Drug Warnings

FDA - Ongoing safety review of Invirase (saquinavir) and possible association with abnormal heart rhythms
(2.23.09)

The Food and Drug Administration (FDA) is reviewing clinical trial data about a potentially serious effect on the heart from the use of Invirase (saquinavir) in combination with Norvir (ritonavir). The data suggest that together the two drugs may affect the electrical activity of the heart.

The changes to the electrical activity of the heart possibly associated with these drugs, known as prolonged QT or PR intervals, can be seen on an electrocardiogram (EKG). A prolonged QT interval can increase the risk for abnormal heart rhythms, including a serious abnormal rhythm called torsades de pointes. A prolonged PR interval can cause the electrical signal responsible for generating a heart beat to slow or even stop; this is known as heart block and can affect how fast the heart is able to beat.

Invirase and Norvir are antiviral medications given together to treat HIV infection. Norvir is given at a low dose with Invirase in order to increase the level of Invirase in the body. This is a process known as "boosting."

FDA's analysis of these data is ongoing. However, healthcare professionals should be aware of this potential risk for changes to the electrical activity of the heart. Invirase and Norvir should not be used in patients already taking medications known to cause QT interval prolongation such as Class IA (such as quinidine,) or Class III (such as amiodarone) antiarrhythmic drugs; or in patients with a history of QT interval prolongation.

Patients should not stop taking their prescribed antiviral medications. Patients who are concerned about possible risks associated with using Invirase and Norvir should talk to their healthcare professional.

This communication is in keeping with FDA's commitment to inform the public about its ongoing safety review of drugs. The agency will update the public as soon as this review is complete.

Additional Information for Patients

Patients currently using Invirase should:

• Not stop taking Invirase without talking with their healthcare professional.
• Discuss any questions or concerns they have about Invirase with their healthcare professional.
• Review their cardiovascular medical history and current medications with their healthcare professional to determine if they should continue using Invirase.
• Report any side effects with Invirase to FDA's MedWatch program using the information at the bottom of the page.

Additional Information for Healthcare Professionals

FDA recommends that healthcare professionals:

• Not use Invirase in patients with a history of QT interval prolongation, preexisting conduction system disease, ischemic heart disease, cardiomyopathy, or underlying structural heart disease.
• Not use Invirase in patients who are currently using Class IA (such as quinidine) or Class III (such as amiodarone) antiarrhythmic drugs or other drugs that may prolong the QT or PR interval.
• Report any adverse events associated with the use of Invirase to FDA's MedWatch program at 1-800-332-1088, or MedWatch Online.

Data Summary

The study data were submitted by Roche, the manufacturer of Invirase, based on FDA's request that all manufacturers of protease inhibitors, including Invirase, conduct a thorough QT study to evaluate the effect these drugs have on the QT and PR intervals.

The preliminary data show that when Invirase boosted with Norvir (1000mg/100mg) was given to healthy patients, ages 18 to 55 years, there was a dose-dependent prolongation of the QT and PR intervals. The magnitude of the effect and clinical implications of QT and PR interval prolongation are still being reviewed by FDA.

These findings suggest that some patients using Invirase boosted with Norvir may be at an increased risk for developing abnormal heart rhythms. In particular, this risk may be increased in patients using other medications known to cause QT interval prolongation such as Class IA and Class III antiarrhythmic drugs or in patients with a history of QT interval prolongation.

FDA Advises Serious Liver Disorder Associated with the Use of Videx/Videx EC (Didanosine)
AIDSinfo At-A-Glance Volume 6 Issue 4 (1.29.10)
"The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals and patients about a rare, but serious, complication in the liver known as non-cirrhotic portal hypertension in patients using Videx or Videx EC (didanosine). Didanosine is a medication used to treat human immunodeficiency virus (HIV) infection. Videx was the first approved didanosine medication. Videx EC is a delayed-release version of Videx.
"Non-cirrhotic portal hypertension (portal hypertension that is not caused by cirrhosis of the liver) is rare in the United States. It occurs when blood flow in the major vein in the liver (the portal vein) slows down. This slowed blood flow can lead to the development of severely enlarged esophageal veins (varices) in the gastrointestinal system. Because esophageal varices are thin and portal hypertension increases the pressure of blood flow in these veins, esophageal varices can break open. This can result in serious bleeding and, in some cases, death.
"FDA became aware of cases of non-cirrhotic portal hypertension through adverse event reports submitted to FDA's Adverse Event Reporting System (AERS). Based on these reports, FDA has revised the didanosine drug label to include information about non-cirrhotic portal hypertension to help ensure the safe use of this drug.
"FDA believes the clinical benefits of didanosine for certain patients with HIV continue to outweigh its potential risks. The decision to use this drug, however, must be made on an individual basis between the treating physician and the patient."

Additional safety information regarding Videx/Videx EC (didanosine) can be found in the FDA press release.
 

