The detailed view includes drug products with safety labeling changes to the BOXED WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, or ADVERSE REACTIONS sections. Deletions or editorial revisions made to these sections are not included in this summary. The prescribing information may be accessed by clicking on the drug name.

Brand (Generic) Name

Summary of Changes to Contraindications and Warnings

Premarin Intravenous (conjugated estrogens, USP) for Injection

(click product name to read prescribing information)

BOXED WARNING

• Cardiovascular and Other Risks

WARNINGS

• Cardiovascular Disorders
  • Stroke
  • Coronary Heart Disease
  • Venous Thromboembolism (VTE)
• Malignant Neoplasms
  • Breast Cancer
• Dementia

PRECAUTIONS

• Geriatric Use

BOXED WARNING

The estrogen-alone substudy of the Women's Health Initiative (WHI) reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 6.8 years and 7.1 years, respectively, of treatment with oral conjugated estrogens (CE 0.625 mg) per day relative to placebo.

WARNINGS

Cardiovascular Disorders

Estrogen-alone therapy has been associated with an increased risk of stroke and DVT.....

Stroke

In the estrogen-alone substudy of the WHI study, a statistically significant increased risk of stroke was reported.....

In the estrogen-plus-progestin substudy of WHI, a statistically significant increased risk of stroke was reported in women receiving CE/MPA 0.625 mg/2.5 mg daily compared to women receiving placebo (31 vs. 24 per 10,000 women-years).....

Coronary Heart Disease

In the estrogen-alone substudy of WHI, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or death, due to CHD) was reported in women receiving estrogen alone compared to placebo.

In the estrogen-plus-progestin substudy of WHI, no statistically significant increase of CHD events was reported in women receiving CE/MPA compared to women receiving placebo.....

Venous Thromboembolism (VTE)

In the estrogen-alone substudy of WHI, the risk of VTE (DVT and pulmonary embolism [PE]), was reported to be increased for women taking conjugated estrogens (30 vs. 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first two years.....

In the estrogen-plus-progestin substudy of WHI, a statistically significant 2-fold greater rate of VTE was reported in women receiving CE/MPA compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated.....

Malignant Neoplasms

Breast Cancer

In the estrogen-alone substudy of WHI, after an average of 7.1 years of follow-up, CE (0.625 mg daily) was not associated with an increased risk of invasive breast cancer (RR 0.80, 95% nCI 0.62-1.04)......

Dementia

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI 1.19-2.60).....

Premarin (conjugated estrogens tablets, USP)

(click product name to read prescribing information)

BOXED WARNING

• Cardiovascular and Other Risks

WARNINGS

• Cardiovascular Disorders
  • Coronary Heart Disease
  • Venous Thromboembolism (VTE)
• Malignant Neoplasms
  • Breast Cancer

PATIENT PACKAGE INSERT

BOXED WARNING

The estrogen-alone substudy of the Women's Health Initiative (WHI) reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 6.8 years and 7.1 years, respectively, of treatment with oral conjugated estrogens (CE 0.625 mg) per day relative to placebo.

WARNINGS

Cardiovascular Disorders

Estrogen-alone therapy has been associated with an increased risk of stroke and DVT.....

Coronary Heart Disease

In the estrogen-alone substudy of WHI, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or death, due to CHD) was reported in women receiving estrogen alone compared to placebo.

Venous Thromboembolism (VTE)

In the estrogen-alone substudy of WHI, the risk of VTE (DVT and pulmonary embolism [PE]), was reported to be increased for women taking conjugated estrogens (30 vs. 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first two years.

Malignant Neoplasms

Breast Cancer

.....In the estrogen-alone substudy of WHI, after an average of 7.1 years of follow-up, CE (0.625 mg daily) was not associated with an increased risk of invasive breast cancer (RR 0.80, 95% nCI 0.62-1.04).

The use of estrogen alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.

