Summary Of Safety-Related Drug Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
July 2001

(Posted: 10/04/01)

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ACTOS (pioglitazone HCl) Tablets

[July 2, 2001: Takeda]

PRECAUTIONS

Hepatic Effects: Revised 2^nd , 3^rd , 5^th , and 6^th paragraphs, added 4^th paragraph

In pre-approval clinical studies worldwide, over 4500 subjects have been were treated with ACTOS. In U.S. clinical studies, over 2500 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies.

During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values >3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS.

In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established.

Although available clinical data show no evidence of ACTOS-induced hepatotoxicity or ALT elevations, p Pioglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which has been was associated with idiosyncratic hepatotoxicity and rare cases of liver failure, liver transplants, and death during postmarketing clinical use. .

Pending the availability of the results of additional large, long-term controlled clinical trials and additional postmarketing safety data following wide clinical use of ACTOS to more fully define its hepatic safety profile, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes.

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AKINETON (biperidine HCl) Tablets

[July 23, 2001: Knoll]

Extensive changes, for FPL details contact the sponsor.

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ALLEGRA (fexofenadine HCl) Tablets and Capsules

[July 11, 2001: Aventis]

ADVERSE REACTIONS:

The following text is added at the end of the section.

Events that have been reported during controlled clinical trials involving seasonal allergic rhinitis and chronic idiopathic urticaria patients with incidences less than 1% and similar to placebo and have been rarely reported during postmarketing surveillance include: insomnia, nervousness, and sleep disorders or paroniria. In rare cases, rash, urticaria, pruritus and hypersensitivity reactions with manifestations such as angioedema, chest tightness, dsypnea, flushing and systemic anaphylaxis have been reported."

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ANAFRANIL (clomipramine HCl)

[July 31, 2001: Tyco healthcare]

PRECAUTIONS:

Revised "Carcinogenesis, Mutagenesis, Impairment of Fertility" and "Pregnancy Category C" and "Animal Toxicology" sections. For FPL details contact the sponsor.

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BREVITAL (methohexytal Na for injection)

[July 13, 2001: Eli Lilly]

ADVERSE REACTIONS:

Gastrointestinal: Nausea, emesis, abdominal pain, and liver function tests abnormal

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BUSPAR (buspirone HCl) Tablets

[July 19, 2001: Bristol-Myers]

CLINICAL PHARMACOLOGY:

4^th paragraph revised

The effects of food upon the bioavailability of BuSpar have been studied in eight subjects. They were given a 20-mg dose with and without food; the area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of unchanged buspirone increased by 84% and 116% respectively, but the total amount of buspirone immunoreactive material did not change. This suggests that food may decrease the extent of presystemic clearance of buspirone. (see DOSAGE AND ADMINISTRATION section) .

PRECAUTIONS:

Pediatric Use

The safety and effectiveness of BuSpar (buspirone hydrochloride) have not been determined in individuals below 18 years of age. buspirone were evaluated in two placebo-controlled 6-week trials involving a total of 559 pediatric patients (ranging from 6 to 17 years of age) with GAD. Doses studied were 7.5-30 mg b.i.d. (15-60 mg/day). There were no significant differences between buspirone and placebo with regard to the symptoms of GAD following doses recommended for the treatment of GAD in adults. Pharmacokinetic studies have shown that, for identical doses, plasma exposure to buspirone and its active metabolite, 1-PP, are equal to or higher in pediatric patients than adults. No unexpected safety findings were associated with buspirone in these trials. There are no long-term safety or efficacy data in this population.

Geriatric use

Revised

In one study of 6632 patients who received Buspar for the treatment of anxiety, 605 patients were > 65 years old and 41 were > 75 years old; the safety and efficacy profiles for these 605 elderly patients (mean age = 70.8 years) were similar to those in the younger population (mean age = 43.3 years). The rReview of other spontaneously reported adverse clinical events has not identified differences in reporting between elderly and younger patients, but greater sensitivity of some older patients cannot be ruled out.

There were no effects of age on the pharmacokinetics of buspirone (see CLINICAL PHARMACOLOGY, Special Populations section).

