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

(Posted: 12/17/2001)

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Revised for ATACAND Tablets and added as a new subsection to the ATACAND HCT Tablets.

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Added

Revised

Revised

Revised

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4^th paragraph revised

Among 839 patients with NYHA class II-III heart failure treated for 26 to 52 weeks in 4 U.S. placebo-controlled trials, the average left ventricular ejection fraction (EF) measured by radionuclide ventriculography increased by 8 9 EF units (%) in Coreg patients and by 2 EF units in placebo patients ( between group difference of 6 EF units) This treatment effect was. at a target dose of 25-50 mg b.i.d. The effects of carvedilol on ejection fraction were related to dose. Doses of 6.25 mg b.i.d., 12.5 mg b.i.d. and 25 mg b.i.d. were associated with placebo-corrected increases in EF of 5 EF units, 6 EF units and 8 EF units, respectively; each of these effects were nominally statistically significant in each trial.

revised

Coreg had a consistent and beneficial effect on all-cause mortality as well as the combined endpoints of all-cause mortality plus hospitalization (total, CV or for heart failure) in the overall study population and in all subgroups examined, including men and women, elderly and non-elderly, black and non-black.

Four U.S. multicenter, double-blind, placebo-controlled studies enrolled 1094 patients (696 randomized to carvedilol) with NYHA class II-III heart failure and ejection fraction <0.35. The vast majority were on digitalis, diuretics, and an ACE inhibitor at study entry. Patients were assigned to the studies based upon exercise ability. An Australia-New Zealand double-blind, placebo-controlled study enrolled 415 patients (half randomized to carvedilol) with less severe heart failure. All protocols excluded patients expected to undergo cardiac surgery during the 6 to 12 months of double-blind follow-up transplantation during the 7.5 to 15 months of double-blind follow-up.. All randomized patients had tolerated a 2-week course on carvedilol 6.25 mg b.i.d.

Mortality: Mortality was not a planned end-point in any of the U.S. or Austrailia-New Zealand studies. Overall, in the U.S. trials, mortality was reduced, nominally significantly so in 2 studies, but the actual effect size and statistical significance of this observation are difficult to define.

Mortality: Overall, in these four U.S. trials, mortality was reduced, nominally significantly so in 2 studies.

first paragraph revised

Coreg is indicated for the treatment of mild or moderate (NYHA class II or III) severe heart failure of ischemic or car-diomyopathic origin, in conjunction with usually in addition to diuretics, ACE inhibitor and digitalis, diuretics, and ACE inhibitor, to reduce the progression of disease as evidenced by cardiovascular death, cardiovascular hospitalization, or the need to adjust other heart failure medications. to increase survival and, also, to reduce the risk of hospitalization.

first paragraph revised

Coreg is contraindicated in patients with NYHA class IV decompensated cardiac failure requiring intravenous inotropic therapy, bronchial asthma (two cases of death from status asthmaticus have been reported in patients receiving single doses of Coreg ) or related bronchospastic conditions, second- or third-degree AV block, sick sinus syndrome or severe bradycardia (unless a permanent pacemaker is in place) ); or in patients with cardiogenic shock or severe bradycardia. who have decompensated heart failure requiring the use of intravenous inotropic therapy. Such patients should first be weaned from intravenous therapy before initiating Coreg.

2^nd and 3^rd paragraphs revised

In controlled studies of primarily mild-to-moderate congestive heart failure, the incidence of liver function abnormalities reported as adverse experiences was 5.0% (38 of 765 patients) in patients receiving Coreg and 4.6% (20 of 437 patients) in those receiving placebo. Three patients receiving carvedilol Coreg (0.4%) and two patients receiving placebo (0.5%) in placebo-controlled trials withdrew for abnormal hepatic function. Similarly, in a long-term, placebo-controlled trial in severe heart failure, there was no difference in the incidence of liver function abnormalities reported as adverse experiences between patients receiving Coreg and those receiving placebo. No patients receiving Coreg and one patient receiving placebo (0.09%) withdrew for hepatitis. In addition, patients treated with Coreg had lower values for hepatic transaminases than patients treated with placebo, possibly because Coreg-induced improvements in cardiac function led to less hepatic congestion and/or improved hepatic blood flow.

