Summary Of Safety-Related Drug Labeling
Changes Approved By FDA Center for Drug
Evaluation and Research (CDER)
June 2002

(Posted: 07/30/2002)

MedWatch Home | What's New | About Medwatch | How to Report | Submit Report | Safety Info
Continuing Education | Download PDF | Comments | Privacy Statement

[Other labeling changes not in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/feb02.htm#accuta,
http://www.fda.gov/medwatch/SAFETY/2002/apr02.htm#accuta,
http://www.fda.gov/medwatch/SAFETY/2002/may02.htm#accuta]

Psychiatric Disorders: Accutane may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. Discontinuation of Accutane therapy may be insufficient; further evaluation may be necessary. No mechanism of action has been established for these events (see ADVERSE REACTIONS: Psychiatric). Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Accutane (isotretinoin).

Psychiatric: suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS: Psychiatric Disorders), emotional instability.

Some patients, while taking Accutane or soon after stopping Accutane, have become depressed or developed other serious mental problems. Symptoms of these problems include sad, "anxious" or empty mood, irritability, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking Accutane have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on Accutane becoming aggressive or violent. No one knows if Accutane caused these No one knows if Accutane caused these behaviors or if they would have happened even if the person did not take Accutane.

•Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence)

There have been reports of patients on Accutane becoming aggressive or violent. No one knows if Accutane caused these problems or behaviors or if they would have happened even if the person did not take Accutane.

•Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence)

4. I understand that some patients, while taking Accutane or soon after stopping Accutane, have become depressed or developed other serious mental problems. Symptoms of these problems include sad, "anxious" or empty mood, irritability, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking Accutane have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been.reports of patients on Accutane becoming aggressive or violent.

•Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence)

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

http://www.fda.gov/medwatch/SAFETY/2002/mar02.htm#actiq]

Other arterial and venous punctures, epidural procedures, intramuscular injections, and the use of urinary catheters, nasotracheal intubation and nasogastric tubes should be minimized.

Bleeding: Intracranial bleeding, retroperitoneal bleeding, hemopericardium, pulmonary (alveolar) hemorrhage, and spinal-epidural hematoma. Fatal bleeding events have been reported rarely.

\Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

Angiomax should be administered via an intravenous line. No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets. The following nine drugs should not be administered in the same intravenous line with Angiomax, since they resulted in haze formation, microparticulate formation, or gross precipitation when mixed with Angiomax: alteplase, amiodarone HCl, amphotericin B, chlorpromazine HCl, diazepam, prochlorperazine edisylate, reteplase, streptokinase, and vancomycin HCl.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

APHTHASOL (amlexanox) Oral Paste

[June 11, 2002: GlaxoSmithKline]

PRECAUTIONS

Geriatric Use: Clinical studies of Aphthasol 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.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

http://www.fda.gov/medwatch/SAFETY/2002/may02.htm#avelox ]

"male/female" was added to the first line in the IV dosing table and now reads: Healthy young male/female (n = 56)

In vitro studies with cytochrome (CYP) P450 enzymes indicate that moxifloxacin does not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2, suggesting that moxifloxacin is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.

The potential for pharmacokinetic drug interactions between moxifloxacin and itraconazole, theophylline, warfarin, digoxin, probenecid, morphine, oral contraceptive, ranitidine, glyburide, calcium, iron, and antacids has been evaluated. There was no clinically significant effect of moxifloxacin on itraconazole, theophylline, warfarin, digoxin, oral contraceptives, or glyburide kinetics. Theophylline, Itraconazole, theophylline, warfarin, digoxin, probenecid, and ranitidine morphine, ranitidine, and calcium did not significantly affect the pharmacokinetics of moxifloxacin. These results and the data from in vitro studies suggests that moxifloxacin is unlikely to significantly alter the metabolic clearance of drugs metabolized by CYP3A4, CYP2D6, CYP2C9, CYP2C19 or CYP1A2 enzymes.

However, a As with all other quinolones, iron and antacids significantly reduced the bioavailability of orally administered moxifloxacin.