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COPAXONE ( glatiramer acetate) Injection

[July 12, 2001: Teva]

Extensive changes to the labeling. For FPL details, contact the sponsor.

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CORDARONE (amiodarone HCl) I.V.

[July 11, 2001: Wyeth]

Changes to the WARNINGS: Neonatal Hypo- or Hyperthyroidism, PRECAUTIONS: Pulmonary Disorders/ARDS; ; Carcinogenesis, Mutagenesis, Impairment of Fertility; Pediatric use; Geriatric Use, ADVERSE REACTIONS, OVERDOSAGE, and DOSAGE AND ADMINISTRATION sections.

WARNINGS/Neonatal Hypo- or Hyperthroidism

First sentence revised:

Although oral Cordarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with its oral administration..

PRECAUTIONS

Pulmonary Disorders/ARDS

A new paragraph added at the end

Postoperatively, occurrences of ARDS have been reported in patients receiving oral Cordarone therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiO2 and the determinants of oxygen delivery to the tissues (e.g., SaO2, PaO2) be closely monitored in patients on Cordarone.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies were conducted with Cordarone I.V. However, oral Cordarone caused a statistically significant, dose-related increase in the incidence of thyroid adenomas tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid adenomas tumors in rats was greater than the incidence in controls even at the lowest dose level tested dose of i.e., 5 mg/kg/day (about 0.1 0.08 times the maximum recommended oral human maintenance dose in mg/m 2 ).

Mutagenicity studies conducted with amiodarone HCl (Ames, micronucleus, and lysogenic induction tests) were negative.

No fertility studies were conducted with Cordarone I.V. However, oral Cordarone administration resulted in reduced fertility of rats at a dose of 90 mg/kg/day (about 1.3 times the maximum recommended oral human maintenance dose in mg/m 2 ). No significant effects on fertility occurred at 30 mg/kg/day. in a study in which amiodarone HCl was orally administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose*).

*600 mg in a 50 kg patient (doses compared on a body surface area basis)

Pediatric Use

added

Cordarone I.V. contains the preservative benzyl alcohol (see DESCRIPTION). There have been reports of fatal "gasping syndrome" in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse.

Geriatric Use

added

Clinical studies of Cordarone I.V. 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.

ADVERSE REACTIONS

Revised last sentence

In postmarketing surveillance, toxic epidermal necrolysis pancytopenia, neutropenia, angioedema, and anaphylactic shock also has have been reported with amiodarone therapy.

DOSAGE AND ADMINISTRATION

added:

Cordarone I.V. has been found to leach out plasticizers, including DEHP [di-(2-ethylhexyl)phthalate] from intravenous tubing (including PVC tubing). The degree of leaching increases when infusing Cordarone I.V. at higher concentrations and lower flow rates than provided in DOSAGE AND ADMINISTRATION.

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DILAUDID-HP (hydromorphone hydrochloride) Injection

[July 18, 2001: Abbott]

HEADER: Deleted "(WARNING: May be habit forming)"

PRECAUTIONS

Special Risk Patients

Reports of mild to severe seizures and myoclonus have been reported in severely compromised patients, administered high doses of parenteral hydromorphone, for cancer and severe pain. Opioid administration is associated with seizures and myoclonus in a variety of diseases where pain control is the primary focus.

Geriatric Use

Clinical studies of Dilaudid 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. Elderly subjects have been shown to have at least twice the sensitivity (as measured by EEG changes) of young adults for some opioids. 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. (see INDIVIDUALIZATION OF DOSAGES……..)

DOSAGE AND ADMINISTRATION:

added 7^th paragraph

CAUTION: The packaging (vial stopper) of this product contains rubber latex which may cause allergic reactions.

HOW SUPPLIED:

STORAGE : Parenteral forms of Dilaudid-HP should be stored at 15°-30°C (59°-86°F) Store at 25° C (77° F); excursions permitted to 15° -30° C (59° - 86° F). [See USP Controlled Room Temperature]".

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Eulexin (flutamide) Capsules

[July 23, 2001: Schering]

CLINICAL PHARMACOLGY

added

"Food has no effect on the bioavailablity of flutamide."

