![[U.S. Food and Drug Administration]](https://webarchive.library.unt.edu/eot2008/20081028094358im_/http://www.fda.gov/icon/header.gif){kind=icon}
(Posted: August 11, 2000)
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 2000 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.
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(zafirlukast) |
(amphotericin B) |
(testosterone gel) |
(vitamin A palmitate) |
|
(candesartan) |
(clarithromycin) |
(ciprofloxacin) |
(dactinomycin) |
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(misoprostol) |
(divalproex sodium, valproate sodium & valproic acid)) |
(venlafaxine HCl) |
(raloxifene HCl) |
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(foscarnet sodium) |
(gemcitibine HCl) |
(somatropin) |
(electrolytes) |
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(isosorbide mononitrate) |
(fluvoxamine maleate) |
(thioridazine HCl) |
(vinorelbine) |
|
(tamoxifen citrate) |
(electrolytes) |
(norgestimate/ ethinyl estradiol) |
(norethindrone/mestranol) |
|
(pravastatin sodium) |
(lansoprazole) |
(quinidine gluconate) |
(metoclopramide) |
|
(budesonide) |
(salmeterol xinafoate) |
(nefazodone HCl) |
|
|
|
|
(ticlopidine HCl) |
(tocainide HCl) |
|
(sterile urea) |
"Patients should be told that a rare side effect of Accolate is elevation of liver enzymes and that if they experience signs and/or symptoms of liver dysfunction (e.g., right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, and flu-like symptoms), they should contact their physician immediately."
Replaced with revisions incorporated below -
"Patients should be told that a rare side effect of Accolate is hepatic dysfunction, and to contact their physician immediately if they experience symptoms of hepatic dysfunction (e.g., right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, and anorexia)."
Hepatic: Section revised -
Rarely, elevations of one or more liver enzymes may occur during Accolate therapy. Most of these have been observed in clinical trials with Accolate at doses four times higher than the recommended dose. The clinical significance of these elevations are unknown. Cases of symptomatic hepatitis and hyperbilirubinemia without other attributable cause, have been reported from the post-marketing experience in patients who have received the recommended dose of Accolate (40 mg/day). In rare cases, patients have progressed to hepatic failure. In most, but not all patients, the clinical symptoms abated and the liver enzymes returned to normal or near normal after stopping Accolate. If clinical signs or symptoms of liver dysfunction (e.g., right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, and flu-like symptoms) are noted, it is reasonable to recommend that standard liver tests be obtained and the patient managed accordingly. A decision to discontinue Accolate should be individualized to the patient's condition weighing the risk of hepatic dysfunction against the clinical benefit of Accolate to the patient. (See PRECAUTIONS, Information for Patients and ADVERSE REACTIONS sections.)
Replaced with revisions incorporated below -
"Rarely, elevations of one or more liver enzymes have occurred in patients receiving Accolate in controlled clinical trials. In clinical trials, most of these have been observed at doses four times higher than the recommended dose. The following hepatic events (which have occurred predominantly in females) have been reported from postmarketing adverse event surveillance of patients who have received the recommended dose of Accolate (40 mg/day): cases of symptomatic hepatitis (with or without hyperbilirubinemia) without other attributable cause; and rarely, hyperbilirubinemia without other elevated liver function tests. In most, but not all, postmarketing reports, the patient's symptoms abated and the liver enzymes returned to normal or near normal after stopping Accolate. In rare cases, patients have progressed to hepatic failure.
"If liver dysfunction is suspected based upon clinical signs or symptoms (e.g., right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, anorexia, and enlarged liver) Accolate should be discontinued. Liver function tests, in particular serum ALT, should be measured immediately and the patient managed accordingly. If liver function tests are consistent with hepatic dysfunction, Accolate therapy should not be resumed. Patients in whom Accolate was withdrawn because of hepatic dysfunction where no other attributable cause is identified should not be re-exposed to Accolate. (See PRECAUTIONS, Information for patients and ADVERSE REACTIONS sections).
"Rarely, elevations of one or more liver enzymes have occurred in patients receiving ACCOLATE in controlled clinical trials. Most of these have been observed in asymptomatic patients at doses four times higher than the recommended dose. The clinical significance of these elevations are unknown. Cases of symptomatic hepatitis and hyperbilirubinemia, without other attributable cause have been reported from the post-marketing experience in patients who have received the recommended daily dose of ACCOLATE (40 mg/day). In rare cases, patients have progressed to hepatic failure. In most, but not all patients, the clinical symptoms abated and the liver enzymes returned to normal or near normal after stopping ACCOLATE."
