Additions: Color green and underlined: text
addition example
Deletions: Color red and strikethrough: text
deletion example
ACCUPRIL (quinapril HCl) Tablets
[June 21, 2001: Pfizer]
ADVERSE REACTIONS:
Hypertension and/or Heart Failure body system
Gastrointestinal: flatulence, dry mouth or throat, constipation, gastrointestinal hemorrhage, pancreatitis, abnormal liver function tests
Urogenital: urinary tract infection, impotence, acute renal failure, worsening renal failure
Other: amblyopia, edema, arthralgia, pharyngitis, agranulotosis, hepatitis, thrombocytopenia
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ANDROGEL (testosterone gel)
[June 27, 2001: Unimed Pharmaceuticals]
CONTRAINDICATIONS
AndroGel® should not be used in patients with known hypersensitivity to any of its ingredients, including testosterone USP that is chemically synthesized from soy."
Patient Package Insert:
Who should not take AndroGel® Section
"AndroGel® must not be used by women or by those individuals with known hypersensitivity to any of its components, including individuals who are hypersensitive to testosterone that is chemically synthesized from soy."
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ARICEPT (donepezil) Tablets
[June 20, 2001: Eisai Inc.]
WARNINGS:
Cardiovascular Conditions: Because of their pharmacological action,
cholinesterase inhibitors may have vagotonic effects on heart
rate (e.g., bradycardia) the sinoatrial
and atrioventricular nodes. The
potential for this action may be particularly important to patients with "sick
sinus syndrome" or other supraventricular cardiac conduction conditions. "This
effect may manifest as bradycardia or heart block in patinets both with and
without known underlying cardiac conduction abnormalities. Syncopal
episodes have been reported in association with the use of ARICEPT.
ADVERSE REACTIONS: Post-Introduction Reports: added: " Neuroleptic Malignant Syndrome"
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CEFAZOLIN for Injection, USP and Dextrose
Injection, USP in the DUPLEX Container
[June 1, 2001: B. Braun Medical Inc.]
Labeling revised to be consistent with that of other cefazolin products.
Container Label:
The storage temperature information on the container label revised to read:
"Store at 20-25ºC (68-77ºF). Excursions to 15-30ºC (59-86ºF)."
Package Insert:
WARNINGS
The first paragraph of the section has been revised to read:
"BEFORE THERAPY WITH CEFAZOLIN FOR INJECTION USP AND DEXTROSE INJECTION USP IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFAZOLIN, CEPHALOSPORINS, , OR OTHER DRUGS. IF THIS DRUG PRODUCT IS GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG BETA-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO CEFAZOLIN FOR INJECTION USP AND DEXTROSE INJECTION USP OCCURS, DISCONTINUE TREATMENT WITH THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, IV FLUIDS, IV ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED."
The second sentence of the third paragraph has been revised to read:
"Studies indicate that a toxin produced by Clostridium difficile is a primary cause of ‘antibiotic-associated colitis’."
The third sentence of the fourth paragraph has been revised to read:
"In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an oral antibacterial drug clinically effective against C. difficile colitis."
PRECAUTIONS
Pediatric Use subsection has been revised to read:
"The potential for toxic effect in pediatric patients from chemicals that may leach from the single-dose IV preparation in plastic has not been determined."
DUPLEX Drug Delivery System Directions for Use subsection,
The first step under Removal from Multi-Pack Tray has been revised to read:
"Tear tape strips from one or both sides of the tray. Remove top tray."
The second subheader is retitled "Patient labeling and Drug Powder/Diluent Inspection" and the sixth bullet ("Apply patient-specific label on foil side of container. USE CARE to avoid activation.") was moved to the first position under the subheader.
HOW SUPPLIED
The storage information was revised to read:
"Store the unactivated unit at 20-25ºC (68-77ºF). Excursions permitted to 15-30ºC (59- 86ºF)."
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CELEXA (citalopram hydrobromide) Tablets
and Oral Solution
[June 27, 2001: Forest Laboratories]
CLINICAL PHARMACOLOGY
Drug-Drug Interactions
In vitro enzyme inhibition data did not reveal an inhibitory effect
of citalopram on CYP3A4, -2C9, or –2E1,
but did suggest that it is a weak inhibitor of CYP-1A2, -2D6, and -2C19. Citalopram
would be expected to have little inhibitory effect on in vivo metabolism
mediated by these cytochromes. However, in vivo data to address this
question are very limited.
