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

(Posted: 5/29/98, Daraprim & Lupron added 7/7/98)

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.

Quick Reference:

(Click on name of the product to go directly to the summary.)

ATROVENT (ipratropium bromide)	AXID AR (nizatidine)	CIPRO (ciprofloxacin & ciprofloxacin HCl)	CLARITIN-D (loratadine/ pseudoephedrine sulfate)	CORVERT (ibutilide fumarate)
COZAAR (losartan potassium)	DARAPRIM (pyrimethamine)	DIDRONEL (etidronate disodium)	DOPAMINE HCl	HYZAAR (losartan potassium/ hydrochlorothiazide)
IDAMYCIN (idarubicin HCl)	LUPRON (leuprolide acetate)	MEVACOR (lovastatin)	NITROLINGUAL (nitroglycerin)	ORTHO-CYCLEN & ORTHO TRI-CYCLEN (norgestimate/ ethinyl estradiol)
PARLODEL (bromocriptine mesylate)	PONSTEL (mefenamic acid)	PRIMAXIN (imipenem/ cilastatin)	RISPERDAL (risperidone)	SEPTRA & SEPTRA DS (trimethoprim/ sulfamethoxazole)
TAXOL (paclitaxel)	UNIVASC (moexipril HCl)	VIDEX (didanosine)	ZOLADEX (goserelin acetate)

CLINICAL PHARMACOLOGY:

Pharmacokinetics: Section extensively revised. See the new labeling/package insert.

PRECAUTIONS:

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

"The safety of Atrovent (ipratropium bromide) Nasal Spray 0.03% at a dose of two sprays (42 mcg) per nostril two or three times daily (total dose 168 to 252 mcg/day) has been demonstrated in 77 pediatric patients 6-12 years of age in placebo-controlled, 4-week trials and in 55 pediatric patients in active controlled, 6-month trials. The effectiveness of Atrovent (ipratropium bromide) Nasal Spray 0.03% for the treatment of rhinorrhea associated with allergic and nonallergic perennial rhinitis in this pediatric age group is based on an extrapolation of the demonstrated efficacy of Atrovent (ipratropium bromide) Nasal Spray 0.03% in adults with these conditions and the likelihood that the disease course, pathophysiology, and the drug's effects are substantially similar to that of the adults. The recommended dose for the pediatric population is based on within and cross-study comparisons of the efficacy of Atrovent (ipratropium bromide) Nasal Spray 0.03% in adults and pediatric patients and on its safety profile in both adults and pediatric patients. The safety and effectiveness of Atrovent (ipratropium bromide) Nasal Spray 0.03% in patients ["below the age of 12 years" deleted] under 6 years of age have not been established."

DIRECTIONS

Labeling and labels revised to change the time to take the drug prior to a meal to prevent meal-induced heartburn symptoms from "...one-half hour to one hour before eating..." to "...right before eating or up to 60 minutes before consuming...".

The graphical representations of the pivotal study results concerning the prevention of heartburn symptoms have been revised (See new labeling/package insert.)

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PRECAUTIONS:

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

"Safety and effectiveness in pediatric patients and adolescents less than 18 years of age have not been established. Ciprofloxacin causes arthropathy in juvenile animals. (See WARNINGS.)

"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 definitively determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as part of their underlying disease process."

Note: In Tablet labeling, ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, HOW SUPPLIED and CLINICAL STUDIES Sections revised to include information about Oral Suspension.

CLINICAL PHARMACOLOGY:

Clinical Studies:

Paragraph added to subsection -

"In a single-rising dose study of loratadine alone in which doses up to 160 mg (16 times the clinical dose) were administered, no clinically significant changes on the QTc interval in the ECGs were observed."

PRECAUTIONS:

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Subsection revised (new text in italics) -

"No animal studies have been conducted to determine the carcinogenic potential of Corvert; however, it was not genotoxic in a battery of assays (["including the" deleted] Ames assay, mammalian cell forward gene mutation assay, unscheduled DNA synthesis assay, and mouse micronucleus assay).

"Similarly, no drug-related effects on fertility or mating were noted in a reproductive study in rats in which ibutilide was administered orally to both sexes up to doses of 20 mg/kg/day. On a mg/m² basis, corrected for 3% bioavailability, the highest dose tested was approximately four times the maximum recommended human dose (MRHD)."

Pregnancy: Pregnancy Category C:

First sentence revised (new text in italics) -

"Ibutilide administered orally was teratogenic (abnormalities included adactyly, ["cleft palate" deleted] interventricular septal defects, and scoliosis) and embryocidal in reproduction studies in rats."

ADVERSE REACTIONS:

Post-Marketing Experience: Subsection revised (new text in italics) -

"The following additional adverse reactions have been reported in post-marketing experience: Hypersensitivity: Angioedema (involving 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; Digestive: Hepatitis (reported rarely).

"Hyperkalemia has been reported."

INDICATIONS AND USAGE:

Section reorganized and revised (new text in italics) -

"Treatment of Toxoplamosis: Daraprim is ["also" deleted] indicated for the treatment of toxoplasmosis [". For this purpose the drug should be" deleted] when used conjointly with a sulfonamide, since synergism exists with this combination.

