(Posted: 10/8/97, Vira-A added 10/10/97, Orudis/Oruvail added 10/15/97)
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.
Compiled with the help of:
Anjali Purohit, PharmD candidate
School of Pharmacy
The University of North Carolina at Chapel Hill
ALDOCLOR
and
ALDORIL (methyldopa/hydrochlorothiazide) Tablets
[August 5, 1997: Merck]
ALDOMET
and
ALDOMET ESTER HCl (methyldopate HCl) Injection
[August 5, 1997: Merck]
AMPHOTEC
[August 27, 1997: Sequus]
From previous renal subsection deletion of "In a randomized, double blind study of Amphotec (4 mg/kg/day) and amphotericin B deoxycholate (0.8 mg/kg/day) as empiric treatment in febrile neutropenic patients, it was demonstrated that, in patients with normal baseline renal function, the incidence of nephrotoxicity was significantly lower with Amphotec than with amphotericin B deoxycholate."
Addition of
"In a randomized, double-blind, multicenter study, 213 febrile neutropenic patients were given empirically either 4 mg/kg/day of Amphotec or 0.8 mg/kg/day of amphotericin B deoxycholate for a maximum of 14 days. This study was primarily designed to compare the safety profiles of these two treatments. NOTE: Amphotec is NOT approved for empirical treatment in febrile neutropenic patients.
"In the above study, patients had largely normal renal function at baseline; median serum creatinine levels were 0.8 mg/dL for both treatment groups. The mean change in serum creatinine was evaluated for patients with baseline creatinine < or = 1.5 mg/dL. As shown in the graph, patients in both treatment groups showed an increase in serum creatinine while on study, however Amphotec patients experienced significantly less creatinine increase at each time point."
Addition of graph "Changes in Mean Serum Creatinine Over Time in Patients with Febrile Neutropenia, and Baseline Serum Creatinine < or = 1.5 mg/dL" - [see label/package insert.]
Hypokalemia (new subsection): "In the same empiric study, significantly more amphotericin B deoxycholate patients had at least one laboratory result of serum potassium < 3.0 mEq/L at least one time in the study compared with Amphotec patients (23% vs. 7%), although concomitant supplemental potassium was allowed in the study design. Both groups received approximately equal amounts of potassium supplementation."
Hypomagnesemia (new subsection): "In the same empiric study, there was no overall trend for decreasing serum magnesium in either group."
Drug Interactions: Cyclosporine and Tacrolimus: Current text deleted and replaced with "In the same randomized, double-blind, empiric trial to compare Amphotec and amphotericin B deoxycholate, patients with normal baseline serum creatinine were prospectively enrolled into four strata: adults receiving cyclosporine or tacrolimus (n=89); or pediatric patients (< 16 years old) receiving cyclosporine or tacrolimus (n=15); adults not receiving cyclosporine or tacrolimus (n=75); or pediatric patients not receiving cyclosporine or tacrolimus (n=34). Patients were assessed for renal toxicity defined as either a doubling or an increase of 1.0 mg/dL or more from baseline serum creatinine, or > 50% decrease from baseline calculated creatinine clearance. Adults and pediatric patients receiving cyclosporine or tacrolimus in addition to Amphotec had a significantly lower rate of renal toxicity (31%, 16/51), compared to the amphotericin B deoxycholate patients receiving cyclosporine or tacrolimus (68%, 34/50). In the adults and pediatric patients not receiving cyclosporine or tacrolimus, only 8% (4/51) of the Amphotec patients experienced renal toxicity compared to 35% (17/49) of the amphotericin B deoxycholate patients."
Pediatric Use: First sentence revised (new text in italics) - "["Seventy" deleted] Ninety-seven pediatric patients with systemic fungal infections have been treated with Amphotec, at daily doses (mg/kg) similar to those ["in" deleted] given to adults."
Addition of paragraph at end of subsection - "In the same empiric, multicenter trial, pediatric patients (< 16 years) treated with Amphotec had significantly less renal toxicity than amphotericin B deoxycholate patients. Only 12% (3/25) of pediatric patients treated with amphotec developed nephrotoxicity compared to 52% (11/21) of pediatric patients receiving amphotericin B deoxycholate. Renal toxicity defined as either a doubling or an increase of 1.0 mg/dL or more from baseline serum creatinine, or > 50% decrease from baseline calculated creatinine clearance."
Geriatric Use: First sentence revised (new text in italics) - "Sixty-["one" deleted] eight patients at least 65 years of age have been treated with Amphotec."