Since CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of citalopram, it is expected that potent inhibitors of 3A4, e.g., ketoconazole, itraconazole, and macrolide antibiotics and potent inhibitors of CYP2C19, e.g., omeprazole, might decrease the clearance of citalopram. However, coadministration of citalopram and the potent 3A4 inhibitor ketoconazole did not significantly affect the pharmacokinetics of citalopram. Because citalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease citalopram clearance. Citalopram steady state levels were not significantly different in poor metabolizers and extensive 2D6 metabolizers after multiple dose administration of Celexa, suggesting that coadministration, with Celexa, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on TM citalopram metabolism. See Drug Interactions under Precautions for more detailed information on available drug interaction data.
PRECAUTIONS-
Drug Interactions
Theophylline – Combined administration of Celexa (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. Effect of theophylline on the pharmacokinetics of citalopram was not evaluated.
Triazolam - Combined administration of Celexa (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam.
CYP3A4 and 2C19 Inhibitors – In vitro studies indicated that CYP3A4 and 2C19
are the primary enzymes involved in the metabolism of citalopram. As
data are not available from clinical pharmacokinetic studies, the possibility
that the clearance of citalopram will be decreased when citalopram is administered
with a potent inhibitor of CYP3A4 (e.g., ketoconazole, itraconazole, fluconazole,
or erythromycin), or a potent inhibitor of CYP2C19 (e.g., omeprazole), should
be considered. However, coadministration of citalopram (40 mg)
and ketoconazole (200 mg), a potent inhibitor of CYP3A4, did not significantly
affect the pharmacokinetics of citalopram. Because citalopram is metabolized
by multiple enzyme systems, inhibition of a single enzyme may not appreciably
decrease citalopram clearance.
Ketoconazole – Combined administration of Celexa (40 mg) and ketoconazole (200mg) d decreased the Cmax and AUC of ketoconazole by 21% and 10%,, respectively, and did not significantly affect the pharmacokinetics of citalopram.
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DALMANE (flurazepam) Capsules
[June 14, 2001: ICN Pharmaceuticals]
CLINICAL PHARMACOLOGY
Added –
Geriatric Pharmacokinetics: The single dose pharmacokinetics of flurazepam were studied in 12 healthy geriatric subjects (aged 61 to 85 years). The mean elimination half-life of desalkyl-flurazepam was longer in elderly male subjects (160 hours) compared with younger male subjects (74 hours), while mean elimination half-life was similar in geriatric female subjects (120 hours) and younger female subjects (90 hours). After multiple dosing, mean steady-state plasma levels of desalkyl-flurazepam were higher in elderly male subjects (81 ng/ml) compared with younger male subjects (53ng/ml), while values were similar between elderly female subjects (85 ng/mg) and younger female subjects (86 ng/ml). The mean washout half-life of desalkyl-flurazepam was longer in elderly male and female subjects (126 and 158 hours, respectively) compared with younger male and female subjects (111 and 113 hours, respectively).
PRECAUTIONS
Added –
Geriatric Use: Since the risk of the development of oversedation, dizziness, confusion and/or ataxia increases substantially with larger doses in elderly and debilitated patients, it is recommended that in such patients the dosage be limited to 15 mg. Staggering and falling have also been reported, particularly in geriatric patients.
A pharmacokinetic study in flurazepam demonstrated a longer elimination half-life for desalkyl-flurazepam in elderly male subjects compared with younger male subjects after single-dose dose administration, while values for elderly female subjects were not significantly different from those seen in younger female subjects. After multiple dosing, elimination half-life of desalkyl-flurazepam was longer in all elderly subjects compared with younger subjects, and mean steady-state serum concentrations were higher only in elderly male subjects relative to younger subjects (see CLINICAL PHARMACOLOGY: Geriatric Pharmacokinetics).
ADVERSE REACTION
Added –
Flumazenil, a specific benzodiazepine- receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be useful in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to , not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, should be consulted prior to use.
HOW SUPPLIED
Deleted -
Tel-E-Dos packages of 100, available in boxes containing 10 strips of 10, in trays of 4 boxes each containing a reverse-numbered roll of 25, and in boxes of 4 reverse-numbered cards of 25; Prescription Paks of 30, available in trays of 10.
REFERENCE
Added
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EPIVIR (lamivudine) Tablets and Syrup
[June 19, 2001: GlaxoSmithKline]
PRECAUTIONS:
Patients with HIV and Hepatitis B Virus Coinfection: Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients dually infected with HIV and HBV. In non-HIV-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see EPIVIR-HBV package insert for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. Posttreatment exacerbations of hepatitis have also been reported (see WARNINGS)
Drug Interactions: TMP 160 mg/SMX 800 mg once daily has been shown to
increase lamivudine exposure (AUC) by 44%.
The effect of higher doses of TMP/SMX on lamivudine
pharmacokinetics has not been investigated (see CLINICAL PHARMACOLOGY).
