SUMMARY OF SAFETY-RELATED DRUG LABELING CHANGES APPROVED BY FDA
May 1997

(Posted: 6/30/97
Updated: 7/7/97, 7/8/97, 7/9/97 - completed)

Note: The following summaries include only those safety-related sections that have been modified, and therefore do not contain all the information needed for safe and effective prescribing. Contact the manufacturer for the complete labeling/package insert.

NB: Comparison made to 1997 Physicians' Desk Reference (PDR) if drug's labeling included in the PDR.

Quick Reference:

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

BECONASE AQ (beclomethasone dipropionate) - CEDAX (ceftibuten) - CEFZIL (cefprozil) - CITANEST PLAIN (prilocaine HCl) - CITANEST FORTE (prilocaine and epinephrine) - COREG (carvedilol) - ETHMOZINE (moricizine HCl) - FEMSTAT (butoconazole nitrate) - GLUCAGON - INTAL (cromolyn Na) - LUPRON DEPOT (leuprolide acetate) - MAXIPIME (cefepime HCl) - MEPRON (atovaquone) - METHERGINE (methylergonovine maleate) - METHOTREXATE SODIUM - METROGEL (metronidazole) - MIRALUMA (technetium Tc99m sestamibi) - NEBCIN (tobramycin sulfate) - NIZORAL (ketoconazole) - PAXIL (paroxetine HCl) - PRONESTYL (procainamide HCl) - SERZONE (nefazodone HCl) - TIMOPTIC (timolol maleate) - VANCOCIN (vancomycin HCl) - VIVELLE (estradiol) - YUTOPAR (ritodrine HCl) - ZOCOR (simvastatin) - ZOVIRAX (acyclovir)

BECONASE AQ (beclomethasone dipropionate) Nasal Spray
[May 30, 1997 - GlaxoWellcome]

PRECAUTIONS:

Pediatric Use: New first sentence added - "The safety and effectiveness of Beconase AQ Nasal Spray have been established in children aged 6 years and above through evidence from extensive clinical use in adult and pediatric patients."

Former only sentence now second sentence revised to read (new text in italics) - "Safety and effectiveness of Beconase AQ Nasal Spray in children below 6 years of age have not been established."

New second paragraph added- "Glucocorticoids have been shown to cause a reduction in growth velocity in children and teenagers with extended use. If a child or teenager on any glucocorticoid appears to have growth suppression, the possibility that they are particularly sensitive to this effect of glucocorticoids should be considered."

DOSAGE AND ADMINISTRATION:

Language was added to clarify the use of Beconase AQ Nasal Spray in children between the ages of 6 and 12 years of age:

Adults and Children 12 Years of Age and Older: 12 replaces "6" in the name of the subsection.

Children 6 to 12 Years of Age (new subsection): "Patients should be started with one inhalation in each nostril twice a day; patients not adequately responding to 168 mcg or those with more severe symptoms may use 336 mcg (two inhalations in each nostril. Beconase AQ Nasal Spray is not recommended for children below 6 years of age."

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CEDAX (ceftibuten) Capsules and Oral Suspension
[May 21, 1997 - Schering-Plough]

CLINICAL PHARMACOLOGY:

Tissue Penetration: Middle-ear fluid (MEF): Deletion of previous subsection which read - "Ceftibuten middle-ear fluid levels average approximately 50% of the concomitant plasma ceftibuten level. In a study of 30 children administered 9 mg/kg of ceftibuten, the average Cmax in MEF (2.9 + or - 0.9 ug/mL) occurred at 4 hours postdose and the average Cmax in plasma (6.7 + or - 1.9 ug/mL) occurred at 2 hours postdose."

Subsection now reads - "In a study of 12 children administered 9 mg/kg, ceftibuten MEF area under the curve (AUC) averaged approximately 70% of the plasma AUC. In the same study, C_max values were 14.3 + or - 2.7 ug/ml in MEF at 4 hours postdose and 14.5 + or - 3.7 ug/ml in plasma at 2 hours postdose."

CEFZIL (cefprozil) Tablets and Oral Suspension
[May 29, 1997 - Bristol-Myers Squibb]

PRECAUTIONS:

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Deletion of previous subsection which read - "No mutagenic potential of cefprozil was found in appropriate prokaryotic or eukaryotic cells in vitro or in vivo. No in vivo long-term studies have been performed to evaluate carcinogenic potential."

