Co-administration of multiple 10 mg doses of atorvastatin with 80 mg of ACCUPRIL resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

Fexofenadine HCl: Co-administration of ACTOS for 7 days with 60 mg fexofenadine administered orally twice daily resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS had no significant effect on fexofenadine pharmacokinetics.

Ranitidine HCl: Co-administration of ACTOS for 7 days with ranitidine administered orally twice daily for either 4 or 7 days resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS showed no significant effect on ranitidine pharmacokinetics.

Nifedipine ER: Co-administration of ACTOS for 7 days with 30 mg nifedipine ER administered orally once daily for 4 days to male and female volunteers resulted in a log_e transformed AUC ratio of 0.88 (CI 0.81 - 0.95). In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown.

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DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL FUNCTION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE DOSES OF AREDIA SHOULD NOT EXCEED 90 MG (See DOSAGE AND

ADMINISTRATION for appropriate infusion durations). Bisphosphonates, including Aredia, have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure. Patients who receive Aredia should have serum creatinine assessed prior to each treatment.

Patients treated with Aredia for bone metastases should have the dose withheld if renal function has deteriorated. (See DOSAGE AND ADMINISTRATION).

PREGNANCY:

AREDIA SHOULD NOT BE USED DURING PREGNANCY. Aredia may cause fetal harm when administered to a pregnant woman, (See PRECAUTIONS, Pregnancy Category D). There are no studies in pregnant women using Aredia. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Renal Insufficiency: Aredia is excreted intact primarily via the kidney, and the risk of renal adverse reactions may be greater in patients with impaired renal function. Patients who receive Aredia should have serum creatinine assessed prior to each treatment. In patients receiving Aredia for bone metastases, who show evidence of deterioration in renal function, Aredia treatment should be withheld until renal function returns to baseline (See WARNINGS and DOSAGE AND ADMINISTRATION.)

For the treatment of bone metastases, the use of Aredia in patients with severe renal impairment is not recommended.

Caution is indicated when Aredia is used with other potentially nephrotoxic drugs.

Renal Toxicity

Single doses of Aredia should not exceed 90 mg and the duration of the intravenous infusion should be no less than 2 hours. (See WARNINGS.)

Patients who receive Aredia should have serum creatinine assessed prior to each treatment. Treatment should be withheld for renal deterioration. In a clinical study, renal deterioration was defined as follows:

• For patients with normal baseline creatinine, increase of 0.5 mg/dL.
• For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.

In this clinical study, Aredia treatment was resumed only when the creatinine returned to within 10% of the baseline value.

There must be strict adherence to the intravenous administration recommendations for Aredia in order to decrease the risk of deterioration in renal function.

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WARNING: This product contains aluminum that may be toxic.

Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Cases of cardiomyopathy have been reported in patients treated with clozapine. The reporting rate for cardiomyopathy in clozapine-treated patients in the United States (8.9 per 100,000 person-years) was similar to an estimate of the cardiomyopathy incidence in the United States general population derived from the 1999 National Hospital Discharge Survey data (9.7 per 100,000 person-years). Approximately 80% of clozapine-treated patients in whom cardiomyopathy was reported were less than 50 years of age; the duration of treatment with clozapine prior to cardiomyopathy diagnosis varied, but was >6 months in 65% of the reports. Dilated cardiomyopathy was most frequently reported, although a large percentage of reports did not specify the type of cardiomyopathy. Signs and symptoms suggestive of cardiomyopathy, particularly exertional dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea, and peripheral edema should alert the clinician to perform further investigations. If the diagnosis of cardiomyopathy is confirmed, the prescriber should discontinue clozapine unless the benefit to the patient clearly outweighs the risk.

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Pharmacokinetic interactions have been reported in patients treated orally with other ergot alkaloids (e.g., increased levels of ergotamine) and macrolide antibiotics, principally troleandomycin, presumably due to inhibition of cytochrome P450 3A metabolism of the alkaloids by troleandomycin. Dihydroergotamine has also been shown to be an inhibitor of cytochrome P450 3A catalyzed reactions and rare reports of ergotism have been obtained from patients treated with dihydroergotamine and macrolide antibiotics (e.g., troleandomycin, clarithromycin, erythromycin), and in patients treated with dihydroergotamine and protease inhibitors (e.g. ritonavir), presumably due to inhibition of cytochrome P450 3A metabolism of ergotamine (See CONTRAINDICATIONS). No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.

