![[U.S. Food and Drug Administration]](https://webarchive.library.unt.edu/eot2008/20090118023203im_/http://www.fda.gov/icon/header.gif){kind=icon}
(Posted: 10/27/99)
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 1999 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.
|
(zafirlukast) |
(amprenavir) |
(aminocaproic acid) |
(nicardipine HCl) |
|
(carvedilol) |
(tranexamic acid) |
(ethynodiol diacetate/ethinyl estradiol) |
(chlorothiazide sodium) |
|
(dobutamine) |
(raloxifene HCl) |
(metformin HCl) |
(heparin sodium) |
|
(eptifibatide) |
(norepinephrine bitartrate) |
(pramipexole dihydrochloride) |
(niacin) |
|
(mesalamine) |
(grepafloxacin) |
(aprotinin) |
(simvastatin) |
[Other labeling changes not appearing in 1999 PDR: Mar99]
"Table 9: Selected Laboratory Abnormalities Grades 1-4 Reported in equal to or greater than 5% of Patients
|
PROAB3001 Therapy-Naive Patients |
PROAB3006 NRTI-Experienced Patients |
|||
|
Laboratory Abnormality (non-fasting specimens) |
AGENERASE/ Lamivudine/ Zidovudine (n = 113) |
Lamivudine/ Zidovudine (n = 109) |
AGENERASE/ NRTI (n = 245) |
Indinavir/ NRTI (n = 241) |
|
Hyper- Glycemia (greater than 160 mg/dL)deleted (greater than 116mg/dl) |
37% |
29% |
41% |
44% |
|
Hypertri-glceridemia (greater than 399 mg/dL) deleted (greater than 213 mg/dL) |
36% |
22% |
47% |
40% |
|
Hyperchol-esterolemia (greater than 260 mg/dL) deleted (greater than 283 mg/dL) |
4% |
3% |
9% |
10% |
"potassium sorbate 0.2% and sodium benzoate 0.1%"
Replaced with the following text -
"methylparaben 0.2%, propylparaben 0.05%, and edetate disodium 0.3%"
"Thrombosis with severe sequelae (acute myocardial infarction, gangrene) has been rarely reported in patients with hemophilia receiving combined treatment with Factor IX concentrate and Amicar. Amicar should not be administered concomitantly with prothrombin complex concentrates or with activated prothrombin concentrates unless the risk of thrombosis is outweighed by the anticipated clinical benefit."
Replaced with -
"Epsilon-aminocaproic acid should not be administered with Factor IX Complex concentrates or Anti-Inhibitor Coagulant concentrates, as the risk of thrombosis may be increased."
Cardene - "Pharmacokinetic parameters did not differ between elderly hypertensive patients (equal to or greater than 65 years) and healthy controls after 1 week of Cardene treatment at 20 mg tid. Plasma Cardene concentrations in elderly hypertensive subjects were similar to plasma concentrations in healthy young adult subjects when Cardene was administered at doses of 10, 20, and 30 mg tid, suggesting that the pharmacokinetics of Cardene are similar in young and elderly hypertensive patients. No significant differences in responses to Cardene have been observed in elderly patients and the general adult population of patients who participated in clinical studies."
Cardene SR - "Pharmacokinetic parameters did not differ significantly between elderly hypertensive subjects (mean age: 70 years) and younger hypertensive subjects (mean age: 44 years) after 1 week of treatment with Cardene SR (see CLINICAL PHARMACOLOGY: Geriatric Pharmacokinetics)."
Cardene and Cardene SR - "Clinical studies of nicardipine 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 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."
"Cyclosporin: Modest increases in mean trough cyclosporin concentrations were observed following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection. In about 30% of patients, the dose of cyclosporin had to be reduced in order to maintain concentrations within the therapeutic range, while in the remainder no adjustment was needed. On the average for the group, the dose of cyclosporin was reduced about 20% in these patients. Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporin concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporin be adjusted as appropriate. "
"3. In patients with active intravascular clotting."
"The dose of Cyklokapron Tablets and Injection should be reduced in patients with renal insufficiency because of the risk of accumulation. (See DOSAGE AND ADMINISTRATION.)"
New second through sixth paragraphs:
"Ureteral obstruction due to clot formation in patients with upper urinary tract bleeding has been reported in patients treated with Cyklokapron.
"Venous and arterial thrombosis or thromboembolism has been reported in patients treated with Cyklokapron. In addition, cases of central retinal artery and central retinal vein obstruction have been reported.
"Patients with a previous history of thromboembolic disease may be at increased risk for venous or arterial thrombosis.
"Cyklokapron should not be administered concomitantly with Factor IX Complex concentrates or Anti-inhibitor Coagulant concentrates, as the risk of thrombosis may be increased.
"Patients with disseminated intravascular coagulation (DIC), who require treatment with Cyklokapron, must be under strict supervision of a physician experienced in treating this disorder."