Premarin (conjugated estrogens) Vaginal Cream

(click product name to read prescribing information)

BOXED WARNING

• Cardiovascular and Other Risks

WARNINGS

• Cardiovascular Disorders
  • Stroke
  • Coronary Heart Disease
  • Venous Thromboembolism (VTE)
• Malignant Neoplasms
  • Breast Cancer
• Dementia

PRECAUTIONS

• Geriatric Use

PATIENT PACKAGE INSERT

BOXED WARNING

The estrogen-alone substudy of the Women's Health Initiative (WHI) reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 6.8 years and 7.1 years, respectively, of treatment with oral conjugated estrogens (CE 0.625 mg) per day relative to placebo.

WARNINGS

Cardiovascular Disorders

Estrogen-alone therapy has been associated with an increased risk of stroke and DVT.....

Stroke

In the estrogen-alone substudy of the WHI study, a statistically significant increased risk of stroke was reported....

In the estrogen-plus-progestin substudy of WHI, a statistically significant increased risk of stroke was reported in women receiving CE/MPA 0.625 mg/2.5 mg daily compared to women receiving placebo (31 vs. 24 per 10,000 women-years).....

Coronary Heart Disease

In the estrogen-alone substudy of WHI, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or death, due to CHD) was reported in women receiving estrogen alone compared to placebo.

In the estrogen-plus-progestin substudy of WHI, no statistically significant increase of CHD events was reported in women receiving CE/MPA compared to women receiving placebo (39 vs. 33 per 10,000 women-years). An increase in relative risk was demonstrated in year one, and a trend toward decreasing relative risk was reported in years 2 through 5.

Venous Thromboembolism (VTE)

In the estrogen-alone substudy of WHI, the risk of VTE (DVT and pulmonary embolism [PE]), was reported to be increased for women taking conjugated estrogens (30 vs. 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first two years.

In the estrogen-plus-progestin substudy of WHI, a statistically significant 2-fold greater rate of VTE was reported in women receiving CE/MPA compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women years) were also demonstrated.....

Malignant Neoplasms

Breast Cancer

.....In the estrogen-alone substudy of WHI, after an average of 7.1 years of follow-up, CE (0.625 mg daily) was not associated with an increased risk of invasive breast cancer (RR 0.80, 95% nCI 0.62-1.04).

The use of estrogen alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.

Dementia

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI 1.19-2.60).....

Prempro (conjugated estrogens/medroxyprogesterone acetate tablets)

Premphase (conjugated estrogens/medroxyprogesterone tablets)

Please contact Wyeth Pharmaceuticals Inc. at 1-800-395-9938 for prescribing information.

• Cardiovascular and Other Risks

WARNINGS

• Cardiovascular Disorders
  • Stroke
  • Coronary Heart Disease
  • Venous Thromboembolism (VTE)
• Malignant Neoplasms
  • Breast Cancer
• Dementia

PRECAUTIONS

• Geriatric Use

PATIENT PACKAGE INSERT

This supplemental NDA includes labeling revisions based on final adjudicated data for 7.1 years of treatment from the Women's Health Initiative (WHI) estrogen-alone substudy on coronary heart disease (CHD), deep vein thrombosis (DVT), stroke, and breast cancer.

Brand (Generic) Name

Summary of Changes to Contraindications and Warnings

Camptosar (irinotecan hydrochloride injection) for Intravenous Use Only

(click product name to read prescribing information)

PRECAUTIONS

• General
  • Patients at Particular Risk
    • Irinotecan commonly causes neutropenia, leucopenia, and anemia, any of which may be severe and therefore should not be used in patients with severe bone marrow failure. Patients must not be treated with irinotecan until resolution of the bowel obstruction. Patients with hereditary fructose intolerance should not be given Camptosar, as this product contains sorbitol.
  • Information for Patients
    • Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus.
    • Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of Camptosar.....

ADVERSE REACTIONS

• Overview of Adverse Events
  • Respiratory
    • Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy.....
• Post-marketing Experience

Camptosar Injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients.

Oncaspar (pegaspargase) Intravenous or Intramuscular Injection

(click product name to read prescribing information)

Read about new prescription drug label format.

