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Back To Vidyya Summary Of Safety-Related Drug Labeling Changes

Approved By FDA For October 2000

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 2000 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.)

ALTACE
(ramipril)
ARTHROTEC
(diclofenac sodium/,misoprostol)
ATROVENT
(ipratropium bromide)
BIAXIN
(clarithromycin)
CAFERGOT
(ergotamine tartrate/caffeine)
CARDURA
(doxazocin mesylate)
CHLOROPTIC
(chloramphenicol)
CLINIMIX E
(amino acid with electrolytes)
COLYTE
(PEG 3350/electrolytes)
CRIXIVAN
(indinavir sulfate)
FOSAMAX
(alendronate sodium)
LESCOL
(fluvastatin sodium)
LORABID
(loracarbef)
LOZOL
(indapamide)
MIRCETTE
(desogestrel/ethinyl estradiol & ethinyl estradiol)
MYLOTARG
(gemtuzumab ozogamycin)
NEORAL
(cyclosporine)
NEURONTIN
(gabapentin)
NITROGLYCERIN
PLAQUENIL
(hydroxychloroquine sulfate)
PRIFTIN
(rifapentine)
SANDIMMUNE
(cyclosporine)
SEROSTIM
(somatropin)
SINGULAIR
(montelukast sodium)
Return to Quick Reference

ALTACE (ramipril) Capsules
[October 4, 2000: Monarch Pharmaceuticals]

Labeling information revised to provide for a new indication - use for reduction in risk of myocardial infarction, stroke, and death from cardiovascular causes. Contact the company for a copy of the new labeling/package insert.

Return to Quick Reference

ARTHROTEC (diclofenac sodium/misoprostol) Tablets
[October 3, 2000: Searle]

Boxed WARNING AND CONTRAINDICATIONS:
First paragraph revised with changes incorporated, second paragraph unchanged and new third and fourth paragraphs added -

"ARTHROTEC (diclofenac sodium/misoprostol) ADMINISTRATION BY ANY ROUTE IS CONTRAINDICATED, BECAUSE ITS MISOPROSTOL COMPONENT CAN CAUSE ABORTION, IN WOMEN WHO ARE PREGNANT (See WARNINGS and PRECAUTIONS).
· Anecdotal reports have been received, primarily from Brazil, of congenital anomalies and reports of fetal death in pregnancies in which misoprostol has been used as an abortifacient.

"PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE THE DRUG TO OTHERS.

"UTERINE RUPTURE HAS BEEN REPORTED WHEN MISOPROSTOL WAS ADMINISTERED INTRAVAGINALLY IN PREGNANT WOMEN TO INDUCE ABORTION BEYOND THE FIRST TRIMESTER OF PREGNANCY.

"UTERINE PERFORATION HAS BEEN REPORTED FOLLOWING ADMINISTRATION OF COMBINED VAGINAL-AND-ORAL MISOPROSTOL IN PREGNANT WOMEN TO INDUCE ABORTION. IN EACH OF THESE REPORTED CASES, THE GESTATIONAL AGE OF THE PREGNANCIES WAS UNKNOWN."

PRECAUTIONS:
Information for Patients:

"Patients should be advised of the following:
SPECIAL NOTE FOR WOMEN: Arthrotec contains misoprostol. Because of its abortifacient property, misoprostol is contraindicated for use by pregnant women. Misoprostol may cause miscarriage if given to pregnant women at any time during pregnancy. Miscarriages caused by misoprostol may be incomplete, which could lead to dangerous bleeding, hospitalization, surgery, infertility, or maternal or fetal death."

Geriatric Use: Previous subsection text deleted and replaced with the following:

"Of the more than 2,100 subjects in clinical studies with Arthrotec, 25% were 65 and over, while 6% were 75 and over. In studies with diclofenac, 31% of subjects were 65 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, but greater sensitivity of some older individuals cannot be ruled out. As with any NSAID, the elderly are likely to tolerate adverse events less well than younger patients.

"Diclofenac is known to be substantially excreted by the kidney, and the risk of toxic reactions to Arthrotec may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see PRECAUTIONS-Renal effects).

Based on studies in the elderly, no adjustment of the dose of Arthrotec is necessary in the elderly for pharmacokinetic reasons (see Pharmacokinetics of Arthrotec-Special populations), although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging."