"Treatment of Acute Malaria: Daraprim is also indicated for the treatment of acute malaria. It should not be used alone to treat ["an" deleted] acute ["attack of" deleted] malaria. Fast-acting schizonticides such as chloroquine or quinine are indicated and preferable for the treatment of acute malaria. However, conjoint use of Daraprim with a sulfonamide (e.g., sulfadoxine) will initiate transmission control and ["suppressive cure for" deleted] suppression of susceptible strains of plasmodia.

"Chemoprophylaxis of Malaria: Daraprim ["pyrimethamine" deleted] is indicated for the chemoprophylaxis of malaria due to susceptible strains of plasmodia. However, resistance to pyrimethamine is prevalent worldwide. It is not suitable as a prophylactic agent for travelers to most areas."

WARNINGS:

New text added as second and third paragraphs -

"Data in two humans indicate that pyrimethamine may be carcinogenic: a 51-year-old female who developed chronic granulocyctic leukemia after taking pyrimethamine for 2 years for toxoplasmosis, ³ and a 56-year-old patient who developed reticulum cell sarcoma after 14 months of pyrimethamine for toxoplamosis.⁴

"Pyrimethamine has been reported to produce a significant increase in the number of lung tumors in mice when given intraperitoneally at doses of 25 mg/kg.⁵"

PRECAUTIONS:

Information For Patients: Paragraph revised at end of subsection (new text in italics) -

"Women of childbearing potential who are taking Daraprim should be warned against becoming pregnant. Patients should be warned to keep Daraprim out of the reach of children. Patients should be advised not to exceed recommended doses. Patients should be warned that if anorexia and vomiting occur, they may be minimized by taking the drug with meals.

"Concurrent administration of folinic acid is strongly recommended when used for the treatment of toxoplasmosis in all patients."

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Sentence added at beginning of subsection -

"See WARNINGS section for information on carcinogensis."

Carcinogenesis: Subsection deleted.

Impairment of Fertility: Subsection deleted.

Pregnancy: Teratogenic Effects: Pregnancy Category C: First paragraph, first sentence revised (new text in italics) -

"Pyrimethamine has been shown to be teratogenic in rats [", hamsters, and Goettingen miniature pigs." deleted] when given in oral doses 7 times the human dose for chemoprophylaxis of malaria or 2.5 times the human dose for treatment of toxoplasmosis. At these doses in rats, there was a significant increase in abnormalities such as cleft palate, brachygnathia, oligodactyly, and microphthalmia. Pyrimethamine has also been shown to produce terata such as meningocele in hamsters and cleft palate in miniature pigs when given in oral doses 170 and 5 times the human dose, respectively, for chemoprophylaxis of malaria or for treatment of toxoplasmosis."

Last three paragraphs in subsection beginning "Thiersch reported that when rats ...", "Sullivan and Takacs found that less than 10% of hamster ...", and "Hayama and Kokue reported on the administration of ..." deleted.

Nursing Mothers: Subsection revised (new text in italics) -

"Pyrimethamine is excreted in human milk. ["Milk samples obtained from lactating mothers after treatment with pyrimethamine were found to have measurable concentrations of the drug, with peak concentration at 6 hours postadministration. It is estimated that after a single 75 mg dose of oral pyrimethamine, approximately 3 to 4 mg of the drug would be passed on to the feeding child over a 48-hour period. " deleted]

"Because of the potential for serious adverse reactions in nursing infants from ["Daraprim" deleted] pyrimethamine, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see ["Carcinogenesis, Mutagenesis, Impairment of Fertility and Pregnancy subsections" deleted] WARNINGS and PRECAUTIONS: Pregnancy)."

ADVERSE REACTIONS:

Section revised (new text in italics) -

"Hypersensitivity reactions, occasionally severe (such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and anaphylaxis), and hyperphenylalaninemia, can occur ["at any dose," deleted] particularly when pyrimethamine is administered concomitantly with a sulfonamide. With ["large" deleted] doses of pyrimethamine used for the treatment of toxoplasmosis, anorexia and vomiting may occur. Vomiting may be minimized by giving the medication with meals; it usually disappears promptly upon reduction of dosage. Doses used in toxoplasmosis may produce megaloblastic anemia, leukopenia, thrombocytopenia, pancytopenia, atrophic glossitis, hematuria, and disorders of cardiac rhythm. Hematologic effects, however, may also occur at low doses in certain individuals (see PRECAUTIONS: General).

"["Insomnia, diarrhea, headache, light-headedness, dryness of the mouth or throat, fever, malaise, dermatitis, abnormal skin pigmentation, depression, seizures," deleted]. Pulmonary eosinophilia, [", and hyperphenylalaninemia have" deleted] has been reported rarely."

OVERDOSAGE:

First sentence deleted -

"Acute intoxication may follow the ingestion of an excessive amount of pyrimethamine."

"Following the ingestion of 300 mg or more of pyrimethamine," added to beginning of next sentence which begins "Gastrointestinal and/or central nervous system ...."

Sentence added at end of section -

"Due to the long half-life of pyrimethamine, daily monitoring of peripheral blood counts is recommended for up to several weeks after the overdose until normal hematologic values are restored."

