![[U.S. Food and Drug Administration]](https://webarchive.library.unt.edu/eot2008/20090118022522im_/http://www.fda.gov/icon/header.gif){kind=icon}
(Posted: September 7, 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.
|
(ketorolac tromethamine) |
(rosiglitazone maleate) |
(trimethoprim/sulfamethoxazole) |
(cerivastatin sodium) |
|
(sotalol HCl) |
(cefuroxime axetil) |
(mycophenolate mofetil) |
(glatiramer acetate) |
|
(venlafaxine HCl) |
(norethindrone acetate/ethinyl estradiol) |
(enalapril maleate/felodipine) |
(amlodipine besylate) |
|
(porfimer sodium) |
(procainamide HCl) |
(menotropins) |
(somatropin) |
|
(fluoxetine HCl) |
(somatropin) |
(nefazodone HCl) |
(tromethamine) |
|
(aprotinin) |
(bepridil) |
(didanosine) |
(abacavir sulfate) |
"Ketorolac tromethamine was not carcinogenic in rats given up to 5 mg/kg/day orally for 24 months (151 times the maximum recommended human topical ophthalmic dose, on a mg/kg basis, assuming 100% absorption in humans and animals) nor in mice given 2 mg/kg/day orally for 18 months (60 times the maximum recommended human topical ophthalmic dose, on a mg/kg basis, assuming 100% absorption in humans and animals).
Ketorolac tromethamine was not mutagenic in vitro in the Ames assay or in forward mutation assays. Similarly, it did not result in an in vitro increase in unscheduled DNA synthesis or in an in vivo increase in chromosome breakage in mice. However, ketorolac tromethamine did result in an increased incidence in chromosomal aberration in Chinese hamster ovary cells.
Ketorolac tromethamine did not impair fertility when administered orally to male and female rats at doses up to 272 and 484 times the maximum recommended human topical ophthalmic dose, respectively, on a mg/kg basis, assuming 100% absorption in humans and animals."
Pregnancy: Teratogenic Effects: Pregnancy Category C: Subsection significantly revised with changes incorporated below -
Ketorolac tromethamine, administered during organogenesis, was not teratogenic in rabbits or rats at oral doses up to 109 times and 303 times the maximum recommended human topical ophthalmic dose, respectively, on a mg/kg basis assuming 100% absorption in humans and animals. When administered to rats after Day 17 of gestation at oral doses up to 45 times the maximum recommended human topical ophthalmic dose, respectively, on a mg/kg basis, assuming 100% absorption in humans and animals, ketorolac tromethamine resulted in dystocia and increased pup mortality. There are no adequate and well-controlled studies in pregnant women. Acular PF ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."
Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients."
"Therapy with Avandia, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking Avandia. (See PRECAUTIONS, Pregnancy, Pregnancy Category C.) Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical studies so the frequency of this occurrence is not known."
Edema: Third paragraph added -
"Since thiazolidinediones can cause fluid retention, which can exacerbate congestive heart failure, patients at risk for heart failure (particularly those on insulin) should be monitored for signs and symptoms of heart failure (See PRECAUTIONS, Use in Patients with Heart Failure)."
Information for Patients: New last paragraph -
"Therapy with Avandia, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking Avandia. (See PRECAUTIONS, Pregnancy, Pregnancy Category C.) Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical studies so the frequency of this occurrence is not known."
Pregnancy, Pregnancy Category C: Last paragraph revised (new text in italics) -
Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible."
" Cough, shortness of breath and pulmonary infiltrates (see WARNINGS)."
" To minimize the risk of induced arrhythmia, patients initiated or re-initiated on Betapace should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Calculations of creatinine clearance should be calculated prior to dosing. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. Sotalol is also indicated for the maintenance of normal sinus rhythm [delay in time to recurrence of atrial fibrillation/atrial flutter (AFIB/AFL)] in patients with symptomatic AFIB/AFL who are currently in sinus rhythm and is marketed under the brand name BETAPACE AF. BETAPACE is not approved for the AFIB/AFL indication and should not be substituted for BETAPACE AF because only BETAPACE AF is distributed with a patient package insert that is appropriate for patients with AFIB/AFL."
