![[U.S. Food and Drug Administration]](https://webarchive.library.unt.edu/eot2008/20081028094649im_/http://www.fda.gov/icon/header.gif){kind=icon}
(Posted: June 20, 2000)
Note: The following summaries include only those safety-related sections that have been modified, and therefore do not contain all the information needed for safe and effective prescribing. Contact the manufacturer for the complete labeling/package insert.
NB: Comparison made to 2000 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.
|
(estradiol/norethindrone acetate) |
(risedronate sodium) |
(amprenavir) |
(estradiol) |
|
(rosiglitazone maleate) |
(norethindrone acetate) |
(sulfasalazine) |
(caffeine citrate) |
|
(calcitriol) |
(irinotecan HCl) |
(dinoprostone) |
(amino acid/electrolytes in dextrose with calcium) |
|
(indinavir sulfate) |
(cabergoline) |
(amitriptyline HCl) |
(lidocaine/prilocaine) |
|
(epoprostenol sodium) |
(zalcitabine) |
(insulin lispro) |
(norgestrel/ethinyl estradiol) |
|
(trandolopril) |
(telmisartan) |
(desogestrel/ethinyl estradiol) |
(multi-vitamins) |
|
(levonorgestrel/ethinyl estradiol) |
NUTROPIN AQ (somatropin) |
(clopidogrel bisulfate) |
(zanamivir) |
|
(rifampin) |
(rifampin/isoniazid/ pyrazinamide) |
(somatropin) |
(doxepin HCl) |
|
(carbamazepine) |
(diltiazem HCl) |
(amino acid in dextrose) |
(fenofibtate) |
|
(moexipril HCl/ hydrochlorothiazide) |
(valacyclovir HCl) |
(protriptyline HCl) |
(bupropion HCl) |
|
(hyaluronidase) |
(orlistat) |
(abacavir sulfate) |
(simvastatin) |
|
(ondansetron HCl) |
[Other information regarding these changes: Letter]
From the April 24, 2000 Approval letter for Capsule and Oral Solution -
"Concomitant use of Agenerase with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including Agenerase, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin or cerivastatin). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including amprenavir, are used in combination with these drugs."
* "It is not recommended that you take Agenerase with the cholesterol-lowering drugs Mevacor (lovastatin) or Zocor (simvastatin) because of the possible drug interactions. There is also an increased risk of drug interactions between Agenerase and Lipitor (atorvastatin) and Baycol (cerivastatin). Talk to your doctor if you are taking or planning to take these or other drugs for lowering cholesterol."
From the April 28, 2000 Approval letter -
There are now two separate Agenerase professional and patient labels, one each for Agenerase Oral Solution and Agenerase Capsules, respectively.
FOR THE CAPSULE LABEL -
"Because of the potential risk of toxicity from the large amount of the excipient propylene glycol contained in Agenerase Oral Solution, that formulation is contraindicated in certain patient populations and should be used with caution in others. Consult the compete prescribing information for Agenerase Oral Solution for full information."
"Agenerase Oral Solution is contraindicated in infants and children below the age of 4 years due to the potential risk of toxicity from the large amount of the excipient propylene glycol. Please see the complete prescribing information for Agenerase Oral Solution."
"Because of the potential risk of toxicity from the large amount of the excipient propylene glycol contained in Agenerase Oral Solution, that formulation is contraindicated in certain patient populations and should be used with caution in others. Consult the compete prescribing information for Agenerase Oral Solution for full information."
"Because of the potential risk of toxicity from the large amount of the excipient propylene glycol contained in Agenerase Oral Solution, that formulation is contraindicated in certain patient populations and should be used with caution in others. Consult the compete prescribing information for Agenerase Oral Solution for full information."
"Patients treated with Agenerase Capsules should be cautioned against switching to Agenerase Oral Solution because of the increased risk of adverse events from the large amount of propylene glycol in Agenerase Oral Solution. Please see the complete prescribing information for Agenerase Oral Solution for full information."
Pregnancy and Reproduction:
"Agenerase Oral Solution is contraindicated during pregnancy due to the potential risk of toxicity to the fetus from the high propylene glycol content."
Pediatric Use:
"Agenerase Solution is contraindicated in infants and children below the age of 4 years due to the potential risk of toxicity from the large amount of the excipient propylene glycol. Please see the complete prescribing information for Agenerase Oral Solution for full information."
DOSAGE AND ADMINISTRATION:
"Before using Agenerase Oral Solution, the complete prescribing information should be consulted."
FOR THE ORAL SOLUTION LABEL -
" Because of the potential risk of toxicity from the large amount of the excipient propylene glycol, Agenerase Oral Solution is contraindicated in infants and children below the age of 4 years, pregnant women, patients with hepatic or renal failure, and patients treated with disulfiram or metronidazole (see CONTRAINDICATIONS AND WARNINGS). Agenerase Oral Solution should be used only when Agenerase Capsules or other protease inhibitor formulations are not therapeutic options."
"Propylene glycol is in the formulation to achieve adequate solubility of amprenavir. The recommended daily dose of Agenerase Oral Solution of 22.5 mg/kg twice daily corresponds to a propylene glycol intake of 1650 mg/kg per day. Acceptable intake of propylene glycol for pharmaceuticals has not been established."
"Agenerase Oral Solution is contraindicated in patients with hepatic failure.
"Patients with hepatic impairment are at increased risk of propylene glycol-associated adverse events (see WARNINGS). Agenerase oral solution should be used with caution in patients with hepatic impairment."
Drug Interactions: Last paragraph, first sentence revised (new text in italics) -
"Drug interaction studies were performed with amprenavir capsules and other drugs likely to be coadministered or drugs used as probes for pharmacokinetic interactions."