Return to Quick Reference

ATROVENT (ipratropium bromide) Nasal Spray
[October 27, 2000: Boehringer Ingelheim]

Labeling revised to include information on a new indication - the use for symptomatic relief of rhinorrhea associated with seasonal allergic rhinitis in patients 5 years of age and older. Contact the company for a copy of the new labeling/package insert.

Return to Quick Reference

BIAXIN (clarithromycin) Tablets
[October 20, 2000: Abbott]

[Other labeling changes not appearing in 2000 PDR: Mar00, Jun00]

CLINICAL PHARMACOLOGY:
Microbiology:

Susceptibilty Testing Excluding Mycobacteria and Helocobacter:
Dilution Techniques: and Diffusion Techniques: have been extensively revised. Contact the company for a copy of the new labeling/package insert.

INDICATIONS AND USAGE:
Adults: Haemophilus influenzae added to indication for pneumonia.

Return to Quick Reference

CAFERGOT (ergotamine tartrate/caffeine) Suppositories
[October 31, 2000: Novartis]

Labeling extensively revised. Contact the company for a copy of the new labeling/package insert.
Return to Quick Reference

CARDURA (doxazosin mesylate) Tablets
[October 10, 2000: Pfizer]

CONTRAINDICATIONS:
Section revised (new text in italics) -

"Cardura is contraindicated in patients with a known sensitivity to quinazolines (e.g., prazosin, terazosin), doxazosin, or any of the inert ingredients."

ADVERSE REACTIONS:
New last paragraph -

"In post-marketing experience the following additional adverse reactions have been reported: Autonomic Nervous System: priapism; Central Nervous System: hypoesthesia; Endocrine System: gynecomastia; Gastrointestinal System: vomiting; General Body System: allergic reaction; Heart Rate/Rhythm: bradycardia; Hematopoietic: leukopenia, thrombocytopenia; Liver/Biliary System: hepatitis, hepatitis cholestatic; Respiratory System: bronchospasm aggravated; Urinary System: hematuria, micturition disorder, micturition frequency, nocturia."

Return to Quick Reference

CHLOROPTIC (chloramphenicol) Ophthalmic Solution
[October 3, 2000: Allergan]

BOXED WARNING:
Paragraph revised (new text in italics) -

"Bone marrow hypoplasia including aplastic anemia and death has been reported following ["local" deleted] topical application of chloramphenicol. Chloramphenicol should not be used when less potentially dangerous agents would be expected to provide effective treatment."

CLINICAL PHARMACOLOGY:
Microbiology: First paragraph revised with revisions incorporated below -

"Chloramphenicol is a broad-spectrum antibiotic originally isolated from Streptomyces venezuelae. It is primarily bacteriostatic and acts by inhibition of protein synthesis by interfering with the transfer of activated amino acids from soluble RNA to ribosomes."

INDICATIONS AND USAGE:
First paragraph revised (new text in italics) -

"Chloramphenicol should be used only in those serious infections for which less ["potent" deleted] potentially dangerous drugs are ineffective or contraindicated. (See Boxed Warning)."

Second paragraph, first sentence revised (new text in italics) - Chloroptic is indicated for the treatment of surface ocular infections involving the conjunctiva and/or cornea caused by chloramphenicol-susceptible organisms."

PRECAUTIONS:
General: Subsection revised (new text in italics) -

"["As with other antibiotics," deleted] The prolonged use of antibiotics may occaisionally result in overgrowth of nonsusceptible organisms, including fungi. If ["superinfection occurs, or if clinical improvement is not noted within a reasonable period, discontinue use" deleted] new infections appear during medication or clinical improvement is not observed within 1 week, the drug should be discontinued and appropriate measures should be taken."

Information for patients: Do not touch bottle tip to any surface as this may contaminate the solution."

Pregnancy
Pregnancy Category C
Subsection revised (new text in italics) -

"Chloramphenicol has been shown to be embryocidal and teratogenic in rat, mouse, rabbit and chicken embryos/fetuses (see below). There are no adequate and well-controlled studies in pregnant women. Chloramphenicol has been shown to cross the placental barrier, but it is not known whether chloramphenicol can cause fetal harm when administered to a pregnant woman. Chloramphenicol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."

