AGRYLIN (anagrelide HCl)

BIAXIN (clarithromycin)

BRETHINE (terbutaline sulfate)

CLOZARIL (clozapine)

DEXTROSE 5%

DEXTROSE 5% & 0.225%/0.3% NaCl

EFFEXOR & EFFEXOR XR (venlafaxine HCl)

INTEGRILIN (eptifibatide)

MAGNEVIST (gadopentetate dimeglumine)

MONOPRIL HCT (fosinopril sodium/hydrochlorothiazide)

MUSTARGEN (mechlorethamine HCl)

MYLERAN (busulfan)

NORVASC (amlodipine besylate)

OPTISON (human albumin micrspheres)

HEPARIN

PATANOL (olopatadine HCl)

PROGESTRONE

SINGULAIR (montelukast sodium)

TECZEM (enalapril maleate/diltiazem maleate)

TIAZAC (diltiazem HCl)

TIMOPTIC (timolol maleate)

TRIPHASIL 21 & 28 (levonorgestrel/ethinyl estradiol)

VIOXX (rofecoxib)

VIRACEPT (nelfinavir mesylate)

XELODA (capecitabine)

ZADITOR (ketotifen fumarate)

ZOVIRAX (acyclovir)

ZYPREXA (olanzapine)

Return to Quick Reference

CLINICAL STUDIES:

The word "Thrombocytosis" in the title of the graph has been revised to "Thrombocythemia".

PRECAUTIONS:

Geriatric Use: New subsection -

"Of the total number of subjects in clinical studies of Agrylin, 42.1% were 65 years and over, while 14.9% were 75 years 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 response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out."

ADVERSE REACTIONS:

First paragraph, third sentence, the following words have been added - "pericardial effusion" and "pleural effusion".

Cardiovascular System: "hypertension" has been added.

Hemic & Lymphatic System: "lymphadenopathy" has been revised to lymphadenoma".

Nervous System: "hypertension" has been deleted.

DOSAGE AND ADMINISTRATION:

First paragraph, last sentence revised (new text in italics) -

"The decision to treat asymptomatic young adults with essential thrombocythemia ["secondary to myeloproliferative disorders" deleted] should be individualized. There are no special requirements for dosing the geriatric population."

[Other labeling changes not appearing in 2000 PDR: Jul99

ADVERSE REACTIONS:

Post-Marketing Experience: First paragraph, first and second sentences revised (new text in italics) -

"Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred. Other spontaneously reported adverse events include glossitis, stomatitis, oral moniliasis, anorexia, vomiting, tongue discoloration, thrombocytopenia, leukopenia, and dizziness."

Return to Quick Reference

PRECAUTIONS:

Geriatric Use: New subsection-

"Clinical studies of clozapine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

"Orthostatic hypotension can occur with Clozaril (clozapine) treatment and tachycardia, which may be sustained has been observed in about 25% of patients taking Clozaril (clozapine) (see WARNINGS, Adverse Cardiovascular and Respiratory Effects). Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects.

"Also, elderly patients may be particularly susceptible to the anticholinergic effects of Clozaril (clozapine), such as urinary retention and constipation. (See PRECAUTIONS, Anticholinergic Toxicity)

"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. Other reported clinical experience does suggest that the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women (see WARNINGS, Tardive Dyskinesia)."

PRECAUTIONS:

Geriatric Use: Subsection added -

"An evaluation of current literature revealed no clinical experience identifying differences in response 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 hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."

PRECAUTIONS:

Geriatric Use: Subsection added -

"An evaluation of current literature revealed no clinical experience identifying differences in response 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 hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Sodium ions are known to be substantially excreted by the kidney, and the risk of toxic reactions 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.""

DRUG ABUSE AND DEPENDENCE:

Physical and Psychological Dependence: New third paragraph -

"Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND ADMINISTRATION)."