"Agenerase Oral Solution should be used only when Agenerase Capsules or other protease inhibitor formulations are not therapeutic options."
"Because of the potential risk of toxicity from the large amount of the excipient propylene glycol, Agenerase Oral Solution is contraindicated in infants and children below the age of 4 years, pregnant women, patients with hepatic or renal failure, and patients treated with disulfiram or metronidazole (see WARNINGS and PRECAUTIONS)."
"Because of the potential risk of toxicity from the large amount of the excipient propylene glycol, Agenerase Oral Solution is contraindicated in infants and children below the age of 4 years, pregnant women, patients with hepatic or renal failure, and patients treated with disulfiram or metronidazole (see CLINICAL PHARMACOLOGY, CONTRAINDICATIONS, and PRECAUTIONS).
"Because of the possible toxicity associated with the large amount of propylene glycol and the lack of information on chronic exposure to large amounts of propylene glycol, Agenerase Oral Solution should be used only when Agenerase Capsules or other protease inhibitor formulations are not therapeutic options. Certain ethnic populations (Asians, Eskimos, Native Americans) and women may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol; no data are available on propylene glycol metabolism in these groups (see CLINICAL PHARMACOLOGY: Special Populations: Gender and Race).
"If patients require treatment with Agenerase Oral Solution, they should be monitored closely for propylene glycol-associated adverse events, including seizures, stupor, tachycardia, hyperosmolality, lactic acidosis, renal toxicity, and hemolysis. Patients should be switched from Agenerase Oral Solution to Agenerase Capsules as soon as they are able to take the capsule formulation.
"Use of alcoholic beverages is not recommended in patients treated with Agenerase Oral Solution."
PRECAUTIONS: Information for Patients: New second, third, fourth and tenth sentences -
"Agenerase Oral Solution is contraindicated in infants and children below the age of 4 years, pregnant women, patients with hepatic or renal failure, and patients treated with disulfiram or metronidazole Agenerase Oral Solution should be used only when Agenerase Capsule or other protease inhibitor formulations are not therapeutic options. Patients treated with Agenerase Capsules should be cautioned against switching to Agenerase Oral Solution because of the increased risk of adverse events from the large amount of propylene glycol in Agenerase Oral Solution. Women, Asians, Eskimos, or Native Americans, as well as patients who have hepatic or renal insufficiency, should be informed that they may be at increased risk of adverse events from the large amount propylene glycol in Agenerase Oral Solution."
"Patients should be advised that drinking alcoholic beverages is not recommended while taking Agenerase Oral Solution."
Pregnancy and Reproduction:
Agenerase Oral Solution is contraindicated during pregnancy due to the potential risk of toxicity to the fetus from the high propylene glycol content. Therefore, if Agenerase is used in pregnant women, the Agenerase Capsules formulation should be used (see complete prescribing information for Agenerase Capsules).)
Pediatric Use: New first paragraph -
"Agenerase Oral Solution is contraindicated in infants and children below the age of 4 years due to the potential risk of toxicity from the excipient propylene glycol (see CONTRAINDICATIONS and WARNINGS). Alcohol dehydrogenase (ADH), which metabolizes propylene glycol, is present in the human fetal liver at 2 months of gestational age, but at only 3% of adult activity. Although the data are limited, it appears that by 12 to 30 months of postnatal age, ADH activity is equal to or greater than that observed in adults.
"The recommended dose of Agenerase Oral Solution based on body weight and age is shown in Table 10."
Table 10: Recommended Dossages of Agenerase Oral Solution
|
Age/Weight Criteria |
Dose |
|
|
b.i.d. |
t.i.d. |
|
|
4 - 12 years or 13 - 16 years and less than 50 kg |
22.5 mg/kg (1.5 mL/kg) (maximum dose 2800 mg per day) |
17 mg/kg (1.0 mL/kg)(maximum dose 2800 mg per day) |
|
13 - 16 years and 50 kg or greater than 16 years |
1400 mg |
NA |
Consideration should be given to switching patients from Agenerase Oral Solution to Agenerase Capsules as soon as they are able to take the capsule formulation (see WARNINGS).
"Patients with Hepatic Impairment: Agenerase Oral Solution is contraindicated in patients with hepatic failure (see CONTRAINDICATIONS).
"Patients with hepatic impairment are at increased risk of propylene glycol-associated adverse events (see WARNINGS). Agenerase Oral Solution should be used with caution in patients with hepatic impairment. Based on a study with Agenerase Capsules, adult patients with a Child-Pugh score ranging from 5 to 8 should receive a reduced dose of Agenerase Oral Solution of 513 mg (34 mL) twice daily, and adult patients with a Child-Pugh score ranging from 9 to 12 should receive a reduced dose of Agenerase Oral Solution of 342 mg (23 mL) twice daily (see CLINICAL PHARMACOLOGY: Hepatic Insufficiency).
"Agenerase Oral Solution has not been studied in children with hepatic impairment.
"Renal Insufficiency: Agenerase Oral Solution is contraindicated in patients with renal failure (see WARNINGS).
"Patients with renal impairment are at increased risk of propylene glycol-associated adverse events. Agenerase Oral Solution should be used with caution in patients with renal impairment (see WARNINGS).
" Agenerase Capsules and Agenerase Oral Solution are not interchangeable on a milligram per milligram basis (see CLINICAL PHARMACOLOGY).
"The safety and effectiveness in geriatric patients (over age 65) have not been established."