The subsection now reads - "Long term in vivo have not been performed to evaluate the carcinogenic potential of cefprozil.

"Cefrozil was not found to be mutagenic in either the Ames Salmonella or E. Coli WP2 urvA reversion assays or the Chinese hamster ovary cell HGPRT forward gene mutation assay and it did not induce chromosomal abnormalities in Chinese hamster ovary cells or unscheduled DNA synthesis in rat hepatocytes in vitro. Chromosomal aberrations were not observed in bone marrow cells from rats dosed orally with over 30 times the highest recommended human dose based upon mg/m².

"Impairment of fertility was not observed in male or female rats given oral doses of cefprozil up to 18.5 times the highest recommended human dose based upon mg/m²."

Pregnancy: Teratogenic Effects: Pregnancy Category B: first sentence in subsection revised to read (new text in italics) - "Reproduction studies have been performed in rabbits (N.B. previously listed last), mice and rats ("at doses 14, 7, and 0.7" - deleted) using oral doses of cefprozil of 0.8, 8.5 and 18.5 times the maximum daily human dose (1000 mg) based upon mg/m², and have revealed no harm to the fetus ("due to cefprozil" deleted).

ADVERSE REACTIONS:

Other: Angioedema added to the list of adverse events, regardless of established causal relationship to Cefzil, that have been rarely reported to post-marketing surveillance.

OVERDOSE:

New first paragraph added - "Single 5000 mg/kg oral doses of cefprozil caused no mortality or signs of toxicity in adult, weaning, or neonatal rats, or adult mice. A single oral dose of 3000 mg/kg caused diarrhea and loss of appetite in cynomolgus monkeys, but no mortality."

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CITANEST PLAIN (prilocaine HCl) Injection
and
CITANEST FORTE (prilocaine and epinephrine) Injection
[May 9, 1997 - Astra USA]

WARNINGS:

Methemoglobinemia (new subsection): "Prilocaine has been associated with the development of methemoglobinemia. Very young patients, patients with congenital or idiopathic methemoglobinemia, or patients with glucose-6-phosphate deficiencies are more susceptible to methemoglobinemia.

"Patients taking drugs associated with drug induced methemoglobinemia such as sulfonamides, acetaminophen, acetanild, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, para-aminsosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine, quinine are also at greater risk for developing methemoglobinemia."

PRECAUTIONS:

Clinically Significant Drug Interactions: New paragraph added - "Prilocaine may contribute to the formation of methemoglobinemia in patients treated with other drugs known to cause this condition (see methemoglobinemia subsection of WARNINGS)."

OVERDOSAGE:

Paragraph revised to read (new text in italics) - "("Administration of prilocaine in doses exceeding 400 mg has been associated with methemoglobinemia in adult patients and with proportionately lower doses in children." deleted) The development of methemoglobinemia is generally dose related but may occur at any dose in susceptible individuals. While methemoglobin values of less than 20% do not generally produce any clinical symptoms, the appearance of cyanosis at 2-4 hours following administration should be evaluated in terms of the general health status of the patients."

DOSAGE AND ADMINISTRATION:

Deletion of last sentence in fourth paragraph that reads - "No more than 600 mg (15 mL; 8 cartridges) should ever be administered within a two hour period in normal healthy adults."

Addition of text at end of fourth paragraph that reads - "The maximum recommended dose that ever be administered within a two hour period in normal healthy adults should be calculated based upon the patient's weight as follows;

Weight	Maximum recommended dose
<150 lbs or <70 kg	4 mg/lb or 8mg/kg
> or = 150 lbs or > or = 70 kg	600 mg (15ml) or 8 cartridges

Maximum Recommended Dosages: Deletion of first sentence that reads - "Normal Healthy Adults: No more that 600 mg (8 mg/kg or 4 mg/lb) of prilocaine HCl should be administered as a single injection."

Addition of new text - "In patients weighing > or = 150 lbs (or 70 kg), no more than 4 mg/lb(8 mg/kg) should be administered. In patients weight < 150 lbs, no more than 600 mg (8 cartridges) of prilocaine HCl should be administered as a single injections."

COREG (carvedilol) Tablets
[May 29, 1997 - SmithKline Beecham]

Labeling extensively revised to incorporate information on new indication of congestive heart failure. Contact company for copy of the label/package insert.