Itraconazole: In a study involving 11 healthy volunteers, there was no significant effect of itraconazole (200 mg once daily for 9 days), a potent inhibitor of cytochrome P4503A4, on the pharmacokinetics of moxifloxacin (a single 400 mg dose given on the 7 th day of itraconazole dosing). In addition, moxifloxacin was shown not to affect the pharmacokinetics of itraconazole.

Prolongation of the QT interval in the ECG has been observed in some patients receiving moxifloxacin.

Oral administration of quinolones with antacids containing aluminum or magnesium or calcium with sucralfate, with metal cations such as iron, or with multivitamins containing iron or zinc, or with formulations containing divalent and trivalent cations such as Videx (didanosine) chewable/buffered tablets or the pediatric powder for oral solution, may substantially interfere with the absorption of quinolones, resulting in systemic concentrations considerably lower than desired.

No clinically significant drug-drug interactions between itraconazole, theophylline, warfarin, digoxin, oral contraceptives or glyburide have been observed with moxifloxacin. Theophylline, Itraconazole, theophylline, digoxin, probenecid, and ranitide morphine, ranitidine, and calcium have been shown not to significantly alter the pharmacokinetics of moxifloxacin. (See CLINICAL PHARMACOLOGY.)

RESPIRATORY: dyspnea, cough increased, pneumonia, pharyngitis, rhinitis, sinusitis

SKIN/APPENDAGES: rash (maculopapular, purpuric, pustular), pruritus, sweating, dry Skin

UROGENITAL: vaginal moniliasis, vaginitis, cystitis

Tell your doctor about all other prescription and non-prescription medicines or supplements you are taking. You should avoid taking AVELOX with certain medicines used to treat an abnormal heartbeat. These include quinidine, procainamide, amiodarone, and sotalol. Some medicines also produce an effect on the electrocardiogram test, including cisapride, erythromycin, some antidepressants and some antipsychotic drugs. These may increase the risk of heart beat problems when taken with AVELOX. For this reason it is important to let your health care provider know all of the medicines that you are using.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

Concomitant administration of clarithromycin with cisapride, pimozide, astemizole, or terfenadine is contraindicated. There have been postmarketing reports of drug interactions when clarithromycin and/or erythromycin are co-administered with cisapride, pimozide, astemizole, or terfenadine resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to the inhibition of metabolism of these drugs by erythromycin and clarithromycin. Fatalities have been reported.

ADVERSE REACTIONS – Post-Marketing Experience

First paragraph - "pancreatitis" has been added to the list of reported adverse events.

Transient CNS events in the second paragraph - "convulsions" has been included.

Coadministration of ergotamine with potent CYP 3A4 inhibitors (ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, and troleandomycin) has been associated with acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities (see PRECAUTIONS: Drug Interactions), with some cases resulting in amputation. There have been rare reports of cerebral ischemia in patients on protease inhibitor therapy when CAFERGOT (ergotamine tartrate and caffeine) was coadministered, at least one resulting in death. Because of the increased risk for ergotism and other serious vasospastic adverse events, ergotamine use is contraindicated with these drugs and other potent inhibitors of CYP 3A4 (e.g., ketoconazole, itraconazole) (see WARNINGS: CYP 3A4 Inhibitors).

Coadministration of ergotamine with potent CYP 3A4 inhibitors such as protease inhibitors or macrolide antibiotics has been associated with serious adverse events; for this reason, these drug should not be given concomitantly with ergotamine (See CONTRAINDICATIONS). While these reactions have not been reported with less potent CYP 3A4 inhibitors, there is a potential risk for serious toxicity including vasospasm when these drugs are used with ergotamine. Examples of less potent CYP 3A4 inhibitors include: saquinavir, nefazodone, fluconazole, fluoxetine, grapefruit juice, fluvoxamine, zileuton, metronidazole, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP3A4 of other agents being considered for concomitant use with ergotamine.

[Moved from ADVERSE REACTIONS Section] There have been a few reports of patients on CAFERGOT (ergotamine tartrate and caffeine) therapy developing retroperitoneal and/or pleuropulmonary fibrosis. There have also been rare reports of fibrotic thickening of the aortic, mitral, tricuspid, and/or pulmonary valves with long-term continuous use of CAFERGOT (ergotamine tartrate and caffeine). CAFERGOT (ergotamine tartrate) suppositories should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION).

CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) See CONTRAINDICATIONS and WARNINGS.

