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

(Posted: 10/10/2001)

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Additions: Color green and underlined: text addition example
Deletions: Color red and strikethrough: text deletion example

 

ACIPHEX (rabeprazole Na) Tablets
[August 15, 2001: Eisai]

ADVERSE REACTIONS

Post-Marketing Adverse Events:

Post-Marketing Adverse Events: Additional adverse events reported from marketing experience with rabeprazole sodium are: sudden death, coma and hyperammonemia, jaundice, rhabdomyolysis, disorientation and delirium, anaphylaxis, angioedema, bullous and other drug eruptions of the skin, interstitial pneumonia, and TSH elevations. In most instances, the relationship to rabeprazole sodium was unclear. In addition, agranulocytosis, hemolytic anemia, leukopenia, pancytopenia, and thrombocytopenia have been reported.

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ADENOSCAN (adenosine) Injection
[August 31, 2001: Fujisawa]

PRECAUTIONS/Drug Interactions:

First sentence, second paragraph:

"alkylxanthines" has been changed to "methylxanthines"

PRECAUTIONS/Carcinogenesis, Mutagenesis, Impairment of Fertility:

The second paragraph has been changed from:

Adenosine, however, like other nucleosides at millilmolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations. In rats and mice, adenosine administered intraperitoneally once a day for five days at 50, 100, and 150 mg/kg [10-30 (rats) and 5-15 (mice) times human dosage on a mg/M 2 basis] caused decreased spermatogenesis and increased numbers of abnormal sperm, a reflection of the ability of adenosine to produce chromosomal damage.

To the following:

Adenosine, however, like other nucleosides at millimolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations.

Fertility studies in animals have not been conducted with adenosine.

Geriatric Use:

Clinical studies of Adenoscan did not include sufficient numbers of subjects aged younger than 65 years to determine whether they respond differently. Other reported experience has not revealed clinically relevant differences of the response of elderly in comparison to younger patients. Greater sensitivity of some older individuals, however, cannot be ruled out.

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AGGRENOX (aspirin/extended-release dipyridamole) Capsules
[August 10, 2001:Boehringer Ingelheim]

CLINICAL PHARMACOLOGY:

Pharmacokinetics/Dipyridamole/Effect of Food:

No food effect study has been conducted with the AGGRENOX formulation.

To the following:

When AGGRENOX capsules were taken with a high fat meal, dipyridamole peak plasma levels (Cmax) and total absorption (AUC) were decreased at steady-state by 20-30% compared to fasting. Due to the similar degree of inhibition of adenosine uptake at these plasma concentrations, this food effect is not considered clinically relevant.

CLINICAL PHARMACOLOGY:

Pharmacokinetics/Aspirin:

Effect of Food: When AGGRENOX capsules were taken with a high fat meal, there was no difference for aspirin in AUC at steady-state, and the approximately 50% decrease in Cmax was not considered clinically relevant based on a similar degree of cyclo-oxygenase inhibition comparing the fed and fasted state.

 

DOSAGE AND ADMINISTRATION:

Addition of the following sentence as the last sentence of the first paragraph:

AGGRENOX capsules may be administered with or without food.

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AREDIA (pamidronate disodium) Injection
[August 17, 2001, Novartis]

CLINICAL PHARMACOLOGY

Pharmacodynamics

Clinical Trials

In a fourth multicenter, randomized, double-blind trial, 103 patients with cancer and hypercalcemia (corrected serum calcium > 12.0 mg/dl) received 90 mg of Aredia as a 2-hour infusion. The mean baseline corrected serum calcium was 14.0 mg/dl. Patients were not required to receive IV hydration prior to drug administration, but all subjects did receive at least 500 ml of IV saline hydration concomitantly with the pamidronate infusion. By day 10 after drug infusion, 70% of patients had normal corrected serum calcium levels (< 10.8 mg/dl).

Unlike Aredia 60 mg, the drug has not been investigated in a controlled clinical trial employing a 90 mg dose infused over a 4 hour period.

 

ADVERSE REACTIONS

Clinical Studies

Hypercalcemia of Malignancy

Second paragraph revised -

Drug-related local soft-tissue symptoms (redness, swelling or induration and pain on palpation) at the site of catheter insertion were most common (18%) in patients treated with 90 mg of Aredia. When all on-therapy events are considered, that rate rises to 41%. Symptomatic treatment resulted in rapid resolution in all patients.

Fourth paragraph revised and a fifth paragraph added -

Five of 231 patients (2%) who received Aredia during the four U.S. controlled hypercalcemia clinical studies were reported to have had seizures, 2 of whom had preexisting seizure disorders. None of the seizures were considered to be drug-related by the investigators. However, a possible relationship between the drug and the occurrence of seizures cannot be ruled out. It should be noted that in the saline arm 1 patient (4%) had a seizure.

There are no controlled clinical trials comparing the efficacy and safety of 90 mg Aredia over 24 hours to 2 hours in patients with hypercalcemia of malignancy. However, a comparison of data from separate clinical trials suggests that the overall safety profile in patients who received 90 mg ArediaÒ over 24 hours is similar to those who received 90 mg Aredia over 2 hours.. The only notable differences observed were an increase in the proportion of patients in the ArediaÒ 24 hour group who experienced fluid overload and electrolyte/mineral abnormalities.

DOSAGE AND ADMINISTRATION

Hypercalcemia of Malignancy

Moderate Hypercalcemia

The recommended dose of Aredia in moderate hypercalcemia (corrected serum calcium* of approximately 12-13.5 mg/dL) is 60 to 90 mg given as a SINGLE DOSE, intravenous infusion over 2 to 24 hours Longer infusions (i.e., > 2 hours) may reduce the risk for renal toxicity, particulary in patients with pre-existing renal insufficiency. The 60 mg dose is given as an initial, SINGLE DOSE, intravenous infusion over at least 4 hours. The 90 mg dose must be given by an initial, SINGLE DOSE, intravenous infusion over 24 hours. For select patients 90 mg can be infused over 2 to 24 hours.

Severe Hypercalcemia

The recommended dose of Aredia in severe hypercalcemia (corrected serum calcium*>13.5 mg/dL) is 90 mg given as a SINGLE DOSE, intravenous infusion over 2 to 24 hours. Longer infusions (i.e., > 2 hours) may reduce the risk for renal toxicity, particularly in patients with pre-existing renal insufficiency. The 90 mg dose must be given by an initial, SINGLE DOSE, intravenous infusion over 24 hours. For select patients 90 mg can be infused over 2 to 24 hours.

*Albumin-corrected serum calcium (CCa,mg/dL) = serum calcium, mg/dL + 0.8 (4.0-serum albumin, g/dL).

Preparation of Solution

Hypercalcemia of Malignancy

The daily dose must be administered as an intravenous infusion over at least -4- 2 to 24 hours for the 60-mg dose, and 2 to 24 hours for the and 90-mg doses. The recommended dose should be diluted in 1000 mL of sterile 0.45% or 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP. This infusion solution is stable for up to 24 hours at room temperature.

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AZULFIDINE EN-TABS (sulfasalazine) Tablets
[August 16, 2001, Pharmacia & Upjohn]

PRECAUTIONS:

Drug Interactions:

Second and third paragraphs added -

When daily doses of sulfasalazine 2 g and weekly doses of methotrexate 7.5 mg were coadministered to 15 rheumatoid arthritis patients in a drug-drug interaction study, the pharmacokinetic disposition of the drugs was not altered.

Daily doses of sulfasalazine 2g (maximum 3g) and weekly doses of methotrexate 7.5mg (maximum 15 mg) were administered alone or in combination to 310 rheumatoid arthritis patents in two controlled 52-week clinical studies. The overall toxicity profile of the combination revealed an increased incidence of gastrointestinal adverse events, especially nausea, when compared to the incidence associated with either drug administered alone.