Pediatric Use:
"children"
Replaced with -
"pediatric patients"
"Worldwide Postmarketing Reports: Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, and central retinal artery and vein obstruction) have been rarely reported in patients receiving Cyklokapron for indications other than hemorrhage prevention in patients with hemophilia. However, due to the spontaneous nature of the reporting of medical events and the lack of controls, the actual incidence and causal relationship of drug and event cannot be determined."
"For dental extraction in patients with hemophilia: Immediately before surgery, substitution therapy is given together with tranexamic acid, 10 mg per kg body weight I.V.. After surgery, 25 mg per kg body weight are given orally three to four times daily for two to eight days."
Deleted and replaced with -
"Immediately before dental extraction in patients with hemophilia, administer 10 mg per kg body weight of Cyklokapron intravenously together with replacement therapy (see PRECAUTIONS). Following surgery, a dose of 25 mg per kg body weight may be given orally three to four times daily for 2 to 8 days."
"with 0.4 mg thimerosal (mercury derivative) added as a preservative"
"Unused solution may be stored at room temperature for 24 hours, after which it must be discarded."
"Store reconstituted solution at room temperature, 15-30oC (59-86oF), and discard unused portion after 24 hours."
Replaced with -
"For single use only. Discard unused portion of the reconstituted solution."
[Labeling changes for other formulations not appearing in 1999 PDR: Feb99, Apr99]
"adults with" has been deleted
"Clinical studies of Dobutamine did not include sufficient numbers of subjects aged 65 and over being treated for acute cardiac decompensation to determine whether they respond differently from younger subjects. Other reported clinical experience suggests that the incidence of significant hypotension is a function of both dose and age, older individuals having a greater incidence of hypotension. 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."
[Other labeling changes not appearing in 1999 PDR: Oct98]
Subsection deleted -
"The administration of oral antidiabetic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 1027 patients who were randomly assigned to one of five treatment groups (Diabetes, 19 (Suppl.2):747-830, 1970; Diabetes, 24 (Suppl.1):65-184, 1975)
"The UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 g per day) or diet plus a fixed dose of phenformin (100 mg per day) had a rate of cardiovascular mortality approximately 2.5 times that of patients treated with diet alone, resulting in discontinuation of both these treatments in the UGDP study. Total mortality was increased in both the tolbutamide- and phenformin-treated groups and this increase was statistically significant in the phenformin-treated group. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and benefits of Glucophage and alternative modes of therapy.
"Although only one drug in the sulfonylurea category (tolbutamide) and one in the biguanide category (phenformin) were included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other related oral antidiabetic drugs, in view of the similarities in mode of action and chemical structure among the drugs in each category."
Deleted -
"Q17. Are there other risks associated with Glucophage?
There is some evidence that any oral diabetes drug may increase the risk of heart problems. Experts are not sure what the real risk is for heart problems, if any, from taking oral diabetes medicine."
"Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age."
"A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age."
Geriatric Use: Text revised to read -
"A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (see PRECAUTIONS, General). Clinical studies indicate that lower doses of heparin may be indicated in these patients (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION)."
"Patients over 60 years of age may require lower doses of heparin."
[Other labeling changes not appearing in 1999 PDR: Sep98, Jul99]
"Follow-up data were available through 165 days for 10,611 patients enrolled in the PURSUIT trial (96.9 percent of the initial enrollment). This follow-up included 4566 patients who received eptifibatide at the 180/2.0 dose. As reported by the investigators, the occurrence of death from any cause or new myocardial infarction for patients followed for at least 165 days was reduced from 13.6 percent with placebo to 12.1 percent with eptifibatide 180/2.0."
"Clinical studies of Levophed 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 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.
"Levophed infusions should not be administered into the veins in the leg in the elderly patients (see PRECAUTIONS, General). "
"Store at room temperature. Protect from light."
Replaced with the following:
"Store at 25oC (77oF); excursions permitted to 15-30oC (59-86oF) (see USP Controlled Room Temperature0. Protect from light."
[Other information regarding these changes: Letter]
[Other labeling changes not appearing in the 1999 PDR: Feb98]
"Patients treated with Mirapex have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles which sometimes resulted in accidents. Although many of these patients reported somnolence while on Mirapex, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported as late as one year after initiation of treatment.
"Somnolence is a common occurrence in patients receiving Mirapex at doses above 1.5 mg/day. Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
"Before initiating treatment with Mirapex, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with Mirapex such as concomitant sedating medications, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine - see PRECAUTIONS, Drug Interactions). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), Mirapex should ordinarily be discontinued. If a decision is made to continue Mirapex, patients should be advised not to drive and to avoid other potentially dangerous activities. While dose reduction clearly reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living."
"Patients should be advised that Mirapex may cause somnolence and that they should neither drive a car nor operate other complex machinery until they have gained sufficient experience on Mirapex to gauge whether or not it affects their mental and/or motor performance adversely. Because of the possible additive sedative effects, caution should also be used when patients are taking other CNS depressants in combination with Mirapex."