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ETHMOZINE (moricizine HCl) Tablets
[May 27, 1997 - Roberts]

WARNINGS:

Boxed Warning: Last sentence of first paragraph revised (new text in italics): "The study was discontinued because of the unlikely possibility of demonstrating a benefit toward improved survival with Ethmozine and because of an evolving adverse trend after long-term treatment, although there was no statistical significance versus placebo." Last paragraph in boxed warning revised to read (new text in italics) - "The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) is uncertain. Considering the known proarrhythmic properties of Ethmozine and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of Ethmozine, as well as other antiarrhythmic agents, should be reserved for patients with ("structural heart disease" - deleted) life-threatening ventricular arrhythmias.

FEMSTAT (butoconazole nitrate) Vaginal Cream
[May 13, 1997 - Hoffman-LaRoche]

CLINICAL PHARMACOLOGY:

Deletion of the following statements -

"It is also active in vitro against some gram positive bacteria." (Femstat labeling)

"It is also active against some grma positive bacteria." (Femstat Prefill labeling)

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GLUCAGON Injection
[May 12, 1997 - Eli Lilly]

PRECAUTIONS:

Usage in pediatric patient (new subsection): "For the treatment of hypoglycemia: The use of glucagon in pediatric patients has been reported to be safe and effective.^2-6<

"For use as a diagnostic aid: Effectiveness has not been established in pediatric patients."

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INTAL (cromolyn Na) Nebulizer Solution
[May 27, 1997 - Rhone-Poulenc Rorer]

WARNINGS:

New sentence added to end of section - "Anaphylactic reactions with cromolyn sodium administration have been reported rarely."

PRECAUTIONS:

Information for Patients: New third paragraph - "Drug stability and safety of Intal Nebulizer Solution when mixed with other drugs in a nebulizer have not been established."

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Subsection revised as follows (new text in italics) - "Long term studies of cromolyn sodium in mice (12 months intraperitoneal administration at doses up to 150 mg/kg three days per week), hamsters (intraperitoneal administration at doses up to 52.6 mg/kg three days per week for 15 weeks followed by 17.5 mg/kg three days per week for 37 weeks), and rats (18 months subcutaneous administration at doses up to 75 mg/kg six days per week) showed no neoplastic effects. The average daily maximum dose levels administered in these studies were 192.9 mg/m² for mice, 47.2 mg/m² for hamsters and 385.8 mg/m² for rats. These doses correspond to approximately 330%, 80%, and 650% of the maximum daily human dose of 59.2 mg/m².

"Cromolyn sodium showed no mutagenic potential in Ames Salmonella/microsome plate assays, mitotic gene conversion in Saccharomyces cerevisiae and in an in vitro cytogenetic study in human peripheal lymphocytes.

"No evidence of impaired fertility was shown in laboratory reproductive studies conducted subcutaneously in rats in the highest doses tested, 175 mg/kg/day (1050 mg/m²) in males and 100 mg/kg/day (600 mg/m²) in females. These doses are approximately 18 and 10 times the maximum daily human dose, respectively, based on mg/m²."

Pregnancy: Pregancy Category B. First paragraph revised as follows (new text in italics) - "Reproduction studies with cromolyn sodium administered subcutaneously to pregnant mice and rats at maximum daily doses of 540 mg/kg (1620 mg/m²) and 164 mg/kg (984 mg/m²), respectively, and intravenously to rabbits at a maximum daily dose of 485 mg/kg (5820 mg/m²) produced no evidence of fetal malformations. These doses represent approximately 27, 16, and 98 times the maximum daily human dose, respectively, on a mg/m² basis. Adverse fetal effects (increased resorptions and decreased fetal weight) were noted only at the very high parenteral doses that produced maternal toxicity. There are, however, no adequate and well-controlled studies in pregnant women."

DOSAGE AND ADMINISTRATION:

New second paragraph added - "Drug stability and safety of Intal Nebulizer Solution when mixed with other drugs in a nebulizer have not been established."

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LUPRON DEPOT (leuprolide acetate) 4-month, 30mg.
[May 30, 1997 - TAP]

New labeling available that provides for a 4-month dosage form to be used for the palliative treatment of advanced prostatic cancer. Contact the company for a copy of the label/package insert.

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MAXIPIME (cefepime HCl) Injection
[May 16, 1997 - Bristol-Myers Squibb]

Labeling revised to incorporate information on the new indication for the empiric use as monotherapy in febrile neutropenic patients. Contact the company for a copy of the label/package insert.