Embryotoxic effects: New last sentence added -

"Chloramphenicol (2.5 mg) injected into chicken eggs resulted in a 20% embryo mortality rate one day after administration, which increased to 100% embryo mortality on the 11th day of incubation."

Nursing Mothers: New first sentence added -

"Chloramphenicol appears in human milk following oral administration of the drug. Systemic absorption of chloramphenicol may occur when applied topically."

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

The safety and efficacy in ["children" deleted] pediatric patients below 1 year of age have not been established."

ADVERSE REACTIONS:
Third paragraph revised -

"Reactions occurring most often from the use of topical anti-infectives are allergic sensitizations. These reactions include stinging, itching, angioneurotic edema, urticaria, vesicular and maculopapular dermatitis."

Has been deleted and replaced with the following:

"The most frequently reported adverse reactions have been burning, stinging, ocular irritation and conjunctival hyperemia. Blood dyscrasias, allergic or inflammatory reactions due to individual hypersensitivity, angioneurotic edema, urticaria, vesicular and maculopapular dermatitis have also been reported (See Warnings and Box Warnings)."

DOSAGE AND ADMINISTRATION:
Subsection revised (new text in italics) -

"One or two drops 4 to 6 times a day for the first 72 hours[", depending upon the severity of the condition" deleted] should be placed in the lower conjunctival sac. ["Intervals between applications may be increased after the first two days. Since the action of the drug is primarily bacteriostatic, therapy should be continued for 48 hours after an apparent cure has been attained" deleted] Treatment should be continued for approximately 7 days but should not be continued for more than three weeks without re-evaluation by the prescribing physician."

HOW SUPPLIED:
Subsection revised (new text in italics) -

"Refrigerate until dispensed. Then store below 30°C (86°F). Discard solution within 21 days from date dispensed."

Return to Quick Reference

CLINIMIX (amino acid in dextrose) Injection
[October 19, 2000: Baxter]

[Other labeling changes not appearing in 2000 PDR: Apr00]
WARNINGS:
New last paragraph -

"In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage."

PRECAUTIONS:
Pediatric Use: New text added:

"Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants.

"Safety and effectiveness of Clinimix -sulfite-free (Amino Acid in Dextrose) Injections in pediatric patients have not been established by adequate and well controlled studies. However, the use of amino acid injections in pediatric patients as an adjunct in the offsetting of nitrogen loss or in the treatment of negative nitrogen balance is referenced in the medical literature. See Dosage and Administration."

DOSAGE AND ADMINISTRATION:
Third paragraph, last sentence revised -

"Daily amino acid doses of approximately 1.0 to 1.5 g/kg of body weight for adults ["and 2 to 3 g/kg of body weight for infants" deleted] with adequate calories are generally sufficient to satisfy protein needs and promote positive nitrogen balance."

Pediatric Use: New subsection -

"Use of Clinimix - sulfite-free (Amino Acid in Dextrose) Injections in pediatric patients is governed by the same considerations that affect the use of any amino acid solution in pediatrics. The amount administered is dosed on the basis of grams of amino acids/kg of body weight/day. Two to 3 g/kg of body weight for infants with adequate calories are generally sufficient to satisfy protein needs and promote positive nitrogen balance. Solution administrations by peripheral vein should not exceed twice normal serum osmolality (718 mOsmol/L).

Peripheral Vein Administration: New second sentence -

"In pediatric patients, the final solution should not exceed twice normal serum osmolality (718 mOsmol/L)."

Return to Quick Reference

COLYTE (PEG 3350 & electrolytes) Oral Solution
[October 16, 2000: Schwarz]

CONTRAINDICATIONS:
New first sentence -

"Colyte is contraindicated in patients known to be hypersensitive to any of the components."

PRECAUTIONS:
Geriatric Use: New subsection -

"Published literature contains isolated reports of serious adverse reactions following the administration of PEG-ELS products in patients over 60 years of age. These adverse events include upper GI bleeding from Mallory-Weiss Tear, esophageal perforation, asystole, sudden dyspnea with pulmonary edema, and "butterfly-like" infiltrate on chest x-ray after vomiting and aspirating PEG."