Infusion-Related Adverse Events: First sentence revised (new text in italics) - "["Acute" deleted] Infusion-related adverse events (1 to 3 hours after starting intravenous infusion) occurred most frequently in association with the first infusion of Amphotec."
Revision of table "Summary of Probably and Possibly Related Adverse Events Reported by > or = 5% of Amphotec Patients" [See label/package insert.]
In the paragraph "Additionally, the following adverse events also occurred in 5% or more of Amphotec patients; however, the causal relationship of these adverse events is uncertain:"
General: "abdomen enlarged" moved up from 1% to less than 5%; "injection site inflammation" added; "chills and fever" deleted.
Cardiovascular system: "cardiovascular disorder" added; "hemorrhage" and "postural hypotension" moved up from 1% to less than 5%.
Digestive system: "diarrhea" and "dry mouth" added; "hematemesis" and "jaundice" moved up from 1% to less than 5%.
Hemic and lymphatic system: "prothrombin decreased" added; "prothrombin time increased" deleted.
Metabolic and nutritional disorders (new category replacing "Altered laboratory data"): "generalized edema" and "weight gain" added; "hypocalcemia" moved from table and added.
Nervous system: "dizziness", "somnolence" and "tremor" moved up from 1% to less than 5%; "insomnia" added.
Respiratory system: "asthma" moved up from 1% to less than 5%; "rhinitis" added.
Skin and appendages: "sweating" added.
In the paragraph "The following adverse events occurred in 1% to less than 5% of Amphotec patients. The causal relationship of these adverse events and Amphotec is uncertain:"
General: "accidental injury", "death", "hypothermia", "immune system disorder" and "neck pain" added; "asthenia" moved down from 5% or more.
Cardiovascular system: "vasodilatation" and "venoocclusive liver disease" added; "arrhythmia" moved down from 5% or more.
Digestive system: "bloody diarrhea", "constipation", "dyspepsia", "fecal incontinence", "gamma glutamyl transpeptidase increased", "gingivitis", "glossitis", "hepatic failure", "mouth ulceration", "oral moniliasis" and "rectal disorder" added; "melena" moved down from 5% or more
Hemic and lymphatic system: "ecchymosis", "fibrinogen increased", "petechia", and "thromoplastin decreased" added.
Metabolic and nutritional disorders (new category replacing "Altered laboratory data"): "dehydration", "hyperlipemia", "hypernatremia", "hypoproteinemia, and "weight loss" added; "hyperglycemia acidosis" changed to "acidosis."
Nervous system: "nervousness", "psychosis", and "speech disorder" added; "depression" moved down from 5% or more.
Respiratory system: "pharyngitis", "pleural effusion", and "sinusitis" added; "hemoptysis" moved down from 5% or more.
Skin and appendages: "acne", "alopecia", "petechial rash", "skin discoloration", "skin nodule", "skin ulcer", "urticaria", and "vesiculobullous rash" added.
Special senses: "amblyopia", "deafness", and "ear disorder" added.
Urogenital system: "albuminuria", "dysuria", "glycosuria", "oliguria", "urinary incontinence", "urinary retention", and "urinary tract disorder" added; "kidney failure" moved down from 5% or more; "kidney function abnormal" deleted.
Second sentence deleted - "The dose may be increased to 6 mg/kg/day if there is no improvement or if there is evidence of progression of the fungal infection."
ASACOL
[August 19, 1997: Procter & Gamble]
BIAXIN
[August 26, 1997: Abbott]
Microbiology: NOTE: Second paragraph revised (new text in italics) -
"Clarithromycin has been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections when combined with omeprazole or ranitidine bismuth citrate as described in the INDICATIONS AND USAGE section."
Helicobacter: Helicobacter pylori: New second paragraph -
"Emerging clarithromycin resistance was not assessed for the ranitidine bismuth citrate plus clarithromycin regimen because there were no patients that had H. pylori isolates with both pre-treatment and post-treatment susceptibility tests. No adequate data were collected during clinical trials or in vitro studies to indicate that ranitidine bismuth citrate can either decrease or increase emerging clarithromycin resistance."
"Biaxin (clarithromycin) Filmtab tablets in combination with Prilosec (omeprazole) capsules or Tritec (ranitidine bismuth citrate) tablets is indicated for the treatment of patients with an active duodenal ulcer associated with H. pylori infection."
"Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with creatinine clearance less than 25 mL/min. (See DOSAGE AND ADMINISTRATION.)
"Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of acute porphyria."