FDA Warning New Intelence labeling: severe skin and hypersensitivity reactions
(8.28.09)

Tibotec Therapeutics, in cooperation with the U.S. Food and Drug Administration, would like to inform you of an important safety update to the Severe Skin Reactions WARNINGS AND PRECAUTIONS section (5.1) of the INTELENCE (etravirine) tablets prescribing information.
Specifically, the existing Warning and Precaution regarding Severe Skin Reactions has been strengthened to reflect that there have been postmarketing reports of:
• fatality due to toxic epidermal necrolysis
• hypersensitivity reactions, sometimes accompanied by hepatic failure
Additionally, Guidance has been added that INTELENCE should be immediately discontinued when signs and symptoms of severe skin or hypersensitivity reactions develop. Given the clinical relevance of these adverse reactions, the following information regarding severe skin and hypersensitivity reactions has been included in the INTELENCE Prescribing Information:
5 WARNINGS AND PRECAUTIONS

5.1 Severe Skin and Hypersensitivity Reactions

Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. In Phase 3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving INTELENCE™ compared to 0.2% of placebo subjects. A total of 2% of HIV-1-infected subjects receiving INTELENCE™ discontinued from Phase 3 trials due to rash [see Adverse Reactions (6)]. Rash occurred most commonly during the first 6 weeks of therapy.
Discontinue INTELENCE™ immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping INTELENCE™ treatment after the onset of severe rash may result in a life-threatening reaction.
In addition, the following sections of the INTELENCE Prescribing Information have been updated to include this new information: Highlights of Prescribing Information, Adverse Reactions and Patient Counseling. Furthermore the “What are the possible side effects of INTELENCE?” section of the patient Package Insert has also been updated.
 

FDA Warning Testoterone Gel Product Risk Exposure to Children
(5.18.09)

The Food and Drug Administration is requiring manufacturers of two prescription topical testosterone gel products, AndroGel 1% and Testim 1%, to include a boxed warning on the products’ labels after receiving reports of adverse effects in children who were inadvertently exposed to testosterone through contact with a person being treated with these products (secondary exposure).
The gels are approved for use in men who either no longer produce testosterone or produce it in very low amounts, and are often used by men living with HIV who have below normal testosterone levels.
Although the Precautions in the current labels instruct users to wash their hands after using the product and to cover the treated skin with clothing, FDA has received reports of secondary exposure to testosterone in children ranging in age from nine months to five years. In most of the cases, users of these products failed to follow appropriate use instructions, resulting in direct contact between treated skin and the child.

The FDA recommends the following precautions be taken to minimize the potential for secondary exposure:

• Adults who use testosterone gels should wash their hands with soap and warm water after every application;
• Adults should cover the application site with clothing once the gel has dried;
• Adults should wash the application site thoroughly with soap and warm water prior to any situation where skin-to-skin contact with another person is anticipated;
• Children and women should avoid contact with testosterone application sites on the skin of men who use these products; and
• Adults should note that use of any similar, but unapproved, products from the marketplace –including the Internet– that can result in the same serious adverse effects should be avoided.

Health care professionals and consumers may report serious adverse events (side effects) or product quality problems with the use of these gels to the FDA's MedWatch Adverse Event Reporting program:

• Online: www.fda.gov/MedWatch/report.htm
• Fax: (800) FDA-0178
• Phone: (800) FDA-1088

FDA: Atazanavir Label Updated
"The Reyataz (atazanavir) package insert has been updated to include important drug-drug interaction information regarding the administration of Reyataz with or without ritonavir and nevirapine, efavirenz, hormonal contraceptives, orally and parenterally administered midazolam, H₂-receptor antagonists and drugs that are substrates of cytochrome P450 2C8." For more information, read the FDA press release and the AIDSinfo atazanavir drug fact sheet.

Important safety-related label update for Ziagen (abacavir sulfate)
On July 18, 2008, FDA approved changes to the package insert for Ziagen (abacavir sulfate) highlighting information about the association of the HLA-B*5701 allele (a part of a gene) and hypersensitivity reactions (HSR) caused by abacavir-containing therapy.
Abacavir is associated with serious and sometimes fatal HSR. Abacavir HSR is a multi-organ syndrome characterized by 2 or more clinical signs or symptoms including fever, rash, gastrointestinal symptoms (nausea, vomiting, diarrhea or abdominal pain), respiratory symptoms (dyspnea, cough or pharyngitis) and constitutional symptoms (generalized malaise, fatigue or myalgia). Occurrence of abacavir HSR requires immediate and permanent discontinuation of abacavir therapy.
The product label for abacavir has been updated to include the following new information:

WARNING: Risk of hypersensitivity Reactions, Lactic Acidosis
    
    Patients who carry the HLA‑B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA‑B*5701 allele is recommended; this approach has been found to decrease the risk of hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA‑B*5701 status who have previously tolerated abacavir. HLA‑B*5701‑negative patients may develop a suspected hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA‑B*5701‑positive patients.
    Regardless of HLA‑B*5701 status, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible.

The following new information has been added to the Medication Guide:

Under What is the most important information I should know about ZIAGEN?
Serious Allergic Reaction to Abacavir. ZIAGEN contains abacavir (also contained in EPZICOM® and TRIZIVIR®). Patients taking ZIAGEN may have a serious allergic reaction (hypersensitivity reaction) that can cause death. Your risk of this allergic reaction is much higher if you have a gene variation called HLA B*5701 than if you do not. Your doctor can determine with a blood test if you have this gene variation. If you get a symptom from 2 or more of the following groups while taking ZIAGEN, call your doctor right away to determine if you should stop taking this medicine.

Under Who should not take ZIAGEN?
Before starting ZIAGEN, tell your doctor about all of your medical conditions, including if you:
have been tested and know whether or not you have a particular gene variation called HLA B*5701.

FDA Notice on Invirase Drug Interactions
6/11/08
Roche Laboratories, Inc. has updated their package insert for their protease inhibitor, Invirase (saquinavir) to include the following drug interaction information and include new warnings regarding coadministration of Invirase/ritonavir and digoxin (used in the treatment of various cardiac conditions).

Updated drug interaction information has been added on five products in the product package insert revision:

1. Digoxin (see Warnings; see also Clinical Pharmacology Table 2, Precautions, Drug Interactions, Table 6) A new Warning has been added. Caution should be exercised when Invirase and digoxin are coadministered. Coadministration results in a significant increase in serum concentration of digoxin; therefore, the serum concentration of digoxin should be monitored and the dose of digoxin may need to be reduced.

