BECONASE AQ (beclomethasone dipropionate, monohydrate) - CIPRO (ciprofloxacin) - CORTISPORIN OTIC SOLUTION (polymyxin B sulfate-neomycin sulfate-hydrocortisone) - LUVOX (fluvoxamine maleate) - NOLVADEX (tamoxifen citrate) - NORMODYNE (labetalol HCl) - PROZAC (fluoxetine HCl) - REDUX (dexfenfluramine HCl)- RESERPINE - RHINOCORT (budesonide) - VISTIDE (cidofovir)

PRECAUTIONS:

General: Beconase AQ: Cataracts added to list of rare instances of adverse reactions that have been reported following the use of intranasal beclomethasone dipropionate (previously, "intranasal application of aerosolized corticosteroids");

The next sentence "Although these have not been observed in clinical trials with Beconase AQ Nasal Spray, vigilance should be maintained" has been deleted.

ADVERSE REACTIONS:

Beconase AQ: Statement added that reports of dryness and irritation of the nose and throat, and unpleasant taste and smell have been received.

PATIENTS INSTRUCTIONS FOR USE:

The following instruction has been added:
"8. The correct amount of medication in each spray cannot be assured after a specified number of sprays even though the bottle is not completely empty. Before the discard date you should consult your doctor to determine whether a refill is needed. Just as you should not take extra doses without consulting your doctor, you should also not stop Beconase AQ Nasal Spray without consulting your doctor."

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ADVERSE REACTIONS:

Post-Marketing Adverse Events: Agitation, delirium, and myoclonus added to Central Nervous System category, and methemoglobinemia added to Hemic/Lymphatic category.

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CONTRAINDICATIONS:

Revised to indicate that Cortisporin should not be used if the external auditory canal disorder is suspected or known to be due to cutaneous viral infection (for example, herpes simplex virus or varicella zoster virus).

WARNINGS:

First two paragraphs of section replaced by the following three paragraphs:
"Neomycin can induce permanent sensorineural hearing loss due to cochlear damage, mainly destruction of hair cells in the organ of Corti. The risk of ototoxicity is greater with prolonged use; therefore, duration of therapy should be limited to 10 consecutive days. (See PRECAUTIONS - General.)

"Patients being treated with eardrops containing neomycin should be under close clinical observation. Due to its acidity which may cause burning and stinging, Cortisporin Otic Solution should not be used in any patient with a perforated tympanic membrane.

"Neomycin sulfate may cause cutaneous sensitization. A precise incidence of hypersensitivity reactions (primarily skin rash) due to topical neomycin is not known. Discontinue this product promptly if sensitization or irritation occurs."

DOSAGE AND ADMINISTRATION:

Recommendation added that therapy with this product should be limited to 10 consecutive days.

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PRECAUTIONS:

Potential Interactions with Drugs that Inhibit or are Metabolized by Cytochrome P450 Isozymes: Subsection revised to include information concerning extensive and poor metabolizers [see complete subsection in package insert].

Tricyclic Antidepressants (TCAs): Revised to note that plasma TCA concentrations may need to be monitored, and TCA dose may need to be reduced, during co-administration with fluvoxamine.

ADVERSE REACTIONS:

Non-US Postmarketing Reports: Hepatitis added.

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ADVERSE REACTIONS:

The second sentence of section "If adverse reactions are severe, it is sometimes possible to control them by a simple reduction of dosage without loss of control of the disease." has been deleted.

WARNINGS:

Statement added that several deaths have occurred when Normodyne Injection was used during surgery (including when used in cases to control bleeding).

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WARNINGS:

Rash and Possibly Allergic Events: First sentence revised to indicate that in U.S. fluoxetine clinical trials, 7% of 10,782 patients developed various types of rashes and/or urticaria.

PRECAUTIONS:

General: Based on data from U.S. placebo-controlled clinical trials, incidence rates of specific events revised in the following subsections [see complete package insert for specifics]: Anxiety and Insomnia, Altered Appetite and Weight, Activation of Mania/Hypomania, and Seizures.

Suicide: Second paragraph revised to include notation of the well-established comorbidity between bulimia and depression, and that the same precautions observed when treating patients with depression should be observed when treating patients with bulimia.

Drug Interactions: Drugs Metabolized by Cytochrome P450IIIA4 (new subsection): In an in vivo interaction study involving co-administration of fluoxetine with single doses of terfenadine (a cytochrome P450IIIA4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of P450IIIA4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine's extent of inhibition of cytochrome P450IIIA4 activity is not likely to be of clinical significance.

CNS Active Drugs: Statement added that in evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status (See Accumulation and Slow Elimination under CLINICAL PHARMACOLOGY).

Anticonvulsants (new subsection): Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment.