"Although significant beta-blockade occurs at oral doses as low as 25 mg, significant Class III effects are seen only at daily doses of 160 mg and above."
"Sotalol is also indicated for the maintenance of normal sinus rhythm [delay in time to recurrence of atrial fibrillation/atrial flutter (AFIB/AFL)] in patients with symptomatic AFIB/AFL who are currently in sinus rhythm and is marketed under the brand name BETAPACE AF. BETAPACE is not approved for the AFIB/AFL indication and should not be substituted for BETAPACE AF because only Betapace AF is distributed with a patient package insert that is appropriate for patients with AFIB/AFL."
"Sotalol is primarily eliminated by renal excretion; therefore, drugs that are metabolized by CYP450 are not expected to alter the pharmacokinetics of sotalol. Sotalol is not expected to inhibit or induce any CYP450 enzymes, therefore, it is not expected to alter the PK of drugs that are metabolized by these enzymes."
Drugs prolonging the QT interval: Subsection revised (new text in italics) -
Betapace should be administered with caution in conjunction with other drugs known to prolong the QT interval such as Class I and Class III antiarrhythmic agents, phenothiazines, tricyclic antidepressants, ["terfenadine" deleted], astemizole, bepridil, certain oral macrolides, and certain quinolone antibiotics (See WARNINGS)."
"The occurrence of hypotension following an overdose may be associated with an initial slow drug elimination phase (half life of 30 hours) thought to be due to a temporary reduction of renal function caused by the hypotension "
"Dosage of Betapace should be adjusted gradually, allowing ["2-3" deleted] 3 days between dosing increments in order to attain steady-state plasma concentrations, and to allow monitoring of QT intervals."
Transfer to Betapace AF from Betapace New subsection added -
"Patients with a history of symptomatic AFIB/AFL who are currently receiving Betapace for the maintenance of normal sinus rhythm should be transferred to Betapace AF because of the significant differences in labeling (i.e., patient package insert for Betapace AF, dosing administration and safety information)."
"Store at controlled room temperature, between 15o to 30oC (59o to 86oF)"
Replaced with -
"Store at 25oC (77oF); excursions permitted to 15 - 30oC (59o - 86oF) [See USP Controlled Room Temperature]."
"The safety and effectiveness of Ceftin have been established for pediatric patients aged 3 months to 12 years for acute bacterial maxillary sinusitis based on its approval in adults. Use of Ceftin in pediatric patients is supported by pharmacokinetic and safety data in adults and pediatric patients, and by clinical and microbiological data from adequate and well-controlled studies of the treatment of acute bacterial maxillary sinusitis in adults and of acute otitis media with effusion in pediatric patients. It is also supported by post-marketing adverse events surveillance (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, and CLINICAL STUDIES)."
First paragraph revised with revisions incorporated below:
"In addition to the adverse events reported from clinical trials, the following events have been identified during post-approval use of Ceftin. 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 combination of their seriousness, frequency of reporting, or potential causal connection to Ceftin."
Adverse events added:
Blood and Lymphatic: Increased prothrombin time.
Hepatobiliary Tract and Pancreas: (Previously " Hepatic: jaundice")
Hepatic impairment including hepatitis and cholestasis, jaundice.
Neurologic: Seizure.
Urologic: Renal dysfunction.
"Acute bacterial maxillary sinusitis" (Population/Infection)
"250 mg b.i.d."(Dosage)
"10"[Duration (days)] "
Table 8: Ceftin for Oral Suspension
"Acute bacterial maxillary sinusitis" (Population/Infection)
"30 mg/kg/day divided b.i.d." (Dosage)
"1000 mg" (Daily Maximum Dose)
"10" [Duration (days)]
"Because glatiramer acetate is an antigenic material it is possible that its use may lead to the induction of host responses that are untoward."