Fibrotic Complications: (see WARNINGS).

Analgesia, including primary dysmenorrhea: In acute analgesic models of post-oral surgery pain, post-orthopedic surgical pain, and primary dysmenorrhea, CELEBREX relieved pain that was rated by patients as moderate to severe. Single doses (see DOSAGE AND ADMINISTRATION) of CELEBREX provided pain relief within 60 minutes.

CLASS Study: The estimated cumulative rates at 9 months of complicated and symptomatic ulcers (an adverse event similar but not identical to the "upper GI ulcers, gross bleeding or perforation" described in the preceding paragraphs) for patients treated with CELEBREX 400 mg BID (see Special Studies - Use with Aspirin) are described in Table 5. Table 5 also displays results for patients less than or greater than or equal to the age of 65 years. The differences in rates between the CELEBREX alone and CELEBREX with ASA groups may be due to the higher risk for GI events in ASA users.

Fluid Retention, Edema, and Hypertension: Fluid retention and edema have been observed in some patients taking CELEBREX (see ADVERSE REACTIONS). In the CLASS study (see Special Studies-Use with Aspirin), the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on CELEBREX 400 mg BID (4-fold and 2-fold the recommended OA and RA doses, respectively, and the approved dose for FAP), ibuprofen 800 mg TID and diclofenac 75 mg BID were 4.5%, 6.9% and 4.7%, respectively. The rates of hypertension in the CELEBREX, ibuprofen and diclofenac treated patients were 2.4%, 4.2% and 2.5%, respectively. As with other NSAIDs, CELEBREX should be used with caution in patients with fluid retention, hypertension, or heart failure.

Aspirin: CELEBREX can be used with low-dose aspirin. However, concomitant administration of aspirin with CELEBREX increases the may result in an increased rate of GI ulceration or other complications, compared to use of CELEBREX alone (see CLINICAL STUDIES - Special Studies – Gastrointestinal Use with Aspirin and WARNINGS – Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation – CLASS Study).

During this study (see Special Studies-Use with Aspirin), the incidence of clinically significant decreases in hemoglobin (>2 g/dL) confirmed by repeat testing was lower in patients on CELEBREX 400 mg BID (4-fold and 2-fold the recommended OA and RA doses, respectively, and the approved dose for FAP) compared to patients on either diclofenac 75 mg BID or ibuprofen 800 mg TID: 0.5%, 1.3% and 1.9%, respectively. The lower incidence of events with

[Other labeling changes not in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/feb02.htm#cenest]

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

[Other labeling changes not in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/jan02.htm#crixiv]

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving protease inhibitors antiretroviral therapy.

Hypersensitivity: anaphylactoid reactions; urticaria; vasculitis.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

6. – Hale T. Medications and Mothers Milk. 9 th . edition. Amarillo, TX: Pharmasoft Publishing 2000; 225 - 226.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

[Other labeling changes not in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/mar02.htm#epivir]

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

The evaluated population consisted of 39 patients in the low-dose Ferrlecit (sodium ferric gluconate complex in sucrose injection) group 50% female, 50% male; 74% white, 18% black, 5% Hispanic, 3% Asian; mean age 54 years, range 22-83 years, 44 patients in the high-dose Ferrlecit group 50% female, 48% male, 2% unknown; 75% white, 11% black, 5% hispanic, 7% other, 2% unknown; mean age 56 years, range 20- 87 years, and 25 historical control patients 68% female, 32% male; 40% white 32% black, 20% Hispanic, 4% Asian, 4% unknown; mean age 52 years, range 25 –84 years.

Inclusion and exclusion criteria were identical to those of Study A as was the historical control population. Sixty-three patients were evaluated in this study: 38 in the Ferrlecit treated group 37% female, 63% male; 95% white, 5% Asian; mean age 56 years, range 22-84 years and 25 in the historical control group 68% female, 32% male; 40% white, 32% black, 20% Hispanic, 4% Asian, 4% unknown; mean age 52 years, range 25-84 years.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

ALERT: Find out about medicines that should not be taken with INVIRASE. This statement is included on the product’s bottle label.

Information for Patients: A statement to patients and health care providers is included on the product’s bottle label: ALERT: Find out about medicines that should NOT be taken with INVIRASE.