2. Garlic capsules (see Warnings; see also Precautions, Drug Interactions) No data are available for the coadministration of Invirase/ritonavir with garlic capsules. A Warning has been added that the coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir, which may result in subtherapeutic saquinavir concentrations.

3. Methadone (see Precautions, Drug Interactions; see also Clinical pharmacology, Table 2) Methadone levels are decreased and the dosage of methadone may need to be increased when coadministered with Invirase/ritonavir.

4. Tipranavir/ritonavir (see Precautions, Drug Interactions) Combining saquinavir with tipranavir/ritonavir is not recommended due to a decrease in saquinavir levels with coadministration.

5. Omeprazole (see Precautions, Drug Interactions) When Invirase/ritonavir is coadministered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with Invirase/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis.
 

FDA To Review Safety of GSK, BMS Antiretrovirals Abacavir, Didanosine
http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=51205

FDA HIV/AIDS Update - Updates to Prezista (darunavir) tablets labeling
(3/11/08)

Updates have been made to Prezista (darunavir) tablets labeling to reflect significant new risk information. Changes have been made to the CLINICAL PHARMACOLOGY section to include data from 6 pharmacokinetic, drug interaction Phase 1 trials, and to the WARNINGS, PRECAUTIONS AND ADVERSE REACTIONS sections of the package insert to include hepatotoxicity information. Other updates include those made to PRECAUTIONS, updates to DOSAGE AND ADMINISTRATION, and changes to Table 11 to include information regarding a potential drug-drug interaction with rosuvastatin.

In the WARNINGS section, the following has been added:

"Hepatotoxicity
Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/rtv. During the clinical development program (N=3063), hepatitis has been reported in 0.5% of patients receiving combination therapy with PREZISTA/rtv. Patients with preexisting liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.

Post-marketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with PREZISTA/rtv therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/rtv and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of PREZISTA/rtv treatment.

If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA/rtv, interruption or discontinuation of treatment must be considered."

The PRECAUTIONS section has been changed to read as follows:

"Patients with co-existing conditions
Hepatic Impairment: No dose adjustment of PREZISTA/rtv is necessary for patients with either mild or moderate hepatic impairment. There are no pharmacokinetic or safety data available for subjects with severe hepatic impairment, therefore, PREZISTA/rtv is not recommended for use in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults, Special Populations, Hepatic Impairment and DOSAGE AND ADMINISTRATION)."

Table 11, Established and Other Potentially Significant Drug Interactions, has been modified, under HMG-CoA Reductase Inhibitors, to include rosuvastatin, indicating increased concentration of rosuvastatin, with the following clinical comment: "Use the lowest possible dose of atorvastatin, pravastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with PREZISTA/rtv."

The following sentence has been added to the CLINICAL PHARMACOLOGY section, under Absorption and Bioavailabilty: "In vivo data suggests that darunavir/ritonavir is an inhibitor of the p-glycoprotein (p-gp) transporters."

The following has been added under: Special Populations
"Hepatic Impairment: Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of PREZISTA/rtv 600/100 mg b.i.d. to subjects with normal hepatic function (n=16), mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated (see PRECAUTIONS, Patients with co-existing conditions, Hepatic Impairment and DOSAGE AND ADMINISTRATION)."

In addition, there are updates to Table 4: Drug Interactions Pharmacokinetic Parameters for Darunavir in the Presence of Co-administered Drugs, and Table 5: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Darunavir/Ritonavir.

The last paragraph of the ADVERSE REACTIONS section now reads: "Patients co-infected with hepatitis B and/or hepatitis C virus: In subjects co-infected with hepatitis B or C virus receiving PREZISTA/rtv, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving PREZISTA/rtv who were not co-infected, except for increased hepatic enzymes (see WARNINGS, Hepatotoxicity). The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection."

In addition, the following has been added:

"Additional adverse reactions identified in clinical studies, occurring in less than 1% of the patients, are listed below by body system:

Hepatobiliary System: acute hepatitis, cytolytic hepatitis, hepatotoxicity, hyperbilirubinemia

Skin and Appendages: erythema multiforme, Stevens-Johnson Syndrome
[this duplicate information was deleted from the Skin and Appendages section under the treatment-emergent adverse events occurring in less than 2% of de novo subjects]"

Changes were also made to DOSAGE AND ADMINISTRATION, to include the following: "Hepatic Impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment. There are no data regarding the use of PREZISTA/rtv when co-administered to subjects with severe hepatic impairment; therefore, PREZISTA/rtv is not recommended for use in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults, Special Populations, Hepatic Impairment and PRECAUTIONS, Patients with co-existing conditions, Hepatic Impairment)."

FDA, Pfizer Warn of Possible Carcinogen in Antiretroviral Treatment Viracept
http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=47404

FDA Issues Warning for BMS Hepatitis B Drug Entecavir
http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=46965

Abbott, FDA Warn About Possible Overdose of Antiretroviral Kaletra in Children
http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=46879
 

July 22, 2007 Celsentri (Maraviroc) Interaction Warning
Based on a recent drug interaction study, Pfizer is warning that the dose of Celsentri (maraviroc) needs to be altered if the drug is combined with Tibotec’s etravirine and/or Prezista. POZ Update

BARCLUDE may increase the chance of HIV resistance to HIV medication
FDA-HIV-AIDS Digest - 18 Jul 2007 to 25 Jul 2007 (#2007-22)

FDA approved revised labeling on July 24, 2007 for BARACLUDE (entecavir) 0.5 mg and 1.0 mg Film-Coated Tablets, and BARACLUDE (entecavir) 0.05 mg/mL Oral Solution for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. The amended label includes safety information related to the use of entecavir (ETV) in patients with human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfection who are not receiving simultaneous highly active antiretroviral therapy (HAART).  Specifically, a recommendation against the use of BARACLUDE in HIV/HBV co-infected patients who are not also receiving adequate therapy for their HIV were added to the Boxed Warnings and the WARNINGS sections of the label. Corresponding changes were made to PRECAUTIONS: Information for Patients section, and in the Patient Information (also referred to as the Patient Package Insert).