Replaced with revisions incorporated below -
"Rarely, elevations of one or more liver enzymes have occurred in patients receiving Accolate in controlled clinical trials. In clinical trials, most of these have been observed at doses four times higher than the recommended dose. The following hepatic events (which have occurred predominantly in females) have been reported from postmarketing adverse event surveillance of patients who have received the recommended dose of Accolate (40 mg/day): cases of symptomatic hepatitis (with or without hyperbilirubinemia) without other attributable cause; and rarely hyperbilirubinemia without other elevated liver function tests. In most, but not all, postmarketing reports, the patient's symptoms abated and the liver enzymes returned to normal or near normal after stopping Accolate. In rare cases, patients have progressed to hepatic failure."
Sixth paragraph revised (new text in italics) -
"Hypersensitivity reactions, including urticaria, angioedema and rashes, with or without blistering, have been reported in association with Accolate therapy. Additionally, there have been reports of patients experiencing agranulocytosis, bleeding, bruising, edema, arthralgia, and myalgia in association with Accolate therapy."
"breast cancer (a rare condition for men)
["heart, kidney, or liver disease" deleted]"
"Vitamin A treatment for deficiency states has been recognized as an especially effective and important therapy in the peditic population. Vitamin A supplementation for deficiency states in this population has been addressed by the Committee on Clinical Practice Issues of the American Society for Clinical Nutrition, by the American Society for Parenteral and Enteral Nutrition, and by the World Health Organization."
"Pediatric Use: Polysorbates have been associated with the E-Ferol syndrome (thrombocytopenia, renal dysfunction, hepatomegaly, cholestasis, ascites, hypotension and metabolic acidosis) in low-birth weight infants."
2. Specific manifestations: (new text in italics)
"d. Systemic: hepatotoxicity, hypomenorrhea, hepatosplenomegaly, jaundice, leukopenia, vitamin A plasma level over 1,200 Units/mL."
"Follow-up therapy with an oral therapeutic multi-vitamin preparation containing 10,000 to 20,000 Units vitamin A for ["persons" deleted] adults and for pediatric patients over 8 years old, and 5,000 to 10,000 Units for infants and ["children" deleted] other pediatric patients under 8 years old, is recommended daily for two months. Low-birth-weight infants may require additional vitamin A though the exact dosing in these pediatric patients has not been established. In malabsorption, the parenteral route must be used for an equivalent preparation."
"Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effects on P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected."
"Other adverse events reported for candesartan cilexetil where a causal relationship could not be established include very rare cases of neutropenia, leukopenia and agranulocytosis."
"Rarely, erythromycin and clarithromycin have been associated with ventricular arrhythmias, including ventricular tachycardia and torsades de pointes, in individuals with prolonged Qtc intervals."
Replaced with revisions incorporated below -
"As with other macrolides, clarithromycin has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and torsades de pointes."
"After a 250-mg oral dose, urine concentrations of ciprofloxacin usually exceed ["200 mg/mL" deleted] 200 ug/mL during the first two hours and are approximately ["30 mg/mL" deleted] 30 ug/mL at 8 to 12 hours after dosing."
[I.V. Solution & Tablets and Oral Suspension labeling] new eighth and fifteenth paragraphs added respectively -
"Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65 years) as compared to young adults. Although the Cmax is increased 16-40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant. (See PRECAUTIONS: Geriatric Use.)"
"that ciprofloxacin may be taken with or without meals and to drink fluids liberally. ["The preferred time of dosing is two hours after a meal. Patients should be advised to drink fluids liberally and not take antacids containing magnesium, aluminum, or calcium, products containing iron, or multivitamins containing zinc." deleted] As with other quinolones, concurrent administration of ciprofloxacin with magnesium/aluminum antacids, or sucralfate, Videx (didanosine) chewable/buffered tablets or pediatric powder, or with other products containing calcium, iron or zinc should be avoided. These products may be taken two hours after or six hours before ciprofloxacin."
Drug Interactions: Third paragraph, first sentence revised [Tablets & Oral Suspension labeling] (new text in italics) -
"Concurrent administration of ["ciprofloxacin" deleted] a quinolone, including ciprofloxacin, ["with antacids containing magnesium, aluminum, or calcium; with sucralfate or divalent and trivalent cations such as iron may substantially interfere with the absorption of ciprofloxacin, resulting in serum and urine levels considerably lower than desired." deleted] with multivalent cation-containing products such as magnesium/aluminum antacids, sucralfate, Videx (didanosine) chewable/buffered tablets or pediatric powder, or products containing calcium, iron, or zinc may substantially decrease its absorption, resulting in serum and urine levels considerably lower than desired. ["To a lesser extent this effect is demonstrated with zinc-containing multivitamins." deleted] (See DOSAGE AND ADMINISTRATION for concurrent administration of these agents with ciprofloxacin.)
New fourth paragraph -
Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin.
Geriatric Use: New subsection added [I.V. Solution & Tablets and Oral Suspension] -
"In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65 years of age and10% were greater than or equal to 75 years of age. 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 responses between the elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. However, since some older individuals experience reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)"
"In acute uncomplicated cystitis in females, the usual dosage is 100-mg or 250-mg every 12 hours."