No change in dose of either drug is recommended. There
is no information regarding the effect on lamivudine pharmacokinetics of higher
doses of TMP/SMX such as those used to treat Pneumocystis carinii pneumonia.
No data are available regarding the potential for interaction with other drugs
that have renal clearance mechanisms similar to that of lamivudine.
Lamivudine and zalcitabine may inhibit the intracellular
phosphorylation of one another. Therefore, use of lamivudine in combination
with zalcitabine is not recommended.
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ESTROSTEP 21 AND ESTROSTEP/FE 21
(norethindrone acetate 1 mg and ethinyl estradiol 35 mcg) Tablets
June 29, 2001: Parke Davis
INDICATION AND USAGE
Added -
for the treatment of moderate acne vulgaris in females, > 15 years of age, who have no known contraindications to oral contraceptive therapy, desire oral contraception, have achieved menarche, and are unresponsive to topical anti-acne medications.
For other changes to the labeling, contact the sponsor.
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FML (fluorometholone opthalmic solution)
).1%
June 28, 2001: Allergan, Inc.
DESCRIPTION:
FML (fluorometholone opthalmic suspension, USP)
0.1% Liquifilm is
a sterile, opthalmio
suspension is a topical anti-inflammatory agent for opthalmic
use.
Contains: Active: fluorometholone 0.1%. Preservative:
benzalkonium
chloride 0.004% Inactives: Liquifilm
(polyvinyl alcohol-) 1.4%; benzalkonium chloride
0.004% ; edetate disodium; sodium chloride; sodium phosphate,
monobasic: sodium phosphate, dibasic; polysorbate 80; sodium hydroxide to adjust
the pH; and purified water.
CLINICAL PHARMACOLOGY: 3RD paragraph revised
Corticosteroids are capable of producing a rise in intraocular pressure. In
clinical studies on patients’ eyes treated with
both dexamethasone and fluorometholone 0.1% suspensions, fluorometholone demonstrated
a lower propensity to increase intraocular pressure than did dexamethasone.
of documented steroid-responders, fluorometholone
demonstrated a significantly longer average time to produce a rise in intraocular
pressure than dexamethasone phosphate; however, in a small percentage of individuals,
a significant rise in intraocular pressure occurred within one week. The ultimate
magnitude of the rise was equivalent for both drugs.
PRECAUTIONS:
Information for Patients: added as third paragraph:
The preservative in FML suspension, benzalkonium chloride, may be absorbed by soft contact lenses. Patients wearing soft contact lenses should be instructed to wait at least 15 minutes after instilling FML suspension to insert soft contact lenses.
Added - Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and young patients.
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INTEGRILIN (eptifibatide) Injection
[June 8, 2001: COR Therapeutics]
Labeling revised to reflect the findings of the ESPRIT ("Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (the ‘ESPRIT Study); A Phase III Study in Patients Undergoing Percutaneous Coronary Intervention with Stent Implantation") study. The revisions include a new dosing recommendation for patients undergoing Percutaneous Coronary Intervention (PCI) and a revised recommended target range for the activated clotting time (ACT) during PCI.
Also, addition of information to the package insert on bleeding events from post-marketing adverse event reports.
Extensive changes, For FPL details contact the sponsor.
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LEUKERAN (chlorambucil) Tablets
[June 20, 2001: GlaxoSmithKline]
ADVERSE REACTIONS:
CNS: added - myoclonia
Dermatologic: added - Allergic reactions such as urticaria and angioneurotic edema have been reported following initial or subsequent dosing.
Note: The references (46) will be revised. Reference items 1-39 will be deleted and the remaining references will be renumbered as follows:
REFERENCES:
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LIMBITROL (chlordiazepoxide and amitriptyline
HCl) Tablets
[June 5, 2001: ICN Pharmaceuticals]
PRECAUTIONS – Geriatric Use section added
Geriatric Use: In elderly and debilitated patients it is recommended that dosage be limited to the smallest effective amount to preclude the development of ataxia, oversedation, confusion or anti-cholinergic effects.
Of the total number of subjects in clinical studies of Limbitrol, 74 individuals were 65 years and older. An additional 34 subjects were between 60 and 69 years of age. No overall differences in safety and effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
The active ingredients in Limbitrol are known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be started on low doses of Limbitrol and observed closely.
Clinical studies of Limbitrol did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.
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LIPITOR (Atorvastatin) Tablets
[June 8, 2001: Pfizer]
CLINICAL PHARMACOLOGY: Special Populations
Geriatric: added - Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age > 65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults (see PRECAUTIONS section; Geriatric Use subsection).