Hepatic injury has been reversible and has occurred after short- and/or long-term therapy with minimal clinical symptomatology. No deaths due to liver function abnormalities have been reported in association with the use of Coreg.

first sentence revised

In general, b -blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.

first paragraph revised

Since Coreg (carvedilol) has b -blocking activity, it should not be discontinued abruptly, particularly in patients with ischemic heart disease. Instead, it should be discontinued over 1 to 2 weeks, whenever possible.

3^rd paragraph revised

In clinical trials of primarily mild-to-moderate heart failure, Hhypotension and postural

hypotension occurred in 9.7% and syncope in 3.4% of patients receiving carvedilolCoreg compared to 3.6% and 2.5% of placebo patients, respectively. The risk for these events was highest during the first 30 days of dosing, corresponding to the up-titration period and was a cause for discontinuation of therapy in 0.7% of carvedilolCoreg patients, compared to 0.4% of placebo patients. In a long-term, placebo-controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure patients receiving Coreg compared to 8.7% and 2.3% of placebo patients, respectively. These events were a cause for discontinuation of therapy in 1.1% of Coreg patients, compared to 0.8% of placebo patients.

7^th paragraph revised

Worsening cardiac heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes (see DOSAGE AND ADMINISTRATION). Occasionally, it is necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of or a favorable response to carvedilol. In a placebo-controlled trial of patients with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in patients treated with carvedilol than with placebo. Worsening heart failure observed during long-term therapy is more likely to be related to the patients’ underlying disease than to treatment with carvedilol.

Deleted

Hypertensive Patients with Left Ventricular Failure: In hypertensive patients who have congestive heart failure controlled with digitalis, diuretics and/or an angiotensin-converting enzyme inhibitor, Coreg (carvedilol) may be used. However, since it is likely that such patients are dependent, in part, on sympathetic stimulation for circulatory support, it is recommended that dosing follow the instructions for patients with congestive heart failure.

first paragraph revised

Of the 765 patients with congestive heart failure randomized to Coreg in U.S. clinical trials, 31% (235) were 65 years of age or older. Of 1,869 patients receiving Coreg in congestive heart failure trials worldwide, 39% were 65 years of age or older. Of the 1156 patients randomized to Coreg in a long-term, placebo-controlled trial in severe heart failure, 47% (547) were 65 years of age or older. Of 3,025 patients receiving Coreg in congestive heart failure trials worldwide, 42% were 65 years of age or older. There were no notable differences in efficacy or the incidence of adverse events between older and younger patients.

revised

Coreg has been evaluated for safety in congestive heart failure in more than 1,900 3,000 patients worldwide of whom 1,300 more than 2100 participated in U.S. placebo-controlled clinical trials. Approximately 54% 60%of the total treated population received Coreg for at least 6 months and 20% 30% received Coreg for at least 12 months. The adverse experience profile of Coreg in congestive heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In U.S. clinical trials comparing Coreg in in mild-to-moderate heart failure that compared Coreg daily doses up to 100 mg (n=765) to placebo (n=437), 5.4% of Coreg patients discontinued for adverse experiences vs. 8.0% of placebo patients. In a multinational clinical trial in severe heart failure (COPERNICUS) that compared Coreg in daily doses up to 50 mg (n=1156) with placebo (n=1133), 9.4% of Coreg patients discontinued treatment for adverse experiences vs. 11.2% of placebo patients.

Table 1 2 shows adverse events reported in patients with mild-to-moderate heart failure enrolled in U.S. placebo-controlled clinical trials of congestive heart failure patients that occurred with an incidence of greater than 2% regardless of causality and were more frequent in drug-treated patients than placebo-treated patients. Median study medication exposure was 6.33 months for both Coreg (carvedilol) and placebo patients. Shown are adverse events that occurred more frequently in drug-treated patients than placebo-treated patients with an incidence >2% regardless of causality. Median study medication exposure was 6.33 months for both carvedilol and placebo patients.

2^nd paragraph and the table revised

Table 2 4 shows adverse events in U.S. placebo-controlled clinical trials for hypertension that occurred with an incidence of greater than 1% regardless of causality, and that were more frequent in drug-treated patients than placebo-treated patients.