WARNINGS AND PRECAUTIONS

• Thrombosis

ADVERSE REACTIONS

• Clinical Trials Experience
  • First-Line ALL
• Clinical Allergic Reactions
  • First-Line ALL

PATIENT COUNSELING INFORMATION

CONTRAINDICATIONS

History of serious thrombosis with prior L-asparaginase therapy.

WARNINGS AND PRECAUTIONS

Serious thrombotic events, including sagittal sinus thrombosis can occur in patients receiving Oncaspar. Discontinue Oncaspar in patients with serious thrombotic event.

Symbyax (olanzapine and fluoxetine HCl capsules)

(click product name to read prescribing information)

• Pimozide

PRECAUTIONS

• Drug Interactions
  • Pimozide
• Pediatric Use
  • Fluoxetine

ADVERSE REACTIONS

• Other Events Observed with Olanzapine or Fluoxetine Monotherapy
  • Erythema Multiforme

Zanaflex (tizanidine hydrochloride) Capsules and Tablets

(click product name to read prescribing information)

WARNINGS

• Hypotension
• Use in Patients with Hepatic Impairment
• Potential Interaction with Fluvoxamine or Ciprofloxacin

PRECAUTIONS

• Information for Patients
  • Because of the potential for the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation.....
• Drug Interactions
  • Fluvoxamine
  • Ciproflaxacin
  • CYP1A2 Inhibitors

See prescribing information for new text.

Brand (Generic) Name

Summary of Changes to Contraindications and Warnings

Adderall (mixed salts of a single-entity amphetamine product) Tablets

(click product name to read prescribing information)

• Serious Cardiovascular Events
  • Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems
    • Children and Adolescents
    • Adults
  • Hypertension and other Cardiovascular Conditions
  • Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications
• Psychiatric Adverse Events
  • Pre-Existing Psychosis
  • Bipolar Illness
  • Emergence of New Psychotic or Manic Symptoms
  • Aggression
• Long-Term Suppression of Growth
• Seizures
• Visual Disturbances

PRECAUTIONS

• General
• Drug Interactions
  • Alkalinizing Agents
    • Co-administration of Adderall and gastrointestinal alkalizing agents, such as antacids....
• Carcinogenesis/Mutagenesis and Impairment of Fertility
• Pregnancy - Teratogenic Effects: Pregnancy Category C
• Using in Nursing Mothers

ADVERSE REACTIONS

• Allergic
  • .....rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens Johnson Syndrome.....

See prescribing information for new WARNINGS information.

Adderall XR (mixed salts of a single entity amphetamine product) Extended-Release Capsules

(click product name to read prescribing information)

• Serious Cardiovascular Events
  • Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems
    • Children and Adolescents
    • Adults
  • Hypertension and other Cardiovascular Conditions
  • Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications
• Psychiatric Adverse Events
  • Pre-Existing Psychosis
  • Bipolar Illness
  • Emergence of New Psychotic or Manic Symptoms
  • Aggression
• Long-Term Suppression of Growth
• Seizures
• Visual Disturbances

PRECAUTIONS

• General
• Drug Interactions
  • Alkalinizing Agents
    • Co-administration of Adderall XR and gastrointestinal alkalizing agents, such as antacids....
• Carcinogenesis/Mutagenesis and Impairment of Fertility
• Pregnancy - Teratogenic Effects: Pregnancy Category C
• Using in Nursing Mothers

ADVERSE REACTIONS

• Allergic
  • .....rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens Johnson Syndrome.....

Alimta (pemetrexed for injection)

(click product name to read prescribing information)

• Bone Marrow Suppression

ADVERSE REACTIONS

• Post-marketing Experience
  • The following adverse events have been identified during post-approval use of Alimta. These events have occurred with Alimta when used as a single-agent and in combination therapies.....
  • Gastrointestinal
    • Rare cases of colitis.....

Biaxin Filmtab (clarithromycin tablets, USP)

Biaxin XL Filmtab (clarithromycin extended-release tablets)

Biaxin Granules (clarithromycin for oral suspension, USP)

Please contact Abbott Laboratories at 1-800-633-9110 for prescribing information.