PRECAUTIONS: Geriatric Use
Added - The safety and efficacy of atorvastatin (10-80 mg) in the geriatric population >65 years of age) was evaluated in the ACCESS study. In this 54-week open-label trial 1,958 patients initiated therapy with atorvastatin 10 mg. Of these, 835 were elderly > 65 years) and 1,123 were non-elderly. The mean change in LDL-C from baseline after 6 weeks of treatment with atorvastatin 10 mg was –38.2% in the elderly patients versus –34.6% in the nonelderly group. The rates of discontinuation due to adverse events were similar between the two age groups. There were no differences in clinically relevant laboratory abnormalities between the age groups.
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MENTAX (butenafine HCl) Cream 1%
[June 6, 2001: Bertek Pharmaceuticals]
INDICATION AND USAGE:
new indication added - use of Mentax (butenafine HCl cream) Cream, 1%, for the topical treatment of tinea (pityriasis) versicolor due to Malassezia furfur (formerly Pityrosporum orbiculare).
Extensive changes. For FPL details contact the sponsor.
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MINIPRESS (prazosin) Capsules
[June 12, 2001: Pfizer]
CONTRAINDICATIONS
None known. MINIPRESS
is contraindicated in patients with known sensitivity to quinazolines, prazosin
or any of the inert ingredients.
WARNINGS
added - As with all alpha-blockers, MINIPRESS (prazosin hydrochloride) may cause syncope with sudden loss of consciousness. (class labeling statement)
ADVERSE REACTIONS
The following statement and new subsections have been added to the section:
In post-marketing experience, the following adverse events have been reported:
Autonomic Nervous System: flushing.
Body As A whole: allergic reaction, asthenia, malaise, pain.
Cardiovascular, General: angina pectoris, hypertension.
Endocrine: gynecomastia.
Heart Rate/Rhythm: bradycardia.
Psychiatric: insomnia.
Skin/Appendages: urticaria.
Vascular (Extracardiac): vasculitis.
Vision: eye pain.
HOW SUPPLIED
Revised to include sizes and strengths marketed currently.
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MINTEZOLE (thiabendazole) Tablets and
Suspension
[June 29, 2001/Merck]
WARNINGS
"Abnormal sensation in eyes, xanthopsia, blurred vision, drying of mucous membranes, and Sicca syndrome have been reported in patients treated with MINTEZOL."
ADVERSE REACTIONS
Gastrointestinal:
"Abdominal pain" added
Special Senses:
"Sicca syndrome" added
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MIRALAX (Polyethylene Glycol 3350, NF
Powder)
[June 20, 2001: Braintree Laboratories]
Front ECL
Step number 4. of the "Directions" revised:
"Stir the powder in a cup (8 oz.) of water, juice, soda, coffee or tea until completely dissolved."
Patient Information Sheet
The second sentence of the "How to take" subsection revised:"Measure the dose using the measuring cap (or use one heaping tablespoon of powder), stir and dissolve in a glass (8 oz.) of water, juice, soda, coffee or tea."
PRECAUTIONS
General: "MiraLax should be administered after being dissolved in approximately 8 ounces of water, juice, sodas, coffee, or tea."
Information for Patients
"It should always be taken by mouth after being dissolved in 8 ounces of water, juice, soda, coffee or tea."
DOSAGE AND ADMINISTRATION
"The usual dose is 17 grams (about 1 heaping tablespoon) of powder per day (or as directed by physician) in 8 ounces of water, juice, soda, coffee or tea."
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ORGARAN (danaparoid sodium) Injection
[June 26, 2001: Organon Inc.]
CLINICAL PHARMACOLOGY
a new subsection titled "Special Populations"added as follows:
Special Populations
Geriatrics
There are insufficient pharmacokinetic data to determine if the absorption, distribution, and elimination of ORGARAN (danaparoid sodium) for Injection are different in elderly ( _ 65 years) subjects when compared with younger subjects.
Pediatrics
The safety and efficacy of ORGARAN ® in pediatric patients have not been established.
Race
There is no information to determine the effect of race on the pharmacokinetics of ORGARAN .
Hepatic Insufficiency
No formal studies were conducted to evaluate the effect of hepatic disease of disposition of ORGARAN.
Renal Insufficiency
No formal studies were conducted to evaluate the effect of renal disease on the disposition of ORGARAN although ORGARAN is mainly eliminated in the kidneys. In patients with severely impaired renal function, the half-life of elimination of plasma anti-Xa activity may be prolonged, therefore, careful monitoring of such patients is recommended (see PRECAUTIONS).
Drug-Drug Interactions
In clinical studies for the prophylaxis of DVT, no significant drug interactions have been noted in the following drugs: digoxin, cloxacillin, ticarcillin, chlorthalidone, and pentobarbital (see PRECAUTIONS).