Paragraph added to end of subsection - "For information on ranitidine bismuth citrate, refer to the PRECAUTIONS section of the Tritec package insert."
Drug Interactions: New fifth paragraph added -
"Co-administration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14-hydroxy-clarithromycin plasma concentrations (31%). These effects are clinically insignificant."
New table and text added to end of subsection -
(28 day therapy) Clarithromycin + ranitidine Bismuth Citrate |
|
Days 1 to 14 |
Days 15 to 28 |
tablet t.i.d plus ranitidine Bismuth Citrate 400 mg tablet b.i.d. |
400 mg tablet b.i.d. |
"Biaxin and ranitidine bismuth citrate combination therapy is not recommended in patients with creatinine clearance less than 25 mL/min.
"For information on ranitidine bismuth citrate, refer to the DOSAGE AND ADMINISTRATION section of the Tritec package insert."
Duodenal Ulcer Healing: Title of table revised (new text in italics) -
Clarithromycin + Ranitidine Bismuth Citrate Therapy (new subsection): "Biaxin alone and in combination with ranitidine bismuth citrate was evaluated in two U.S. double-blind, randomized, multicenter, placebo-controlled trials. Four hundred and nine (409) patients were enrolled and 265 had H. pylori infection and active duodenal ulcer prestudy. Clarithromycin 500 mg t.i.d. for the first 2 weeks plus ranitidine bismuth citrate 400 mg b.i.d. for 4 weeks was found to have a significantly higher H. pylori eradication rate when compared to clarithromycin 500 mg t.i.d. for 2 weeks, ranitidine bismuth citrate 400 mg b.i.d. for 4 weeks, or placebo.
"Duodenal Ulcer Healing at 4 weeks (End of Treatment): Ulcer healing rates for the two U.S. double-blind, randomized, multicenter, placebo-controlled trials are represented in the table below.
Percent of Patients Healed + [95% Confidence Interval] (number of patients) |
||||
Study |
+ Ranitidine Bismuth Citrate |
Bismuth Citrate |
Clarithromycin |
Placebo |
Study 305
Study 306 |
[53%-90%] (n = 24)
[51%-87%] (n = 28) |
[54%-88%] (n = 30)
79% |
[50%-86%] (n = 27)
53% |
[30%-80%] (n = 16)
21% |
* This analysis excludes dropouts and patients with major protocol violations.+ Ranitidine bismuth citrate alone has not been proven to be superior to ranitidine for duodenal ulcer healing.^ P < 0.05 for clarithromycin + ranitidine bismuth citrate versus placebo |
"Eradication of H. pylori Associated with Active Duodenal Ulcer:
The combination of clarithromycin and ranitidine bismuth citrate was effective in eradicating H. pylori.
Percent of Patients Cured [95% Confidence Interval] (number of patients) |
||||
Study |
+ Ranitidine Bismuth Citrate |
Bismuth Citrate |
|
Placebo |
Study 305
Study 306 |
[60%-97%] (n = 19) 73% ^ [50%-89%] (n = 22) |
[0%-14%] (n = 25) 0% [0%-15%] (n = 22) |
[10%-47%] (n = 24) 25% [10%-47%] (n = 24) |
[0%-21%] (n = 16) 0% [0%-23%] (n = 14) |
* H. pylori eradication was defined as no positive test (CLOtestTM, culture, histology) at 4 weeks following the end of treatment. Patients must have had two tests performed and these must have been negative to be considered eradicated of H. pylori. The following patients were excluded: patients not infected with H. pylori prestudy, dropouts, patients with major protocol violations, patients with missing H. pylori tests, and patients that were not assessed for H. pylori eradication 4 weeks after the end of treatment becauses they were found to have an unhealed ulcer and were H. pylori negative at the end of treatment.^ P < 0.001 for clarithromycin + ranitidine bismuth citrate versus all other treatment groups. |
"The relationship between H. pylori eradication and duodenal ulcer recurrence was assessed in a combined analysis of six U.S. randomized, double-blind, multicenter, placebo-controlled trials using ranitidine bismuth citrate with or without antibiotics. The results from approximately 65-U.S. patients showed that the risk of ulcer recurrence within 6 months of completing treatment was two times less likely in patients whose H. pylori infection was eradicated compared to patients in whom H. pylori infection was not eradicated.
"Safety: Placebo-controlled trials in patients with active duodenal ulcer in the United States included 240 patients given clarithromycin alone or in combination with ranitidine bismuth citrate, 903 patients given ranitidine bismuth citrate alone, and 469 patients given placebo.
