Important Label Update for Norvir (Ritonavir)

November 23, 2009

On November 23, 2009, FDA approved changes to the Norvir package insert (product label) to include drug-drug interaction information for concurrent ritonavir administration with:

• inhaled medicines such as salmeterol or salmeterol in combination with fluticasone propionate (Serevent, Advair)
• sildenafil (Revatio)

Also other revisions to the Contraindications, Warnings, Precautions: Drug Interactions and Dosage and Administration as follows.

The CONTRAINDICATIONS was updated as follows:
When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information.
NORVIR is contraindicated in patients with known hypersensitivity to ritonavir or any of its ingredients.
Co-administration of NORVIR is contraindicated with the drugs listed in Table 4 (also see PRECAUTIONS -- Table 5. Drugs that Should Not be Co-administered with NORVIR) because ritonavir mediated CYP3A inhibition can result in serious and/or life-threatening reactions. Voriconazole and St. John's Wort are exceptions in that co-administration of NORVIR and voriconazole results in a significant decrease in plasma concentrations of voriconazole, and co-administration of NORVIR with St. John's Wort may result in decreased ritonavir plasma concentrations.

Table 4. Drugs that are Contraindicated with NORVIR
Drug Class	Drugs Within Class That Are CONTRAINDICATED With NORVIR**
Alpha1-adrenoreceptor antagonist	Alfuzosin HCL
Antiarrhythmics	Amiodarone, bepridil, flecainide, propafenone, quinidine
Antifungal	Voriconazole
Ergot Derivatives	Dihydroergotamine, ergonovine, ergotamine, methylergonovine
GI Motility Agent	Cisapride
Herbal Products	St. John's Wort (hypericum perforatum)
HMG-CoA Reductase Inhibitors:	Lovastatin, simvastatin
Neuroleptic	Pimozide
PDE5 enzyme inhibitor	Sildenafil* (Revatio®) only when used for the treatment of pulmonary arterial hypertension (PAH)
Sedative/hypnotics	Oral midazolam, triazolam
* see WARNINGS - Drug Interactions and PRECAUTIONS -- Table 6. Established and Other Potentially Significant Drug Interactions for coadministration of sildenafil in patients with erectile dysfunction. ** For additional information for these contraindicated drugs, see also PRECAUTIONS -- Table 5. Drugs that Should Not be Co-administered with NORVIR.

The WARNINGS section for Drug Interactions was updated as follows
Drug Interactions
See CONTRAINDICATIONS- Table 4 for a listing of drugs that are contraindicated with NORVIR due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity. Also, see PRECAUTIONS -- Table 5 and Table 6 for drugs that should not be co-administered with NORVIR and for a listing of drugs with established and other significant drug interactions.

The PRECAUTIONS section with regard to drug interactions was updated as follows:

Table 5. Drugs that Should Not be Co-administered with NORVIR
Drug Class: Drug Name	Clinical Comment
Alpha Adrenergic Antagonist: alfuzosin	CONTRAINDICATED due to potential for serious reactions such as hypotension.
Antiarrhythmics: amiodarone, bepridil, flecainide, propafenone, quinidine	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Antifungal: voriconazole	CONTRAINDICATED due to significant decreases in voriconazole plasma concentrations and may lead to loss of antifungal response.
Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system.
GI Motility Agent: cisapride	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John's wort (hypericum perforatum)	CONTRAINDICATED as the combination may lead to loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors.
HMG-CoA Reductase Inhibitors: lovastatin, simvastatin	CONTRAINDICATED due to potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: pimozide	CONTRAINDICATED due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
PDE5 enzyme inhibitor: Sildenafil* (Revatio®)	CONTRAINDICATED in the treatment of pulmonary arterial hypertension (PAH). A safe and effective dose has not been established when used with ritonavir. There is an increased potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope.
Sedative/hypnotics: oral midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

Table 6 below was revised to include updated information on coadministration with darunavir, tipranavir, maravoric, voriconazole, PDE5 inhibitor for pulmonary arterial hypertension (sildenafil (Revatio)) and parenteral midazolam