Third paragraph, first sentence added -
"Although glatiramer acetate is intended to minimize the autoimmune response to myelin, there is the possibility that continued alteration of cellular immunity due to chronic treatment with glatiramer acetate might result in untoward effects."
"Postmarketing experience has shown an adverse profile similar to that presented above. Reports of adverse reactions occurring under treatment with Copaxone (glatiramer acetate) not mentioned above, that have been received since market introduction and that may have or not have causal relationship to the drug include the following:
Body as a Whole: sepsis, LE syndrome, hydrocephalus, enlarged abdomen, injection site hypersensitivity, allergic reaction, anaphylactoid reaction
Cardiovascular System: thrombosis, peripheral vascular disease, pericardial effusion, myocardial infarct, deep thrombophlebitis, coronary occlusion, congestive heart failure, cardiomyopathy, cardiomegaly, arrhythmia, angina pectoris
Digestive System: tongue edema, stomach ulcer hemorrhage, liver function abnormality, liver damage, hepatitis, eructation, cirrhosis of the liver, cholelithiasis
Hemic and Lymphatic System: thrombocytopenia, lymphoma-like reaction, acute leukemia
Metabolic and Nutritional Disorders: hypercholesterolemia
Musculoskeletal System: rheumatoid arthritis, generalized spasm
Nervous System: myelitis, meningitis, CNS neoplasm, cerebrovascular accident, brain edema, abnormal dreams, aphasia, convulsion, neuralgia
Respiratory System: pulmonary embolus, pleural effusion, carcinoma of lung, hay fever
Special Senses: glaucoma, blindness, visual field defect
Urogenital System: urogenital neoplasm, urine abnormality, ovarian carcinoma, nephrosis, kidney failure, breast carcinoma, bladder carcinoma; urinary frequency"
"A twelve-week placebo-controlled, multicenter, randomized clinical trial was conducted to determine the safety and efficacy of femhrt 1/5 for the treatment of vasomotor symptoms. The study assessed the efficacy of femhrt 1/5 in 266 symptomatic women who had at least 56 moderate to severe hot flashes during the week prior to randomization. On average, patients had 12 hot flashes per day upon study entry."
The efficacy of femhrt 1/5 for the treatment of moderate to severe vasomotor symptoms (WMS) is demonstrated in figure 2.
Replaced with -
"A twelve-week placebo-controlled, multicenter, randomized clinical trial was conducted in 266 symptomatic women who had at least 56 moderate to severe hot flashes during the week prior to randomization. On average, patients had 12 hot flashes per day upon study entry.
A total of 65 women were randomized to receive femhrt 1/5 and 66 women were randomized to the placebo group. The efficacy of femhrt 1/5 for the treatment of moderate to severe vasomotor symptoms (WMS) is demonstrated in Figure 2.
"Pain
Edema generalized
Constipation
Upper respiratory infections"
"Because of the enalapril component, Lexxel is contraindicated in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema."
"Aortic Stenosis/Hypertrophic Cardiomyopathy - As with all vasodilators, enalapril should be given with caution to patients with obstruction in the outflow tract of the left ventricle."
Drug Interactions: New subsection -
"Non-steroidal Anti-inflammatory Agents - In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the coadministration of enalapril may result in a further deterioration of renal function. These effects are usually reversible."
Addition of "eosinophilic pneumonitis"
In vitro data in human plasma indicate that Norvasc has no effect on the protein binding of drugs tested (digoxin, phenytoin, warfarin, and indomethacin).
Special Studies: Effect of other agents on Norvasc.
CIMETIDINE: Co-administration of Norvasc with cimetidine did not alter the pharmacokinetics of Norvasc.