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GENOTROPIN (somatropin [rDNA origin] for injection)

[July 25, 2001: Pharmacia Upjohn]

CLINICAL STUDIES

Pediatric Patients Born Small for Gestational Age (SGA) Who Fail to Manifest Catch-up Growth by Age 2

The safety and efficacy of GENOTROPIN in the treatment of children born small for gestational age (SGA) were evaluated in 4 randomized, open-label, controlled clinical trials. Patients (age range of 2 to 8 years) were observed for 12 months before being randomized to receive either GENOTROPIN (2 doses per study, most often 0.24 and 0.48 mg/kg/week) as a daily SC injection, or no treatment, for the first 24 months of the studies. After 24 months in the studies, all patients received GENOTROPIN.

Patients who received any dose of GENOTROPIN showed significant increases in growth during the first 24 months of study compared with patients who received no treatment (see Table 4). Children receiving 0.48 mg/kg/week demonstrated a significant improvement in height standard deviation score (SDS) compared with children treated with 0.24 mg/kg/week. Both of these doses resulted in a slower but constant increase in growth continued at a slower but constant rate from between months 24 to 72 (data not shown).

Table 4

Efficacy of GENOTROPIN in Children Born Small for Gestational Age (Mean ±SD)

* p = 0.0001 vs Untreated Control group

† p = 0.0001 vs group treated with GENOTROPIN 0.24 mg/kg/week

INDICATIONS AND USAGE

GENOTROPIN Lyophilized Powder is indicated for:

• Long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone.

• Long-term treatment of pediatric patients who have growth failure due to Prader-Willi syndrome (PWS). The diagnosis of PWS should be confirmed by appropriate genetic testing.

• Long-term treatment of growth failure in children who were born small for gestational age (SGA) who fail to manifest catch-up growth by age 2.

Other causes of short stature in pediatric patients should be excluded.

• Long-term replacement therapy in adults with growth hormone deficiency (GHD) of either childhood- or adult-onset etiology. GHD should be confirmed by an appropriate growth hormone stimulation test.

PRECAUTIONS

General: 5^th paragraph revised

Caution should be used if growth hormone is administered to patients with diabetes mellitus, and insulin dosage may need to be adjusted. Because growth hormone may induce a state of insulin resistance, patients should be observed for evidence of glucose intolerance. Patients with diabetes or glucose intolerance should be monitored closely during treatment with GENOTROPIN. Patients with risk factors for glucose intolerance, such as obesity (including obese patients with PWS) or a family history of Type II diabetes, should be monitored closely as well. Because growth hormone may induce a state of insulin resistance, patients should be observed for evidence of glucose

intolerance.

ADVERSE REACTIONS

7^th paragraph revised

In four clinical studies with GENOTROPIN in 273 pediatric patients born small for gestational age, the following drug-related clinically significant events were reported in more than 1 patient: eczema, nevus, increased sweating, musculoskeletal problems, aggressive reaction, myopia, hyperglycemia, and injection site reactions. mild transient hyperglycemia, 1 patient with benign intracranial hypertension, 2 patients with central precocious puberty, 2 patients with jaw prominence, and several patients with aggravation of pre-existing scoliosis, injection site reactions, and self-limited progression of pigmented nevi. Anti-hGH antibodies were not detected in any of the patients treated with Genotropin.

Table 4 becomes Table 5

DOSAGE AND ADMINISTRATION

The dosage of GENOTROPIN Lyophilized Powder must be adjusted for the individual patient. The weekly dose should be divided into 6 or 7 subcutaneous injections. GENOTROPIN may be given in the thigh, buttocks, or abdomen; the site of SC injections should be rotated daily to help prevent lipoatrophy.

Pediatric GHD Patients: Generally, a dose of 0.16 to 0.24 mg/kg body weight/week is recommended.

Pediatric PWS Patients: Generally, a dose of 0.24 mg/kg body weight/week is recommended.

Pediatric SGA Patients: Generally, a dose of 0.48 mg/kg body weight/week is recommended.

