SUMMARY OF SAFETY-RELATED DRUG LABELING CHANGES APPROVED BY FDA
September 1998

(Posted: 10/30/98)

Note: The following summaries include only those safety-related sections that have been modified, and therefore do not contain all the information needed for safe and effective prescribing. Contact the manufacturer for the complete labeling/package insert.

NB: Comparison made to 1998 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.

Compiled with the help of:
Molly Tolle, Pharmacy Student
The Raabe College of Pharmacy
Ohio Northern University
Ada, OH

AREDIA (pamidronate disodium)	BIAXIN (clarithromycin)	CECLOR (cefaclor)	CIPRO (ciprofloxacin HCl)
CIPRO I.V. (ciprofloxacin HCl)	HEPARIN	INTEGRILIN (eptifibatide)	ISUPREL (isoproterenol HCl)
LIDOCAINE	LOXITANE (loxapine succinate & loxapine HCl)	NEURONTIN (gabapentin)	PHENERGAN (promethazine HCl)
PRECOSE (acarbose)	PROVENTIL HFA (albuterol sulfate)	RAXAR (grepafloxacin HCl)	ROMAZICON (flumazenil)
SEREVENT DISKUS (salmeterol xinafoate)	SINGULAIR (montelukast Na)	TROVAN (trovafloxacin mesylate & alatrovafloxacin mesylate)	VENTOLIN (albuterol sulfate)
VEXOL (rimexolone)	VIRAMUNE (nevirapine)	ZERIT (stavudine)	ZYFLO (zileuton)

Return to Quick Reference

INDICATIONS AND USAGE:

Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma: Last sentence revised (new text in tialics) -

The Aredia treatment effect appeared to be smaller in the study of breast cancer patients receiving hormonal therapy than in the study of those receiving chemotherapy, however, overall evidence of clinical benefit has been demonstrated (see CLINICAL PHARMACOLOGY, Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma, Clinical Trials section).

Return to Quick Reference

Return to Quick Reference

CLINICAL PHARMACOLOGY:

Microbiology: Subsection extensively revised. Contact the company for a copy of the new labeling/package insert.

Return to Quick Reference

CLINICAL PHARMACOLOGY:

New text added after 2nd paragraph sentence -

"A 500-mg oral dose given every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours. A 750-mg oral dose given every 12 hours has been shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400 mg given over 60 minutes every 8 hours. A 750-mg oral dose results in a C_max similar to that observed with a 400-mg I.V. dose. A 250-mg oral dose given every 12 hours produces an AUC equivalent to that produced by an infusion of 200 mg ciprofloxacin given every 12 hours."

A new chart entitled "Steady-state Pharmacokinetic Parameter Following Multiple Oral and I.V. Doses" added - see new labeling/package insert.

WARNINGS:

First sentence revised (new text in italics) -

"The safety and effectiveness of ciprofloxacin in ["children" deleted] pediatric patients and adolescents (less than 18 years of age), pregnant women, and lactating women have not been established. (See PRECAUTIONS - Pediatric Use, Pregnancy, and Nursing Mothers subsections.)"

PRECAUTIONS:

Information for Patients: First paragraph revised. New text in italics -

"Patients should be advised:

• that ciprofloxacin may be taken with or without meals. The preferred time of dosing is two hours after a meal. Patients should also be advised to drink fluids liberally and not take antacids containing magnesium, aluminum, or calcium, products containing iron, or multivitamins containing zinc. Ciprofloxacin should not be taken concurrently with milk or yogurt alone, since absorption of ciprofloxacin may be significantly reduced. Dietary calcium as part of a meal, however, does not significantly affect ciprofloxacin absorption. ["However, usual dietary intake of calcium has not been shown to alter the absorption of ciprofloxacin." deleted]

• Patients should be advised that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to notify their physician before taking this drug if there is a history of this condition."

PRECAUTIONS:

Pediatric Use:

"pediatric patients" replaces "children" in first paragraph.

Text added at end of subsection -

"Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age were not studied. Safety monitoring in the study included periodic range of motion examinations and gait assessments by treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0-93 days). This study was not designed to determine long-term effects and the safety of repeated exposure to ciprofloxacin.

