![[U.S. Food and Drug Administration]](https://webarchive.library.unt.edu/eot2008/20081028101025im_/http://www.fda.gov/icon/header.gif){kind=icon}
(Posted: 7/21/98)
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 1998 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.
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(captopril/ hydrochlorothiaizde) |
(amiodarone HCl) |
(warfarin Na) |
(estradiol valerate) |
(famciclovir) |
|
(estradiol) |
|
(atorvastatin calcium) |
(cisatracurium besylate) |
(lansoprazole) |
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(omeprazole)) |
(quinidine sulfate) |
|
(polythiazide) |
(paclitaxel) |
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(docetaxel) |
(clobetasol propionate) |
(latanoprost) |
(simvastatin) |
(acyclovir Na) |
"Carcinogenicity and fertility studies have not been conducted with Capozide, however, in animals they have been conducted with the individual components as noted below. Mutagenicity studies indicate that captopril in a 2:1 combination with hydrochlorothiazide was not mutagenic or clastogenic, with or without metabolic activation, in the following in vitro assays: 1) Ames reverse-mutation in Salmonella; 2) forward mutation study in Saccharomyces pombe; 3) mitotic gene conversion test in Saccharomyces cerevisiae; and 4) sister-chromatid-exchange study in human lymphocytes.
"In a cytogenetics study using human lymphocytes, there were no increases in chromosomal abnormalities without metabolic activation, nor with metabolic activation at 28 hours post-treatment. A statistically significant increase was found at 22 hours with metabolic activation at the three concentrations tested (captopril/hydrochlorothiazide in a 2:1 combination at 5, 25, 50 ug/mL total weight); however, there was no dose response, and the difference is probably attributable to the unusual absence of any abnormalities in the negative-control cultures in this test.
"In an oral micronucleus study in mice, the captopril/hydrochlorothiazide combination (2:1 mixture at 2500 mg/kg total weight) was not genotoxic."
"Cases of optic neuropathy and/or optic neuritis, usually resulting in visual impairment, have been reported in patients treated with amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and/or neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. If symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision, prompt ophthalmic examination is recommended. Appearance of optic neuropathy and/or neuritis calls for re-evaluation of Cordarone therapy. The risks and complications of antiarrhythmic therapy with Cordarone must be weighed against its benefits in patients whose lives are threatened by cardiac arrhythmias. Regular ophthalmic examination, including fundoscopy and slit-lamp examination, is recommended during administration of Cordarone. (see "ADVERSE REACTIONS.")" [NOTE: This change does appear in the 1998 PDR.]
"Cases of opticneuropathy and optic neuritis have been reported. (see 'WARNINGS')." [NOTE: This change does appear in the 1998 PDR.]
Corneal Microdeposits: Last sentence revised (new text in italics) -
"Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment (see 'ADVERSE REACTIONS')." [NOTE: This change does appear in the 1998 PDR.]
Neurogic (new subsection) -
"Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete."
Surgery: Adult Respiratory Distress Syndrome (ARDS): Last sentence in subsection -
"One possible mechanism of this deleterious effect may be the generation of superoxide radicals during oxygenation; therefore, the operative FiO2 should be kept as close to room air as possible."
deleted and replaced with -
"Until further studies have been performed, it is recommended that FiO2 and the determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on Cordarone." [NOTE: This change does appear in the 1998 PDR.]
"They are often reversible with dose reduction ["and virtually always reversible with" deleted] or cessation of Cordarone treatment." [NOTE: This change does appear in the 1998 PDR.]
Second paragraph revised (new text in italics) -
"Neurologic problems are extremely common, occurring in 20 to 40% of patients and including malaise and fatigue, tremor and involuntary movements, poor coordination and gait, and peripheral neuropathy; they are rarely a reason to stop therapy and may respond to dose reductions or discontinuation (see 'PRECAUTIONS')."
Text added as new fourth paragraph -
"Ophthalmic abnormalities including optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness, papilledema, corneal degeneration, photosensitivity, eye discomfort, scotoma, lens opacities, and macular degeneration have been reported (see 'WARNINGS')." [NOTE: This change does appear in the 1998 PDR.]
