![[U.S. Food and Drug Administration]](https://webarchive.library.unt.edu/eot2008/20081028100646im_/http://www.fda.gov/icon/header.gif){kind=icon}
(Posted: 5/1/98)
(Updated: 5/4/98 - Meretek, Omnipaque, Opticrom, Rev-Eyes, Timoptic(s) & Tritec added)
(Updated: 5/7/98: - Desogen added)
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 1998 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.
|
(testosterone) |
HCl) |
(irinotecan HCl) |
(alprostadil) |
|
(cefuroxime axetil) |
(clindamycin phosphate) |
(clozapine) |
(desmopressin acetate) |
(desogestrel/ ethinyl estradiol) |
(bromfenac Na) |
(zalcitabine) |
(ammonium lactate) |
||
(enalapril maleate/ felodipine) |
(enoxaparin Na) |
(alprostadil) |
(multi-vitamins) |
|
(iohexol) |
(cromolyn Na) |
(tripelennamine HCl) |
(pravastatin Na) |
(lansoprazole) |
(finasteride) |
(medroxyprogesterone acetate) |
(fluoxetine HCl) |
(zidovudine) |
(dapiprazole HCl) |
xinafoate) |
(nefazodone HCl) |
& STADOL NS (butorphanol tartrate) |
(timolol maleate) |
(timolol maleate) |
(timolol maleate) |
(rantidine bismuth citrate) |
(bepridil HCl) |
(simvastatin) |
"Chronic skin irritation caused 5% of patients to discontinue treatment. Mild skin irritation may be ameliorated by treatment of affected skin with over-the-counter topical hydrocortisone cream ["or topical antihistamine products" deleted] applied after system removal."
New sixth paragraph added -
"Applying a small amount of 0.1% triamcinolone acetonide cream (Rx) to the skin under the central drug reservoir of the Androderm system has been shown to reduce the incidence and severity of skin irritation. The administration of 0.1% triamcinolone acetonide cream (Rx) does not significantly alter transdermal absorption of testosterone from the system. Ointment formulations should not be used for pretreatment as they may significantly reduce testosterone absorption."
"Mild skin irritation may be ameliorated by treatment of the affected skin with over-the-counter topical hydrocortisone cream applied after system removal."
"Applying a small amount of 0.1% triamcinolone cream (Rx) to the skin under the central drug reservoir of the Androderm system has been shown to reduce the incidence and severity of skin irritation. The administration of 0.1% triamcinolone acetonide cream (Rx) does not significantly alter transdermal absorption of testosterone from the system. Ointment formulations should not be used for pretreatment as they may significantly reduce testosterone absorption."
"Studies with solutions in polypropylene syringes have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility."
Pediatric Use: Subsection revised (new text in italics) -
"The safety and effectiveness ["in children" deleted] of Bretylium Tosylate have not been established. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use."
"In man, approximately 95% of buspirone is plasma protein bound, but other highly bound drugs, e.g., phenytoin, propranolol, and warfarin are not displaced by buspirone from plasma protein in vitro. However, in vitro binding studies show that buspirone does displace digoxin."
deleted and replaced with -
"An in vitro binding study indicated that approximately 86% of buspirone is bound to plasma proteins. It was also observed that aspirin increased the plasma levels of free buspirone by 23 %, while flurazepam decreased the plasma levels of free buspirone by 20%. However, it is not known whether these drugs cause similar effects on plasma levels of free buspirone in vivo or whether such changes, if they do occur, cause clinically significant differences in treatment outcome. An in vitro study indicated that buspirone did not displace highly protein-bound drugs such as phenytoin, warfarin, and propranolol from plasma protein, and that buspirone may displace digoxin."
Last paragraph deleted -
"The pharmacokinetics of BuSpar in patients with hepatic or renal dysfunction has not been determined, nor has the effect of age. The effect of BuSpar on drug metabolism or concomitant drug disposition has not been investigated."
Special Populations (new subsection): -
"Age and Gender Effects: After single or multiple doses in adults, no significant differences in buspirone pharmacokinetics (AUC and Cmax) were observed between elderly and younger subjects or between men and women.
"Hepatic Impairment: After multiple-dose administration of buspirone to patients with hepatic impairment, steady-state AUC of buspirone increased 13-fold compared with healthy subjects (see PRECAUTIONS Section).
"Renal Impairment: After multiple-dose administration of buspirone to renally impaired (CLcr=10-70 mL/min/1.73 m2) patients, steady-state AUC of buspirone increased 4-fold compared with healthy (CLcr> or = 80 mL/min/1.73 m2) subjects (see PRECAUTIONS Section).
"Race Effects: The effects of race on the pharmacokinetics of buspirone have not been studied."
"MAO Inhibitors: It is recommended that BuSpar (buspirone hydrochloride, USP) not be used concomitantly with MAO inhibitors (see WARNINGS Section)."
First paragraph, second sentence revised and moved to become fourth to last paragraph in subsection (new text in italics) -
"Other Psychotropics: Because the effects of concomitant administration of BuSpar with most other psychotropic drugs have not been studied, the concomitant use of BuSpar with other CNS-active drugs should be approached with caution."
First paragraph, third and fourth sentences revised into a new subsection (new text in italics) -
"Trazodone: There is one report suggesting that ..."
Second paragraph revised into a new subsection (new text in italics) -
"Haloperidol: In a study in normal volunteers, concomitant ..."
Amitriptyline (new subsection): "After addition of buspirone to the amitriptyline dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (Cmax, AUC, and Cmin) of amitriptyline or its metabolite nortriptyline were observed."
Diazepam (new subsection): "After addition of buspirone to the diazepam dose regimen, no statistically significant differences in the steady-state pharmacokinetic parameters (Cmax, AUC, and Cmin) were observed for diazepam, but increases of about 15% were seen for nordiazepam, and minor adverse clinical effects (dizziness, headache, and nausea) were observed."
Triazolam/Flurazepam (new subsection): "Coadministration of buspirone with either triazolam or flurazepam did not appear to prolong or intensify the sedative effects of either benzodiazepine. Coadministration of buspirone with either triazolam or flurazepam also did not alter the plasma levels of buspirone, either benzodiazepine, or the desalkyl metabolite of flurazepam."
Cimetidine (new subsection): "Coadministration of buspirone with cimetidine was found to increase Cmax (40%) and Tmax (2-fold), but had minimal effects on the AUC of buspirone."
New last paragraph added to subsection -
"Therapeutic levels of aspirin, desipramine, diazepam, flurazepam, ibuprofen, propranolol, thioridazine, and tolbutamide had only a limited effect on the extent of binding of buspirone to plasma proteins (see CLINICAL PHARMACOLOGY Section)."
Use in the Elderly: Existing text -
"BuSpar has not been systemically evaluated in older patients, however, several hundred elderly patients have participated in clinical studies with BuSpar and no unusual adverse age-related phenomena have been identified. In 87 elderly patients for whom dosage data were available, the modal total daily dose of BuSpar was 15 mg per day, the same as that in the total sample of patients treated with BuSpar."
deleted and replaced with -
"The safety and efficacy profiles of buspirone in 605 anxious, elderly patients (mean age = 70.8 years) were similar to those in a younger population (mean age = 43.3 years). There were no effects of age on the pharmacokinetics of buspirone."
