(Posted: 6/30/97
Updated: 7/7/97, 7/8/97, 7/9/97 - completed)
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 1997 Physicians' Desk Reference (PDR) if drug's labeling included in the PDR.
(Click on name of the product to go directly to the summary.)
Former only sentence now second sentence revised to read (new text in italics) - "Safety and effectiveness of Beconase AQ Nasal Spray in children below 6 years of age have not been established."
New second paragraph added- "Glucocorticoids have been shown to cause a reduction in growth velocity in children and teenagers with extended use. If a child or teenager on any glucocorticoid appears to have growth suppression, the possibility that they are particularly sensitive to this effect of glucocorticoids should be considered."
Adults and Children 12 Years of Age and Older:
Children 6 to 12 Years of Age (new subsection): "Patients should be started with one inhalation in each nostril twice a day; patients not adequately responding to 168 mcg or those with more severe symptoms may use 336 mcg (two inhalations in each nostril. Beconase AQ Nasal Spray is not recommended for children below 6 years of age."
Subsection now reads - "In a study of 12 children administered 9 mg/kg, ceftibuten MEF area under the curve (AUC) averaged approximately 70% of the plasma AUC. In the same study, Cmax values were 14.3 + or - 2.7 ug/ml in MEF at 4 hours postdose and 14.5 + or - 3.7 ug/ml in plasma at 2 hours postdose."
The subsection now reads - "Long term in vivo have not been performed to evaluate the carcinogenic potential of cefprozil.
"Cefrozil was not found to be mutagenic in either the Ames Salmonella or E. Coli WP2 urvA reversion assays or the Chinese hamster ovary cell HGPRT forward gene mutation assay and it did not induce chromosomal abnormalities in Chinese hamster ovary cells or unscheduled DNA synthesis in rat hepatocytes in vitro. Chromosomal aberrations were not observed in bone marrow cells from rats dosed orally with over 30 times the highest recommended human dose based upon mg/m2.
"Impairment of fertility was not observed in male or female rats given oral doses of cefprozil up to 18.5 times the highest recommended human dose based upon mg/m2."
Pregnancy: Teratogenic Effects: Pregnancy Category B: first sentence in subsection revised to read (new text in italics) - "Reproduction studies have been performed in rabbits (N.B. previously listed last), mice and rats ("at doses 14, 7, and 0.7" - deleted) using oral doses of cefprozil of 0.8, 8.5 and 18.5 times the maximum daily human dose (1000 mg) based upon mg/m2, and have revealed no harm to the fetus ("due to cefprozil" deleted).
"Patients taking drugs associated with drug induced methemoglobinemia such as sulfonamides, acetaminophen, acetanild, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, para-aminsosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine, quinine are also at greater risk for developing methemoglobinemia."
Addition of text at end of fourth paragraph that reads - "The maximum recommended dose that ever be administered within a two hour period in normal healthy adults should be calculated based upon the patient's weight as follows;
Weight |
Maximum recommended dose |
<70 kg |
8mg/kg |
> or = 70 kg |
600 mg (15ml) or 8 cartridges |
Maximum Recommended Dosages: Deletion of first sentence that reads - "Normal Healthy Adults: No more that 600 mg (8 mg/kg or 4 mg/lb) of prilocaine HCl should be administered as a single injection."
Addition of new text - "In patients weighing > or = 150 lbs (or 70 kg), no more than 4 mg/lb(8 mg/kg) should be administered. In patients weight < 150 lbs, no more than 600 mg (8 cartridges) of prilocaine HCl should be administered as a single injections."
Labeling extensively revised to incorporate information on new indication of congestive heart failure. Contact company for copy of the label/package insert.
"It is also active in vitro against some gram positive bacteria." (Femstat labeling)
"It is also active against some grma positive bacteria." (Femstat Prefill labeling)
"For use as a diagnostic aid: Effectiveness has not been established in pediatric patients."
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Subsection revised as follows (new text in italics) - "Long term studies of cromolyn sodium in mice (12 months intraperitoneal administration at doses up to 150 mg/kg three days per week), hamsters (intraperitoneal administration at doses up to 52.6 mg/kg three days per week for 15 weeks followed by 17.5 mg/kg three days per week for 37 weeks), and rats (18 months subcutaneous administration at doses up to 75 mg/kg six days per week) showed no neoplastic effects. The average daily maximum dose levels administered in these studies were 192.9 mg/m2 for mice, 47.2 mg/m2 for hamsters and 385.8 mg/m2 for rats. These doses correspond to approximately 330%, 80%, and 650% of the maximum daily human dose of 59.2 mg/m2.
"Cromolyn sodium showed no mutagenic potential in Ames Salmonella/microsome plate assays, mitotic gene conversion in Saccharomyces cerevisiae and in an in vitro cytogenetic study in human peripheal lymphocytes.
"No evidence of impaired fertility was shown in laboratory reproductive studies conducted subcutaneously in rats in the highest doses tested, 175 mg/kg/day (1050 mg/m2) in males and 100 mg/kg/day (600 mg/m2) in females. These doses are approximately 18 and 10 times the maximum daily human dose, respectively, based on mg/m2."