Addition of "temporary cortical blindness" and "temporary amnesia".

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

• chronic IBS symptoms (generally lasting 6 months or longer),
• had anatomic or biochemical abnormalities of the gastrointestinal tract excluded, and
• failed to respond to conventional therapy

• frequent and severe abdominal pain/discomfort
• frequent bowel urgency or fecal incontinence
• disability or restriction of daily activities due to IBS

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. (Sixty-three (0.19%) of the controls and 56 (0.30%) of the cases were treated with doxycycline.) This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation) with the exception of a marginal relationship with neural tube defect based on only two exposed cases ⁴ .

Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines, including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated; however, the effects of prolonged exposure to doxycycline in breast milk are unknown ⁶ . Because of the potential for adverse reactions in nursing infants from tetracyclines doxcycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. (See WARNINGS.)

Drugs That May Potentiate Renal Dysfunction [Table]

Anti-inflammatory Drugs - "colchicine" added. [Not in 2001 PDR]

Cyclosporine is extensively metabolized Cyclosporine concentrations may be influenced by drugs that affect microsomal enzymes, particularly cytochrome P-450 III-A 3A.

The HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit cytochrome P-450 IIIA 3A and thus could potentially increase the concentrations of drugs metabolized by the cytochrome P-450 system. The interaction between HIV protease inhibitors and cyclosporine has not been studied. cyclosporine, however no formal studies of the interaction are available.

Drugs That Increase Cyclosporine Concentrations [Table]

Antifungals - "ketoconazole" added.

Antibiotics - "quinupristin/daldopristin" added.

Other Drugs - "colchicine and amiodarone" added.

Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations

Other Drugs/Dietary Supplements - [Table] "Orlistat and St. John’s Wort" added. [Not in 2001 PDR]

Results of a dose-titration clinical trial with Neoral indicate that an improvement of psoriasis by 75% or more (based on PASI) was achieved in 51% of the patients after 8 weeks and in 79% of the patients after 12 16 weeks.

To make Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED more palatable, it should be diluted preferably with orange or apple juice that is at room temperature. Patients should avoid switching diluents frequently. Grapefruit juice affects metabolism of cyclosporine and should be avoided. The combination of Neoral solution with milk can be unpalatable. The effect of milk on the bioavailability of cyclosporine when admininstered as Neoral Oral Solution has not been evaluated.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

Administration NephrAmine to children, especially in high dose ranges, may result in hyperammonemia. Administration of NephrAmine to infants, particularly neonates and low birth weight infants, may result in elevated plasma amino acid levels (e.g. hypermethionemia) and hyperammonemia. In these very young age groups, amino acid formulations developed specifically for nutritional support of infants and children should be considered.

For infants, especially neonates and low birth weight infants, amino acid formulations developed specifically for nutritional support of infants and children should be considered. If NephrAmine is administered to these very young patients, extra caution in frequent monitoring of plasma amino acid levels and serum ammonia is strongly recommended.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

After reconstitution, the solution is stable for 2 days at room temperature, 5 days at refrigeration (2-8ºC) or 8 days frozen (10-20ºC).should be used immediately; however, the solution is stable for 6 hours at room temperature (20 to 25ºC), or 24 hours under refrigeration (2-8°C).

Reconstituted Prior to administration, the reconstituted solution should be further diluted with 5% Dextrose Injection, USP, to yield a final concentration of 0.25 to 2 mg of trimetrexate per mL. The diluted solution should be administered by intravenous infusion over 60 minutes. Neutrexin should not be mixed with solutions containing either chloride ion or leucovorin, since precipitation occurs instantly. It The diluted solution is stable under refrigeration or at room temperature for up to 24 hours. Do not freeze. Discard any unused portion after 24 hours. The intravenous line must be flushed thoroughly with at least 10 mL of 5% Dextrose Injection, USP, before and after administering Neutrexin.

Store at controlled room temperature 15° to 30° C (59° to 86° F). 20° to 25° C (68° to 77° F).