DOSAGE AND ADMINISTRATION:

The three subsections in the section reorganized and revised (new text in italics) -

"For Treatment of Toxoplasmosis: The dosage of Daraprim for the treatment of toxoplasmosis must be carefully adjusted so as to provide maximum therapeutic effect and a minimum of side effects. At the ["high" deleted] dosage required, there is marked variation in the tolerance to the drug. Young patients may tolerate higher doses than older individuals. Concurrent administration of folinic acid is strongly recommended in all patients.

"The adult starting dose is 50 to 75 mg of the drug daily together with 1 to 4 g daily of a sulfonamide of the sulfapyrimidine type, e.g. ["sulfadiazine" deleted] sulfadoxine. This dosage is ordinarily continued for 1 to 3 weeks, depending on the response of the patient and ["his" deleted] tolerance to ["the" deleted] therapy. The dosage may then be reduced to about one-half that previously given for each drug and continued for an additional 4 to 5 weeks.

"The pediatric dosage of Dararpim is 1 mg/kg per day divided into two equal daily doses; after 2 to 4 days this dose may be reduced to one-half and continued for approximately 1 month. The usual pediatric sulfonamide dosage is used in conjunction with Daraprim.

"For Treatment of Acute ["Attacks" deleted] Malaria: ["Daraprim is recommended in areas where only susceptible plasmodia exist. This drug is not recommended alone in the treatment of acute attacks of malaria in nonimmune persons." deleted] Daraprim is NOT recommended alone in the treatment of acute malaria. Fast-acting schizonticides, such as chloroquine or quinine, are indicated for treatment of acute ["attacks" deleted] malaria. However, ["conjoint" deleted] Daraprim at a dosage of 25 mg daily for 2 days with a sulfonamide will initiate transmission control and ["duppressive cure" deleted] suppression of non-falciparum malaria. Daraprim is only recommended for patients infected in areas where susceptible plasmodia exist. Should circumstances arise wherein Daraprim must be used alone in semi-immune persons, the adult dosage for ["an" deleted] acute ["attack"] malaria is 50 mg for 2 days; children 4 through 10 years old may be given 25 mg daily for 2 days. In any event, clinical cure should be followed by the once-weekly regimen described ["above" deleted] below for chemoprophylaxis. Regimens which include suppression should be extended through any characteristic periods of early recrudescence and late relapse, i.e., for at least 10 weeks in each case.

"For Chemopropylaxis of Malaria:
Adults and pediatric patients over 10 years - 25 mg (1 tablet) once weekly
Children 4 through 10 years - 12.5 mg (1/2 tablet) once weekly
Infants and children under 4 years - 6.25 mg (1/4 tablet) once weekly.
["Regimens planned to include suppressive cure should be extended through any characteristic periods of early recrudescence and late relapse for at least 10 weeks in each case." deleted and moved as last sentence in 'For Treatment of Acute Malaria' subsection.]"

CLINICAL PHARMACOLOGY:

Hypercalcemia of Malignancy: Text added as new third to last paragraph in subsection -

"In a multicenter study of Didronel I.V. Infusion, patients with elevated albumin-adjusted calcium levels received a single 24-hour infusion of 25 mg/kg body weight (13 patients: mean baseline adjusted calcium 13.3 +/- 0.3 mg/dl) or 30 mg/kg body weight (12 patients: 13.8 +/- 0.4 mg/dl). Following treatment, mean nadir adjusted calcium levels were 10.9 +/- 0.4 mg/dl and 10.5 +/- 0.3 mg/dl for the two doses respectively. There was a dose-related response with 69% of patients in the 25 mg/kg group and 92% in the 30 mg/kg group achieving at least a 15% reduction in adjusted calcium. The adjusted calcium returned to normal in 38% and 67% of patients in the 25 mg/kg and 30 mg/kg groups, respectively."

WARNINGS:

First paragraph, new text added before last sentence -

"In a study of Didronel I.V. Infusion administered in a 24-hour infusion, one patient with evidence of pre-existing renal insufficiency developed anuria 18 hours after initiation of the 30 mg/kg dose. (See PRECAUTIONS)"

OVERDOSAGE:

Text added as new third paragrpah -

"A dose of 30 mg/kg body weight per day of Didronel I.V. Infusion was continuously administered for 72 hours in one patient (total dose 90 mg/kg). No adverse experiences associated with the infusion were reported. Another patient with one kidney and slowly rising creatinine prior to therapy received 30 mg/kg body weight per day of Didronel I.V. Infusion for 48 hours (total dose 60 mg/kg). This patient reported altered taste and a further gradual increase in serum creatinine from 2.1 mg/dl to 2.7 mg/dl during the week after therapy was observed. (See PRECAUTIONS)"

DOSAGE AND ADMINISTRATION:

Didronel I.V. Infusion:

Table inserted at beginning of subsection -

Dosage Regimen
Dose	7.5 mg/kg body weight	25-30 mg/kg body weight
Duration of Treatment	3-7 days	1 day
Infusion Time	³ 2 Hours	24 Hours
Diluent Volume	³ 250 ml	³ 1000 ml

First paragraph revised (new text in italics) -

"The recommended dose of Didronel I.V. Infusion is 7.5 mg/kg body weight/day for three successive days. This daily dose must be diluted in at least 250 ml of sterile normal saline and may be added to volumes of fluid greater than 250 ml when this is convenient. Doses of 25 and 30 mg/kg body weight given as a single infusion over 24 hours have been administered to a limited number of patients. This single dose must be diluted in at least 1000 ml of sterile normal saline. (See Table Above) Stability studies show that diluted solution stored at controlled room temperature (59^oF to 86^oF or 15^oC to 30^oC) shows no loss of drug for a 48-hour period."