There have been reports of pleural and retroperitoneal fibrosis in patients following prolonged daily use of injectable dihydroergotamine mesylate. Rarely, prolonged daily use of other ergot alkaloid drugs has been associated with cardiac valvular fibrosis. Rare cases have also been reported in association with the use of injectable dihydroergotamine mesylate; however, in those cases, patients also received drugs known to be associated with cardiac valvular fibrosis.

Administration of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION).

Administration of Migranal (dihydroergotamine mesylate, USP) Nasal Spray, should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION).

Fibrotic Complications: see WARNINGS: Fibrotic Complications

Administration of D.H.E. 45 (dihydroergotamine mesylate) Injection , USP, should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION).

Administration of Migranal (dihydroergotamine mesylate, USP) Nasal Spray, should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION).

See CONTRAINDICATIONS and WARNINGS.

Fibrotic complications have been reported in association with long term use of injectable dihydroergotamine mesylate (see WARNINGS: Fibrotic Complications).

D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, should not be used for chronic daily administration.

Migranal (dihydroergotamine mesylate, USP) Nasal Spray, should not be used for chronic daily administration.

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Of the 1893 patients in clinical studies who were treated with dobutamine, 930 (49.1%) were 65 and older. No overall differences in safety or effectiveness were observed between these and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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 drug therapy.

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In a study evaluating the effects of mometasone furoate cream on the hypothalamic-pituitary- adrenal (HPA) axis, 15 grams were applied twice daily for 7 days to 6 adult patients with psoriasis or atopic dermatitis. The cream was applied without occlusion to at least 30% of the body surface. The results show that the drug caused a slight lowering of adrenal corticosteroid secretion.

8. Other corticosteroid-containing products should not be used with ELOCON Cream without first consulting with the physician.

ELOCON Cream caused HPA axis suppression in approximately 16% of pediatric

patients ages 6 to 23 months, who showed normal adrenal function by Cortrosyn test before starting treatment, and were treated for approximately 3 weeks over a mean body surface area of 41% (range 15% to 94%). The criteria for suppression were: basal cortisol level of ≤5 mcg/dL, 30-minute post-stimulation level of ≤18 mcg/dL, or an increase of <7 mcg/dL. Follow-up testing 2 to 4 weeks after study completion, available for 5 of the patients, demonstrated suppressed HPA axis function in one patient, using these same criteria. Long-term use of topical corticosteroids has not been studied in this population (see CLINICAL PHARMACOLOGY – Pharmacokinetics Section).

Mometasone furoate increased chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, but did not increase chromosomal aberrations in an in vitro Chinese hamster lung cell assay. Mometasone furoate was not mutagenic in the Ames test or mouse lymphoma assay, and was not clastogenic in an in vivo mouse micronucleus assay, a rat bone marrow chromosomal aberration assay, or a mouse male germ-cell chromosomal aberration assay. Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes.

In reproductive studies in rats, impairment of fertility was not produced in male or female rats by subcutaneous doses up to 15 mcg/kg (approximately 0.01 times the estimated maximum clinical topical dose from ELOCON Cream on a mcg/m ² basis).

When administered to pregnant rats, rabbits, and mice, mometasone furoate increased fetal malformations. The doses that produced malformations also decreased fetal growth, as measured by lower fetal weights and/or delayed ossification. Mometasone furoate also caused dystocia and related complications when administered to rats during the end of pregnancy.

In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 mcg/kg and above. Fetal survival was reduced at 180 mcg/kg. No toxicity was observed at 20 mcg/kg. (Doses of 20, 60 and 180 mcg/kg in the mouse are approximately 0.01, 0.02 and 0.05 times the estimated maximum clinical topical dose from ELOCON Cream on a mcg/m ² basis).