Replaced with the following text:
"Patients should be alerted to the potential sedating effects associated with Mirapex, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with Mirapex to gauge whether or not it affects their mental and/or motor performance adversely. Patients should be advised that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects, caution should be advised when patients are taking concomitant medications that increase plasma levels of pramipexole (e.g., cimetidine).
"In a fixed-dose study in early Parkinson's disease, occurrence of the following events increased in frequency as the dose increased over the range from 1.5 mg/day to 6 mg/day: postural hypotension, nausea, constipation, somnolence, and amnesia. The frequency of these events was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence with pramipexole at a dose of 1.5 mg/day was comparable to that reported for placebo."
Other Adverse Events Observed During All Phase 2 and 3 Clinical Trials: Last category added:
"Falling Asleep During Activities of Daily Living: Patients treated with Mirapex have reported falling asleep while engaged in activities of daily living, including operation of a motor vehicle which sometimes resulted in accidents (see bolded WARNING).
"However, in the same fixed-dose study, the following adverse events were dose related: postural hypotension, nausea, constipation, somnolence and amnesia. The frequency of these events was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence reported with pramipexole at a dose of 1.5 mg/day was comparable to placebo."
"["Long-term studies of the carcinogenic potential of mesalamine in mice and rats are ongoing." deleted] In a 104-week dietary carcinogenicity study of mesalamine, CD-1 mice were treated with doses up to 2500 mg/kg/day and it was not tumorogenic. For a 50 kg person of average height (1.46 m2 body surface area), this represents 2.5 times the recommended human dose on a body surface area basis (2960 mg/m2/day). In a 104-week dietary carcinogenicity study in Wistar rats, mesalamine up to a dose of 800 mg/kg/day was not tumorigenic. This dose represents 1.5 times the recommended human dose on a body surface area basis.
"No evidence of mutagenicity was observed in an in vitro Ames test and in an in vivo mouse micronucleus test.
"No effects on fertility or reproductive performance were observed in male or female rats at oral doses of mesalamine up to 400 mg/kg/day["(2360 mg/M2)" deleted] (0.8 times the recommended human dose based on body surface area). ["For a 50-kg person (1.3 M2 body surface area), this represents five times the recommended clinical dose (80 mg/kg/day) on a mg/kg basis and 0.8 times the clinical dose (2960 mg/M2)on a body surface area basis." deleted]
"Semen abnormalities and infertility in men, which has been reported in association with sulfasalazine, have not been seen with Pentasa capsules during controlled clinical trials."
"Published case reports and/or spontaneous postmarketing surveillance have described infrequent instances of pericarditis, fatal myocarditis, chest pain and T-wave abnormalities, hypersensitivity pneumonitis, pancreatitis, nephrotic syndrome, interstitial nephritis, hepatitis, aplastic anemia, pancytopenia, leukopenia, agranulocytosis, or anemia while receiving mesalamine therapy. Anemia can be part of the clinical presentation of inflammatory bowel disease. Allergic reactions, which could involve eosinophilia, can be seen in connection with Pentasa therapy."
Postmarketing Reports: New subsection -
"The following events have been identified during post-approval use of products which contain (or are metabolized to) mesalamine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to mesalamine.
Gastrointestinal: Reports of hepatotoxicity, including elevated liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. One case of Kawasaki-like syndrome which included hepatic function changes was also reported."
[Other labeling changes not appearing in 1999 PDR: Sep98]
[Newly released safety information: Press Release ]
First and second sentences, second paragraph revised (new text in italics) -
"["Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones." deleted] Convulsions have been reported in patients receiving quinolones, including grepafloxacin. Increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones."
"that convulsions have been reported in patients taking quinolones, including grepafloxacin, and to notify their physician before taking this drug if there is a history of this condition."
Pediatric use: "children" replaced with "pediatric patients"
[Other labeling changes not appearing in 1999 PDR: Aug98, Mar99]
"Of the total of 3083 subjects in clinical studies of Trasylol, 1100 (35.7 percent) were 65 and over, while 297 (9.6 percent) were 75 and over. Of patients 65 years and older, 479 (43.5 percent) received Regimen A and 237 (21.5 percent) received Regimen B. No overall differences in safety or effectiveness were observed between these subjects and younger subjects for either dose regimen, and other reported clinical experience has not identified differences in responses between the elderly and younger patients."
"These include cyclosporine, itraconazole, ketoconazole and other antifungal azoles, the macrolide antibiotics erythromycin and clarithromycin, HIV protease inhibitors, and the antidepressant nefazodone."
"Cyclosporine, Itraconazole, Ketoconazole, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin, Clarithromycin, HIV protease inhibitors, Nefazodone (see WARNINGS, Skeletal Muscle)."
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