Second paragraph, second sentence deleted -

"Didronel I.V. infusion may be added to volumes of sterile normal saline greater than 250 ml when this is convenient."

Third paragraph, second sentence revised (new text in italic) -

"The minimum infusion time of two hours at the recommended dose (7.5 mg/kg body weight) or smaller doses should be observed."

Fourth paragraph, fourth sentence revised (new text in italics) -

"Retreatment with 7.5 mg/kg body weight for more than three days has not been adequately studied."

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ADVERSE REACTIONS:

Post-Marketing Experience: Subsection revised (new text in italics) -

"The following additional adverse reactions have been reported in post-marketing experience: Hypersensitivity: Angioedema (involving 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; Digestive: Hepatitis has been reported rarely in patients treated with losartan.

"Hyperkalemia has been reported with losartan."

CLINICAL STUDIES:

Hormonal Replacement Therapy (new subsection):

"Clinical studies suggest that the addition of hormone replacement therapy (estrogen and/or progestin) to Lupron is effective in reducing loss of bone mineral density which occurs with Lupron, without compromising the efficacy of Lupron in relieving symptoms of endometriosis. The optimal drug/dose is not established."

PRECAUTIONS:

Information for Patients: Bullet #5: Text added at end of last paragraph -

"Clinical studies suggest that the addition of hormone replacement therapy (estrogen and/or progestin) to Lupron is effective in reducing loss of bone mineral density which occurs with Lupron, without compromising the efficacy of Lupron in relieving symptoms of endometriosis. The optimal drug/dose is not established."

ADVERSE REACTIONS:

Changes in Bone Density: Subsection revised (new text in italics) - "In controlled clinical studies, patients with endometriosis (six months of therapy) or uterine fibroids (three months of therapy) were treated with Lupron Depot 3.75 mg. In endometriosis patients, vertebral bone density as measured by dual energy x-ray absorptionmetry (DEXA) decreased by an average of ["3.9%" deleted] 3.2% at six months compared with the pretreatment value. ["For those patients who were tested at six or twelve months after discontinuation of therapy, mean bone density returned to within 2% of pretreatment." deleted] .

"In this same study, Lupron Depot 3.75 mg alone and Lupron Depot 3.75 mg plus three different hormonal add-back regimens were compared for one year. All add-back groups demonstrated mean changes in bone mineral density of < or = 1% from baseline and showed statistically significantly (P-value < 0.001) less loss of bone density than the group treated with Lpron Depot 3.75 mg alone, at all time points. Clinical studies suggest that the addition of hormone replacement therapy (estrogen and/or progestin) to Lupron is effective in reducing loss of bone mineral density which occurs with Lupron, without compromising the efficacy of Lupron in relieving symptoms of endometriosis. The optimal drug/dose is not established.

"When Lupron Depot 3.75 mg was administered for three months in uterine fibroid patients, vertebral trabecular bone mineral density as assessed by quantitative digital radiography (QDR) revealed a mean decrease of 2.7% at three months compared with the pretreatment value. Six months after discontinuation of therapy a trend toward recoery was observed. Use of Lupron Depot 3.75 mg for uterine leiomyomata for longer than three months or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss and is not recommended."

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MEVACOR (lovastatin) Tablets
[April 22, 1998: Merck]

[Other labeling changes not reflected in the 1998 PDR: Aug97]

WARNINGS:

Skeletal Muscle: First paragraph, first sentence revised -

"Rhabdomyolysis has been associated with lovastatin therapy alone, when combined with immunosuppresive therapy including cyclosporine in ["cardiac" deleted] transplant patients, and when combined in non-transplant patients with either gemfibrozil of lipid-lowering doses (³ 1g/day) of nicotinic acid."

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

"Myopathy or rhabdomyolysis has occurred in transplant and non-transplant patients receiving Mevacor or another HMG-CoA reductase inhibitor following the initiation of treatment with the antifungal agents itraconazole and ketoconazole."

Third paragraph revised (new text in italics) -

"Rhabdomyolysis with or without renal impairment has been reported in ["seriously ill" deleted] patients receiving the macrolide antibiotics erythromycin and clarithroymycin concomitantly with lovastatin. Rhabdomyolysis has also been reported with the concomitant use of the antidepressant nefazodone and another HMG-CoA reductase inhibitor. Therefore, patients receiving concomitant lovastatin and ["erythromycin" deleted] macrolide antibiotics or nefazodone should be carefully monitored."

Sixth paragraph, beginning "Lovastatin therapy should be temporarily withheld...", sentence added at end of paragraph -

"Also, as there are no known adverse consequences of brief interruption of therapy, treatment with lovastatin should be stopped a few days before elective major surgery."

