AMINOHIPPURATE(PAH) (aminohippurate sodium)	AMINOSYN-HBC (amino acid injection)	CERVIDIL (dinoprostone)	CILOXAN (ciprofloxacin HCl)
DIOVAN (valsartan)	FLOLAN (epoprostenol sodium)	FOSAMAX (alendronate sodium)	HEPARIN (heparin)
HUMEGON (menotropins)	IOBENGUANE (iobenguane sulfate)	LOESTRIN & LOESTRIN FE (norethindrone acetate/ethinyl estradiol/+ ferrous fumarate)	MEGACE (megestrol acetate)
MERIDIA (sibutramine HCl monohydrate)	NEGGRAM (nalidixic acid)	NITROLINGUAL (nitroglycerin)	NOR-QD (norethindrone)
NUTROPIN (somatropin)	OCUFLOX (ofloxacin)	OMNICEF (cefdinir)	ORAP (pimozide)
PARAPLATIN (carboplatin)	PARLODEL (bromocriptine)	PREGNYL (chorionic gonadotropin)	VEXOL (rimexolone)
VIRACEPT (nelfinavir)	ZOCOR (simvastatin)	ZOLADEX (goserelin acetate)

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PRECAUTIONS:

Geriatrics: New subsection -

"Clinical studies of PAH did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients."

ADVERSE REACTIONS:

First sentence revised (new text in italics)-

" Hypersensitivity reactions, vasomotor disturbances, flushing, tingling nausea, vomiting, and cramps."

PRECAUTIONS:

Geriatric: New subsection:

"Clinical studies of Aminosyn-HBC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."

DOSAGE AND ADMINISTRATION:

Last sentence revised (new text in italics) -

"Patients should remain in the ["supine" deleted] recumbent position for 2 hours following insertion, but thereafter may be ambulatory."

STORAGE CONDITIONS:

Text revised (new text in italics) -

"Solution: Store at ["2^o to 30^o C (36^o to 86^o F)." deleted] 36^o to 77^o F (2^o to 25^o C). "

[Other labeling changes not appearing in the 1999 PDR: Nov98, Jun99]

PRECAUTIONS:

Impaired Renal Function: First paragraph, last sentence deleted -

"Diovan would be expected to behave similarly"

Replaced with -

"Similar outcomes have been reported with Diovan."

ADVERSE REACTIONS:

Post-Marketing Experience: The following three categories added after "Digestive" -

"Renal: Impaired renal function;
Clinical Laboratory Tests: Hyperkalemia;
Dermatologic: Alopecia."

Clinical Laboratory Test Findings: Serum Potassium: Last sentence deleted -

"No patient treated with valsartan discontinued therapy for hypekalemia."

PRECAUTIONS:

Geriatric Use: Subsection revised (new text in italics) -

"Clinical studies of Flolan in pulmonary hypertension did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy."

[Other labeling changes not appearing in 1999 PDR: May98, Mar99, Jun99]

CLINICAL PHARMACOLOGY:

Clinical Studies: Subsection extensively revised including the addition of a new subsection: "Concomitant use with estrogen/hormone replacement therapy (HRT)" Contact the company for a copy of the new labeling/package insert.

PRECAUTIONS:

Subsection: "Estrogen" Deleted -

"The safety and effectiveness of the concomitant use of hormone replacement therapy and Fosamax in postmenopausal women has not been established."

Replaced with -

Estrogen/hormone replacement therapy (HRT):

"Concomitant use of HRT (estrogen ± progestin) and Fosamax was assessed in two clinical studies of one or two years' duration in postmenopausal osteoporotic women. In these studies, the safety and tolerability profile of the combination was consistent with those of the individual treatments; however, the degree of suppression of bone turnover (as assessed by mineralizing surface) was significantly greater with the combination than with either component alone. The long-term effects of combined Fosamax and HRT on fracture occurrence have not been studied (see CLINICAL PHARMACOLOGY, Clinical Studies, Concomitant use with estrogen/hormone replacement therapy (HRT) and ADVERSE REACTIONS, Clinical Studies, Concomitant use with estrogen/hormone replacement therapy)."