In rats, mometasone furoate produced umbilical hernias at topical doses of 600 mcg/kg and above. A dose of 300 mcg/kg produced delays in ossification, but no malformations. (Doses of 300 and 600 mcg/kg in the rat are approximately 0.2 and 0.4 times the estimated maximum clinical topical dose from ELOCON Cream on a mcg/m ² basis). In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical doses of 150 mcg/kg and above (approximately 0.2 times the estimated maximum clinical topical dose from ELOCON Cream on a mcg/m ² basis). In an oral study, mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly and domed head) at 700 mcg/kg. At 2800 mcg/kg most litters were aborted or resorbed. No toxicity was observed at 140 mcg/kg. (Doses of 140, 700 and 2800 mcg/kg in the rabbit are approximately 0.2, 0.9 and 3.6 times the estimated maximum clinical topical dose from ELOCON Cream on a mcg/m ² basis).

When rats received subcutaneous doses of mometasone furoate throughout pregnancy or during the later stages of pregnancy, 15 mcg/kg caused prolonged and difficult labor and reduced the number of live births, birth weight and early pup survival. Similar effects were not observed at 7.5 mcg/kg. (Doses of 7.5 and 15 mcg/kg in the rat are approximately 0.005 and 0.01 times the estimated maximum clinical topical dose from ELOCON Cream on a mcg/m ² basis).

population (see CLINICAL PHARMACOLOGY – Pharmacokinetics Section).

Geriatric Use: Clinical studies of ELOCON Cream included 190 subjects who were 65 years of age and over and 39 subjects who were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.

Like other topical corticosteroids, mometasone furoate has anti-inflammatory, anti-pruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A₂ inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A₂.

Studies performed with ELOCON Lotion indicate that it is in the medium range of potency as compared with other topical corticosteroids.

In a study evaluating the effects of mometasone furoate lotion on the hypothalamic-pituitary- adrenal (HPA) axis, 15 mL were applied without occlusion twice daily (30 mL per day) for 7 days to 4 adult patients with scalp and body psoriasis. At the end of treatment, the plasma cortisol levels for each of the 4 patients remained within the normal range and changed little from baseline.

ELOCON Lotion, 0.1%, is a medium potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.

Since safety and efficacy of ELOCON Lotion have not been established in pediatric patients below 12 years of age, its use in this age group is not recommended. (see PRECAUTIONS - Pediatric Use).

6. This medication should not be used on the face, underarms, or groin areas unless directed by the physician.

7. As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, contact the physician.

8. Other corticosteroid-containing products should not be used with ELOCON Lotion without first consulting with the physician.

Mometasone furoate increased chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, but did increase chromosomal aberrations in an in vitro Chinese hamster lung cell assay. Mometasone furoate was not mutagenic in the Ames test or mouse lymphoma assay, and was not clastogenic in an in vivo mouse micronucleus assay, a rat bone marrow chromosomal aberration assay, or a mouse male germ-cell chromosomal aberration assay. Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes.

In reproductive studies in rats, impairment of fertility was not produced in male or female rats by subcutaneous doses up to 15 mcg/kg (approximately 0.01 times the estimated maximum clinical topical dose from ELOCON Lotion on a mcg/m ² basis).

Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals.

When administered to pregnant rats, rabbits, and mice, mometasone furoate increased fetal malformations. The doses that produced malformations also decreased fetal growth, as measured by lower fetal weights and/or delayed ossification. Mometasone furoate also caused dystocia and related complications when administered to rats during the end of pregnancy.

In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 mcg/kg and above. Fetal survival was reduced at 180 mcg/kg. No toxicity was observed at 20 mcg/kg. (Doses of 20, 60 and 180 mcg/kg in the mouse are approximately 0.01, 0.02 and 0.05 times the estimated maximum clinical topical dose from ELOCON Lotion on a mcg/m ² basis).

In rats, mometasone furoate produced umbilical hernias at topical doses of 600 mcg/kg and above. A dose of 300 mcg/kg produced delays in ossification, but no malformations. (Doses of 300 and 600 mcg/kg in the rat are approximately 0.2 and 0.4 times the estimated maximum clinical topical dose from ELOCON Lotion on a mcg/m² basis).