PRECAUTIONS:

Drug Interactions: First sentence revised (new text in italics) -

"Immunosuppressive Drugs, Itraconazole, Ketoconazole, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin, Clarithromycin, Nefazodone: See WARNINGS, Skeletal Muscle."

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NITROLINGUAL (nitroglycerin) Lingual Aerosol Spray
[April 24, 1998: Rhone-Poulenc Rorer]

PRECAUTIONS:

Carcinogenicity, Mutagenicity, Impairment of Fertility:

Second paragraph, third sentence deleted -

"Incidences of pituitary adenomas and female mammary tumors normally seen in aged rats were significantly reduced, consistent with treatment-related decrease in food intake and body weight; increased life span was also seen in the high dose females."

Pediatric Use Subsection revised (new text in italics) -

"The safety and effectiveness of nitroglycerin in ["children" deleted] pediatric patients have not been established."

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ORTHO-CYCLEN and ORTHO TRI-CYCLEN (norgestimate/ethinyl estradiol) Tablets
[April 20, 1998: RW Johnson]

CLINICAL PHARMACOLOGY:

Acne (new subsection):

"Acne is a skin condition with a multifactorial etiology. The combination of ethinyl estradiol and norgestimate may increase sex hormone binding globulin (SHBG) and decrease free testosterone resulting in a decrease in the severity of facial acne in otherwise healthy women with this skin condition." [Note: This change appears in the 1998 PDR.]

INDICATIONS AND USAGE:

Text added as new second paragraph -

"Ortho Tri-Cyclen is indicated for the treatment of moderate acne vulgaris in females, ³ 15 years of age, who have no known contraindications to oral contraceptive therapy, desire contraception, have achieved menarche and are unresponsive to topical anti-acne medications." [Note: This change appears in the 1998 PDR.]

WARNINGS:

1. Thomboembolic Disorders and Other Vascular Problems: a. Myocardial Infarction:

Text added as new last paragraph -

"Norgestimate has minimal androgenic activity (see CLINICAL PHARMACOLOGY), and there is some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestogen has minimal androgenic activity than when the activity is greater (97)."

3. Carcinoma of the Reproductive Organs and Breast: Second paragraph -

"A meta-analysis of 54 studies reports that women who are currently using combined oral contraceptives or have used them in the past 10 years are at a slightly increased risk of having breast cancer diagnosed although the additional cancers tend to be localized to the breast. There is no evidence of an increased risk of having breast cancer diagnosed 10 or more years after cessation of use."

deleted and replaced with -

"A meta-analysis of 54 studies found a small increase in the frequency of having breast cancer diagnosed for women who are currently using combined oral contraceptives or had used them within the past 10 years. this increase in the frequency of breast cancer diagnosis, within ten years of stopping use, was generally accounted for by cancers localized to the breast. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of use."

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

Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women (45-48)."

4. Hepatic Neoplasia: First sentence revised (new text in italics) -

"Benign hepatic adenomas are associated with combined oral contraceptive use, ..."

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PARLODEL (bromocriptine mesylate) Tablets & Capsules
[April 2, 1998: Novartis]

[Note: The following change appears in the 1998 PDR.]

PRECAUTIONS:

Pediatric Use: Subsection revised (new text in italics) "Safety and effectiveness in pediatric patients under the age of 15 have not been established."

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DOSAGE AND ADMINISTRATION:

Pediatric Use (new subsection):

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

DESCRIPTION:

First paragraph revised (new text in italics) -

"Septra (trimethoprim and sulfamethoxazole) is a synthetic antibacterial combination product. Each Septra Tablet contains 80 mg trimethoprim and 400 mg sulfamethoxazole and the inactive ingredients docusate sodium (0.4 mg per tablet), FD&C Red No. 40, magnesium stearate, povidone, and sodium starch glycolate.

"Each Septra DS (double strength) Tablet contains 160 mg trimethoprim and 800 mg sulfamethoxazole and the inactive ingredients docusate sodium (0.8 mg per tablet), FD&C Red No. 40, magnesium stearate, povidone, and sodium starch glycolate."

In addition the following changes are noted:

ADVERSE REACTIONS:

Respiratory: Sentence moved from "Other Clinical Events" and added to end of subsection -

"Rare reports of radiation pneumonitis have been received in patients receiving concurrent radiotherapy."

Other Clinical Events: Second paragraph revised (new text in italics) -

"Rare reports of skin abnormalities related to radiation recall as well as reports of maculopapular rash and pruritus have been received as part of the continuing surveillance of Taxol safety."

Text added as new third paragraph -

"Reports of asthenia and malaise have been received as part of the continuing surveillance of Taxol safety."

ADVERSE REACTIONS:

Respiratory: "Eosinophilic pneumonitis" has been added.

BOXED WARNING:

Text deleted and replaced with -

"WARNING
Pancreatitis, which has been fatal in some cases, has occurred during therapy with Videx. Videx use should be suspended in patients with signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis (see WARNINGS).

"Lactic acidosis and severe hepatomegaly with steatosis including fatal cases have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including didanosine (see WARNINGS)."