Return to Quick Reference

CRIXIVAN (indinavir sulfate) Capsules
[October 23, 2000: Merck]

[Other labeling changes not appearing in 2000 PDR: Apr00]

[For a full description of the following revisions, contact the company for a copy of the new labeling/package insert.]

CLINICAL PHARMACOLOGY:
Gender: Labeling provides for revisions regarding gender-based pharmacokinetic analysis, including a new table (Table 1).
Pediatric: Labeling provides for pediatric safety data.

Drugs That Should Not Be Coadministered With Crixivan: Labeling provides information related to concomitant use of Crixivan and St. John's Wort.

INDICATIONS AND USAGE:
Recalculation of HIV RNA suppression rates and new figure (Figure 1) for the ACTG 320 study.

WARNINGS:
Drug Interactions: Revisions related to the concomitant use of Crixivan and St. John's Wort.
Nephrolithiasis/Urolithiasis: Labeling provides for pediatric safety data.

PRECAUTIONS:
Antiviral Pregnancy Registry: New subsection - "To monitor maternal-fetal outcomes of pregnant women exposed to Crixivan, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263."
Pediatric Use: Labeling provides for pediatric safety data.

Return to Quick Reference

FOSAMAX (alendronate sodium) Tablets
[October 20, 2000: Merck]

[Other labeling changes not appearing in 2000 PDR: Sep00]

Labeling revised to provide for two new dosage strengths, 35 and 70 mg, for once weekly dosing for the prevention and treatment of postmenopausal osteoporosis, respectively. Contact the company for a copy of the new physician's and patient's package insert.
Return to Quick Reference

LESCOL (fluvastatin sodium) Capsules
[October 23, 2000: Novartis]

CLINICAL PHARMACOLOGY:
Distribution: New last sentence - "At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide."

Metabolism: New second paragraph -

"In vitro studies that fluvastatin undergoes oxidative metabolism, predominantly via 2C8 isoenzyme systems (75%). Other isoenzymes that contribute to fluvastatin metabolism are 2C8 (~5%) and 3A4 (~20%). (see PRECAUTIONS Drug Interactions Section).

PRECAUTIONS:
Drug Interactions:

Immunosuppressive Drugs, Gemfibrizol, Niacin (Nicotinic Acid), Erythromycin: (See WARNINGS: Skeletal Muscle).
Previous subsection text deleted and replaced with the following:

"In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P-450 (CYP) isoenzymes. CYP 2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (~75%), while CYP 2C8 and CYP 3A4 isoenzymes are involved to a much less extent, i.e. ~5% and ~20%, respectively. If one pathway is inhibited in the elimination process of fluvastatin other pathways may compensate.

In vivo drug interaction studies with CYP3A4 inhibitors/substrates such as cyclosporine, erythromycin, and itraconazole result in minimal changes in the pharmacokinetics of fluvastatin, confirming less involvement of CYP 3A4 isoenzyme. Concomitant administration of fluvastatin and phenytoin increased the levels of phenytoin and fluvastatin, suggesting predominant involvement of CYP 2C9 in fluvastatin metabolism."

Cyclosporine: Plasma cyclosporine levels remain unchanged when fluvastatin (20 mg qd) was administered concurrently in renal transplant recipients on stable cyclosporine regimens. Fluvastatin AUC increased 1.9 fold, and Cmax increased 1.3 fold compared to historical controls.

Erythromycin: Erythromycin (500 mg, single dose) did not affect steady state plasma levels of fluvastatin (40 mg qd).

Itraconazole: Concomitant administration of fluvastatin (40 mg) and itraconazole (100 mg qd x 4 days) does not affect plasma itraconazole or fluvastatin levels.

Gemfibrozil: There is no change in either fluvastatin (20 mg bid) or gemfibrozil (600 mg bid) plasma levels when these drugs are coadministered.

Phenytoin Single morning dose administration of phenytoin (300 mg extended release) increased mean steady-state fluvastatin (40 mg) Cmax by 27% and AUC by 40% whereas fluvastatin increased the mean phenytoin Cmax by 5% and AUC by 20%. Patients on phenytoin should continue to be monitored appropriately when fluvastatin therapy is initiated or when the fluvastatin dosage is changed.

