AZULFIDINE EN-TABS (sulfasalazine) - CALCIJEX (calcitrol) - DIDRONEL (etidronate disodium) - ERYTHROCIN (erythromycin lactobionate for injection, USP) - LOZOL (indapamide) - MEFOXIN (cefoxitin) - MEGACE(megestrol acetate) - MIACALCIN(calcitonin-salmon) - NIMOTOP (nimodipine) - NOVANTRONE (mitoxantrone) - PAXIL (paroxetine HCl) - RETROVIR (zidovudine) - ROCALTROL (calcitriol) - SULAR (nisoldipine) - VALTREX (valacyclovir HCl) - ZOLOFT (sertraline HCl)

CLINICAL PHARMACOLOGY:

Revised, with several specific new subsections including Pharmacodynamics, Pharmacokinetics (In vivo, Absorption, Distribution, Metabolism and Excretion), Special Populations (Elderly, Acetylator Status and Gender) [see complete section in package insert].

PRECAUTIONS:

Information for Patients subsection revised, with notation that occurrence of sore throat, fever, pallor, purpura or jaundice may indicate a serious blood disorder, and that patients should seek medical advice should any of these occur. Patients are now advised to swallow the tablets whole.

Rheumatoid Arthritis (new sub-subsection): Rheumatoid arthritis rarely remits, therefore continued administration of Azulfidine is indicated; patients requiring sulfasalazine should follow up with their physicians to determine need for continued administration.

Laboratory Tests: Revised, with notation that CBCs, including differential WBC and LFTs, should be performed prior to starting Azulfidine and every second week during the first three months of therapy. During the second three months, the same tests should be done once monthly and thereafter every three months, and as clinically indicated. Periodic urinalysis renal function assessment should also be done during Azulfidine treatment. Determination of serum sulfapyridine levels may be useful since concentrations > 50 ug/ml appear to be associated with an increased incidence of adverse reactions.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Revised to include results of two year oral carcinogenicity studies in male and female rats and mice, and results of mutagenicity studies; previously noted reproductive studies performed in rats and rabbits regarding impairment of male fertility to have added mg/kg and mg/m2 dosing information [see complete section in package insert].

Pediatric Use: Revised to note that the safety and effectiveness of Azulfidine in 1) children below two years of age with ulcerative colitis, and 2) juvenile rheumatoid arthritis, has not been established, and that it has been reported that the frequency of adverse events in patients with systemic onset of juvenile arthritis is high.

DOSAGE AND ADMINISTRATION:

Revised, including separating into individual subsections for Ulcerative Colitis and Rheumatoid Arthritis [see complete section in package insert].

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PRECAUTIONS:

Essential Laboratory Tests: Statement added -

"Adynamic bone disease may develop if PTH levels are suppressed to abnormal levels. If biopsy is not being done for other (diagnostic) reasons, PTH levels may be used to indicate the rate of bone turnover. If PTH levels fall below 20 pmol/L or 200 mg/ml in patients treated with Calcijex, the Calcijex dose should be reduced or therapy discontinued."

DOSAGE AND ADMINISTRATION:

Paragraph on the recommended initial dose of Calcijex deleted and replaced with -

"The recommended initial dose of Calcijex, depending on the severity of the hypocalcemia and/or secondary hyperparathyroidism, is 1.0 mcg (0.02 mcg/kg) to 2.0 mcg administered three times weekly, approximately every other day. Doses as small as 0.5 mcg and as large as 4.0 mcg three times weekly have been used as an initial dose. If a satisfactory response is not observed, the dose may be increased by 0.5 to 1.0 mcg at two to four week intervals. During this titration period, serum calcium and phosphorus levels should be obtained at least twice weekly. If hypercalcemia or a serum calcium times phosphate product greater than 70 is noted, the drug should be immediately discontinued until these parameters are appropriate. Then, the Calcijex dose should be reinitiated at a lower dose. Doses may need to be reduced as the PTH levels decrease in response to the therapy. Thus, incremental dosing must be individualized and commensurate with PTH, serum calcium and phosphorus levels. The following is a suggested approach in dose titration:

PTH Levels	Calcijex Dose
the same or increasing	increase
decreasing by > 30%, < 60%	maintain
decreasing by > 60%	decrease
one and on-half to three times normal range	maintain

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ADVERSE REACTIONS:

Worldwide Postmarketing Experience: Addition of statement that there have been rare reports of exacerbation of asthma.