GRAPEFRUIT JUICE: Co-administration of 240 ml of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
MAALOX (antacid): Co-administration of the antacid Maalox with a single dose of Norvasc had no effect on the pharmacokinetics of Norvasc.
SILDENAFIL: A single 100 mg dose of sildenafil (Viagra) in subjects with essential hypertension had no effect on the pharmacokinetic parameters of Norvasc. When Norvasc and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Special Studies: Effect of Norvasc on other agents.
ATORVASTATIN: Co-administration of multiple 10 mg doses of Norvasc with 80 mg of atorvastatin resulted in no significant change in the steady state pharmacokinetic parameters of atorvastatin.
DIGOXIN: Co-administration of Norvasc with digoxin did not change serum digoxin levels or renal clearance in normal volunteers.
ETHANOL (alcohol): Single and multiple 10 mg doses of Norvasc had no significant effect on the pharmacokinetics of ethanol.
WARFARIN: Co-administration of Norvasc with warfarin did not change the warfarin prothrombin response time.
In clinical trials, Norvasc has been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
Geriatric Use: Clinical studies of Norvasc 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. Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40-60%, and a lower initial dose may be required (see DOSAGE AND ADMINISTRATION).
"All patients who receive Photofrin will be photosensitive and must observe precautions to avoid exposure of skin and eyes to direct sunlight or bright indoor light (from examination lamps, including dental lamps, operating room lamps, unshaded light bulbs at close proximity, etc.) for at least 30 days."
New second sentence -
"Some patients may remain photosensitive for up to 90 days or more."
Last sentence revised (new text in italics) -
" Conventional UV (ultraviolet) sunscreens are of no value in protecting against photosensitivity reactions because photoactivation is caused by visible light."
"Photosensitivity reactions ["(mostly mild erythema on the face and hands) deleted] occurred in approximately 20% of patients treated with Photofrin in clinical studies."
First paragraph, new fourth through seventh sentences -
"Typically these reactions were mostly mild to moderate erythema but they also included swelling, itching, burning sensation, feeling hot, or blisters. In a single study of 24 healthy subjects, some evidence of photosensitivity reactions occurred in all subjects. Other less common skin manifestations were also reported in areas where photosensitivity reactions had occurred such as increased hair growth, skin discoloration, skin nodules, increased wrinkles and increased skin fragility. These manifestations may be attributable to a pseudoporphyria state (temporary drug-induced cutaneous porphyria)."
"Clinical studies of procainamide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting out 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. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to the 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 by calculating creatinine clearance and to monitor the plasma levels of procainamide and its major metabolite, N-acetyl procainamide."
"The safety and effectiveness of Saizen in patients aged 65 and over has not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of Saizen, and may be more prone to develop adverse reactions."
"For patients treated in open-label extension studies, no significant additional efficacy was observed beyond 12 weeks. There are no data available from controlled studies for patients that start, stop, and re-start treatment."
"The administration of 200 mg BID of nefazodone for 1 week did not increase the fraction of unbound warfarin in subjects whose prothrombin times had been prolonged by warfarin therapy to 120-150% of the laboratory control (see PRECAUTIONS section, Drug Interactions subsection)."
Third sentence revised -
While nefazodone did not alter the in vitro protein binding of chlorpromazine, desipramine, diazepam, diphenylhydantoin, lidocaine, prazosin, propranolol, or verapamil ["warfarin" deleted]."
"Coadministration of terfenadine, astemizole, cisapride, pimozide, or carbamazepine with Serzone (nefazodone hydrochloride) is contraindicated (see WARNINGS and PRECAUTIONS sections)."