Under "DOSAGE GUIDELINES" table, the section for "Urinary Tract Infection, Acute Uncomplicated" -
"or 250-mg" was added to the unit dose column.
See Instructions To The Pharmacist for Use/Handling of Cipro Oral Suspension: New last sentence added -
"Cipro (ciprofloxacin) 5% and 10% Oral Suspension should not be administered through feeding tubes due to its physical characteristics."
The paragraph with the heading " Concurrent Use With Antacids or Multivalent Cations:" has been deleted and replaced with the sentence -
"Ciprofloxacin should be administered at least 2 hours before or 6 hours after magnesium/aluminum antacids, or sucralfate, Videx (Didanosine) chewable/buffered tablets or pediatric powder for oral solution, or other products containing calcium, iron or zinc."
Instructions To The Patient For Taking Cipro Oral Suspension: Information concerning shaking the bottle before each use and "the product can be used" was added to the following paragraph to read:
"Swallow the prescribed amount of suspension. Do not chew the microcapsules. Reclose the bottle completely after use according to the instructions on the cap. Shake vigorously each time for approximately 15 seconds. The product can be used for 14 days when stored in the refrigerator or at room temperature (below 86oF). After treatment has been completed, any remaining suspension should not be reused."
CYTOTEC (MISOPROSTOL) ADMINISTRATION BY ANY ROUTE IS CONTRAINDICATED, BECAUSE IT CAN CAUSE ABORTION, IN WOMEN WHO ARE PREGNANT (See WARNINGS and PRECAUTIONS). ["Cytotec (misoprostol) is contraindicated, because of its abortifacient property in women who are pregnant. (See Precautions).)" deleted]
Anecdotal reports have been received, primarily from Brazil, of congenital anomalies and reports of fetal death in pregnancies in which misoprostol has been used as an abortifacient. ["Anecdotal reports, primarily from Brazil, of congenital anomalies and reports of fetal death subsequent to misuse of misoprostol as an abortifacient have been received." Deleted]
Two new paragraphs added -
"UTERINE RUPTURE HAS BEEN REPORTED WHEN CYTOTEC WAS ADMINISTERED INTRAVAGINALLY IN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION BEYOND THE FIRST TRIMESTER OF PREGNANCY.
"UTERINE PERFORATION HAS BEEN REPORTED FOLLOWING ADMINISTRATION OF COMBINED VAGINAL-AND-ORAL CYTOTEC IN PREGANT WOMEN TO INDUCE ABORTION. IN EACH OF THESE REPORTED CASES, THE GESTATIONAL AGE OF THE PREGNANCIES WAS UNKNOWN."
PRECAUTIONS: SPECIAL NOTE FOR WOMEN: Subsection revised -
"Cytotec must not be used by pregnant women. Cytotec may cause miscarriage. Miscarriages caused by Cytotec may be incomplete, which could lead to potentially dangerous bleeding, hospitalization, surgery, infertility, or maternal or fetal death."
Replaced with revisions incorporated below -
"Because of its abortifacient property, Cytotec is contraindicated for use by pregnant women. Cytotec may cause miscarriage if given to pregnant women at any time during pregnancy. Miscarriages caused by Cytotec may be incomplete, which could lead to dangerous bleeding, hospitalization, surgery, infertility, or maternal or fetal death."
"There have been reports in which intravaginal administration of misoprostol in pregnant women resulted in rupture of the uterus and death of the infant. (See boxed CONTRAINDICATIONS AND WARNINGS.)"
"CASES OF LIFE-THREATENING PANCREATITIS HAVE BEEN REPORTED IN BOTH CHILDREN AND ADULTS RECEIVING VALPROATE. SOME OF THE CASES HAVE BEEN DESCRIBED AS HEMORRHAGIC WITH A RAPID PROGRESSION FROM INITIAL SYMPTOMS TO DEATH. CASES HAVE BEEN REPORTED SHORTLY AFTER INITIAL USE AS WELL AS AFTER SEVERAL YEARS OF USE. PATIENTS AND GUARDIANS SHOULD BE WARNED THAT ABDOMINAL PAIN, NAUSEA, VOMITING, AND/OR ANOREXIA CAN BE SYMPTOMS OF PANCREATITIS THAT REQUIRE PROMPT MEDICAL EVALUATION. IF PANCREATITIS IS DIAGNOSED, VALPROATE SHOULD ORDINARILY BE DISCONTINUED. ALTERNATIVE TREATMENT FOR THE UNDERLYING MEDICAL CONDITION SHOULD BE INITIATED AS CLINICALLY INDICATED (See WARNINGS and PRECAUTIONS.)"
"Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416 patients, representing 1044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated (see BOXED WARNING)."
Somnolence in the Elderly: New subsection -
"In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse events. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence (see DOSAGE AND ADMINISTRATION)."
"There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically."