Addition of item 6 -
"Data suggest that progestin therapy may have adverse effects on lipid and carbohydrate metabolism. The choice of progestin, its dose, and its regimen may be important in minimizing these adverse effects, but these issues will require further study before they are clarified. Women with hyperlipidemias and/or diabetes should be monitored closely during progestin therapy."
"Clinical studies of Calcijex did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."
[Other labeling changes not appearing in 2000 PDR: Feb00, Nov99]
"The safety and efficacy of Cervidil has been established in women of reproductive age and women who are pregnant. Although safety and efficacy has not been established in pediatric patients, safety and efficacy are expected to be the same for adolescents."
"In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage."
"Dextrose is safe for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of an increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants.
"Safety and effectiveness of Clinimix - sulfite-free (amino acid with electrolytes in Dextrose with Calcium) Injections in pediatric patients have not been established by adequate and well-controlled studies. However, the use of amino acid injections in pediatric patients as an adjunct in the offsetting of nitrogen loss or in the treatment of negative nitrogen balance is referenced in the medical literature. See Dosage and Administration."
"Daily amino acid doses of approximately 1.0 to 1.5 g/kg of body weight for adults ["and 2 to 3 g/kg body weight for infants" deleted] with adequate calories are generally sufficient to satisfy protein needs and promote positive nitrogen balance."
Pediatric Use: New subsection -
"Use of Clinimix - sulfite-free (Amino Acid in Dextrose) Injections in pediatric patients is governed by the same considerations that affect the use of any amino acid solution in pediatrics. The amount administered is dosed on the basis of grams of amino acids/kg of body weight/day. Two to 3 g/kg of body weight for infants with adequate calories are generally sufficient to satisfy protein needs and promote positive nitrogen balance. Solution administrations by peripheral vein should not exceed twice normal serum osmolality (718 mOsmol/L).
Peripheral Vein Administration: New second sentence -
"In pediatric patients, the final solution should not exceed twice normal serum osmolality (718 mOsmol/L)."
[Other labeling changes not appearing in 2000 PDR: Jun99]
"The risk of myopathy including rhabdomyolysis may be increased when protease inhibitors, including Crixivan, are used in combination with HMG-CoA reductase inhibitors that are metabolized by the CYP3A4 pathway (e.g., atorvastatin, cerivastatin, lovastatin, or simvastatin)."
The current text appears as follows -
Concomitant use of Crixivan with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including Crixivan, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin or cerivastatin). The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including Crixivan, are used in combination with these drugs."
"Nephrolithiasis/urolithiasis, including flank pain with or without hematuria (including microscopic hematuria), has been reported in approximately 9.3% (193/2071) of patients receiving Crixivan in clinical trials at the recommended dose, compared to ["2.1%" deleted in 1999 PDR] 1.8% in the control ["arms" deleted in 1999 PDR] arm."
Second paragraph revised (new text in italics) -
Asymptomatic hyperbilirubinemia (total bilirubin greater than or equal to 2.5 mg/dL), reported predominantly as elevated indirect bilirubin, has occurred in approximately ["10%" deleted] 14% of patients treated with Crixivan. In less than 1% this was associated with elevations in ALT or AST."
Table 4 - "Clinical Adverse Experiences Reported in greater than or equal to 2% of Patients" extensively revised. Contact the company for a copy of the new labeling/package insert.
Cardiovascular System: New subsection -
"cardiovascular disorders including myocardial infarction and angina pectoris."
"Clinical studies of Dostinex did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from other subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."
"Clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic function, concomitant disease and other drug therapy in elderly patients."
Geriatric patients are particularly sensitive to the anticholinergic side effects of tricyclic antidepressants including Elavil. Peripheral anticholinergic effects include tachycardia, urinary retention, constipation, dry mouth, blurred vision, and exacerbation of narrow-angle glaucoma. Central nervous system anticholinergic effects include cognitive impairment, psychomotor slowing, confusion, sedation, and delirium. Elderly patients taking Elavil may be at increased risk for falls. Elderly patients should be started on low doses of Elavil and observed closely (see DOSAGE AND ADMINISTRATION)."
"A syndrome resembling neuroleptic malignant syndrome (NMS) has been very rarely reported after starting or increasing the dose of Elavil, with and without concomitant medications known to cause NMS. Symptoms have included muscle rigidity, fever, mental status changes, diaphoresis, tachycardia, and tremor.
"Very rare cases of serotonin syndrome (SS) have been reported with Elavil in combination with other drugs that have a recognized association with SS."
[Other labeling changes not appearing in 2000 PDR: Mar99]
"During intravenous studies, the elimination half-life of lidocaine was statistically significantly longer in elderly patients (2.5 hours) than in younger patients (1.5 hours). No studies are available on the intravenous pharmacokinetics of prilocaine in elderly patients."
"Of the total number of patients in clinical studies of EMLA, 180 were 65 to 74 and 138 were 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
"Plasma levels of lidocaine and prilocaine in geriatric and non-geriatric patients following application of a thick layer of EMLA are very low and well below potentially toxic levels. However, there are no sufficient data to evaluate quantitative differences in systemic plasma levels of lidocaine and prilocaine between geriatric and non-geriatric patients following application of EMLA. Consideration should be given for those elderly patients who have enhanced sensitivity to systemic absorption. (See PRECAUTIONS).)
"After intravenous dosing, the elimination half-life of lidocaine is significantly longer in elderly patients ( 2.5 hours) than in younger patients (1.5 hours). (See CLINICAL PHARMACOLOGY).
[Other labeling changes not appearing in 2000 PDR: Nov99]
"Labeling revised to incorporate information for use in the long-term intravenous treatment of pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy. Contact the company for a copy of the new labeling/package insert."