PRECAUTIONS

• Drug Interactions
  • Colchicine
• Geriatric Use

ADVERSE REACTIONS

• Post-marketing Experience

WARNINGS

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients.

PRECAUTIONS/Drug Interactions

Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity.

PRECAUTIONS/Geriatric Use

In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500 mg every 12 hours, the maximum serum concentrations and area under the curves of clarithromycin and 14-OH clarithromycin were increased compared to those achieved in healthy young adults. These changes in pharmacokinetics parallel known age-related decreases in renal function. In clinical trials, elderly patients did not have an increased incidence of adverse events when compared to younger patients. Dosage adjustment should be considered in elderly patients with severe renal impairment.

ADVERSE REACTIONS

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients.

Celestone Soluspan (betamethasone sodium phosphate and betamethasone acetate injectable suspension, USP)

(click product name to read prescribing information)

• General
• Infections
  • Special Pathogens
    • Strongyloides (threadworm) Infestation

PRECAUTIONS

• Endocrine
  • .....Therefore, in any situation of stress occurring during that period, naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, rather than betamethasone, are the appropriate choices as replacement therapy in adrenocortical deficiency states.

In patients on corticosteroid therapy subjected to any unusual stress hydrocortisone or cortisone is the drug of choice as a supplement during and after the event.

Infections/Special Pathogens

Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Celestone (betamethasone syrup, USP)

(click product name to read prescribing information)

• General
• Infection
  • Special Pathogens
    • Strongyloides (threadworm) Infestation

PRECAUTIONS

• Endocrine
  • .....Therefore, in any situation of stress occurring during that period, naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, rather than betamethasone, are the appropriate choices as replacement therapy in adrenocortical deficiency states.

In patients on corticosteroid therapy subjected to any unusual stress hydrocortisone or cortisone is the drug of choice as a supplement during and after the event.

Infection/Special Pathogens

Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

(click product name to read prescribing information)

• Serious Cardiovascular Events
  • Sudden Death and Pre-existing Cardiac Abnormalities or Other Serious Heart Problems
    • Children and Adolescents
    • Adults
  • Hypertension and Other Cardiovascular Conditions
  • Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications
• Psychiatric Adverse Events
  • Pre-existing Psychosis
  • Bipolar Illness
  • Emergence of New Psychotic or Manic Symptoms
  • Aggression
• Long-term Suppression of Growth
• Seizures
• Visual Disturbance

INFORMATION FOR PARENTS OR CAREGIVERS Using Daytrana (methylphenidate transdermal system) on a Child for the Treatment of Attention Deficit Disorder (ADHD)

See prescribing information for new WARNINGS information.

(click product name to read prescribing information)

• Use with Interferon- and Ribavirin-Based Regimens

PRECAUTIONS

• Immune Reconstitution Syndrome

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was coadministered with zidovudine in HIV/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and Retrovir should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of Retrovir should be considered as medically appropriate.

Famvir (famciclovir) Tablets

(click product name to read prescribing information)

• Carcinogenesis, Mutagenesis, Impairment of Fertility

• Pregnancy: Teratogenic Effects

• Geriatric Use

ADVERSE REACTIONS

• Immunocompetent Patients

  • Table 5: Selected Adverse Events (all grades and without regard to causality) Reported by ≥2% of Patients.....

Oxytrol (oxybutynin transdermal system)

(click product name to read prescribing information)

• Information for Patients
  • Dizziness

ADVERSE REACTIONS

• Post-marketing Surveillance

  • Dizziness

PATIENT PACKAGE INSERT

Propranolol Hydrochloride Injection, USP

(click product name to read prescribing information)

• Drug Interactions
  • Non-Cardiovascular Drugs
    • Warfarin
• Carcinogenesis, Mutagenesis, Impairment of Fertility
• Pregnancy: Pregnancy Category C
• Nursing Mothers
• Geriatric Use
• Hepatic Insufficiency

ADVERSE REACTIONS

• Initial Section

Protonix (pantoprazole sodium) Delayed-Release Tablets

(click product name to read prescribing information)

• General
  • Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term pantoprazole, particularly in patients who were H. pylori positive.