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BIAXIN XL FILMTABS (clarithromycin) Tablets
[August 2, 2001: Abbott]

INDICATIONS AND USAGE:

Adults (BIAXIN Filmtab tablets and Granules for oral suspension):

Community-Acquired Pneumonia due to Haemophilus influenzae, Mycoplasma pneumoniae, Streptococcus pneumoniae, or Chlamydia pneumoniae (TWAR)

Children (BIAXIN Filmtabs and Granules for oral suspension):

Community-Acquired Pneumonia due to Mycoplasma pneumoniae, Streptococcus pneumoniae, or Chlamydia pneumoniae (TWAR)

Adults (BIAXIN XL Filmtab tablets):

Community-Acquired Pneumonia due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Streptococcus pneumoniae, Chlamydia pneumoniae (TWAR), or Mycoplasma pneumoniae

ADVERSE REACTIONS:

First, third and fifth paragraphs -

The majority of side effects observed in clinical trials were of a mild and transient nature. Fewer than 3% of adult patients without mycobacterial infections and fewer than 2% of pediatric patients without mycobacterial infections discontinued therapy because of drug-related side effects. Fewer than 3% 2% of adult patients taking BIAXIN XL tablets discontinued therapy because of drug-related side effects.

The most frequently reported events in adults taking BIAXIN XL were diarrhea (6%), abnormal taste (6%) (7%), and nausea (3%). Most of these events were described as mild or moderate in severity. Of the reported adverse events, less than 2% 1% were described as severe.

In community-acquired pneumonia studies conducted in adults comparing clarithromycin to erythromycin base or erythromycin stearate, there were fewer adverse events involving the digestive system in clarithromycin-treated patients compared to erythromycin-treated patients (13% vs 32%; p<0.01). Twenty percent of erythromycin-treated patients discontinued therapy due to adverse events compared to 4% of clarithromycin-treated patients.

DOSAGE AND ADMINISTRATION:

ADULT DOSAGE GUIDELINES

BIAXIN Tablets
BIAXIN XL Tablets

Infection
Dosage
(q12h)
Duration
(days)
Dosage
(q24h)
Duration
(days)
Community-Acquired Pneumonia due to
H. influenzae
250 mg
7
2 x 500 mg
7
H. parainfluenzae
-
-
2 x 500 mg
7

M. catarrhalis
-
-
2 x 500 mg

7
S. pneumoniae
250 mg
7-14
2 x 500 mg
7
C. pneumoniae
250 mg
7-14
2 x 500 mg
7
M. pneumoniae
250 mg
7-14
2 x 500 mg
7

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CEREBYX (fosphenytoin) Injection
[August 13, 2001: Parke-Davis]

Labeling provides for revision of carton/container labeling to reflect

concentration as a function of total container content rather than content per mL. This change was effected in response to several reports of overdose where health care providers mistakenly assumed that the amount of Cerebyx ® per mL was the final amount provided by the total vial. Contact the company for a copy of the new carton/container labeling.

OVERDOSAGE:

There is no experience with Cerebyx overdosage in humans.

Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with fosphenytoin.

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CEREZYME (imiglucerase) Injection
[August 13, 2001: Genzyme]

WARNINGS:

[Not in 2000 PDR]

Last paragraph added:

Anaphylactoid reaction has been reported in less than 1% of the patient population. Further treatment with imiglucerase should be conducted with caution. Most patients have successfully continued therapy after a reduction in rate of infusion and pretreatment with antihistamines and/or corticosteroids.

PRECAUTIONS:

General

[Not in 2000 PDR]

New first pargraph:

In less than 1% of the patient population, pulmonary hypertension has also been observed during treatment with Cerezyme. Pulmonary hypertension is a known complication of Gaucher disease, and has been observed both in patients receiving and not receiving Cerezyme. No causal relationship with Cerezyme has been established. Patients with respiratory symptoms should be evaluated for the presence of pulmonary hypertension.

ADVERSE REACTIONS:

[Not in 2000 PDR]

Revisions to first, second and third paragraphs:

Experience in patients treated with Cerezyme (imiglucerase for injection) has revealed that approximately 8.5% 9.8% of patients experienced adverse events which were judged to be related to Cerezyme administration…

Symptom suggestive of hypersensitivity have been noted in approximately 4.0% 4.4% of patients. Onset of such symptoms has occurred during or shortly after infusion; these symptoms include pruritus, flushing, urticaria/angioedema, chest discomfort, respiratory symptoms, cyanosis and hypotension. Anaphylactoid reaction has also been reported. (see WARNINGS). Each of these events were found to occur in < 1% of the total patient population. Pre-treatment with antihistamines and/or corticosteroids and reduced rate of infusion has allowed continued use of Cerezyme in most patients.

Additional adverse reactions that have been reported in approximately 4.5% 5.4% of patients treated with Cerezyme include: nausea, abdominal pain, diarrhea, rash…

DOSAGE AND ADMINISTRATION:

Second paragraph revised:

Cerezyme should be stored at 2-8° C. (36-46° F.). After reconstitution, Cerezyme should be inspected visually before use. Being a protein solution, slight flocculation (described as thin translucent fibers) occurs occasionally after dilution. The diluted solution may be filtered through an in-line low protein-binding 0.2 µm filter during administration. Any vials exhibiting opaque particles or discoloration should not be used. DO NOT USE Cerezyme

after the expiration date on vial.

Fourth paragraph, third sentence revised:

Cerezyme is administered by intravenous infusion over 1-2 hours or at a rate between 0.5 – 1.0 unit per kg body weight per minute. Aseptic techniques should be used…

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CLOZARIL (clozapine) Tablets
[August 29, 2001: Novartis]

INDICATIONS AND USAGE:

First paragraph - "antipsychotic" replaced with "for schizophrenia" and "antipsychotic drugs" replaced with "treatments for schizophernia".

CONTRAINDICATIONS:

Clozaril (clozapine) is contraindicated in patients with severe renal disease, including acute renal failure. In addition, Clozaril is poorly dialyzable because it is highly protein bound. Therefore patients on dialysis should not take Clozaril (clozapine).

WARNINGS:

General:

First paragraph - "ANTIPSYCHOTIC" replaced with "FOR SCHIZOPHRENIA".

PRECAUTIONS:

Anticholinergic Toxicity

Prostate

Clozaril (clozapine) has potent anticholinergic effects and care should be exercised in using this drug in the presence of prostatic enlargement.

Drug Interactions

Pharmacodynamic-related interactions -

Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, and isolated cases of delirium where Clozaril (clozapine) was coadministered with valproic acid have been reported.

Clozaril (clozapine) may potentiate the hypotensive effects of antihypertensive drugs and the anticholinergic effects of atropine-like drugs. The administration of epinephrine should be avoided in the treatment of drug induced hypotension because of a possible reverse epinephrine effect. - moved from Pharmacokinetic-related interactions.

Pharmacokinetic-related interactions -

Clozapine is a substrate for many CYP 450 isoenzymes, in particular 1A2, 2D6, and 3A4. The risk of metabolic interactions caused by an effect on an individual isoform is therefore minimized. Nevertheless, caution should be used in patients receiving concomitant treatment with other drugs which are either inhibitors or inducers of these enzymes. Because Clozaril (clozapine) is highly bound to serum protein, the administrationof Clozaril (clozapine) to a patient taking another drug which is highly bound to protein (e.g., warfarin, digitoxin) may cause an increase in plasma concentrations of these drugs, potentially resulting in adverse effects. Conversely, adverse effects may result from displacement of protein bound Clozaril (clozapine) by other highly bound drugs.

Cimetidine and erythromycin may both increase plasma levels of Clozaril (clozapine), potentially resulting in adverse effects. Concomitant administration of drugs known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine. Phenytoin, nicotine, and rifampin may decrease Clozaril (clozapine) plasma levels, resulting in a decrease in effectiveness of a previously effective Clozaril (clozapine) dose.

Concomitant administration of drugs known to inhibit the activity of cytochrome P450 isoenzymes may increase the plasma levels of clozapine. Cimetidine, caffeine, and erythromycin may increase plasma levels of Clozaril (clozapine), potentially resulting in adverse effects. Moved from third paragraph - Although concomitant use of Clozaril (clozapine) and carbamazepine is not recommended, it should be noted that discontinuation of concomitant carbamazepine administration may result in an increase in Clozaril (clozapine) plasma levels.