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

Table 6 presents pharmacokinetic data from clinical trials and a published study in pediatric patients (<1 year of age; N=27) given famotidine I.V. 0.5 mg/kg and from published studies of small numbers of pediatric patients (1-15 years of age) given famotidine intravenously. Areas under the curve (AUCs) are normalized to a dose of 0.5 mg/kg I.V. for pediatric patients 1–15 years of age and compared with an extrapolated 40 mg intravenous dose in adults (extrapolation based on results obtained with a 20 mg I.V. adult dose).

Plasma clearance is reduced and elimination half-life is prolonged in pediatric patients 0-3 months of age compared to older pediatric patients. The pharmacokinetic parameters for pediatric patients, ages >3 months. Values of pharmacokinetic parameters for pediatric patients, ages 1-15 years, are comparable to those obtained for adults.

Bioavailability studies of 8 pediatric patients (11-15 years of age) showed a mean oral bioavailability of 0.5 compared to adult values of 0.42 to 0.49. Oral doses of 0.5 mg/kg achieved AUCs of 645 ±249 ng-hr/mL and 580 ± 60 ng-hr/mL in pediatric patients <1 year of age (N=5) and pediatric patients 11-15 years of age, respectively, compared to 482 ± 181 ng-hr/mL in adults treated with 40 mg orally.

Four Five published studies (Table 8) examined the effect of famotidine on gastric pH and duration of acid suppression in pediatric patients. While each study had a different design, acid suppression data over time are summarized as follows:

In a double-blinded, randomized, treatment-withdrawal study, 35 pediatric patients <1 year of age who were diagnosed as having gastroesophageal reflux disease were treated for up to 4 weeks with famotidine oral suspension (0.5 mg/kg/dose or 1 mg/kg/dose). Although an intravenous famotidine formulation was available, no patients were treated with intravenous famotidine in this study. Also, caregivers were instructed to provide conservative treatment including thickened feedings. Enrolled patients were diagnosed primarily by history of vomiting (spitting up) and irritability (fussiness). The famotidine dosing regimen was once daily for patients <3 months of age and twice daily for patients < 3 months of age. After 4 weeks of treatment, patients were randomly withdrawn from the treatment and followed an additional 4 weeks for adverse events and symptomatology. Patients were evaluated for vomiting (spitting up), irritability (fussiness) and global assessments of improvement. The study patients ranged in age at entry from 1.3 to 10.5 months (mean 5.6 ± 2.9 months), 57% were female, 91% were white and 6% were black. Most patients (27/35) continued into the treatment withdrawal phase of the study. Two patients discontinued famotidine due to adverse events. Most patients improved during the initial treatment phase of the study. Results of the treatment withdrawal phase were difficult to interpret because of small numbers of patients. Of the 35 patients enrolled in the study, agitation was observed in 5 patients on famotidine that resolved when the medication was discontinued; agitation was not observed in patients on placebo (see ADVERSE REACTIONS, Pediatric Patients).

GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120 ° F (49° C).

Geriatric Use: Safety and effectiveness in a geriatric population have not been established. Clinical studies of RETIN-A did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients.

RETIN- A GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120° F (49° C).

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

Lifetime oral carcinogenicity studies were conducted in CD-1 mice and Sprague-Dawley rats. Pilocarpine did not induce tumors in mice at any dosage studied (up to 30mg/kg/day, which yielded a systemic exposure approximately 50 times larger than the maximum systemic exposure observed clinically). In rats, a dosage of 18mg/kg/day, which yielded a systemic exposure approximately 100 times larger than the maximum systemic exposure observed clinically, resulted in a statistically significant increase in the incidence of benign pheochromocytomas in both males and females, and a statistically significant increase in the incidence of hepatocellular adenomas in female rats. The tumorigenicity observed in rats was observed only at a large multiple of the maximum labeled clinical dose, and may not be relevant to clinical use.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

[Other labeling changes not in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/jan02.htm#serzon]

[Other labeling changes not in 2002 PDR: http://www.fda.gov/medwatch/SAFETY/2002/may02.htm#skelax]

CLINICAL PHARMACOLOGY

Pharmacokinetics

CLINICAL PHARMACOLOGY:

Impaired Hepatic Function: TRIZIVIR: A reduction in the daily dose of zidovudine may be necessary in patients with mild to moderate impaired hepatic function or liver cirrhosis. Because TRIZIVIR is a fixed-dose combination that cannot be adjusted for this patient population, TRIZIVIR is not recommended for patients with impaired hepatic function.