Table 6. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies or Predicted Interaction (see CLINICAL PHARMACOLOGY -- Table 2 and Table 3 for Magnitude of Interaction)
Concomitant Drug Class: Drug Name	Effect on Concentration of Ritonavir or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents
HIV Protease Inhibitor: darunavir	When co-administered with reduced doses of ritonavir ↑ darunavir (↑ AUC, ↑ Cmax, ↑ Cmin)	See the complete prescribing information for Prezista® (darunavir) for details on co-administration of darunavir 600 mg b.i.d with ritonavir 100 mg b.i.d. or darunavir 800 mg q.d. with ritonavir 100 mg q.d.
HIV Protease Inhibitor: tipranavir	When co-administered with reduced doses of ritonavir ↑ tipranavir (↑ AUC, ↑ Cmax, ↑ Cmin)	See the complete prescribing information for Aptivus® (tipranavir) for details on co-administration of tipranavir 500 mg b.i.d with ritonavir 200 mg b.i.d. There have been reports of clinical hepatitis and hepatic decompensation including some fatalities. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with tipranavir/ritonavir, and frequently throughout the duration of treatment.
HIV Protease Inhibitor: fosamprenavir	When co-administered with reduced doses of ritonavir ↑ amprenavir (↑ AUC, ↑ Cmax, ↑ Cmin)	See the complete prescribing information for Lexiva® (fosamprenavir) for details on co administration fosamprenavir 700 mg b.i.d with ritonavir 100 mg b.i.d., fosamprenavir 1400 mg q.d. with ritonavir 200 mg q.d. or fosamprenavir 1400 mg q.d. with 100 mg q.d.
HIV CCR5 -- antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with ritonavir will increase plasma levels of maraviroc. For specific dosage adjustment recommendations, please refer to the complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antifungal: voriconazole	↓ voriconazole	Coadministration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated. Coadministration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Long-acting beta-adrenoceptor agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
PDE5 Inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with sildenafil is expected to substantially increase sildenafil concentrations (11-fold increase in AUC). Use of sildenafil, tadalafil or vardenafil may result in an increase in associated adverse events, including hypotension, syncope, visual changes, and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with ritonavir (see CONTRAINDICATIONS and PRECAUTIONS -- Drug Interactions, Table 5). Use of PDE5 inhibitors for erectile dysfunction: Sildenafil: The starting does should not, in any case, exceed 25 mg in a 48-hour period in patients receiving concomitant ritonavir therapy (see WARNINGS). Tadalafil: Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring for adverse events(see WARNINGS). Vardenafil: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events(see WARNINGS).
Sedative/hypnotics: Parenteral midazolam	↑ midazolam	Co-administration of oral midazolam with NORVIR is CONTRAINDICATED. Concomitant use of parenteral midazolam with NORVIR may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.

The DOSAGE AND ADMINISTRATION section was revised to include the following statement.

Adults
Dose modification for NORVIR
Dose reduction of NORVIR is necessary when used with other protease inhibitors: amprenavir, atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir. Prescribers should consult the full prescribing information and clinical study information of these protease inhibitors if they are co-administered with a reduced dose of ritonavir.

The complete revised labeling will be available at Drugs@FDA.

Norvir is a protease inhibitor, marketed by Abbott Laboratories.

Despite Gains, HIV/AIDS Remains Public-Health Priority, UNAIDS, WHO Say

November 25, 2009

News outlets continued to examine the 2009 AIDS epidemic update released Tuesday by the WHO and UNAIDS:

"The U.N. report said 'AIDS continues to be a major public-health priority' and called for more funds to support efforts to curb the epidemic and to distribute lifesaving drugs," the Wall Street Journal reports. "The U.N. report also suggested that health authorities need to focus resources on those most at risk" (Fairclough, 11/25).