ORGARAN should be used with caution in patients receiving oral anticoagulants and/or platelet inhibitors. Monitoring of anticoagulants by Prothrombin Time and Thrombotest is unreliable within 5 hours after ORGARAN administration (see PRECAUTIONS).
PRECAUTIONS: added
Geriatric Use
Of the total number of patients undergoing elective hip replacement surgery who received ORGARAN ® (danaparoid sodium) Injection in clinical studies, 62% (397/645 patients) were 65 years and 22% (141/645 patients) were 75 years old. No overall differences in safety and effectiveness of ORGARAN ® were observed between elderly ( _ 65 years) subjects and younger subjects. Other reported clinical experience with ORGARAN has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals to ORGARAN cannot be ruled out. ORGARAN is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
DOSAGE AND ADMINISTRATION: added
Use in Geriatrics
No overall differences in safety and effectiveness of ORGARAN ® (danaparoid sodium) Injection were observed in patients 65 years when compared with patients <65 years undergoing elective hip replacement surgery. No dosage adjustments are recommended in elderly patients.
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ORTHO-CEPT (desogestrel/ethinyl estradiol)
[June 19, 2001: Johnson Pharmaceutical research]
CLINICAL PHARMACOLOGY
"Receptor binding studies, as well as studies in animals and humans, have shown that 3-keto-desogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity. The relevance of this latter finding in humans in unknown."
WARNINGS
1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS
a. Thromboembolism (Note the change in order for this subcategory).
"An increased risk of thromboembolic and thrombotic disease associated with
the use of oral contraceptives is well established. Data
from cCase-control and cohort studies report that oral contraceptives containing
desogestrel (OTRHO-CEPT contains desogestrel) are associated with a two-fold
increase in the risk of venous thromboembolic disease as compared to other low-dose
(containing less than 50 mcg of estrogen) pills containing other progestins.
According to these studies, this two-fold risk increases the yearly occurrence
of venous thromboembolic disease by about 10-15 cases per 100,000 women.
Earlier case control studies on older formulations
have found the relative risk of users compared to nonusers to be 3 for the first
episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or
pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for
venous thromboembolic disease. Cohort studies have shown the relative risk to
be somewhat lower , about 3 for new cases and about 4.5 for new cases requiring
hospitalization. The risk of thromboembolic disease is not related to the length
of use and disappears after pill use is stopped."
have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower , about 3 for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped."
"Several epidemiologic studies indicate that third generation oral contraceptives, including those containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives. In general, these studies indicate an approximate 2-fold increased risk, which corresponds to an additional 1-2 cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this 2-fold increase in risk."
WARNINGS
1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS
b. Myocardial Infarction
"Oral contraceptives must be used with caution in women with cardiovascular
disease risk factors.": "Desogestrel has minimal
androgenic activity (see CLINICAL PHARMACOLOGY) and there is some evidence that
the risk of myocardial infarction associated with oral contraceptives is lower
when the progestagen has minimal androgenic activity than when the activity
is greater (100)."
Detailed Patient Package Insert:
RISKS OF TAKING ORAL CONTRACEPTIVES
1. Risks of developing blood clots.
"These risks are greater with desogestrel-containing
oral contraceptives, such as ORTHO-CEPT®, than with other low-dose pills."
"The risks of these side effects may be greater with
desogestrel-containing oral contraceptives such as ORTHO-CEPT® than with
certain other low-dose pills."
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PRAVACHOL (pravastatin) Tablets
[June 15, 2001: Bristol Myers]
WARNINGS
HMG-CoA reductase inhibitors, like some other
lipid-lowering therapies, have been associated with biochemical abnormalities
of liver function. Increases of
serum transaminase (ALT, AST) values to more than 3 times the upper limit of
normal occurring on 2 or more (not necessarily sequential) occasions have been
reported in 1.3% of patients treated with pravastatin in the US over an average
period of18 months. These abnormalities were not associated with cholestasis
and did not appear to be related to treatment duration. In those patients in
whom these abnormalities were believed to be related to pravastatin and who
were discontinued from therapy, the transaminase levels usually fell slowly
to pretreatment levels. These biochemical findings are usually asymptomatic
although worldwide experience indicates that anorexia, weakness, and/or abdominal
pain may also be present in rare patients.
In the largest long-term placebo-controlled clinical trial with pravastatin (Pravastatin Primary Prevention Study; (see CLINICAL PHARMACOLOGY), the overall incidence of AST and/or ALT elevations to greater than three times the upper limit of normal was 1.05% in the pravastatin group as compared to 0.75% in the placebo group. One (0.03%) pravastatin-treated patient and 2 (0.06%) placebo-treated patients were discontinued because of transaminase elevations. Of the patients with normal liver function at week 12, three of 2875 treated with pravastatin (0.10%) and one of the 2919 placebo patients (0.03%) had elevations of AST greater than three times the upper limit of normal on two consecutive measurements and/or discontinued due to elevations in transaminase levels during the 4.8 years (median treatment) of the study.