Use in Patients with Impaired Hepatic or Renal Function: Existing text -
"Since BuSpar is metabolized by the liver and excreted by the kidneys, its administration to patients with severe hepatic or renal impairment cannot be recommended."
deleted and replaced with -
"Buspirone is metabolized by the liver and excreted by the kidneys. A pharmacokinetic study in patients with impaired hepatic or renal function demonstrated increased plasma levels and a lengthened half-life of buspirone. Therefore, the administration of BuSpar to patients with severe hepatic or renal impairment cannot be recommended ( see CLINICAL PHARMACOLOGY Section)."
"However, patients with even modest elevations in total serum bilirubin levels (1.0 to 2.0 mg/dL) have had a significantly greater likelihood of experiencing first-course grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% versus 17.7%; p < 0.001). Patients with abnormal glucoronidation of bilirubin, such as those with Gilbert's syndrome, may also be at greater risk of myelosuppression when receiving therapy with Camptosar. An association between bilirubin elevations and an increased risk of late diarrhea has not been observed."
"Colonic ulceration, sometimes with gastrointestinal bleeding, has been observed in association with administration of Camptosar."
Hematology: Sentence added as second to last sentence in the subsection -
"Patients with total serum bilirubin levels of 1.0 mg/dL or more also have had a significantly greater likelihood of experiencing first-course grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% versus 17.7%; p < 0.001)."
"The usual recommended starting dose of Camptosar Injection is 125 mg/m2 (see First 6-week Dosing Schedule table). In patients with a combined history of prior pelvic/abdominal irradiation and modestly elevated total serum bilirubin levels (1.0 to 2.0 mg/dL) prior to treatment with Camptosar, there may be substantially increased likelihood of grade 3 or 4 neutropenia. Consideration may be given to starting Camptosar at a lower dose (e.g., 100 mg/m2) in such patients (See PRECAUTIONS). Definite recommendations regarding the most appropriate starting doses in patients who have pretreatment total serum bilirubin elevations above 2.0 mg/dL are not yet available, but it is likely that lower starting doses will need to be considered in such patients.
"After initiation of treatment with Camptosar, subsequent doses should be adjusted to as high as 150 mg/m2 or to as low as 50 mg/m2 in 25 to 50 mg/m2 increments depending upon individual patient tolerance of treatment (see Recommended Dose Modifications table ["at right" deleted]).
"All doses should be administered as an intravenous infusion over 90 minutes (see Preparation of Infusion Solution). The recommended treatment regimen (one treatment course) is ["125 mg/m2 administered" deleted] once weekly treatment for 4 weeks, followed by a 2-week rest period. The first treatment course is shown in the following table. Thereafter, additional courses of treatment may be repeated every 6 weeks (4 weeks on therapy, followed by 2 weeks ["off therapy" deleted] rest). Provided intolerable toxicity does not develop, treatment and additional courses of Camptosar may be continued indefinitely in patients who attain a response or in patients whose disease remains stable. Patients should be carefully monitored for toxicity."
|
First 6-Week Dosing Schedule For CAMPTOSAR For a Patient Experiencing No Toxicity Requiring Dosing Delays |
||||||
|
Week (day) |
1 (1) |
2 (8) |
3 (15) |
4 (22) |
5 (29) |
6* (36) |
|
Treatment (given on first day of weeks 1-4) |
One 90-min IV infusion |
One 90-min IV infusion |
One 90-min IV infusion |
One 90-min IV infusion |
Rest |
Rest |
|
* The second 6-week course of treatment may begin week 7 (day 43). |
||||||
"If the needle is severely bent at any time, do not use it for injecting Caverject and do not attempt to straighten it prior to injecting Caverject. A severely bent and restraightened needle may be predisposed to breakage. Needle breakage, with a portion of the needle remaining in the penis, has been reported and, in some cases, required hospitalization and surgical removal. If the needle is severely bent while preparing the injection , remove it from the syringe, discard, and attach a new, unused sterile needle to the syringe as described under "Prepare the Dose" below."
Prepare the Dose: New instruction added as Step #4 -
"4. With the needle cover still in place, slowly push the plunger slightly forward toward the needle end of the syringe. Allow the plunger to slide back to its initial position. Repeat this procedure several times to spread the plunger stopper lubricant evenly."
Steps #8 (previously #7) and #13 (previously #12) revised to instruct the patient to hold the syringe/needle in a straight line with the vial of Caverject when injecting diluent into the sterile powder vial and when removing the correct dose for injecting from the vial.
"Note: Shake the Oral Suspension Well Before Each Use. Replace cap securely after each opening. The reconstituted ["125 mg/5 mL" deleted] suspension should be stored between 2o and 25oC (36o and 77oF) (either in the refrigerator or at room temperature). ["The reconstituted 250 mg/5 mL suspension should be stored between 2o and 30oC (36o and 86oF) (either at room temperature or in the refrigerator)." deleted] Discard After 10 Days."
"Ceftin for Oral Suspension is provided as dry, white to pale yellow,
tutti-frutti-flavored powder. When reconstituted as directed, Ceftin for Oral
Suspension provides the equivalent of 125 mg or 250 mg of cefuroxime (as cefuroxime axetil) per 5 mL of suspension. It is supplied in amber glass bottles as follows:
125mg/ 5 mL:
50-mL Suspension NDC 0173-0406-01
100-mL Suspension NDC 0173-0406-00
["200-mL Suspension NDC 0173-0406-04" deleted
[ Note: The following 3 lines were moved up.]
250mg/ 5 mL:
50-mL Suspension NDC 0173-0554-00
100-mL Suspension NDC 0173-0555-00
Before reconstitution, store dry powder between 2o and 30oC
(36o and 86oF).
After reconstitution, store suspension between 2o and 25oC
(36o and 77oF) in a refrigerator or at room temperature. Discard
After 10 Days.
"["250 mg/5 mL:
Before reconstitution, store dry powder between 2o and 30oC (36o
and 86oF).
After reconstitution, store suspension between
2o and 30oC (36o and 86oF) at room
temperature or in a refrigerator. Discard After 10 Days." deleted]"
"Patients who are being treated with Clozaril (clozapine) must have a baseline white blood cell (WBC) and differential count before initiation of treatment, and a WBC count every week ["throughout treatment" deleted] for the first six months. Thereafter, if acceptable WBC counts (WBC greater than or equal to 3,000/mm3, ANC > or = 1500/mm3) have been maintained during the first 6 months of continuous therapy, WBC counts can be monitored every other week. WBC counts must be monitored weekly for at least 4 weeks after the discontinuation of Clozaril (clozapine)." Third paragraph revised (new text in italics) -
"Clozaril (clozapine) is available only through a distribution system that ensures ["weekly WBC testing" deleted] monitoring of WBC counts according to the schedule described below prior to delivery of the next ["week's" deleted] supply of medication."
New chart "Interrupted Therapy (WBC < 3000/mm3 ANC < 1500/mm3 for Bi-Weekly Monitoring" added after the Boxed Warning - Contact the company for a copy of the new labeling/package insert.