ADVERSE REACTIONS:

Postmarketing Clinical Experience

Vision Disorders: narrow angle glaucoma

DOSAGE AND ADMINISTRATION

Initial Treatment

Second paragraph - "antipsychotic" replaced with "for schizophrenia".

Therapeutic Dose Adjustment

Second paragraph - Clozaril (clozapine) can cause EEG changes, including the occurrence of spike and wave complexes. It lowers the seizure threshold in a dose- dependent manner and may induce myoclonic jerks or generalized seizures. These symptoms may be likely to occur with rapid dose increase in patients with pre-existing epilepsy. In this case, the dose should be reduced and, if necessary, anticonvulsant treatment initiated.

Maintenance Treatment

"antipsychotic" replaced with "used to treat schizophrenia"

Discontinuation of Treatment

In the event of planned termination of Clozaril (clozapine) therapy, gradual reduction in dose is recommended over a 1-2 week period. However, should a patient's medical condition require abrupt discontinuation (e.g., leukopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as headache, nausea, vomiting, and diarrhea.

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COZAAR (losartan potassium) Tablets &
HYZAAR (losartan potassium/hydrochlorothiazide) Tablets
[August 24, 2001: Merck]

ADVERSE REACTIONS:

Post-Marketing Experience

Hypersensitivity: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported rarely in patients treated with losartan; some of these patients previously

experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schoenlein purpura, has been reported with losartan. Anaphylactic reactions have been reported.

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Cupric Chloride Injection
[August 29, 2001: Abbott]

CLINICAL PHARMACOLOGY:

Osteoporosis - Added to the list of copper deficiency symptoms.

Pediatric Use:

See DOSAGE AND ADMINISTRATION section. There are limited data in infants weighing less than 1500 grams.

DOSAGE AND ADMINISTRATION:

The statement following the sentence:

"For pediatric patients, the suggested additive…."

Infants weighing less than 1500 gm may have increased requirements because of their low body reserves and increased requirements for growth.

OVERDOSAGE:

Copper toxicity can also result in hemolysis and liver toxicity, including hepatic necrosis which may be fatal Added prior to the last sentence "D-penicillamine has been reported…."

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Dextrose 5% & Sodium Chloride 0.225% w/ Potassium Chloride 0.075%, 0.224% & 0.3% Injection
&
Dextrose 5% & Sodium Chloride 0.3% w/ Potassium Chloride 0.075%, 0.15% & 0.224% Injection
[August 24, 2001: Abbott]

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differencesin 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. Sodium and potassium ions are 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 function, care should be taken in dose selection, and it may be useful to monitor renal function.

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DILAUDID (hydromorphone HCl) Oral Liquid & Tablets
[August 22, 2001: Knoll]

PRECAUTIONS:

Special Risk Patients

A third paragraph is added as follows:

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. 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 and PRECAUTIONS)."

SAFETY AND HANDLING INSTRUCTIONS:

First paragraph, second sentence:

…..DILAUDID ORAL LIQUID should be treated by removal of any

contaminated clothing and rinsing the affected area with cool water.

HOW SUPPLIED:

STORAGE:

DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS should be stored at 15 0 -25 0 C (590-77 0 F). Protect from light.

Changed to:

Store at 25 0 C (77 0 F); excursions permitted to 15 0 -30 0 C (59 0 -86 0 F). [See USP Controlled Room Temperature].

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DOPRAM (doxapram HCl) Injection
[August 23 , 2001: Wyeth-Ayerst]

INDICATIONS AND USAGE

Postanesthesia.

To pharmacologically stimulate deep breathing in the so-called " stir-up " regimen in the

postoperative patient. (A quantitative method of assessing oxygenation, such as pulse oximetry, is recommended.) (Simultaneous administration of oxygen is desirable.)

Chronic pulmonary disease associated with acute hypercapnia.

Doxapram is indicated as a temporary measure in hospitalized patients with acute respiratory insufficiency superimposed on chronic obstructive pulmonary disease. Its use should be for a short period of time (approximately 2 hours see DOSAGE AND ADMINISTRATION) as an aid in the prevention of elevation of arterial CO2 tension during the administration of oxygen. It should not be used in conjunction with mechanical ventilation.

CONTRAINDICATIONS

Due to its benzyl alcohol content, Dopram Injectable is contraindicated should not be used in neonates newborns.

(See WARNINGS and PRECAUTIONS, Pediatric use.

WARNINGS

Doxapram should not be used in conjunction with mechanical ventilation.

This product contains benzyl alcohol as a preservative. Benzyl alcohol has been associated with a fatal "gasping syndrome" in neonates (see CONTRAINDICATIONS and PRECAUTIONS, Pediatric use.)

In postanesthetic use.

a. Doxapram is neither an antagonist to muscle relaxant drugs nor a specific narcotic antagonist. More specific tests (e.g., peripheral nerve stimulation, airway pressures, head-lift, pulse oximetry, and end-tidal carbon dioxide) to assess adequacy of ventilation are recommended before administering doxapram. Adequacy of airway and oxygenation must be assured prior to doxapram administration.

e. In patients who have received general anesthesia utilizing a volatile agent known to sensitize the myocardium to catecholamines, administration of doxapram should be delayed until the volatile agent has been excreted in order to lessen the potential for arrhythmias, including ventricular tachycardia and ventricular fibrillation (see PRECAUTIONS, Drug interactions.)

PRECAUTIONS

General.

c. Monitoring of the blood pressure, pulse rate, and deep tendon reflexes is recommended to prevent overdosage.

g. Anticonvulsants such as intravenous short-acting barbiturates, along with oxygen and resuscitative equipment should be readily available to manage overdosage manifested by excessive central nervous system stimulation. Slow administration of the drug and careful observation of the patient during administration and for some time subsequently are advisable. These precautions are to assure that the protective reflexes have been restored and to prevent possible post-hyperventilation or hypoventilation.

In chronic obstruction pulmonary disease.

b. Arterial blood gases should be drawn prior to the initiation of doxapram infusion and oxygen administration, then at least every 1/2 hour during the infusion period to prevent development of CO2 retention and acidosis in patients with chronic obstructive pulmonary disease with acute hypercapnia. Doxapram administration does not diminish the need for careful monitoring of the patient or the need for supplemental oxygen in patients with acute respiratory failure. Doxapram should be stopped if the arterial blood gases deteriorate, and mechanical ventilation initiated.

DRUG INTERACTIONS:

Third paragraph:

In patients who have received general anesthesia utilizing a volatile agent anesthetics known to sensitize the myocardium to catecholamines, such as halothane, cyclopropane and enflurane, administration initiation of doxapram therapy should be delayed until the volatile agent has been excreted in order to lessen the potential for arrhythmias, including ventricular tachycardia and ventricular fibrillation (see WARNINGS) for at least 10 minutes following discontinuance of anesthesia, since an increase in epinephrine release has been noted with doxapram.

Pediatric use.

Safety and effectiveness in pediatric patients below the age of 12 years have not been established. This product contains benzyl alcohol as a preservative. Benzyl alcohol has been associated with a fatal "gasping syndrome" in neonates (see CONTRAINDICATIONS and WARNINGS). The "gasping syndrome", characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine, has been associated with exposure to benzyl alcohol in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal

failure, hypotension, bradycardia, and cardiovascular collapse.

The use of the preservative benzyl alcohol in the newborn has been associated with metabolic, CNS, respiratory, circulatory, and renal dysfunction. Safety and effectiveness in children below the age of 12 years have not been established.