Table 4. Adverse Events in U.S. Placebo-Controlled Hypertension Trials

In addition to the events in Table 24, abdominal pain, back pain, chest pain, dependent edema, dyspepsia, dyspnea, fatigue, headache, injury, nausea, pain, rhinitis, sinusitis somnolence, and upper respiratory tract infection were also reported, but rates were at least as great in placebo-treated patients.

The following adverse events not described above were reported as possibly or probably related to Coreg in worldwide open or controlled trials with Coreg (carvedilol) in patients with hypertension or congestive heart failure.

deleted

Urinary System: Micturition frequency increased.

Metabolic and Nutritional: Hypokalemia, diabetes mellitus, hypertriglyceridemia

Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non-elderly, blacks and non-blacks).

revised

DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP-TITRATION. Prior to initiation of Coreg, the dosing of digitalis, diuretics and ACE inhibitors (if used) should be stabilized it is recommended that fluid retention be minimized. The recommended starting dose of Coreg is 3.125 mg twice daily for two weeks. If this dose is tolerated, it can then be increased to 6.25 mg twice daily. Dosing should then be doubled every 2 weeks to the highest level tolerated by the patient. At initiation of each new dose, patients should be observed for signs of dizziness or light-headedness for one hour. The maximum recommended dose is 25 mg twice daily in patients weighing less than 85 kg (187 lbs) and 50 mg twice daily in patients weighing more than 85 kg. Coreg (carvedilol) should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects.

The following BOX WARNING: is added:

INDICATIONS AND USAGE:

revised

INAPSINE (droperidol) is indicated:

CONTRAINDICATIONS:

Revised

WARNINGS:

revised

FLUIDS AND OTHER COUNTERMEASURES TO MANAGE HYPOTENSION SHOULD BE READILY AVAILABLE.

As with other CNS depressant drugs, patients who have received INAPSINE (droperidol) should have appropriate surveillance.

It is recommended that opioids, when required, initially be used in reduced doses. As with other neuroleptic agents, very rare reports of neuroleptic malignant syndrome (altered consciousness, muscle rigidity and autonomic instability) have occurred in patients who have received INAPSINE (droperidol).

Since it may be difficult to distinguish neuroleptic malignant syndrome from malignant hyperpyrexia in the perioperative period, prompt treatment with dantrolene should be considered if increases in temperature, heart rate or carbon dioxide production occur.

fourth paragraph revised

Vital signs and ECG should be monitored routinely.

Drug Interactions:

added

Potentially Arrhythmogenic Agents: Any drug known to have the potential to prolong the QT interval should not be used together with INAPSINE. Possible pharmacodynamic interactions can occur between INAPSINE and potentially arrhythmogenic agents such as class I or III antiarrhythmics, antihistamines that prolong the QT interval, antimalarials, calcium channel blockers, neuroleptics that prolong the QT interval, and antidepressants.

CNS Depressant Drugs: Other CNS depressant drugs (e.g., barbiturates, tranquilizers, opioids, and general anesthetics) have additive or potentiating effects with INAPSINE. When patients have received such drugs, the dose of INAPSINE required will be less than usual. Following the administration of INAPSINE, the dose of other CNS depressant drugs should be reduced.

ADVERSE REACTIONS:

added

OVERDOSAGE:

1^st paragraph revised

Manifestations: The manifestations of INAPSINE (droperidol) overdosage are an extension of its pharmacologic actions and may include QT prolongation and serious arrhythmias (e.g., torsade de pointes) (see BOX WARNING, WARNINGS, and PRECAUTIONS).

4^th paragraph revised

The intravenous LD₅₀ Median Lethal Dose of INAPSINE is 20-43 mg/kg in mice; 30 mg/kg in rats: 25 mg/kg in dogs and 11-13 mg/kg in rabbits. The intramuscular intravenous LD₅₀ Median Lethal Dose of INAPSINE is 195 mg/kg in mice; 104-110 mg/kg in rats; 97 mg/kg in rabbits and 200 mg/kg in guinea pigs.

DOSAGE AND ADMINISTRATION:

Revised

Vital signs and ECG should be monitored routinely.

See WARNINGS and PRECAUTIONS for use of INAPSINE with other CNS depressants and in patients with altered response.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If such abnormalities are observed, the drug should not be administered.