"They should be informed that weekly blood tests are required for the first 6 months, if acceptable WBC counts (WBC greater than or equal to 3,000/mm3, ANC > or = 1500/mm3) have been maintained during the first 6 months of continuous therapy, then WBC counts can be monitored every other week in order to monitor for the occurrence of agranulocytosis and that ..."
"In order to minimize the risk of agranulocytosis, Clozaril (clozapine) is available only through a distribution system that ensures weekly WBC testing prior to delivery of the next week's supply of medication."
"Clozaril (clozapine) is available ["only through a distribution system that ensures weekly WBC testing prior to delivery of the next week's supply of medication. Clozaril (clozapine) is available" deleted] as 25 mg and 100 mg round, pale-yellow, uncoated tablets with a facilitated score."
"Percentage of Women Experiencing a Contraceptive Failure During the First Year of Typical Use and the First Year of Perfect Use and the Percentage Continuing Use at the End of the First Year, United States." [See the new labeling/package insert for the contents of the table.]
"Mortality rates associated with circulatory disease have been shown to increase substantially in smokers,especially in those over the age of 35 years of age and older among women who use oral contraceptives. (See Table II)." deleted and replaced with -
"Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age 40 (Table II) among women who use oral contraceptives."
Table II. "Circulatory Disease Mortality Rates Per 100,000 Woman-Years By Age, Smoking Status and Oral Contraceptive Use" revised to depict a table rather than a bar graph. [See new labeling/package insert.]
c. Cerebrovascular diseases: First paragraph, second sentence revised (new text in italics) -
"Hypertension was found to be a risk factor for both users and non-users, for both types of strokes, and smoking interacted to increase the risk of hemorrhagic stroke (27-29)."
d. Dose-related risk of vascular disease from oral contraceptives: Second paragraph , second sentence revised (new text in italics) -
"New acceptors of oral contraceptive agents should be started on preparations containing ["0.035 mg or less of estrogen" deleted] the lowest estrogen content which produces satisfactory results in the individual."
2. Estimates Of Mortality From Contraceptive Use: Second paragraph revised (new text in italics) -
"The observation of ["an" deleted] a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's -but not reported until 1983 (35). However, current clinical ["recommendations" deleted] practice involves the use of lower estrogen ["dose" deleted] formulations combined ["and a " deleted] with careful consideration of risk factors."
Third paragraph, first sentence revised (new text in italics) -
"["In 1989," deleted] Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed (104, 105), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the ["use of oral contraceptives in women 40 years of age and over:" deleted] topic in 1989.
Fourth paragraph revised (new text in italics) -
"Therefore, the Committee recommended that the benefits of low-dose oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older woman, as all women who take oral contraceptives, should take ["an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs" deleted] the lowest possible dose formulation that is effective."
6. Oral Contraceptive Use Before Or During Early Pregnancy: First paragraph, second sentence revised (new text in italics) -
"["The majority of recent" deleted] Studies also do not ["indicate" deleted] suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned (55,56,58,59), when oral contraceptives are taken inadvertently during early pregnancy."
8. Carbohydrate And Lipid Metabolic Effects: First paragraph revised (new text in italics) -
"Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users (17). ["This effect has been shown to be directly related to estrogen dose." deleted] Oral contraceptives containing greater than 75 micrograms of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance (65). ["In general," deleted] Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents (17, 66). However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose (67). Because of these demonstrated effects, prediabetic and diabetic women should be carefully monitored while taking oral contraceptives."
9. Elevated Blood Pressure: Subsection revised (new text in italics) -
"An increase in blood pressure has been reported in women taking oral contraceptives (68) and this increase is more likely in older oral contraceptive users (69) and with ["extended duration of" deleted] continued use (61). Data from the Royal College of General Practitioners (12) and subsequent randomized trials have shown that the incidence of hypertension increases with increasing ["progestational activity" deleted] quantities of progestogens.
"Women with a history of hypertension or hypertension-related diseases, or renal disease (70) should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives (69), and there is no difference in the occurrence of hypertension ["among former" deleted] between ever- and never-users (68, 70, 71)."
"There is some evidence of an association between the following conditions and use of oral contraceptives.
- Mesenteric thrombosis
- Retinal thrombosis"
"Hatcher RA, Trussell J, Stewart F et al. Contraceptive Technology: Sixteenth Revised Edition, New York: Irvington Publishers, 1994."
New references added -
"104. Porter JB, Hunter J, Jick H et al. Oral contraceptives and nonfatal vascular disease. Obstet Gynecol 1985;66:1-4." "105. Porter JB, Jick H, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol 1987;7029-32."
"Long term animal studies have not been performed to evaluate the carcinogenic potential of dopamine HCl.
"Dopamine HCl at doses approaching maximal solubility showed no clear genotoxic potential in the Ames test. Although there was a reproducible dose-dependent increase in the number of revertant colonies with strains TA100 and TA98, both with and without metabolic activation, the small increase was considered inconclusive evidence of mutagenicity. In the L5178Y TK+/- mouse lymphoma assay, dopamine HCl at the highest concentrations used of 750 ug/ml without metabolic activation, and 3000 ug/ml with activation, was toxic and associated with increases in mutant frequencies when compared to untreated and solvent controls; at the lower concentrations no increases over controls were noted.
"No clear evidence of clastogenic potential was reported in the in vivo mouse or male rat bone marrow micronucleus test when the animals were treated intravenously with up to 224 mg/kg and 30 mg/kg of dopamine HCl, respectively."
Pregnancy: Pregnancy Category C: Existing text deleted and replaced with -
"Teratogenic Effects: Teratogenicity studies in rats and rabbits at dopamine HCl dosages up to 6 mg/kg/day intravenously during organogenesis produced no detectable teratogenic or embryotoxic effects, although maternal toxicity consisting of mortalities, decreased body weight gain, and pharmacotoxic signs were observed in rats. In a published study, dopamine HCl administered at 10 mg/kg subcutaneously for 30 days, markedly prolonged metestrus and increased mean pituitary and ovary weights in female rats. Similar administration to pregnant rats throughout gestation or for 5 days starting on gestation day 10 or 15 resulted in decreased body weight gains, increased mortalities and slight increases in cataract formation among the offspring. There are no adequate and well-controlled studies in pregnant women, and it is not known if dopamine HCl crosses the placental barrier. Dopamine HCl should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."
"While not recommended, if a physician determines that the risk of longer use ifs justified by the potential benefit, the patient's transaminases (particularly ALT), and bilirubin, must be closely monitored for signs of hepatoxicity.
"Patients should be advised to take this medication as directed."
"Duract is indicated for the short-term (["generally less than" deleted] 10 days or less} management of acute pain."
"Severe hepatic reactions, including jaundice, potentially fatal fuminant hepatitis and liver failure (some requiring transplantation), have occurred in patients taking Duract for longer than the recommended duration (See Boxed Warning).
"Duract is indicated only for the short-term (10 days or less) management of acute pain. While not recommended, if a physician determines that the risk of longer use is justified by the potential benefit, a patient's transaminases (particularly ALT), and bilirubin, must be closely monitored for signs of hepatoxicity. Hepatotoxicity may develop without a prodrome of distinguishing symptoms."