Premature neonates given doxapram doses of 2 to 2.5 mg/kg/h have developed irritability, jitteriness, hyperglycemia, glucosuria, abdominal distension, increased gastric residuals, vomiting, erratic limb movements, excessive crying, disturbed sleep, and, in premature neonates with risk factors such as perinatal asphyxia and intracerebral hemorrhage, seizures, and second- degree heart block caused by QT prolongation. In all instances, doxapram was administered following administration of xanthine derivatives such as aminophylline or theophylline

ADVERSE REACTIONS

The following Adverse reactions reported coincident with the administration of Dopram include: have been reported:

3. Cardiovascular.

Phlebitis, variations in heart rate, lowered T-waves, arrhythmias (including ventricular tachycardia and ventricular fibrillation), chest pain, tightness in chest. A mild to moderate increase in blood pressure is commonly noted and may be of concern in patients with severe cardiovascular diseases.

5. Genitourinary.

Stimulation of urinary bladder with spontaneous voiding; urinary retention. Elevation of BUN and albuminuria. have also been observed [text relocated from #6 below]

6. Hemic and Lymphatic. Laboratory determinations.

A decrease in hemoglobin, hematocrit, or red blood cell count has been observed in postoperative patients. In the presence of pre-existing leukopenia, a further decrease in WBC has been observed following anesthesia and treatment with doxapram hydrochloride. Elevation of BUN and albuminuria have also been observed. As some of the patients cited above had received mukltiple drugs concomitnatly, a cause and effect relationship could not be determined.

DOSAGE AND ADMINISTRATION

In postanesthetic use.

By infusion.

The solution is prepared by adding 250 mg of doxapram (12.5 mL) to 250 mL of dextrose 5% or 10% in water or normal saline solution.

METHOD TWO

By Intermittent I.V. Infusion

Chronic obstructive pulmonary disease associated with acute hypercapnia.

a. One vial of doxapram (400 mg) should be mixed with 180 mL of dextrose 5% or 10% or normal saline solution (concentration of 2.0 mg/mL).

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EpiPen & EpiPen Jr. (epinephrine) AutoInjectiors
[August 27, 2001:Meridian Medical Technologies]

New labeling provides for an additional packaging configuration for the EpiPen and EpiPen Jr. AutoInjectors. In addition, the labeling provides for revisions in the labeling and patient package insert as well as inclusion of a new trainer patient package insert. Contact the company for a copy of the new labeling material.

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EPIVIR-HBV (lamivudine) Tablets & Oral Solution.
[August 16, 2001: GlaxoSmithKline]

New labeling provides for the use of Epivir-HBV in the treatment of hepatitis B in pediatric patients ages 2-17 years. Contact the company for a copy of the new labeling/package insert.

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Heparin Sodium in 0.9% NaCl
[August 21, 2001:Baxter Healthcare]

CLINICAL PHARMACOLOGY

Third paragraph revised to:

Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age.

PRECAUTIONS

General

Increased Risk

c. Increased Risk in Older Patients, Especially Women:

A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age."

Pediatric Use:

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use:

A higher incidence of bleeding has been reported in patients over 60 years

of age, especially women (see Precautions, General). Clinical studies indicate that lower doses of heparin may be indicated in these patients (see Precautions, General and Clinical Pharmacology).

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LOPID (gemfibrozil) Tablets
[August 8, 2001: Pfizer]

Other safety related information regarding Lopid: http://www.fda.gov/medwatch/safety/2001/safety01.htm#bayco2

CONTRAINDICATIONS:

1. Combination therapy of LOPID with cerivastatin due to the increased risk of myopathy and rhabdomyolysis (see WARNINGS).

2. Hepatic or severe renal dysfunction, including primary biliary cirrhosis.

3. Preexisting gallbladder disease (see WARNINGS).

4. Hypersensitivity to gemfibrozil.

WARNINGS:

5. Concomitant therapy with Lopid and Mevacor (lovastatin) has been associated with rhabdomyolysis, markedly elevated creatine kinase (CK) levels and myoglobinuria, leading in a high proportion of cases to acute renal failure. IN VIRTUALLY ALL PATIENTS WHO HAVE HAD AN UNSATISFACTORY LIPID RESPONSE TO EITHER DRUG ALONE, ANY POTENTIAL LIPID BENEFIT OF COMBINED THERAPY WITH LOVASTATIN AND GEMFIBROZIL DOES NOT OUTWEIGH THE RISKS OF SEVERE MYOPATHY, RHABDOMYOLYSIS, AND ACUTE RENAL FAILURE (see Drug Interactions).

5. Concomitant therapy with LOPID and an HMG-CoA reductase inhibitor is associated with an increased risk of skeletal muscle toxicity manifested as rhabdomyolysis, markedly elevated creatine kinase (CPK) levels and myoglobinuria, leading in a high proportion of cases to acute renal failure and death. Because of an observed marked increased risk of myopathy and rhabdomyolysis, the specific combination of LOPID and cerivastatin is absolutely contraindicated (see CONTRAINDICATIONS). IN

PATIENTS WHO HAVE HAD AN UNSATISFACTORY LIPID RESPONSE TO

EITHER DRUG ALONE, THE BENEFIT OF COMBINED THERAPY WITH LOPID AND HMG-CoA REDUCTASE INHIBITORS OTHER THAN CERIVASTATIN DOES NOT OUTWEIGH THE RISKS OF SEVERE MYOPATHY, RHABDOMYOLYSIS, AND ACUTE RENAL FAILURE (refs. 7, 8, 9, 10) (see Drug Interactions). The use of fibrates alone, including LOPID may occasionally be associated with myositis. Patients receiving LOPID and complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myositis, including serum creatine-kinease level determination. If myositis is suspected or diagnosed, LOPID therapy should be withdrawn.

PRECAUTIONS:

Drug Interactions

3. Drug Interactions–(A) HMG-CoA reductase inhibitors: Rhabdomyolysis has occurred with combined gemfibrozil and lovastatin therapy. It may be seen as early as 3 weeks after initiation of combined therapy or after several months. In most subjects who have had an unsatisfactory lipid response to either drug alone, the possible benefit of combined therapy with lovastatin (or other HMG CoA reductase inhibitors) and gemfibrozil does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. There is no assurance that periodic monitoring of creatine kinase will prevent the occurrence of severe myopathy and kidney damage.

3. Drug Interactions–(A) HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase inhibitor therapy (see CONTRAINDICATIONS). Myopathy or rhabdomyolysis with or without acute renal failure have been reported as early as three weeks after initiation of combined therapy or after several months (refs. 7, 8, 9, 10). (See WARNINGS.) There is no assurance that periodic monitoring of creatine kinase will prevent the occurrence of severe myopathy and kidney damage.

OVERDOSAGE:

There have been reported cases of overdosage with LOPID. In one case, a 7-year-old child recovered after ingesting up to 9 grams of LOPID. Symptoms reported with overdosage were abdominal cramps, abnormal liver function tests, diarrhea, increased CPK, joint and muscle pain, nausea and vomiting. Symptomatic supportive measures should be taken, should an overdose occur.

REFERENCES:

7. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin/gemfibrozil combination therapy. JAMA 1990;264:71-75.

8. Bermingham RP, Whitsitt TB, Smart ML et al. Rhabdomyolysis in a patient receiving the combination of cerivastatin and gemfibrozil. Am J Health-Syst Pharm 2000;57:461-464.

9. Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after taking atorvastatin with gemfibrozil. Am J Cardiol 1998;81:368-369.

10. Tal A, Rajeshawari M, Isley W. Rhabdomyolysis associated with simvastatin/gemfibrozil therapy. South Med J 1997;90:546-547.

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LOPROX (ciclopirox) Cream
[August 17, 2001: Aventis]

Labeling provides for elimination of the inactive ingredient Cocamide DEA from the formulation, substitution of Mineral Oil, USP, with new inactive ingredient Mineral Oil Light, NF.

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MAXAIR (pirbuterol acetate) Inhaler
[August 14, 2001: 3M Pharmaceuticals]

DESCRIPTION: and PRECAUTIONS: Information for Patients: sections

As with all aerosol medications, it is recommended to prime (test) MAXAIR Inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks. Prime by releasing three "test sprays" into the air away from yourself and other people.

DOSAGE AND ADMINISTRATION: section and the PATIENT’S

INSTRUCTIONS FOR USE:

It is recommended to "test spray" MAXAIR Inhaler into the air before using for the first time and in cases where the aerosol has not been used for a prolonged period of time.