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

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Contact sponsor for the details.

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[other safety-related labeling changes not found in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/sep01.htm#lupron]

Added as #5

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new subheadings added and the text re-ordered and revised

Absorption:Following a single oral dose of 300 mg to nine healthy adult volunteers, rifabutin was readily absorbed from the gastrointestinal tract with mean (+/-SD) peak plasma levels (Cmax) of 375 (+/-267) ng/mL (range: 141 to 1033 ng/mL) attained in 3.3 (+/-0.9) hours (Tmax range: 2 to 4 hours). Absolute bioavailability assessed in five HIV-positive patients, who received both oral and intravenous doses, averaged 20%. Total recovery of radioactivity in the urine indicates that at least 53% of the orally administered rifabutin dose is absorbed from the gastrointestinal tract. The bioavailability of rifabutin from the capsule dosage form, relative to an oral solution, was 85% in 12 healthy adult volunteers. High-fat meals slow the rate without influencing the extent of absorption from the capsule dosage form. Plasma concentrations post-Cmax declined in an apparent biphasic manner. kinetic Pharmacokinetic dose-proportionality was has been established over the 300 to 600 mg dose range in nine healthy adult volunteers (crossover design) and in 16 early symptomatic human immunodeficiency virus (HIV)-positive patients over a 300 to 900 mg dose range.

Distribution: Rifabutin, Due to its high lipophilicity, rifabutin demonstrates a high propensity for distribution and intracellular tissue uptake. Estimates of apparent steady-state distribution volume (9.3 ± 1.5 L/kg) in five HIV-positive patients, following I.V. dosing, exceed total body water by approximately 15-fold. Substantially higher intracellular tissue levels than those seen in plasma have been observed in both rat and man. . Following intravenous dosing, estimates of apparent steady-state distribution volume (9.3 +/- 1.5 L/kg) in five HIV-positive patients exceeded total body water by approximately 15-fold. Substantially higher intracellular tissue levels than those seen in plasma have been observed in both rat and man. The lung to plasma concentration ratio, obtained at 12 hours, was found to be approximately 6.5 in four surgical patients administered an oral dose. Mean rifabutin steady-state trough levels (Cp,min SS ; 24-hour post-dose) ranged from 50 to 65 ng/mL in HIV-positive patients and in healthy adult volunteers. About 85% of the drug is bound in a concentration-independent manner to plasma proteins over a concentration range of 0.05 to 1 mg/mL. Binding does not appear to be influenced by renal or hepatic dysfunction. Rifabutin was slowly eliminated from plasma in seven healthy adult volunteers, presumably because of distribution-limited elimination, with a mean terminal half-life of 45 (+/- 17) hours (range: 16 to 69 hours). Although the systemic levels of rifabutin following multiple dosing decreased by 38%, its terminal half-life remained unchanged.

Metabolism: Of the five metabolites that have been identified, 25-O-desacetyl and 31-hydroxy are the most predominant, and show a plasma metabolite:parent area under the curve ratio of 0.10 and 0.07, respectively. The former has an activity equal to the parent drug and contributes up to 10% to the total antimicrobial activity.

Excretion:"Mean systemic clearance (CLS/F) in healthy adult volunteers following a single oral dose was 0.69 (±0.32) L/hr/kg (range: 0.46 to 1.34 L/hr/kg). Renal and biliary clearance of unchanged drug each contribute approximately 5% to CLS/F. About 30% of the dose is excreted in the feces. A mass-balance study in three healthy adult volunteers with 14 C-labeled drug has shown that 53% of the oral dose was excreted in the urine, primarily as metabolites.

·Pharmacokinetics in Special Populations:

Compared to healthy volunteers, steady-state kinetics of MYCOBUTIN are more variable in elderly patients (>70 years).

Pediatric: The pharmacokinetics of MYCOBUTIN have not been studied in subjects under 18 years of age.

Drug-Drug Interactions (see also PRECAUTIONS-Drug Interactions)

Delavirdine: In 7 HIV-infected patients, rifabutin (300 mg/day) decreased delavirdine (400 mg q 8h) AUC by about 80%, Cmax by about 75%, and mean trough plasma concentrations by about 95%. Based on comparisons with historical data, delavirdine appeared to increase the AUC of rifabutin by at least 100% (see PRECAUTIONS-Drug Interactions).