Text added as new eighth paragraph -
"Hepatitis, cholestatic hepatitis, cirrhosis, epididymitis, vasculitis, pseudotumor cerebri, thrombocytopenia, angioedema, bronchiolitis obliterans organizing pneumonia (possibly fatal), pleuritis, pancreatitis, toxic epidermal necrolysis, pancytopenia, and neutropenia also have been reported in patients receiving Cordarone." [NOTE: This paragraph does appear in the 1998 PDR it was moved from under "The following side effects were each reported in less than 1% of patients", the terms in italics do not appear in the 1998 PDR.]
"Caution should be observed when Coumadin is administered in any situation or in the presence of any predisposing condition where added risk of hemorrhage ["or" deleted], necrosis, and/or gangrene is present."
New subsection added after sixth paragraph -
"Heparin-Induced Thrombocytopenia: Coumadin should be used with caution in patients with heparin-induced thrombocytopenia and deep venous thrombosis. Cases of venous limb ischemia, necrosis, and gangrene have occurred in patients with heparin-induced thrombocytopenia and deep venous thrombosis when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients sequelae have included amputation of the involved area and/or death (Warkentin et al, 1997)."
"5-lipoxygenase Inhibitor", "Antiandrogen" and "Leukotriene Receptor Antagonist" added to alphabetical list.
Exogenous Factors: Specific Drugs Reported:
"flutamide", "zafirlukast", and "zileuton" added to alphabetical list.
Information for Patients: Sentence added at end of subsection -
"Patients should be informed that all warfarin sodium, USP, products represent the same medication, and should not be taken concomitantly, as overdosage may result."
"In patients with risk factors for recurrent venous thromboembolism including venous insufficiency, inherited thrombophilia, idiopathic venous thromboembolism, and a history of thrombotic events, consideration should be given to longer term therapy (Schulman et al, 1995 and Schulman et al, 1997)."
Laboratory Control: First paragraph, last sentence revised (new text in italics) -
"To ensure adequate control, it is recommended that additional PT tests are done when other warfarin products are interchanged with ["Coumadin and also if" deleted] warfarin sodium tablets, USP, as well as whenever other medications are ["coadministered with Coumadin" deleted] initiated, discontinued, or taken irregularly (see PRECAUTIONS)."
"While the effects of added progestins on the risk of breast cancer are also unknown, available epidemiological evidence suggests that progestins do not reduce, and may enhance, the moderately increased breast cancer incidence that has been reported with prolonged estrogen replacement therapy."
"Studies of the addition of a progestin for ["seven" deleted] 10 or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia ["which would otherwise" deleted] than would be induced by estrogen treatment alone. Morphological and biochemical studies of ["endometrium" deleted] endometria suggest that 10 to 14 days of progestin are needed to provide maximal maturation of the endometrium and to ["eliminate any" deleted] reduce the likelihood of hyperplastic changes.
"There are, however, possible ["additional" deleted] risks which may be associated with the ["inclusion" deleted] use of progestins in estrogen replacement regimens. These include: (1) adverse effects on lipoprotein metabolism (lowering HDL and raising LDL) which ["may" deleted] could diminish the ["possible" deleted] purported cardioprotective effect of estrogen therapy (see PRECAUTIONS ["D.4." deleted] below); (2) impairment of glucose tolerance; and (3) possible enhancement of mitotic activity in breast epithelial tissue, although few epidemiological data are available to address this point (see WARNINGS).
"The choice of progestin, its dose, and its regimen may be important in minimizing these adverse effects, but these ["remain to be" deleted] issues will require further study before they are clarified."
General: 2.Cardiovascular Risk (new subsection): -
"A causal relationship between estrogen replacement therapy and reduction of cardiovascular disease in postmenopausal women has not been proven. Furthermore, the effect of added progestin on this putative benefit is not yet known.