Pregnancy: Pregancy Category B. First paragraph revised as follows (new text in italics) - "Reproduction studies with cromolyn sodium administered subcutaneously to pregnant mice and rats at maximum daily doses of 540 mg/kg (1620 mg/m2) and 164 mg/kg (984 mg/m2), respectively, and intravenously to rabbits at a maximum daily dose of 485 mg/kg (5820 mg/m2) produced no evidence of fetal malformations. These doses represent approximately 27, 16, and 98 times the maximum daily human dose, respectively, on a mg/m2 basis. Adverse fetal effects (increased resorptions and decreased fetal weight) were noted only at the very high parenteral doses that produced maternal toxicity. There are, however, no adequate and well-controlled studies in pregnant women."
New labeling available that provides for a 4-month dosage form to be used for the palliative treatment of advanced prostatic cancer. Contact the company for a copy of the label/package insert.
Labeling revised to incorporate information on the new indication for the empiric use as monotherapy in febrile neutropenic patients. Contact the company for a copy of the label/package insert.
Note: This change appears in the 1997 PDR.
Physician Insert
"8. Like other cytotoxic drugs, methotrexate may induce 'tumor lysis syndrome' in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.
"9. Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy. (See PRECAUTIONS, Organ System Toxicity, Skin)
"10. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy."
to - "Potentially fatal opportunistic infections, expecially Pneumocystis carinii pneumonia, may occur with methotrexate therapy."
Neurologic: A new second sentence has been added - "Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m2). Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies."
Skin (new subsection) - "Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases."
Central Nervous System: The third sentence has been revised (new text in italics) - "Following low doses, there have been occasional ("patients have reported" - deleted) reports of transient subtle cognitive dysfunction, mood alteration, ("or" - deleted) unusual cranial sensations, leukoencephalopathy or encephopathy."
Infection (new subsection): "There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic disease. Pneumocystis carinii pneumonia was the most common infection. Other reported infections included nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, H. simplex hepatitis, and disseminated H. simplex."
Skin: "skin necrosis, and exfoliative dermatitis" added after "Stevens-Johnson Syndrome".
Urogenital System: "gynecomasatia" added prior to "infertility".
First sentence of final paragraph revised to read (new text in italics) - "Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, ("opportunistic infections" deleted) arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, ("and" deleted) reversible lymphomas, and tumor lysis syndrome."
New fourth sentence added to second paragraph - "Skin rash and other skin disorders are an infrequent side effect of methotrexate therapy. Should you develop any unusual skin rash, contact your physician at once."
"Notify your physician at once if you think you are getting an infection."
Labeling extensively revised to incorporate new information based on approval for a once-a-day dosing regimen. Contact the company for a copy of the label/package insert.
New labeling to incorporate new information based on approval of new indication of planar imaging as a second line diagnostic drug after mammogram or a palpable breast mass. Contact the company for a copy of the label/package insert.
"If an allergic reaction occurs, the drug should be discontinued and appropriate therapy instituted."
Labeling revised to incorporate new information based on approval for new indication of treatment of tinea (pityriasis) versicolor caused by or presumed to be caused by Pityrosporum orbiculare (also known as Malassezia furfur or M. orbiculare). Contact the company for a copy of the label/package insert.
"The applicability of the CAST results to other populations (e.g., those without recent myocardial infarctions) is uncertain. Considering the known proarrhythmic properties of Pronestyl and the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, the use of Pronestyl as well as other antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias."
Subsection now reads - "Anorexia, nausea, vomiting, abdominal pain, bitter taste, or diarrhea may occur in 3 to 4 percent of patients taking oral procainamide."
Elevated Liver Enzymes (new subsection): "Elevations of transaminase with and without elevations of alkaline phosphatase and bilirubin have been reported. Some patients have had clinical symptoms (e.g., malaise, right upper quadrant pain). Deaths from liver failure have been reported."
Text added to end of section - "Because not all commercially available dosage forms of triazolam permit sufficient dosage reduction, coadministration of triazolam with Serzone should be avoided for most patients, including the elderly. In the exceptional case where coadministration of triazolam with Serzone may be considered appropriate, only the lowest possible dose of triazolam should be used (see CONTRAINDICATIONS and PRECAUTIONS Sections).
Priapism: Subsection revised to read (new text in italics) - "While priapism did not occur during premarketing experience with nefazodone, ("priapism has been reported with a structurally related drug, trazodone." deleted) rare reports of priapism have been received since market introduction. A causal relationship to nefazodone has not been established (see ADVERSE REACTIONS Section). If patients present with prolonged or inappropriate erections, they should discontinue therapy immediately and consult their physicians. If the condition persists for more than 24 hours, a urologist should be consulted to determine appropriate management."