Clarithromycin: In studies conducted in HIV-infected patients, coadministration of rifabutin (300 mg/day) and clarithromycin (500 mg q 12h) decreased the AUC of clarithromycin by about 50% (n=12) and increased the AUC of rifabutin by about 75% (n=14) (see PRECAUTIONS-Drug Interactions).

Methadone: Rifabutin did not alter the pharmacokinetics of methadone in 24 HIV-infected, methadone-maintained, former intravenous drug users.

revised

Effects on Other Drugs: Rifabutin induces CYP3A enzymes and therefore may reduce the plasma concentrations of drugs metabolized by those enzymes. This effect may reduce the efficacy of standard doses of such drugs, which include itraconazole, clarithromycin, and saquinavir (see CLINICAL PHARMACOLOGY-Drug-Drug Interactions).

Effects on Rifabutin: Some drugs that inhibit CYP3A may significantly increase the plasma concentration of rifabutin. Because high plasma levels of rifabutin may increase the risk of adverse reactions, carefully monitor patients receiving coadministration of such drugs, which include fluconazole and clarithromycin (see CLINICAL PHARMACOLOGY-Drug-Drug Interactions). In some cases, the dosage of MYCOBUTIN may need to be reduced when it is coadministered with such a drug (see below).

revised statement is added at the end.

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Clinical studies of PRIMAXIN I.M. did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects; however, clinical studies of PRIMAXIN I.V. in a sufficient number of subjects aged 65 and over have not revealed overall differences in safety or effectiveness between these subjects and younger subjects (refer to the package circular for PRIMAXIN I.V.). 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.

PRECAUTIONS:

Pediatric Use

revised

Safety and effectiveness of 20% ProSol™ - sulfite-free (Amino Acid) Injection solution have not been established by adequate and well controlled studies in pediatric patients have not been established.

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Added for Reglan Injection

added after the second paragraph

second sentence of the last paragraph revised

Although adverse events related to this possibility have not been reported to date, the This possibility should be considered and weighed when deciding whether to use metoclopramide or nasogastric suction in the prevention of postoperative nausea and vomiting."

Hypotension…fluid retention, acute congestive heart failure, and possible AV block (see CONTRAINDICATIONS and PRECAUTIONS).

added after the paragraph which begins,

"Store vials and ampuls in carton until used…" "This product is light sensitive. It should be inspected before use and discarded if either color or particulate is observed."

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Revisions same as that approved August 25, 2000 for Rocephin (ceftriaxone injection)

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

added

revised

The safety of SINGULAIR 4-mg chewable tablets in pediatric patients 2 to 5 years of age has been demonstrated in an interim analysis of 314 pediatric patients in a 12-week double-blind, placebo-controlled study in approximately 650 patients by adequate and well-controlled data (see ADVERSE REACTIONS ). The efficacy of SINGULAIR is supported in this age group is extrapolated by extrapolation from the demonstrated efficacy in adolescent and adult patients 15 6 years of age and older and pediatric patients 6 to 14 years of age with asthma based and is based on similar mean systemic exposure (AUC) pharmacokinetic data, and as well as the assumption that the disease course, pathophysiology and the drug's effect are substantially similar among these populations. Efficacy in this age group is further supported by efficacy assessments from a large, well- controlled safety study conducted in patients 2 to 5 years of age.

Safety data for SINGULAIR in pediatric patients 2 to 5 years of age are available from an interim analysis of 314 pediatric patients from a 12-week, double-blind, placebo-controlled clinical study in approximately 650 patients. The safety profile of SINGULAIR in this interim analysis of patients who received SINGULAIR for at least 6 weeks was generally similar to the safety profile in pediatric patients 6 to 14 years of age. SINGULAIR has been evaluated for safety in 573 pediatric patients 2 to 5 years of age in single and multiple dose studies. Cumulatively, 426 pediatric patients 2 to 5 years of age were treated with SINGULAIR for at least 3 months, 230 for 6 months or longer, and 63 patients for one year or longer in clinical trials. SINGULAIR 4 mg administered once daily at bedtime was generally well tolerated in clinical trials.In pediatric patients 2 to 5 years of age receiving SINGULAIR, the following events occurred with a frequency >2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: fever, cough, abdominal pain, diarrhea, headache, rhinorrhea, sinusitis, otitis,influenza, bronchitis, leg pain, thirst, sneezing rash, ear pain, gastroenteritis, eczema, urticaria, varicella, pneumonia, dermatitis, and conjunctivitis.

