CLARITIN-D (loratadine/pseudoephedrine sulfate) - DIFLUCAN (fluconazole) - INVIRASE (saquinavir mesylate) - MAXAQUIN (lomefloxacin HCl) - MEVACOR (lovastatin) - ORTHO-CEPT (desogestrel/ethinyl estradiol) - PENTAM 300 (pentamidine isethionate) - PREVACID (lansoprazole) - SULAR (nisoldipine) - THALLOUS CHLORIDE T1 201 - UNASYN (ampicillin Na/sulbactam Na) - XYLOCAINE (lidocaine HCl) - ZOLADEX (goserelin acetate)

CLINICAL PHARMACOLOGY:

Clinical Studies: New paragraph added at end of sub-section: "In a six week, placebo-controlled study of 193 patients with seasonal allergic rhinitis and concomitant mild to moderate asthma, Claritin-D 12 Hour Tablets twice daily improved seasonal allergic rhinitis signs and symptoms with no decrease in pulmonary function or adverse effect on asthma symptoms. This supports the safety of administering Claritin-D 12 Hour Tablets to seasonal allergic rhinitis patients with asthma."

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CONTRAINDICATIONS:

Sentence added at end of section: "Coadministration of terfenadine is contraindicated in patients receiving Diflucan (fluconazole) at multiple doses of 400 mg or higher based upon results of a multiple dose interaction study. (See PRECAUTIONS.)"

WARNINGS:

(4) Cisapride (new subsection): "There have been reports of cardiac events including torsade de pointes in patients receiving concomitant administration of fluconazole with cisapride. Patients should be carefully monitored if fluconazole is to be coadministered with cisapride. (See PRECAUTIONS.)"

PRECAUTIONS:

Cisapride and astemizole added to list of agents/classes described in greater detail in the Drug Interactions subsection.

Drug Interactions: Terfenadine: Deletion of "Definitive interaction studies at higher doses of Diflucan have not been conducted. The use of fluconazole in patients concurrently taking drugs metabolized by the cytochrome P450 system (i.e., terfenadine, cisapride and astemizole) may be associated with elevations in serum levels of these other drugs. In the absence of definitive information at higher doses of fluconazole, the coadministration of Diflucan and such agents should be carefully monitored."

Addition of "Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that Diflucan taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. (See CONTRAINDICATIONS, DRUG INTERACTION STUDIES.)"

Cisapride and Astemizole (new subsection): "There have been reports of cardiac events including torsade de pointes in patients to whom fluconazole and cisapride were coadministered. The use of fluconazole in patients concurrently taking cisapride, astemizole or other drugs metabolized by the cytochrome P450 system may be associated with elevations in serum levels of these drugs. In the absence of definitive information, caution should be used when coadministering fluconazole. Patients should be carefully monitored."

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CLINICAL PHARMACOLOGY:

Pharmacokinetics: Drug Interactions: Ritonavir (new subsection): "Ritonavir extensively inhibits the metabolism of saquinavir resulting in greatly increased saquinavir plasma concentrations. Coadministration of ritonavir 400 or 600 mg bid regimens produced greater than twentyfold increases in steady-state dose-normalized saquinavir concentrations in healthy subjects. The appropriate doses for this combination, with respect to activity and safety, have not been established."

PRECAUTIONS:

General: New paragraph at end of subsection: "There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In some patients additional factor VIII was required. In the majority of reported cases treatment with protease inhibitors was continued or restarted. A causal relationship between protease inhibitor therapy and these episodes has not been established."

ADVERSE REACTIONS:

Thrombocytopenia and intracranial hemorrhage leading to death; peripheral vasoconstriction; and intestinal obstruction added to list of rare serious adverse experiences reported during clinical trials.

Monotherapy and Combination Studies:

Body as a Whole: Addition of anorexia, fatigue and weakness generalized.

Endocrine/Metabolic: Addition of diabetes mellitus.

Gastrointestinal: Addition of colic abdominal, dyspepsia, esophagitis, flatulence, hepatitis, infectious diarrhea, jaudice, liver enzyme disorder, stomach upset and toothache.

Hematologic: Addition of bleeding dermal and neutropenia.

Musculoskeletal: Addition of cramps leg and creatine phosphokinase increased.

Neurological: Addition of light-headed feeling, myelopolyradiculoneuritis, prickly sensation, and unconsciousness.

Psychological: Addition of anxiety attack, psychosis and suicide attempt.

Reproductive System: Addition of impotence.

Resistance Mechanism: Addition of cellulitis and moniliasis. Hepatitis deleted.

Respiratory: Addition of pulmonary disease.

Skin and Appendages: Addition of alopecia, chalazion, nail disorder, night sweats, and papillomatosis.

Urinary System: Addition of renal calculus and urinary tract bleeding.

PRECAUTIONS:

Drug Interactions: Caffeine: The second sentence was revised to read "This did not result in any statistically or clinically relevant changes in the pharmacokinetic parameters of either caffeine or its major metabolite, paraxanthine. (Words in italics relacing "lomefloxacin")."

INDICATIONS AND USAGE:

Sentence deleted: "Most subjects in the angiographic studies were middle aged men; therefore, it is not clear to what extent these data can be extrapolated to women and the elderly (see CLINICAL PHARMACOLOGY, Clinical Studies."

WARNINGS:

Thromboembolic Disorders and Other Vascular Problems: a. Myocardial Infarction: Sentence added after prior last paragraph: "Desogestrel 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."

PRECAUTIONS:

Pediatric Use (new subsection): "Intravenous and intramuscular pentamidine has been described as an effective treatment for Pneumocystis carinii pneumonia (PCP) in immunocompromised pediatric patients beyond 4 months of age. The efficacy and safety profiles in these pediatric patients were similar to those observed in adult patients (see DOSAGE AND ADMINISTRATION and OVERDOSAGE)."