"In recent years many published studies have suggested that there may be a cause-effect relationship between postmenopausal oral estrogen replacement therapy without added progestins and a decrease in cardiovascular disease in women. Although most of the observational studies which assessed this statistical association have reported a 20% to 50% reduction in coronary heart disease risk and associated mortality in estrogen takers, the following should be considered when interpreting these reports:
"(1) Because only one of these studies was randomized and it was too small to yield statistically significant results, all relevant studies were subject to selection bias. Thus, the apparently reduced risk of coronary artery disease cannot be attributed with certainty to estrogen replacement therapy. It may instead have been caused by life-style and medical characteristics of the women studied with the result that healthier women were selected for estrogen therapy. In general, treated women were of higher socioeconomic and educational status, more slender, more physically active, more likely to have undergone surgical menopause, and less likely to have diabetes than the untreated women. Although some studies attempted to control for these selection factors, it is common for properly designed randomized trials to fail to confirm benefits suggested by less rigorous study designs. Thus, ongoing and future large-scale randomized trials may fail to confirm this apparent benefit.
"(2) Current medical practice often includes the use of concomitant progestin therapy in women with intact uteri (see PRECAUTIONS and WARNINGS). While the effects of added progestins on the risk of ischemic heart disease are not known, all available progestins reverse at least some of the favorable effects of estrogens on HDL and LDL levels.
[NOTE: Subsequent bullets renumbered.]
H. Pediatric Use: Subsection revised (new text in italics) -
"Safety and effectiveness in pediatric patients have not been established. ["Because of the effects of estrogens on epiphyseal closure, they should be used judiciously in young patients n whom bone growth is not complete." deleted] Large and repeated doses of estrogen over an extended period of time may accelerate epiphyseal closure. Therefore, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended in patients in whom bone growth is not complete."
"1. Estrogens increase the risk of developing a condition (endometrial hyperplasia) that may lead to cancer of the lining of the uterus. Taking progestins, another hormone drug, with estrogens lowers the risk of developing this condition. Therefore, if your uterus has not been removed, your doctor may prescribe a progestin for you to take together with the estrogen.
"You should know, however, that taking estrogens with progestins may have additional risks. These include: (a) unhealthy effects on blood fats (especially the lowering of HDL blood cholesterol, the "good" blood fat which protects against heart disease); (b) unhealthy effects on blood sugar (which might make a diabetic condition worse); and (c) a possible further increase in breast cancer risk which may be associated with long-term estrogen use.
"Some research has shown that estrogens taken without progestins may protect women against developing heart disease. However, this is not certain. The protection shown may have been caused by the characteristics of the estrogen-treated women, and not by the estrogen treatment itself. In general, treated women were slimmer, more physically active, and were less likely to have diabetes than the untreated women. These characteristics are known to be associated with a reduced risk for heart disease.
"You are cautioned to discuss very carefully with your doctor or health care provider all the possible risks and benefits of long-term estrogen and progestin treatment as they affect you personally."
Sequential numbers have been added to the subsequent paragraphs in the "Other Information" sections.
"Estrogen are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secrets 70 to 500 ug of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
"Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism and estrogen replacement therapy acts to reduce the elevated levels of these hormones seen in postmenopausal women."
"Absorption: When FemPatch (estradiol) transdermal system; 0.025 mg/day) was applied to the buttocks of 79 healthy postmenopausal women, serum estradiol concentrations increased steadily over the first 24 hours and then remained relatively constant for the remainder of the 7-day application period (Figure 1). Serum concentrations of approximately 22 pg/mL above baseline were achieved with a nominal estradiol delivery rate of 0.025 mg per day.
"The estradiol/estrone serum concentration ratio increased from an average baseline value of 0.3 to a value of 1.0 during application of FemPatch. This value is comparable to the ratio observed during the early follicular phase of the menstrual cycle in premenopausal women. A summary of estradiol and estrone pharmacokinetic parameters is presented in Table 1.
"Dose proportionality was demonstrated for FemPatch in a study in 23 healthy postmenopausal women who received a 1-week application of 1 or 2 systems (Figure 2). The mean increase in serum estradiol concentrations over baseline during application of 2 systems was twice that during application of one system.