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MEPRON (atovaquone) Suspension
[May 2, 1997 - GlaxoWellcome]

PRECAUTIONS:

Carcinogenesis, Mutagenesis, Impairment of Fertility:Revision of subsection to read (new text in italics) - "Carcinogenicity studies in rats ("and mice have not been completed." deleted) were negative; 24-month studies in mice showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested which ranged from 1.4 to 3.6 times the average steady-state plasma concentrations in humans during acute treatment of Pneumocystis carinii pneumonia. Atovaquone was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay, the Mouse Lymphoma mutagenesis assay, and the Cultured Human Lymphogenetic assay. No evidence of genotoxicity was observed in the in vivo Mouse Micronucleus assay."

Note: This change appears in the 1997 PDR.

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METHERGINE (methylergonovine maleate) Tablets and Injection
[May 27, 1997 - Sandoz]

PRECAUTIONS:

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

METHOTREXATE SODIUM Tablets and Injection
[May 20, 1997 - Lederle]

Physician Insert

BOXED WARNING:

The following new statements have been added -

"8. Like other cytotoxic drugs, methotrexate may induce 'tumor lysis syndrome' in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.

"9. Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy. (See PRECAUTIONS, Organ System Toxicity, Skin)

"10. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy."

PRECAUTIONS:

Organ System Toxicity: Infection or Immunologic States: The first sentence of the second paragraph has been changed from - "Opportunistic infections, including Pneumocystis carinii infections, have been reported rarely in patients receiving low dose methotrexate."

to - "Potentially fatal opportunistic infections, expecially Pneumocystis carinii pneumonia, may occur with methotrexate therapy."

Neurologic: A new second sentence has been added - "Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m²). Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies."

Skin (new subsection) - "Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases."

ADVERSE REACTIONS:

Cardiovascular (new subsection): "pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus)."

Central Nervous System: The third sentence has been revised (new text in italics) - "Following low doses, there have been occasional ("patients have reported" - deleted) reports of transient subtle cognitive dysfunction, mood alteration, ("or" - deleted) unusual cranial sensations, leukoencephalopathy or encephopathy."

Infection (new subsection): "There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic disease. Pneumocystis carinii pneumonia was the most common infection. Other reported infections included nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, H. simplex hepatitis, and disseminated H. simplex."

Skin: "skin necrosis, and exfoliative dermatitis" added after "Stevens-Johnson Syndrome".

Urogenital System: "gynecomasatia" added prior to "infertility".

First sentence of final paragraph revised to read (new text in italics) - "Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, ("opportunistic infections" deleted) arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, ("and" deleted) reversible lymphomas, and tumor lysis syndrome."

Information about Side Effects

The second sentence of the second paragraph revised to read (new text in italics) - "If these or other problems trouble you, or should you develop any signs of infection or unusual bleeding, notify your doctor at once. (", before your next dose of methotrexate is due." deleted)

New fourth sentence added to second paragraph - "Skin rash and other skin disorders are an infrequent side effect of methotrexate therapy. Should you develop any unusual skin rash, contact your physician at once."

SUMMARY:

Two new statements added - "Notify your physician at once if you develop an unusual skin rash.

"Notify your physician at once if you think you are getting an infection."

METROGEL (metronidazole) Vaginal Gel
[May 26, 1997 - 3M]

Labeling extensively revised to incorporate new information based on approval for a once-a-day dosing regimen. Contact the company for a copy of the label/package insert.

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MIRALUMA (technetium Tc99m sestamibi) Kit
[May 23, 1997 - Dupont Merck]

New labeling to incorporate new information based on approval of new indication of planar imaging as a second line diagnostic drug after mammogram or a palpable breast mass. Contact the company for a copy of the label/package insert.

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NEBCIN (tobramycin sulfate) Injection
[May 13, 1997 - Eli Lilly]

WARNINGS:

Text added to end of section - "Serious allergic reactions including anaphylaxis and dermatologic reactions including exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, and Stevens Johnson Syndrome have been reported rarely in patients on tobramycin therapy. Although rare, fatalities have been reported. (See CONTRAINDICATIONS.)

"If an allergic reaction occurs, the drug should be discontinued and appropriate therapy instituted."