"Incidence of Drug-Related Adverse Reactions in Placebo-Controlled Clinical Trials: The following table lists drug-related adverse reactions that occurred at a frequency of > or = 1% among patients treated with ranitidine bismuth citrate who participated in U.S. placebo-controlled trials.
Drug-Related Adverse Reactions During Treatment |
||||
Tritec Tablets |
800 mg + Clarithromycin 1,500 mg < (n = 120)
|
1,500 mg (n = 120)
|
800 mg (n = 903)
|
(N = 469) |
Gastrointestinal Diarrhea Nausea & vomiting Constipation
Neurological
Miscellaneous
Skin
Urogenital |
8% 3% 0%
...
...
...
... |
5% 2% 0%
...
...
...
... |
2% < 1% 1%
...
...
...
... |
1% 1% < 1%
...
...
...
... |
* Total daily dose |
"For information on ranitidine bismuth citrate, refer to the ADVERSE REACTIONS section of the Tritec package insert."
CEFZIL
[August 26, 1997: Bristol-Myers Squibb]
CIPRO
[August 7, 1997: Bayer]
CYTOTEC
[August 13, 1997: G.D. Searle]
DIFLUCAN
[August 5, 1997: Pfizer]
ELDEPRYL
[August 6, 1997: Somerset]
Fifth paragraph, former second sentence revised (new text in italics) - "["However" deleted] In addition, one case of hypertensive crisis has been reported in a patient taking the recommended dose of selegiline and a sympathomimetic medication, ephedrine."
Sixth paragraph revised (new text in italics) - "In short, attention to the dose dependent nature of selegiline's selectivity is critical if it is to be used without elaborate restrictions being placed on diet and concomitant drug use although, as noted above, ["a case" deleted] a few cases of hypertensive reactions have been reported at the recommended dose. (See WARNINGS and PRECAUTIONS.)"
Addition of new third sentence - "Rare hypertensive reactions with selegiline at recommended doses associated with dietary influences have been reported."
HELIDAC
[August 28, 1997: Proctor & Gamble]
Carcinogenesis, Mutagenesis, Impairment of Fertility: First paragraph, fourth sentence revised (new text in italics) - "At very high dose levels, (approximately 500 mg/kg/day, which is approximately ["two" deleted] 33 times the most frequently recommended ["maximum" deleted] human dose for a 50 kg adult based on ["mg/m2)" deleted] mg/kg body weight), there was a statistically significant increase in the incidence of malignant liver tumors in male mice."
Last paragraph, new sentence added to end - "Fertility studies have been performed in mice at doses up to six times the maximum recommended human dose based on mg/m2 and have revealed no evidence of impaired fertility."
Teratogenic Effects. Pregnancy Category D: Subsection revised (new text in italics) - "Category D is based on the pregnancy category for tetracycline hydrochloride. (See CONTRAINDICATIONS and WARNINGS, Tetracycline and Metronidazole subsections.)"
MEGACE
[August 8, 1997: Bristol-Myers Squibb]
New text added - "Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. The effects of zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied."
MEVACOR
[August 12, 1997: Merck]
New fifth paragraph - "At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL-C is > or = 130 mg/dL (see NCEP Guidelines, above)."
Information for Patients: Subsection revised (new text in italics) - "Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. (see WARNINGS, Skeletal Muscle)."
"Safety in pregnant women has not been established.
"Lovastatin has been shown to produce skeletal malformations at
plasma levels 40 times the human exposure (for mouse fetus) and
80 times the human exposure (for rat fetus) based on
mg/m2
surface area (doses were 800 mg/kg/day). No
drug-induced changes were seen in either species at multiples of
8 times (rat) or 4 times (mouse) based on surface area.
No evidence of malformations was noted in rabbits at exposures up
to 3 times the human exposure (dose of 15 mg/kg/day, highest
tolerated dose).
"Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. ["There has been one report of severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took lovastatin with dextroamphetamine sulfate during the first trimester of pregnancy." deleted] In a review +of approximately 100 prospectively followed pregnancies in women exposed to Mevacor or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a 3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with Mevacor during pregnancy (see CONTRAINDICATIONS) treatment should be immediately discontinued as soon as pregnancy is recognized. Mevacor should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. ["If the woman becomes pregnant while taking Mevacor, it should be discontinued and the patient advised again as to the potential hazards to the fetus." deleted]
"+ Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P. Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy. Reproductive Toxicology. 10(6):439-446, 1996."