[Other labeling changes not appearing in 1999 PDR: Mar98, Aug98, Sep98, Sep99]

CLINICAL PHARMACOLOGY:

The following sentence moved from the second paragraph to a third, stand alone paragraph and revised to read:

"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: 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: [(2 USP Units/mL) in 0.9% Sodium Chloride Injection in Flexible Plastic Container] label

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

Geriatric Use:

[(2 USP Units/mL) in 0.9% Sodium Chloride Injection in Flexible Plastic Container] label:
"A higher incidence of bleeding has been reported in patients over 60 years of age, especially women (see PRECAUTIONS, General and CLINICAL PHARMACOLOGY)."

[12,500 or 25,000 USP Units of Heparin Sodium in 0.45% Sodium Chloride Injection and Heparin Sodium in 5% Dextrose Injection] label:
"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 CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION)."

PRECAUTIONS:

Pediatric Use: New subsection -

"Safety and effectiveness in pediatric patients have not been established"

Geriatric Use: New subsection -

"Clinical studies of Humegon (menotropins for injection, USP) did not include subjects aged 65 and older."

GERIATRIC USE:

"Clinical studies of Iobenguane Sulfate I-131 did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy."

[Other labeling changes not appearing in 1999 PDR: Jan98]

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CLINICAL PHARMACOLOGY:

Clinical Studies: MAXALT-MLT Orally Disintegrating Tablets -

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

ADVERSE REACTIONS:

Other Adverse Reactions: Inserted between "hot flashes" and "sweating and rash"

"malaise, asthenia, lethergy,"

ADVERSE REACTIONS:

Glucocorticoid Effects: Subsection revised -

"(See WARNINGS section ["PRECAUTIONS' DELETED])"

ADVERSE REACTIONS:

Second paragraph, first sentence revised (new text in italics) -

"In placebo-controlled obesity studies, the most common events were dry mouth, anorexia, insomnia, constipation and headache."

Urogenital System: "menstrual disorder" changed to: "menstrual disorders"

Postmarketing Reports New subsection - (preceding Other Notable Adverse Events) -

"Voluntary reports of adverse events temporally associated with the use of Meridia are listed below. It is important to emphasize that although these events occurred during treatment with Meridia, they may have no causal relationship with the drug. Obesity itself, concurrent disease states/risk factors, or weight reduction may be associated with increased risk for some of these events.

" Body as a Whole: anaphylactic shock, anaphylactoid reaction, facial edema, fluid retention, lack of drug effect.
Cardiovascular: angina pectoris, abnormal ECG, arrhythmia, atrial fibrillation, cerebrovascular accident, chest pressure, chest tightness, congestive heart failure, heart arrest, heart rate decreased, hemorrhage, myocardial infarction, sudden unexplained death, supraventricular tachycardia, syncope, torsade de pointes, transient ischemic attack, ventricular extrasystoles, ventricular fibrillation, ventricular tachycardia.
Digestive: abnormal stools, cholecystitis, cholelithiasis, duodenal ulcer, eructation, gastrointestinal hemorrhage, increased salivation, intestinal obstruction, mouth ulcer, stomach ulcer, tongue edema.
Endocrine: goiter, hyperthyroidism, hypothyroidism.
Hemic and Lymphatic: anemia, leukopenia, lymphadenopathy, petechiae, thrombocytopenia.
Metabolic and Nutritional: hyperglycemia, hypoglycemia.
Musculoskeletal: arthrosis, bursitis.
Nervous: abnormal dreams, abnormal gait, amnesia, anger, concentration impaired, confusion, depression aggravated, Gilles de la Tourette's syndrome, hypesthesia, libido decreased, libido increased, manic reaction, mood changes, nightmares, serotonin syndrome, short term memory loss, speech disorder, tremor, twitch, vascular headache, vertigo.
Respiratory: epistaxis, nasal congestion, respiratory disorder, yawn.
Skin and Appendages: alopecia, dermatitis, limb pain, photosensitivity, urticaria.
Special Senses: abnormal vision, blurred vision, dry eye, eye pain, increased intraocular pressure, otitis externa, otitis media, photosensitivity, tinnitus.
Urogenital: abnormal ejaculation, hematuria, impotence, increased urinary frequency, micturition difficulty."