Last paragraph, sentences beginning "Short-term management of pain..." and "Because hepatoxicity may develop ..." deleted.
The remaining sentence in that paragraph "Duract should be avoided in patients with ..." moved up to become the third paragraph in the subsection, with "(see PRECAUTIONS)" deleted from end of sentence.
"Duract is used for the short-term (10 days or less) treatment of acute pain."
Existing paragraphs in subsection reordered.
"Jaundice, hepatitis and liver failure (some requiring transplantation) have been reported postmarketing."
"For the short-term (["generally less than" deleted] 10 days or less) management of acute pain., the recommended dose of Duract is 25 mg every 6 to 8 hours, as necessary, except when taken with high-fat food, when a 50 mg dose may be needed (see below)."
"Each liter contains electrolytes sodium and citrate in amounts as listed in HOW SUPPLIED Table."
"In addition, rare cases of hepatic failure and death considered possibly related to underlying hepatitis B and Hivid ["monotherapy" deleted] have been reported (See WARNINGS and PRECAUTIONS)."
The word "children" has been replaced by the words "pediatric patients" throughout the section.
"["Combination therapy:" deleted] Hivid is indicated in combination with ["zidovudine" deleted] antiretroviral agents ["is indicated' deleted] for the treatment of HIV infection ["in patients with limited prior exposure to zidovudine (< 3 months)" deleted]. This indication is based on study results showing a reduction in the rate of disease progression (AIDS-defining events or death) in patients with limited prior antiretroviral therapy who were treated with the combination of Hivid and zidovudine (see Description of Clinical Studies). ["Hivid is also indicated in combination with protease inhibitors for the treatment of HIV based on studies showing greater changes in surrogate markers in regimens when Hivid was initiated concomitantly with a protease inhibitor." deleted]. This indication is also based on a study showing a reduction in both mortality and AIDS-defining clinical events for patients who received Invirase (saquinavir mesylate) in combination with Hivid compared to patients who received either Hivid or Invirase alone.
"["Hivid Monotherapy: Hivid is indicated for the treatment of HIV infection in patients with advanced HIV disease who are intolerant to or who have disease progression while receiving alternative antiretroviral therapy (See Description of Clinical studies)." deleted].
Last paragraph in section revised (new text in italics) and moved to PRECAUTIONS: General as the last paragraph -
"The duration of clinical benefit from antiretroviral therapy may be limited. Alterations in antiretroviral therapy should be considered ["if disease progression occurs during treatment." deleted] in cases of disease progression either clinically or as demonstrated by viral rebound (increase in HIV RNA after initial decline)."
Description of Clinical Study: First paragraph - "Combination Therapy:" deleted
Text added after "Table 1. First AIDS-defining Event or Death and Death Only by Study Arm and Antiretroviral Experience in ACTG 175:"
"Although no antiretroviral agent should be used as monotherapy, a description of CPCRA 002 is included here as it provides a comparison of the safety and efficacy of Hivid compared to ddI."
Second paragraph, first sentence revised (new text in italics) -
"["Hivid Monotherapy: The indication for Hivid use as monotherapy is based on the results of" deleted] CPCRA 002 was a randomized, multicenter ..."
"Significant clinical adverse reactions, some of which are potentially fatal, have been reported with HIVIV ["monotherapy and with Hivid in combination with zidovudine" deleted].
2. Pancreatitis: First paragraph revised (new text in italics) -
"Pancreatitis, which has been fatal in some cases, has been observed with the administration of Hivid ["alone or the combination of Hivid with zidovudine" deleted]. Pancreatitis is an uncommon complication of Hivid ["monotherapy or in combination with zidovudine" deleted], occurring in up to 1.1% of patients. ["The occurrence of asymptomatic elevated serum amylase of any etiology while on Hivid monotherapy was 1.6%." deleted]
Third paragraph, first sentence revised -
"Treatment with Hivid ["monotherapy or Hivid in combination with zidovudine" deleted] should be stopped immediately if clinical signs ..."
3. Hepatic Toxicity: Second sentence revised -
"In addition, rare cases of hepatic failure and death considered possibly related to underlying hepatitis B and Hivid ["monotherapy" deleted] have been reported."
"None of the other comparative studies evaluated showed a statistically significant difference in rates of lymphomas in patients receiving ["either" deleted] Hivid ["monotherapy or combination Hivid and zidovudine" deleted]."
Text added as the fifth and sixth paragraphs -
"Patients receiving Hivid or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infections, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases.
"The duration of clinical benefit from antiretroviral therapy may be limited. Alterations in antiretroviral therapy should be considered in cases of disease progression, either clinical or as demonstrated by viral rebound (increase in HIV RNA after initial decline)."
Information for Patients: Subsection revised (new text in italics) -
"Patients should be informed that Hivid is not a cure for HIV infection and that they may continue to acquire illnesses associated with advanced HIV infection, including opportunistic infections. "["Since it is frequently difficult to determine whether symptoms are a result of drug effect or underlying disease manifestation, patients should be encouraged to report all changes in their condition to their physician. Patients should be informed that the use of Hivid or other antiretroviral drugs does not preclude the ongoing need to maintain practices designed to prevent transmission of HIV. Women of childbearing age should use effective contraception while using Hivid." deleted]
"Patients should be told that there is currently no data demonstrating that Hivid therapy can reduce the risk of transmitting HIV to others through sexual contact or blood contamination.
"Patients should be advised to take Hivid every day as prescribed. Patients should not alter the dose or discontinue therapy without consulting with their doctor. If a dose is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped, the patient should not double the next dose.
"Patients should be instructed that the major toxicity of Hivid is peripheral neuropathy. Pancreatitis and hepatic toxicity are other serious potentially life-threatening toxicities that have been reported in patients treated with Hivid ["monotherapy or in combination with zidovudine." deleted]. Patients should be advised of the early symptoms of these conditions and instructed to promptly report them to their physician. Since the development of peripheral neuropathy appears to be dose-related to Hivid, patients should be advised to follow their physicians' instructions regarding the prescribed dose."
Laboratory Tests: First sentence revised (new text in italics) -
"Complete blood counts and clinical chemistry tests should be performed prior to initiating Hivid ["monotherapy or combination therapy with Hivid and zidovudine" deleted] therapy and at appropriate intervals thereafter."
Pediatric Use: Pharmacokinetics in Pediatric Patients:
The word "children" has been replaced by the words "pediatric patients" throughout the first paragraph [Note: This change appears in the 1998 PDR.]
Last paragraph revised (new text in italics) -
"Safety and effectiveness of Hivid ["in combination with zidovudine or as monotherapy" deleted] in HIV-infected ["children" deleted] pediatric patients younger than 13 years of age have not been established."
Geriatric Use (new subsection): "Safety and effectiveness of Hivid in HIV-infected geriatric patients older than 65 years of age have not been established."