It is recommended that liver function tests be performed prior to and at 12 weeks following initiation of therapy or the elevation of dose. Patients who develop increased transaminase levels or signs and symptoms of liver disease should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of three times the upper limit of normal or greater persist, withdrawal of pravastatin therapy is recommended.
Active liver disease or unexplained transaminase elevations are contraindications to the use of pravastatin (see CONTRAINDICATIONS ). Caution should be exercised when pravastatin is administered to patients with a history of liver disease or heavy alcohol ingestion (see CLINIACL PHARMACOLOGY: Pharmacokinetics/Metabolism ). Such patients should be closely monitored, started at the lower end of the recommended dosing range, and titrated to the desired therapeutic effect.
Liver Enzymes
HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. In three long-term (4.8-5.9 years), placebo- controlled clinical trials (WOS, LIPID, CARE; see CLINICAL PHARMACOLOGY: Clinical Studies), 19,592 subjects (19,768 randomized), were exposed to pravastatin or placebo. In an analysis of serum transaminase values (ALT, AST), incidences of marked abnormalities were compared between the pravastatin and placebo treatment groups; a marked abnormality was defined as a post-treatment test value greater than three times the upper limit of normal for subjects with pretreatment values less than or equal to the upper limit of normal, or four times the pretreatment value for subjects with pretreatment values greater than the upper limit of normal but less than 1.5 times the upper limit of normal. Marked abnormalities of ALT or AST occurred with similar low frequency 1.2%) in both treatment groups. Overall, clinical trial experience showed that liver function test abnormalities observed during pravastatin therapy were usually asymptomatic, not associated with cholestasis, and did not appear to be related to treatment duration.
It is recommended that liver function tests be performed prior to the initiation of therapy, prior to the elevation of the dose, and when otherwise clinically indicated.
Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of pravastatin (see CONTRAINDICATIONS). Caution should be exercised when pravastatin is administered to patients who have a recent history of liver disease, have signs that may suggest liver disease (e.g., unexplained aminotransferase elevations, jaundice), or are heavy users of alcohol (see CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism). Such patients should be closely monitored, started at the lower end of the recommended dosing range, and titrated to the desired therapeutic effect.
Patients who develop increased transaminase levels or signs and symptoms of liver disease should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of three times the upper limit of normal or greater persist, withdrawal of pravastatin therapy is recommended.
ADVERSE REACTIONS
Pravastatin is generally well tolerated; adverse reactions have usually been
mild and transient. In 4-month long placebo-controlled trials, 1.7% of pravastatin-treated
patients and 1.2% of placebo-treated patients were discontinued from treatment
because of adverse experiences attributed to study drug therapy; this difference
was not statistically significant. In long-term
studies, the most common reasons for discontinuation were asymptomatic serum
transaminase increases and mild, non-specific gastrointestinal complaints.
During clinical trials the overall incidence of adverse events in the elderly
was not different from the incidence observed in younger patients. (See also
PRECAUTIONS: Geriatric Use section).
In three large, placebo-controlled trials (West of Scotland Coronary Prevention study [WOS], Cholesterol and Recurrent Events study [CARE], and Long-term Intervention with Pravastatin in Ischemic Disease study [LIPID]) involving a total of 19,768 patients treated with PRAVACHOL (N = 9895) or placebo (N = 9873), the safety and tolerability profile in the pravastatin group was comparable to that of the placebo group over the median 4.8 to 5.9 years of follow-up. In these long-term trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal complaints.
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PROTONOX (pantoprazole sodium) delayed-release
tablets
[June 12, 2001/Wyeth-Ayerst]
Changes to the DESCRIPTION, CLINICAL PHARMACOLOGY, INDICATION AND USAGE, PREACUTIONS, ADVERSE REACTIONS, DOSAGE AND ADMINSITRATION and HOW SUPPLIED sections.
Extensive changes, call the sponsor for the FPL.
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SODIUM CHLORIDE 50 mEq and 100 mEq plastic
vials
[June 7, 2001: Abbott Laboratories]
PRECAUTIONS: A new section was added
"Pediatric Use: The safety and effectiveness of 14.6% Sodium Chloride Injection, USP Additive Solution have not been established. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use."
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SEROSTIM (somatropin) for injection
[June 13, 2001: Serono, Inc.]