Drug Interactions: Drugs for which a potentially important valproate interaction has ben observed:
New first paragraph -
"Amitriptyline/Nortriptyline - Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitrptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate."
CNS Effects: Addition of "parkinsonism" as last entry to third sentence.
Other: Addition of "Anaphylaxis" as first entry to the subsection.
"Dosing in Elderly Patients - Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse events. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fliud intake and in patients with excessive somnolence. The ultimate therapeutic dose should be acheived on the basis of both tolerabilty and clinical response (see WARNINGS)."
"Mydriasis has been reported in association with venlafaxine: therefore patients with raised intra-ocular pressure or at risk of acute narrow angle glaucoma should be monitored."
Drug Interactions: Indinavir
New subsection -
"In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions
at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir
and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics
of venlafaxine and ODV. The clinical significance of this finding is unknown.
"In postmarketing experience, there have been reports of fatalities in patients taking overdoses of venlafaxine, predominantly in combination with alcohol and or other drugs."
Replaced with -
"In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. Electrocardiogram changes (e.g. prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, altered level of consciousness (ranging from somnolence to coma), seizures, vertigo, and death have been reported."
"Raloxifene decreases total and LDL cholesterol levels but does not increase triglyceride levels (see PRECAUTIONS)."
"Limited clinical data suggest that some women with a history of marked hypertriglyceridemia (> 5.6 mmol/L or > 500 mg/dL) in response to treatment with oral estrogen or estrogen plus progestin may develop increased levels of triglycerides when treated with Evista. Women with this medical history should have serum triglycerides monitored when taking Evista."
"In general, it does not change triglycerides or HDL ("good") cholesterol. However, if you have taken estrogen in the past and had extreme elevations in triglycerides, you should talk with your doctor before taking Evista."
"Abnormal renal function has been reported in connection with the use of Foscavir in combination with ritonavir and/or saquinavir has been observed in clinical practice."
Replaced with revisions incorporated below -
"Abnormal renal function has been observed in clinical practice during the use of Foscavir and ritonavir or Foscavir, ritonavir, and saquinavir. (See DOSAGE and ADMINISTRATION.)"
Geriatric Use: New subsection -
"No studies of the efficacy or safety of Foscavir in persons 65 years of age or older have been conducted. However, Foscavir has been used in patients aged 65 years of age and older. The pattern of adverse events in these patients is consistent across all age groups. This drug 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 renal function should be monitored. (See DOSAGE AND ADMINISTRATION.)"
"The diagnosis of Hemolytic-Uremic Syndrome (HUS) should be considered if the patient develops anemia with evidence of microangiopathic hemolysis, ["as indicated by" deleted]" elevation of bilirubin or LDH, reticulocytosis, severe thrombocytopenia, and/or evidence of renal failure (elevation of serum creatinine or BUN)."
Pulmonary - Subsection revised (new text in italics) -
"Dyspnea was reported in 23% of patients, severe dyspnea in 3%. Dyspnea may be due to underlying disease such as lung cancer (40% of study population) or pulmonary manifestations of other malignancies. Dyspnea was occaisionally accompanied by bronchospasm (<2% of patients). ["Rare reports of prenchymal lung toxicity consistent with drug induced pneumonitis have been associated with the use of Gemzar. Rarely pulmonary edema of unknown etiology, sometimes severe, has occurred in association with Gemzar therapy. Gemzar therapy should be discontinued immediately and appropriate supportive care measures instituted." Deleted] Pulmonary effects (including pulmonary edema, interstitial pneumonitis, or adult respiratory distress syndrome (ARDS), sometimes severe, have been reported in association with Gemzar therapy. The etiology of these effects is unknown. If such effects develop, Gemzar should be discontinued. Early use of supportive care measures may help ameliorate these conditions."
"Clinical studies of Ismo did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences 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, although age, renal, hepatic or cardiac dysfunction do not appear to have a clinically significant effect on the clearance of Ismo."
"Co-administration of terfenadine, astemizole, cisapride or pimozide with Luvox tablets is contraindicated (see WARNINGS and PRECAUTIONS).""
First, second and fifth sentences revised (new text in italics) -
"Terfenadine, astemizole, cisapride and pimozide are all metabolized by the cytochrome P450IIIA4 isoenzyme, and it has been demonstrated that ketoconazole, a potent inhibitor of IIIA4, blocks the metabolism of these drugs, resulting in increased plasma concentrations of parent drug. Increased plasma concentrations of terfenadine, astemizole, cisapride and pimozide cause QT prolongation and have been associated with torsades de pointes-type ventricular tachycardia, sometimes fatal."
"Consequently, it is recommended that fluvoxamine not be used in combination with either terfenadine, astemizole, cisapride, and pimozide. (see CONTRAINDICATIONS and PRECAUTIONS)."