Antipsychotics (new subsection): Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between serotonin specific reuptake inhibitors (SSRIs) and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. A single case report has suggested possible additive effects of pimozide and fluoxetine leading to bradycardia.

Benzodiazepines (new subsection): The half-life of concurrently administered diazepam may be prolonged in some patients (see Accumulation and Slow Elimination under CLINICAL PHARMACOLOGY). Co-administration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.

Lithium: That there have been reported cases of increased serotonergic effects when lithium was used concomitantly with fluoxetine has been added.

Warfarin (new subsection): Altered anti-coagulant effects, including increased bleeding, have been reported when fluoxetine is co-administered with warfarin. Patients receiving warfarin therapy should receive careful coagulation monitoring when fluoxetine is initiated or stopped.

ADVERSE REACTIONS:

Section has undergone marked revision [see complete section in package insert] and now contains the following introductory information:

"Multiple doses of Prozac had been administered to 10,782 patients with various diagnoses in US clinical trials as of May 8, 1995. Adverse events were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a limited (i.e., reduced) number of standardized event categories.

"In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse events. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it.

"The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied."

Incidence in US Placebo-Controlled Clinical Trials (excluding data from extensions of trials) (new subsection): Contains two tables: TABLE 1: Enumerates the most common treatment-emergent adverse events associated with Prozac use (incidence of less than or equal to 5% for Prozac and at least twice that for placebo within at least one of the indications) for treatment of depression, OCD, and bulimia in U.S. controlled clinical trials;

TABLE 2: Enumerates treatment-emergent adverse events that occurred in greater than or equal to 2% of patients treated with Prozac and with incidence greater than placebo who participated in U.S. controlled clinical trials comparing Prozac with placebo in treatment of depression, OCD, or bulimia. (TABLE 2 provides combined data for the pool of studies that are provided separately by indication in TABLE 1).

Associated with Discontinuation in US Placebo-Controlled Clinical Trials (excluding data from extensions of trials) (new subsection): Contains one table:

TABLE 3: Lists the adverse events associated with discontinuation of Prozac treatment (incidence at least twice that for placebo and greater than or equal to 1% for Prozac in clinical trials) in depression, OCD, and bulimia.

Other Events Observed In All US Clinical Trials [replaces previous subsection Other Events Observed During Premarketing Evaluation of Prozac (fluoxetine hydrochloride)]: Lists all treatment-emergent adverse events reported at any time by individuals taking fluoxetine in U.S. clinical trials (10,782 patients) except (1) those listed in the body or footnotes of TABLES 1 or 2, or elsewhere in labeling; (2) those for which the COSTART terms were uninformative or misleading; (3) those events for which a causal relationship to Prozac use was considered remote; and (4) events occurring in only one patient treated with Prozac and which did not have a substantial probability of being acutely life threatening.

Postintroduction Reports: Stevens-Johnson syndrome added.

Bulimia Nervosa (new subsection): Initial Treatment information contains same cautions as in Depression and Obsessive-Compulsive Disorder subsections, namely that 1) a lower or less frequent dosage of Prozac should be used in patients with renal and/or hepatic impairment, and 2) a lower or less frequent dosage should also be considered for patients, such as the elderly (see Usage in the Elderly under PRECAUTIONS), with concurrent disease or on multiple medications.

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REDUX (dexfenfluramine HCl)
[November 4, 1996: Interneuron]

WARNINGS:

Introductory sentence added (bolded and in capital letters): "Dexfenfluramine is an appetite suppressant, and appetite suppressants increase the risk of developing primary pulmonary hypertension, an often fatal disorder."

In the paragraph detailing the results of the case-control epidemiology study, the following changes have been made:

The odds ratio has been changed from 9.1 to 23.1, and the 95% confidence interval from 2.6 - 31.5 to 6.9 - 77.7;

The sentence regarding increased risk of primary pulmonary hypertension and time course of usage hs been changed to include only the previous notation that there was no significant increase in risk for persons who had used appetite suppressants for 3 months or less.;

The sentence regarding the estimated risk associated with long-term use of appetite suppressants has been changed to indicate the estimated risk is about 23-46 [increased from 18, as previous] cases per million persons exposed per year, based upon a background estimate of 1-2 cases per million persons.

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RESERPINE, USP
[November 6, 1996: Eon Labs]

CLINICAL PHARMACOLOGY:

The paragraph regarding specific pharmacokinetics parameters revised to: "Mean maximum plasma levels of plasma concentrations after a single dose of 0.5 mg of reserpine, administered as two 0.25 mg tablets or as an aqueous solution, peaked after 2.5 hours. The mean peak level was approximately 1.1 ng/ml. The two formulations were found to be bioequivalent. Absolute bioavailability of reserpine, as established by comparison to an intravenous dose, has been reported to be approximately 50%.