PRECAUTIONS: Added following the 5th Paragraph:
ADVERSE REACTIONS: Added as the last paragraph:
During post-marketing surveillance, cases of new onset glucose intolerance, diabetes mellitus and exacerbation of pre-existing diabetes mellitus have been reported in patients receiving Serostim. Some patients developed diabetic ketoacidosis and diabetic coma. In some patients, these conditions improved when Serostim was discontinued while in others the glucose intolerance persisted. Some patients necessitated initiation or adjustment of antidiabetic treatment while on Serostim.
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VALTREX (valacyclovir HCl) Caplets
[June 25, 2001: GlaxoSmithKline]
MICROBIOLOGY
Mechanism of Antiviral Action,
a. first paragraph, last sentence deleted: "In
cell culture, acyclovir’s highest antiviral activity is against HSV-1, followed
in decreasing order of potency against HSV-2 and VZV."
b. second paragraph, first sentence, revised to read: "The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV."
Drug Resistance,
a. First sentence revised to read: "Resistance of HSV and VZV to acyclovir can result from quantitative and quantitative changes in the viral TK and/or DNA polymerase."
b. First sentence of the second paragraph deleted "antiviral
nucleoside analogues". replaced with "acyclovir".
CLINICAL PHARMACOLOGY
Metabolism the following sentence was deleted. "Neither valacyclovir
nor acyclovir metabolism is associated with liver
microsomal enzymes. is metabolized
by cytochrome P450 enzymes.
Revised Geriatrics: After single-dose administration of 1 gram of VALTREX in healthy geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared to 2.91 ± 0.63 hours in healthy volunteers. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of VALTREX in geriatric volunteers varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Revied Clinical Trials: Recurrent Episodes: Three double-blind trials (2 of them placebo-controlled) in immunocompetent adults with recurrent genital herpes were conducted. Patients self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode. In 1 study, patients were randomized to receive 5 days of treatment with either VALTREX 500 mg b.i.d. (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving VALTREX 500 mg versus 6 days in the placebo group, and the median time to cessation of viral shedding in patients with at least 1 positive culture (42% of the overall study population) was 2 days in the group receiving VALTREX 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving VALTREX 500 mg versus 4 days in the placebo group. Results supporting efficacy were replicated in a second trial. In a third study, patients were randomized to receive VALTREX 500 mg b.i.d. for 5 days (n = 398) or VALTREX 500 mg b.i.d. for 3 days (and matching placebo b.i.d. for 2 additional days) (n = 402). The median time to lesion healing was about 4½ days in both treatment groups. The median time to cessation of pain was about 3 days in both treatment groups.
PRECAUTIONS
Carcinogenesis, Mutagenesis, Impairment of Fertility, the fourth and the fifth paragraph revised.
Paragraph 4:
In the mouse lymphoma assay, valacyclovir was negative
not mutagenic in the absence of metabolic
activation. In the presence of metabolic activation (76% to 88% conversion to
acyclovir), valacyclovir was weakly
mutagenic.
Paragraph 5:
A Valacyclovir was not mutagenic
in a mouse micronucleus assay was negative
at 250 mg/kg but weakly positive
at 500 mg/kg (acyclovir concentrations 26 to 51 times human plasma levels).
Pregnancy: Teratogenic Effects, "There were 756
749 pregnancies followed in women exposed
to systemic acyclovir during the first trimester of pregnancy resulting
in 756 outcomes."
Pediatric Use, revised to read, "Safety and effectiveness of VALTREX in pre-pubertal pediatric patients have not been established.
Revised
Geriatric Use: Of the total number of subjects in clinical studies of VALTREX, 852 were 65 and over, and 346 were 75 and over. In a clinical study of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in patients 65 and older compared with younger adults. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events. With respect to CNS adverse events observed during clinical practice, agitation, hallucinations, confusion, delirium, and encephalopathy were reported more frequently in elderly patients (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS: Observed During Clinical Practice, and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
The tables have been revised. These changes include the following.
The information in Table 2 is now contained in 2 tables, Table 2 and Table 3. The revised Table 2 is now entitled: "Incidence (%) of Adverse Events in Herpes Zoster Study Populations" and Table 3 is now entitled, "Incidence (%) of Adverse Events in Genital Herpes Study Populations".
Table 3 entitled, "Incidence (%) of
Laboratory Abnormalities in Herpes Zoster and Genital Herpes Study Populations",
is now Table 4 in the revised label.
Observed During Clinical Practice, the following CNS symptoms were added to the revised label: aggressive behavior, coma, decreased consciousness, encephalopathy, and psychosis "See PRECAUTIONS".
A category entitled "eye" was added to include visual abnormalities.
the term "Hemic" was replaced
with the word, "Hematologic".
DOSAGE AND ADMINISTRATION
Recurrent Episodes, revised first sentence to "500 mg twice daily for
5 3
days’
Table 4 in the January 21, 2000 label is now Table 5 in the revised label.