DOSAGE AND ADMINISTRATION:

Discontinuing Effexor (venlafaxine HCl): First sentence revised (new text in italics) -

"When discontinuing Effexor after more than 1 week of therapy, it is generally recommended that the dose be tapered to minimize the risk of discontinuation symptoms. Patients who have received Effexor for more than 6 weeks or more should have their dose tapered gradually over at least a 2-week period."

New second paragraph -

"Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in depression. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. It is therefore recommended that the dosage of Effexor be tapered gradually and the patient monitored. The period required for tapering may depend on the dose, duration of therapy and the individual patient. Discontinuation effects are well known to occur with antidepressants."

Discontinuing Effexor XR:

"When discontinuing Effexor XR after more than 1 week of therapy, it is generally recommended that the dose be tapered to minimize the risk of discontinuation symptoms. In clinical trials with Effexor XR, tapering was achieved by reducing the daily dose by 75 mg at one week intervals. Individualization of tapering may be necessary. [The remainder of the paragraph beginning with "While the discontinuation effects of Effexor XR have not been systematically evaluated in controlled clinical trials, retrospective..." has been deleted] and replaced with -

"Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in depression. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. It is therefore recommended that the dosage of Effexor XR be tapered gradually and the patient monitored. The period required for tapering may depend on the dose, duration of therapy and the individual patient. Discontinuation effects are well known to occur with antidepressants."

CLINICAL PHARMACOLOGY:

New third paragraph -

"Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age."

PRECAUTIONS:

Geriatric Use: New subsection -

"A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (see PRECAUTIONS, General). Clinical studies indicate that lower doses of heparin may be indicated in these patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION)."

[Other labeling changes not appearing in 2000 PDR: Sep99]

DOSAGE AND ADMINISTRATION:

1. INTEGRILIN Dosing Chart by Weight for Patients With Acute Coronary Syndrome (180 microgram/kg Bolus and 2.0 microgram/kg/min Infusion)
2. INTEGRILIN Dosing Chart by Weight for Patients Without Acute Coronary Syndromes Undergoing PCI (135 microgram/kg/ Bolus and 0.5 microgram/kg/min Infusion)

Dosing charts revised to reflect Bolus Volume and Infusion Volume based on 0.75 mg/mL concentration and addition of 2 mg/mL concentration. Contact the company for a copy of the new label/package insert.

Return to Quick Reference

DOSAGE AND ADMINISTRATION:

First sentence revised to reflect a lower dosage range of hydrochlorothiazide -

"Fosinopril is an effective treatment of hypertension in once-daily doses of 10-80 mg, while hydrochlorothiazide is effective in doses of 12.5-50 mg per day."

HOW SUPPLIED:

Storage: The following sentence deleted -

"Store at 15^o-30^oC (59^o-86^oF); avoid prolonged exposures to temperatures above this range."

Replaced with -

"Store at 25^oC(77^oF); excursions permitted to 15^o-30^oC(59^o-86^oF)[see USP Controlled Room temperature]."

WARNINGS:

Boxed section - New first paragraph and three sentences added to beginning of second paragraph -

"Mustargen (Mechlorethamine HCl) should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.

"This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Due to the toxic properties of mechlorethamine (e.g., corrosivity, carcinogenicity, mutagenicity, teratogenicity), special handling procedures should be reviewed prior to handling and followed diligently."

PRECAUTIONS:

General: First paragraph, last sentence deleted -

"Rubber gloves should be worn when handling Mustergen"

Replaced with -

"Appropriate protective equipment should be worn when handling Mustergen. Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed."

Carcinogenesis, Mutagenesis, Impairment of Fertility: The following paragraph has been added -

"The International Agency for Research on Cancer has judged that mechlorethamine is a probable carcinogen in humans. This is supported by limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in animals."

DOSAGE AND ADMINISTRATION:

Preparation of Solution for Intravenous Administration: First paragraph, first nine sentences revised (new text in italics) -

"This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care. (See boxed warning and DOSAGE AND ADMINISTRATION, SPECIAL Handling.) Since Mustargen is a powerful vesicant, it is intended primarily for intravenous use, and in most cases is given by this route. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Appropriate protective equipment should be worn when handling Mustargen. ["Rubber gloves should be worn when handling Mustargen." Deleted] Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed. (See DOSAGE AND ADMINISTRATION, Special Handling.)"