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[Other labeling changes not found in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/jul01.htm#tamifl ]

revised

General: Rash, swelling of the face or tongue, toxic epidermal necrolysis

Cardiac: Arrhythmia

Neurologic: Seizure, confusion

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Signs and symptoms of systemic allergic reactions, including anaphylaxis, angioedema, urticaria, and localized and generalized rash.

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VASOTEC (enalapril maleate) I.V. and Tablets
VASERETIC (enalapril maleate/hydrochlorothiazide) Tablets

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

PRECAUTIONS

A second paragraph has been added:

[Other safety-related information: http://www.fda.gov/medwatch/safety/2001/safety01.htm#zerit]

BOXED WARNING, WARNINGS, and PRECAUTIONS sections revised to include the following

Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents." And "The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risks.

Added as third paragrapgh

Added as last paragraph

revised

Body as a Whole - alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).

revised

The most common side effects in adults taking VIDEX are diarrhea, neuropathy (nerve disorders), chills or fever, rash, abdominal pain, weakness, headache, and nausea and vomiting. Children may have similar side effects as adults.

Added

[Table 4 revised. New table shown below:]

added

added:

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

The last sentence in the first paragraph deleted: "In cell culture, acyclovir’s highest antiviral activity is against HSV-1, followed in decreasing order of potency against HSV-2 and VZV."

first sentence revised. "Resistance of VZV to antiviral nucleoside analogues acyclovir can result from qualitative or quantitative changes in the viral TK and/or DNA polymerase."

Geriatrics section added:

Geriatrics: Acyclovir plasma concentrations are higher in geriatric patients compared to younger adults, in part due to age-related changes in renal function. Dosage reduction may be required in geriatric patients with underlying renal impairment (see PRECAUTIONS: Geriatric Use)."

first sentence of the first paragraph revised

"The data presented below include references to peak steady-state plasma acyclovir concentrations observed in humans treated with 800 mg given orally 6 5 times a day (dosing appropriate for treatment of herpes zoster) or 200 mg given orally 6 5 times a day (dosing appropriate for treatment of genital herpes)."

third paragraph revised

"Acyclovir was tested in 16 genetic in vitro and in vivo toxicity assays. No evidence of mutagenicity was observed in 4 microbial assays. ). Acyclovir was positive in 5 of the assays."Acyclovir demonstrated mutagenic activity in 2 in vitro cytogenetic assays (1 mouse lymphoma cell line and human lymphocytes No mutagenic activity was observed in 5 in vitro cytogenetic assays (3 Chinese hamster ovary cell lines and 2 mouse lymphoma cell lines)."

deleted: Paragraphs 4 & 5

Paragraph 5

Pregnancy: Teratogenic Effects

first paragraph, first sentence revised

"Acyclovir administered during organogenesis was not teratogenic in the mouse (450 mg/kg per day, PO), rabbit (50 mg/kg per day, SC and IV), or rat (50 mg/kg per day, SC)."

second paragraph, third sentence revised

"There were 749 756 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes."

Geriatric Use: Clinical studies of ZOVIRAX did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between 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 renal function, and of concomitant disease or other drug therapy."

Pediatric Use, "Safety and effectiveness in pediatric patients less than 2 years of age have not been adequately studied. of oral formulations of acyclovir in pediatric patients less than 2 years of age have not been established."

Observed During Clinical Practice

General: Anaphylaxis, angioedema, …

Nervous: Aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness, delirium, dizziness, encephalopathy, hallucinations, paresthesia, psychosis, seizure, somnolence, tremors. These symptoms may be marked, particularly in older adults or in patients with renal impairment".

Hemic Hematologic and Lymphatic: Anemia, leukocytoclastic vasculitis, ….

Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice

second sentence revised

Overdoses involving ingestion of up to 100 capsules (20 g) have been reported. Adverse events that have been reported only association with overdosage include agitation, coma, convulsions, seizures, and lethargy.

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