"In the study, injection site reactions were more common in the ciprofloxacin group (24%) than in the comparison group (8%). Other adverse events were similar in nature and frequency between treatment arms. Musculoskeletal adverse events were reported in 22% of the patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. One of sixty-seven patients developed arthritis of the knee nine days after a ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities eight months after treatment. However, the relationship of this event to the patient's course of ciprofloxacin can not be definitely determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as part of their underlying disease process."

ADVERSE REACTIONS:

Post-Marketing Adverse Events: Special Senses: Subsection revised (new text in italics) - "anosmia, taste loss"

CLINICAL PHARMACOLOGY:

Microbiology: "Moraxella catarrhalis" added to list of Aerobic gram-negative microorganisms for which in vivo and in vitro activity have been shown.

INDICATIONS AND USAGE:

Acute Sinusitis (new subsection): "Acute Sinusitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis."

Chronic Bacterial Prostatitis (new subsection): "Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis."

WARNINGS:

First sentence revised (new text in italics) -

"The safety and effectiveness of ciprofloxacin in ["children" deleted] pediatric patients and adolescents (less than 18 years of age), pregnant women, and lactating women have not been established. See PRECAUTIONS - Pediatric Use, Pregnancy, and Nursing Mothers subsections.)"

PRECAUTIONS:

Information for Patients:

Text added at end of subsection -

"Patients should be advised that convulsions have been reported in patients taking quinolones, including ciprofloxacin, and to notify their physician before taking this drug if there is a history of this condition."

Pediatric Use:

"pediatric patients" replaces "children" in first paragraph

Text added at end of subsection -

"Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5-17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10-21 days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10-21 days. Patients less than 5 years of age were not studied. Safety monitoring in the study included periodic range of motion examinations and gait assessments by treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0-93 days). This study was not designed to determine long-term effects and the safety of repeated exposure to ciprofloxacin.

"In the study, injection site reactions were more common in the ciprofloxacin group (24%) than in the comparison group (8%). Other adverse events were similar in nature and frequency between treatment arms. Musculoskeletal adverse events were reported in 22% of the patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. One of sixty-seven patients developed arthritis of the knee nine days after a ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities eight months after treatment. However, the relationship of this event to the patient's course of ciprofloxacin can not be definitely determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as part of their underlying disease processe."

ADVERSE REACTIONS:

Skin Hypersensitivity: Last sentence deleted -

"Allergic reactions ranging from urticaria to anaphylactic reactions have been reported."

Post-Marketing Adverse Events: Subsection revised -

CENTRAL NERVOUS SYSTEM: agitation, ["confusion" deleted] delirium, ["dysphasia" deleted] myoclonus, ["nystagmus" deleted] toxic psychosis

HEMIC/LYMPHATIC: ["agranulocytosis" deleted] hemolytic anemia, methemoglobinemia ["prolongation of prothrombin time" deleted]

MUSCULOSKELETAL: myalgia, ["possible exacerbation of myasthenia gravis" deleted] tendinitis/tendon rupture

RENAL/UROGENITAL: ["albuminuria, candiduria, renal calculi," deleted] vaginal candidiasis

DOSAGE AND ADMINISTRATION:

Text added as new sixth paragraph -

"The recommended dosage for mild to moderate Acute Sinusitis and Chronic Bacterial Prostatitis is 400 mg I.V. every 12 hours."

"Acute Sinusitis" and "Chronic Bacterial Prostatitis" added to "Dosage Guidelines Intravenous" Table.

Return to Quick Reference

Return to Quick Reference

ADVERSE REACTIONS:

Allergic Reactions: Text added as new second paragraph -

"The potential for development of antibodies to eptifibatide has been studied in 433 subjects. Eptifibatide was non-antigenic in 412 patients receiving a single administration of eptifibatide(135 ug/kg bolus followed by a continuous infusion of either 0.5 ug/kg/min or 0.75 ug/kg/min), and in 21 subjects to whom eptifibatide (135 ug/kg bolus followed by a continuous infusion of 0.75 ug/kg/min) was administered twice, 28 days apart. In both cases, plasma for antibody detection was collected approximately 30 days after each dose. The development of antibodies to eptifibatide at higher doses has not been evaluated."