Deletion of the seventh paragraph that states - "In the clinical studies which are reported below, ocular pressure reductions to less than 22 mmHg were used as a reasonable reference point to allow comparisons between treatments. Reduction of ocular pressure to just below 22mmHg may not be optimal for all patients; therapy should be individualized."
Deletion of the ninth paragraph that states - "In the multiclinic studies comparing Timoptic with pilocarpine, 61 percent of patients treated with Timoptic had intraocular pressure reduced to less than 22mmHg compared to 32 percent of patients treated with pilocarpine. For patients completing these studies, the mean reduction in pressure at the end of the study from pretreatment was 30.7 percent for patients treated with Timoptic and 21.7 percent for patients treated with pilocarpine."
Deletion of the tenth paragraph that states - "In the multiclinic studies comparing Timoptic with epinephrine, 69 percent of patients treated with Timoptic had intraocular pressure reduced to less than 22mmHg compared to 42 percent of patients treated with epinephrine. For patients completing these studies, the mean reduction in pressure at the end of the study from pretreatment was 33.2 percent for patients treated with Timoptic and 28.1 percent for patients treated with epinephrine."
Deletion of the twelfth paragraph that states - "Timoptic has also been used in patients with glaucoma wearing conventional (PMMA) hard contact lenses, and has generally been well tolerated. Timoptic has not been studied in patients wearing lenses made with materials other than PMMA. (See PRECAUTIONS, Information for Patients.)"
Information for Patients: (Sterile Ophthalmic Solution only) Third paragraph revised to read (new text in italics) - "Patients should also be advised that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma ["ocular surgery" deleted] or infection) they should immediately seek their physician's advice concerning the continued use of the present multidose container."
Drug Interactions: Beta-adrenergic blocking agents: Second sentence revised from "Patients should not usually receive two topical ophthalmic beta-adrenergic blocking agents concurrently."
to read - "The concomitant use of two topical beta-adrenergic blocking agents is not recommended."
(Change appears in 1997 PDR.)
Paragraph beginning "When a patient is transferred from another topical ophthalmic beta-adrenergic blocking agent, ..." deleted.
Paragraph beginning "When a patient is transferred from a single antiglaucoma agent, ..." deleted.
Paragraph beginning "When a patient is transferred from several concomitantly administered antiglaucoma agents, ..." deleted.
New second paragraph - "In the Scandinavian Simvastatin Survival Study (see CLINICAL PHARMACOLOGY, Clinical Studies), the number of patients with more than one transaminase elevation to > 3 times the upper limit of normal over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]). Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1986 simvastatin treated patients in 4S with normal liver function test (LFTs) at baseline, only 8 (0.4%) developed consecutive LFT elevations to > 3 times the upper limit of normal and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg."
First sentence of second paragraph (now third paragraph) revised to read (new text in italics) - "It is recommended that liver function tests be performed before the initiation of treatment, ("at 6 and 12 weeks after initiation of therapy or elevation in dose," deleted) and periodically thereafter (e.g., semiannually) for the first year of treatment or until one year after the last elevation in dose.
Skeletal Muscle: Second paragraph "Muscle weakness accompanied by marked elevation of creatine phosphokinase was observed in a renal transplant patient on cyclosporine and simvastatin following the initiation of therapy with the systemic antifungal agent itraconazole. Rhabdomyolysis with renal failure has been reported in a renal transplant patient receiving cyclosporine and another HMG-CoA. reductase inhibitor shortly after a dose increase in the systemic traconazole. The HMG-CoA reductase inhibitors and the azole derivative antifungal agents inhibit cholesterol biosynthesis at different points in the biosynthetic pathway. In patients receiving cyclosporine, simvastatin should be temporarily discontinued if systemic azole derivative antifungal therapy is required; patents not taking cyclosporine should be carefully monitored if systemic azole derivative antifungal therapy is required." deleted and
replaced with "Myopathy or rhabdomyolysis has occurred in transplant and non-transplant patients receiving Zocor or another HMG-CoA reductase inhibitor following the initiation of treatment with the antifungal agent itraconazole. In a study in normal volunteers, plasma levels of another HMG-CoA reductase inhibitor were increased about 20-fold when administered concomitantly with itraconazole. This is probably related to metabolism of both drugs by the same P-450 isoform. Based on this data, therapy with Zocor should be temporarily interrupted if systemic azole derivative antifungal therapy is required."
New second sentence and table added -"The clinical adverse experiences reported as possibly, probably, or definitely drug-related in > or = 0.5% in either treatment group are shown in the table below:
|
(n=2,221) % |
(n=2,223) % |
Body as a Whole |
|
|
|
0.9 |
0.9 |
Gastrointestinal |
|
|
|
0.5 |
0.3 |
|
0.6 |
0.5 |
|
0.9 |
0.7 |
|
0.4 |
0.6 |
Musculoskeletal |
|
|
|
1.2 |
1.3 |
Skin |
|
|
|
0.8 |
0.8 |
|
0.5 |
0.4 |
|
0.6 |
0.6 |
Special Senses |
|
|
|
0.5 |
0.8 |