Added to the Boxed Warning: Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if BARACLUDE is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated. Therapy with BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART). See WARNINGS: Co-infection with HIV.

Added to WARNINGS section/ Co-infection with HIV: BARCLUDE has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment. Limited clinical experience suggests there is a potential for the development to resistance HIV nucleoside reverse transcriptase inhibitors if BARCLUDE is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated. (see MICROBIOLOGY: Antiviral Activity, Antiviral Activity against HIV). Therefore, therapy with BARCLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART). Before initiating BARCLUDE therapy, HIV antibody testing should be offered to all patients. BARACLUDE has not been studied as a treatment for HIV infection and is not recommended for this use.

Added to PRECAUTIONS/Information for Patients: Patients should be offered HIV antibody testing before starting BARCLUDE therapy. They should be informed that if they have HIV infection and are not receiving effective HIV treatment, BARCLUDE may increase the chance of HIV resistance to HIV medication (see WARNINGS: Co-infection with HIV). 

Added to Patient Information: If you have or get HIV (human immunodeficiency virus) infection be sure to discuss your treatment with your doctor. If you are taking BARCLUDE to treat chronic hepatitis B and are not taking medicines for your HIV at the same time, some HIV treatments that you take in the future may be less likely to work. You are advised to get an HIV test before you start taking BARCLUDE and anytime after that when there is a chance you were exposed to HIV. BARCLUDE will not help your HIV infection.
 

FDA Reports Apparent Combivir Bottle Tampering
AIDSinfo At-A-Glance Volume 3 Issue 15
On Monday, April 9, 2007, the FDA reported on an isolated incident of apparent label tampering involving counterfeit Combivir (lamivudine/zidovudine) labels. The incident occurred at one pharmacy in California, with no reports of similar incidents elsewhere in the United States.

Specifically, a bottle falsely labeled as Combivir actually contained 300 milligram tablets of Ziagen (abacavir sulfate). In some patients, abacavir sulfate has caused a severe allergic reaction sometimes resulting in death. Patients prescribed Combivir may not be advised about this allergic reaction. Legitimate Combivir bottles contain tablets of 150 milligrams of lamivudine and 300 milligrams of zidovudine. The counterfeit labels have been identified as Lot No. 6ZP9760, with expiration dates of April 2009 and April 2010.

It is recommended that pharmacy professionals and patients closely examine the contents of all Combivir bottles. Combivir is a white, capsule-shaped tablet engraved with "GX FC3" on one side; the other side is plain. Ziagen is a yellow, capsule-shaped tablet engraved with "GX 623" on one face; the other side is plain. The FDA report about this incident includes pictures of Combivir and Ziagen for help distinguishing between the two tablets.

If you discover a Combivir bottle that does not contain Combivir tablets, call the GlaxoSmithKline Response Center at 1-888-825-5249 between 8:00 a.m. and 8:00 p.m. ET, Monday through Friday.Revised labeling for Baraclude (entecavir) re: HIV/HBC co-infected.

FDA and Bristol-Myers Squibb are notifying healthcare professionals of revisions to the MICROBIOLOGY/Antiviral Activity and INDICATIONS AND USAGE/Description of Clinical Studies/Special Populations sections of the prescribing information for Baraclude (entecavir), a nucleoside analog used in the treatment of chronic hepatitis B virus (HBV).

The revised labeling is the result of a case report in which a human immunodeficiency virus (HIV) variant containing the M184V resistance substitution was documented during Baraclude treatment for HBV infection in an HIV/HBV co-infected patient who was not simultaneously receiving highly active antiretroviral therapy (HAART).

Current treatment guidelines recommend Baraclude as an option for treatment of HBV in the HIV/HBV co-infected adult patient who does not qualify for HAART.

Healthcare professionals are advised that when considering therapy with Baraclude in an HIV/HBV co-infected patient not receiving HAART, the risk of developing HIV resistance cannot be excluded based on current information.

You can read the manufacturer's Dear Healthcare Provider Letter at: http://www.fda.gov/medwatch/safety/2007/Baraclude_DHCP_02-2007.pdf

The revised labeling can be found at: http://www.fda.gov/medwatch/safety/2007/Baraclude_PI.pdf


 

Study regarding depression, anxiety and stress among patients taking Sustiva.
http://www.medscape.com/viewarticle/550461?src=mp
To access the article, click on this Web address. This article notification service provided by http://www.medscape.com
 

FDA List Serve (1/23/07) - Important update to Sustiva package insert
The Sustiva (efavirenz) package insert has been updated to include drug-drug interaction information regarding coadministration of efavirenz with rifampin, diltiazem, itraconazole, voriconazole, atorvastatin, pravastatin, simvastatin, pimozide and bepridil.

The Clinical Pharmacology section (Tables 1 and 2 ) were revised to include the results of drug-drug interactions studies with diltiazem, itraconazole, voriconazole, atorvastatin, pravastatin, and simvastatin.

The CONTRAINIDCATION section was revised to state Sustiva should not be administered concurrently with bepridil, pimozide and standard doses of voriconazole.