"Patients should be advised that Hivid is recommended for use in combination with active antiretroviral therapy. Greater activity has been observed when new antiretroviral therapies are begun at the same time as Hivid. Concomitant therapy should be based on a patient's prior drug exposure. The recommended regimen is one 0.750 mg tablet of Hivid orally every 8 hours (2.25 mg Hivid total daily dose) in combination with other antiretroviral agents. Please refer to the complete product information for each of the other antiretroviral agents for the recommended doses of these agents. Based on preliminary data, the recommended Hivid dosage reduction for patients with impaired renal function is: creatinine clearance 10 to 40 mL/min: 0.750 mg of Hivid every 12 hours; creatinine clearance < 10 mL/min: 0.750 mg of Hivid every 24 hours."
Monitoring of Patients: First sentence of subsection revised into two sentences (new text in italics) -
"["Periodic" deleted] Complete blood counts and clinical chemistry tests should be performed prior to initiating Hivid therapy and at appropriate intervals thereafter. For comprehensive patient monitoring recommendations for other antiretroviral therapies, physicians should refer to the complete product information for these drugs."
Dose Adjustments for Hivid: New name for subsection formerly called "Dose Adjustment for Monotherapy with Hivid and in Combination Therapy with Hivid and Other Antiretroviral Agents"
"When Lexxel is taken with food ["with a high fat content" deleted] (a substantial meal of 650 kcal or greater), some of the pharmacokinetics of its components are changed.
"Lexxel should regularly be taken either without food or after a light meal (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism)."
"The test may be used for monitoring treatment if used at least four weeks following completion of therapy."
Note: The following changes appear in the 1998 PDR.
"During post-marketing surveillance syncope occurring within one hour of administration has been reported. Patients should be cautioned to avoid activities, such as driving or hazardous tasks, where injury could result if hypotension or syncope were to occur after MUSE administration."
"Because there are low or undetectable (< 2 picograms/mL) amounts of alprostadil found in the peripheral venous circulation following MUSE administration, systemic drug-drug interactions with MUSE are unlikely. Although formal studies have not been conducted, the concomitant use of MUSE and anti-hypertensive medications may increase the risk of hypotension. It is therefore advised that caution be used in the administration of MUSE to individuals on anti-hypertensive medications. In addition, the presence of medications in the circulation that attenuate erectile function may influence the response to MUSE."
response to MUSE."
"Symptomatic lowering of blood pressure (hypotension) occurred in 3% of patients; in addition, some lowering of blood pressure may occur without symptoms. Dizziness was reported in 4% of patients. Syncope (fainting) was reported by 0.4% of patients. (See WARNINGS).
Home Treatment: Paragraph added at end of subsection -
"Other drug-related side effects observed during in-clinic titration and home treatment include swelling of leg veins, leg pain, perineal pain, and rapid pulse, each occurring in < 2% of patients."
"Dose titration should be ["undertaken" deleted] administered under the supervision of a physician to test a patient's responsiveness to MUSE, to demonstrate proper administration technique (see detailed instructions for MUSE administration in patient package insert), and to monitor for evidence of hypotension (see WARNINGS).
2. The Patient Package Insert has also been revised to be consistent with the above information.
"The possibility of hypervitaminosis A or D should be borne in mind. Clinical manifestations of hypervitaminosis A have been reported in patients with renal failure receiving 1.5 mg/day retinol. Therefore, vitamin A supplementation of renal failure patients should be undertaken with caution."
"c. The withdrawal of container contents should be accomplished without delay. However, should this not be possible, a maximum time of ["4" deleted] 8 hours from initial closure entry is permitted to complete fluid transfer operations. The container should not be removed from the aseptic area during the entire ["4" deleted] 8 hour period."
One change of particular note is as follows -
"Patients should be advised to follow the patient instructions ["closely" deleted] listed on the Information for Patients sheet."
Sentence formerly found in the INDICATIONS AND USAGE section revised and moved as last sentence in subsection (new text in italics) -
"Users of ["soft (hydrophilic)" deleted] contact lenses should refrain from wearing lenses while exhibiting the signs and symptoms of vernal keratoconjunctivitis, vernal conjunctivitis, or vernal keratitis and not wear contact lenses during ["under" deleted] treatment with Opticrom. ["(see CONTRAINDICATIONS). Wear can be resumed within a few hours after discontinuation of the drug." deleted]
"After oral administration of PBZ or PBZ-SR, unchanged drug comprises 10% of the plasma levels of apparent drug. With PBZ tablets, peak plasma concentrations of apparent drug are reached within 2 hours of dosing and decline with an apparent elimination half-life of about 2 hours. Administration of PBZ, 50 mg, every 4 hours or PBZ-SR, 100 mg, every 8 hours results in a steady-state average plasma concentration of apparent drug of 0.19 ug/mL. H1 blockers are well absorbed from the gastrointestinal tract and metabolized mainly by the liver. Urinary metabolites consist of three glucuronide conjugates and an N-oxide of tripelennamine. The quaternary ammonium N-glucuronide is a major biotransformation product.
"There is no information available on the effect of food on PBZ or PBZ-SR."
"PBZ and PBZ-SR should not be used in premature infants, neonates, or nursing mothers; ["patients receiving MAO inhibitors;" deleted] patients with ["narrow-angle glaucoma, stenosing peptic ulcer, symptomatic prostatic hypertrophy, bladder neck obstruction, pyloroduodenal obstruction," deleted (NOTE: moved to PRECAUTIONS, General - see below)] lower respiratory sysmptoms ["(including asthma)" deleted], or hypersensitivity to tripelennamine or related compounds."
"Antihistamines may produce excitation ["particularly in children" deleted].
Usage in Pregnancy: Subsection deleted.
Usage in Children: Subsection deleted.
"PBZ and PBZ-SR, like other antihistamines, have atropine-like, anticholinergic activity and should be used with caution in patients with increased intraocular pressure, ["hyperthyroidism, cardiovascular disease, hypertension, or history of bronchial asthma" deleted] narrow-angle glaucoma, stenosing peptic ulcer, symptomatic prostatic hypertrophy, bladder neck obstruction, pyloroduodenal obstruction."
Information for Patients (new subsection): "See WARNINGS."
Drug Interactions (new subsection): "MAO Inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines. See CONTRAINDICATIONS and WARNINGS.
Carcinogenesis, Mutagenesis, Impairment of Fertility (new subsection): "Long-term carcinogenicity studies in animals have not been performed with tripelennamine hydrochloride. Microbial Mutation Assay (Ames Test) revealed no mutagenic activity. No mammalian mutation or cytogenic assays have been performed with tripelennamine hydrochloride. No impairment of fertility studies in animals have been conducted with tripelennamine hydrochloride."
Pregnancy Category B (new subsection): "No teratogenicity was demonstrated in a reproduction study in rats dosed with tripelennamine hydrochloride at an oral dose of 10 mg/kg (approximately 1/4 of the maximum recommended daily oral dose for adults on a mg/m2 basis). there are no adequate and well-controlled studies in pregnant women. Tripelennamine should be used during pregnancy only if th epotential benefit justifies the potential risk to the fetus."
Nursing Mothers (new subsection): "Small amounts of tripelennamine are excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from tripelennamine (see CONTRAINDICATIONS), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother."