CLINICAL PHARMACOLOGY:

All text under Pharmacokinetics: Absorption, Distribution, Elimination: Metabolism and Elimination: Excretion has been deleted and replaced with the following -

Pharmacokinetics: "The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing. Increases in plasma didanosine concentrations were dose proportional over the range of oral doses administered in clinical practice. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines.

Table 1 Mean"SD Pharmacokinetic Parameters for Didanosine in Adult and Pediatric Patients
Parameter	Adult Patients	n	Pediatric Patients	n
Oral Bioavailability	42"12%	6	25"20%	46
Apparent volume of distributiona	1.08"0.22L/kg	6	28"15L/m2	49
CSF-plasma ratiob	21"0.03%	5	46% (range 12-85%)	7
Systemic clearancea	13.0"1.6 mL/min/kg	6	516"184 mL/min/m2	49
Renal clearanced	5.5"2.1 mL/min/kg	6	240"90 mL/min/m2	15
Elimination half-life	1.5"0.4hr	6	0.8"0.3hr	60
Urinary recovery of didanosined	18"8%	6	18"10%	15
CSF=cerebrospinal fluid afollowing IV administration bfollowing IV administration in adults and IV or oral administration in pediatric patients cmean"SE dfollowing oral administration

[NOTE: All tables have been renumbered. See new label/package insert and below.]

"Effect of Food on Absorption of Didanosine: Didanosine peak plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) were decreased by approximately 55% when Videx tablets were administered up to 2 hours after a meal. Administration of Videx tablets up to 30 minutes before a meal did not result in any significant changes in bioavailability. Videx should be taken on an empty stomach at least 30 minutes before or 2 hours after eating. (See DOSAGE AND ADMINISTRATION)."

All text under Special Populations: Renal Impairment:, Hepatic Impairment:, and Pediatric Patients: has been deleted and replaced with the following:

Special Populations: "Renal Insufficiency: It is recommended that the Videx (didanosine) dose be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis.

Table 2 Mean"SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose
Creatinine Clearance (mL/min)
Parameter	³ 90 (n=12)	60-90 (n=6)	30-59 (n=6)	10-29 (n=43)	Dialysis Patients (n=11)
CLcr	112"22	68"8	46"8	13"5	NDa
CL/F (mL/min)	2164"638	1566"833	1023"378	628"104	543"174
CLR	458"164	247"153	100"44	20"8	< 10
T1/2(hr)	1.42"0.33	1.59"0.13	1.75"0.43	2.0"0.3	4.1"1.2
aND=not determined due to anuria Clcr=creatinine clearance CL/F=apparent oral clearance CLR=renal clearance

"Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-infected pediatric patients from 0.7 to 18.9 years of age (see Table 1). Overall, the pharmacokinetics of didanosine in pediatric patients greater than 0.7 years of age are similar to those of didanosine in adults. Didanosine plasma concentrations increased in proportion to oral doses ranging from 80 to 180 mg/m². For information on controlled clinical trials in pediatric patients, see PRECAUTIONS, Pediatric Use."

Geriatric Patients (new subsection):

"Didanosine pharmacokinetics have not been studied in patients over 65 years of age."

Gender (new subsection):

"The effects of gender on didanosine pharmacokinetics have not been studied."

Drug Interactions (new subsection):

"Drug interaction studies have demonstrated that there are no clinically significant pharmacokinetic interactions between Videx and the following: dapsone, loperamide, metoclopramide, ranitidine, rifabutin, stavudine, sulfamethoxazole, trimethoprim, and zidovudine. Studies with loperamide, metoclopramide, ranitidine, sulfamethoxazole, and trimethoprim were single-dose studies, and effects on pharmacokinetics at steady-state are not known."

INDICATIONS AND USAGE:

Second and third paragraphs deleted -

"This indication is based on the results of four randomized, double-blind controlled clinical trials (see "Description of Clinical Data" and "PRECAUTIONS, Pediatric Use" subsections)

"The duration of clinical benefit from antiretroviral therapy may be limited. Alteration in antiretroviral therapy should be considered if disease progression occurs while receiving Videx."

WARNINGS:

Text deleted and replaced with -

"1. Pancreatitis
Pancreatitis, which has been fatal in some cases, has occurred during therapy with videx. Videx use should be suspended in patients with signs and symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. When treatment with other drugs known to cause pancreatic toxicity is required, suspension of Videx (didanosine) therapy is recommended. In patients with risk factors for pancreatitis, Videx should be used with extreme caution and only if clearly indicated. Patients with advanced HIV infection are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment.

"The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with high dose and 1% to 7% with recommended dose.

"In pediatric studies, pancreatitis occurred in 3% (2/60) of patients treated at entry doses below 300 mg/m²/day and in 13% (5/38) of patients treated at higher doses. Videx use should be suspended in pediatric patients with signs or symptoms of pancreatitis and discontinued in pediatric patients with confirmed pancreatitis.

"2. Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including didanosine. A majority of these cases have been in women. Caution should be exercised when administering Videx to any patient, and particularly to those with known risk factors for liver disease. Treatment with Videx should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

"3. Retinal and Visual Changes
Retinal changes and optic neuritis have been reported in adult and pediatric patients. Periodic retinal examinations should be considered for patients receiving Videx. (See ADVERSE REACTIONS.)"