Hyponatremia: New subsection -
"Several cases of hyponatremia have been reported. In cases where the outcome was known, the hyponatremia appeared to be reversible when fluvoxamine was discontinued. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or with concomitant conditions that might cause hyponatremia. In patients receiving Luvox tablets and suffering from Syndrome of Inappropriate Secretion if Antidiuretic Hormone (SIADH), displacement syndromes, edematous states, adrenal disease or conditions of fluid loss, it is recommended that serum electrolytes, especially sodium as well as BUN and plasma creatinine, be monitored regularly."
Drug Interactions: Last paragraph, first sentence (new text in italics) -
A clinically significant fluvoxamine interaction is possible with drugs having a narrow therapeutic ratio such as terfenadine, astemizole, cisapride or pimozide, warfarin, theophylline, certain benzodiazepines and phenytoin."
"Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.
"Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.
"Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluvoxamine are known.
"A specific caution involves patients taking, or recently having taken, fluvoxamine who might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see Tricyclic Antidepressants (TCAs) under Precautions).
"In managing overdosage, consider the possiblity of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physician's Desk Reference (PDR)."
"The influence of age on the pharmacokinetics of vinorelbine was examined using data from 44 cancer patients (average age, 56.7 ± 7.8 years; range, 41 to 74 years; with 12 patients greater than or equal to 60 years and 6 patients greater than or equal to 65 years) in 3 studies. CL (the mean plasma clearance), t1/2 (the terminal phase half-life), and Vz (the volume of distribution during terminal phase) were independent of age. A separate pharmacokinetic study was conducted in 10 elderly patients with metastatic breast cancer (age range, 66 to 81 years; 3 patients > 75 years; normal liver function tests) receiving vinorelbine 30 mg/m2 intravenously. CL, Vss, and t1/2 were similar to those reported for younger adult patients in previous studies. No relationship between age, systemic exposure (AUC0-infinity) and hematological toxicity was observed."
"The pharmacokinetics of vinorelbine in elderly and younger adult patients are similar (see CLINICAL PHARMACOLOGY)."
"Potassium chloride in water dissociates to provide potassium (K+) and (Cl-) ions. Potassium is the chief cation of body cells (160 mEq/liter of intracellular water). It is found in low concentrations in plasma and extracellular fluids (3.5 to 5.0 mEq/liter in a healthy adult and child over 10 days old; 3.5 to 6.0 mEq/liter in a child less than 10 days old.)"
Paragraph describing water as an essential body constituent followed by a new table -
"Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. Average normal adult daily requirement ranges from two to three liters (1.0 to 1.5 liters each for insensible water loss by perspiration and urine production)."
New text and table -
"Average normal pediatric daily requirements are based on the child's weight as described in the table below:
|
Weight |
Fluid Requirements |
|
Up to 10 kg |
100 mL/kg |
|
11 to 20 kg |
1,000 mL + 50 mL/kg for each kg above 10 kg |
|
Above 20 kg |
1,500 mL + 20 mL/kg for each kg above 20 kg |
"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 during fluid replacement with Normosol-R [Normosol-R and Dextrose]."
"Elderly patients may be at increased risk for the development of fluid overloading and dilutional hyponatremia following Normosol-R [Normosol-R and Dextrose] administration."
"The safety and effectiveness in the pediatric population are based on the similarity of the clinical conditions of the pediatric and adult populations. In neonates or very small infants the volume of fluid may affect fluid and electrolyte balance.
"Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants.
"In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage. "
New subsection [Normosol-R and water formulation] -
"The safety and effectiveness of Normosol-R have been established in the age groups of birth to 16 years. Use of Normosol-R is supported by evidence from adequate and well-controlled clinical studies in adults with additional data from post-marketing experience in the pediatric population."
Geriatric Use: [Normosol -R, all formulations, June 15, 2000]
New subsection -
"Clinical studies of Normosol -R did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
"Elderly patients have been shown to secrete higher levels of antidiuretic hormone than younger patients, which may increase the risk of fluid overloading, and dilutional hyponatremia in these patients. See WARNINGS.
"This drug 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. See WARNINGS."
"As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. "
Replaced by new subsection:
To Administer
"1. Attach administration set per manufacturer's instructions."
"2. Regulate rate of administration per institutional policy."
"Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety."
"In comparison, typical failure rates for other non-surgical methods of birth control during the first year of use are as follows:
Implant: <1%
Injection: <1%
IUD: 1 to 2%
Diaphragm with spermicides: ["18%" deleted] 20%
Spermicides alone: ["21%" deleted]26%,
Vaginal sponge: ["18 to 36%" deleted] 20 to 40%
Female sterilization: <1%
Male sterilization: <1%
Cervical Cap with spermicides: ["18 to 36%" deleted] 20 to 40%
Condom alone (male): ["12%" deleted] 14%
Condom alone (female): 21%
Periodic abstinence: ["20%" deleted] 25%
Withdrawal: 19%
No Methods: 85% "
"A meta-analysis of 54 studies reports that women who are currently using combined oral contraceptives or have used them in the past 10 years are at a slightly increased risk of having breast cancer diagnosed although the additional cancers tend to be localized to the breast. There is no evidence of an increased risk of having breast cancer diagnosed 10 or more years after the cessation of use."
has been revised. The revised paragraph reads:
"A meta-analysis of 54 studies found a small increase in the frequency of having breast cancer diagnosed for women who were currently using combined oral contraceptives or had used them in the past 10 years. This increase in the frequency of breast cancer diagnosis, within 10 years of stopping use, was generally accounted for by cancers localized to the breast. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of use."