Acute Toxicity in Animals (new subsection):"The oral lethal dose for tripelennamince hydrochloride in mice is 121 mg/kg (approximately 2 times the maximum recommended daily oral dose for adults on mg/m2 basis). The oral lethal dose for tripelennamince hydrochloride in rats is 515 mg/kg (approximately 15 times the maximum recommended daily oral dose for adults on a mg/m2 basis). The oral lethal dose for tripelennamince hydrochloride in guinea pigs is 155 mg/kg (approximately 6 times the maximum recommended daily oral dose on a mg/m2 basis)."
Signs and Symptoms: Two paragraphs added at end of subsection -
"In a suicide attempt in a young adult (19-year-old), tonic-clonic grand mal seizures developed 6 hours after ingestion of 1 g of tripelennamine, followed by death from cardiorespiratory arrest one hour later.
"In addition, respiratory depression; tachycardia, sometimes leading to cardiovascular insufficiency; hypotension, possibly shock in cases of severe poisoning; psychoses and delirium may occur."
Combined Poisoning (new subsection): "With concomitant use of alcohol, analeptic agents, tricyclic antidepressants, narcotics, MAO inhibitors, or phenothiazines, the signs and symptoms of acute poisoning with antihistamines may be aggravated or modified."
Treatment: First paragraph, first sentence revised (new text in tialics) -
"There is no specific ["therapy for acute overdosage with antihistamines" deleted] antidote.
Second paragraph, first sentence revised (new text in italics) -
"In the conscious patient, vomiting (possible only withing 20 minutes after ingestion of the drug since antihistamines exert an antiemetic effect) should be induced even though it may have occurred spontaneously." Sixth paragraph - "Do not use CNS stimulants" deleted. New sixth and seventh paragraphs added -
"In cases of cardiac insufficiency, cardiac glycosides should be administered. Patients should be monitored for evidence of ventricular tachycardia or conduction disorders.
"Analeptic agents are contraindicated because they tend to lower the convulsion threshold."
Second paragraph from end revised (new text in italics) -
"Convulsions should be controlled by ["careful titration of" deleted] a short-acting barbiturate or diazepam, repeated as necessary, with careful titration since diazepam or barbiturates may aggravate respiratory depression, hypotension, and coma.
Last paragraph revised (new text in italics) -
"Ice packs and ["cooling" deleted] alcohol sponge baths can aid in reducing the fever commonly seen in children."
Surveillance (new subsection) - "Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, and pupillary reflexes should be monitored for several days."
New second paragraph added -
"The safety and effectiveness in pediatric patients have not been established."
"4. Detectable amounts of progestin have been identified in the milk of mothers receiving the drug. The effect of this on the nursing neonate and infant has not been determined."
Text added as #12 -
"12. Safety and effectiveness in pediatric patients below the age of 12 years have not been established."
"Among the most common adverse events associated with discontinuation (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety (< or = 2% in OCD), insomnia (1% in combined indications and < or = 2% in bulimia), and nervousness (< or = 1 % in depression) (see Table 3, below)."
"Table 3 lists the adverse events associated with discontinuation of Prozac treatment (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials collecting only a primary event associated with discontinuation) in depression, OCD, and bulimia.
|
Table 3 Most Common Adverse Events Associated with Discontinuation In US Depression, OCD, and Bulimia Placebo-Controlled Clinical Trials |
|||
|
Depression, OCD, and bulimia combined (N=1108) |
Depression (N=392) |
OCD (N=266) |
Bulimia (N=450) |
|
-- Insomnia (1%) ___ ["Nervousness (1%)" deleted] -- |
-- ["Insomnia (1%)" deleted] ["Nausea (1%)" deleted] Nervousness (1%) -- |
Anxiety (2%) -- __ -- Rash (["3%" deleted] 1% |
-- Insomnia (2%) __ -- -- |
"The long-term consequences of in utero and infant exposure to Retrovir are unknown, including the possible risk of cancer.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Fourth paragraph, first sentence -
"It is not known how predictive the results of rodent carcinogenicity studies may be for humans."
moved (see below)
The four paragraphs beginning "No evidence of mutagenicity...", "In two in vivo micronucleus studies...", "In a study involving 11 AIDS patients ..." and "No effect on male or female fertility..." deleted and replaced with -
"Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg/kg per day or 40 mg/kg per day from gestation day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of zidovudine employed in this study produced zidovudine exposures approximately three times the estimated human exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day (~1000 mg/kg nonpregnant body weight or ~450 mg/kg of term body weight) to pregnant mice from days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.
"It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
"Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus test after repeated doses. It was negative in a cytogenetic study in rats given a single dose.
"Zidovudine, administered to male and female rats at doses up to seven times the usual adult dose based on body surface area considerations, had no effect on fertility judged by conception rates."
Pregnancy: Pregnancy Category C:Text added as new second paragraph -
"Two rodent transplacental carcinogenicity studies were conducted (see Carcinogenesis, Mutagenesis, Impairment of Fertility)."
"Safety and effectiveness in ["children" deleted] pediatric patients below the age of 4 have not been established."
Subsection revised to include updated clinical trial data.
"["The antidepressant effectiveness of Serzone in hospitalized depressed patients has not been adequately studied." deleted]
"["The effectiveness of Serzone in long-term use, that is, for more than 6 to 8 weeks, has not been systematically evaluated in controlled trials." deleted] The efficacy of Serzone in reducing relapse in patients with major depression who were judged to have had a satisfactory clinical response to 16 weeks of open-label Serzone treatment for an acute depressive episode has been demonstrated in a randomized placebo controlled trial (see CLINICAL PHARMACOLOGY Section). Although remitted patients were followed for as long as 36 weeks in the study cited (i.e., 52 weeks total), ["Therefore," deleted] the physician who elects to use Serzone for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient."
"Systematic evaluation of the efficacy of Serzone has shown that efficacy is maintained for periods of up to 36 weeks following 16 weeks of open-label acute treatment (treated for 52 weeks total) at dosages that averaged 438 mg/day. For most patients, their maintenance dose was that associated with response during acute treatment. (See CLINICAL PHARMACOLOGY Section)."
Last sentence revised (new text in italics) -
"["Although there are no efficacy data that specifically address maintenance antidepressant treatment with Serzone" deleted] The safety of ["nefazodone" deleted] Serzone in long-term use is supported by data from both double-blind and open-label trials involving more than 250 patients treated for at least one year."
"Butorphanol and its major metabolites are agonists at k-opioid receptors and mixed agonists-antagonists at u-opioid receptors."
deleted and replaced with -
"Butorphanol is a mixed agonist-antagonist with low intrinsic activity at receptors of the u-opioid type (morphine-like). It is also an agonist at k-opioid receptors."
Pharmacodynamics: Second sentence revised (new text in italics) -
"Onset of analgesia is within a few minutes for intravenous administration, within ["10-15" deleted] 15 minutes for intramuscular injection, and within 15 minutes for the nasal spray doses."