Posttreatment Exacerbations of Hepatitis: In clinical trials in non-HIV-infected patients treated with lamivudine for chronic hepatitis B (HBV), clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from post-marketing experience after changes from lamivudine-containing HIV treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory followup for at least several months after stopping treatment. There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis.

Lamivudine: In clinical trials and postmarketing experience, some patients with HIV infection who have chronic liver disease due to hepatitis B virus infection experienced clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine. Consequences may be more severe in patients with decompensated liver disease.

Lamivudine: Trimethoprim (TMP) 160 mg/sulfamethoxazole (SMX) 800 mg once daily has been shown to increase lamivudine exposure (AUC). The effect of higher doses of TMP/SMX on lamivudine pharmacokinetics has not been investigated (see CLINICAL PHARMACOLOGY). Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of TRIZIVIR in combination with zalcitabine is not recommended.

Abacavir: Carcinogenicity studies in mice and rats are ongoing with abacavir. Abacavir was administered orally at 3 dosage levels to separate groups of mice (60 females and 60 males per group) and rats (56 females and 56 males in each group) in carcinogenicity studies. Single doses were 55, 110, and 330 mg/kg per day in mice and 30, 120, and 600 mg/kg per day in rats. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats.

Lamivudine: Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses up to 4000 mg/kg per day and 1000 mg/kg per day, respectively, producing plasma levels up to approximately 35 times that for the adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times that in humans.

Abacavir, Lamivudine, and Zidovudine: Zidovudine is excreted in breast milk; abacavir and lamivudine are secreted into the milk of lactating rats. there are no data on lamivudine. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving TRIZIVIR.

The following events have been identified during post-approval use of abacavir, lamivudine, and/or zidovudine. 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 their seriousness, frequency of reporting, or potential causal connection to lamivudine and/or zidovudine.

Abacavir: Suspected Stevens-Johnson syndrome (SJS) has been reported in patients receiving abacavir in combination with medications known to be associated with SJS. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases.

Endocrine and Metabolic: Gynecomastia, hyperglycemia.

Gastrointestinal: Oral mucosal pigmentation.

General: Vasculitis, weakness. Sensitization reactions (including anaphylaxis)

Hemic and Lymphatic: Aplastic anemia, anemia, lymphadenopathy, pure red cell aplasia, splenomegaly.

Hepatic and Pancreatic: Hepatobiliary tract and Pancreas Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbation of hepatitis B (see WARNINGS).

Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria.

Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis.

Nervous: Paresthesia, peripheral neuropathy, seizures.

Respiratory: Abnormal breath sounds/wheezing.

Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome. Urticaria

ANIMAL TOXICOLOGY: Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans. The clinical relevance of this finding has not been determined.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines, including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated; however, the effects of prolonged exposure to doxycycline in breast milk are unknown 6 . Because of the potential for adverse reactions in nursing infants from doxcycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. (See WARNINGS.)

Pharmacokinetics: Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of the individual enantiomers have not been studied. In humans, following oral administration of WELLBUTRIN, peak plasma bupropion concentrations are usually achieved within 2 hours, followed by a biphasic decline. The terminal phase has a mean half-life of 14 hours, with a range of 8 to 24 hours. The distribution phase has a mean half- life of 3 to 4 hours. The mean elimination half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of bupropion are reached within 8 days. Plasma bupropion concentrations are dose-proportional following single doses of 100 to 250 mg; however, it is not known if the proportionality between dose and plasma levels are maintained in chronic use.

The mean AUC increased by 28 about 1 ½ fold for hydroxybupropion and 50 about 2 ½ fold for threo/erythrohydrobupropion. The median Tmax was observed 19 hours later for hydroxybupropion and 21 31 hours later for threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and threo/erythrohydrobupropion were increased 5- and -4- 2-fold, respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers (see WARNINGS, PRECAUTIONS, and DOSAGE AND
ADMINISTRATION).

Hemic and Lymphatic: Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.

Return to Product Menu | MedWatch Home | MedWatch Safety Info | Online MedWatch Report | Contact Medwatch

 

HTML by JLW