Return to Quick Reference

DESCRIPTION: Last sentence revised (new text in italics) -

"The Mistometer delivers a measured dose of ["131 mcg" deleted] 103 mcg of the bronchodilator in a fine, even mist for inhalation."

HOW SUPPLIED: First sentence revised (new text in italics) -

"Isuprel Mistometer is supplied in a plastic coated glass vial as a metered dose aerosol providing ["131 mcg" deleted] 103 mcg of isoproterenol hydrochloride per actuation."

Return to Quick Reference

PRECAUTIONS:

Pediatric Use (new subsection): "Safety and effectiveness in pediatric patients have not been established."

DOSAGE AND ADMINISTRATION:

Sentence added at end of seventh paragraph -

"Use of a final filter is recommended during administration of all parenteral solutions, where possible."

Caution: Second sentence revised (new text in italics)-

"Administer the ["0.4% and 0.8%" deleted] Lidocaine Hydrochloride and 5% Dextrose Injection , USP only with a calibrated infusion device."

Pediatric (formerly titled "Usage in Children and Infant"):

Existing text deleted and replaced with -

"Although controlled clinical studies to establish pediatric dosing schedules have not been conducted, the American Heart Association's Standards and Guidelines recommends a bolus dose of 1 mg/kg followed by an infusion rate of 30 ug/kg/min."

PRECAUTIONS:

Drug Interactions (new subsection):

"There have been rare reports of significant respiratory depression, stupor and/or hypotension with the concomitant use of loxapine and lorazepam.

"The risk of using loxapine in combination with CNS-active drugs has not been systematically evaluated. Therefore, caution is advised if the concomitant administration of loxapine and CNS-active drugs is required."

Pediatric Use: (formerly titled "Usage in Children") Existing text -

"Studies have not been performed in children; therefore, this drug is not recommended for use in children below the age of 16."

deleted and replaced with -

"Safety and effectiveness of Loxitane in pediatric patients have not been established."

DOSAGE AND ADMINISTRATION:

Third paragraph revised (new text in italics) -

"The effective dose of Neurontin is 900 to 1800 mg/day and given in divided doses (three times a day) using 300- or 400-mg capsules. ["Titration to an effective dose can take place rapidly, over a few days, giving 300 mg on Day 1, 300 mg twice a day on day 2, and 300 mg three times a day on Day 3. To minimize potential side effects, especially somnolence, dizziness, fatigue, and ataxia, the first dose on Day 1 may be administered at bedtime." deleted] The starting dose is 300 mg three times a day. If necessary, the dose may be increased using 300- or 400-mg capsules three times a day up to 1800 mg/day. Dosages up to 2400 mg/day have been well tolerated in long-term clinical studies. Dose of 3600 mg/day have also been administered to a small number of patients for a relatively short duration, and have been well tolerated. The maximum time between doses in the T.I.D. should not exceed 12 hours."

Return to Quick Reference

Return to Quick Reference

DESCRIPTION:

New sentence added at end of 3rd paragraph -

"It is recommended to prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks by releasing four "test sprays" into the air, away from the face."

CLINICAL PHARMACOLOGY:

Mechanism of Action: First paragraph revised (new text in italics) -

"In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta₂-adrenergic receptors compared with isoproterenol. While it is recognized that beta₂-adrenergic receptors are the predominant receptors on bronchial smooth muscle, ["recent" deleted] data indicate that there is a population of beta₂ receptors in the human heart ["which comprise" deleted] existing in a concentration between 10% and 50% ["of cardiac beta adrenergic receptors" deleted]. The precise function of these receptors [", however, is" deleted] has not ["yet" deleted] been established. (See WARNINGS for Cardiovascular Effects.)"

Third paragraph revised. New text in italics -

"Albuterol has been shown in most clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation [", effect" deleted] than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other ["However, all" deleted] beta-adrenergic agonist drugs, ["including albuterol sulfate," deleted] can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes."

Preclinical: First three paragraphs revised. New text in italics -

"Intravenous ["albuterol" deleted] studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to ["about" deleted] approximately 5% of the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), ["the drug achieves" deleted] albuterol concentrations were found to be ["of more than" deleted] 100 times those in the whole brain.