OVERDOSAGE (new section):

"An 18 month old infant inadvertently received 1600 mg of intravenous pentamidine isethionate which was followed by renal and hepatic function impairment, cardiac arrest and respiratory arrest. The patient recovered from these adverse events, but later died to an unknown cause."

DOSAGE AND ADMINISTRATION:

The word "children" deleted and replaced by pediatric patients beyond 4 months of age.

PRECAUTIONS:

Drug Interactions: Terfenadine and clarithromycin added to the list of compounds metabolized through the cytochrome P-450 system with which lansoprazole has been demonstrated to have no clinically significant interactions.

Statement added "Lansoprazole has also been shown to have no clinically significant interaction with amoxicillin."

Statement deleted "Coadministration of lansoprazole with sucralfate delayed absorption and reduced lansoprazole bioavailability by approximately 30%."

Statement added "In a single-dose crossover study comparing lansoprazole 30 mg and omeprazole 20 mg, each administered alone and concomitantly with sucralfate 1 gram, absorption of the proton pump inhibitors was delayed and their bioavailability was reduced by 17% and 16%, respectively, when administered concomitantly with sucralfate."

In the following sentence, the word "lansoprazole" is replaced with proton pump inhibitors to read "Therefore, proton pump inhibitors should be taken at least 30 minutes prior to sucralfate."

ADVERSE REACTIONS:

Final paragraph in section (regarding immediate release nisoldipine) deleted and replaced with "The following postmarketing event has been reported very rarely in patients receiving Sular: systemic hypersensitivity reaction which may include one or more of the following: angioedema, shortness of breath, tachycardia, chest tightness, hypotension, and rash. A definite causal relationship with Sular has not been established. An unusual event observed with immediate release nisoldipine but not observed with Sular was one case of photosensitivity."

ADVERSE REACTIONS:

Section amended to read "Following the administration of Thallous Chloride T1 201, adverse anaphylactoid reactions have been reported (characterized by cardiovascular, respiratory, and cutaneous symptoms), some severe enough to require treatment. Hypotension, pruritus, flushing, and diffuse rash which responds to antihistamines have been reported. Other reported events include itching, nausea/vomiting, mild diarrhea, tremor, shortness of breath, chills, fever, conjunctivitis, sweating, and blurred vision."

CLINICAL PHARMACOLOGY:

New paragraph added at end of section: "The pharmacokinetics of ampicillin and sulbactam in pediatric patients receiving Unasyn are similar to those observed in adults. Immediately after a 15 minute infusion of 50 to 75 mg Unasyn/kg body weight, peak serum and plasma concentrations of 82 to 446 mcg ampicillin/mL and 44 to 203 mcg sulbactam/mL were obtained. Mean half-life values were approximately 1 hour."

PRECAUTIONS:

Pediatric Use (new subsection): "The safety and effectiveness of Unasyn have been established for pediatric patients one year of age and older for skin and skin structure infections as approved in adults. Use of Unasyn in pediatric patients is supported by evidence from adequate and well-controlled studies in adults with additional data from pediatric pharmacokinetic studies, a controlled clinical trial conducted in pediatric patients and post-marketing adverse events surveillance. (See CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, and CLINICAL STUDIES sections.)

The safety and effectiveness of Unasyn have not been established for pediatric patients for intra-abdominal infections.

ADVERSE REACTIONS:

Pediatric Patients (new subsection): "Available safety data for pediatric patients treated with Unasyn demonstrate a similar adverse events profile to those observed in adult patients. Additionally, atypical lymphocytosis has been observed in one pediatric patient receiving Unasyn."

DOSAGE AND ADMINISTRATION:

Pediatric Patients 1 Year of Age or Older (new subsection): "The recommended daily dose of Unasyn in pediatric patients is 300 mg per kg of body weight administered via intravenous infusion in equally divided dose every 6 hours. This 300mg/kg/day dosage represents the total ampicillin content plus the sulbactam content of Unasyn, and corresponds to 200 mg ampicillin/100 mg sulbactam per kg per day. The safety and efficacy of Unasyn administered via intramuscular injection in pediatric patients have not been established. Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations, and the total dose of sulbactam should not exceed 4 grams per day. The course of intravenouse therapy should not routinely exceed 14 days. In clinical trials, most children received a course of oral antimicrobials following initial treatment with intravenous Unasyn. (See CLINICAL STUDIES section.)"

PRECAUTIONS:

9. Pediatric Use: Previous subsection replaced by "Controlled clinical studies have not been conducted in the pediatric population to establish safety and efficacy in this population (see DOSAGE AND ADMINISTRATION.)"

DOSAGE AND ADMINISTRATION:

Pediatric: First sentence "Although controlled clinical studies to establish pediatric dosing schedules have not been conducted, the American Heart Association's Standard and Guidelines recommends a bolus dose of 1 mg/kg followed by an infusion rate of 30 ug/kg/min." deleted and replaced by "Controlled clinical studies in the pediatric population to establish dosing schedules have not been conducted. The American Heart Association's Standards and Guidelines recommends a bolus dose of 1 mg/kg, and an infusion rate of between 20-50 ug/kg/min for prolonged therapy. When drug clearance is reduced, as in patients with shock , congestive heart failure or cardiac arrest, the infusion rate should not exceed 20 ug/kg/min."

PRECAUTIONS:

General: In first sentence, "... other LHRH agonist analogues.", the word "other" has been deleted.

Sentence deleted: "Currently, no anaphylactic reactions have been reported with the use of Zoladex."

ADVERSE REACTIONS:

General (new subsection): "Hypersensitivity reactions (including urticaria and anaphylaxis) have been reported in patients receiving Zoladex."