PRECAUTIONS:

Information for Patients: New last paragraph added:

"Patients should be advised that convulsions have been reported in patients taking quinolones, including Nalidixic acid, and to notify their physician before taking this drug if there is a history of this condition. Patients should be advised that mineral supplements, vitamins with iron or minerals, calcium-, aluminum-, magnesium-based antacids, sucralfate or Videx, (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution should not be taken within the two-hour period after taking nalidixic acid (see Drug Interactions). "

Drug Interactions: Text revised (new text in italics) -

"Antacids containing magnesium, aluminum, or calcium; sucralfate or divalent or trivalent cations such as iron; multivitamins containing zinc; and Videx, (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution may substantially interfere with the absorption of quinolones, resulting in ["urine" deleted] systemic levels considerably lower than desired. ["They should not be given concomitantly or within two hours of the administration of quinolones." deleted] These agents should not be taken within the two hour period before or within the two-hour period after nalidixic acid administration."

Geriatric Use: New subsection:

"Clinical studies of Negram did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution should therefore be observed in using nalidixic acid in elderly patients. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See PRECAUTIONS, General.)"

DOSAGE AND ADMINISTRATION:

New first paragraph -

"Antacids containing calcium, magnesium, or aluminum; sucralfate; divalent or trivalent cations such as iron; multivitamins containing zinc; or Videx (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution should not be taken within the two hour period before or within the two-hour period after taking naladixic acid."

[Other labeling changes not appearing in 1999 PDR: Jan99]

INFORMATION FOR THE PATIENT:

"200 sprays" has been replaced with "75 or 200 sprays" throughout

DESCRIPTION:

"nitroglycerin lingual spray 0.4 mg"

Replaced with -

"nitroglycerin lingual spay 400 mcg"

And "200 metered sprays"

Replaced with -

"75 or 200 metered sprays"

DOSAGE AND ADMINISTRATION:

Second paragraph -

"Each metered spray of Nitrolingual Pumpspray delivers 48 mg of solution containing 400 mcg of nitroglycerin after an initial priming of 1 spray. It will remain adequately primed for 6 weeks. If the product is not used within 6 weeks it can be adequately primed with 1 spray. There are 75 or 200 metered sprays per bottle. The total number of available doses is dependent, however, on the number of total sprays per use (1 or 2 sprays), and the frequency of repriming."

HOW SUPPLIED:

"Each unit contains 12 g (Net Content) of nitroglycerin lingual spray which will deliver 200 metered sprays containing 400 mcgs of nitroglycerin per spray (NDC 0075-0852-04)."

Replaced with -

"Each unit contains 5.7 g or 12 g (Net Content) of nitroglycerin spray which will deliver 75 or 200 metered sprays containing 400 mcgs of nitroglycerin per spray (NDC 0075-0852-04)."

Store At Room Temperature:

"Do not expose to temperatures exceeding 40^oC (104F)."

Replaced with -

"Store at 25^oC (77^oF); excursions permitted to 15-30^oC (59-86^oF)[see USP Controlled Room Temperature]."

Extensive revisions to the following sections in the 1998 PDR:
WARNINGS
PRECAUTIONS
Contact the company for a copy of the new labeling/package insert.

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CONTRAINDICATIONS:

New first paragraph -

"Growth hormone should not be initiated to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or to patients having acute respiratory failure. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin-treated patients (5.3-8 mg/day) compared to those receiving placebo (see WARNINGS)."