(click product name to read prescribing information)

• General
  • .....In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance......
• Drug Interactions
  • Effects of Revatio on Other Drugs
    • In Vivo Studies
      • Bosentan

Risperdal Consta (risperidone) Long-Acting Injection

(click product name to read prescribing information)

• Pregnancy
  • .....Reversible extrapyramidal symptoms in the neonate were observed following postmarketing use of risperidone during the last trimester of pregnancy.

ADVERSE REACTIONS

• Postintroduction Reports

  • Benign Pituitary Adenomas

Triglide (fenofibrate) Tablets

(click product name to read prescribing information)

Tygacil (tigecycline) for Injection

(click product name to read prescribing information)

• General

Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has lead to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with other tetracyclines, pancreatitis has been reported with the use of Tygacil.

ADVERSE REACTIONS

• Post-marketing Experience
  • Acute Pancreatitis

(click product name to read prescribing information)

• Pregnancy: Teratogenic Effects: Pregnancy Category C

Change in Pregnancy category from Pregnancy Category B to Pregnancy Category C.

Wellbutrin SR (bupropion hydrochloride) Sustained-Release Tablets

(click product name to read prescribing information)

• Pregnancy: Teratogenic Effects: Pregnancy Category C

Change in Pregnancy category from Pregnancy Category B to Pregnancy Category C.

(click product name to read prescribing information)

• Pediatric Use

ADVERSE REACTIONS

• Adverse Events From Clinical Trials
  • Pediatrics
• Post-marketing Experience
  • Post-marketing experience with Zosyn in pediatric patients suggests a similar safety profile to that seen in adults.

(click product name to read prescribing information)

PRECAUTIONS

• Pediatric Use

ADVERSE REACTIONS

• Adverse Events From Clinical Trials
  • Pediatrics
• Post-marketing Experience
  • Post-marketing experience with Zosyn in pediatric patients suggests a similar safety profile to that seen in adults.

Elspar (asparaginase)

(click product name to read prescribing information)

• Pancreatitis
• Coagulopathy
• Central Nervous System Toxicity
  • Seizures

Gemzar (gemcitabine HCl) for Injection

(click product name to read prescribing information)

• Combination Use in Ovarian Cancer
  • Table 12: Adverse Events from Comparative Trial of Gemzar Plus Carboplatin Versus Single-Agent Carboplatin in Ovarian Cancer

Tagamet  (cimetidine) Tablets

Please contact GlaxoSmith Kline at 1-888-825-5249 for prescribing information.

• Respiratory

A large epidemiological study suggested an increased risk of developing pneumonia in current users of histamine-2-receptor antagonists (H₂RAs) compared to patients who had stopped H₂RA treatment, with an observed adjusted relative risk of 1.63 (95% CI, 1.07-2.48). However, a causal relationship between use of H₂RAs and pneumonia has not been established.

Vytorin (ezetimibe/simvastatin) Tablets

(click product name to read prescribing information)

• Post-marketing Experience
  • Ezetimibe
    • Hypersensitivity Reactions
      • Urticaria
      • Arthralgia

PATIENT PACKAGE INSERT

WelChol (colesevelam hydrochloride) Tablets

(click product name to read prescribing information)

• Post-marketing Experience
  • There have been rare reports of elevated thyroid stimulating hormone (TSH) levels in patients who have received WelChol co-administered with thyroid hormone replacement therapy.

Zantac (ranitidine hydrochloride) Injection

Zantac (ranitidine hydrochloride) Injection Premixed

(click product name to read prescribing information)

• Respiratory

Zantac (ranitidine hydrochloride)  Tablets and Syrup

Zantac (ranitidine hydrochloride) EFFERdose Tablets

(click product name to read prescribing information)

• Respiratory

Center for Drug Evaluation and Research/Office of the Center Director/Safety Policy and Communication Staff
Web page last revised by jlw August 31, 2006