In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical doses of 150 mcg/kg and above (approximately 0.2 times the estimated maximum clinical topical dose from ELOCON Lotion on a mcg/m² basis). In an oral study, mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly and domed head) at 700 mcg/kg. At 2800 mcg/kg most litters were aborted or resorbed. No toxicity was observed at 140 mcg/kg. (Doses of 140, 700 and 2800 mcg/kg in the rabbit are approximately 0.2, 0.9 and 3.6 times the estimated maximum clinical topical dose from ELOCON Lotion on a mcg/m² basis).

When rats received subcutaneous doses of mometasone furoate throughout pregnancy or during the later stages of pregnancy, 15 mcg/kg caused prolonged and difficult labor and reduced the number of live births, birth weight and early pup survival. Similar effects were not observed at 7.5 mcg/kg. (Doses of 7.5 and 15 mcg/kg in the rat are approximately 0.005 and 0.01 times the estimated maximum clinical topical dose from ELOCON Lotion on a mcg/m ² basis).

Since safety and efficacy of ELOCON Lotion have not been established in pediatric patients below 12 years of age, its use in this age group is not recommended.

Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA axis suppression and Cushing's syndrome when they are treated with topical corticosteroids. They are, therefore, also at greater risk of glucocorticosteroid insufficiency during and/or after withdrawal of treatment. Pediatric patients may be more susceptible than adults to skin atrophy, including striae, when they are treated with topical corticosteroids. Pediatric patients applying topical corticosteroids to greater than 20% of body surface are at higher risk of HPA axis suppression.

HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

ELOCON (mometasone furoate lotion) Lotion should not be used in the treatment of diaper dermatitis.

Geriatric Use: Clinical studies of ELOCON Lotion did not include sufficient number 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.

In clinical studies involving 209 patients, the incidence of adverse reactions associated with the use of ELOCON Lotion was 3%. Reported reactions included acneiform reaction, 2; burning, 4; and itching, 1. In an irritation/sensitization study involving 156 normal subjects, the incidence of folliculitis was 3% (4 subjects).

The following adverse reactions were reported to be possibly or probably related to treatment with ELOCON Lotion during a clinical study, in 14% of 65 pediatric patients 6 months to 2 years of age: decreased glucocorticoid levels, 4; paresthesia, 2; dry mouth, 1; an unspecified endocrine disorder, 1; pruritus, 1; and an unspecified skin disorder, 1. The following signs of skin atrophy were also observed among 65 patients treated with ELOCON Lotion in a clinical study: shininess 4, telangiectasia 2, loss of elasticity 2, and loss of normal skin markings 3. Striae, thinness and bruising were not observed in this study.

As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary. ELOCON Lotion should not be used with occlusive dressings unless directed by a physician. ELOCON Lotion should not be applied in the diaper area if the patient requires diapers or plastic pants as these garments may constitute occlusive dressing.

In a study evaluating the effects of mometasone furoate ointment on the hypothalamic-pituitary-adrenal (HPA) axis, 15 grams were applied twice daily for 7 days to six adult patients with psoriasis or atopic dermatitis. The ointment was applied without occlusion to at least 30% of the body surface. The results show that the drug caused a slight lowering of adrenal corticosteroid secretion.

8. Other corticosteroid-containing products should not be used with ELOCON Ointment without first consulting with the physician.

Mometasone furoate increased chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, but did not increase chromosomal aberrations in an in vitro Chinese hamster lung cell assay. Mometasone furoate was not mutagenic in the Ames test or mouse lymphoma assay, and was not clastogenic in an in vivo mouse micronucleus assay, a rat bone marrow chromosomal aberration assay, or a mouse male germ-cell chromosomal aberration assay. Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes.

In reproductive studies in rats, impairment of fertility was not produced in male or female rats by subcutaneous doses up to 15 mcg/kg (approximately 0.01 times the estimated maximum clinical topical dose from ELOCON Ointment on a mcg/m ² basis).

When administered to pregnant rats, rabbits, and mice, mometasone furoate increased fetal malformations. The doses that produced malformations also decreased fetal growth, as measured by lower fetal weights and/or delayed ossification. Mometasone furoate also caused dystocia and related complications when administered to rats during the end of pregnancy.