Los Angeles Times: "About 4 million people were receiving AIDS drugs at the end of 2008, compared with 3 million the previous year. Nonetheless, an additional '5 million people need treatment and are not receiving it,' Dr. Teguest Guerma, acting director of the WHO's HIV/AIDS department, said at a Tuesday news conference. She said that about 2.9 million lives had been saved so far by increased access to the drugs as a result of the U.S. President's Emergency Plan for AIDS Relief and other international assistance programs" (Maugh, 11/25).

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VOA News examines the U.S. contributions towards the global fight against HIV/AIDS. The article includes comments by Anthony Fauci, of the National Institute of Allergy and Infectious Diseases, and Michele Moloney-Kitts, assistant coordinator in the office of the global AIDS coordinator. According to Fauci, the National Institutes of Health have "spent about $42 billion from 1982 through fiscal year 2009 on HIV/AIDS research," funding Fauci credited to having helped improve the lives of people living with HIV/AIDS, the news service writes.

"Michele Moloney-Kitts ... said the U.S. government to date has provided about $25 billion, making it the largest donor in the global fight against AIDS, tuberculosis and malaria." The article also includes Moloney-Kitts' comments about the future of PEPFAR under the Obama administration (Butty, 11/24).

"The update cautions that prevention programs often fail to target the populations that are most at risk," Science's "ScienceInsider" blog reports. "Specifically, stigma and local laws prevent many countries from tailoring prevention outreach to highly vulnerable groups like injecting drug users, men who have sex with men, commercial sex workers, and longterm couples in which only one partner is infected. And the sobering bottom line is that five people continue to be infected for every two who start treatment with anti-HIV drugs" (Cohen, 11/24).

Epidemics in Russia, Eastern Europe, China

RIA Novosti examines the findings of the report that "[o]ver 1% of Russian residents are HIV-positive," with the primary route of transmission being injecting drug use. "According to the report, about 37% of Russia's estimated 1.8 million drug users are HIV-infected. Young people account for a considerable number of infections among injecting drug users in the region," the news service writes (11/25).

KyivPost: "'With an adult HIV prevalence of 1.6%, Ukraine has the highest prevalence in all of Europe,' UNAIDS and WHO experts said." The report also found "the estimated number of adults and children living with HIV in Eastern Europe and Central Asia has grown by 66% to 1.5 million since 2001," according to the newspaper (11/25).

The Associated Press examines the report's findings that HIV "is now spreading fastest in China through heterosexual sex, a trend demanding new strategies to stave off a rebound in the epidemic after years of progress in containing it ..." UNAIDS head Michel Sidibe said, "We are seeing a shift in the nature of the epidemic. ... We need to ensure resource allocation is responding to that change."

The article includes details about how "[t]he government remains sensitive about [HIV/AIDS]" and stories of patients living with HIV/AIDS seeking additional support from the government (Kurtenbach, 11/25).

Xinhua/People's Daily Online also reports on the Chinese health minister's response to the UNAIDS report and highlights the efforts of the Chinese government to stop the spread of HIV/AIDS in the country (11/24). In a UNAIDS press release that lauded China's progress on HIV/AIDS Sibide's said, "The world eagerly anticipates China's enhanced role in global governance -- and its leadership in the global response to AIDS" (11/24).

HIV - Up Close and Personal

Since the discovery in 2007 that a component of human semen called SEVI boosts infectivity of the virus that causes AIDS, researchers have been trying to learn more about SEVI and how it works, in hopes of thwarting its infection-promoting activity.

Now, scientists at the University of Michigan have determined the atomic-level, three-dimensional structure of a SEVI precursor known as PAP248-286 and discovered how it damages cell membranes to make them more vulnerable to infection with HIV. The work is described in two new papers. The most recent, describing the structure, was published online Nov. 17 in the Journal of the American Chemical Society. The paper describing how PAP248-286 interacts with cell membranes appeared in the Nov. 4 issue of Biophysical Journal.