"HIVID should be used with caution in patients with a risk of developing peripheral neuropathy: patients with low CD4 cell counts (CD4 less than 50 cells/mm3), diabetes, weight loss and/or patients receiving HIVID concomitantly with drugs that have the potential to cause peripheral neuropathy (see PRECAUTIONS: Drug Interactions). Careful monitoring is strongly recommended for these individuals."
3. Lactic Acidosis/Severe Hepatomegaly With Steatosis and Hepatic Toxicity: First and last sentences revised (new text in italics) -
"Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including HIVID and other antiretrovirals."
"Treatment with HIVID should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations)."
4. Other Serious Toxicities: (new text in italics) -
"d) Anaphylactoid Reaction: An anaphylactoid reaction was reported in a patient
receiving both HIVID and zidovudine. In addition, there have been several
reports of hypersensitivity reactions (including anaphylactic reaction
or urticaria without other signs of anaphylaxis)."
"Lymphoma has been identified as a consequence of HIV infection. This most likely represents a consequence of prolonged immunosuppression; however, an association between the occuence of lymphoma and antiviral therapy can not be excluded."
Drug Interactions: Subsection reordered with separate paragraphs for drugs/drug categories, with the text remaining the same. Three new drug interactions added -
"Zidovudine: There is no significant pharmacokinetic interaction between ZDV and zalcitabine which has been confirmed clinically. Zalcitabine also has no significant effect on the intracellular phosphorylation of ZDV, as shown in vitro in peripheral blood mononuclear cells or in the lymphoblastoid cell line h1A2v2. No information is available on pharmacokinetic interactions of zalcitabine with didanosine, lamivudine, and stavudine.
"Saquinavir: The combination of HIVID, saquinavir, and ZDV has been studied (as triple combination) in adults. Pharmacokinetic data suggest that absorption, metabolism, and elimination of each of these drugs are unchanged when they are used together.
"Doxorubicin: Doxorubicin caused a decrease in zalcitabine phosphorylation (greater than 50% inhibition of total phospahate formation) in U937/Molt 4 cells. Although there may be decreased zalcitabine activity because of lessened active metabolite formation, the clinical relevance of these in vitro results are not known."
Carcinogenesis, Mutagenesis and Impairment of Fertility: Previous subsections
"Carcinogenesis and Mutagenesis" deleted and replaced.
The new subsections are as follows:
"Carcinogenesis: Zalcitabine was administered orally by dietary admixture to CRL:CD-1 (ICR) Br mice at dosages of 3, 83, or 250 mg/kg/day for 2 years. Plasma exposures (as measured by AUC) at these doses were 6-fold to 704-fold greater than the systemic exposure in humans with the therapeutic dose. Zalcitabine was administered orally by dietary admixture to CDF (F-344)/CrlBR/CdBR rats at dosages of 3, 28, 83, or 250 mg/kg/day. At the highest dose tested, the systemic exposure to zalcitabine was 833 times the systemic exposure in humans with the therapeutic dose."
"A significant increase in thymic lymphoma in all zalcitabine dose groups and Harderian gland (a gland of the eye of rodents) adenoma in the two highest dose groups was observed in female CD-1 mice after 2 years of dosing. No increase in tumor incidence was observed in rats or male mice treated with zalcitabine. In an independent study, administration of zalcitabine to B6C3F1 mice at a dose of 1000 mg/kg/day for 3 months induced an increased incidence of thymic lymphoma. A high rate of spontaneous lymphoreticular neoplasms have previuosly been noted in this strain of mice."
"Mutagenesis: Zalcitabine was positive in a cell transformation assay and induced chromosomal aberrations in vitro in human peripheral blood lymphocytes. Oral doses of zalcitabine at 2500 and 4500 mg/kg were clastogenic in the mouse micronucleus assay. Zalcitabine showed no evidence of mutagenicity in Ames tests, Chinese hamster lung cell assays and the mouse lymphoma assay. An unscheduled DNA synthesis in rat hepatocytes showed that zalcitabine had no effect on DNA repair."
Geriatric Use: Previous subsection deleted. New subsection as follows: -
"Clinical studies of HIVID did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. HIVID is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see PRECAUTIONS: General: Renal Impairment and DOSAGE AND ADMINISTRATION)."
"In an initial dose-finding study in which zalcitabine was administered at doses 25 times (0.25 mg/kg every 8 hours) the currently recommended dose, one patient discontinued HIVID after 1 1/2 weeks of treatment subsequent to the development of a rash and fever."
"TABLE I: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF USE OF A CONTRACEPTIVE METHOD
|
Method |
Perfect Use |
Typical Use |
|
Levonorgestrel implants |
0.05 |
0.05 |
|
Male sterilization |
0.1 |
0.15 |
|
Female sterilization |
0.5 |
0.5 |
|
Depo-Provera (injectable progestogen) |
0.3 |
0.3 |
|
Oral contraceptives |
5 |
|
|
Combined |
0.1 |
NA |
|
Progestin only |
0.5 |
NA |
|
IUD |
||
|
Progesterone |
1.5 |
2.0 |
|
Copper T 380A |
0.6 |
0.8 |
|
Condom (male) without spermicide |
3 |
14 |
|
(female) without spericide |
5 |
21 |
|
Cervical cap |
||
|
Nulliparous women |
9 |
20 |
|
Parous women |
26 |
40 |
|
Vaginal sponge |
||
|
Nulliparous women |
9 |
20 |
|
Parous women |
20 |
40 |
|
Diaphram with Spermicidal cream Or jelly |
6 |
20 |
|
Spermicides alone (foam, creams, jellies, and vaginal suppositories) |
6 |
26 |
|
Periodic abstinence (all methods) |
1-9* |
25 |
|
Withdrawal |
4 |
19 |
|
No contraception (planned pregnancy) |
85 |
85 |
NA - not available
*Depending on method (calendar, ovulation, symptothermal, post-ovulation)
Adapted from Hatcher RA et al, Contraceptive Technology: 17th Revised Edition. NY,NY: Ardent Media, Inc., 1998.