In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 mcg/kg and above. Fetal survival was reduced at 180 mcg/kg. No toxicity was observed at 20 mcg/kg. (Doses of 20, 60 and 180 mcg/kg in the mouse are approximately 0.01, 0.02 and 0.05 times the estimated maximum clinical topical dose from ELOCON Ointment on a mcg/m ² basis).

In rats, mometasone furoate produced umbilical hernias at topical doses of 600 mcg/kg and above. A dose of 300 mcg/kg produced delays in ossification, but no malformations. (Doses of 300 and 600 mcg/kg in the rat are approximately 0.2 and 0.4 times the estimated maximum clinical topical dose from ELOCON Ointment on a mcg/m ² basis). In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical doses of 150 mcg/kg and above (approximately 0.2 times the estimated maximum clinical topical dose from ELOCON Ointment on a mcg/m ² basis). In an oral study, mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly and domed head) at 700 mcg/kg. At 2800 mcg/kg most litters were aborted or resorbed. No toxicity was observed at 140 mcg/kg. (Doses of 140, 700 and 2800 mcg/kg in the rabbit are approximately 0.2, 0.9 and 3.6 times the estimated maximum clinical topical dose from ELOCON Ointment on a mcg/m ² basis).

When rats received subcutaneous doses of mometasone furoate throughout pregnancy or during the later stages of pregnancy, 15 mcg/kg caused prolonged and difficult labor and reduced the number of live births, birth weight and early pup survival. Similar effects were not observed at 7.5 mcg/kg. (Doses of 7.5 and 15 mcg/kg in the rat are approximately 0.005 and 0.01 times the estimated maximum clinical topical dose from ELOCON Ointment on a mcg/m ² basis).

Geriatric Use: Clinical studies of ELOCON Ointment included 310 subjects who were 65 years of age and over and 57 subjects who were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.

The following adverse reactions were reported to be possibly or probably related to treatment with ELOCON Ointment during a clinical study, in 5% of 63 pediatric patients 6 months to 2 years of age: decreased glucocorticoid levels, 1; an unspecified skin disorder, 1; and a bacterial skin infection, 1. The following signs of skin atrophy were also observed among 63 patients treated with ELOCON Ointment in a clinical study: shininess 4, telangiectasia 1, loss of elasticity 4, loss of normal skin markings 4, thinness 1. Striae and bruising were not observed in this study.

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Concomitant use of FORTOVASE and St. John’s wort (hypericum perforatum) or products containing St. John’s wort is not recommended. Coadministration of protease inhibitors, including FORTOVASE, with St. John’s wort is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of FORTOVASE and lead to loss of virologic response and possible resistance to FORTOVASE or to the class of protease inhibitors.

A statement to patients and health care providers is included on the product’s bottle label: ALERT: Find out about medicines that should NOT be taken with FORTOVASE. A Patient Package Insert (PPI) for FORTOVASE is available for patient information.

Because GlucaGen depletes glycogen stores, the patient should be given oral carbohydrates as soon as the procedure is completed.

When the diagnostic procedure is over, give oral carbohydrates to restore the liver glycogen and prevent occurrence of secondary hypoglycemia.

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HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. It is not known whether zalcitabine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving HIVID.

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Concomitant use of INVIRASE and St. John’s wort (hypericum perforatum) or products containing St. John’s wort is not recommended. Coadministration of protease inhibitors, including INVIRASE, with St. John’s wort is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of INVIRASE and lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors.

A statement to patients and health care providers is included on the product’s bottle label: ALERT: Find out about medicines that should NOT be taken with INVIRASE.

Contrast media may promote sickling in individuals who are homozygous for sickle cell disease when injected intraveneously or intra-arterially. Although Isovue-M is not injected intravascularly, measurable plasma levels are attained after intrathecal administration of iopamidol.

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Clinical studies of LONITEN Tablets 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.

Of the total number of patients in clinical studies of OMNISCAN, 19.3 percent were 65 to 80, while 1.2 percent were over 80. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions 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.

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Clinical studies of Pergonal did not include sufficient numbers of male 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 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.