Third paragraph, first sentence revised (new text in italics) -
"Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women."
"In addition, combination oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use combination oral contraceptives but to use other forms of contraception until she has completely weaned her child."
Pediatric Use: New subsection -
"Safety and efficacy of ORTHO-NOVUM 1/50 Tablets 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 for users 16 years and older. Use of this product before menarche is not indicated."
"In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately 27% greater and the mean cumulative urinary excretion (CUE) approximately 19% lower in elderly men (65-75 years old) compared with younger men (19 to 31 years old). In a similar study conducted in women, the mean AUC for pravastatin was approximately 46% higher and the mean CUE approximately 18% lower in elderly women (65 to 78 years old) compared to younger women (18 to 38 years old). In both studies Cmax, Tmax and T1/2 values were similar in older and younger subjects."
Clinical Studies: New last sentence in first paragraph regarding the Pravastatin Primary Prevention Study (West of Scotland Coronary Prevention Study - WOS) -
"Median (25th, 75th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total C, LDL-C, TG, and HDL were - 20.3 (-26.9, -11.7), -27.7 (-36.0, -16.9), -9.1 (-27.6, 12.5), and 6.7 (-2.1, 15.6), respectively."
New fourth sentence in the paragraph regarding the Cholesterol and Recurrent Events (CARE) study -
"Median (25th, 75th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total C, LDL-C, TG, and HDL were -22.0 (-28.4, -14.9), -32.4 (-39.9, -23.7), -11.0 (-26.5, 8.6), and 5.1 (-2.9, 12.7), respectively."
Primary Hypercholesterolemia (Fredrickson Type IIa and IIb)
Second paragraph, first sentence revised -
"A single daily dose ["administered in the evening (the recommended dosing)" deleted] is as effective as the same total daily dose given twice a day."
"Pravachol is indicated as an adjunct to diet to reduce elevated Total-C, Apo B, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia (Frederickson Type IIa and IIb)."
"Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of 6,593 subjects treated with pravastatin 40 mg for periods ranging up to 6 years. Across these two studies, 36.1% of pravastatin subjects were 65 and older and 0.8% were aged 75 and older. The beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in modifying lipid profiles was similar to that seen in younger subjects. The adverse event profile in the elderly was similar to that in the overall population. Other reported clinical experience has not identified differences to pravastatin between elderly and younger patients.
Mean pravastatin AUCs are slightly (25-50%) higher in healthy elderly subjects than in healthy younger subjects, but mean Cmax, Tmax and T1/2 values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly (see CLINICAL PHARMACOLOGY: Pharmacokinetics/Metabolism)."
"["During clinical trials the overall incidence of adverse events in the elderly was not different from the incidence observed in younger patients." Deleted] (See also PRECAUTIONS: Geriatric Use section) "
"Additional adverse experiences occurring in <1% of patients or subjects in domestic ["and/or international" deleted] trials [", or occurring since the drug was marketed," deleted] are shown below ["within each body system" deleted]. Refer to Postmarketing for adverse reactions occurring since the drug was marketed.
Body as a Whole - "anaphylactoid-like reaction" moved to Postmarketing
Digestive System - "vomiting" moved to Postmarketing
Hematologic and Lymphatic System - renamed Hemic and Lymphatic System - "agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia and thrombotic thrombocytopenic purpura" moved to Postmarketing."
Urogenital system - "urinary retention" moved to Postmarketing
["The majority of hematologic cases received were foreign-sourced and their relationship to lansoprazole was unclear" deleted]
Postmarketing: new subsection -
On-going Safety Surveillance: Additional adverse experiences have been reported since lansoprazole has been marketed. The majority of these cases are foreign-sourced and a relationship to lansoprazole has not been established. Because these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events are listed below by COSTART body system.
Body as a Whole - anaphylactoid-like reaction; Digestive System - hepatotoxicity, vomiting; Hemic and Lymphatic System - agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia and thrombotic thrombocytopenic purpura; Special Senses - speech disorder; Urogenital System - urinary retention.
"The rate of absorption of quinidine following the ingestion of grapefruit juice may be decreased."
"Grapefruit juice: Grapefruit juice inhibits P450 3A4-mediated metabolism of quinidine to 3-hydroxyquinidine. Although the clinical significance of the interaction is unknown, grapefruit juice should be avoided.