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NIZORAL (ketoconazole) Shampoo
[May 30, 1997 - Janssen]

Labeling revised to incorporate new information based on approval for new indication of treatment of tinea (pityriasis) versicolor caused by or presumed to be caused by Pityrosporum orbiculare (also known as Malassezia furfur or M. orbiculare). Contact the company for a copy of the label/package insert.

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PAXIL (paroxetine HCl) Tablets
[May 19, 1997 - SmithKline Beecham]

PRECAUTIONS:

Drug Interactions: Sumatriptan (new subsection): "There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised."

PRONESTYL (procainamide HCl) Tablets, Capsules and Injection
[May 6, 1997 - Apothecon]

BOXED WARNING:

Two paragraphs added at beginning of section (all bold) - "In the National Heart, Lung and Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicentered, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than six days but less than two years previously, an excessive mortality or non-fatal cardiac arrest rate (7.7%) was seen in patients treated with encainide or flecainide compared with that seen in patients assigned to matched placebo-treated group (3.0%). The average duration of treatment with encainide or flecainide in this study was ten months.

"The applicability of the CAST results to other populations (e.g., those without recent myocardial infarctions) is uncertain. Considering the known proarrhythmic properties of Pronestyl and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of Pronestyl as well as other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias."

ADVERSE REACTIONS:

Gastrointestinal: Second sentence that stated "Hepatomegaly with increased serum aminotransferase activity have been reported after a single oral dose." deleted.

Subsection now reads - "Anorexia, nausea, vomiting, abdominal pain, bitter taste, or diarrhea may occur in 3 to 4 percent of patients taking oral procainamide."

Elevated Liver Enzymes (new subsection): "Elevations of transaminase with and without elevations of alkaline phosphatase and bilirubin have been reported. Some patients have had clinical symptoms (e.g., malaise, right upper quadrant pain). Deaths from liver failure have been reported."

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SERZONE (nefazodone HCl) Tablets
[May 5, 1997 - Bristol-Myers Squibb]

CONTRAINDICATIONS:

Addition of new second paragraph - "The coadministration of triazolam and nefazodone causes a significant increase in the plasma level of triazolam (see WARNINGS and PRECAUTIONS Sections), and a 75% reduction in the initial triazolam dosage is recommended if the two drugs are to be given together. Because not all commercially available dosage forms of triazolam permit a sufficient dosage reduction, the coadministration of triazolam and SERZONE should be avoided for most patients, including the elderly."

WARNINGS:

Triazolam: Deletion of last two sentences of section - "For many patients, e.g., the elderly, it is recommended that triazolam not be used in combination with nefazodone. No dosage adjustment is required for SERZONE."

Text added to end of section - "Because not all commercially available dosage forms of triazolam permit sufficient dosage reduction, coadministration of triazolam with Serzone should be avoided for most patients, including the elderly. In the exceptional case where coadministration of triazolam with Serzone may be considered appropriate, only the lowest possible dose of triazolam should be used (see CONTRAINDICATIONS and PRECAUTIONS Sections).

PRECAUTIONS:

General: Seizures: Subsection revised to read (new text in italics) - "During premarketing testing, a recurrence of a petit mal seizure was observed in a patient receiving nefazodone who had a history of such seizures. ("One nonstudy participant took 2000-3000 mg of nefazodone with methocarbamol and alcohol; this person reportedly experienced a convulsion (type not documented)." deleted) In addition, one nonstudy participant reportedly experienced a convulsion (type not documented) following a multiple-drug overdose (see OVERDOSAGE Section). Rare occurrences of convulsions (including grand mal seizures) following nefazodone administration have been reported since market introduction. A causal relationship to nefazodone has not been established (see ADVERSE REACTIONS Section)"

Priapism: Subsection revised to read (new text in italics) - "While priapism did not occur during premarketing experience with nefazodone, ("priapism has been reported with a structurally related drug, trazodone." deleted) rare reports of priapism have been received since market introduction. A causal relationship to nefazodone has not been established (see ADVERSE REACTIONS Section). If patients present with prolonged or inappropriate erections, they should discontinue therapy immediately and consult their physicians. If the condition persists for more than 24 hours, a urologist should be consulted to determine appropriate management."