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Adverse event data were pooled from seven double-blind, placebo-controlled trials (West of Scotland Coronary Prevention study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term Intervention with Pravastatin in Ischemic Disease study [LIPID]; Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated with pravastatin 40 mg and 10,719 patients treated with placebo. The safety and tolerability profile in the pravastatin group was comparable to that of the placebo group. Patients were exposed to pravastatin for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and REGRESS. In these long-term trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal complaints. Collectively, these seven trials represent 47,613 patient-years of exposure to pravastatin. Events believed to be of probable, possible, or uncertain relationship to study drug, occurring in at least 1% of patients treated with pravastatin in these studies are identified in Table 7.

Events of probable, possible, or uncertain relationship to study drug that occurred in < 1.0% of pravastatin-treated patients in the long-term trials included the following; frequencies were similar in placebo-treated patients:

Dermatologic: pruritus, dermatitis, dryness skin, scalp hair abnormality (including alopecia), urticaria.

Endocrine/Metabolic: sexual dysfunction, libido change.

Gastrointestinal: decreased appetite.

General: fever, flushing.

Immunologic: allergy, edema head/neck.

Musculoskeletal: muscle weakness.

Nervous System: paresthesia, vertigo, insomnia, memory impairment, tremor, neuropathy (including peripheral neuropathy).

Special Senses: lens opacity, taste disturbance.

PRILOSEC Delayed-Release Capsule 40 mg was bioequivalent when administered with and without applesauce. However, PRILOSEC Delayed-Release Capsule 20 mg was not bioequivalent when administered with and without applesauce. When administered with applesauce, a mean 25% reduction in Cmax was observed without a significant change in AUC for PRILOSEC Delayed-Release Capsule 20 mg. The clinical relevance of this finding is unknown.

The pharmacokinetics of omeprazole have been investigated in pediatric patients of different ages.

Pharmacokinetic Parameters of Omeprazole Following Single and Repeated Oral Administration in Pediatric Populations Compared to Adults

Note: * = plasma concentration adjusted to an oral dose of 1 mg/kg.

† Data from single and repeated dose studies

‡ Data from a single and repeated dose study

Doses of 10, 20 and 40 mg Omeprazole as Enteric-Coated Granules

Following comparable mg/kg doses of omeprazole, younger children (2-5 years) have lower AUCs than children 6 – 16 years or adults; AUCs of the latter two groups did not differ. (See DOSAGE AND ADMINISTRATION – Pediatric Patients.)

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis."

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

For patients who have difficulty swallowing capsules, the contents of a PRILOSEC Delayed-Release Capsule can be added to applesauce. One tablespoon of applesauce should be added to an empty bowl and the capsule should be opened. All of the pellets inside the capsule should be carefully emptied on theapplesauce. The pellets should be mixed with the applesauce and then swallowed immediately with a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. The pellets should not be chewed or crushed. The pellets/applesauce mixture should not be stored for future use.

A 26- week p53+/- transgenic mouse carcinogenicity study was not positive.

The safety and effectiveness of Prilosec have been established in the age group 2 years to 16 years for the treatment of acid-related gastrointestinal diseases, including the treatment of symptomatic GERD, treatment of erosive esophagitis, and the maintenance of healing of erosive esophagitis. The safety and effectiveness of Prilosec have not been established for pediatric patients less than 2 years of age. Use of Prilosec in the age group 2 years to 16 years is supported by evidence from adequate and well-controlled studies of Prilosec in adults with additional clinical, pharmacokinetic, and safety studies performed in pediatric patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism: Omeprazole).

Symptomatic GERD

In an uncontrolled, open-label study of patients aged 2 years to 16 years with a history of symptoms suggestive of nonerosive GERD, 113 patients were assigned to receive a single daily dose of omeprazole (10 mg or 20 mg, based on body weight) either as intact capsule or as an open capsule in applesauce. Results showed success rates of 60% (10 mg omeprazole) and 59% (20 mg omeprazole) in reducing the number and intensity of either pain-related symptoms or vomiting/regurgitation episode was shown.