PRECAUTIONS:

General: Text deleted and replaced with -

"The duration of clinical benefit from antiretroviral therapy may be limited. Patients receiving Videx or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases.

"Videx should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating."

Patients with Renal Impairment: Text deleted and replaced with -

"Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of toxicity from Videx due to decreased drug clearance (see CLINICAL PHARMACOLOGY section). A dose reduction is recommended in these patients (see DOSAGE AND ADMINISTRATION section). The magnesium content of each buffered tablet of Videx is 8.6 mEq. This may present an excessive load of magnesium to patients with significant renal impairment, particularly after prolonged dosing."

Patients with Hepatic Impairment: Text deleted and replaced with-

"It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity."

Diarrhea: Text deleted and replaced with -

"Videx Buffered Powder for Oral Solution was associated with diarrhea in 34% of patients in the phase 1 adult studies (see ADVERSE REACTIONS)."

Pediatric Use: Pharmacokinetic Characteristics in Pediatric Patients: Subsection deleted, as information now appears in table 1.

Drug Interactions: Name of subsection changed to Drug Interactions (see also CLINICAL PHARMACOLOGY, Drug Interactions):

Text deleted and replaced with -

"Coadministration of Videx with drugs that are known to cause pancreatitis may increase the risk of this toxicity (see WARNINGS) and should be done with extreme caution and only if clearly indicated. Neuropathy has occurred more frequently in patients with a history of neuropathy or neurotoxic drug therapy and these patients may be at increased risk of neuropathy during Videx therapy (see ADVERSE REACTIONS).

"Allopurinol: The AUC of didanosine was increased about 4-fold when allopurinol at 300 mg/day was coadministered with a single 200-mg dose of Videx to two patients with renal impairment (CL_cr=15 and 18mL/min). The effects of allopurinol on didanosine pharmacokinetics in subjects with normal renal function are not known.

"Antacids: Concomitant administration of antacids containing magnesium or aluminum with Videx Chewable/Dispersible Buffered Tablets or Pediatric Powder for Oral Solution may potentiate adverse events associated with the antacid components.

"Drugs Whose Absorption Can Be Affected by the Level of Acidity in the Stomach: Drugs such as ketoconazole and itraconazole should be administered at least 2 hours prior to dosing with Videx.

"Ganciclovir: Administration of Videx 2 hours prior to or concurrent with oral ganciclovir was associated with a 111 (+114)% increase in the steady-state AUC of didanosine (n=12). A 21 (+17)% decrease in the steady-state AUC of ganciclovir was observed when Videx was administered 2 hours prior to ganciclovir, but not when the two drugs were administered simultaneously (n=12).

"Quinolone Antibiotics: Videx should be administered at least 2 hours after or 6 hours before dosing with ciprofloxacin because plasma concentrations of ciprofloxacin are decreased when administered with antacids containing magnesium, calcium, or aluminum. In eight HIV-infected patients, the steady-state AUC of ciprofloxacin was decreased an average of 26% (95% CI=14%, 37%) when ciprofloxacin was administered 2 hours prior to a marketed chewable/dispersible tablet formulation of Videx. The AUC of ciprofloxacin was decreased an average of 15-fold in 12 healthy subjects given ciprofloxacin and didanosine-placebo tablets concurrently. In a single subject given one dose of ciprofloxacin 2 hours after a dose of didanosine -placebo tablets, a greater than 50% reduction in the AUC of ciprofloxacin was observed.

"Plasma concentrations of quinolone antibiotics are decreased when administered with antacids containing magnesium, calcium, or aluminum. The optimal dosing interval for coadministration with Videx should be determined by consulting the appropriate quinolone package insert."

ADVERSE REACTIONS:

First paragraph deleted and replaced with -

"The major toxicity of Videx (didanosine) is pancreatitis. Other important toxicities include lactic acidosis/severe hepatomegaly with steatosis and retinal/visual changes (see WARNINGS)."

Adults: First sentence deleted and replaced with -

"Clinical adverse events that occurred in at least 5% of adult patients in clinical trials with Videx monotherapy are provided in Table 6."

Table 6 (old Table 5) now entitled: "Clinical Adverse Events: Cumulative Incidence ³ 5%", with the following paragraph added after it -

"The frequency of peripheral neuropathy is related to dose and stage of disease. Patients should be monitored for the development of a neuropathy that is usually characterized by numbness, tingling or pain in the feet or hands. Neuropathy has occurred more frequently in patients with a history of neuropathy or neurotoxic drug therapy and these patients may be at increased risk of neuropathy during Videx therapy."

Third paragraph, first sentence deleted and replaced with -

"The cumulative incidences of serious laboratory abnormalities in clinical trials with Videx monotherapy are listed in Table 7."

Table 7 (old Table 6) now entitled "Cumulative Incidences of Serious Laboratory Abnormalities"

The last 6 paragraphs in ADVERSE REACTIONS:Adults deleted and replaced with -

"Observed during Clinical Practice: The following events have been identified during postapproval use of Videx. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to Videx, or a combination of these factors.