"["Studies in pregnant rats with titrated albuterol have demonstrated that approximately 10% of the circulating maternal drug is transferred to the fetus. Disposition in fetal lungs is comparable to maternal lungs, but fetal liver disposition is 1% of maternal liver levels." deleted]

"Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines were administered concurrently. The clinical significance of these findings ["when applied to humans" deleted] is unknown."

CONTRAINDICATIONS:

Section revised (new text in italics) -

"Proventil HFA (albuterol sulfate) Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to albuterol or any ["of its" deleted] other Proventil HFA components."

PRECAUTIONS:

General: Subsection revised (new text in italics) -

"Albuterol sulfate, as with all ["Preparations containing" deleted] sympathomimetic amines ["such as albuterol sulfate" deleted] should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. ["who are unusually responsive to such agents and in patients with convulsive disorders, hyperthyroidism, or diabetes." deleted] Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after use of any beta-adrenergic bronchodilator.

"Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. As with other beta ["adrenergic" deleted] -agonist s, ["medications" deleted] albuterol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation."

Information for Patients: Sixth paragraph, third sentence revised (new text in italics) -

"Do not increase the ["number of puffs" deleted] dose or frequency of doses of Proventil HFA (albuterol sulfate) Inhalation Aerosol without consulting your physician>"

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Subsection revised (new text in italics) -

"In a 2-year study in Sprague-Dawley rats, albuterol sulfate caused a ["significant" deleted] dose-related increase in the incidence of benign leiomyomas of the mesovarium at ["oral" deleted] and above dietary doses of 2 [", 10, and 50" deleted] mg/kg ["/day" deleted] (approximately ["12, 60, and 300" deleted] 10 times the maximum recommended ["human" deleted] daily inhalation dose for adults on a mg/m² basis). In another study this effect was blocked by the coadministration of propranolol , a non-selective beta-adrenergic antagonist. ["The relevance of these findings to humans is not known." Deleted] In an 18-month study in CD-1 mice albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 500 mg/kg ["/day" deleted] (approximately ["1560" deleted] 1700 times the maximum recommended ["human" deleted] daily inhalation dose for adults on a mg/m² basis) ["revealed no evidence of tumorigenicity" deleted]. In a 22-month study in the Golden Hamster albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 50 mg/kg (approximately 230 times the maximum recommended daily inhalation dose for adults on a mg/m² basis).

"Albuterol sulfate was not mutagenic in the Ames test with or without metabolic activation using tester strains S. typhimurium TA1537, TA1538, and TA98 or E.coli WP2, WP2uvrA, and WP67. No forward mutation was seen in yeast strain S.cerevisiae S9 nor any mitotic gene conversion in yeast strain S.cerevisiae JD1 with or without metabolic activation. Fluctuation assays in S. typhimurium TA98 and E.coli WP2, both with metabolic activation, were negative. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay at intraperitoneal doses of up to 200 mg/kg.

"Reproduction sudies in rats demonstrated ["with albuterol revealed" deleted] no evidence of ["mutagenesis or" deleted] impaired fertility ["in rats" deleted] at oral doses up to 50 mg/kg (approximately ["300" deleted] 340 times the maximum recommended ["human" deleted] daily inhalation dose for adults on a mg/m² basis)."

Teratogenic Effects - Pregnancy Category C: Subsection revised (new text in italics) -

"Albuterol sulfate has been shown to be teratogenic in mice. A ["reproduction" deleted] study in CD-1 mice ["given albuterol sulfate" deleted] at a subcutaneous ["ly" deleted] (sC) dose of ["(0.025," deleted] 0.25[", and 2.5" deleted] mg/kg (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis) showed cleft palate formation in 5 of 111 (4.5%) fetuses. ["at 0.25 mg/kg" deleted] A sc dose of 2.5 mg/kg (approximately ["equal to" deleted] 8 times the maximum recommended ["human" deleted] daily inhalation dose for adults on a mg/m² basis) ["and" deleted] induced cleft palate formation in 10 of 108 (9.3%) fetuses. ["at 2.5 mg/kg (approximately 10 times the maximum recommended human daily inhalation dose on a mg/m² basis)." deleted] The drug did not induce cleft palate formation at the low dose, ["None was observed at" deleted] 0.025 mg/kg ["(approximately one tenth" deleted] (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated with 2.5 mg/kg isoproterenol (positive control) administered subcutaneously (approximately 8 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). A reproduction study ["with oral albuterol" deleted] in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol sulfate was administered orally at 50 mg/kg dose (approximately ["600" deleted] 680 times the maximum recommended ["human" deleted] daily inhalation dose for adults on a mg/m² basis).