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IONOSOL B & 5% Dextrose Injection

[July 11, 2001: Abbott]

PRECAUTIONS:

Geriatric Use:

An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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MESTINON (pyridostigmine bromide) Tablets, Timespan Tablets, Syrup, Injection

[July 26, 2001: ICN Pharmaceuticals]

PRECAUTIONS

Pediatric use: Safety and effectiveness in pediatric patients have not been established. Neonates of myasthenic mothers may have transient difficulty in swallowing, sucking, and breathing. Injectable Mestinon may be indicated-by symptomatology and use of the Tensilon (edrophonium chloride) test-until Mestinon Syrup can be taken (See DOSAGE AND ADMINISTRATION).

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NAVANE ( thiothixene) Capsules, Concentrate

[July 31, 2001: Pfizer]

Approval letter provides for labeling changes, specifically modification of labeling text to more clearly state that these agents are indicated for the treatment of schizophrenia. For FPL contact the sponsor.

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NICOTROL NS (nicotine nasal spray) and NICOTROL Inhaler

[July 9, 2001: Pharmacia]

PRECAUTIONS:

Geriatric Use: Clinical Studies of NICOTROL inhaler did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Other reports on clinical experience have not identified differences between older and younger patients. In general, dosage selection for an elderly patient should be cautious, usually starting at the low end of the dosage range reflecting the greater frequency of decreased hepatic, renal or cardiac function, and concomitant disease.

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OCUFEN ( flurbiprofen Na) Opthalmic Solution

[July 30, 2001: Allergan]

DESCRIPTION:

OCUFEN (flurbiprofen sodium opthalmic solution) 0.03% is a sterile topical non-steroidal anti-inflammatory product for opthalmic use.

Contains: Active ingredient: flurbiprofen sodium0.03 %. Preservative: Inactive ingredients thimerosal 0.005%; Inactives: polyvinyl alcohol 1.4%; thimerosal 0.005%; edetate disodium; potassium chloride; sodium chloride; sodium citrate; citric acid hydrochloric acid and/or sodium hydroxide to adjust the pH; and purified water. May also contain hydrochloric acid and/or sodium hydroxide to adjust the pH

PRECAUTIONS:

Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and young patients.

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ORAMORPH (morphine sulfate) Sustained-Release Tablets

[July 13, 2001: Roxane]

CLINICAL PHARMACOLOGY: Pharmacokinetics:

6th paragraph revised to read:

The possible effect of food upon the systemic bioavailability of ORAMORPH SR has not been evaluated. A pharmacokinetic study in normal volunteers indicates that there is little to no effect on the systemic bioavailability of ORAPMORPH SR when administered with food.

8th paragraph revised to read:

When immediate-release oral morphine or ORAMORPH SR is given on a fixed dosing regimen, steady-state is achieved in about one or to two days.

DOSAGE AND ADMINISTRATION

2nd paragraph revised to read:

As with any potent opioid, it is critical to adjust the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience. "Although it is not possible to enumerate every condition that is important to the selection of the initial dose and dosing interval Attention should be given to the following in determining the initial dose of ORAMORPH SR, attention should be given to (1) the daily dose, potency and characteristics of a pure agonist. , or mixed agonist-antagonist, the patient has been taking previously, (2) the reliability of the relative potency estimate to calculate the dose of morphine needed [N.B.: potency estimates may vary with the route of administration], (3) the fact that roughly only 40% of the morphine sulfate in ORAMORPH SR becomes available after pre-systemic metabolization in the intestinal wall and liver, (4) the degree of opioid tolerance, and (5) the general condition and medical status of the patient.

The note "ORAMORPH SR TABLET MUST BE SWALLOWED WHOLE. DO NOT BREAK THE TABLET IN HALF. DO NOT CRUSH OR CHEW. TAKING BROKEN, CHEWED OR CRUSHED TABLETS COULD LEAD TO THE RAPID RELEASE AND ABSORPTION OF A POTENTIALLY TOXIC DOSE OF MORPHINE." is relocated from the beginning of the DOSAGE AND ADMINISTRATION section to DOSAGE AND ADMINISTRATION/ Conversion from ORAMORPH SR to Parentereal Opioids subsection.