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CLINICAL PHARMACOLOGY:

1. "After absorption" added to beginning of previous sentence "Erythromycin diffuses readily into most body fluids";

2. In phrase "passage of the drug across the blood-brain barrier increases in meningitis", "in meningitis" changed to "when the meninges are inflamed";

3. Previous statement regarding crossing of placental barrier/breast milk excretion changed to "Erythromycin crosses the placental barrier, but fetal plasma levels are low. The drug is excreted in human milk".

CONTRAINDICATIONS:

Revised by addition of statement that erythromycin is contraindicated in patients taking terfenadine or astemizole (see PRECAUTIONS, Drug Interactions).

WARNINGS:

Revised by addition of the following information:

1. There have been reports suggesting that erythromycin does not reach the fetus in adequate concentration to prevent congenital syphilis. Infants born to women treated during pregnancy with oral erythromycin for early syphilis should be treated with an appropriate penicillin regimen;

2. Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with lovastatin. Therefore, patients receiving concomitant lovastatin and erythromycin should be carefully monitored for creatine kinase (CK) and serum transaminase levels (see package insert for lovastatin);

3. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants;

4. Pseudomembranous colitis has been reported with nearly all antibacterial agents, including erythromycin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. 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 difficule 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 drug discontinuation 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 C. difficule colitis.

PRECAUTIONS:

Drug Interactions: Revised by addition of the following information (*revisions made for consistency with labeling of other erythromycin preparations):

1. Statement that increased anticoagulation effects due to this drug may be more pronounced in the elderly added to previous statement regarding reports of increased anticoagulant effects with concomitant erythromycin/oral anticoagulants;

*2. Statement that concurrent use of erythromycin and ergotamine or dihydroergotamine has been associated in some patients with acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia;

*3. Statement that erythromycin has been reported to decrease the clearance of triazolam and midazolam and, thus, may increase the pharmacologic effect of these benzodiazepines.

Drug/Laboratory Test Interactions (new subsection): Erythromycin interferes with the fluorometric determination of urinary catecholamines.

ADVERSE REACTIONS:

Revised by addition of the following information:

1. Previous statement regarding cardiac arrhythmias revised to note that rarely erythromycin has been associated with the production of ventricular arrhythmias, including ventricular tachycardia and torsades de pointes, in individuals with prolonged QTc intervals;

2. Statement that skin reactions ranging from mild eruptions to erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely added to previous statement regarding allergic reactions;

3. Statement that onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS) added.

OVERDOSAGE:

*Revised to note that in the case of overdosage, erythromycin should be discontinued. Overdosage should be handled with the prompt elimination of unabsorbed drug and all other appropriate measures should be instituted. Erythromycin is not removed by peritoneal dialysis or hemodialysis.

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WARNINGS:

Paragraph regarding hyponatremia revised to indicate that severe cases of hyponatremia, accompanied by hypokalemia, have been reported with recommended doses of indapamide. This occurred primarily in elderly females and appears to be dose-related. In addition, a large case-controlled pharmacoepidemiology study indicates there is an increased risk of hyponatremia with indapamide 2.5 mg and 5 mg doses. As before, it is noted that hyponatremia considered possibly clinically significant (less than 125 mEq/L) has not been observed in clinical trials with the 1.25 mg dosage (see PRECAUTIONS). Thus, patients should be started at the 1.25 mg dose and maintained at the lowest possible dose (see DOSAGE AND ADMINISTRATION).