Special Handling The following sentences have been added -

"Animal studies have shown mechlorethamine to be corrosive to skin and eyes, a powerful vesicant, irritating to the mucous membranes of the respiratory tract and highly toxic by the oral route. It has also been shown to be carcinogenic, mutagenic and teratogenic."

"Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided."

The following text revised (new text in italics) -

The National Institutes of Health presently recommends that the preparation of injectable anti-neoplastic drugs should be performed in a Class II laminar flow biological safety cabinet. ["...and that personnel preparing drugs of this class should wear surgical gloves and a closed front surgical-type gown with knit cuffs." Deleted] Personnel preparing drugs of this class should wear chemical resistant, impervious gloves, safety goggles, outer garments and shoe covers. Additional body garments should be based upon the task being performed (e.g., sleevelets, apron, gauntlets, disposable suits) to avoid exposed skin surfaces and inhalation of vapors and dust. Appropriate techniques should be used to remove potentially contaminated clothing. Several other guidelines for proper handling and disposal of anti-cancer drugs have been published and should be considered. ["There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate." Deleted]

Accidental Contact Measures: Previously "Accidental Contact:", first sentence revised (new text in italics) -

"Should accidental eye contact occur, copious irrigation for at least 15 minutes with water , normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation."

New sentence added to end of paragraph -

"Medical attention should be sought immediately. Contaminated clothing should be destroyed. (See PRECAUTIONS, General and DOSAGE AND ADMINISTRATION, Preparation of Solution for Intravenous Administration.)"

CONTRAINDICATIONS:

Last paragraph added -

"Myleran should not be given to patients who have previously suffered a hypersensitivity reaction to busulfan or any other component of the preparation."

WARNINGS:

Second paragraph, tenth sentence revised (new text in italics) -

"There is no specific therapy for this complication ["other than the immediate discontinuation of busulfan." Deleted]. Myleran should be discontinued if this lung toxicity develops.

Sixth paragraph, first sentence revised (new text in italics) and addition of new second sentence -

"["A number of malignant tumors" deleted] Malignant tumors and acute leukemias have been reported in patients who have received busulfan therapy, and this drug may be a human carcinogen. The World Health Organization has concluded that there is a causal relationship between busulfan exposure and the development of secondary malignancies."

Seventh paragraph, addition of new second sentence -

"Busulfan has been associated with ovarian failure including failure to achieve puberty in females.

Eighth paragraph, first sentence revised (new text in italics) -

"Hepatic veno-occlusive disease, which may be life threatening, has been reported ["following the investigational use of very high doses of busulfan in combination with" deleted] in patients receiving busulfan, usually in combination with cyclophosphamide or other chemotherapeutic agents prior to bone marrow transplantation."

PRECAUTIONS:

General: Second paragraph, first and second sentences revised (new text in italics) -

"Seizures have been reported in patients receiving ["very high, investigational doses of busulfan." deleted] busulfan. As with any potentially epileptogenic drug, caution should be exercised when administering ["very high doses" deleted] busulfan to patients with a history of seizure disorder, head trauma, or receiving other potentially epileptogenic drugs."

Drug Interactions: Second paragraph, first sentence revised (new text in italics) -

In one study, 12 of approximately 330 patients receiving continuous busulfan and thioguanine therapy for treatment of chronic myelogenous leukemia were found to have portal hypertension and esophageal varices associated with abnormal liver function tests.

New third and fourth paragraphs -

"Busulfan-induced pulmonary toxicity may be additive to the effects produced by other cytotoxic agents."

"Patients should be monitored for signs of busulfan toxicity when itraconazole is used concomitantly with Myleran."

ADVERSE REACTIONS:

Ocular: Second sentence deleted -

"In the few cases reported in humans, cataracts have occurred only after the prolonged administration of busulfan."