As with all aerosol medications, it is recommended to prime (test) MAXAIR Inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks. Prime by releasing three "test sprays" into the air away from yourself and other people.

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NORVIR (ritonavir) Capsules & Oral Solution
[August 21, 2001: Abbott]

 

[Other labeling changes not appearing in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/mar01.htm#norvir]

CLINICAL PHARMACOLOGY:

Pharmacokinetics:

Hepatic Insufficiency:

Ritonavir pharmacokinetics have not been studied in In six HIV-infected adult subjects with mild hepatic insufficiency (see PRECAUTIONS).

dosed with NORVIR 400 mg BID, ritonavir exposures were similar to control subjects dosed with 500 mg BID. Adequate pharmacokinetic data are not available for patients with moderate hepatic impairment. Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS:

Second paragraph -

NORVIR should not be administered concurrently Co-administration of NORVIR is contraindicated with the drugs listed in Table 3 (also see PRECAUTIONS Table 4: Drugs That Should Not Be Co-administered with NORVIR) because competition for primarily CYP3A by ritonavir could result in inhibition of the metabolism of these drugs and create the potential for serious and/or life-threatening reactions such as cardiac arrhythmias, prolonged or increased sedation, and respiratory depression.

WARNINGS:

Drug Interactions:

Ritonavir is an inhibitor of cytochrome P450 3A (CYP3A) both in vitro and in vivo. Ritonavir also inhibits CYP2D6 in vitro, but to a lesser extent than CYP3A. Co-administration of ritonavir and drugs primarily metabolized by CYP3A or CYP2D6 may result in increased plasma concentrations of other drugs that could increase or prolong its therapeutic and adverse effects (see Pharmacokinetics: Drug-Drug Interactions, CONTRAINDICATIONS – Table 3 Drugs

That Are Contraindicated with NORVIR, PRECAUTIONS – Table 4 Drugs That Should Not Be Co-administered with NORVIR, Established Drug Interactions and Predicted Drug Interactions).

The magnitude of the interactions and therapeutic consequences between ritonavir and the drugs listed in Table 4 Predicted Drug Interactions: Use With Caution cannot be predicted with any certainty. When co-administering ritonavir with any agent listed in Table 4 Predicted Drug Interactions: Use With Caution, special attention is warranted. Refer to PRECAUTIONS: Established Drug Interactions and Predicted Drug Interactions for additional information.

PRECAUTIONS:

General

Ritonavir is principally metabolized by the liver. Therefore, caution should be exercised when administering this drug to patients with impaired hepatic function (see WARNINGS, CLINICAL PHARMACOLOGY: Hepatic Insufficiency and DOSAGE AND ADMINISTRATION: Dose Adjustment in Hepatic Insufficiency).

Fat Redistribution: "protease inhibitors" was deleted and replaced with "antiretroviral therapy."

Information For Patients: "protease inhibitors" was deleted and replaced with "antiretroviral therapy" in the sixth paragraph to be consistent with prior subsection on Fat Redistribution.

Drug Interactions:

Table 4: Drug Interactions With NORVIR has been renamed and reformatted. The renamed table now reads Table 4: Drugs That Should Not be Co-administered with NORVIR.

Table 4

Drugs That Should Not Be Co-administered with NORVIR

Drug Interactions With NORVIR

CONTRAINDICATED DRUGS (Same as Table 3)

DRUGS THAT ARE CONTRAINDICATED WITH NORVIR USE

Drug Class: Drug Name

Drugs Within Class That Are CONTRAINDICATED With

NORVIR

Clinical Comment

Antiarrhythmics: amiodarone, bepridil, flecainide, propafenone, quinidine

CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.

Antihistamines: astemizole, terfenadine

CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

Ergot Derivatives:

dihydroergotamine, ergonovine, ergotamine, methylergonovine

CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.

GI Motility Agent: cisapride

CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

Herbal Products:

St. John’s wort (hypericum perforatum)

May lead to loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors.

HMG-CoA Reductase Inhibitors:

lovastatin, simvastatin

Potential for serious reactions such as risk of myopathy including rhabdomyolysis.

Neuroleptic: pimozide

CONTRAINDICATED due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

Sedative/hypnotics:

midazolam, triazolam

CONTRAINDICATED due to the potential for serious and/or life- threatening reactions such as prolonged or increased sedation or respiratory depression.

Established Drug Interactions: Alteration in Dose or

Regimen Recommended Based on Drug Interaction Studies

(see CLINICAL PHARMACOLOGY, Table 2 for Magnitude of Interaction)

Concomitant

Drug Class:

Drug Name

 

Effect on Concentration of Ritonavir or Concomitant Drug

Clinical Comment

HIV-Antiviral Agents

HIV Protease Inhibitor:

Indinavir

When co-administered with reduced doses of indinavir and ritonavir

­ indinavir (« AUC ¯ Cmax ­ Cmin )

Alterations in concentrations are noted when reduced doses of indinavir are co-administered with Norvir.

Appropriate doses for this combination, with respect to efficacy and safety, have not been established

HIV Protease Inhibitor:

saquinavir

When co- Administered with reduced doses of saquinavir and ritonavir

­ saquinavir

(­ AUC ­ Cmax ­ Cmin )

Other Agents

Antimycobacterial:

rifampin

¯ ritonavir

May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered (see Antimycobacterial: rifabutin, for dose reduction recommendations)

Table 4: Predicted Drug Interactions: Use With Caution, Dose Decrease of

Coadministered Drug May Be Needed (see WARNINGS) had two revisions. Under the Examples of Drugs subheading, rapamycin was added but lovastatin and simvastatin were moved to Table 4: Drugs That Should Not Be-Co-administered with NORVIR. Additionally, a footnote 2 was added to this table and reads, " 2Use lowest possible dose of atorvastatin or cerivastatin with careful monitoring or consider HMG-CoA reducatase inhibitor such as pravastatin or fluvastatin."

Carcinogenesis and Mutagenesis:

Long term carcinogenicity studies of ritonavir in animal systems have not been completed. However, ritonavir was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames) using S. typhimurium and E. coli, mouse lymphoma, mouse micronucleus, and chromosome aberrations in human lymphocytes.

Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, at levels of 50, 100 or 200 mg/kg/day, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 0.3-fold for males that of the exposure in humans with the recommended therapeutic dose (600 mg BID). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 0.6-fold for the females that of the exposure in humans. In rats dosed at levels of 7, 15 or 30 mg/kg/day there were no carcinogenic effects. In this study, the exposure at the high dose was approximately 6% that of the exposure in humans with the recommended therapeutic dose. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known. However, ritonavir was found to be negative for mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to NORVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers: It is not known whether this drug is excreted in human milk. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not known whether ritonavir is secreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving NORVIR. Because many drugs are excreted in human milk, caution should be exercised when ritonavir is administered to a nursing woman. However, the U.S. Public Heath Service Centers for Disease Control and Prevention advises HIV infected women not to breast feed to avoid postnatal transmission of HIV to a child who may not be infected.

Geriatric Use:

Clinical studies of NORVIR 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 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.

OVERDOSAGE:

Management of Overdosage:

The following paragraph was added to the beginning of this subsection:

NORVIR oral solution contains 43% alcohol by volume. Accidental ingestion of the product by a young child could result in significant alcohol-related toxicity and could approach the potential lethal dose of alcohol.

DOSAGE AND ADMINISTRATION:

Pediatric Patients:

Dose Adjustment in Hepatic Insufficiency

The ritonavir dose does not need to be adjusted in patients with mild hepatic impairment. At this time, there are insufficient data in patients with moderate to severe hepatic impairment; therefore, NORVIR should be used with caution in this patient population (see Special Populations: Hepatic Insufficiency and PRECAUTIONS).

Patient Package Insert

What is NORVIR and how does it work?