"Safety and efficacy of Lo/Ovral, Lo/Ovral-28, Nordette-21 and Nordette-28 have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and users 16 and older. Use of this product before menarche is not indicated."
"Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors."
"Micardis is available as tablets for oral administration, containing ["either" deleted] 20 mg, 40 mg or 80 mg of telmisartan."
"This condition should be corrected prior to administration of Micardis tablets, or treatment should start under close medical supervision with reduced dose. ["of an AII antagonist (this may require use of a drug other than Micardis as it is not possible to give less than 40 mg at present)" deleted]."
"Micardis tablets should be used with caution in these patients. ["but there is no way to reduce the dose below 40 mg; an alternative treatment can be considered." Deleted]"
[Other labeling changes not appearing in 2000 PDR: Feb00]
"Desogestrel has minimal androgenic activity (see CLINICAL PHARMACOLOGY) and there is some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestogen has minimal androgenic activity than when the activity is greater."
b. Thromboembolism
First paragraph, second sentence revised -
"Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thromboembolic ["thrombosis" deleted] disease (2,3,19-24) [",4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease" deleted]
New second paragraph -
"In two case-controlled studies and one cohort study of venous thromboembolism, third generation oral contraceptives including those containing desogestrel, were reported to have relative risk between 1.5 and 2.4 when compared to certain second generation oral contraceptives (101-103). These risks are within the above-mentioned range for deep vein thrombosis and pulmonary embolism. A relative risk of 2 would translate into an additional 1-2 cases of non-fatal venous thromboembolism per 10,000 women-years of use. The risk of venous thromboembolic disease associated with oral contraceptives does not increase with length of use and disappears after pill use is stopped."
Blood clots and blockage of blood vessels are one of the most serious side effects of taking oral contraceptives and can cause death or serious disability. In particular, a clot in the leg can cause thrombophlebitis and a clot that travels to the lungs can cause a sudden blockage of the vessel carrying blood to the lungs. These risks may be greater with desogestrel-containing oral contraceptives, such as Mircette, than with other low-dose pills. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision."
Replaced with -
"Store under refrigeration, 2-8oC (36-46oF)"
[Other changes not appearing in 2000 PDR: Dec99, Nov99]
[Other labeling changes not appearing in 2000 PDR: Feb00]
"The following events have been reported spontaneously from worldwide postmarketing experience: very rare cases of hypersensitivity reactions including angioedema, bronchospasms, and anaphylactoid reactions. Suspected thrombotic thrombocytopenic purpura (TTP) has been reported as part of the world-wide postmarketing experience, see WARNINGS."
" Thrombotic thrombocytopenic purpura (TTP): TTP has been reported rarely following use of Plavix, sometimes after a short exposure (less than 2 weeks). TTP is a serious condition requiring prompt treatment. It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever. TTP was not seen during clopidogrel's clinical trials, which included over 11,300 clopidogrel-treated patients. In world-wide postmarketing experience, however, TTP has been reported at a rate of about four cases per million patients exposed, or about 11 cases per million patient-years. The background rate is thought to be about four cases per million person-years. "
[Other information regarding these changes: Letter]
"Clinical studies of Rifadin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution should therefore be observed in using rifampin in elderly patients. (See WARNINGS.)"
"Clinical studies of Rifater did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution should therefore be observed in using rifampin in elderly patients. (See WARNINGS.)"
"Growth hormone should not be initiated to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or to patients having acute respiratory failure. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin treated patients (doses 5.3-8 mg/day) compared to those receiving placebo (see WARNINGS)."
"See CONTRAINDICATIONS for information on increased mortality in patients with acute critical illnesses in intensive care units due to complications following open heart or abdominal surgery, multiple accidental trauma or with acute respiratory failure. The safety of continuing growth hormone treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with growth hormone in patients having acute critical illnesses should be weighed against the potential risk.""
"Growth hormone should not be initiated to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or to patients having acute respiratory failure. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin treated patients (doses 5.3-8 mg/day) compared to those receiving placebo (see WARNINGS)."
"See CONTRAINDICATIONS for information on increased mortality in patients with acute critical illnesses in intensive care units due to complications following open heart or abdominal surgery, multiple accidental trauma or with acute respiratory failure. The safety of continuing growth hormone treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with growth hormone in patients having acute critical illnesses should be weighed against the potential risk."
"Sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of Sinequan and observed closely (see PRECAUTIONS-Geriatric Use)."
Geriatric Use: New section -
"A determination has not been made whether controlled clinical studies of Sinequan included sufficient numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy."
"Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac, hepatic, or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or interrupted courses of therapy with Tegretol."
New fourth through seventh paragraphs added -
"Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects may progress despite discontinuation of the drug.
"Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases (see ADVERSE REACTIONS, Other and PRECAUTIONS, Information for Patients).
"Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops.
"Hypersensitivity reactions to carbamazepine have been reported in patients who previuosly experienced this reaction to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions should be obtained for a patient and the immediate family members. If positive, caution should be used in prescribing carbamazepine."
Information for Patients: First paragraph revised (new text in italics) -
"Patients should be made aware of the early signs and symptoms of a potential hematologocal problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or occurring after extended use."