In an uncontrolled, open-label dose-titration study, healing of erosive esophagitis in pediatric patients aged 1 to 16 years required doses that ranged from 0.7 to 3.5 mg/kg/day (80 mg/day). Doses were initiated at 0.7 mg/kg/day. Doses were increased in increments of 0.7 mg/kg/day (if intraesophageal pH showed a pH of < 4 for less than 6% of a 24-hour study). After titration, patients remained on treatment for 3 months. Forty-four percent of the patients were healed on a dose of 0.7 mg/kg body weight; most of the remaining patients were healed with 1.4 mg/kg after an additional 3 months’ treatment. Erosive esophagitis was healed in 51 of 57 (90%) children who completed the first course of treatment in the healing phase of the study. In addition, after 3 months of treatment, 33% of the children had no overall symptoms, 57% had mild reflux symptoms, and 40% had less frequent regurgitation/vomiting.

In an uncontrolled, open-label study of maintenance of healing of erosive esophagitis in 46 pediatric patients, 54% of patients required half the healing dose. The remaining patients increased the healing dose (0.7 to a maximum of 2.8 mg/kg/day) either for the entire maintenance period, or returned to half the dose before completion. Of the 46 patients who entered the maintenance phase, 19 (41%) had no relapse. In addition, maintenance therapy in erosive esophagitis patients resulted in 63% of patients having no overall symptoms.

The safety of PRILOSEC Delayed-Release Capsules has been assessed in 310 pediatric patients aged 0 to 16 years and 62 physiologically normal volunteers aged 2 years to 16 years. Of the 310 pediatric patients with acid-related disease, a group of 46 who had documented healing of erosive esophagitis after 3 months of treatment continued on maintenance therapy for up to 749 days.

PRILOSEC Delayed-Release Capsules administered to pediatric patients was generally well tolerated with an adverse event profile resembling that in adults. Unique to the pediatric population, however, adverse events of the respiratory system were most frequently reported in both the 0 to 2 year and 2 to 16 year age groups (46.2% and 18.5%, respectively). Similarly, otitis media was frequently reported in the 0 to 2 year age group (22.6%), and accidental injuries were reported frequently in the 2 to 16 year age group (3.8%).

As with the management of any overdose, the possibility of multiple drug ingestion should be considered. For current information on treatment of any drug overdose, a certified Regional Poison Control Center should be contacted. Telephone numbers are listed in the Physicians’ Desk Reference (PDR) or local telephone book.

For the treatment of GERD or other acid-related disorders, the recommended dose for pediatric patients 2 years of age and older is as follows:

On a per kg basis, the doses of omeprazole required to heal erosive esophagitis are greater than those for adults.

For pediatric patients unable to swallow an intact capsule see Alternative Administration Options subsection below.

For patients who have difficulty swallowing capsules, the contents of a PRILOSEC Delayed-Release Capsule can be added to applesauce. One tablespoon of applesauce should be added to an empty bowl and the capsule should be opened. All of the pellets inside the capsule should be carefully emptied on the applesauce. The pellets should be mixed with the applesauce and then swallowed immediately with a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. The pellets should not be chewed or crushed. The pellet/applesauce mixture should not be stored for future use.

No dosage adjustment is necessary for patients with renal impairment or for the elderly.

PRILOSEC Delayed-Release Capsules should be taken before eating. In the clinical trials, antacids were used concomitantly with PRILOSEC.

Patients should be cautioned that the PRILOSEC Delayed-Release Capsule should not be opened, chewed or crushed, and should be swallowed whole.

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Patients with liver cirrhosis showed prolonged elimination of drug, with octreotide t 1/2 increasing to 3.7 hr and total body clearance decreasing to 5.9 L/hr, whereas patients with fatty liver disease showed t 1/2 increased to 3.4 hr and totally body clearance of 8.2 L/hr.

Experience with Sandostatin (octreotide acetate) in the pediatric population is limited.

Although formal controlled clinical trials have not been performed to evaluate safety and effectiveness in this age group, there are reports of 49 cases in the literature of neonates and infants with congenital hyperinsulinism [also called familial hyperinsulinism (HI), persistent hyperinsulinemic hypoglycemia of infancy (PHHI), or nesidioblastosis] who have received Sandostatin as an inhibitor of insulin release. The following efficacy and safety information is derived from these 49 patients.