NORVIR is in a class of drugs medicines called the HIV protease (PRO-tee-ase) inhibitors. NORVIR is used in combination with other anti-HIV drugs medicines to treat people with human immunodeficiency virus (HIV) infection. NORVIR is for adults and for children age 2 years and older.

How should I take NORVIR?

NORVIR is available only with a doctor's prescription. You should stay under a doctor’s care when taking NORVIR. Do not change your treatment or stop treatment without first talking with your doctor.

When your NORVIR supply starts to run low, get more from your doctor or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to NORVIR and become harder to treat.

What happens if I take too much NORVIR?

If you think that you took more than the prescribed dose of this medicine, contact your local poison control center or emergency room immediately.

As with all prescription medicines, NORVIR should be kept out of the reach of young children. NORVIR liquid contains a large amount of alcohol. If a toddler or young child accidentally drinks more than the recommended dose of NORVIR, it could make him/her sick from too much alcohol. Contact your local poison control center or emergency room immediately if this happens.

Who should not take NORVIR?

Do not take NORVIR if you are taking certain medicines. These could cause serious side effects that could cause death. Before you take NORVIR, you must tell your doctor about all the medicines you are taking or are planning to take. These include other prescription and non-prescription and herbal supplements.

For more information about medicines you should not take with NORVIR, please read the section "MEDICINES YOU SHOULD NOT TAKE WITH NORVIR."

Do not take NORVIR if you are taking certain medications. Taking certain drugs with NORVIR could create the potential for serious side effects that could be life threatening. You must tell your doctor about all the drugs you are taking or are planning to take before you take NORVIR. More information about drugs that interact with NORVIR can be found in the section "Can I take NORVIR with other medications?"

MEDICINES YOU SHOULD NOT TAKE WITH NORVIR.

Ergotamine, ergonovine, methylergonovine, and dihydroergotamine such as Cafergot , Migranal , D.H.E 45 , and others

Do not take NORVIR with the cholesterol-lowering medicines Mevacor (lovastatin) or Zocor (simvastatin) because of possible serious reactions. There is also an increased risk of drug interactions between NORVIR and Lipitor (atorvastatin) and Baycol (cerivastatin); talk to your doctor before you take any of these cholesterol-reducing medicines withNORVIR.

Drugs Medicines that require dosage adjustments:

The following drugs medicines require dose reduction if taken with NORVIR:

Mycobutin ® (rifabutin) Your doctor will lower your dose of Mycobutin

The following drug reduces blood levels of NORVIR: If you are taking Mycobutin (rifabutin), your doctor will lower the dose of Mycobutin.

Other Special Considerations:

NORVIR oral solution contains alcohol. Talk with your doctor if you are taking or planning to take metronidazole or disulfiram. Severe nausea and vomiting can occur.

If you are taking both didanosine (Videx) and NORVIR: Didanosine and Norvir should be separated by at least 2.5 hours.

Rifamate , may reduce blood levels of NORVIR. Be sure to tell your doctor if you are taking rifampin.

What are the possible side effects might I have while taking of NORVIR?

This list of side effects is not complete. Your doctor or pharmacist can discuss with you a more complete list of possible side effects with NORVIR. Talk to your doctor promptly about any side effects you have. If you have questions about side effects, ask your, doctor, nurse, or pharmacist. You should report any new or continuing symptoms to your doctor right away. Your doctor may be able to help you manage these side effects.

Abnormal liver function Blood tests have been reported in patients taking NORVIR may show possible liver problems. People with liver disease such as Hepatitis B and Hepatitis C who take NORVIR may have worsening liver disease. Liver problems including rare cases of death have occurred in patients taking NORVIR. It is unclear if NORVIR caused these liver People with pre-existing liver disease may have worsening of liver disease. Some problems

because some patients had other illnesses or were taking other medicines.

drugs. It is uncertain if NORVIR caused these liver problems.

Some patients taking NORVIR can develop serious problems with their pancreas

(pancreatitis) which may cause death. Tell your doctor if you have nausea, vomiting, or abdominal pain. These may be signs of pancreatitis.

Some patients have large increases in triglycerides and cholesterol. The long-term chance of getting complications such as heart attacks or stroke due to increases in triglycerides and cholesterol caused by protease inhibitors is not known at this time.

Changes in body fat have been seen in some patients taking protease inhibitors. anti-HIV medicines. These changes may include increased amount of fat in the upper back and neck ("buffalo hump"), breast and abdomen (stomach area). Loss of fat from the face, legs, and arms may also happen. The cause and long-term health effects of these conditions are not known at this time.

Inflammation of their pancreas (pancreatitis), including some deaths, have occurred in some patients taking NORVIR.

Some patients have had large increases in triglycerides and cholesterol. The long-term risks for complications such as heart attacks or stroke due to increases in triglycerides and cholesterol are not known at this time. with hemophilia have increased bleeding with protease inhibitors.

Increased bleeding has been reported in some patients with hemophilia.

There have been other side effects noted in patients receiving NORVIR; however, these side effects may have been due to other drugs medicines that patients were taking or to the illness itself. Some of these side effects can be serious. If you have questions about side effects, ask your doctor, nurse, or pharmacist. You should report any new or persistent symptoms to your doctor immediately.

What Should should I tell my doctor before taking NORVIR?

If you are pregnant or planning to become pregnant: The effects of NORVIR on pregnant women or their unborn babies are not known. If you are pregnant or plan to become pregnant, you should tell your doctor before taking NORVIR.

If you are breast-feeding: Do not breast-feed if you are taking NORVIR. You should not breast-feed if you have HIV. If you are a woman who has or will have a baby, talk with your doctor about the best way to feed your baby. You should be aware that if your baby does not already have HIV, there is a chance that HIV can be transmitted through breast-feeding.

....Other medical problems: Certain medical problems may affect the use of NORVIR. If you have diabetes: Some people taking protease inhibitors have developed develop new or more serious diabetes or high blood sugar. Be sure to tell your doctor if you have diabetes or an increase in thirst and/or frequent urination.

If you have hemophilia: Some people with hemophilia have had increased bleeding. It is not known whether the protease inhibitors caused these problems. Be sure to tell your doctor if you have hemophilia types A and B, diabetes mellitus, or an increase in thirst and/or frequent urination.

Whom should I call if I have questions about NORVIR?

If you would like more information about NORVIR, ask your doctor or pharmacist. If you have any questions or concerns about taking NORVIR, talk with your doctor.

If you suspect that you took more than the prescribed dose of this medicine, contact your local poison control center or emergency room immediately.

General advice about prescription medicines:

Talk to your doctor or other health care provider if you have any questions about this medicine or your condition. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. If you have any concerns about this medicine, ask you doctor. Your doctor or pharmacist can give you information about this medicine that was written for health care professionals. Do not use this medicine for a condition for which it was not prescribed. Do not share this medicine with other people.

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ParaGard T380A (interuterine copper contraceptive)
[August 24, 2001: R.W. Johnson Pharmaceutical Research Institute]

The ParaGard T380A should only be inserted, managed, and removed by clinicians that have demonstrated clinical competence for these procedures received under supervision.

INSTRUCTIONS FOR USE:

CLINICIANS SHOULD HAVE DEMONSTRATED CLINICAL COMPENTENCE IN PARAGARD T380A INSERTIONS, MANAGEMENT, AND REMOVAL RECEIVED UNDER SUPERVISION. PREVIOUS EDUCATION RE: SURGICAL PROCEDURES WILL REQUIRE VARYING LEVELS OF EXPERIENCE.

PATIENT PACKAGE INSERT:

How the ParaGard T380A Is Inserted and Removed

The ParaGard T380A should be inserted, managed, and removed by clinicians that have demonstrated clinical compentence for these procedures received under supervision.

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PRINIVIL (lisinopril) &
PRINZIDE (lisinopril/hydrochlorothiazide) Tablets

[August 7, 2001: Merck]

CLINICAL PHARMACOLOGY:

Pharmacodynamics

The following paragraph has been added:

In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril maleate. (See PRECAUTIONS, Drug Interactions.)