Laboratory Tests: Second paragraph revised (new text in italics) -
"Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgement, if indicated by newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the case of active liver disease."
Effect of Tegretol on Plasma Levels of Concomitant Agents (new text in italics) -
"Tegretol induces hepatic CYP activity. Tegretol causes, or would be expected to cause,
decreased levels of the following:
acetaminophen, alprazolam, clonazepam, clozapine, dicumarol, doxycycline, ethosuximide,
haloperidol, lamotrigine, methsuximide, ["oral contraceptives" deleted]
other hormonal contraceptives, phensuximide, phenytoin, theophylline, tigabine,
topiramate, valproate, warfarin."
Last paragraph deleted -
"Breakthrough bleeding has been reported among patients receiving concomitant oral and subdermal implant contraceptives and their reliabiblty may be adversely affected."
Replaced with -
"Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal implant contraceptives) may render the contraceptive less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported. Alternative or back-up methods of contraception should be considered."
"Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of hepatic failure."
Other: New first paragraph -
"Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepato-splenomegaly and abnormal liver function tests. These signs and symptoms may occur in various combinations and not necessarily concurrently. Signs and symptoms may initially be mild. Various organs, including but not limited to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (see PRECAUTIONS, General and PRECAUTIONS, Information for Patients)."
[Other labeling changes not appearing in 2000 PDR: Mar00]
" Diltiazem is both a substrate and an inhibitor of the cytochrome P-450 3A4 enzyme system. Other drugs that are specific substrates, inhibitors, or inducers of the enzyme system may have a significant impact on the efficacy and side effect profile of diltiazem. Patients taking other drugs that are substrates of CYP450 3A4, especially patients with renal and/or hepatic impairment, may require dosage adjustment when starting or stopping concomitantly administered diltiazem in order to maintain optimum therapeutic blood levels."
Three new interactions added -
"Benzodiazepines: Studies showed that diltiazem increased the AUC of midazolam and triazolam by 3-4 fold and the Cmax by 2-fold, compared to placebo. The elimination half life of midazolam and triazolam also increased (1.5-2.5 fold) during coadministration with diltiazem. These pharmacokinetic effects seen during diltiazem coadministration can result in increased clinical effects (e.g., prolonged sedation) of both midazolam and triazolam."
" Lovastatin: In a ten-subject study, coadministration of diltiazem (120 mg bid) with lovastatin resulted in a 3-4 times increase in mean lovastatin AUC and Cmax vs. lovastatin alone; no change in pravastatin AUC and Cmax was observed during diltiazem coadministration. Diltiazem plasma levels were not significantly affected by lovastatin or pravastin."
" Rifampin: Coadministration of rifampin with diltiazem lowered the diltiazem plasma concentrations to undetectable levels. Coadministration of diltiazem with rifampin or any known CYP3A4 inducer should be avoided when possible, and alternative therapy considered."
Geriatric Use: New subsection -
"Clinical studies of diltiazem did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."
"In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage."
"Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and Usage). As reported in the literature, the dosage selection and constant infusion rates of intravenous dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants.
Safety and effectiveness of Travasol sulfite-free (Amino Acid) with Electrolytes in Dextrose Injection in pediatric patients have not been established by adequate and well-controlled studies. However, the use of amino acid injections in pediatric patients as an adjunct in the offsetting of nitrogen loss or in the treatment of negative nitrogen balance is referenced in the medical literature. See Dosage and Administration."
"Use of Travasol sulfite-free (Amino Acid) with Electrolytes in Dextrose Injection in pediatric patients is governed by the same considerations that affect the use of any amino acid solution in pediatrics. The amount administered is dosed on the basis of grams of amino acids/kg of body weight/day. Two to 3 g/kg of body weight for infants with adequate calories are generally sufficient to satisfy protein needs and promote positive nitrogen balance. Solution administrations by peripheral vein should not exceed twice normal serum osmolarity (718 mOsmol/L)."
Peripheral Vein Administration: New second sentence -
"In pediatric patients, the final solution should not exceed twice normal serum osmolarity (718 mOsmol/L)."
"This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function."
"There are no adequate and well-controlled studies of Valtrex or Zovirax in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy ["has been ongoing since" deleted] was established in 1984 and completed in April 1999. There were 756 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable ["and" deleted] or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. Valtrex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."
Pregnancy Exposure Registry: Subsection deleted, the registry officially closed April 1999.
Hepatobiliary Tract and Pancreas: Liver enzyme abnormalities, hepatitis.
Skin: Erythema multiforme, rashes including photosensitivity.
"Vivactil is contraindicated in patients taking cisapride because of the possibility of adverse cardiac interactions including prolongation of the QT interval, cardiac arrhythmias and conduction system disturbances."
"Tricyclic antidepressants may enhance the seizure risk in patients taking Ultram (tramadol hydrochloride)."
Geriatric Use: Appears in 2000 PDR, not in 1999 PDR -
"Clinical studies of Vivactil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."
Replaced with -
"Store at 25oC (77oF), excursions permitted to 15-30oC (59-86oF) [see USP Controlled Room Temperature], Keep container tightly closed."
WELLBUTRIN 2000 PDR labeling changes
[The 1999 labeling contained extensive revisions. Contact the company for a copy of the new labeling/package insert.]
"Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity have been reported in association with bupropion. These symptoms may resemble serum sickness."
Use in Patients with Systemic Illness: heading deleted. New heading titles Cardiovascular Effects: (new text and reordered text under new heading) and Renal or Hepatic Impairment: (text reordered under new heading).