Hepatic Effects: Second sentence revised -

Hepatic veno-occlusive disease has been observed in patients receiving ["higher than recommended doses of" deleted] busulfan. (see WARNINGS).

Observed During Clinical Practice: New subsection -

"The following events have been identified during post-approval use of busulfan. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to busulfan.
Blood and Lymphatic: Aplastic anemia.
Eye: Cataracts, corneal thinning, and lens changes.
Hepatobiliary Tract and Pancreas: Centrilobular sinusoidal fibrosis, hepatic veno-occlusive disease, hepatocellular necrosis, and hyperbilirubinemia (see WARNINGS).
Non-site Specific: Infection, mucositis, and sepsis.
Respiratory: Pneumonia.
Skin: Rash. An increased local cutaneous reaction has been observed in patients receiving radiotherapy soon after busulfan."

OVERDOSAGE:

Third sentence deleted -

"Survival after a single 140-mg dose has been reported in an 18-kg, 4-year-old child, but hematologic toxicity is likely to be more profound with chronic overdosage."

New second paragraph -

"Gastrointestinal toxicity with mucositis, nausea, vomiting, and diarrhea has been observed when Myleran was used in association with bone marrow transplantation."

ADVERSE REACTIONS:

Cardiovascular: Addition of "vasculitis"

Central and Peripheral Nervous System: Addition of "neuropathy peripheral"

Gastrointestinal: Addition of "pancreatitis"

General: Addition of "allergic reaction"

Skin and Appendages: Addition of "angioedema, erythema multiforme"

Metabolic and Nutritional: Addition of "hyperglycemia"

Hemopoietic: Addition of "leukopenia" and "thrombocytopenia"

Next to last paragraph, second sentence revised (new text in italics) -

In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis) in some cases severe enough to require hospitalization have been reported in association with use of amlodipine."

WARNINGS:

Third paragraph added:

"This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral disease. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral disease or CJD have ever been identified for albumin."

DOSAGE AND ADMINISTRATION:

Section revised (new text in italics) -

"The recommended dose of Optison is 0.5 mL injected into a peripheral vein. ["This may be repeated after 10 minutes." Deleted] This may be repeated for further contrast enhancement as needed. See individualization of dose below.

1. The injection rate should not exceed 1 mL per second.
2. Follow the Optison injection with rapid flush of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.
3. The maximum total dose should not exceed 5.0 mL in any 10 minute period.
4. The maximum total dose should not exceed 8.7 mL in any one patient study.

Individualization of dose: Image quality in cardiac ultrasound is a function of the acoustic window which is influenced by many variables including body habitus, intervening ling tissue, adequacy of transducer skin interface and other acoustic factors. These variables may influence the ultrasound contrast effect."

Third paragraph deleted -

"If the contrast enhancement is inadequate after the dose of 0.5 mL, then after 10 minutes a second injection of Optison 3.0 mL may be injected intravenously. If the contrast enhancement is still inadequate, then after another 10 minutes, a third injection with Optison 5.0 mL can be injected intravenously."

Replaced with -

"If the contrast enhancement is inadequate after the dose of 0.5 mL, additional doses in increments of 0.5 mL up to 5.0 mL cumulatively in a 10 minute period may be injected intravenously up to a maximum total dose of 8.7 mL in any one patient study."

CLINICAL PHARMACOLOGY:

New second paragraph -

"Results from an environmental study demonstrated that Patanol was effective in the treatment of the signs and symptoms of allergic conjunctivitis when dosed twice daily for up to 6 weeks."

INDICATIONS AND USAGE:

Previous paragraph deleted -

"Patanol (olopatadine hydrochloride ophthalmic solution) 0.1% is indicated for the temporary prevention of itching of the eye due to allergic conjunctivitis."

Replaced with -

Patanol (olopatadine hydrochloride ophthalmic solution) 0.1% is indicated for the treatment of the signs and symptoms of allergic conjunctivitis."