The PRECAUTION: Drug Interaction section (Tables 5 and 6) were updated to include information regarding coadministration of efavirenz with rifampin, diltiazem (and other calcium channel blockers), itraconazole, ketoconazole, voriconazole, pimozide and bepridil.

The Dosing and Administration section was updated to include dosing information for the co administration of efavirenz and voriconazole. Specifically, if Sustiva is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation (three 100-mg capsules or one 200-mg and one 100-mg capsule). SUSTIVA tablets should not be broken. FDA-HIV-AIDS Digest - 23 Jan 2007 to 31 Jan 2007 (#2007-2)

FDA List Serve (1/31/07) - Important changes to Fuzeon product labeling

Important additions have been made to the Fuzeon (enfuvirtide) for injection product label to include a description of nerve bundle pain, hematoma, and cautionary wording regarding Biojector use in patients with coagulopathy. The changes add language to the Precautions, Adverse Reactions, and Dosage and Administration sections of the Physician's Insert (PI), as well as corresponding changes to the Patient's Package Insert (PPI), to provide additional safety information regarding the use of the Biojector 2000 to administer Fuzeon as follows:

1. The following section was added under PRECAUTIONS:

Administration with Biojector(r) 2000

Nerve pain (neuralgia and/or paresthesia) lasting up to 6 months associated with administration at anatomical sites where large nerves course close to the skin, bruising and hematomas (see ADVERSE REACTIONS) have occurred with use of the Biojector 2000 needle-free device for administration of FUZEON. Patients receiving anticoagulants or persons with hemophilia, or other coagulation disorders, may have a higher risk of postinjection bleeding.


2. The following bullet was added under PRECAUTIONS, Information for Patients

section:

* Patients and caregivers should be instructed on the preferred anatomical sites for administration (upper arm, abdomen, anterior thigh). FUZEON should not be injected near any anatomical areas where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial sections of the buttocks, skin abnormalities, including directly over a blood vessel, into moles, scar tissue, bruises, or near the navel, surgical scars,

tattoos or burn sites.


3. The following paragraph was added under ADVERSE REACTIONS, Local

Injection Site Reactions section:

Biojector 2000 Needle-Free Device

Adverse events associated with the use of the Biojector 2000 needle-free device for administration of FUZEON have included: nerve pain (neuralgia and/or paresthesia) lasting up to 6 months associated with administration at anatomical sites where large nerves course close to the skin, bruising and hematomas (see Error! Reference source not found.).


4. The following section under DOSAGE AND ADMINISTRATION changed from:

Adults

The recommended dose of FUZEON is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen. Each injection should be given at a site different from the preceding injection site, and only where there is no current injection site reaction from an earlier dose. FUZEON should not be injected into moles, scar tissue, bruises or the navel. Additional detailed information regarding the administration of FUZEON is described in the FUZEON Injection Instructions.

to:

Adults

The recommended dose of FUZEON is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen. Each injection should be given at a site different from the preceding injection site, and only where there is no current injection site reaction from an earlier dose. FUZEON should not be injected near any anatomical areas where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial section of the buttocks, skin abnormalities, including directly over a blood vessel, into moles, scar tissue, bruises, or near the navel, surgical scars, tattoos or burn sites. Additional detailed information regarding the administration of FUZEON is described in the FUZEON Injection Instructions.


5. The second to last paragraph under Subcutaneous Administration now reads:

The reconstituted solution should be injected subcutaneously in the upper arm, abdomen or anterior thigh. The injection should be given at a site different from the preceding injection site and only where there is no current injection site reaction. Also, do not inject near any anatomical areas where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial sections of the buttocks, skin abnormalities, including directly over a blood vessel, into moles, scar tissue, bruises or near the navel, surgical scars, tattoos or burn sites. A vial is suitable for single use only; unused portions must be discarded (see FUZEON Injection Instructions).


6. The following was added under the HOW SUPPLIED section:

Biojector is a trademark of Bioject Medical Technologies, Inc. Patient Package Insert (compared to S-007 final printed labeling)


7. The following bullet under How should I use FUZEON? Section was changed from:

* Do not inject FUZEON in the same area as you did the time before. Do not inject FUZEON into the following areas: around the navel (belly button), scar tissue, a bruise or a mole, and where there is an injection site reaction.

To:

* Do not inject FUZEON in the same area as you did the time before. Do not inject FUZEON into the following areas: near the elbow, knee, groin, the lower or inner buttocks, directly over a blood vessel, around the navel (belly button), scar tissue, a bruise, a mole, a surgical scar, tattoo or burn site, or where there is an injection site reaction.


8. The following section was added under What are the possible side effects of

FUZEON?

Injection using Biojector(r) 2000

Shooting nerve pain and tingling lasting up to 6 months from injecting close to large nerves or near joints, and bruising and/or collections of blood under the skin have been reported with use of the Biojector 2000 needle-free device to inject FUZEON. If you are taking any blood thinners, or have hemophilia or any other bleeding disorder, you may be at higher risk of bruising or bleeding after using the Biojector.


9. The following sentence was added under the Changes since the last version of this

leaflet section:

Clarification of appropriate injection sites for FUZEON and addition of side effects when injecting with Biojector 2000 needle-free device.


10. The following statement was added to the last page:

Biojector is a trademark of Bioject Medical Technologies, Inc.

You can access the complete, revised label on the Daily Med site, at http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=2705#nlm42232-9

Fuzeon is a distributed by Roche Pharmaceuticals.