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Oxycontin (oxycodone HCl) Tablets

[July 18, 2001: Purdue]

Extensive changes to the labeling. For FPL, contact the sponsor.

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PAMELOR (nortriptyline HCl) Tablets and Syrup

[July 31, 2001: Novartis]

PRECAUTIONS-

Geriatric Use

Clinical studies of Pamelor did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience indicates that, as with other tricyclic antidepressants, hepatic adverse events (characterized mainly by jaundice and elevated liver enzymes) are observed very rarely in geriatric patients and deaths associated with cholestatic liver damage have been reported in isolated instances. Cardiovascular function, particularly arrhythmias and fluctuations in blood pressure, should be monitored. There have also been reports of confusional states following tricyclic antidepressant administration in the elderly. Higher plasma concentrations of the active nortriptyline metabolite, 10-hydroxynortriptyline, have also been reported in elderly patients. As with other tricyclic antidepressants, dose selection for an elderly patient should usually be limited to the smallest effective total daily dose (see DOSAGE AND ADMINISTRATION).

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PROGRAF (tacrolimus) Capsules and Injection

July 25, 2001: Fujisawa

Revisions to the PRECAUTIONS and ADVERSE REACTIONS sections. A new Patient’s Information leaflet is added to the PROGRAF Capsules labeling

PRECAUTIONS

*Drugs That May Decrease Tacrolimus Blood Concentrations:

Anticonvulsants Antibiotics

carbamazepine rifabutin

phenobarbital rifampin

phenytoin

Herbal Preparations

St. John’s Wort

*This table is not all inclusive.

St. John’s Wort (hypericum perforatum) induces CYP3A4 and P-glycoprotein. Since tacrolimus is a substrate for CYP3A4, there is the potential that the use of St. John’s Wort in patients receiving Prograf could result in reduced tacrolimus levels.

ADVERSE REACTIONS

Post Marketing

The following have been reported: increased amylase including pancreatitis, hearing loss including deafness, leukoencephalopathy, thrombocytopenic purpura, hemolytic-uremic syndrome, acute renal failure, Stevens-Johnson syndrome, stomach ulcer, glycosuria, and cardiac arrhythmia and gastroenteritis.

Patient Information

PROGRAF

(tacrolimus capsules)

Read this important information before you start using PROGRAF [PRO-graf] and each time you refill your prescription. This summary does not take the place of talking with your transplant team.

Talk with your transplant team if you have any questions or want more information about PROGRAF. You can also visit the Fujisawa Internet site at www.fujisawa.com.

What Is PROGRAF?

PROGRAF is a medicine that slows down the body’s immune system. For this reason, it works as an anti-rejection medicine.

PROGRAF helps patients who have had a liver or kidney transplant protect their new organ and prevent it from being rejected by the body.

How Does PROGRAF Protect My New Organ?

The body’s immune system protects the body against anything that it does not recognize as part of the body. For example, when the immune system detects a virus or bacteria it tries to get rid of it to prevent infection. When a person has a liver or kidney transplant, the immune system does not recognize the new organ as a part of the body and tries to get rid of it, too. This is called "rejection." PROGRAF protects your new organ by slowing down the body’s immune system.

Who Should Not Take PROGRAF?

Do not take PROGRAF if you are allergic to any of the ingredients in PROGRAF. The active ingredient is tacrolimus. Ask your doctor or pharmacist about the inactive ingredients.

Tell your transplant team about all your health conditions, including kidney and/or liver problems. Discuss with your transplant team the use of any other prescription and non- prescription medications, including any herbal or over-the-counter remedies that you may take while on Prograf. In very rare cases you may not be able to take Prograf.

Tell your transplant team if you are pregnant, planning to have a baby or are breastfeeding. Talk with your transplant doctor about possible effects PROGRAF could have on your child. Do not nurse a baby while taking PROGRAF since the medicine will be in the breast milk.

How Should I Take PROGRAF?

PROGRAF can protect your new kidney or liver only if you take the medicine correctly.