ADVERSE REACTIONS:

Postintroduction Clinical Experience (new subsection): "Postmarketing experience with Serzone has shown an adverse experience profile similar to that seen during the premarketing evaluation of nefazodone. Voluntary reports of adverse events temporally associated with Serzone that have been received since market introduction that are not listed above and for which a causal relationship has not been established include rare occurrence of convulsions (including grand mal seizures) and priapism (see PRECAUTIONS Section)."

TIMOPTIC (timolol maleate) Ophthalmic Solution and in Ocudose
[May 16, 1997 - Merck]

CLINICAL PHARMACOLOGY:

In sixth paragraph, deletion of the text that states - "Unlike miotics, Timoptic reduces intraocular pressure with little or no effect on accommodation or pupil size. Thus, changes in visual acuity due to increased accommodation are uncommon, and dim or blurred vision and night blindness produced by miotics are not evident. In addition, in patients with cataracts, the inability to see around lenticular opacities when the pupil is constricted is avoided."

Deletion of the seventh paragraph that states - "In the clinical studies which are reported below, ocular pressure reductions to less than 22 mmHg were used as a reasonable reference point to allow comparisons between treatments. Reduction of ocular pressure to just below 22mmHg may not be optimal for all patients; therapy should be individualized."

Deletion of the ninth paragraph that states - "In the multiclinic studies comparing Timoptic with pilocarpine, 61 percent of patients treated with Timoptic had intraocular pressure reduced to less than 22mmHg compared to 32 percent of patients treated with pilocarpine. For patients completing these studies, the mean reduction in pressure at the end of the study from pretreatment was 30.7 percent for patients treated with Timoptic and 21.7 percent for patients treated with pilocarpine."

Deletion of the tenth paragraph that states - "In the multiclinic studies comparing Timoptic with epinephrine, 69 percent of patients treated with Timoptic had intraocular pressure reduced to less than 22mmHg compared to 42 percent of patients treated with epinephrine. For patients completing these studies, the mean reduction in pressure at the end of the study from pretreatment was 33.2 percent for patients treated with Timoptic and 28.1 percent for patients treated with epinephrine."

Deletion of the twelfth paragraph that states - "Timoptic has also been used in patients with glaucoma wearing conventional (PMMA) hard contact lenses, and has generally been well tolerated. Timoptic has not been studied in patients wearing lenses made with materials other than PMMA. (See PRECAUTIONS, Information for Patients.)"

PRECAUTIONS:

General: Muscle Weakness: Deletion of second paragraph that states - "As with the use of other antiglaucoma drugs, diminished responsiveness to Timoptic after prolonged therapy has been reported in some patients. However, in one long-term study in which 96 patients have been followed for at least 3 years, no significant difference in mean intraocular pressure has been observed after initial stabilization."

Information for Patients: (Sterile Ophthalmic Solution only) Third paragraph revised to read (new text in italics) - "Patients should also be advised that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma ["ocular surgery" deleted] or infection) they should immediately seek their physician's advice concerning the continued use of the present multidose container."

Drug Interactions: Beta-adrenergic blocking agents: Second sentence revised from "Patients should not usually receive two topical ophthalmic beta-adrenergic blocking agents concurrently."

to read - "The concomitant use of two topical beta-adrenergic blocking agents is not recommended."

ADVERSE REACTIONS:

Special Senses: "Ocular pemphigoid" changed to pseudopemphigoid.

(Change appears in 1997 PDR.)

DOSAGE AND ADMINISTRATION:

Fourth paragraph revised to read (new text in italics) - "Dosages above one drop of 0.5 percent Timoptic twice a day generally have not been shown to produce further reduction in intraocular pressure. If the patient's intraocular pressure is still not at a satisfactory level on this regimen, concomitant therapy with ("pilocarpine and other miotics, and/or epinephrine, and/or systemically administered carbonic anhydrase inhibitors, such as acetazolamide" deleted) other agent(s) for lowering intraocular pressure can be instituted. The concomitant use of two topical beta-adrenergic blocking agents is not recommended. (See PRECAUTIONS, Drug Interactions, Beta-adrenergic blocking agents.)"

Paragraph beginning "When a patient is transferred from another topical ophthalmic beta-adrenergic blocking agent, ..." deleted.

Paragraph beginning "When a patient is transferred from a single antiglaucoma agent, ..." deleted.

Paragraph beginning "When a patient is transferred from several concomitantly administered antiglaucoma agents, ..." deleted.