 

FDA Public Health Advisory for Nevirapine (Viramune)
1/19/05
The Food and Drug Administration (FDA) is issuing a  public health advisory to inform health care providers and patients about recent safety-related changes to the nevirapine (Viramune) label (package insert) and about appropriate use of HIV triple combination therapy containing nevirapine, which is one treatment option in the United States and which is increasingly being used globally.  The nevirapine label has been revised several times over the last two years to include more information on liver toxicity associated with long term nevirapine use.  The Indications and Usage section of the Viramune label now recommends against starting nevirapine treatment in women with CD4+cell counts greater than 250 cells/mm³ unless benefits clearly outweigh risks.  This recommendation is based on a higher observed risk of serious liver toxicity in patients with higher CD4 cell counts prior to initiation of therapy.  In addition, the revised label now includes a Medication Guide to inform patients about risks associated with nevirapine when used for the treatment of HIV.

Both clinically symptomatic and asymptomatic liver toxicity are observed with long term use of nevirapine in combination with other HIV drugs.  Asymptomatic liver toxicity is defined as increases in liver enzymes without any associated clinical signs or symptoms and is similar to that seen with other antiretroviral drugs.  Symptomatic liver toxicity is more common with nevirapine compared to other antiretroviral drugs.  Important information regarding symptomatic nevirapine liver toxicity is summarized below:

• Symptomatic nevirapine liver toxicity consists of elevated liver enzymes plus at least one symptom, which is typically rash but may include flu-like symptoms or fever.  The severity of symptomatic liver toxicity ranges from mild symptoms with liver enzyme abnormalities to rapidly occurring liver failure and death.
• Symptomatic nevirapine liver toxicity typically occurs after only a few weeks of dosing and may progress to liver failure despite monitoring of laboratory tests, which is not characteristic of other antiretrovirals. 
• Females and patients with higher CD4+ cell counts are at increased risk of liver toxicity.  Females have a three fold higher risk of symptomatic nevirapine liver toxicity than males, and females with CD4+ cell counts > 250 cells/mm³ have a 12 fold higher risk of symptomatic liver toxicity than females with CD4+ cell counts < 250 (11% vs. 0.9%).  Males with CD4+ cell counts > 400 cells/mm³ have a three fold higher risk of symptomatic liver toxicity than males with CD4+ cell counts < 400 (6.3% vs. 2.3%).
• Nevirapine-related deaths due to symptomatic liver toxicity, including some in HIV-infected pregnant women, have been reported to FDA's Medwatch program.  Serious and fatal liver toxicity has not been reported after single doses of nevirapine.

• Triple antiretroviral regimens have been shown to have a large impact on the reduction of AIDS morbidity and mortality.  Triple antiretroviral drug regimens containing a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI), such as nevirapine, are standard of care for HIV treatment and are needed to adequately and durably suppress virus. 
• Many options are needed for HIV-infected patients since resistance to antiretroviral drugs or to an entire antiretroviral class can develop.
• Symptomatic liver toxicity has not been reported with the use of single doses of nevirapine to the mother and to the child for prevention of perinatal HIV infection.
• Alternatives to nevirapine are limited by other toxicities, potential drug interactions, and by the risk of drug related birth defects if given to a female in the first trimester of pregnancy.
• Nevirapine liver toxicity is less frequent (<2% for both males and females with CD4+ cell counts <250 cells/mm³) when started in patients with lower CD4 counts.  Therefore, symptomatic liver toxicity in resource poor countries is likely to be much lower if World Health Organization standards are used for starting treatment.  The WHO recommends the initiation of ART treatment in patients with advanced disease or with CD4 counts < 200 cells/mm³.
• Nevirapine is chemically stable in environmental conditions where other antiretrovirals are not.
• Symptomatic liver toxicity has not been reported in HIV-infected children, and nevirapine is available in a liquid formulation while many other antiretrovirals are not.

Atazanavir, with or without ritonavir should not be coadministered with proton pump inhibitors

FDA List Serve (12/20/04)

Bristol-Meyers Squibb has issued a Dear Healthcare Provider letter regarding important new pharmacokinetic data concerning the coadministration of REYATAZ (atazanavir) and Norvir (ritonavir) with Prilosec (omeprazole). Omeprazole is a proton-pump inhibitor (PPI) for the treatment of acid-related diseases that works by suppressing gastric acid secretion.

The following observations were made from a randomized, open-label, multiple-dose drug interaction study.

A 76% reduction in atazanavir area under the concentration-time curve (AUC) and a 78% reduction in atazanavir trough plasma concentration (Cmin) were observed when REYATAZ/ritonavir 300/100 mg was coadministered with omeprazole 40 mg.

Based on the study results:
* DO NOT COADMINISTER REYATAZ OR REYATAZ/ritonavir with omeprazole due to the reduction in atazanavir exposure levels. This recommendation is consistent with the current REYATAZ U.S. Package Insert.
* It is not known whether the over-the-counter dose of omeprazole (20 mg once daily) would produce similar results; therefore, coadministration is not recommended.
* Increasing the REYATAZ/ritonavir dose to 400/100 mg in combination with omeprazole DID NOT result in REYATAZ exposures comparable to those observed with a regimen of REYATAZ/ritonavir 300/100 mg without omeprazole.
* Simultaneous administration of 8 ounces of cola given in an effort to decrease (acidify) gastric pH did not appear to affect this reduction.

Investigations regarding the potential drug interaction between REYATAZ (atazanavir sulfate) and H2-Receptor antagonists (another type of gastric medication) when coadministered are ongoing. Until data are available, clinicians should note the following statements from the REYATAZ Package Insert: "Reduced plasma concentrations of atazanavir are expected if H2-receptor antagonists are administered with REYATAZ (atazanavir sulfate). This may result in loss of therapeutic effect and development of resistance. To lessen the effect of H2 -receptor antagonists on atazanavir exposure, it is recommended that an H2-receptor antagonist and REYATAZ be administered as far apart as possible, preferably 12 hours apart."