PRECAUTIONS:

General: Seventh paragraph deleted -

"Studies of the addition of progestin product to an estrogen replacement regimen for seven or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia. Morphological and biochemical studies of endometria suggest that 10 to 30 days of a progestin are needed to provide maximal maturation of the endometrium and to eliminate any hyperplastic changes. Whether that will provide protection from endometrial carcinoma has not been clearly established."

Eighth paragraph revised (new text in italics) -

"There are possible risks which may be associated with the ["inclusion" deleted] use of progestin ["in replacement regimen" deleted] treatment, including adverse effects on carbohydrate and lipid metabolism.

[Other labeling changes not appearing in 2000 PDR: Feb99]

Return to Quick Reference

[Other labeling changes not appearing in 2000 PDR: Feb99]

PRECAUTIONS:

Drug Interactions:
Enalapril Maleate: Non-steroidal Anti-inflammatory Agents - Text added to subsection:

"In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril maleate. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.""

DOSAGE AND ADMINISTRATION:

Sprinkling the Capsule Contents on Food: New subsection -

"Tiazac Extended Release Capsules may also be administered by carefully opening the capsules and sprinkling the capsule contents on a spoonful of applesauce. The applesauce should be swallowed immediately without chewing, and followed with a glass of cool water to ensure complete swallowing of the capsule contents. The applesauce should not be hot and it should be soft enough to be swallowed without chewing, Any capsule contents/applesauce mixture should be used immediately and not stored for future use. Subdividing the contents of a Tiazac Extended Release Capsule is not recommended."

PRECAUTIONS:

Drug Interactions:
Clonidine: "Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate."

ADVERSE REACTIONS:

Hypersensitivity: Paragraph revised (new text in italics) -

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

[Other labeling changes not appearing in 2000 PDR: Feb00]

INDICATIONS AND USAGE:

Previous TABLE I extensively revised. The new TABLE I is shown below -

"TABLE I: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF USE OF A CONTRACEPTIVE METHOD

Method	Perfect Use	Typical Use
Levonorgestrel implants	0.05	0.05
Male sterilization	0.1	0.15
Female sterilization	0.5	0.5
Depo-Provera (injectable progestogen)	0.3	0.3
Oral contraceptives		5
Combined	0.1	NA
Progestin only	0.5	NA
IUD
Progesterone	1.5	2.0
Copper T 380A	0.6	0.8
Condom (male) without spermicide	3	14
(female) without spericide	5	21
Cervical cap
Nulliparous women	9	20
Parous women	26	40
Vaginal sponge
Nulliparous women	9	20
Parous women	20	40
Diaphram with Spermicidal cream Or jelly	6	20
Spermicides alone (foam, creams, jellies, and vaginal suppositories)	6	26
Periodic abstinence (all methods)	1-9*	25
Withdrawal	4	19
No contraception (planned pregnancy)	85	85

NA - not available
*Depending on method (calendar, ovulation, symptothermal, post-ovulation)
Adapted from Hatcher RA et al, Contraceptive Technology: 17th Revised Edition. NY,NY: Ardent Media, Inc., 1998.

PRECAUTIONS:

12. Pediatric Use: New subsection -

"Safety and efficacy of Triphasil have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and users 16 and older. Use of this product before menarche is not indicated."

[Other labeling changes not appearing in 2000 PDR: Oct99]

PRECAUTIONS:

Drug Interactions: Previous subsection deleted and replaced with -

"Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing Vioxx therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding complications. In single and multiple dose studies in healthy subjects receiving both warfarin and rofecoxib, prothrombin time (measured as INR) was increased by approximately 8% to 11%. In post-marketing experience, bleeding events have been reported, predominately in the elderly, in association with increases in prothrombin time in patients receiving Vioxx concurrently with warfarin."

Labor and Delivery: New second paragraph -

"Merck & Co., Inc. maintains a registry to monitor the pregnancy outcomes of women exposed to Vioxx while pregnant. Healthcare providers are encouraged to report any prenatal exposure to Vioxx by calling the Pregnancy Registry at (800) 986-8999."