Reserpine is extensively bound (95%) to plasma proteins. Reserpine is almost completely metabolized in the body, and only about 1% is excreted as unchanged drug in the urine. No definitive studies on the human metabolism of reserpine have been made. After oral administration, an initial half-life of approximately 5 hours is followed by a terminal half-life of the order of 200 hours. Plasma levels may be measurable 14 days after a single dose. The clinical significance of the long terminal half-life is unknown."

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RHINOCORT (budesonide) Nasal Inhaler
[November 15, 1996: Astra USA]

PATIENT'S INSTRUCTIONS FOR USE:

Instruction 2 (addition of new sentence): Instruction to press straight down on the canister to actuate a dose, and notation that Rhinocort Nasal Inhaler must be sprayed into the air 4 times before using for the first time.

Instruction 5 (new): If Rhinocort Nasal Inhaler is not used for a period of 8 weeks, test spray the unit by spraying into the air 4 times before reuse.

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VISTIDE (cidofovir)
[November 14, 1996: Gilead Sciences]

BOXED WARNING:

Renal function (serum creatinine and urine protein) must [rather than "should", as previous] be monitored within 48 hours prior to each dose of Vistide;

New statement added that Vistide is contraindicated in patients who are receiving other nephrotoxic agents.

CONTRAINDICATIONS:

New statement added that initiation of therapy with Vistide is contraindicated in patients with a serum creatinine greater than 1.5 mg/dL, a calculated creatinine clearance less than or equal to 55 mL/min, or a urine protein greater than or equal to 100 mg/dL (equivalent to greater than or equal to 2+ proteinuria);

New statement added that Vistide is contraindicated in patients receiving agents with nephrotoxic potential. Such agents must be discontinued at least seven days prior to starting therapy with Vistide;

Prior notation regarding contraindication against direct intraocular injection of Vistide revised to note that direct injections of cidofovir has been associated with iritis, ocular hypotony, and permanent impairment of vision.

WARNINGS:

Nephrotoxicity: Revised to include the following:

New statement that renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each dose of vistide;

Acute renal failure, in some cases, resulting in the need for dialysis, added to list of possible results of additional proximal tubular cell injury to which continued administration of Vistide may lead;

Intravenous aminoglycosides (e.g., tobramycin, gentamicin, and amikacin), vancomycin, and non-steroidal anti-inflammatory agents added to list of other known potentially nephrotoxic agents for which the safety of Vistide has not been evaluated in patients receiving these agents (see DOSAGE AND ADMINISTRATION);

Preexisting Renal Impairment: Revised to note that initiation of therapy with Vistide is contraindicated in patients with a baseline serum creatinine greater than 1.5 mg/dL, a creatinine clearance less than or equal to 55 mL/min, or a urine protein greater than or equal to 100 mg/dL (equivalent to greater than or equal to 2+ proteinuria).

PRECAUTIONS:

General: Revised to note that due to the potential for increased nephrotoxicity, doses greater than the recommended dose must [rather than "should", as previous] not be administered and the frequency or rate of administration must [rather than "should", as previous] not be exceeded (see DOSAGE AND ADMINISTRATION);

Drug Interactions, Nephrotoxic Agents: Intravenous amiknoglycosides (e.g., tobramycin, gentamicin, and amikacin), vancomycin, and non-steroidal anti-inflammatory agents added to list of other known potentially nephrotoxic agents, all of which are now contraindicated. In addition, there is a new statemnt that such agents must be discontinued at least seven days prior to starting therapy with Vistide.

ADVERSE REACTIONS:

Nephrotoxicity: Revised to indicate that as prior foscarnet use has been associated with an increased risk of nephrotoxicity, such patients must [rather than should, as previous] be monitored closely.

OVERDOSAGE:

Previous overdosage information deleted; new section information as follows: "Two cases of cidofovir overdosage have been reported. These patients received single doses of Vistide at 16.3 mg/kg and 17.4 mg/kg, respectively, with comcomitant oral probenecid and intravenous hydration. In both cases the patients were hospitalized and received oral probenecid (one gran three times daily) and vigorous intravenous hydration with normal saline for 3 to 5 days. Significant changes in renal function were not observed in either patient."

DOSAGE AND ADMINISTRATION:

Revisions made in several subsections [Induction Treatment; Dose Adjustment (Changes in Renal Function During Vistide Therapy; Preexisting Renal Impairment); Hydration] [see complete section in package insert].

Patient Monitoring: Revised to indicate that serum creatinine and urine protein must be monitored within 48 hours prior to each dose.

Previous section Dose Adjustment, Changes in Renal Function During Vistide Therapy removed.

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