"Dietary salt: The rate and extent of quinidine absorption may be affected by changes in dietary salt intake; a decrease in dietary salt intake may lead to an increase in plasma quinidine concentrations."
Non-interactions of quinidine with other drugs: Second paragraph, first sentence revised -
"Conversely, the pharmacokinetics of quinidine are not significantly affected by caffeine, ciprofloxacin, digoxin, ["diltiazem" deleted], felodipine, omeprazole, or quinine.
"Following quinidine overdose, drugs that delay elimination of quinidine (cimetidine, carbonic-anhydrase inhibitors, diltiazem, thiazide diuretics) should be withdrawn unless absolutely required."
"Clinical studies of Rhinocort Nasal Inhaler did not include a sufficient number of patients 65 years of age and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in either clinical safety or efficacy between the elderly and younger patients. In general, 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."
"In 4 clinical trials in adult and adolescent patients with asthma (n = 1922), the effect of adding salmeterol to inhaled corticosteroid therapy was evaluated. The studies utilized the inhalation aerosol formulation of salmeterol xinafoate for a treatment period of 6 months. They compared the addition of salmeterol therapy to an increase (at least doubling) of the inhaled corticosteroid dose.
"Two randomized, double-blind, parallel group clinical trials (n = 997) enrolled patients (ages 18 - 82 years) with persistent asthma who were previously maintained but not adequately controlled on inhaled corticosteroid therapy. During the 2-week run-in period, all patients were switched to beclomethasone dipropionate 168 mcg twice daily. Patients still not adequately controlled were randomized to either the addition of salmeterol inhalation aerosol 42 mcg twice daily or an increase of beclomethasone dipropionate to 336 mcg twice daily. As compared to the doubled dose of beclomethasone dipropionate, the addition of salmeterol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reduction in supplemental albuterol use. The percent of patients who experienced asthma exacerbations overall was not different between groups (i.e., 16.2% in the salmeterol group versus 17.9% in the higher dose beclomethasone dipropionate group).
"Two randomized, double-blind, parallel group clinical trials (n = 925) enrolled patients (ages 12 - 78 years) with persistent asthma who were previously maintained but not adequately controlled on prior therapy. During the 2 - 4 week run-in period, all patients were switched to fluticasone propionate 88 mcg twice daily. Patients still not adequately controlled were randomized to either the addition of salmeterol inhalation aerosol 42 mcg twice daily or an increase of fluticasone propionate to 220 mcg twice daily. As compared to the increased (2.5 times) dose of fluticasone propionate, the addition of salmeterol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reduction in supplemental albuterol use. Fewer patients receiving salmeterol experienced asthma exacerbations than those receiving the higher dose of fluticasone propionate (8.8% versus 13.8%)."
"pimozide" is included with "terfenidine, astemizole, cisapride" regarding interactions.
"There have been reports of increased blood concentrations of cyclosporine and tacrolimus into toxic ranges when patients received these drugs concomitantly with Serzone. Both cyclosporine and tacrolimus are substrates of CYP3A4, and nefazodone is known to inhibit this enzyme. If either cyclosporine or tacrolimus is administered with Serzone, blood concentrations of the immunosuppressive agent should be monitored and dosage adjusted accordingly."
"Rare reports of liver necrosis and liver failure, in some cases leading to liver transplantation and/or death."
"There is very limited experience with nefazodone overdose."
Overdose Management [Extensive revisions to the 1999 PDR subsection] Revisions incorporated in the following paragraphs:
"Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.
"Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.
"Activated charcoal should be administered. Due to the wide distribution of nefazodone in body tissues, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for nefazodone are known.
"In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physician's Desk Reference."
"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 (and potassium) 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."
"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 and phosphorus 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."
"The safety and effectiveness in the pediatric population are based on the similarity of the clinical conditions of the pediatric and adult populations. In neonates or very small infants the volume of fluid may affect fluid and electrolyte balance."
"WARNING: Ticlid can cause life-threatening hematological adverse reactions, including neutropenia/agranulocytosis, ["and" deleted] thrombocytopenia purpura (TTP) and aplastic anemia."
New fourth paragraph -
" Aplastic Anemia: Aplastic anemia was not seen during clinical trials, but US physicians reported about 50 cases between 1992 and 1998. Based on an estimated patient exposure of 2 million to 4 million, and assuming an event reporting rate of 10% (the true rate is not known), the incidence of ticlopidine-associated aplastic anemia may be as high as one case in every 4000 to 8000 patients exposed."
Fifth paragraph (new text in italics) -
"Monitoring of Clinical and Hematologic Status: Severe hematological adverse reactions may occur within a few days of the start of therapy. The incidence of TTP peaks after about 3 to 4 weeks of therapy and neutropenia peaks at approximately 4 to 6 weeks ["with both declining thereafter" deleted]. The incidence of aplastic anemia peaks after about 4 to 8 weeks of therapy. The incidence of the hematologic adverse reactions declines thereafter. Only a few cases of neutropenia, TTP, or aplastic anemia have arisen after more than 3 months of ["treatment" deleted] therapy."