"The coadministration of carbamazepine 200 mg BID with nefazodone 200 mg BID, at steady state for both drugs, resulted in almost 95% reductions in AUCs for nefazodone and hydroxynefazodone, likely resulting in insufficient plasma nefazodone and hydroxynefazodone concentrations for achieving an antidepressant effect for Serzone. Consequently, it is recommended that Serzone not be used in combination with carbamazepine (see CONTRAINDICATIONS and PRECAUTIONS sections). "
Drug Interactions: Drugs Highly Bound to Plasma Protein
New subsection -
"Warfarin-There were no effects on the prothrombin or bleeding times or upon the pharmacokinetics of R-warfarin when nefazodone (200 mg BID) was administered for 1 week to subjects who had been pretreated for 2 weeks with warfarin. Although the coadministration of nefazodone did decrease the subjects' exposure to S-warfarin by 12%, the lack of effects on the prothrombin and bleeding times indicate this modest change is not clinically significant. Although these results suggest no adjustments in warfarin dosage are required when nefazodone is administered to patients stabilized on warfarin, such patients should be monitored as required by standard medical practice."
CNS-Active Drugs
New subsections -
"Fluoxetine-When fluoxetine (20 mg QD) and nefazodone (200 mg BID) were administered at steady state there were no changes in the pharmacokinetic parameters for fluoxetine or its metabolite, norfluoxetine. Similarly, there were no changes in the pharmacokinetic parameters of nefazodone or HO-NEF; however, the mean AUC levels of the nefazodone metabolites mCPP and triazole-dione increased by 3-6 fold and 1.3-fold, respectively. When a 200-mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient adverse events such as headache, lightheadedness, nausea, or paresthesia, possibly due to the elevated mCPP levels. Patients who are switched from fluoxetine to nefazodone without an adequate washout period may experience similar transient adverse events. The possibility of this happening can be minimized by allowing a washout period before initiating nefazodone therapy and by reducing the initial dose of nefazodone. Because of the long half-life of fluoxetine and its metabolites, this washout period may range from one to several weeks depending on the dose of fluoxetine and other individual patient variables."
"Phenytoin-Pretreatment for 7 days with 200 mg BID of nefazodone had no effect on the pharmacokinetics of a single 300-mg oral dose of phenytoin. However, due to the nonlinear pharmacokinetics of phenytoin, the failure to observe a significant effect on the single-dose pharmacokinetics of phenytoin does not preclude the possibility of a clinically significant interaction with nefazodone when phenytoin is dosed chronically. However, no change in the initial dosage of phenytoin is considered necessary and any subsequent adjustment of phenytoin dosage should be guided by usual clinical practices."
"Desipramine-When nefazodone (150 mg BID) and desipramine (75 mg QD) were administered together there were no changes in the pharmacokinetics of desipramine or its metabolite, 2-hydroxy desipramine. There were also no changes in the pharmacokinetics of nefazodone or its triazole-dione metabolite, but the AUC and Cmax of mCPP increased by 44% and 48%, respectively, while the AUC of the HO-NEF decreased by 19%. No changes in doses of either nefazodone or desipramine are necessary when the two drugs are given concomitantly. Subsequent dose adjustments should be made on the basis of clinical response."
Lithium-In 13 healthy subjects the coadministration of nefazodone (200 mg BID) with lithium (500 mg BID) for 5 days (steady-state conditions) was found to be well tolerated. When the two drugs were coadministered, there were no changes in the steady-state pharmacokinetics of either lithium, nefazodone or its metabolite HO-NEF; however, there were small decreases in the steady-state plasma concentrations of two nefazodone metabolites, mCPP and triazole-dione, which are considered not to be of clinical significance. Therefore, no dosage adjustment of either lithium or nefazodone is required when they are coadministered."