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VANCOCIN (vancomycin HCl) Capsules
[May 12, 1997 - Eli Lilly]

PRECAUTIONS:

Nursing Mothers: New third sentence added - "It is not known whether oral vancomycin is excreted in human milk, as no studies of vancomycin concentration in human milk after oral administration have been done."

VIVELLE (estradiol) Transdermal System
[May 29, 1997 - Novartis]

PRECAUTIONS:

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

YUTOPAR (ritodrine HCl) Injection
[May 13 - Astra USA]

PRECAUTIONS:

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

ZOCOR (simvastatin) Tablets
[May 19 & 23, 1997 - Merck]

WARNINGS:

Liver Dysfunction: In first sentence approximately added before "1%".

New second paragraph - "In the Scandinavian Simvastatin Survival Study (see CLINICAL PHARMACOLOGY, Clinical Studies), the number of patients with more than one transaminase elevation to > 3 times the upper limit of normal over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]). Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1986 simvastatin treated patients in 4S with normal liver function test (LFTs) at baseline, only 8 (0.4%) developed consecutive LFT elevations to > 3 times the upper limit of normal and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg."

First sentence of second paragraph (now third paragraph) revised to read (new text in italics) - "It is recommended that liver function tests be performed before the initiation of treatment, ("at 6 and 12 weeks after initiation of therapy or elevation in dose," deleted) and periodically thereafter (e.g., semiannually) for the first year of treatment or until one year after the last elevation in dose.

Skeletal Muscle: Second paragraph "Muscle weakness accompanied by marked elevation of creatine phosphokinase was observed in a renal transplant patient on cyclosporine and simvastatin following the initiation of therapy with the systemic antifungal agent itraconazole. Rhabdomyolysis with renal failure has been reported in a renal transplant patient receiving cyclosporine and another HMG-CoA. reductase inhibitor shortly after a dose increase in the systemic traconazole. The HMG-CoA reductase inhibitors and the azole derivative antifungal agents inhibit cholesterol biosynthesis at different points in the biosynthetic pathway. In patients receiving cyclosporine, simvastatin should be temporarily discontinued if systemic azole derivative antifungal therapy is required; patents not taking cyclosporine should be carefully monitored if systemic azole derivative antifungal therapy is required." deleted and

replaced with "Myopathy or rhabdomyolysis has occurred in transplant and non-transplant patients receiving Zocor or another HMG-CoA reductase inhibitor following the initiation of treatment with the antifungal agent itraconazole. In a study in normal volunteers, plasma levels of another HMG-CoA reductase inhibitor were increased about 20-fold when administered concomitantly with itraconazole. This is probably related to metabolism of both drugs by the same P-450 isoform. Based on this data, therapy with Zocor should be temporarily interrupted if systemic azole derivative antifungal therapy is required."

PRECAUTIONS:

Drug Interactions: Antipyrine: Subsection revised to read (new text in italics) - " ("Because" deleted) Simvastatin had no effect on the pharmacokinetics of antipyrine (", interactions with other drugs metabolized via the same cytochrome isozymes are not expected." deleted). However, since simvastatin is metabolized by the cytochrome P-450 isoform 3A4, this does not preclude an interaction with other drugs metabolized by the same isoform."

ADVERSE REACTIONS:

Scandinavian Simvastatin Survival Study: Clinical Adverse Experiences (new subsection): Existing sentence "In the Scandinavian Simvastatin Survival (4S) (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 4444 patients treated with 20-40 mg/day of Zocor (n=2221) or placebo (n=2223), the safety and tolerability profiles were comparable between groups over the median 5.4 years of the study." is moved to be first sentence in subsection.

New second sentence and table added -"The clinical adverse experiences reported as possibly, probably, or definitely drug-related in > or = 0.5% in either treatment group are shown in the table below:

	Zocor (n=2,221) %	Placebo (n=2,223) %
Body as a Whole
Abdominal pain	0.9	0.9
Gastrointestinal
Diarrhea	0.5	0.3
Dyspepsia	0.6	0.5
Flatulence	0.9	0.7
Nausea	0.4	0.6
Musculoskeletal
Myalgia	1.2	1.3
Skin
Eczema	0.8	0.8
Pruritis	0.5	0.4
Rash	0.6	0.6
Special Senses
Cataract	0.5	0.8

ZOVIRAX (acyclovir) Tablets, Capsules and Suspension
[May 29, 1997 - GlaxoWellcome