"Because Ticlid is associated with a risk of life-threatening blood dyscrasias including thrombotic thrombocytopenic purpura (TTP),["and" deleted] neutropenai/agranolocytosis and aplastic anemia (see BOXED WARNING and WARNINGS), Ticlid should be reserved for patients who are intolerant or allergic to aspirin therapy or who have failed aspirin therapy."
"• Presence of hematopoietic disorders such as neutropenia and thrombocytopenia or a past history of either TTP or aplastic anemia"
"Bone-marrow examination typically shows a reduction in ["myeloid" deleted] white blood cell precursors."
Aplastic Anemia: New subsection -
"Aplastic anemia is characterized by anemia, thrombocytopenia and neutropenia together with a bone marrow examination that shows decreases in the precursor cells for red blood cells, white blood cells, and platelets. Patients may present with signs or symptoms suggestive of infection, in association with low white blood cell and platelet counts. Prompt treatment, which may include the use of drugs to stimulate the bone marrow, can minimize the mortality associated with aplastic anemia."
Monitoring for Hematologic Adverse Reactions: Second paragraph, first sentence revised (new text in italics) -
"Clinically, fever might suggest ["either" deleted] neutropenia,["or" deleted], TTP, or aplastic anemia; TTP might also be suggested by weakness, pallor, petechiae or purpura, dark urine (due to blood, bile pigments, or hemoglobin) or jaundice, or neurological changes."
Third paragraph; second, fifth sentences revised (new text in italics), new fourth sentence (in italics) -
"Ticlopidine is occasionally associated with thrombocytopenia unrelated to TTP or aplastic anemia."
" A simultaneous decrease in platelet count and WBC count should prompt further investigation for a diagnosis of aplastic anemia."
"If there are laboratory signs of TTP, or if the neutrophil count is confirmed to be < 1200/mm3, then ["the drug" deleted] Ticlid should be discontinued immediately."
Other Hematological Effects: First sentence revised (new text in italics) -
"Rare cases of agranulocytosis, pancytopenia, or ["aplastic anemia" deleted] leukemia have been reported in postmarketing experience, some of which have been fatal."
"Ticlid therapy has been associated with elevations of alkaline phosphatase, bilirubin, and transaminases, which generally occurred within 1 to 4 months of therapy initiation."
Second paragraph revised (new text in italics) -
Postmarketing experience includes rare individuals with elevations in their transaminases and bilirubin to > 10X above the upper limits of normal. Based on postmarketing and clinical trial experience, liver function testing, including ["SGPT and GGTP" deleted] ALT, AST, and GGT, should be considered whenever liver dysfunction is suspected, particularly during the first 4 months of treatment."
"Neutropenia/thrombocytopenia, TTP, aplastic anemia , (see BOXED WARNING and WARNINGS), leukemia, agranulocytosis, eosinophilia, pancytopenia, thrombocytosis and bone-marrow depression have been reported."
Less Frequent Adverse Reactions (Probably Related): Paragraph at end of subsection revised (new text in italics)-
"In addition, rarer, relatively serious and potentially fatal events associated with the use of Ticlid have also been reported from postmarketing experience: Hemolytic anemia with reticulocytosis, ["aplastic anemia" deleted], immune thrombocytopenia, hepatitis, hepatocellular jaundice, cholestatic jaundice, hepatic necrosis, hepatic failure, peptic ulcer, renal failure, nephrotic syndrome, hyponatremia, vasculitis, sepsis, allergic reactions (including angioedema, allergic pneumonitis, and anaphylaxis), systemic lupus (positive ANA), peripheral neuropathy, serum sickness, arthropathy and myositis."
"Rarely, decreases in the white blood cells, red blood cells and platelets can occur together. This condition is called aplastic anemia and can be fatal.
"Things you should watch for as possible early signs of aplastic anemia are feeling of excessive weakness and tiredness, paleness, bruising, and bleeding from areas such as your nose or gums. You may also develop signs of infection such as fever. If any of these occur, contact your doctor immediately."
Other Warnings and Precautions: Second paragraph (new text in italics) -
"If any of the symptoms described above for neutropenia, TTP, aplastic anemia or jaundice occur, contact your doctor immediately."
"Store below 40oC (104oF), preferably between 15oC and 30oC (59oF and 86oF). Store in a well-closed container."
Replaced with -
"Store at 25oC (77oF): excursions permitted to 15-30oC (59-86oF) [see USP Controlled Room Temperature]. Keep container tightly closed."
"Ureaphil (Sterile Urea, USP) should not be infused in veins of the lower extremities of elderly patients. See CONTRAINDICATIONS.
"This drug is known to be substantially excreted by the kidneys, 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. See PRECAUTIONS.
In general, dose selection for an elderly patient should be cautious, generally 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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