hepatic Failure). The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Health care providers caring for HIV-infected women receiving stavudine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.

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ZINACEF (cefuroxime) Injection

[October 12, 2001: GlaxoSmithKline]

PRECAUTIONS:

General:

Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous Vitamin K administered as indicated.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Although lifetime studies in animals have not been performed to evaluate carcinogenic potential, no mutagenic activity was found for cefuroxime in the mouse lymphoma assay and a battery of bacterial mutation tests. Positive results were obtained in an in vitro chromosome aberration assay, however, negative results were found in an in vivo micronucleus test at doses up to 10 g/kg. Reproduction studies in mice at doses up to 3200 mg/kg per day (3.1 times the recommended maximum human dose based on mg/m 2 ) have revealed no impairment of fertility.

Reproductive studies revealed no impairment of fertility in animals.

Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in mice at doses up to 6400 mg/kg per day (6.3 times the recommended maximum human dose based on mg/m 2 ) and rabbits at doses up to 400 mg/kg per day (2.1 times the recommended maximum human dose based on mg/m 2 ) and have revealed no evidence of impaired fertility or harm to the fetus due to cefuroxime. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Geriatric Use: Of the 1914 subjects who received cefuroxime in 24 clinical studies of ZINACEF, 901 (47%) were 65 and over while 421 (22%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater susceptibility of some older individuals to drug effects cannot be ruled out. 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 (see DOSAGE AND ADMINISTRATION).

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ZOLOFT (sertraline HCl) Tablets & Oral Concentrate

[October 12, 2001: Pfizer]

[Other labeling changes not in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/aug01.htm#zoloft ,

http://www.fda.gov/medwatch/SAFETY/2001/feb01.htm#zoloft ]

PRECAUTIONS

Pediatric Use–The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17 (see Clinical Trials under CLINICAL PHARMACOLOGY). The effectiveness efficacy of ZOLOFT in pediatric patients with major depressive disorder, or panic disorder or PTSD has not been systematically evaluated.

The safety of ZOLOFT use in children and adolescents, ages 6-18, was evaluated in a 12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible dose, 52 week open extension study of 137 patients, ages 6-18, who had completed the initial 12-week, double-blind, placebo-controlled study. ZOLOFT was administered at doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in weekly 25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based upon clinical response. The mean dose for completers was 157 mg/day. In the acute 12 week pediatric study and in the 52 week study, ZOLOFT had an adverse event profile generally similar to that observed in adults.

Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 18 years of age with major depressive disorder and/or OCD and revealed similar drug exposures to those of adults when plasma concentration was adjusted for weight (see Pharmacokinetics under CLINICAL PHARMACOLOGY).

The risks, if any, that may be associated with sertraline’s extended use in children and adolescents with OCD have not been systematically assessed. The risks, if any, that may be associated with Zoloft’s use beyond 1 year in children and adolescents with OCD have not been systematically assessed. The prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for use in children and adolescents derives from relatively short-term clinical studies that were 12 to 52 weeks in duration and from the extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long-term sertraline use on the growth, development, and maturation of children and adolescents. Although there is no affirmative finding to suggest that sertraline possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of sertraline to have adverse effects in chronic use.

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