Sandostatin has been used to stabilize plasma glucose levels prior to pancreatectomy and to treat recurrent post-operative hypoglycemia. Although most use of octreotide in this setting is short-term, a few reports in the literature have documented longer-term therapy in pediatric patients (2.2-5.5 years). Octreotide is an alternative medical treatment to diazoxide for control of hypoglycemia in this disorder. Of 31 pediatric patients who received Sandostatin as prescribed for congenital hyperinsulinism and for which long-term follow-up was available, octreotide obviated the need for surgery in 3 patients (10%) and was replaced by diazoxide in 4 patients (13%) due to uncontrolled hypoglycemia. Although the remainder of these patients required surgery, there have been a few reports in the literature of patients who have responded to octreotide after failing treatment with surgery and/or diazoxide. Doses of 3-40 mcg/kg/day have been used. At these doses, the majority of side effects were gastrointestinal: diarrhea, steatorrhea, vomiting, and abdominal distension, each reported in 22-35% (n = 11-17) of patients. However, they were generally short-lived – with resolution of vomiting and distention in 2-4 days, and diarrhea/steatorrhea, within 2-4 weeks. Steatorrhea was controlled in most patients with pancreatic enzyme supplements. Poor growth was reported in 37% of patients (n = 7) who received Sandostatin for 1-4.33 years. It was associated with low serum growth hormone and/or IGF-1 levels in 4/6 patients in whom these parameters were measured. Catch-up growth occurred in 3/3 patients who were followed after Sandostatin was discontinued. Poor weight gain was reported in 32% of patients (n = 6). Tachyphylaxis was reported in 35% (n = 17) of patients. Asymptomatic gallstones with sludge was reported in one infant after one year of therapy and was treated with ursodeoxycholic acid. There has been a single report of an infant with nesidioblastosis who experienced a seizure thought to be independent of Sandostatin therapy. A single death has been reported in a 16-month-old male with enterocutaneous fistula who developed sudden abdominal pain and increased nasogastric drainage and expired 8 hours after receiving a single 100 mcg subcutaneous dose of Sandostatin.

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Rare cases of serious hepatotoxicity have been observed with Sporanox treatment, including some cases within the first week. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with Sporanox is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving Sporanox. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction.

If neuropathy occurs that may be attributable to Sporanox capsules, the treatment should be discontinued.

Worldwide post-marketing experiences with the use of SPORANOX include adverse events of gastrointestinal origin, such as dyspepsia, nausea, vomiting, diarrhea, abdominal pain and constipation. Other reported adverse events include peripheral edema, congestive heart failure and pulmonary edema, headache, dizziness, peripheral neuropathy, menstrual disorders, reversible increases in hepatic enzymes, hepatitis, liver failure, hypokalemia, hypertriglyceridemia, alopecia, allergic reactions (such as pruritus, rash, urticaria, angioedema, anaphylaxis), Stevens-Johnson syndrome, and neutropenia. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information).

The following adverse events have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.

Cutaneous: rare cases of bullous eruption such as erythema multiforme or Stevens-Johnson syndrome. Multiple factors may have contributed to the development of these effects.

Hematologic: bleeding episodes

Hepatic: rare cases of hepatitis have been reported.

Ophthalmologic: conjunctivitis, lacrimation or lacrimation with or without conjunctivitis. Excessive tearing which may be attributable to lacrimal duct obstruction has been reported.

Of the total number of patients in eight Phase 1, 2 and 3 clinical studies of TESLASCAN, 218 of 678 (32.2%) were 65 to 80 years old, while 8 of 678 (1.2%) were over 80 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious usuallystarting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions 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.

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The following adverse events have been reported with macrolide products: ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, in individuals with prolonged QT intervals.

Community-Acquired Pneumonia: For the recommended dosage regimen of 10 mg/kg on Day 1 followed by 5 mg/kg on Days 2-5, the most frequent side effects attributed to treatment were diarrhea/loose stools, abdominal pain, vomiting, nausea, and rash.

The incidence is described in the table below:

Pharyngitis/tonsillitis: For the recommended dosage regimen of 12 mg/kg on Days 1-5, the most frequent side effects attributed to treatment were diarrhea/loose stools, vomiting, abdominal pain, nausea, and headache.

The incidence is described in the table below:

In multiple-dose clinical trials involving approximately 4700 pediatric patients, no patients discontinued therapy because of treatment-related laboratory abnormalities.

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