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ADVERSE REACTIONS:

Renal Function: Subsection revised to indicate that in addition to the adverse events listed in relation to Mefoxin, the following adverse reactions/altered laboratory test results have been reported for cephalosporin class antibiotics: urticaria, erythema multiforme, Stevens-Johnson syndrome, serum sickness-like reactions, abdominal pain, colitis, renal dysfunction, toxic nephropathy, false-positive test for urinary glucose, hepatic dysfunction including cholestasis, elevated bilirubin, aplastic anemia, hemorrhage, prolonged prothrombin time, pancytopenia, agranulocytosis, superinfection, and vaginitis including vaginal candidiasis. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced (see DOSAGE). If seizures associated with drug therapy occur, the drug should be discontinued; anticonvulsant therapy can be given if clinically indicated.

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CONTRAINDICATIONS:

History of hypersensitivity to megestrol acetate or any component of the formulation added as a contraindication.

WARNINGS:

Revised to include new paragraph stating that although the glucocorticoid activity of Megace Oral Suspension has not been fully evaluated, laboratory evidence of adrenal suppression has been observed. Clinical cases of new onset diabetes, exacerbation of pre-existing diabetes, and Cushing's syndrome have been reported in association with the use of Megace. Rare cases of clinically apparent adrenal insufficiency have also been reported in association with the use of Megace. The possibility of adrenal suppression should be considered in any patient taking or withdrawing from chronic Megace therapy who presents with symptoms of adrenal insufficiency such as hypotension, nausea, vomiting, dizziness, or weakness. Laboratory evaluation for adrenal insufficiency and replacement stress doses of a rapidly acting glucocorticoid may be indicated for such patients.

PRECAUTIONS:

General: Previous statement regarding glucocorticoid effects/adrenal suppression deleted (see new WARNINGS paragraph outlined above).

Use in Diabetics (new subsection): Exacerbation of pre-existing diabetes with increased insulin requirements have been reported in association with the use of Megace.

Drug Interactions: Revised to note that pharmacokinetic studies show that there are no alterations in pharmacokinetic parameters when megestrol acetate is administered with zidovudine or with rifabutin.

ADVERSE REACTIONS:

Postmarketing (new subsection): Postmarketing reports associated with Megace Oral Suspension include thromboembolic phenomena including thrombophlebitis and pulmonary embolism, and glucose intolerance (see WARNINGS and PRECAUTIONS sections).

STORAGE:

Previous instruction to store Megace Oral Suspension at or below 25 degrees C revised, with new instruction to store between 15-25 degrees C (59-77 degrees F).

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PRECAUTIONS:

Information for Patients: Revised to include the following, of which patients should be advised:

1. Store new, unassembled bottles in the refrigerator between 360-460F (20-80C);
2. Protect the product from freezing;
3. Before priming the pump and using a new bottle, allow it to reach room temperature;
4. After a new bottle is assembled, it should be stored at room temperature in an upright position. Each bottle contains 14 doses;
5. Discard all unrefrigerated bottles after 30 days;
6. See DOSAGE AND ADMINISTRATION, Priming (Activation) of Pump for complete instructions on priming the pump and administering Miacalcin (calcitonin-salmon) Nasal Spray.

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PRECAUTIONS:

General: Advisement added that intravenous administration of the contents of Nimotop Capsules has resulted in serious adverse consequences including hypotension, cardiovascular collapse, and cardiac arrest.

DOSAGE AND ADMINISTRATION:

Advisement added that the contents of NimotopR Capsules must not be administered by intravenous injection or other parenteral routes.

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PRECAUTIONS and ADVERSE REACTIONS:

Statement added that Topoisomerase II inhibitors, including Novantrone, in combination with other antineoplastic agents, have been associated with the development of acute leukemia.