PRECAUTIONS:

Drug Interactions

Non-Steroidal Anti-inflammatory Agents:

In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril maleate. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

 

Lisinopril

in a study in 36 patients with mild to moderate hypertension where the antihypertensive effects of lisinopril alone were compared to lisinopril given concomitantly with indomethacin, the use of

indomethacin was associated with a reduced effect, although the difference between the two

regimens was not significant

In a study in 36 patients with mild to moderate hypertension where the antihypertensive effects of lisinopril (40 mg q.d.) alone were compared to lisinopril (40 mg q.d.) given concomitantly with indomethacin (50 mg b.i.d.), the use of indomethacin was associated with a reduced antihypertensive effect of lisinopril, although the difference between the two regimens was not significant. Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

DOSAGE AND ADMINISTRATION:

The following statement has been added to the end of the fourth paragraph:

Dosage higher than lisinopril 80 mg and hydrochlorothiazide 50 mg should not be used.

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QUINIDEX EXTENTABS (quinidine sulfate) Tablets
[August 18, 2001: Wyeth-Ayerst]

PRECAUTIONS:

Drug and Diet Interactions

Altered pharmacokinetics of quinidine:

Grapefruit juice inhibits P450 3A4-mediated metabolism of quinidine to

3-hydroxyquinidine. Although the clinical significance of this interaction is unknown, grapefruit juice should be avoided.

The rate and extent of quinidine absorption may be affected by changes in dietary salt intake; a decrease in dietary salt intake may lead to an increase in plasma quinidine concentrations

 

Geriatric Use:

Safety and efficacy of quinidine in elderly patients have not been systematically studied.

Clinical studies of quinidine generally were not adequate to determine if significant safety or efficacy differences exist between elderly patients (65 years or older) and younger patients.

Quinidine clearance is apparently independent of age (see CLINICAL PHARMACOLOGY-Pharmacokinetics). However, renal or hepatic dysfunction causes the elimination of quinidine to be slowed (see WARNINGS-Pharmacokinetic Considerations), and since these conditions are more common in the elderly, appropriate dosing reductions should be considered in these individuals.

OVERDOSAGE:

The following paragraph was added after the first paragraph:

A case of tablet ingestion by a 16-month-old infant has been reported in which a concretion or bezoar was formed in the stomach, resulting in nondeclining toxic levels of quinidine. The mass was only dimly visible on plain radiographs, but a gastric aspirate revealed quinidine levels approximately 50 times higher than those in plasma. In cases of massive overdose with prolonged high plasma levels, diagnostic/therapeutic endoscopy may be appropriate.

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SERAX (oxazepam) Tablets
[August 8, 2001: Faulding]

PRECAUTIONS:

New subsection -

Geriatric Use:

Clinical studies of Serax were not adequate to determine whether subjects aged 65 and over respond differently than younger subjects. Age (<80 years old) does not appear to have a clinically significant effect on oxazepam kinetics (see CLINICAL PHARMACOLOGY).

Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered. Greater sensitivity of some older individuals to the effects of Serax (e.g., sedation, hypotension, paradoxical excitation) cannot be ruled out. (see PRECAUTIONS, General; see ADVERSE REACTIONS). In general, dose selection for Serax for elderly patients should be cautious, usually starting at the lower end of the dosing range (see DOSAGE AND ADMINISTRATION).

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SINGULAIR (montelukast Na) Tablets
[August 2, 2001: Merck]

ADVERSE REACTIONS:

myalgia including muscle cramps, and very rarely seizure; and very rarely pancreatitis; increased bleeding tendency, bruising; and edema

Patient Product Information

What are the possible side effects of Singulair?

muscle aches, muscle cramps, seizure, pancreatitis, increased bleeding tendency, bruising and edema

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Sodium Lactate Injection
[August 15, 2001: Abbott]

PRECAUTIONS:

Carcinogenesis, mutagenesis, impairment of fertility:

Studies with Sodium Lactate Injection have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.

Nursing Mothers:

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 Sodium Lactate Injection is administered to a nursing mother.

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SUFENTA (sufentanil citrate) Injection
[August 28, 2001: Akorn]

 

CLINICAL PHARMACOLOGY:

Pharmacokinetics, Intravenous use subsection, a 2 nd sentence is added as follows:

The elimination half-life of SUFENTA is shorter (e.g. 97 ± 42 minutes) in infants and children, and longer in neonates (e.g. 434±160 minutes) compared to that of adolescents and adults.

PRECAUTIONS:

Pediatric Use:

The safety and efficacy of intravenous SUFENTA in children under two years of age undergoing cardiovascular surgery has been documented in a limited number of cases

Replaced by the following:

The safety and efficacy of intravenous SUFENTA in pediatric patients as young as 1 day old undergoing cardiovascular surgery have been documented in a limited number of cases. The clearance of SUFENTA in healthy neonates is approximately on-half that in adults and children. The clearance rate of SURENTA can be further reduced by up to a third in neonates with cardiovascular disease, resulting in an increase in the elimination

half-life of the drug.

ADVERSE REACTIONS:

Probably Causally related: Incidence Less than 1%-Derived from Clinical Trials:

At the end of the subsection, the word Incidence added before 0.3% to 1%

A new subsection that reads: Body as a whole: Anaphylaxis is added.

Cardiovascular: cardiac arrest is added.

DOSAGE AND ADMINISTRATION:

A last sentence added as follows:

Because the clearance of SUFENTA is reduced in neonates, especially those with cardiovascular disease, the dose of SUFENTA should be reduced accordingly (see PRECAUTIONS).

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TEQUIN (gatifloxacin) Tablets
[August 20, 2001: Bristol Myers-Squibb]

CLINICAL PHARMACOLOGY

Glucose Homeostasis

The following paragraph was added and now appears first in this subsection:

As with other quinolones, clinical experience has shown that disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported in patients treated concomitantly with TEQUIN and oral hypoglycemic agents with or without insulin. Therefore, careful monitoring of blood glucose is recommended when TEQUIN is administered to diabetic patients receiving treatment with oral hypoglycemic agents with or without insulin. (See PRECAUTIONS: General, Information for Patients, and Drug Interactions.)

PRECAUTIONS

General

The last paragraph was revised as follows:

As with other quinolones, disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with TEQUIN, usually in diabetic patients receiving concomitant treatment with oral hypoglycemic agents (e.g., glyburide) or with or without insulin. In these patients, the careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs in a patient being treated with TEQUIN, appropriate therapy should be initiated immediately and TEQUIN should be discontinued. (See CLINICAL PHARMACOLOGY, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS.)

Information for Patients

The twelfth bullet was revised as follows:

·that if they are diabetic and are being treated with insulin or an oral hypoglycemic agent and a hypoglycemic reaction occurs, they should discontinue gatifloxacin and consult a physician (see PRECAUTIONS: General)."

·that if they are diabetic, disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported in patients treated concomitantly with TEQUIN (as with other quinolones) and oral hypoglycemic agents with or without insulin. If a hypoglycemic reaction occurs, they should initiate appropriate therapy immediately, discontinue TEQUIN, and contact a physician (see PRECAUTIONS: General and Drug Interactions).

Drug Interactions

Antidiabetic agents has been added and appears second in this subsection as follows:

Antidiabetic agents: No significant pharmacokinetic interactions have been observed when glyburide was administered concomitantly with TEQUIN. However, disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported in patients treated concomitantly with TEQUIN (as with other quinolones) and oral hypoglycemic agents with or without insulin. Therefore, careful monitoring of blood glucose is recommended when TEQUIN is administered to diabetic patients receiving treatment with oral hypoglycemic agents with or without insulin. (See CLINICAL PHARMACOLOGY and PRECAUTIONS: General and

Information for Patients.)