In the VIROLOGY section, under Drug Resistance, revised sentence:
"Resistance of HSV and VZV to acyclovir
occurs by the same mechanisms as resistance to
VZV."
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WELLBUTRIN (bupropion) Tablets
[June 11, 2001: GlaxoSmithKline]
CLINICAL PHARMACOLOGY-
Clinical Trials, inserted as the final paragraph
In a longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder, recurrent type, who had responded during an 8-week open trial on Wellbutrin SR (150 mg bid) were randomized to continuation of their same Wellbutrin SR dose or to placebo, for up to 44 weeks of observation for relapse. Response during the open phase was defined as a CGI Improvement score of 1 (very much improved) or 2 (much improved) for each of the final three weeks. Relapse during the double-blind phase was defined as the investigator’s judgement that drug treatment was needed for worsening depressive symptoms. Patients receiving continued Wellbutrin SR treatment experienced significantly lower relapse rates over the subsequent 44 weeks compared to those receiving placebo.
INDICATIONS AND USAGE
Added
The efficacy of Wellbutrin SR in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. (see Clinical Pharmacology). Nevertheless, the physician who elects to use Wellbutrin SR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Under DOSAGE AND ADMINISTRATION-Maintenance Treatment
added
It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In a study in which patients with major depressive disorder, recurrent type who had responded during 8 weeks of acute treatment with Wellbutrin SR were assigned randomly to placebo or to the same dose of Wellbutrin SR (150 mg bid) during 44 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. (see Clinical Trials under CLINICAL PHARMACOLOGY). Based on these limited data, it is unknown whether or not the dose of Wellbutrin SR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
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XENICAL (orlistat) Capsules
[June 25, 2001: HLR Techlnology]
CLINICAL PHARMACOLOGY: Pharmacokinetics
Drug-Drug Interactions: Drug-drug interaction studies indicate that
XENICAL had no effect on pharmacokinetics and/or pharmacodynamics of alcohol,
digoxin, glyburide, nifedipine (extended-release tablets), oral contraceptives,
phenytoin, pravastatin or warfarin. XENICAL
induced a modest increase of
the bioavailability and lipid-lowering effect
of pravastatin (see CLINICAL STUDIES and PRECAUTIONS). Alcohol
did not affect the pharmacodynamics of orlistat.
PRECAUTIONS: Drug Interactions
Pravastatin: In a two-way crossover
parallel study of 24 normal-weight,
mildly hypercholesterolemic patients subjects
receiving XENICAL 120 mg three times a day for 6
10 days, the effect of
XENICAL was additive to the lipid-lowering effect
did not effect the pharmacokinetics of pravastatin.
Modest increases (approximately 30%) in pravastatin
plasma concentrations were observed during coadministration with XENICAL.
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ZEMURON ( rocuronium bromide) Injection
[June 5, 2001: Organon]
DESCRIPTION:
In the first sentence of the last paragraph of this section the phrase "that is clear, colorless to yellow/orange," has been added to this paragraph which describes the solution.
CLINICAL PHARMACOLOGY:
The titles of table 1 – 4 have been revised
PRECAUTIONS:
Pregnancy category B C
Revised
"A teratogenicity study has been conducted in rats using intravenously administered doses of ZEMURON® (rocuronium bromide) Injection approximating the clinical dose in humans (0.3 mg/kg). No teratogenic effects were observed in this study. There are no adequate and well controlled studies in pregnant women. ZEMURON® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."
"Developmental toxicology studies have been performed in pregnant, conscious, non ventilated rabbits and rats. Inhibition of neuromuscular function was the endpoint for high-dose selection. The maximum tolerated dose served as the high-dose and was administered intravenously three times a day to rats (0.3 mg/kg, 15-30% of human intubation dose of 0.6 to 1.2 mg/kg based on the body surface unit of mg/m 2 ) from day 6 to 17 and to rabbits (0.02 mg/kg, 25% human dose) from day 6 to 18 of pregnancy. High-dose treatment caused acute symptoms of respiratory dysfunction due to the pharmacological activity of the drug. Teratogenicity was not observed in these animal species. The incidence of late embryonic death was increased at the high-dose in rats most likely due to oxygen deficiency. Therefore, this finding probably has no relevance for humans because immediate mechanical ventilation of the intubated patient will effectively prevent embryofetal hypoxia. However, there are no adequate and well-controlled studies in pregnant women. ZEMURON® (rocuronium bromide) Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."
ADVERSE REACTIONS:
In the last sentence of the main heading, the words "reactions and shock" have been added.
"In clinical practice, there have been rare reports of allergic reactions
(anaphylactic and anaphylactoid reactions and shock) with ZEMURON®."
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