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OVERDOSAGE:

Human Experience: Revised to note that overdose with Paxil (up to 2000 mg) alone and in combination with other drugs has been reported. Signs and symptoms of overdose with Paxil include nausea, vomiting, sedation, dizziness, sweating, and facial flush; there are no reports of coma or convulsions following overdosage with Paxil alone. A fatal outcome has been reported rarely when Paxil was taken in combination with other agents, or when taken alone.

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CLINICAL PHARMACOLOGY:

Pharmacokinetics: Nursing Mothers (new subsection): Previous advisement against breastfeeding by HIV-infected women (see PRECAUTIONS, Nursing Mothers) included, as is new information that after administration of a single dose of 200 mg zidovudine to 13 HIV-infected women, mean concentration of zidovudine was similar in human milk and serum.

PRECAUTIONS:

Nursing Mothers: Paragraph concerning whether zidovudine is excreted in human milk or reduced potential for HIV transmission in breast milk removed; replaced by statement that zidovudine is excreted in human milk (see Pharmacokinetics).

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ADVERSE REACTIONS:

Statement added that one case of erythema multiforme and one case of allergic reaction (swelling of lips and hives all over the body) were confirmed by rechallenge.

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PRECAUTIONS:

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

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CLINICAL PHARMACOLOGY:

Clinical Trials: Section revised to provide information supporting new indication "Treatment of initial episode of genital herpes".

INDICATIONS AND USAGE:

Section revised to incorporate new indication.

WARNINGS:

Last two sentences - "Valtrex is not indicated for the treatment of immunocompromised patients. This syndrome has not been observed in immunocompetent patients treated with Valtrex in clinical trials." deleted.

The section now reads (all bold) "Thombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), in some cases resulting in death, has occurred (replacing "been reported") in patients with advanced HIV disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of Valtrex at doses of 8 grams per day." (Italicized words are new.)

PRECAUTIONS:

First sentence revised to read "The efficacy of Valtrex has not been established for the treatment of disseminated herpes zoster, or suppression of recurrent genital herpes, or in immunocompromised patients."

Information for Patients: Genital Herpes (formerly called "Recurrent Genital Herpes"): Last sentence of subsection - "There are no data on the effectiveness of treatment with Valtrex when initiated more than 24 hours after the onset of signs or symptoms." deleted and replaced by

New second paragraph - "There are no data on the effectiveness of treatment initiated more than 72 hours after the onset of signs and symptoms of a first episode of genital herpes or more than 24 hours of the onset of signs and symptoms of a recurrent episode."

ADVERSE REACTIONS

Table 1. "Incidence (%) of Adverse Events in Herpes Zoster and Genital Herpes Study Populations" revised - see labeling/package insert.

DOSAGE AND ADMINISTRATION:

Section revised to incorporate information about new indication, including revision of Table 2: Dosages for Patients with Renal Impairment.

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ZOLOFT (sertraline HCl)
[October 25, 1996: Pfizer]

PRECAUTIONS:

General: Activation of Mania/Hypomania: Revised to indicate that activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed antidepressant and antiobsessional drugs [italicized words added].

Seizure: Revised to indicate that while no seizures were observed among approximately 3000 patients treated with Zoloft in the depression development program, 4 patients out of approximately 1800 exposed during the obsessive compulsive disorder (OCD) development program experienced seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two with a seizure disorder and one with a family history of seizure disorder, none of whom were receiving anticonvulsant medication. Thus, like other antidepressant and antiobsessional drugs, Zoloft should be introduced with care in patients with a seizure disorder.

Information for Patients: Advisement against concomitant use of Zoloft and alcohol in depressed patients expanded to OCD patients.

Drug Interactions: Drugs Metabolized by P450 3A4 (new subsection): Sertraline was co-administered with cytochrome P450 3A4 substrates (terfenadine or carbamazepine), under steady-state conditions, in two separate in vivo interaction studies. The results of these studies demonstrated that sertraline co-administration did not increase plasma concentrations of terfenadine or carbamazepine, suggesting that sertraline's extent of inhibition of P450 3A4 activity is not likely to be of clinical significance.