ADVERSE REACTIONS:

The fifth and sixth paragraphs were revised to include additional adverse events as follows:

Body as a Whole: allergic reaction, asthenia, back pain, chest pain, chills, face edema, fever, halitosis

Cardiovascular System: hypertension, palpitation

Digestive System: abdominal pain, anorexia, constipation, dyspepsia, flatulence, gastritis, glossitis, mouth ulcer, oral moniliasis, stomatitis, vomiting

Hemic/Lymphatic System: ecchymosis

Metabolic/Nutritional System: hyperglycemia, peripheral edema, thirst

Musculoskeletal System: arthralgia, leg cramp

Nervous System: abnormal dream, agitation, anxiety, confusion, hallucination, insomnia, nervousness, paresthesia, somnolence, tremor, vasodilatation, vertigo

Respiratory System: dyspnea, pharyngitis

Skin/Appendages: dry skin, pruritus, rash, sweating

Special Senses: abnormal vision, eye pain, taste perversion, tinnitus

Urogenital System: dysuria, hematuria

Additional drug-related adverse events considered clinically relevant that occurred in <0.1% (rare adverse events) of patients receiving gatifloxacin in single- and multiple-dose clinical trials are as follows: abnormal thinking, agitation, alcohol intolerance, anorexia, anxiety, arthalgia, arthritis, asthenia, asthma (bronchospasm), ataxia, bone pain, bradycardia, breast pain, cheilitis, colitis, confusion, convulsion, cyanosis, depersonalization, depression, diabetes mellitus, dry skin, dysphagia, ear pain, ecchymosis, edema, epistaxis, euphoria, eye pain, face edema, flatulence,

gastritis, gastrointestinal hemorrhage, gingivitis, halitosis, hallucination, hematemesis, hostility, hyperesthesia, hyperglycemia, hypertension, hypertonia, hyperventilation, hypoglycemia, leg cramp, lymphadenopathy, maculopapular rash, metrorrhagia, migraine, mouth edema, myalgia, myasthenia, neck pain, nervousness, panic attack, paranoia, parosmia, pruritus, pseudomembranous colitis, psychosis, ptosis, rectal hemorrhage, somnolence, stress, substernal chest pain, tachycardia, taste loss, thirst, tongue edema, vesiculobullous rash.

Patient Information About Tequin

What about other medications I am taking?

The following bullet was added and now appears third as follows:

· If you have diabetes, it is important to let your healthcare provider know if you are on oral hypoglycemic agents with or without insulin."

What are the possible side effects of TEQUIN?

A paragraph was added to the end of this section as follows:

If you have diabetes, you should know that disturbances of blood sugar, including symptoms of hyperglycemia (high blood sugar) and hypoglycemia (low blood sugar), have been reported in patients treated concomitantly with TEQUIN (as with other quinolone antibiotics) and oral antidiabetic drugs with or without insulin. If you develop symptoms of low blood sugar while on TEQUIN, you should take immediate measures to increase your blood sugar, stop taking TEQUIN, and contact your healthcare professional at once.

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TOPAMAX (topiramate) Tablets & Sprinkle Capsule
[August 28, 2001: R.W. Johnson]

Other safety related information: http://www.fda.gov/medwatch/safety/2001/safety01.htm#topama

Labeling provides for the use of Topamax (topiramate) Tablets,

Topamax (topiramate) Sprinkle Capsule as adjunctive therapy in patients 2 years and older with seizures associated with Lennox-Gastaut syndrome. Contact the company for a copy of the new labeling.

WARNINGS:

Acute myopia and secondary angle closure glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving TOPAMAX. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating TOPAMAX therapy. In contrast to primary

narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of TOPAMAX as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of TOPAMAX, may be helpful.

Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.

PRECAUTIONS:

Information for Patients

Patients taking TOPAMAX® should be told to seek immediate medical attention if they experience blurred vision or periorbital pain.

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ULTANE (sevoflurane) Liquid for Inhalation
[August 8, 2001: Abbott]

Other information not appearing in the 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/mar01.htm#ultane

PRECAUTIONS:

Hepatic Function

Third paragraph added:

Very rare cases of mild, moderate, and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported from postmarketing experiences. Clinical judgement should be exercised when sevoflurane is used in patients with underlying hepatic conditions or under treatment with drugs known to cause hepatic dysfunction (see ADVERSE REACTIONS).

ADVERSE REACTIONS:

Adverse Events During Post-Marketing Experience:

Last sentence of first paragraph removed:

One death has been reported in association with sevoflurane administration and seizures.

Third paragraph added:

Very rare cases of mild, moderate and severe post-operative hepatic dysfunction or hepatitis with or without jaundice have been reported. Histological evidence was not provided for any of the reported hepatitis cases. In most of these cases, patients had underlying hepatic conditions or were under treatment with drugs known to cause hepatic dysfunction. Most of the reported events were transient and resolved spontaneously (see PRECAUTIONS).

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VALTREX (valacyclovir HCl) Caplets
[August 30, 2001: GlaxoSmithKline]

Labeling provides for a shorter treatment course of three days in the treatment of recurrent episodes of genital herpes. Contact the company for a copy of the new labeling/package insert.

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VISUDYNE (verteporfin) Injection
[August 22, 2001: QLT]

Labeling provides for the use of Visudyne (verteporfin for injection) therapy for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to macular degeneration, presumed ocular histoplasmosis or pathologic myopia. Contact the company for a copy of the new labeling/package insert.

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XALATAN(latanoprost) Ophthalmic Solution
[August 7, 2001: Pharmacia & Upjohn]

WARNINGS:

Fourth paragraph -

XALATAN may gradually change eyelashes and vellus hair; these changes include increased length, thickness, pigmentation, and number of lashes or hairs, and misdirected growth of eyelashes.

PRECAUTIONS:

Information for Patients (see Warnings):

Second paragraph -

ADVERSE REACTIONS:

Clinical Practice: The following events have been identified during postmarketing use of XALATAN in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to

XALATAN, or a combination of these factors, include: asthma and exacerbation of asthma; corneal edema and erosions; dyspnea; eyelash and vellus hair changes (increased length, thickness, pigmentation, and number of lashes); eyelid skin darkening; herpes keratitis; intraocular inflammation (iritis/uveitis); keratitis; macular edema, including cystoid macular edema; misdirected eyelashes sometimes resulting in eye irritation; and toxic epidermal necrolysis.

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ZAROXOLYN (metolazone) Tablets &
MYKROX (metolazone) Tablets
[August 10, 2001: Celltech Pharmaceuticals]

(Zaroxolyn)

(Mykrox)

WARNINGS: Rapid Onset Hyponatremia and/or Hypokalemia:

Hypokalemia:

Second sentence:

"Serum potassium should be determined at regular and appropriate intervals, and dose reduction…."

(Zaroxolyn)

ADVERSE REACTIONS: Dermatologic/Hypersensitivity:

Toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome, necrotizing angiitis (cutaneous vasculitis), purpura, dermatitis (photosensitivity), urticaria, and skin rashes.

Thrombocytopenia was deleted from the paragraph describing adverse reactions reported with similar antihypertensive-diuretics and added to Hematologic:

Hematologic:

Aplastic/hypoplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.

Dry mouth was deleted from the paragraph describing adverse reactions reported with similar antihypertensive-diuretics and added to Other:

Other:

Transient blurred vision, chills, dry mouth.

(Mykrox)

ADVERSE REACTIONS: Dermatologic/Hypersensitivity:

Toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome, necrotizing angiitis (cutaneous vasculitis), purpura, dermatitis, photosensitivity, urticaria.

Thrombocytopenia was deleted from the paragraph describing rare adverse experiences reported in association with similar antihypertensive-diuretics and was added to:

Other Adverse Experiences:

Hematologic:

Hematologic: Aplastic (hypoplastic) anemia, agranulocytosis, leukopenia, thrombocytopenia.

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ZOLOFT (sertraline HCl) Tablets & Oral Concentrate
[August 6, 2001: Pfizer]

Other labeling changes not found in 2001 PDR: http://www.fda.gov/medwatch/SAFETY/2001/feb01.htm#zoloft , http://www.fda.gov/medwatch/safety/2000/nov00.htm#zoloft

Labeling provides for the use of Zoloft (sertraline hydrochloride) for the long-term treatment of posttraumatic stress disorder. Contact the company for a copy of the new labeling/package insert.

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