Your new organ needs around-the-clock protection so your body does not reject it. The success of your transplant depends a great deal upon how well you help PROGRAF do its job. Here is what you can do to help.

Take PROGRAF exactly as prescribed

It is important to take PROGRAF capsules exactly as your transplant team tells you to.

PROGRAF comes in several different strength capsules--0.5 mg, 1 mg and 5 mg. Your transplant team will tell you what dose to take and how often to take it. Your transplant team may adjust your dose until they find what works best for you.

Never change your dose on your own. Never stop taking PROGRAF even if you are feeling well. However, if you feel poorly on Prograf, discuss this with your transplant team.

Take PROGRAF two times a day, 12 hours apart

Try to pick times that will be easy for you. For example, if you take your first dose at 7:00 a.m. you should take your second dose at 7:00 p.m. Do not vary the times. You must take PROGRAF at the same times every day. If you decide to take PROGRAF at 7:00 a.m. and 7:00 p.m., take it at these same times every day. This will make sure you always have enough medicine in your body to give your new organ the around-the-clock protection it needs.

Take PROGRAF the same way each day

Some people prefer to take PROGRAF with food to help reduce possible stomach upset. Whether you take PROGRAF with or without food, it is important to take PROGRAF the same way every day. For example, if you take PROGRAF with food, you should always take it with food. Do not eat grapefruit or drink grapefruit juice in combination with your medicine unless your transplant teams approves. Do not change the way you take this medicine without telling

your transplant team, since this could change the amount of protection you get from PROGRAF.

Take all your doses

It is important to take your doses twice a day exactly as prescribed by your doctor. If you miss even two doses, your new liver or kidney could lose the protection it needs to defend itself against rejection by your body.

If you miss one dose, do not try to catch up on your own. Call your transplant team right away for instructions on what to do.

If you travel and change time zones, be sure to ask your transplant team how to adjust your dosage schedule so your new organ does not lose its protection.

Plan ahead so that you do not run out of PROGRAF

Make sure you have your prescription for PROGRAF refilled and at home before you need it. Circle the date on a calendar when you need to order your refill. Allow extra time if you receive your medicines through the mail.

Your transplant team will follow your progress and watch for early signs of side effects. This is why you will have blood tests done often after your transplant. On the days you are going to have a blood test to measure the amount of PROGRAF in your body, your transplant team may ask you not to take your morning dose until after the blood sample is taken. Check with your transplant team before skipping this dose.

Can Other Medicines Affect How PROGRAF Works?

Some medicines and alcohol can affect how well PROGRAF works. After you start taking PROGRAF:

• Be sure to tell your transplant team, family doctor, dentist, pharmacist and any other health care professional treating you the names of all the medicines you are taking. This includes PROGRAF as well as all other prescription medicines and non- prescription medicines, natural or herbal remedies, nutritional supplements, and vitamins. This is the only way that your health care team can help prevent drug interactions that could be serious.

• Always check with your transplant team before you start taking any new medicine.

• While you are taking PROGRAF, do not get any vaccinations without your transplant team’s approval. The vaccination may not work as well as it should.

• Liver transplant patients, including those taking PROGRAF, should not drink alcohol.

What Are the Possible Side Effects of PROGRAF?

Tell your transplant team right away if you think you might be having a side effect. Your transplant team will decide if it is a medicine side effect or a sign that has nothing to do with the medicine but needs to be treated. Infection or reduced urine can be signs of serious problems that you should discuss with your transplant team.

Your transplant team will also follow your progress and watch for the early signs of any side effects. This is why you will have blood tests done often during the first few months after your transplant. On the days you are going to have a blood test to measure the amount of PROGRAF in your body, your transplant team may ask you not to take your morning dose until after the blood sample is taken. Check skipping this dose.

For Kidney Transplant Patients:

The most common side effects of PROGRAF for kidney transplant patients are infection, headache, tremors (shaking of the body), diarrhea, constipation, nausea, high blood pressure, changes in the amount of urine, and trouble sleeping.