Diclofenac: Concurrent administration of fluvastatin (40 mg) increased the mean Cmax and AUC of diclofenac by 60% and 25% respectively.

Tolbutamide: In healthy volunteers, concurrent administration of either single or multiple daily doses of fluvastatin sodium (40 mg) with tolbutamide (1 g) did not affect the plasma levels of either drug to a clinically significant extent.

Glibenclamide (Glyburide): In glibenclamide-treated NIDDM patients (n =32), administration of fluvastatin (40 mg bid for 14 days) increased the mean Cmax, AUC, and t1/2 of glibenclamide approximately 50%, 69% and 121%, respectfully. Glibenclamide (5-20 mg qd) increased the mean Cmax and AUC of fluvastatin by 44% and 51%, respectively. In this study there were no changes in glucose, insulin and C-peptide levels. However, patients on concomitant therapy with glibenclamide (glyburide) and fluvastatin should continue to be monitored appropriately when their fluvastatin dose is increased to 40 mg bid.

Losartan: Concomitant administration of fluvastatin with losartan has no effect on the bioavailability of either losartan or its active metabolite.

Return to Quick Reference

LORABID (loracarbef) Oral Suspension & Pulvules
[October 5, 2000: Eli Lilly]

ADVERSE REACTIONS:
Paragraph following Genitourinary: revised (new text in italics) -

"As with other ß-lactam antibiotics, the following potentially severe adverse experiences have been reported rarely with loracarbef in worldwide post-marketing surveillance: anaphylaxis, hepatic dysfunction including cholestasis (with or without jaundice), prolongation of the prothrombin time with clinical bleeding in patients taking anticoagulants, and Stevens-Johnson syndrome."

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LOZOL (indapamide) Tablets
[October 10, 2000: Aventis]

ADVERSE REACTIONS:
Next to last paragraph revised (new text in italics) -

"The following reactions have been reported with clinical usage of Lozol: jaundice (intrahepatic cholestatic jaundice), hepatitis, pancreatitis and abnormal liver function tests. These reactions were reversible with discontinuance of the drug."

Return to Quick Reference

MIRCETTE (desogestrel/ethinyl estradiol & ethinyl estradiol) Tablets
[October 3, 2000: Organon]

[Other labeling changes not appearing in 2000 PDR: Feb00, Apr00]

CLINICAL PHARMACOLOGY:
Second paragraph revised (new text in italics) -

"Receptor binding studies, as well as studies in animals, have shown that etonogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity (91,92). The relevance of this latter finding in humans is unknown."

WARNINGS:
Thromboembolic Disorders And Other Vascular Problems:
a. Thromboembolism (new text added to end of first paragraph) -

"Several epidemiologic studies indicate that third generation oral contraceptives, including those containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives (102-104). In general, these studies indicate an approximate 2-fold increased risk, which corresponds to an additional 1-2 cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this 2-fold increase in risk."

The following paragraph was deleted -

"In two case-controlled studies and one cohort study of venous thromboembolism, third generation oral contraceptives including those containing desogestrel, were reported to have relative risk between 1.5 and 2.4 when compared to certain second generation oral contraceptives (101-103). These risks are within the above-mentioned range for deep vein thrombosis and pulmonary embolism. A relative risk of 2 would translate into an additional 1-2 cases of non-fatal venous thromboembolism per 10,000 women-years of use. The risk of venous thromboembolic disease associated with oral contraceptives does not increase with length of use and disappears after pill use is stopped."

b. Myocardial Infarction
Last paragraph, last sentence deleted -

"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."

d. Dose-related risk of vascular disease from oral contraceptives
Second paragraph, new last sentence added -

"New acceptors of oral contraceptive agents should be started on preparations containing 0.035 mg or less of estrogen."

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MYLOTARG (gemtuzumab ozogamicin) Injection
[October 27, 2000: Wyeth]

CLINICAL STUDIES:
First paragraph, new fifth and sixth sentences added -

"Patients with secondary leukemia or white blood cell (WBC) counts greater than or equal to 30,000/µL were excluded. Some patients were leukoreduced with hydroxyurea or leukophoresis to lower WBC counts below 30,000/µL in order to minimize the risk of tumor lysis syndrome."