Carbamazepine-The coadministration of nefazodone (200 mg BID) for 5 days to 12 healthy subjects on carbamazepine who had achieved steady state (200 mg BID) was found to be well tolerated. Steady-state conditions for carbamazepine, nefazodone, and several of their metabolites were achieved by day 5 of coadministration. With coadministration of the two drugs there were significant increases in the steady-state Cmax and AUC of the carbamazepine (23% and 23%, respectively), while the steady-state Cmax and the AUC of the carbamazepine metabolite, 10,11 epoxycarbamazepine, decreased by 21% and 20%, respectively. The coadministration of the two drugs significantly reduced the steady-state Cmax and AUC of nefazodone by 86% and 93%, respectively. Similar reductions in Cmax and AUC of HO-NEF were also observed (85% and 94%), while the reductions in Cmax and AUC of mCPP and triazole dione were more modest (13% and 44% for the former and 28% and 57% for the latter). Due to the potential for coadministration of carbamazepine to result in insufficient plasma nefazodone and hydroxynefazodone concentrations for achieving an antidepressant effect for Serzone, it is recommended that Serzone not be used in combination with carbamazepine (see CONTRAINDICATIONS and WARNINGS sections)."
Theophylline-When nefazodone (200 mg BID) was given to patients being treated with theophylline (600-1200 mg/day) for chronic obstructive pulmonary disease, there was no change in steady-state pharmacokinetics of either nefazodone or theophylline. FEV1 measurements taken when theophylline and nefazodone were coadministered did not differ from baseline dosage (i.e., when theophylline was administered alone). Therefore, dosage adjustment is not necessary for either drug when coadministered."
"Tham Solution (tromethamine injection) is contraindicated in anuria and uremia. In neonates it is also contraindicated in chronic respiratory acidosis and salicylate intoxication."
"Studies of tromethamine in animals to evaluate the effect of fertility have not been conducted."
Replaced with -
"Studies with THAM Solution have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility."
Pediatric Use: New first paragraph -
"The safety and effectiveness of THAM Solution in pediatric patients is based on over 30 years' clinical experience documented in the literature and on safety surveillance. THAM Solution has been used to treat severe cases of metabolic acidosis with concurrent respiratory acidosis because it does not raise PCO2 as bicarbonate does in neonates and infants with respiratory failure. It has also been used in neonates and infants with hypernatremia and metabolic acidosis to avoid the additional sodium given with the bicarbonate. However, because the osmotic effects of THAM Solution are greater and large continuous doses are required, bicarbonate is preferred to THAM Solution in the treatment of acidotic neonates and infants with RDS."
Nursing Mothers: New subsection -
"It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when THAM Solution is administered to a nursing mother.
"Infusion via low-lying umbilical venous catheters has been associated with hepatocellular necrosis."
"The initial dose of THAM Solution should be based on initial pH and birthweight amounting to approximately 1 mL per kg for each pH unit below 7.4. Further doses have been given according to changes in PaO2, pH and PCO2."
"Both regimens include a 1 mL test dose, a loading dose, a dose to be added ["to" deleted] while recirculating the priming fluid of the cardiopulmonary bypass circuit ("pump prime" dose), and a constant infusion dose."
Second paragraph, new fifth sentence -
"To avoid physical incompatibility of Trasylol and heparin when adding to the pump prime solution, each agent must be added during recirculation of the pump prime to assure adequate dilution prior to admixture with the other component."
Third paragraph, fifth sentence revised (new text in italics) -
"The "pump prime" dose is added to the recirculating priming fluid of the cardiopulmonary bypass circuit, by replacement of an aliquot of the priming fluid, prior to the institution of cardiopulmonary bypass."
"Bepridil is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug is greater in patients with impaired renal function. Peak plasma concentration of bepridil was increased 3-fold and t1/2 was increased more than 2-fold in elderly (> 74 years) receiving oral bepridil 100 mg twice daily for 3 weeks compared to younger volunteers (see PRECAUTIONS-Geriatric Use)."
"Clinical studies of bepridil did not include sufficient numbers of subjects 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. Bepridil is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug is greater in patients with impaired renal function (see CLINICAL PHARMACOLOGY- Pharmacokinetics and Metabolism)."
"In an Expanded Access Program for patients with advanced HIV infection, patients aged 65 and older had a higher frequency of pancreatitis (10%) than younger patients (5%)(see WARNINGS). Clinical studies of didanosine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine 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. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see DOSAGE AND ADMINISTRATION: Dose Adjustment)."