"FemPatch provides consistent, controlled delivery of estradiol from application to application. Weekly applicatin of FemPatch to the buttocks for 3 consecutive weeks in 18 healthy postmenopausal women produced constant mean serum estradiol and estrone concentrations throughout the 3-week application period. There was little variation in average serum estradiol concentration within an individual subject from week to week. Intentional early replacement midway through a 7-day wear period resulted in a small and transient increase in average serum estradiol concentration. In a 12-week, double-blind, placebo-controlled multicenter study in symptomatic, hysterectomized postmenopausal women who received weekly applications of 1 or 2 FemPatch systems, serum estradiol and estrone concentrations were also consistent for the duration of dosing. Mean increases in estradiol concentrations achieved by Week 1 were maintained over the remainder of the 12-week application period.
"Distribution: The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs.
"Estradiol in plasma is approximately 99% bound to plasma proteins, with approximately 40% bound to sex hormone binding globulin and 60% bound to albumin.
"Metabolism: Administered estradiol is handled within the body essentially the same as endogenous estradiol. Estradiol is extensively metabolized in the liver, primarily to estrone, which, in turn, is further oxidized to estriol and a number of other minor metabolites. These oxidative metabolites of estradiol are eliminated as inactive sulfate and glucuronide conjugates. Estrogen drug products administered by nonoral routes such as FemPatch, are not subject to first-pass metabolism, but also undergo significant hepatic uptake, metabolism, and enterohepatic recycling.
"Excretion: Estradiol, estrone, and estriol are excreted in the urine along with glucyronide and sulfate conjugates.
"When FemPatch was removed, serum estradiol concentrations declined to baseline within 24 hours (Figure 2). The mean (SD) elimination half-life of estradiol following removal of one or two FemPatch systems was 4.0 (1.8) hours.
"Special Populations:
"Race: There is no apparent influence of race on steady-state estradiol concentrations during application of FemPatch.
"Age: Steady-state estradiol concentrations resulting from treatment with FemPatch decline with increasing patient age, apparently due to a decline in skin permeability with increasing age. However, the extent of decline does not appear to be clinically important and dosage adjustment based on patient age is not necessary.
"Smoking: Steady-state estradiol concentrations are similar in smoking and nonsmoking patients treated with FemPatch.
"Hepatic Insufficiency: The effect of hepatic disease on the disposition of estradiol delivered by FemPatch has not been evaluated. Higher estradiol and estrone concentrations and lower estrone sulfate concentrations have been reported in postmenopausal women with cirrhosis compared to normal postmenopausal women.
"Renal Insufficiency: The effect of renal disease on the disposition of estradiol delivered by FemPatch has not been evaluated. Postmenopausal women with end-stage renal disease undergoing hemodialysis have been reported to have higher plasma estradiol concentrations at baseline and after oral estradiol administration compared to postmenopausal women with normal renal function.
"Drug-Drug Interactions: No formal studies have evaluated drug-drug interactions for estradiol delivered by FemPatch. Effects of other drugs on serum concentrations of endogenous estradiol have been reported. Concurrent administration of alcohol, rifampicin, and cimetidine increase estradiol concentrations.
"Clinical Studies: The effectiveness of FemPatch in reducing menopausal vasomotor symptoms was established in two 12-week, double-blind, parallel-group, multicenter clinical studies in 324 postmenopausal women with 54 to 140 hot flushes/week at baseline who had undergone total hysterectomy. In the larger study (989-1), efficacy was based on comparing 1 or 2 active transdermal systems to comparable placebo treatment for reduction in hot flush frequency.
"In this study a total of 213 postmenopausal women, 35 to 66 years of age, were enrolled. Both one or two FemPatch systems significantly reduced the number of hot flushes at Weeks 4, 8 and 12 of treatment compared to placebo (Table 2)."
"TABLE 2. Study 989-1: Mean (SE) Hot Flush Frequency per Week - Intent to-Treat Analysis (LOCF)" [See new labeling/package insert for contents of Table 2.]
"The choice of progestin, its dose, and its regimen may be important in minimizing these adverse effects [", but these issues will require further study before they are clarified" deleted]."