MEZLIN
[August 5, 1997: Bayer]
"Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Mezlin, 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 difficile is one 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. difficile colitis."
NAVELBINE
[August 29, 1997: GlaxoWellcome]
"In addition to the adverse experiences reported during clinical trials, the following adverse events have been ["reported in patients receiving marketed" deleted] identified during postapproval use of Navelbine in clinical practice. [For these events the frequency and causality for Navelbine has not been established." deleted] Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, causal connection to Navelbine, or a combination of these factors.
"Body As A Whole: Systemic allergic reactions reported as anaphylaxis, pruritis, urticaria, and angioedema; flushing; and radiation recall events such as dermatitis and esophagitis (see PRECAUTIONS) have been reported.
. "Hematologic: Thromboembolic events including pulmonary embolus and deep venous thrombosis, have been reported primarily in seriously ill and debilitated patients with known predisposing risk factors for these events.
"Neurologic: Peripheral neurotoxicities such as, but not limited to, muscle weakness and disturbance of gait, have been observed in patients with and without prior symptoms. There may be increased potential for neurotoxicity in patients with pre-existing neuropathy, regardless of etiology, who receive Navelbine.
"Skin: Injection site reactions, including localized rash and urticaria, blister formation, and skin sloughing have been observed in clinical practice. Some of these reactions may be delayed in appearance.
"Gastrointestinal: Dysphagia and mucositis have been reported.
"Cardiovascular: Hypertension, hypotension, vasodilation, and tachycardia have been reported.
"Pulmonary: Pneumonia has been reported.
"Musculoskeletal: Headache has been reported, with and without other musculoskeletal aches and pains.
"Other: Pain in tumor-containing tissue and back pain have been reported. Electrolyte abnormalities, including hyponatremia, have been reported in seriously ill and debilitated patients.
"Combination Use: Patients with prior exposure to paclitaxel and who have demonstrated neuropathy should be monitored closely for new or worsening neuropathy. Patients who have experienced neuropathy with previous drug regimens should be monitored for symptoms of neuropathy while receiving Navelbine. Navelbine may result in radiosensitizing effects with prior or concomitant radiation therapy (see PRECAUTIONS)."
NEUTREXIN
[August 5, 1997: U.S. Bioscience]
"Neutrexin and leucovorin may alternatively be dosed on a mg/kg basis, depending on the patient's body weight, using the conversion factors shown in the table below:"
(kg) |
(mg/kg/day) |
(mg/kg/qid) |
< 50 |
1.5 |
0.6 |
50-80 |
1.2 |
0.5 |
> 80 |
1.0 |
0.5 |
NYDRAZID
[August 8, 1997: Apothecon]
ORAP
[August 27, 1997: Teva]
"Because Orap prolongs the QT interval of the electrocardiogram it is contraindicated in patients with congenital long QT syndrome, patients with a history of cardiac arrhythmias, or patients taking other drugs which prolong the QT interval of the electrocardiogram (see Precautions - DRUG INTERACTIONS)."
#6 (new contraindication) -
"Ventricular arrhythmias have been rarely associated with the use of macrolide antibiotics in patients with prolonged QT intervals, as might be produced by Orap. Specifically, two sudden deaths have been reported when clarithromycin was added to ongoing pimozide therapy. [Note: These preceding two sentences appear in the 1997 PDR.] Furthermore, some evidence suggests that pimozide is metabolized partly by the enzyme system P450 3A (CYP 3A). Macrolide antibiotics are inhibitors of CYP 3A, and thus could potentially impede pimozide metabolism. For these reasons, Orap is contraindicated in patients receiving the macrolide antibiotics clarithromycin, erythromycin, azithromycin, and dirithromycin." [Note: The preceding sentence atarting with "Orap.." appears in the 1997 PDR.]
"Because azole antifungal agents are also inhibitors of the CYP 3A enzymes and thus may likewise impair pimozide metabolism, Orap is contraindicated in patients receiving the azole antifungal agents intraconazole and ketoconazole."
"Also, the use of macrolide antibiotics in patients with prolonged QT intervals has been rarely associated with ventricular arrhythmias." [Note: This sentence appears in the 1997 PDR.]
"The following experiences were described in spontaneous postmarketing reports.
These reports do not provide sufficient information to establish a clear causal
relationship with the use of Orap.
Gastrointestinal: Gingival hyperplasia in one patient.
Hematologic: Hemolytic anemia
Metabolic/Nutritional: Hyponatremia
Other: Seizure ["has been reported in one patient" deleted]." [Note: These changes appear in
the 1997 PDR.]