"Body as a Whole - alopecia and anaphylactoid reaction.
Digestive Disorders - anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders - sialoadenitis, parotid gland enlargement, dry mouth and dry eyes.
Liver-lactic acidosis and hepatic steatiosis (see WARNINGS); hepatitis and liver failure.
Metabolic Disorders - diabetes mellitus, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders - myalgia (with or without increases in creatinine phosphokinase), rhabdomyolysis including acute renal failure and hemodialysis, arthalgia, and myopathy.
Optical Disorders - Retinal depigmentation and optic neuritis (see WARNINGS).

Pediatric Patients: Third paragraph revised (new text in italics) - "Retinal changes and optic neuritis have been reported in ["several pediatric patients who received Videx at and above the recommended dose" deleted] pediatric patients.

DOSAGE AND ADMINISTRATION:

Dosage: Adults: Second sentence revised (new text in italics) -

"All Videx formulations should be administered on an empty stomach, at least 30 minutes before ["a meal" deleted] or 2 hours after eating."

Pediatric Patients: Second sentence revised (new text in italics) -

"All Videx formulations should be administered on an empty stomach, at least 30 minutes before ["a meal" deleted] or 2 hours after eating."

Dose Adjustment: First paragaraph, second sentence

"Only after pancreatitis has been ruled out should dosing be resumed."

deleted and replaced with -

"Videx use should be discontinued in patients with confirmed pancreatitis."

Paragraph beginning "In anuric patients requiring dialysis ..." deleted and replaced with -

"In adult patients with impaired renal function, the dose of Videx should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of Videx in adult patients with renal insufficiency are presented in Table 10."

Table 10 Recommended Dose (mg) of Videx by Body Weight
		$60 kg		#60 kg
Creatinine Clearance (mL/min)	Tableta	Solutionb	Tableta	Solutionb	Interval (hr)
$60	200	250	125	167	12
30-59	100	100	75	100	12
10-29	150	167	100	100	24
<10	100	100	75	100	24
a Videx Chewable/Dispersible Buffered Tablet. Two Videx tablets must be taken with each dose; different strengths of tablets may be combined to yield the recommended dose. b Videx Buffered Powder for Oral Solution

"Urinary excretion is also a major route of elimination of didanosine in pediatric patients; therefore, the clearance of didanosine may be altered in children with renal impairment. Although there are insufficient data to recommend a specific dose adjustment of Videx in this patient population, a reduction in the dose and/or an increase in the interval between doses should be considered.

Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis (new subsection): "It is recommended that one fourth of the total daily dose of Videx be administered once a day (see Table 10, recommended dosage for patients with CL_cr < 10mL/min). It is not necessary to administer a supplemental dose of Videx following hemodialysis."

Hepatic Impairment (new subsection): "See PRECAUTIONS."

DOSAGE AND ADMINISTRATION:

Method of Preparation: Videx Pediatric Powder for Oral Solution: 10 mg/mL Fianl Admixture: Next to last sentence in first paragraph revised (new text in italics) -

"For patient home use, the admixture should be dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with child-resistant closures."

PRECAUTIONS:

Information For Patients: Females: Bullet #4: Text added at end of paragraph -

"Clinical studies in endometriosis suggest the addition of Hormone Replacement Therapy (estrogens and/or progestins) to Zoladex may decrease the occurrence of vasomotor symptoms and vaginal dryness associated with hypoestrogenism without compromising the efficacy of Zoladex in relieving pelvic symptoms. The optimal drugs, dose and duration of treatment has not been established."

Bullet #5: Text added at end of paragraph -

"Clinical studies suggest the addition of Hormone Replacement Therapy (estrogens and/or progestins) to Zoladex is effective in reducing the bone mineral loss which occurs with Zoladex alone. The optimal drugs, dose and duration of treatment has not been established."

ADVERSE REACTIONS:

Hormone Replacement Therapy (new subsection):

"Clinical studies suggest the addition of Hormone Replacement Therapy (estrogens and/or progestins) to Zoladex may decrease the occurrence of vasomotor symptoms and vaginal dryness associated with hypoestrogenism without compromising the efficacy of Zoladex in relieving pelvic symptoms. The optimal drugs, dose and duration of treatment has not been established."

Changes in Bone Mineral Density: Text added to end of subsection -

"Clinical studies suggest the addition of Hormone Replacement Therapy (estrogens and/or progestins) to Zoladex is effective in reducing the bone mineral loss which occurs with Zoladex alone without compromising the efficacy of Zoladex in relieving the symptoms of endometriosis. The optimal drugs, dose and duration of treatment has not been established."

DOSAGE AND ADMINISTRATION:

Endometriosis: Text added to end of subsection -

"Clinical studies suggest the addition of Hormone Replacement Therapy (estrogens and/or progestins) to Zoladex is effective in reducing the bone mineral loss which occurs with Zoladex alone without compromising the efficacy of Zoladex in relieving the symptoms of endometriosis. The addition of Hormone Replacement Therapy may also reduce the occurrence of vasomotor symptoms and vaginal dryness associated with hypoestrogenism. The optimal drugs, dose and duration of treatment has not been established."

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