Less common side effects are abdominal pain (stomach pain), numbness or tingling in your hands or feet; loss of appetite; indigestion or "upset stomach"; vomiting; urinary tract infections; fever; pain; swelling of the hands, ankles or legs; shortness of breath or trouble breathing; cough; leg cramps; heart "fluttering", palpitations or chest pain; unusual weakness or tiredness; dizziness; confusion; changes in mood or emotions; itchy skin, skin rash, and diabetes.

For Liver Transplant Patients:

The most common side effects of PROGRAF for liver transplant patients are headache, tremors (shaking of the body), diarrhea, high blood pressure, nausea and changes in the amount of urine.

Less common side effects are numbness or tingling in your hands or feet; trouble sleeping; constipation; loss of appetite; vomiting; urinary tract infections; fever; pain (especially in the back or abdomen [stomach area]); swelling of the hands, ankles, legs or abdomen; shortness of breath or trouble breathing; cough; unusual bruising; leg cramps; heart "fluttering" or palpitations; unusual weakness or tiredness; confusion; changes in mood or emotions; itchy skin, and skin rash.

Be sure to tell your transplant team right away if you notice that you are thirstier than usual, have to urinate more often, have blurred vision or seem to get confused. These may be the early signs of high blood sugar or diabetes.

All anti-rejection medicines, including PROGRAF, suppress your body’s immune system. As a result, they may increase your chances of getting infections and some kinds of cancer, including skin and lymph gland cancer (lymphoma). As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high sun protection factor (SPF $ 15). However, getting cancer from taking an anti-rejection medicine is not common. Talk with your transplant team about any concerns or questions you have.

How Should I Store PROGRAF?

Store PROGRAF in a dry area at room temperature (77º F/25º C). Do not let the medicine get colder than 59º F (15º C) or hotter than 86ºF (30º C). For instance, do not leave PROGRAF in the glove compartment of your car in the summer or winter. Do not keep PROGRAF capsules in a hot or moist place such as the medicine cabinet in the bathroom.

General Advice about Prescription Medicines

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use PROGRAF for a condition for which it was not prescribed. Do not give PROGRAF to other people.

This leaflet summarizes the most important information about PROGRAF. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about PROGRAF that is written for health professionals. You can also visit the Fujisawa Internet site at www.fujisawa.com.

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PROTONIX (pantoprazole Na) I.V.

[July 3, 2001: Wyeth-Ayerst]

DOSAGE AND ADMINISTRATION

Added at the end of the fourth paragraph .

Treatment with PROTONIX I.V. for Injection should be discontinued as soon as the patient is able to resume treatment with PROTONIX Delayed-Release Tablets. Safety and efficacy of PROTONIX I.V. for Injection as a treatment for GERD for more than 10 days have not been demonstrated (see INDICATIONS AND USAGE). Also, data on safe and effective dosing for other conditions (including life-threatening upper gastrointestinal bleeds) are not available. PROTONIX I.V. 40 mg once daily does not raise gastric pH to levels sufficient to contribute to the treatment of such life-threatening conditions.

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PROTONIX (pantoprazole Na) Delayed-release Tablets

[July 20, 2001: Wyeth-Ayerst]

OVERDOSAGE

revised

Some reports of overdosage with pantoprazole have been received. A spontaneous report of a suicide involving an overdosage of pantoprazole (560 mg) has been received; however, the death was more reasonably attributed to the unknown doses of chloroquine and zopiclone which were also taken since two other reported cases of pantoprazole overdosage involved similar amounts of pantoprazole (400 and 600 mg) with no adverse effects observed. One patient in a flexible dosing study of refractory peptic ulcer disease received a dose of 320 mg per day for 3 months; treatment was well tolerated. Doses of up to 240 mg per day, given intravenously for seven days, have been administered to healthy subjects and have been well tolerated."

Experience in patients taking very high doses of pantoprazole is limited. There have been spontaneous reports of overdosage with pantoprazole including a suicide in which pantoprazole 560 mg and undetermined amounts of chloroquine and zopiclone were also ingested. There have also been spontaneous reports of patients taking similar amounts of pantoprazole (400 and 600 mg with no adverse effects."

Pantoprazole is not removed by hemodialysis. In case of overdosage, treatment should be symptomatic and supportive.