Cardiovascular Effects: (new text in italics) -
"In clinical practice, hypertension, in some cases severe, requiring acute treatment, has been reported in patients receiving bupropion alone and in combination with nicotine replacement therapy. These events have been observed in both patients with and without evidence of preexisting hypertension.
"Data from a comparative study of the sustained-release formulation of bupropion (Zyban Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this study, 6.1% of patients treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of patients treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these patients had evidence of preexisting hypertension. Three patients (1.2%) treated with a combination of Zyban and NTS and one patient (0.4%) treated with NTS had study medication discontinued due to hypertension compared to none of patients treated with Zyban or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.
"There is no clinical experience establishing the safety of Wellbutrin in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be exercised if it is used in these groups. Bupropion was well tolerated in depressed patients who had previously developed orthostatic hypotension while receiving tricyclic antidepressants and was also generally well tolerated in a group of 36 depressed inpatients with stable congestive heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in the study of patients with CHF, resulting in discontinuation of treatment in two patients for exacerbation of baseline hypertension."
Body (General): New subsection -
"arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness (see PRECAUTIONS)."
Cardiovascular: (new text in italics) - hypertension (in some cases severe, see PRECAUTIONS), orthostatic hypotension, third degree heart block"
WELLBUTRIN SR 2000 PDR labeling changes -
[The 1999 labeling contained extensive revisions. Contact the company for a copy of the new labeling/package insert.]
"These data suggest there is no prominent effect of age on bupropion concentration; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites (see PRECAUTIONS: Geriatric Use)""
Use in Patients with Systemic Illness: heading deleted. New heading titles Cardiovascular Effects: (new text and reordered text under new heading) and Renal or Hepatic Impairment: (text reordered under new heading).
Cardiovascular Effects: (new text in italics) -
"In clinical practice, hypertension, in some cases severe, requiring acute treatment, has been reported in patients receiving bupropion alone and in combination with nicotine replacement therapy. These events have been observed in both patients with and without evidence of preexisting hypertension.
"Data from a comparative study of the sustained-release formulation of bupropion (Zyban Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this study, 6.1% of patients treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of patients treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these patients had evidence of preexisting hypertension. Three patients (1.2%) treated with a combination of Zyban and NTS and one patient (0.4%) treated with NTS had study medication discontinued due to hypertension compared to none of patients treated with Zyban or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.
"There is no clinical experience establishing the safety of Wellbutrin in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be exercised if it is used in these groups. Bupropion was well tolerated in depressed patients who had previously developed orthostatic hypotension while receiving tricyclic antidepressants and was also generally well tolerated in a group of 36 depressed inpatients with stable congestive heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in the study of patients with CHF, resulting in discontinuation of treatment in two patients for exacerbation of baseline hypertension."
"Also observed were arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness (see PRECAUTIONS)."
Cardiovascular: Third sentence revised (new text in italics) -
Also observed were complete atrioventricular block, extrasystoles, hypotension, hypertension (in some cases severe, see PRECAUTIONS), myocardial infarction, phlebitis, and pulmonary embolism."
"Hyaluronidase should not be used to enhance the absorption and dispersion of dopamine and/or alpha agonist drugs."
"Patients receiving large doses of salicylates, cortisone, ACTH, estrogens, or antihistamines may require larger amounts of hyaluronidase for equivalent dispersing effect, since these drugs apparently render tissues partly resistant to the action of hyaluronidase."
PREGNANCY
Teratogenic Effects-Pregnancy Category C
Second sentence revised (new text in italics) -
It is also not known whether hyaluronidase can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity."
PEDIATRIC USE New second and third paragraphs -
During hypodermoclysis, special care must be taken in pediatric patients to avoid overhydration by controlling the rate and total volume of the clysis. (See "Dosage and Administration, HYPODERMOCLYSIS.")
As in adults, a preliminary test for sensitivity should be conducted prior to the use of this product in pediatric patients. Also, hyaluronidase should not be injected into acutely inflamed or cancerous areas or to enhance absorption of vasoconstricting agents. (See "Contraindications" and "Warnings".)"
"["The subcutaneous administration of hyaluronidase has been associated with very few adverse reactions." Deleted] Allergic reactions (urticaria, angioedema) are rare. Anaphylactic-like reactions following retrobulbar block or intravenous injections have occurred. ["in isolated cases" deleted] Cardiac fibrillation has been encountered once."
" For infants and children less than 3 years old, the volume of a single clysis should be limited to 200 mL; and in premature infants or during the neonatal period, the daily dosage should not exceed 25 mL/kg of body weight; the rate of administration should not be greater than 2 mL per minute." "
"Preliminary data from a Xenical and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when Xenical was coadministered with cyclosporine. Therefore, Xenical and cyclosporine should not be coadministered. To reduce the chance of a drug-drug interaction, cyclosporine should be taken at least 2 hours before or after Xenical in patients taking both drugs. In addition, in those patients whose cyclosporine levels are being measured, more frequent monitoring should be considered."
"Preliminary data from a Xenical and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when Xenical was coadministered with cyclosporine (see WARNINGS)."
"PATIENTS DEVELOPING SIGNS OR SYMPTOMS OF HYPERSENSITIVITY (WHICH INCLUDE FEVER; SKIN RASH; FATIGUE; GASTROINTESTINAL SYMPTOMS SUCH AS NAUSEA, VOMITING, DIARRHEA, OR ABDOMINAL PAIN; AND RESPIRATORY SYMPTOMS SUCH AS PHARYNGITIS, DYSPNEA, OR COUGH) SHOULD DISCONTINUE ZIAGEN AS SOON AS A HYPERSENSITIVITY REACTION IS SUSPECTED."