"In the ["unlikely" deleted] event that FemPatch becomes more than 50% detached, it should be removed and a new system should be applied to a different skin site on the buttocks."
"Adverse events associated with Lipitor that have been received since market introduction, that are not listed above, and that may have no causal relationship to drug include the following: angioneurotic edema and rhabdomyolysis."
"The cardiovascular profile of Nimbex allows it to be administered by rapid bolus at higher multiples of the ED95 than atracurium. ["Cisatracurium" deleted] Nimbex has no dose-related effects on mean arterial blood pressure (MAP) or heart rate (HR) following doses ranging from 2 to 8 x ED95 (> 0.1 to > 0.4 mg/kg), administered over 5 to 10 seconds, in healthy adult patients (figure 1) or in patients with serious cardiovascular disease (Figure 2).
"["In patients with serious cardiovascular disease, Nimbex has no clinically significant effects on MAP or HR following doses up to and including 6 x ED95 (0.3 mg/kg), administered over 5 to 10 seconds (Figure 2). In two comparative studies involving patients undergoing coronary artery bypass grafting (CABG), there were no clinically significant differences in the hemodynamic effects following equipotent doses ranging from 0.1 to 0.3 mg/kg cisatracurium or vecuronium. Doses higher than 6 x ED95 have not been studied in patients with serious cardiovascular disease." deleted]
"A total of 141 patients undergoing coronary artery bypass (CABG) have been administered Nimbex in three active, controlled clinical trials and have received doses ranging from 2 to 8 x ED95. While the hemodynamic profile was comparable in both the Nimbex and active control groups, data for doses above 0.3 mg/kg in this population are limited.
"Unlike atracurium, ["cisatracurium" deleted] Nimbex, at therapeutic doses of 2 x ED95 to 8 x ED95 (0.1 to 0.4 mg/kg), administered over 5 to 10 seconds, does not cause dose-related elevations in mean plasma histamine concentration. ["The cardiovascular profile of Nimbex allows it to be administered by rapid bolus at higher multiples of the ED95 than atracurium." deleted]
"No clinically significant changes in MAP or HR were observed following administration of doses up to 0.1 mg/kg ["cisatracurium" deleted] Nimbex over 5 to 10 seconds in 2- to 12-year-old children receiving halothane/nitrous oxide/oxygen or opioid/nitrous oxide/oxygen anesthesia."
Figure 2 titled -
"Figure 2. Percent Change from Preinjection in Heart Rate (HR) and Mean Arterial Pressure (MAP) 10 Minutes Following Administration of Nimbex (2 to 6 x ED95) to Patients Undergoing CABG Surgery Receiving Etomidate/Fentanyl/Midazolam/Oxygen Anesthesia (n = 90)"
deleted and replaced with -
"Figure 2. Percent Change from Preinjection in Heart Rate (HR) and Mean Arterial Pressure (MAP) 2 Minutes After an Initial 4 x ED95 to 8 x ED95 Dose of Nimbex in Patients Undergoing CABG Surgery Receiving Oxygen/Fentanyl/Midazolam/Anesthesia (n = 58)" (see new labeling/package insert)
"Doses up to 8 x ED95 Nimbex have been safely administered to healthy adult patients and patients with serious cardiovascular disease ["and the" deleted]. These doses are associated with longer clinically effective durations of action (see CLINICAL PHARMACOLOGY)."
Body as a Whole: "anaphylactoid-like reaction" added.
Special Senses: "amblyopia" deleted and replaced with "blurred vision"
New paragraph added as second to last paragraph in subsection -
"Diltiazem significantly decreases the clearance and increases the t1/2 of quinidine, but quinidine does not alter the kinetics of diltiazem."
Drug Interactions: Non-interactions of quinidine with other drugs: -
Last paragraph, first sentence revised -
"Conversely, the pharmacokinetics of quinidine are not significantly affected by caffeine, ciprofloxacin, digoxin, ["diltiazem" deleted], felodipine, omeprazole, or quinine."
Text added as new last paragraph in subsection -
"Diltiazem significantly decreases the clearance and increases the t1/2 of quinidine, but quinidine does not alter the kinetics of diltiazem."