Pharmacokinetics:Ninth paragraph revised (new text in italics) -
"The major metabolite of butorphanol is hydroxybutorphanol, while norbutorphanol is produced in small amounts. Both have been detected in plasma following administration of butorphanol, with norbutorphanol present at trace levels at most time points. ["Preliminary evidence suggest the elimination half-life of hydroxybutorphanol may be greater than that of its parent." deleted] The elimination half-life of hydroxybutorphanol is about 18 hours and as a consequence considerable accumulation occurs when butorphanol is dosed to steady state."
Individualization of Dosage: First paragraph deleted -
"The usual starting doses of butorphanol are: 1 mg repeated every 3-4 hours IV; 2 mg repeated every 3-4 hours IM; and 1 mg followed by 1 mg in 60-90 minutes nasally repeated every 3-4 hours (see DOSAGE AND ADMINISTRATION)."
Stadol NS (butorphanol tartrate) Nasal Spray: First paragraph deleted -
"Since Stadol NS does not require an injection, it allows the physician to initiate therapy with a low dose and repeat the dose if needed."
Previous third paragraph revised (new text in italics) -
"The initial dose sequence outlined above may be repeated in 3-4 hours after the last dose as required."
"All routes of administration of butorphanol tartrate have been associated with episodes of abuse with most reports involving outpatient treatment of chronically painful conditions. Of the cases received, there were more reports of abuse with the nasal spray formulation than with the formulation administered parenterally. In general, patients receiving opioid treatment for an extended period of time are at a higher risk for abuse.
"Drug Dependence, Tolerance and Withdrawal:
Prolonged use of butorphanol tartrate
for the treatment of chronically painful conditions may also result in dependence.
The development of dependence may be marked by tolerance (a decrease in response
to a given dose) which may lead to non-medical dose escalation and craving, or drug
seeking behavior. Abrupt cessation of use by dependent patients may result in symptoms
of withdrawal.
"Proper patient selection, dose and prescribing limitations, appropriate directions for use, and frequent monitoring are important to minimize the risk of abuse and dependence. (See DRUG ABUSE AND DEPENDENCE section below.)"
First bullet, first two sentences revised (new text in italics) -
"1. Opioid analgesics, including butorphanol, impair the mental and physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. ["Effects such as drowsiness or dizziness can appear, usually within the first hour after dosing, and may last up to several hours" deleted] These effects may persist for varying periods of time after dosing."
New fourth bullet added -
"4. This is one of a class of drugs known to be abused and thus should be handled accordingly."
Drug Interactions: First paragraph, second sentence revised (new text in italics) -
"When used concurrently with such drugs, the dose of butorphanol should be the smallest effective dose and the frequency of dosing reduced as much as possible when administered concomitantly with drugs that potentiate the action of opioids."
New second paragraph added-
"The pharmacokinetics of a 1 mg dose of butorphanol administered as Stadol NS were not affected by the coadministration of cimetidine (300 mg QID). Conversely, the administration of Stadol NS (1 mg butorphanol QID) did not alter the pharmacokinetics of a 300 mg dose of cimetidine."
Information for Patients (Subsection previously named "Use in Ambulatory Patients"):
Existing text deleted and replaced with -
"See PRECAUTIONS, Use in Ambulatory Patients."
Carcinogenesis, Mutagenesis, Impairment of Fertility: First paragraph -
"The carcingenic potential of butorphanol has not been adequately evaluated."
deleted and replaced with -
"Two year carcinogenicity studies were conducted in mice and rats given butorphanol tartrate in the diet up to 60 mg/kg/day (180mg/m2 for mice and 354 mg/m2 for rats). There was no evidence of carcinogenicity in either species in these studies."
Labor and Delivery: First paragraph revised (new text in ialics) -
"["Although" deleted] There have been rare reports of infant respiratory/apnea following the administration of Stadol (butorphanol tartrate) Injection during labor [", this adverse effect was not attributed to Stadol Injection as used during controlled clinical trials" deleted]. The reports of respiratory distress/apnea have been assoicated with administration of a dose within two hours of delivery, use of multiple doses, use with additional analgesic or sedative drugs, or use in preterm pregnancies. (See OVERDOSAGE, Treatment)."
Nervous: "DRUG DEPENDENCE* or WITHDRAWAL SYNDROME* (see DRUG ABUSE AND DEPENDENCE)." added at end of list.
In the section listing those adverse experiences reported from postmarketing experience or with a frequency of less than 1% in clinical trials -
Nervous: "excessive drug effect associated with transient difficulty speaking and/or executing purposeful movements," added to alphabetical list. "drug dependence" deleted from list.
"Stadol (butorphanol tartrate) injectable and Stadol NS (butorphanol tartrate) Nasal Spray are listed in Schedule IV of Controlled Substances Act (CSA).
"Clinical Trial Experience: Some patients in clinical trials conducted in patients who were largely opiate-naive, had experiences typically associated with opioid abuse or dependence. These included rapid development of tolerance to the drug in which patients increased their dosage to higher levels than prescribed and reports of euphoria.
"Withdrawal symptoms were identified in patients using Stadol NS in controlled clinical trials. Patients abruptly discontinuing Stadol NS after extended use or high doses were at greater risk. Withdrawal symptoms included anxiety, agitation, tremulousness, diarrhea, chills, sweats, insomnia, confusion, incoordination, drug cravings and hallucinations.
"Postmarketing Experience: Butorphanol tartrate has been associated with episodes of abuse and dependence. Of the cases received, there were more reports of abuse with the nasal spray formulation than with the injectable formulation.
"Proper patient selection, dose and prescribing limitations, appropriate directions for use, and frequent monitoring are important to minimize the risk of abuse and dependence with butorphanol tartrate. Special care should be exercised in administering butorphanol to patients with a history of drug abuse or to patients receiving the drug on a repeated basis for an extended period of time."
"The clinical manifestations of butorphanol overdose are those of opioid drugs in general. Consequences of overdose vary with the amount of butorphanol ingested and the degree of tolerance of the patient to the effects of opiates. The most serious ["of which" deleted] symptoms are hypoventilation, cardiovascular insufficiency and/or coma. ["Rare cases of overdosage with a fatal outcome were usually associated with ingestion of multiple drugs, and a causal relationship to butorphanol could not be determined." deleted]
"Other symptoms of overdose may include excessive drug effect (e.g., sedation, dizziness, nausea or vomiting). This may be associated with transient difficulty speaking or executing purposeful movements. Many of the reported cases have involved people who are not tolerant to the effects of opiates and who use larger doses of butorphanol to initiate therapy (more than 1 mg Stadol NS or more than 2 mg Stadol injection)."
Treatment: Paragraph added at end of subsection -
"In managing cases of suspected butorphanol overdosage, the possibility of multiple drug ingestion should always be considered."
"The initial dose sequence outlined above may be repeated in 3-4 hours after the last dose as needed."
"Store below 86o F (30o C)."
deleted and replaced with -
"Store below 77o F (25o C)."
"Patients should also be instructed that ocular solutions, if handled improperly, or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections."
Third paragraph revised (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."
Last paragraph in subsection deleted and replaced with -
"Patients should be advised that Timoptic contains benzalkonium chloride which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following Timoptic administration."
Drug Interactions: Quinidine (new subsection): "Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via the P-450 enzyme, CYP2D6."