Tricyclic Antidepressants (TCAs) (new subsection): The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with Zoloft, because sertraline may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and TCA dose may need to be reduced, during co-administration with Zoloft (see Drugs Metabolized by P450 2D6 under PRECAUTIONS).

Alcohol: Recommendation against concomitant use of Zoloft and alcohol in depressed patients expanded to OCD patients.

Carcinogenesis: Revised by deleting maximum recommended human dose (MRHD) comparisons based on mg/kg; all the previously delineated carcinogenesis studies now have MRHD values expressed on a mg/m² basis.

Impairment of Fertility: Revised by deleting MRHD comparison based on mg/kg.

PREGNANCY - PREGNANCY CATEGORY C:

Pregnancy Category has been changed from B to C.

Teratogenic Effects and Non-teratogenic Effects subsection designations have been eliminated, with the following new paragraph under PREGNANCY - PREGNANCY CATEGORY C:

"Reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to approximately 4 times the maximum recommended human dose (MRHD) on a mg/m² basis. There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.5 times the MRHD on a mg/m² basis) in rats and 40 mg/kg (4 times the MRHD on a mg/m² basis) in rabbits. When female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in the number of stillborn pups and in the number of pups dying during the first 4 days after birth. Pup body weights were also decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg (1 times the MHRD on a mg/m² basis). The no effect dose for rat pup mortality was 10 mg/kg (0.5 times the MRHD on a mg/m² basis). The decrease in pup survival was shown to be due to in utero exposure to sertraline. The clinical significance of these effects is unknown. There are no adequate and well-controlled studies in pregnant women. Zoloft should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."

ADVERSE REACTIONS:

Commonly Observed: Among patients treated with Zoloft in placebo controlled premarketing studies added to beginning of subsection outlining the most commonly observed adverse events associated with Zoloft use and not seen at an equivalent incidence among placebo treated patients.

New paragraph added: "In placebo-controlled clinical trials for OCD, adverse events observed at an incidence of at least 5% for Zoloft and at an incidence that was twice or more the incidence among placebo-treated patients included: nausea, insomnia, diarrhea, decreased libido, anorexia, dyspepsia, ejaculation failure (primarily ejaculatory delay), tremor, and increased sweating."

Associated with Discontinuation of Treatment: Patients substituted for "subjects" in first sentence.

New paragraph added: "In placebo-controlled clinical trials for OCD, 10% of patients treated with Zoloft discontinued treatment due to an adverse event. The more common events were nausea, insomnia, and diarrhea."

Incidence in Controlled Clinical Trials: Depression: Table outlining treatment-emergent adverse experience incidence in placebo-controlled clinical trials for depression (now called Table 1) has been revised, with percentages rounded to the nearest whole number. As before, events reported by at least 1% of patients treated with Zoloft are included in Table 1, with the new exception of those events which had an incidence on placebo greater than or equal to Zoloft. The latter are listed below, but are not included in, Table 1.

Obsessive Compulsive Disorder (new subsection): Contains a table (Table 2) which enumerates adverse events that occurred at a frequency of 2% or more among patients on Zoloft who participated in controlled trials comparing Zoloft with placebo in the treatment of OCD [see complete subsection in package insert].

Other Events Observed During the Premarketing Evaluation of Zoloft (sertraline hydrochloride) New notation added: "The safety profile observed in OCD patients treated with Zoloft is similar to the safety profile in depressed patients."

DOSE AND ADMINISTRATION:

Initial Treatment: With respect to effect/effectiveness, or/and antiobsessive added to antidepressant where appropriate. A new statement recommends a dose of 50 mg, administered once daily, as the initial dose.

Maintenance/Continuation/Extended Treatment:

New paragraph added: "Although the efficacy of Zoloft beyond 12 weeks of dosing for OCD has not been documented in controlled trials, OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments may be needed to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment."

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