ORUDIS
and
ORUVAIL (ketoprofen) Extended-Release Capsules
[August 5, 1997: Wyeth-Ayerst]
"Rare adverse reactions (incidence less than 1%) were collected from one or more of the following sources: foreign reports to manufacturers and regulatory agencies, publications, ["and" deleted] U.S. clinical trials, and/or U.S. postmarketing spontaneous reports."
Incidence less than 1% (probable cause relationship): Digestive: addition of "hepatic dysfunction, hepatitis, cholestatic hepatitis, jaundice".
Metabolic and Nutritional: deletion of "hepatic dysfunction".
Skin and Appendages: addition of "toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome."
Incidence less than 1% (causal relationship unknown): Digestive: deletion of "jaundice".
OVRAL
and
OVRAL-28 (norgestrel/ethinyl estradiol) Tablets
[August 14, 1997: Wyeth-Ayerst]
Effectiveness of oral contraceptives: Deletion of "Vaginal sponge: 18% to 28%"
OXISTAT
[August 18, 1997: GlaxoWellcome]
PRELAY
[August 4, 1997: Sankyo U.S.A.]
and
REZULIN (troglitazone) Tablets
[August 4, 1997: Parke Davis]
PROCARDIA
and
PROCARDIA XL (nifedipine) Extended Release Tablets
[August 12, 1997: Pfizer]
PROSTIN E2
[August 5, 1997: Pharmacia & Upjohn]
"["As experience in the pediatric population is limited, a
practical" deleted] Although an optimal dosage schedule
has not been established, standard texts(6-7) list
a usual pediatric dose of 240mg/kg/day of anhydrous
cholestyramine resin in two to three divided doses, normally not
to exceed 8gm/day with dose titration based on response and
tolerance."
Third paragraph, text added at end - "Also see 'ADVERSE
REACTIONS'."
New last sentence -
"Rare reports of intestinal obstruction, including two deaths,
have been reported in pediatric patients."
"6. Behrman RE et al (eds): Nelson, Textbook of Pediatrics, ed 15.
Philadelphia, PA, WB Saunders Company, 1996.
"7. Takemoto CK et al (eds): Pediatric Dosage Handbook, ed 3.
Cleveland/Akron, OH, Lexi-Comp Inc., 1996/1997."
QUESTRAN (cholestyramine) Powder & Light
[August 22, 1997: Bristol-Myers Squibb] SELDANE
and
SELDANE-D
[August 14, 1997: Hoechst Marion Roussel]
SERZONE
[August 6, 1997: Bristol-Myers Squibb]
Postintroduction Clinical Experience: Addition of a statement describing rare reports of rhabdomyolysis in patients receiving the combination of Serzone and lovastatin or simvastatin.
SPORANOX
[August 6, 1997: Janssen]
Pediatric use: First paragraph revised (new text in italics) - "The efficacy and safety of Sporanox have not been established in pediatric patients. No pharmacokinetic data on capsules are available in children. A small number of patients age 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections and no serious unexpected adverse effects have been reported. Sporanox Oral Solution (5mg/kg/day) has been administered to pediatric patients (n=26, age 0.5-12 years) for two weeks and no serious unexpected adverse events were reported."
N.B.: Where the label refers to the Capsules (e.g., WARNING box, CONTRAINDICATIONS, OVERDOSAGE, reference to the Oral Solution was added.
TAXOL
[August 4, 1997: Bristol-Myers Squibb]
TIMOPTIC
[August 5, 1997: Merck]
TORECAN
[August 6, 1997: Novartis]
TRASYLOL
[August 8, 1997: Bayer]
"Re-exposure to aprotinin: In a retrospective review of 387 European patient records with documented re-exposure to Trasylol, the incidence of hypersensitivity/anaphylactic reactions per re-exposure was 2.7%. Two patients who experienced hypersensitivity/anaphylactic reactions subsequently died, 24 hours and five days after surgery, respectively. The relationship of these two deaths to Trasylol is unclear. This retrospective review also showed that the incidence of a hypersensitivity or anaphylactic reaction following re-exposure is increased when re-exposure occurs within six months of the initial administration (5.0% for re-exposures within six months and 0.9% for re-exposures greater than six months). Other smaller studies have confirmed that in case of re-exposure, the incidence of hypersensitivity/anaphylactic reactions may reach the five percent level.