"TO AVOID A DELAY IN DIAGNOSIS AND MINIMIZE THE RISK OF A LIFE-THREATENING HYPERSENSITIVITY REACTION, ZIAGEN SHOULD BE PERMANENTLY DISCONTINUED IF HYPERSENSITIVITY CAN NOT BE RULED OUT, EVEN WHEN OTHER DIAGNOSES ARE POSSIBLE (E.G., ACUTE ONSET RESPIRATORY DISEASES, GASTROENTERITIS, OR REACTIONS TO OTHER MEDICATIONS)."
New third paragraph -
"SEVERE OR FATAL HYPERSENSITIVITY REACTIONS CAN OCCUR WITHIN HOURS AFTER REINTRODUCTION OF ZIAGEN IN PATIENTS WHO HAVE NO IDENTIFIED HISTORY OR UNRECOGNIZED SYMPTOMS OF HYPERSENSITIVITY TO ABACAVIR THERAPY (see WARNINGS, PRECAUTIONS: Information for Patients, and ADVERSE REACTIONS).
WARNINGS: Hypersensitivity Reaction: Second sentence added -
"To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity reaction, Ziagen should be permanently discontinued if hypersensitivity can not be ruled out, even when other diagnoses are possible (e.g., acute onset respiratory diseases, gastroenteritis, or reactions to other medications)."
Fourth sentence added -
"Severe or fatal hypersensitivity reactions can occur within hours after reintroduction of Ziagen in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy."
New second paragraph -
"When therapy with Ziagen has been discontinued for reasons other than symptoms of a hypersensitivity reaction, and if reinitiation of therapy is under consideration, the reason for discontinuation should be evaluated to ensure that the patient did not have symptoms of a hypersensitivity reaction. If hypersensitivity can not be ruled out, abacavir should NOT be reintroduced. If symptoms consistent with hypersensitivity are not identified, reintroduction can be undertaken with continued monitoring for symptoms of a hypersensitivity reaction. Patients should be made aware that a hypersensitivity reaction can occur with reintroduction of abacavir, and that abacavir reintroduction should be undertaken only if medical care can be readily accessed by the patient or others (see ADVERSE REACTIONS)."
"Patients who have interrupted Ziagen for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply) should be made aware that a severe or fatal hypersensitivity reaction can occur with reintroduction of babcavir. Patients should be instructed not to reintroduce abacavir without medical consultation and that reintroduction of abacavir should be undertaken only if medical care can be readily accessed by the patient or others (see ADVERSE REACTIONS and WARNINGS)."
"To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity reaction, Ziagen should be permanently discontinued if hypersensitivity can not be ruled out, even when other diagnoses are possible (e.g., acute onset respiratory diseases, gastroenteritis, or reactions to other medications). Severe or fatal hypersensitivity reactions can occur within hours after reintroduction of Ziagen in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy (see WARNINGS and PRECAUTIONS: Information for Patients)."
New paragraph -
"When therapy with Ziagen has been discontinued for reasons other than symptoms of a hypersensitivity reaction, and if reinitiation of therapy is under consideration, the reason for discontinuation should be evaluated to ensure that the patient did not have symptoms of a hypersensitivity reaction. If hypersensitivity can not be ruled out, abacavir should NOT be reintroduced. If symptoms consistent with hypersensitivity are not identified, reintroduction can be undertaken with continued monitoring for symptoms of a hypersensitivity reaction. Patients should be made aware that a hypersensitivity reaction can occur with reintroduction of abacavir, and that abacavir reintroduction should be undertaken only if medical care can be readily accessed by the patient or others (see WARNINGS)."
![[FDA Home Page]](https://webarchive.library.unt.edu/eot2008/20090118022522im_/http://www.fda.gov/icon/iconhome.gif){kind=icon}