 

“Antibiotic Can Trigger Cardiac Deaths”
Associated Press (09.09.04)::Linda A. Johnson
     The antibiotic erythromycin dramatically increases the risk of cardiac arrest, especially when it is taken with certain newer drugs, according to a new study published today. Erythromycin has been commonly prescribed for 50 years to treat numerous illnesses, including syphilis. CDC Summary

Atazanavir drug interaction with tenofovir

FDA List-serve 3.19.04

New drug interaction information has led to t in the CLINICAL PHARMACOLOGY section of the REYATAZ (atazanavir sulfate) label - tenofovir interaction studies.
The following information was added to the PRECAUTION: Drug Interaction section &#8211; Table 9: Established and Other Potentially Significant Drug Interactions. Specifically the following statement was included ·
Tenofovir decreases the AUC (area under the curve) and Cmin (minimum
concentration) of REYATAZ. When coadministered with tenofovir, it is
recommended that REYATAZ 300 mg is given with ritonavir 100 mg and
tenofovir 300 mg (all as a single daily dose with food). REYATAZ
without ritonavir should not be coadministered with tenofovir.
REYATAZ increases tenofovir concentrations. The mechanism of this interaction is unknown.
Higher tenofovir concentrations could potentiate tenofovir-associated
adverse events, including renal disorders. Patients receiving REYATAZ
and tenofovir should be monitored for tenofovir-associated adverse events.
The following information was added to the DOSAGE AND ADMINISTRATION section. · When coadministered with tenofovir, it is recommended that REYATAZ 300 mg is given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be coadministered with tenofovir. Further, information regarding PDE5 inhibitors (sildenafil [Viagra], tadalafil [Cialis] and vardenafil [Levitra]) was added to the WARNINGS and PRECAUTION sections. The information included is consistent with the recently approved Invirase and Fortovase label. In addition, the patient package insert was revised to include information regarding tenofovir and PDE5 inhibitors (sildenafil, tadalafil, vardenafil).
 

"New Clarifications on Liver Dangers of Nevirapine (PDF)
Side effects of any drug can vary from individual to individual and from one gender to another. In a recent letter to healthcare providers, nevirapine (Viramune) producer Boehringer Ingelheim notes that the risk of severe liver damage is much higher for women, including pregnant women already receiving treatment for their HIV infection, whose CD4 counts are over 250. As with all medication-related issues, be sure to talk with your healthcare provider about any concerns you may have about using nevirapine." from What's New at The Body (2.4.04)
http://www.thebody.com/treat/pdfs/nevirapine_risk.pdf?m32h

IMPORTANT DRUG WARNING from Gilead Sciences, Inc
October 14, 2003

RE: High Rate of Virologic Failure in Patients with HIV Infection Treated With a Once- Daily Triple NRTI Regimen containing Didanosine, Lamivudine, and Tenofovir

Gilead Sciences, Inc (Gilead) today released a letter to health care professionals regarding a high rate of early virologic failure and
emergence of nucleoside reverse transcriptase inhibitor (NRTI) resistance associated mutations observed in a clinical study of HIV-infected treatment-naove patients receiving a once-daily triple NRTI regimen containing didanosine enteric coated beadlets (Videx EC, Bristol-Myers Squibb), lamivudine (Epivir, GlaxoSmithKline), and tenofovir disoproxil fumarate (Viread, Gilead).

These new data are consistent with the high rates of virologic failure observed in several recent clinical studies that have evaluated the use of triple NRTI regimens. Based on these results:

• 7 Tenofovir DF in combination with didanosine and lamivudine is not recommended when considering a new treatment regimen for therapy-naove or experienced patients with HIV infection. Patients currently on this regimen should be considered for treatment
  modification.
  

See the Project Inform article "Herbs, Supplements and HIV" http://www.projinf.org/fs/herbs.html

SPECIAL NOTICE TO THOSE USING ZERIT (stavudine, d4T). Changes have been made in the WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and PATIENT INFORMATION sections of the ZERITlabel to describe the occurrence of lactic acidosis and neuromuscular toxicity in patients using stavudine. A total of 25 patients with neuromuscular weakness resembling Guillian-Barre syndrome in association with lactic acidosis were reported to the FDA's Adverse Event Reporting System. In most cases, antiretroviral therapy was continued in the presence of symptoms that might have been due to lactic acidosis, such as abdominal pain, nausea, and fatigue, leading to death in six of the patients. Most of these patients (22 out of 25) were receiving antiretroviral combinations containing stavudine. Although causality has not been established, these findings were consistent with recent reports in peer-reviewed journals that the use of stavudine in antiretroviral combination therapy may increase the risk of lactic acidosis. Therefore, the stavudine label now includes a warning that its use may increase the risk of lactic acidosis, which represents a rare, but serious adverse event. The label now includes the symptoms of the newly described symptomatic hyperlactemia syndrome, and the recommendation for prompt suspension of all antiretroviral therapy in suspected cases of lactic acidosis with or without neuromuscular weakness. Permanent discontinuation of stavudine should be considered in confirmed cases of lactic acidosis. Please refer to the Zerit label for full prescribing information. A copy of the revised labeling is available at: http://www.fda.gov/cder/foi/label/2002/20412S017.pdf.

Garlic Supplements Can Impede HIV Medication
NIH News Release 12/05/01

Researchers have found garlic supplements can cause a potentially harmful side effect when combined with a type of medication to treat HIV/AIDS. Investigators from the National Institutes of Health (NIH) observed garlic supplements sharply reduced blood levels of the anti-HIV drug saquinavir. The study results appear this week in an on-line edition of Clinical Infectious Diseases ( http://www.journals.uchicago.edu/CID/journal/home.html ).