"Before initiating treatment with Trasylol in a patient with a history of prior exposure, the recommendations below should be followed to manage a potential hypersensitivity or anaphylactic reaction:
New text added to end of subsection - "However, even after the uneventful administration of the initial 1 mL-dose, the therapeutic dose may cause an anaphylactic reaction. If this happens the infusion of aprotinin should immediately be stopped, and standard emergency treatment for anaphylaxis should be applied. Patients who experience any allergic reaction to the test dose of aprotinin should not receive further administration of the drug. (See WARNINGS)"
Allergic Reactions: Text deleted and replaced with - "Patients with a history of allergic reactions to drugs or other agents may be at greater risk of developing a hypersensitivity or anaphylactic reaction upon exposure to Trasylol (see WARNINGS)."
Laboratory Monitoring of Anticoagulation during Cardiopulmonary Bypass: Text deleted and replaced with -
"Trasylol prolongs whole blood clotting times by a different mechanism than heparin. In the presence of aprotinin, prolongation is dependent on the type of whole blood clotting test employed. If an activated clotting time (ACT) is used to determine the effectiveness of heparin anticoagulation, the prolongation of the ACT by aprotinin may lead to an overestimation of the degree of anticoagulation, thereby leading to inadequate anticoagulation. During extended extracorporeal circulation, patients may require additional heparin, even in the presence of ACT levels that appear adequate.
"In patients undergoing CPB with Trasylol therapy, one of the following methods may be employed to maintain adequate anticoagulation:
"ACT - An ACT is not a standardized coagulation test, and different formulations of the assay are affected differently by the presence of aprotinin. The test is further influenced by variable dilution effects and the temperature experienced during cardiopulmonary bypass. It has been observed that kaolin-based ACTs are not increased to the same degree by aprotinin as are diatomaceous earth-based (celite) ACTs. While protocols vary, during bypass a minimal celite ACT of 750 seconds or kaolin-ACT of 480 seconds, independent of the effects of hemodilution and hypothermia, is recommended in the presence of aprotinin. Consult the manufacturer of the ACT test regarding the interpretation of the assay in the presence of Trasylol.
"Fixed Heparin Dosing - A standard loading dose of heparin, administered prior to cannulation of the heart, plus the quantity of heparin added to the prime volume of the CPB circuit, should total at least 350 IU/kg. Addition heparin should be administered in a fixed-dose regiment based on patient weight and duration of CPB.
"Heparin Titration - Protamine titration, a method that is not affected by aprotinin can be used to measure heparin levels. A heparin dose response, assessed by protamine titration, should be performed prior to administration of aprotinin to determine the heparin loading dose. Addition heparin should be administered on the basis of heparin levels measured by protamine titration. Heparin levels during bypass should not be allowed to drop below 2.7 U/mL (2.0 mg/kg) or below the level indicated by heparin dose-response testing performed prior to administration of aprotinin.
"Protamine Administration - In patients treated with Trasylol, the amount of protamine administered to reverse heparin activity should be based on the actual amount of heparin administered, and not on the ACT values."
ADVERSE REACTIONS:
Myocardial Infarction (new subsection): "In a pooled analysis of all patients undergoing CABG surgery, there was no significant difference in the incidence of investigator-reported myocardial infarction (MI) in Trasylol treated patients as compared to placebo treated patients. However, because no uniform criteria for the diagnosis of myocardial infarction were utilized by investigators, this issue was addressed prospectively in three later studies (two studies evaluated Regimen A, Regimen B, and pump prime regimen; one study evaluated only Regimen A) in which data were analyzed by a blinded consultant employing an algorithm for possible, probable or definite MI. Utilizing this method, the incidence of definite myocardial infarction was 5.9% in the aprotinin treated patients versus 4.7% in the placebo treated patients. This difference in the incidence rates was not statistically significant. Data from these three studies are summarized below." [See Table "Incidence of Myocardial Infarction by Treatment Group Population: All CABG Patients Valid for Safety Analysis" in labeling/package insert.]
Graft Patency (new subsection): "In a recently completed multi-center, multi-national study to determine the effects of Trasylol Regimen A vs. placebo on saphenous vein graft patency in patients undergoing primary CABG surgery, patients were subjected to routine postoperative angiography. Of the 13 study sites, 10 were in the United States and three were non-U.S. centers (Denmark (1), Israel (2)). The results of this study are summarized below." [See Table "Incidence of Graft Closure, Myocardial Infarction and Death by Treatment Group" in labeling/package insert.]