WARNINGS:
Allergic Reactions: New last paragraph added -

"Anaphylaxis was not reported in the three phase II clinical studies (see CLINICAL STUDIES section). However, Mylotarg contains a humanized anti-CD33 antibody. As with any protein product, the possibility of anaphylaxis cannot be excluded."

PRECAUTIONS:
Tumor Lysis Syndrome: New second sentence added -

"Physicians should consider leukoreduction with hydroxyurea or leukophoresis to reduce the peripheral white blood count to <30,000/µL prior to administration of Mylotarg (see CLINICAL STUDIES)."

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NEURONTIN (gabapentin) Oral Solution, Capsules & Tablets
[October 12, 2000: Parke-Davis]

Labeling revised to include information on a new indication - use as an adjunctive therapy in the treatment of partial seizures in pediatric patients age 3 years and above. Contact the company for a copy of the new labeling/package insert.

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NITROGLYCERIN (nitroglycerin in 5% Dextrose) Injection
[October 6, 2000: Baxter]

PRECAUTIONS:
Geriatric Use: Subsection added -

"Clinical studies of Nitroglycerin 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."

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PLAQUENIL (hydroxychloroquine sulfate) Tablets
[October 5, 2000: Sanofi]

ADVERSE REACTIONS:
Neuromuscular Reactions: Previous text deleted and replaced with the following:

"Skeletal muscle palsies or skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups which may be associated with mild sensory changes, depression of tendon reflexes and abnormal nerve conduction."

Dermatologic Reactions: Text revised (new text in italics) -

Bleaching of hair, alopecia, pruritis, skin and mucosal pigmentation, photosensitivity, and skin eruptions (urticarial, morbilliform, lichenoid, maculopapular, purpuric, erythema annulare centrifugum, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, and exfoliative dermatitis)."

Gastrointestinal Reactions: Anorexia, nausea, vomiting, diarrhea, and abdominal cramps. Isolated cases of abnormal liver function and fulminant hepatic failure.

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PRIFTIN (rifapentine) Tablets
[October 20, 2000: Aventis]

[Other labeling changes not appearing in 2000 PDR: Sep00]

INDICATIONS AND USAGE:
First paragraph, the following text deleted:

"This indication is based on the 6 month follow up treatment outcome observed in the controlled clinical trial as a surrogate for the 2 year follow up generally accepted as evidence of efficacy in the treatment of pulmonary tuberculosis."

WARNINGS:
Second paragraph, new last sentence added -

"Hepatotoxicity of other antituberculosis drugs (eg, isoniazid, pyrazinamide) used in combination with rifapentine should also be taken into account."

PRECAUTIONS:
General: Second sentence revised (new text in italics) -

"Contact lenses or dentures may become permanently stained."

New second paragraph added -

"Rifapentine should not be used in patients with porphyria. Rifampin has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase. Isolated reports have associated porphyria exacerbation with rifampin administration. Based on these isolated reports with rifampin, it may be assumed that rifapentine has a similar effect."

Information for Patients: First sentence revised (new text in italics) -

"The patient should be told that Priftin may produce a reddish coloration of the urine, sweat, sputum, tears and breast milk and the patient should be forwarned that contact lenses or dentures may be permanently stained."

Carcinogenesis, Mutagenesis, Impairment of Fertility New third sentence added -

The 25-desacetyl metabolite of rifapentine was also negative in the in vitro gene mutation assay in bacteria (Ames test), the in vitro Chinese hamster ovary cell/hypoxanthine-guanine-phosphoribosyl transferase (CHO/HGPRT) forward mutation assay, and the in vivo mouse bone marrow micronucleus assay. This metabolite did induce chromosomal aberrations in an in vitro chromosomal aberration assay."

Nursing Mothers New last sentence added -

"Since rifapentine may produce a red-orange discoloration of body fluids, there is a potential for discoloration of breast milk."

ADVERSE REACTIONS:
Fourth paragraph, first and third sentences revised (new text in italics) -

"["Eighteen" deleted] Twenty-two deaths occurred in study 008 (["nine" deleted] eleven in the rifampin combination therapy group and ["nine" deleted] eleven in the rifapentine combination therapy group). None of the deaths were attributed to study medication. In the study, 18/361 (5.0%) rifampin combination therapy patients discontinued the study due to adverse event compared to ["9" deleted]11/361 (["2.5" deleted]3.0%) rifapentine combination therapy patients."