"In the presence of garlic supplements, blood concentrations of saquinavir decreased by about 50 percent among our study participants," explains the study's senior co-author Judith Falloon, M.D., an AIDS clinical researcher at the National Institute of Allergy and Infectious Diseases (NIAID). "We saw a definite, prolonged interaction. The clear implication is that doctors and patients should be cautious about using garlic supplements during HIV therapy," she says.

For the first three days of the study, nine healthy, HIV-negative volunteers received doses of saquinavir, part of a class of drugs called protease inhibitors that are effective at slowing the progression of HIV infection. The research team drew samples from the volunteers' blood to measure their baseline levels of the amount of saquinavir in the bloodstream.

Next, the volunteers took garlic caplets twice daily for three weeks. When the researchers again analyzed blood samples, the average overall levels of saquinavir had decreased 51 percent, and the average maximum concentrations had fallen 54 percent.

Even after a ten-day "wash-out" period with no garlic supplements, when the volunteers again used only the protease inhibitor for three days, their blood levels of saquinavir still averaged about 35 percent lower than the expected baseline amount.

The research paper's lead author was Stephen C. Piscitelli, Pharm D., formerly with the NIH Clinical Center Pharmacy Department and now the Associate Director of Clinical Pharmacology at Tibotec-Virco. Noting that some dietary supplements can cause detrimental interactions with medications, Dr. Piscitelli and his colleagues set out to investigate the effects of a number of herbal therapies. As Dr. Falloon explains, "We set out to learn more about these alternative medicine products because there simply was not a lot of clinical data available on them." In their first study, the team found a potentially dangerous interaction between the herbal remedy St. John's wort and the protease inhibitor indinavir.

Garlic became the next focus because of its reputation as a natural cholesterol fighter, which has made it particularly popular for patients whose cholesterol levels have risen due to a side effect from HIV medications. The research team also suspected a strong possibility of a drug interaction because both garlic and protease inhibitors share the same pathway into the body, a metabolic route known as the CYP450 enzyme system. Exactly how garlic supplements disrupt the uptake of saquinavir is still unclear.

Other questions remain as well, says Dr. Falloon. Usually, doctors prescribe saquinavir to be taken together with several anti-HIV drugs, and it is unknown how garlic supplements would affect such a combined drug regimen. "More research is needed in this area, but it's clear from this study that any patient using saquinavir as the sole protease inhibitor should avoid using garlic supplements," says Dr. Falloon.

NIAID and the Warren Grant Magnuson Clinical Center are components of NIH. NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies. The Clinical Center is the clinical research hospital for NIH. Through clinical research, physicians and scientists translate laboratory discoveries into better treatments, therapies and interventions to improve the nation's health.

###

Reference: Piscitelli, S. C., et al. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clinical Infectious Diseases Electronic Edition (December 3, 2001).

"Increased Mitochondrial Toxicity with Ribavirin in HIV/HCV
Coinfection" - see Peer-Reviewed Journals.

"Euro Doctors Warned of HIV Drug Risks in Pregnancy"
Reuters Health Information Services (www.reutershealth.com)
(02/01/01)
     Physicians in Europe are being warned by the European Medicines
Evaluation Agency that pregnant women with HIV who take the
anti-AIDS drugs Zerit (stavudine) and Videx (didanosine) may
experience lactic acidosis, even to a fatal degree.  The disorder
occurs when the body is unable to process food into usable
energy, causing a build-up of acid in the body that can damage
vital organs.  The warning comes a month after a similar alert
from the Food and Drug Administration to U.S. doctors, with both
organizations noting the class of HIV drugs--called nucleoside
reverse transcriptase inhibitors--is not recommended for use
during pregnancy unless the benefits are much higher than the
risks.  The warning includes information about seven cases of
lactic acidosis, including three fatal cases, in pregnant women
taking the two drugs in combination.

Serostim Warning
Wall Street Journal (www.wsj.com) (01/23/01) P. A1
     The U.S. Food and Drug Administration is warning AIDS patients
about a fake version of the drug Serostim, one that is powdery
instead of caked.  The counterfeit drug carries the lot number
MNK612A with an expiration date of 08/02. See Michigan News.

ddI/d4T Combination Can Be Fatal for Pregnant Women

WASHINGTON (AP) - Three pregnant women with the AIDS virus recently died from a severe side effect caused by taking two AIDS drugs together, the government said Friday in warning pregnant women to try to avoid a combination of the drugs ddI and d4T.

Four other pregnant women suffered nonfatal cases of lactic acidosis, an emergency condition where acid builds up in the body and can seriously damage the liver or pancreas.

A class of older AIDS medicines called nucleoside analogs comes with warnings that such drugs occasionally cause lactic acidosis, and that women seem to be at higher risk than men.

But the recent deaths prompted the Food and Drug Administration to issue a special warning for pregnant women. Officials couldn't say why the problem seemed to suddenly arise, although it has become more common for HIV-infected women once restricted to a single drug during pregnancy to instead take multidrug combinations.

Bristol-Myers Squibb manufactures both drugs under the brand names Zerit and Videx, and wrote thousands of doctors Friday alerting them to the warning.

The FDA also has received two reports of pregnant women suffering lactic acidosis while taking a combination of the AIDS drugs d4T and 3TC, and one where the woman took ddI alone. The agency will investigate those cases.

As for ddI and d4T, the FDA says pregnant women should avoid taking those drugs together unless they have exhausted other treatment options. Women  using the combination should be closely monitored by HIV experts who can quickly take them off the drugs and begin emergency therapy if lactic acidosis arises, the FDA said.

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