"Although there was a statistically significantly increased risk of graft closure for Trasylol treated patients compared to patients who received placebo (p=0.035), further analysis showed a significant treatment by site interaction for one of the non-U.S. sites vs. the U.S. centers. When the analysis of graft closures was repeated for U.S. centers only, there was no statistically significant difference in graft closure rates in patients who received Trasylol vs. placebo. These results are the same whether analyzed as the proportion of patients who experienced at least one graft closure postoperatively or as the proportion of grafts closed. There were no differences between treatment groups in the incidence of myocardial infarction as evaluated by the blinded consultant (2.9% Trasylol vs. 3.8% placebo) or of death (1.4% Trasylol vs. 1.6% placebo) in this study."
Hypersensitivity and Anaphylaxis: Text added - "Hypersensitivity and anaphylactic reactions during surgery were rarely reported in U.S. controlled clinical studies in patients with no prior exposure to Trasylol (1/1424 patients or < 0.1% on Trasylol vs. 1/861 patients or 0.1% on placebo). In case of re-exposure the incidence of hypersensitivity/anaphylactic reactions has been reported to reach the 5% level."
VIRA-A
[August 4, 1997: Parke-Davis]
"Vira-A is rapidly deaminated to arabinosylhypoxanthine (Ara-Hx), the principal metabolite. Ara-Hx also possesses in vitro antiviral activity but this activity is less than that of Vira-A. Because of the low solubility of Vira-A, trace amounts of both Vira-A and Ara-Hx can be detected in the aqueous humor only if there is an epithelial defect in the cornea. If the cornea is normal, only trace amounts of Ara-Hx can be recovered from the aqueous humor.
"Systemic absorption of Vira-A should not be expected to occur following ocular administration and swallowing lacrimal secretions. In laboratory animals, Vira-A is rapidly deaminated in the gastrointestinal tract to Ara-Hx.
"In contrast to topical idoxuridine, Vira-A demonstrated less cellular toxicity in the regenerating corneal epithelium of the rabbit.
"In controlled and uncontrolled clinical trials, an average of seven and nine days of continuous Vira-A Ophthalmic Ointment, 3%, therapy was required to achieve corneal re-epithelialization. In the controlled trials, 70 of 81 subjects (86%) re-epithelialized at the end of three weeks of therapy. In the uncontrolled trials, 101 of 142 subjects (71%) re-epithelialized at the end of three weeks. Seventy-five percent of the subjects in these uncontrolled trials had either not healed previously or had developed hypersensitivity to topical idoxuridine therapy. [Note: This paragraph was moved from the previous INDICATIONS AND USAGE section.]
"Microbiology: Vidarabine is a purine nucleoside obtained from fermentation cultures of Streptomyces antibioticus. The antiviral mechanism of action has not been established. Vidarabine appears to interfere with the early steps of viral DNA synthesis.
"Vidarabine has been shown to possess antiviral activity against the following viruses in vitro:
Herpes simplex types 1 and 2
Vaccinia
Varicella-Zoster
"Except for Rhabdovirus and Oncornavirus, vidarabine does not display in vitro antiviral activity against other RNA or DNA viruses, including Adenovirus.
"Susceptibility Tests - No universal, standardized, quantitative in vitro procedures have as yet been developed to estimate the susceptibility of viruses to antiviral agents."
YUTOPAR
[August 5, 1997: Astra USA]
ZOCOR
[August 12, 1997: Merck & Co.]
New fifth paragraph - "At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL-C is > or = 130 mg/dL (see NCEP Guidelines, above)."
Information for Patients: Subsection revised (new text in italics) - "Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. (see WARNINGS, Skeletal Muscle)."
"Safety in pregnant women has not been established.
"Simvastatin was not teratogenic in rats at doses of 25 mg/kg/day or in rabbits at doses up to 10 mg/kg daily. These doses resulted in 6 times (rat) or 4 times (rabbit) the human exposure based on mg/m2 surface area. However, in studies with another structurally- related HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice.
"Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. ["There has been one report of severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took another HMG-CoA reductase inhibitor with dextroamphetamine sulfate during the first trimester of pregnancy." deleted] In a review +of approximately 100 prospectively followed pregnancies in women exposed to Zocor or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a three-to-four-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with Zocor during pregnancy (see CONTRAINDICATIONS), treatment should be immediately discontinued as soon as pregnancy is recognized. Zocor should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. ["If the woman becomes pregnant while taking simvastatin, it should be discontinued and the patient advised again as to the potential hazards to the fetus." deleted]
"+ Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P. Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy. Reproductive Toxicology. 10(6):439-446, 1996."