New last sentence added -
"(see WARNINGS, PRECAUTIONS: Information for Patients, and ADVERSE REACTIONS)."
"Patients developing signs or symptoms of hypersensitivity (which include fever; skin rash; fatigue; gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain; and respiratory symptoms such as pharyngitis, dyspnea, or cough) should discontinue Ziagen as soon as a hypersensitivity reaction is first suspected, and should seek medical evaluation immediately. The diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of acute onset respiratory diseases, even if alternative respiratory diagnoses (pneumonia, bronchitis, pharyngitis, or flu-like illness) are possible. Ziagen SHOULD NOT be restarted following a hypersensitivity reaction because more severe symptoms will recur within hours and may include life-threatening hypotension and death ( see PRECAUTIONS; Information for Patients and ADVERSE REACTIONS). "
"Patients developing signs or symptoms of hypersensitivity (which include fever; skin rash; fatigue; gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain; and respiratory symptoms such as sore throat, shortness of breath, or cough) should discontinue treatment with Ziagen and seek medical evaluation immediately."
"Other signs and symptoms include malaise, lethargy, myalgia, myolysis, arthralgia, edema, pharyngitis, cough, dyspnea, ["shortness of breath" deleted] headache, and paresthesia. Some patients who experienced a hypersensitivity reaction were initially thought to have acute onset or worsening respiratory disease. The diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of acute onset respiratory diseases, even if alternative respiratory diagnoses (pneumonia, bronchitis, pharyngitis, or flu-like illness) are possible. "
* "sore throat, shortness of breath, or cough"
[Other labeling changes not appearing in 2000 PDR: Aug99, Sep99, Nov99]
"The patient should be placed on a standard cholesterol-lowering diet before receiving Zocor and should continue on this diet during treatment with Zocor. The dosage should be individualized according to the baseline LDL-C level, the recommended goal of therapy (see NCEP Treatment Guidelines), ["for details on dietary therapy" deleted] and the patient's response. The dosage range is 5-80 mg/day (see below).
"The recommended usual starting dose is 20 mg once a day in the evening. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg/day in the evening. ["Patients who require only a moderate reduction of LDL-C may be started at 10 mg." deleted] Adjustments of dosage should be made at intervals of 4 weeks or more. See below for dosage recommendations for patients receiving concomitant therapy with cyclosporine, fibrates or niacin, and for those with severe renal insufficiency."
Third and fourth paragraph deleted -
"The recommended dosing range is 5-80 mg/day as a single dose in the evening. Doses should be individualized according to baseline LDL-C levels, the recommended goal of therapy (see NCEP Treatment Guidelines) and the patient's response. Adjustments of dosage should be made at intervals of four weeks or more.
Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of Zocor if cholesterol falls significantly below the targeted range."
Subsection "General Recommendations" deleted -
"In the elderly, maximum reductions in LDL-C may be achieved with daily doses of 20 mg of Zocor or less."
New subsection title "Dosage in Patients taking Cyclosporine" and text added (new text in italics) -
"In patients taking cyclosporine concomitantly with ["simvastatin" deleted] Zocor (see WARNINGS, Skeletal Muscle), therapy should begin with 5 mg/day ["of Zocor" deleted] and should not exceed 10 mg/day."
Concomitant Lipid-Lowering Therapy Third sentence revised (new text in italics) -
"However, if Zocor is used in combination with fibrates or niacin, the dose of Zocor should not exceed 10 mg/day (see WARNINGS, Skeletal Muscle)."
"In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of oral formulations of Zofran. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Zofran"
General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm, shortness of breath, hypotension, laryngeal edema, stridor) have also been reported. Laryngospasm, shock, and cardiopulmonary arrest have occurred during allergic reactions in patients receiving injectable ondansetron.
Hepatobiliary: Liver enzyme abnormalities
Lower Respiratory: Hiccups
Neurology: Oculogyric crisis, appearing alone, as well as with other dystonic reactions
Skin: Urticaria"
Observed During Clinical Practice: (Injection)
New adverse events added to several subsections and two new subsections added (new text in italics) -
General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm, cardiopulmonary arrest, hypotension, laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been reported.
Hepatobiliary: Liver enzyme abnormalities have been reported. Liver failure
and death have been reported in patients with cancer receiving concurrent medications including potentially hepatotoxic
cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear.
Lower Respiratory: Hiccups
Skin: Urticaria"
"There is no specific antidote for ondansteron overdose. Patients should be managed with appropriate supportive therapy. Individual doses as large as 150 mg ["145 mg" deleted] and total daily dosages (three doses) as large as 252 mg have been administered intravenously without significant adverse events. These doses are more than 10 times the recommended daily dose.
" In addition to the adverse events listed above, the following events have been described in the setting of ondansetron overdose: "Sudden blindness" (amaurosis) of 2 to 3 minutes' duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in another patient that took 48 mg of oral ondansetron. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second degree heart block was observed. In all instances, the events resolved completely."
ORAL Labeling (new text in italics) -
"There is no specific antidote for ondansteron overdose. Patients should be managed with appropriate supportive therapy. Individual intravenous doses as large as 150 mg ["145 mg" deleted] and total daily intravenous doses as large as 252 mg have been inadvertently administered without significant adverse events. These doses are more than 10 times the recommended daily dose.
" In addition to the adverse events listed above, the following events have been described in the setting of ondansetron overdose: "Sudden blindness" (amaurosis) of 2 to 3 minutes' duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in another patient that took 48 mg of Zofran tablets. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second degree heart block was observed. In all instances, the events resolved completely."
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