ADVERSE REACTIONS:

The following paragraph deleted -

"Other serious adverse reactions which occur rarely (less than 0.1%), regardless of causality: The following serious adverse events have occurred rarely in patients taking Vioxx."

Replaced with -

"The following serious adverse events have been reported rarely (less than 0.1%) in patients taking Vioxx, regardless of causality. Cases reported only in the post-marketing experience are indicated in italics."

(In addition to being in italics, the post-marketing cases are also new text) -

"Cardiovascular:" cerebrovascular accident, congsetive heart failure, deep venous thrombosis, myocardial infarction, pulmonary embolism, transient ischemic attack, unstable angina"

"Gastrointestinal: cholecystitis, colitis, colonic malignant neoplasm, duodenal perforation, duodenal ulcer, esophageal ulcer, gastric perforation, gastric ulcer, gastrointestinal bleeding, intestinal obstruction, pancreatitis."

"Hemic and lymphatic: lymphoma"

The three following subsections have been added -

"Immune system: anaphylactoid reaction, angioedema"

"Nervous system: aseptic meningitis"

"Psychiatric: hallucinations"

"Urogenital System: acute renal failure, breast malignant neoplasm, worsening chronic renal failure, interstitial nephritis, prostatic malignant neoplasm, urolithiasis."

[Other labeling changes not appearing in the 2000 PDR: Nov99, May99]

PATIENT PACKAGE INSERT:

What are the side effects of Viracept? Fourth sentence revised (new text in italics) -

"In clinical studies, about 14-20% of patients receiving Viracept 750 mg (three tablets) three times daily or 1250 mg (five tablets) two times daily had four or more loose stools a day."

How should I take Viracept? First paragraph revised (new text in italics) -

"Viracept is available only with your doctor's prescription. ["The" deleted] Your doctor may prescribe the light blue Viracept Tablets ["should be" deleted] either as 1250 mg (five tablets) taken two times a day or as 750 mg (three tablets) taken three times a day. Viracept should always be taken with a meal or a light snack. ["You do not have to take Viracept exactly every 8 hours. Instead, you can take it at normal times when you are eating." Deleted]"

CLINICAL PHARMACOLOGY:

Pharmacokinetics: New paragraph added -

"Phenytoin and fosphenytoin: Increased phenytoin plasma concentrations have been reported during concomitant use of Xeloda with phenytoin, suggesting a potential interaction. Patients taking phenytoin or fosphenytoin concomitantly with Xeloda should be monitored for increased phenytoin plasma concentrations and associated clinical symptoms such as nystagmus, diplopia, ataxia and confusion. (See Drug-Drug Interations/PRECAUTIONS)."

CLINICAL PHARMACOLOGY:

New paragraph added -

"Ketotifen has been shown to have little systemic exposure following topical ocular administration. A study conducted with 15 volunteers dosed bilaterally with ketotifen fumarate ophthalmic solution twice daily for 14 days demonstrated plasma concentrations generally below the quantation limit of assay (less than 20 pg/mL). "

DESCRIPTION:

First sentence revised (new text in italics) -

"Zovirax is the brand name for acyclovir,["an antiviral drug" deleted] a synthetic nucleoside analogue active against herpesviruses."

VIROLOGY:

Drug Resistance: Subsection revised (new text in italics) -

"Resistance of HSV and VZV to antiviral nucleoside analogues can result from qualitative or quantitative changes in the viral TK or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with ["AIDS" deleted] advanced HIV infection.["TK deficient mutants of VZV have been recovered" deleted]

"["Resistance of HSV to antiviral nucleoside analogues occurs by the same mechanisms as resistance to VZV." Deleted] While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have ["also" deleted] been isolated. TK-negative mutants may cause severe disease in infants and immunocompromised adults. ["patients" deleted] The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy."