Drug Interactions: 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."
"pneumonitis" added to list between "bronchospasm" and "psoriasiform rash"
"Factors contributing to QTc prolongation (especially ["hypothermia" deleted] hypokalemia and hypomagnesemia [", hypocalcemia" deleted]) should be sought out and (if possible) aggressively corrected."
Accelerated Removal: Fourth paragraph revised (new text in italics) -
"Following quinidine overdose, drugs that delay elimination of quinidine (cimetidine, carbonic-anhydrase inhibitors, diltiazem, thiazide diuretics) should be withdrawn unless absolutely required."
"Note: Am J Health-Syst Pharm, March 1996: A study suggests that minimization of PVC tubing enhances bioavailability. In this study, 112 inches of tubing resulted in a 30% loss of quinidine; whereas, 12 inches (attached to the winged IV catheter) minimized drug loss to under 3%."
"Store between ["15o" deleted] 2o and 30oC (["59o" deleted] 36o and 86oF). ["Temovate Gel should not be refrigerated." deleted]
"Xalatan ["(latanoprost solution)" deleted] Sterile Ophthalmic Solution is supplied as a sterile, isotonic, buffered aqueous solution of latanoprost with a pH of approximately 6.7 and an osmolality of approximately 267 mOsmol/kg."
"Xalatan has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris and periorbital tissue (eyelid) and increased pigmentation and growth of eyelashes. These changes may be permanent.
"Xalatan Sterile Ophthalmic Solution may gradually change eye color, increasing the amount of brown pigment in the iris by increasing the number of melanosomes (pigment granules) in melanocytes. The long term effects on the melanocytes and the consequences of potential injury to the melanocytes and/or deposition of pigment granules to other areas of the eye is currently unknown. The change in iris color occurs slowly and may not be noticeable for several months to years. Patients should be informed of the possibility of iris color change.
"Eyelid skin darkening has also been reported in association with the use of Xalatan.
"Xalatan may gradually change eyelashes; these changes include increased length, thickness, pigmentation, and number of lashes.
"Patients who are expected to receive treatment in only one eye should be informed about the potential for increased brown pigmentation of the iris, periorbital tissue, and eyelashes in the treated eye and thus, heterochromia between the eyes. They should also be advised of the potential for a disparity between the eyes in length, thickness, and/or number of eyelashes. ["The increased" deleted] These changes in pigmentation and lash growth may be permanent."
"Xalatan should be used with caution in patients with active intraocular inflammation (iritis/uveitis).
"Macular edema, including cystoid macular edema, has been reported during treatment with Xalatan. These reports have mainly occurred in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. Xalatan should be used with caution in these patients."
Current fourth paragraph, now the sixth paragraph revised (new text in italics) -
"There is ["no" deleted] limited experience with Xalatan in the treatment of angle closure, inflammatory or neovascular glaucoma ["and only limited experience in pseudophakic patients" deleted]."
Information for Patients (see WARNINGS) (name changed from "Information for Patients"): Text added as new second, third and fourth paragraphs -
"Patients should also be informed of the possibility of eyelash changes in the treated eye, which may result in a disparity between eyes in lash length, thickness, pigmentation, and/or number.
"Patients should also be informed about the possibility of eyelid skin darkening.
"The increased pigmentation to the iris and eyelid, as well as the changes to the eyelashes, may be permanent."
"Eyelash changes (increased length, thickness, pigmentation, and number of lashes); eyelid skin darkening; intraocular inflammation (iritis/uveitis); iris pigmentation changes; and macular edema, including cystoid macular edema (see WARNINGS and PRECAUTIONS)."
Controlled Clinical Trials (new subsection):
Text in current ADVERSE REACTION section moved into this new subsection.
Clinical Practice (new subsection):
"The following events have been identified during post-marketing use of Xalatan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to Xalatan, or a combination of these factors, include: eyelash changes (increased length, thickness, pigmentation, and number of lashes); eyelid skin darkening; intraocular inflammation (iritis/uveitis); macular edema, including cystoid macular edema, and toxic epidermal necrolysis."
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