Changes to the CLINICAL TRIALS section and minor changes to Table 2-3 may be obtained by contacting the company.

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SANDIMMUNE (cyclosporine) Oral Solution & Capsules
NEORAL (cyclosporine) Oral Solution & Capsules

[October 4, 2000: Novartis]
WARNINGS:
Paragraph added immediately after sentence concerning convulsions:

"Encephalopathy has been described both in post-marketing reports and in the literature. Manifestations include impaired consciousness, convulsions, visual disturbances (including blindness) loss of motor function, movement disorders and psychiatric disturbances. In many cases, changes in the white matter have been detected using imaging techniques and pathogenic specimens. Predisposing factors such as hypertension, hypomagnesemia, hypocholesterolemia, high-dose corticosteroids, high cyclosporine blood concentrations, and graft-versus-host disease have been noted in many but not all of the reported cases. The changes in most cases have been reversible upon discontinuation of cyclosporine, and in some cases improvement was noted after reduction of dose. It appears that patients receiving liver transplant are more susceptible to encephalopathy than those patients receiving kidney transplant."

ADVERSE REACTIONS:
The following paragraph was deleted: "There have been post-marketing reports of neurotoxicity associated with cyclosporine therapy. Signs of encephalopathy, convulsions, vision and movement disturbances and impaired consciousness have been described, especially in liver transplant patients. These alterations appear to be multifactorial in origin. Generally, reduction of dose has been observed to result in reversal of these changes."

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SEROSTIM (somatropin) Injection
[October 27, 2000: Serono]

[Other labeling changes not appearing in 2000 PDR: Jul00]

PRECAUTIONS:
Geriatric Use: New subsection -

"Clinical studies with Serostim did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients may be more sensitive to growth hormone action, and may be more prone to develop adverse reactions. Thus, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range."

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SINGULAIR (montelukast sodium) Tablets
[October 17, 2000: Merck]

[Other labeling changes not appearing in 2000 PDR: Mar00, May00]
ADVERSE REACTIONS:
Post-Marketing Experience: First paragraph (new text in italics) -

"The following additional adverse reactions have been reported in post-marketing use: hypersensitivity reactions (including anaphylaxis, angioedema, pruritus, urticaria, and very rarely, hepatic eosinophilic infiltration), dream abnormalities, drowsiness, irritability, and restlessness, insomnia, nausea, vomiting, dyspepsia and diahhrea."

PATIENT INFORMATION:
What are the possible side effects of SINGULAR?: Subsection revised with revisions incorporated below:

The side effects of Singulair are usually mild.

· The side effects in patients treated with Singulair were similar in type and frequency to side effects in patients who were given a placebo (a pill containing no medication).

The list below is NOT a complete list of side effects reported with Singulair. Your doctor can discuss with you a more complete list of side effects. The most common side effects are listed below.

    tiredness
    fever
    abdominal (stomach) pain
    stomach or intestinal upset (gastroenteritis)
    heartburn
    dizziness
    headache
    rash
    cough
    flu
    stuffy nose

"Less common side effects included the following
· allergic reactions including

    · swelling of the face, lips, tongue, and/or throat, which may cause difficulty in breathing or swallowing
    · hives
    · itching
· bad/vivid dreams
· irritability
· restlessness
· insomnia
· nausea
· vomiting
· dyspepsia
· diarrhea

Rarely, patients taking Singulair have experienced a condition that includes a combination of certain symptoms that do not go away or that get worse. These symptoms may include:

    · a flu-like illness
    · rash
    · a feeling of pins and needles or numbness of arms and legs
    · severe inflammation (pain and swelling) of the sinuses (sinusitis)

These have occurred usually, but not always, in patients who were taking oral corticosteroid pills for asthma and those corticosteroids were being slowly lowered or stopped. Although Singulair has not been shown to cause this condition, you must tell your doctor right away if you develop one or more of these symptoms.

Remember, anytime you have a medical problem you think may be related to Singulair, talk to your doctor."


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Editor: Susan K. Boyer, RN
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