WARNINGS:

New first paragraph -

"See CONTRAINDICATIONS for information on increased mortality in patients with acute critical illnesses in intensive care units due to complications following open heart or abdominal surgery, multiple accidental trauma or with acute respiratory failure. The safety of continuing growth hormone treatment in patients receiving replacement doses for approved indications who currently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with growth hormone in patients having acute critical illnesses should be weighed against the potential risk."

PRECAUTIONS:

New third paragraph -

"Geriatric Usage: Clinical studies of Nutropin (AQ) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."

PRECAUTIONS:

Geriatric Use: New subsection -

"No overall differences in safety or effectiveness have been observed between elderly and younger patients."

ADVERSE REACTIONS:

Ophthalmic Use: Second and third sentences revised (new text in italics) -

"Other reported reactions include stinging, redness, itching, chemical conjunctivitis/keratitis, ocular/periocular/facial edema, foreign body sensation, photophobia, blurred vision, tearing, dryness and eye pain. Rare reports of dizziness and nausea have been received."

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[Other information regarding these changes: Letter PDF Format ]

CLINICAL PHARMACOLOGY:

Metabolism and Pharmacokinetics: Second paragraph, new second sentence -

"This metabolism is catalyzed mainly by the cytochrome P450 3A (CYP 3A) enzymatic system and to a lesser extent, by cytochrome P450 1A2 (CYP 1A2)."

New fourth paragraph -

"Effects of food and disease upon the absorption, distribution, metabolism and elimination of pimozide are not known. Effects of concomitant medication on pimozide metabolism are described in the CONTRAINDICATIONS section."

CONTRAINDICATIONS:

Item number 6., last sentence revised (new text in italics) -

"For these reasons, Orap is contraindicated in patients receiving the macrolide antibiotics clarithromycin, erythromycin, azithromycin, dirithromycin, and troleandomycin."

New third and fourth sentences added to paragraph following the numbered items -

"Nefazodone is a potent inhibitor of CYP 3A, and its concomitant use with Orap is also contraindicated. Other drugs that are relatively less potent inhibitors of CYP 3A should be avoided, in view of the risks; e.g. zileuton."

PRECAUTIONS:

Information for Patients: New last paragraph -

"Because substances in grapefruit juice may inhibit the metabolism of pimozide by CYP 3A, patients should be advised to avoid grapefruit juice."

Drug Interactions: New second, third and fifth paragraphs -

"Since Orap is partly metabolized via CYP 3A, it should not be administered concomitantly with inhibitors of this metabolic system, such as azole antifungal agents and protease inhibitor drugs (see CONTRAINDICATIONS).

"As CYP 1A2 may also contribute to the metabolism of Orap, prescribers should be aware of the theoretical potential for drug interactions with inhibitors of this enzymatic system.

"A single case report has suggested possible additive effects of pimozide and flouxetine leading to bradycardia."

Interactions with Food New subsection -

"Patients should avoid grapefruit juice because it may inhibit the metabolism of pimozide by CYP 3A."

WARNINGS:

Fourth paragraph, second sentence added -

"Clinically significant hearing loss has been reported to occur in pediatric patients when Paraplatin was administered at higher than recommended doses in combination with other ototoxic agents"

Eighth paragraph, last sentence added -

"There is increased risk of allergic reactions including anaphylaxis in patients previously exposed to platinum therapy. (See CONTRAINDICATIONS and ADVERSE REACTIONS: Allergic Reactions.)"

PRECAUTIONS:

Carcinogenesis, Mutagenesis, Impairment of Fertility: New last sentence:

"Secondary malignancies have been reported in association with multi-drug therapy."

Pediatric Use: Text revised (new text in italics) -

Safety and effectiveness in pediatric patients have not been established (see WARNINGS; "audiologic toxicity".

ADVERSE REACTIONS:

Allergic Reactions: New third sentence:

"Anaphylactic reactions have been reported as part of postmarketing surveliiance (see WARNINGS)."