Nervous System/Psychiatric: Subsection rearranged and "insomnia", "nightmares", and "memory loss" moved up from the oral timolol paragraph and added to list.
Skin: Subsection revised (new text in italics) -
"[Hypersensitivity, including localized and generalized rash; urticaria;" deleted and moved to new subsection] Alopecia and psoriasiform rash or exacerbation of psoriasis."
Hypersensitivity (new subsection): "Signs and symptoms of allergic reactions, including angioedema, urticaria, and localized and generalized rash."
Special Senses: "dry eyes" and "tinnitus" moved up from the oral timolol paragraph and added to list.
Urogenital: "decreased libido" and "Peyronie's disease" moved up from the oral timolol paragraph and added to list.
In the oral timolol paragraph, the adverse experiences noted above as being moved from that paragraph have been deleted.
Nervous System/Psychiatric: Subsection rearranged and "insomnia", "nightmares", and "memory loss" moved up from the oral timolol paragraph and added to list.
Skin: Subsection revised (new text in italics) -
"[Hypersensitivity, including localized and generalized rash; urticaria;" deleted and moved to new subsection] Alopecia and psoriasiform rash or exacerbation of psoriasis."
Hypersensitivity (new subsection): "Signs and symptoms of allergic reactions, including angioedema, urticaria, and localized and generalized rash."
Special Senses: "dry eyes" and "tinnitus" moved up from the oral timolol paragraph and added to list.
Urogenital: "decreased libido" and "Peyronie's disease" moved up from the oral timolol paragraph and added to list.
In the oral timolol paragraph, the adverse experiences noted above as being moved from that paragraph have been deleted.
"Patients should also be instructed that ocular solutions, if handled improperly, or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections."
Third paragraph revised (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."
New paragraph added at end of subsection -
"Transient blurred vision, generally lasting from 30 seconds to 5 minutes, following instillation, and potential visual disturbances may impair the ability to perform hazardous tasks such as operating machinery or driving a motor vehicle."
Drug Interactions: Beta-adrenergic blocking agents: Last sentence - "Patients should not usually receive two topical ophthalmic beta-adrenergic blocking agents concurrently." deleted and replaced with -
"The concomitant use of two topical beta-adrenergic blocking agents is not recommended."
Quinidine (new subsection): "Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via the P-450 enzyme, CYP2D6."
Cardiovascular: "edema, claudication, Raynaud's phenomenon, and cold hands and feet" moved up from the oral timolol paragraph and added to list.
Nervous System/Psychiatric: Subsection rearranged and "insomnia", "nightmares", and "memory loss" moved up from the oral timolol paragraph and added to list.
Skin: Subsection revised (new text in italics) -
"[Hypersensitivity, including localized and generalized rash; urticaria;" deleted and moved to new subsection] Alopecia and psoriasiform rash or exacerbation of psoriasis."
Hypersensitivity (new subsection): "Signs and symptoms of allergic reactions, including angioedema, urticaria, and localized and generalized rash."
Urogenital: "decreased libido" and "Peyronie's disease" moved up from the oral timolol paragraph and added to list.
In the oral timolol paragraph, the adverse experiences noted above as being moved from that paragraph have been deleted.
"The concomitant use of two topical beta-adrenergic blocking agents is not recommended. (See PRECAUTIONS, Drug Interactions, Beta-adrenergic blocking agents.)"
Clinical Studies: Entire subsection revised. Contact the company for a copy of the new labeling/package insert.
"Tritec in combination with clarithromycin is indicated for the treatment of patients with an active duodenal ulcer associated with H. pylori infection. Most patients not eradicated of H. pylori following Tritec plus clarithromycin treatment will have clarithromycin resistant H. pylori isolates. Therefore, for those patients who fail therapy, clarithromycin susceptibility testing should be done when possible. Patients with clarithromycin resistant H. pylori should not be treated with Tritec plus clarithromycin or with regimens which include clarithromycin as the sole antimicrobial agent.
"The eradication of H pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence. (See DOSAGE AND ADMINISTRATION and CLNICAL STUDIES.)
"["It is recommended that all patients not eradicated of H. pylori following ranitidine bismuth citrate plus clarithromycin treatment be considered to have H. pylori resistant to clarithromycin. (See Microbiology subsection.) Patients who fail therapy should not be re-treated with a regimen containing clarithromycin." deleted]
"NOTE: Tritec should not be prescribed alone for the treatment of active duodenal ulcer."
"Placebo-controlled trials in patients with active duodenal ulcer in the United States included ["1,023" deleted] 1,428 patients given Tritec alone or in combination with clarithromycin, 120 patients given clarithromycin alone, and 469 patients given placebo."
Table 3 - "Drug-related Adverse Reactions During Treatment" revised (new text in italics) -
|
Table 3: Drug-Related Adverse Reactions During Treatment* |
|||||
|
Adverse Reaction |
(n = 469) |
800 mg (n = 903) |
1,500 mg (n = 120)
|
800 mg + Clarithromycin 1,000 mg (n = 196) |
800 mg + Clarithromycin 1,500 mg (n=["120" deleted] 329) |
|
Gastrointestinal Diarrhea Nausea & vomiting Constipation Gas |
1% 1% <1% <1% |
2% <1% 1% <1% |
5% 2% 0% 2% |
4% 5% 2% 1% |
["8%" deleted] 5% 3% ["0%" deleted] 2% <1% |
|
Neurological Headache Dizziness |
<1% <1% |
1% <1% |
<1% 2% |
2% 0% |
["5%" deleted] 3% ["0%" deleted] <1% |
|
Miscellaneous Disturbance of taste Sleep disorder ["Chest symptoms" deleted] |
<1% <1% ["<1%" deleted] |
<1% <1% ["0%" deleted] |
11% <1% ["0% deleted] |
8% <1% |
["10%" deleted] 11% 2% ["2%"deleted] |
|
Skin Pruritus <I>Rashes</I> |
0% <1% |
<1% <1% |
0% 0% |
<1% 2% |
["3%" deleted] 1% <1% |
|
Urogenital Gynecological |
0% (n = 159) |
<1% (n = 267) |
6% (n = 32) |
1% (n = 69) |
["3%" deleted] 2% (n = ["34" deleted] |
|
*Total daily doses. +* n = number of females |
|||||
"The recommended dosage of Tritec is 400 mg b.i.d. for 4 weeks (28 days) in conjunction with clarithromycin 500 mg ["t.i.d."deleted] b.i.d. for the first two weeks (14 days). Tritec and clarithromycin can be taken wih or without food.
"Days 1-14
Tritec 400 mg b.i.d.
plus
clarithromycin 500 mg ["t.i.d." deleted] b.i.d.
"Days 15-28
Tritec 400 mg b.i.d.
"An alternative dosage regimen of Tritec 400 mg b.i.d. for 4 weeks (28 days) in conjunction with clarithromycin 500 mg t.i.d. for the first 2 weeks (14 days) has been shown to be equally effective."
"In postmarketing experience with other calcium channel blockers, gynecomastia has been rarely observed."
"In a few reported cases, overdose with calcium channel blockers has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride."
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