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REBETOL (ribavirin) Capsules

[July 25, 2001: Schering]

New package configuration of a stand-alone 84 capsule container of ribavirin 200-mg capsules, along with appropriate labeling. For FPL contact the sponsor.

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Sulfamylon (mafenide acetate) 5% Topical Solution

[July 12, 2001: Mylan ]

Revisions to the Carton/Container label, and DESCRIPTION, DOSAGE AND ADMINISTRATION, and HOW SUPPLIED sections of the labeling.

In the DESCRIPTION, DOSAGE AND ADMINISTRATION, and HOW SUPPLIED sections, reference to this product is changed to "sterile" product.

The carton and the container labels, the storage statements are revised.

This solution may be held for up to 28 days if stored in unopened containers. Once a container is opened, any unused solution must be discarded within 48 HOURS.

Store solution at 20° to 25°C (68° to 77°F) excursions 15° to 30°C (59° to 86° F).

DESCRIPTION and DOSAGE AND ADMINISTRATION sections

Storage information revised to read

Rreconstituted solution may be held up to 28 days after preparation if stored in unopened containers. ONCE A CONTAINER IS OPENED, ANY UNUSED PORTION SHOULD BE DISCARDED AFTER 48 HOURS. Store the reconstituted solution at 20° to 25° C (68° to 77° F). Limited storage periods at 15° to 30° C (59° to 86° F) are acceptable.

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TAMIFLU (oseltamivir phosphate) Capsules and Suspension

[July 24, 2001: Roche]

Revised DESCRIPTION, CLINICAL PHARMACOLOGY, INDICATION AND USAGE, PRECAUTIONS, ADVERSE EVENTS, OVERDOSAGE, DOSAGE AND ADMINISTRATION, and HOW SUPPLIED sections, and Patient’s Information leaflet. For FPL contact the sponsor.

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VIDEX (didanosine) Tablets, Buffered Powder for Oral Solution, and Pediatric Powder

[July 27, 2001: Bristo-Myers]

PRECAUTIONS

Drug Interactions/Allopurinol

Added

In 14 healthy volunteers, the mean AUC of didanosine increased approximately 2-fold when a 300-mg dose of allopurinol (daily for 7 days) was given with a single 400- mg dose of VIDEX. Coadministration of didanosine and allopurinol is not recommended.

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ZADITOR (ketotifen fumarate) Opthalmic Solution

[July 20, 2001: Novartis]

DOSAGE AND ADMINISTRATION

The recommended dose is one drop in the affected eye(s) twice daily, every 8 to 12 hours.

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ZINACEF(CEFUROXIME Na)

July 12, 2001: GlaxoSmithKline

PRECAUTIONS

added

General

Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous Vitamin K administered as indicated.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Although no long-term studies in animals have been performed to evaluate carcinogenic potential, no mutagenic potential of cefuroxime was found in standard laboratory tests.

Although lifetime studies in animals have not been performed to evaluate carcinogenic potential, no mutagenic activity was found for cefuroxime axetil in the mouse lymphoma assay and a battery of bacterial mutation tests. Positive results were obtained in an in vitro chromosome aberration assay, however, negative results were found in an in vivo micronucleus test at

doses up to 10 g/kg. Reproduction studies in mice at doses up to 3200 mg/kg per day (3.1 times the recommended maximum human dose based on mg/m 2 ) have revealed no impairment of fertility.

Reproductive studies revealed no impairment of fertility in animals."

Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in mice and rabbits at doses up to 60 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cefuroxime. at doses up to 6400 mg/kg per day (6.3 times the recommended maximum human dose based on mg/m 2 ) and rabbits at doses up to 400 mg/kg per day (2.1 times the recommended maximum human dose based on mg/m 2 ) and have revealed no evidence of impaired fertility or harm to the fetus due to cefuroxime. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed."

ADVERSE REACTIONS

Observed During Clinical Practice:

Neurologic. Seizure

Cephalosporin-class Adverse Reactions

Several cephalosporins, including ZINACEF ® , have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced (see DOSAGE AND ADMINISTRATION). If seizures associated with drug therapy should occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

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