Other Events: New last paragraph:

"Malaise, anorexia, and hypertension has been reported as part of postmarketing surveillance."

PRECAUTIONS:

Pediatric Use: Previous paragraph deleted -

"Safety and effectiveness in pediatric patients under the age of 15 have not been established."

Replaced with -

"The safety and effectiveness of bromocriptine for the treatment of prolactin-secreting pituitary adenomas have been established in patients age 16 to adult. No data are available for bromocriptine use in pediatric patients under the age of 8 years. A single 8-year old patient treated with bromocriptine for a prolactin-secreting pituitary macroadenoma has been reported without therapeutic response.

"The use of bromocriptine for the treatment of prolactin-secreting adenomas in pediatric patients in the age group 11 to under 16 years is supported by evidence from well-controlled trials in adults, with additional data in a limited number (n=14) of children and adolescents 11 to 15 years of age with prolactin-secreting pituitary macro- and microadenomas who have been treated with bromocriptine. Of the 14 reported patients, 9 had successful outcomes, 3 partial responses, and 2 failed to respond to bromocriptine treatment. Chronic hypopituitarism complicated macroadenoma treatment in 5 of the responders, both in patients receiving bromocriptine alone and in those who received bromocriptine in combination with surgical treatment and/or pituitary irradiation.

"Safety and effectiveness of bromocriptine in pediatric patients have not been established for any other indication listed in the INDICATION AND USAGE section."

DOSAGE AND ADMINISTRATI0N:

Hyperprolactinemia Indications: New second paragraph -

"Based on limited data in children of age 11 to 15, (see Pediatric Use subsection) the initial dose is one-half to one 2.5 mg scored tablet daily. Dosing may need to be increased as tolerated until a therapeutic response is achieved. The therapeutic dosage ranged from 2.5-10 mg daily in children with prolactin-secreting pituitary adenomas"

DESCRIPTION:

Next to last sentence revised (new text in italics) -

"Each package also contains a 10 mL vial of solvent containing: water for injection with 0.56% sodium chloride and 0.9% BENZYL ALCOHOL, WHICH IS NOT FOR USE IN NEWBORNS."

PRECAUTIONS:

Geriatric Use New subsection:

"Clinical studies of Pregnyl (chorionic gonadotropin for injection, USP) did not include subjects aged 65 and over."

Subsections renamed as follows:

Number 1. to "Pediatric Use"
Number 2. to "General"

STORAGE:

The following text deleted:

"Store at 40^oF to 86^oF (4^oC to 30^oC)"

Replaced with:

"Store at 40^oF to 77^oF (4^oC to 25^oC)"

[Other labeling changes not appearing in 1999 PDR: May99]

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[Other labeling changes not appearing in 1999 PDR: Aug99, Sep99]

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[Other labeling changes not appearing in 1999 PDR: Jul98]

INDICATIONS AND USAGE:

Prostatic Carcinoma: The following text deleted from the 10.8 mg label -

"Zoladex offers an alternative treatment of prostatic cancer when orchiectomy or estrogen administration are either not indicated or unacceptable to the patient."

CONTRAINDICATIONS:

New first sentence for the 3.6 mg label (in 1999 PDR for the 10.8 mg label) -

"A report of an anaphylactic reaction to synthetic GnRH (Factrel) has been reported in the medical literature."

ADVERSE REACTIONS:

General: Text added -

"Changes in blood pressure, manifest as hypotension or hypertension, have been occasionally observed in patients administered Zoladex. The changes are usually transient, resolving either during continued therapy or after cessation of therapy with Zoladex. Rarely, such changes have been sufficient to require medical intervention including withdrawal of treatment from Zoladex."

Males - Prostatic Carcinoma: (General subsection for 10.8 mg label) Text added -

"Osteoporosis, decreased bone mineral density and bony fracture associated with osteoporosis have been reported rarely in men treated with Zoladex for prostate cancer."