"Studies in pregnant rats with titrated albuterol have demonstrated that approximately 10% of the circulating maternal drug is transferred to the fetus. Disposition in fetal lungs is comparable to maternal lungs, but fetal liver disposition is 1% of maternal liver levels.

"In ["a separate" deleted] an inhalation reproduction study in Sprague-Dawley rats, ["using" deleted] the albuterol sulfate/HFA-134a formulation, ["albuterol sulfate" deleted] did not exhibit any teratogenic effects at 10.5 mg/kg ["/day" deleted] (approximately ["65" deleted] 70 times the maximum recommended ["human" deleted] daily inhalation dose for adults on a mg/m² basis)."

Tocolysis: (new subsection) -

"Albuterol has not been approved for the management of pre-term labor. The benefit:risk ratio when albuterol is administered for tocolysis has not been established. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta₂-agonists, including albuterol."

OVERDOSAGE:

Section revised (new text in italics) -

"The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeraton of any of the symptoms listed under ADVERSE REACTIONS, eg, seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Hypokalemia may also occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of Proventil HFA (albuterol sulfate) Inhalation Aerosol. Treatment consists of discontinuation of Proventil HFA (albuterol sulfate) Inhalation Aerosol together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Proventil HFA (albuterol sulfate) Inhalation Aerosol.

"The oral median lethal dose of albuterol sulfate in mice ["and rats was" deleted] is greater than 2,000 mg/kg (approximately ["6,000 and 12,000" deleted] 6800 times the maximum recommended ["human" deleted] daily inhalation dose [",respectively," deleted] for adults on a mg/m² basis). In mature rats, the subcutaneous median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately 3000 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). In small young rats, the subcutaneous median lethal dose is approximately 2000 mg/kg (approximately 14,000 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). The inhalation median lethal dose ["could" deleted] has not been determined in animals.

"["Treatment consists of discontinuation of Proventil HFA (Albuterol Sulfate Inhalation Aerosol) together with appropriate symptomatic therapy. The judicious use of a cardioselective beta receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Proventil HFA (albuterol sulfate) Inhalation Aerosol." deleted]

DOSAGE AND ADMINISTRATION:

Sentence added at the end of the first paragraph -

"It is recommended to prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks by releasing four "test sprays" into the air, away from the face."

Exercise Induced Bronchospasm Prevention: Text added as new first sentence -

"The usual dosage for adults and children 12 years of age and older is 2 inhalations 30 minutes before exercise."

Text added as new third paragraph -

"If a previously effective dosage regimen fails to provide the usual response, this may be a marker of destabilization of asthma and requires reevaluation of the patient and the treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids."

CAUTION:

Third paragraph revised (new text in italics) -

"The yellow actuator supplied with Proventil HFA (albuterol sulfate) Inhalation Aerosol) should not be used with any other product canisters, and ["only with the actuator provided. The" deleted] actuator from other products should not be used with ["other aerosol medications" deleted] a Proventil-HFA canister. The correct amount of medication in each canister cannot be assured after 200 actuations, even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations have been used."

PATIENT'S INSTRUCTIONS FOR USE:

Bullet #7 moved to become new bullet #2 and revised (new text in italics) -

"2. As with all aerosol medications, it is recommended to prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks. ["Test" deleted] Prime by releasing four 'test sprays" into the air, away from your face."

The subsequent bullets renumbered appropriately.