CLINICAL PHARMACOLOGY:

Drug Interactions: Subsection revised (new text in italics) -

"Coadministration of probenecid with intravenous acyclovir has been shown to increase the mean acyclovir half-life and the ["systemic exposure" deleted] the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced.

CONTRAINDICATIONS

Section revised (new text in italics) -

"Zovirax is contraindicated for patients who develop hypesensitivity ["or intolerance" deleted] to acyclovir or valacyclovir ["the components of the formulations." Deleted]

WARNINGS

Section revised (new text in italics) -

"Zovirax Capsules, Tablets, and Suspension are intended for oral ingestion only. Renal failure, in some cases resulting in death, has been observed with acyclovir therapy (see ADVERSE REACTIONS: Observed During Clinical Practice and OVERDOSAGE). Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS, which has resulted in death, has occurred in immunocompromised patients receiving acyclovir therapy.

PRECAUTIONS:

Carcinogenesis, Mutagenesis, Impairment of Fertility: Fourth paragraph, last sentence revised -

"No ["mutagenic" deleted] activity was demonstrated in another, possibly less sensitive, in vitro cell transformation assay."

Fifth paragraph , first sentence revised (new text in italics) -

"Acyclovir ["was clastogenic" deleted] caused chromosomal damage in chinese hamsters at 380 to 760 times human dose levels."

Pregnancy: Teratogenic Effects: First paragraph, fourth and fifth sentences deleted -

"In a nonstandard test, rats were given three SC doses of 100 mg/kg acyclovir on gestation day 10, resulting in plasma levels 63 and 125 times human levels. In this test, there were fetal abnormalities, such as head and tail anomalies, and maternal toxicity."

Second paragraph revised (new text in italics) -

There are no adequate and well-controlled studies in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy ["has collected data since June" deleted] was established in 1984 and completed in April 1999. ["As of December 1997, outcomes of live births have been documented in 552" deleted] There were 756 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to ["specific defects or to" deleted] permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. Acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."

Nursing Mothers: Second sentence revised (new text in italics) -

These concentrations would potentially expose the nursing infant to a dose of acyclovir ["as high as " deleted] up to 0.3 mg/kg per day.

ADVERSE REACTIONS:

Observed During Clinical Practice: Third sentence and categories/events revised (new text in italics) -

"These events have been chosen for inclusion due to either ["a combination of" deleted] their seriousness, frequency of reporting, ["or" deleted] potential causal connection to Zovirax, or a combination of these factors."

General: Anaphylaxis, fever, headache, pain, peripheral edema. ["and rarely, anaphylaxis" deleted]"
Nervous: Agitation, coma, confusion, delirium, dizziness, hallucinations, parethesia, psychosis, seizure, somnolence. These symptoms may be marked, particularly in older adults (see PRECAUTIONS).
Digestive: Diarrhea, ["elevated liver function tests" deleted], gastrointestinal distress, nausea.
Hemic and Lymphatic: Leukopenia, lymphadenopathy, thrombocytopenia.
Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, jaundice.
Musculoskeletal: Myalgia.
Skin: Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.
Special Senses: Visual abnormalities.
Urogenital: Renal failure, elevated blood urea nitrogen, elevated creatinine, hematuria (see WARNINGS).

OVERDOSAGE:

Section revised (new text in italics) -

"["Patients have ingested intentional" deleted] Overdoses involving ingestion of up to 100 capsules (20 g) have been reported. ["of Zovirax, with no unexpected adverse effects" deleted] Adverse events that have been reported only in association with overdosage include convulsions and lethargy. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Overdosage has been reported following bolus injections or inappropriately high doses and in patients whose fluid and electrolyte balance were not properly monitored. This has resulted in elevated BUN and serum creatinine and subsequent renal failure. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored (see DOSAGE AND ADMINISTRATION)."

[Other labeling changes not appearing in 2000 PDR: Jan99]

Labeling revised to incorporate information on a new indication - the use of Zyprexa in the treatment of bipolar mania. Also, "Geriatric Use" subsection revised. Contact company for a copy of the new labeling/package insert.

Return to Quick Reference