Bullet #8 revised (new text in italics) -

"The correct amount of medication in each inhalation cannot be assured ["Proventil HFA (Albuterol Sulfate Inhalation Aerosol) will deliver at least" deleted] after 200 ["spray" deleted] actuations even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations have been used. ["However, after 200 sprays, the amount of drug delivered per spray may not be consistent. You should keep track of the number of sprays used from each canister of Proventil HFA (Albuterol Sulfate Inhalation Aerosol) and discard the canister after 200 sprays." deleted] Before you reach the specific number of actuations, you should consult your physician to determine whether a refill is needed. Just as you should not take extra doses without consulting your physician, you also should not stop using Proventil HFA without consulting your physician."

Warnings: First paragraph, next to last sentence revised (new text in italics) -

"Use Proventil HFA (albuterol sulfate) Inhalation Aerosol only with the yellow actuator supplied with the product."

CLINICAL PHARMACOLOGY:

Microbiology: In "The following in vitro data are available, but their clinical significance is unknown." subsection (latter clause added to subsection title)

the following new subsection is added -

"Other Microorganisms: Legionella pneumophila"

Return to Quick Reference

Return to Quick Reference

ADVERSE REACTIONS:

Post-Marketing Experience (new subsection): -

"The following adverse reactions have been reported in post-marketing use: hypersensitivity reactions, including anaphylaxis, angioedema, pruritus, and urticaria"

PATIENT PACKAGE INSERT:

What are the possible side effects of Singulair? -

Addition of the following text -

"Additionally, the following have been reported: allergic reactions including swelling of the face, lips, tongue, and/or throat, which may cause difficulty in breathing or swallowing; hives, and itching."

Return to Quick Reference

PRECAUTIONS:

General: Subsection revised -

First paragraph, first sentence deleted -

"Because Trovan can cause elevations of liver function tests during or soon after prolonged therapy (i.e., >/= 21 days), periodic assessment of hepatic function is advisable."

Paragraph added at end of subsection -

"During the post-marketing period, Trovan-associated liver enzyme abnormalities and/or symptomatic hepatitis have occurred during short-term or long-term therapy. Liver enzyme abnormalities have been reported in both men and women. Liver failure (including acute hepatic necrosis with eosinophilic infiltration) has also been reported rarely. Symptomatic pancreatitis has been reported on therapy. Clinicians should monitor liver function tests and pancreatic tests in patients who develop symptoms consistent with hepatitis and/or pancreatitis as clinically indicated."

ADVERSE REACTIONS:

Laboratory Changes: Last sentence revised (new text in italics) -

"["(See PRECAUTIONS - General)" deleted] (See ADVERSE REACTIONS: Post-marketing experience subsection.)"

Post-marketing experience (new subsection):

"Adverse reactions reported with Trovan during the post-marketing period include: anaphylaxis, symptomatic hepatitis (some patients experienced an associated peripheral eosinophilia), liver failure (including acute hepatic necrosis with eosinophilic infiltration), Stevens-Johnson Syndrome, and symptomatic pancreatitis.

"During the post-marketing period, Trovan-associated liver enzyme abnormalities and/or symptomatic hepatitis have occurred during short-term or long-term therapy. (See PRECAUTIONS.)"

Return to Quick Reference

ADVERSE REACTIONS:

-

Text added as new paragraph or existing paragraph revised to be consistent with the following text -

"Cases of urticaria, angioedema, rash, bronchospasm, hoarseness [Note: in inhlation solution & nebules inhalation solution only], oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles) have been reported after the use of Ventolin Tablets/Syrup/Inhalation Solution/Nebules Inhalation Solution."

PRECAUTIONS:

General: Text added as new second and third paragraphs -

"For ophthalmic use only. The initial prescription and renewal of the medication order beyond 14 days should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. If signs and symptoms fail to improve after two days, the patient should be re-evaluated.

"If this product is used for 10 days or longer, intraocular pressure should be monitored even though it may be difficult in children and uncooperative patients (see WARNINGS)."

Return to Quick Reference

Return to Quick Reference

PRECAUTIONS:

Antiretroviral Pregnancy Registry: (new subsection) -

"To monitor maternal-fetal outcomes of pregnant women exposed to stavudine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263."

Return to Quick Reference

ADVERSE REACTIONS:

Post-Marketing Experience: (new subsection) -

"Rash and urticaria have been reported with Zyflo."

Return to Quick Reference