PAP248-286 is a peptide---a chain of amino acids not long enough to be considered a protein. Individual PAP248-286 peptides have a tendency to clump together to form amyloid fibers called SEVI (semen enhancer of viral infection). Amyloid fibers are of great interest because they are the calling cards of many neurodegenerative diseases, such as Alzheimer's and Parkinson's, and aging-related diseases like type-2 diabetes. Using NMR (nuclear magnetic resonance) spectroscopy, a technique that not only yields atomic-level details of a molecule's structure, but also shows how the molecule nestles into the membrane with which it interacts, researcher Ayyalusamy Ramamoorthy and coworkers found that the structure of PAP248-286 is unlike that of most other amyloid-forming peptides and proteins.

In solution, SEVI is completely unstructured or has no definite shape and is therefore ineffective. On the other hand, "when bound to the membrane, it's in a spaghetti-like arrangement---a disorganized, loose coil," said Ramamoorthy, a professor of chemistry and of biophysics. In contrast, most other amyloid proteins assume a more ordered, helical configuration. Also unlike other amyloid peptides, SEVI does not penetrate deep into the greasy region of the cell membrane, but is located near the surface. Ramamoorthy and coauthors believe the spread-out, disordered configuration and its location in the cell membrane may explain the ability of SEVI fibers to enhance HIV infection, as the arrangement provides more surface area with which the virus can interact.

A key finding of the second study is that PAP248-286 "shocks" the membrane, inducing a structural change---a kind of dimple that allows HIV to attach to and enter the cell.

Next, Ramamoorthy and colleagues hope to discern more structural details of PAP248-286 and SEVI. They also plan to screen antioxidant compounds such as green tea extract, curcumin and resveratrol (found in red wine) to see if such compounds are capable of blocking SEVI's HIV-enhancing activity.

Ramamoorthy's coauthors on the Journal of the American Chemical Society paper are graduate student Ravi Nanga, post-doctoral fellows Jeffrey Brender and Nataliya Popovych and NMR specialist Subramanian Vivekanandan. His coauthors on the Biophysical Journal paper are Brender, graduate student Kevin Hartman, former post-doctoral fellow Lindsey Gottler, former graduate student Marchello Cavitt and biophysics undergraduate student Daniel Youngstrom.

This research was supported by funds from the National Institutes of Health.

Source: Nancy Ross-Flanigan
University of Michigan

AIDS Virus in this Lifetime?

Experts at an international HIV/AIDS conference in Winnipeg say researchers around the world are closer than ever to finding a vaccine against the virus.

Frank Plummer, director of Winnipeg's National Microbiology Laboratory, said he expects to see a vaccine in his lifetime.

"I'm confident that we will get there eventually," Plummer said. "It's not a simple problem. If it was, we would have done it already."

He said there are cases around the world of people who have had contact with the virus but haven't become infected. Plummer said some of that is luck, but it may also be due to natural immunity.

Case studies shared

Case studies were shared at a gathering of about 75 international experts at the conference.

Researchers at the conference pointed out that many breastfeeding infants who are born to HIV-positive women escape infection. Some groups of sex-trade workers who are repeatedly exposed to the virus also appear to be immune.

'We don't understand it fully yet and that needs to be expanded. We don't understand how to produce it artificially, which is what a vaccine is all about.'—Frank Plummer

"Sometimes that's because of luck but sometimes that's because, I believe, they're immune in some way to HIV," Plummer said. "We don't understand it fully yet and that needs to be expanded. We don't understand how to produce it artificially, which is what a vaccine is all about."

In September, researchers announced that a two-vaccine combination cut the risk of becoming infected with HIV by more than 31 per cent in a trial of more than 16,000 volunteers in Thailand.

Canada's chief public health officer, David Butler-Jones, said some of the greatest vaccine discoveries have come from figuring out natural immunity.

"The original vaccine for smallpox was a recognition that milk maids who had cowpox were not susceptible to smallpox," he said.

Although some of the world's great minds are grappling with the virus, Butler-Jones said it is a very difficult illness to crack. People are capable of developing antibodies to HIV/AIDS but they aren't enough to protect against the virus, he said.

"It is one of the great scientific and medical challenges moving forward. Every day we are one day closer but exactly when that day will come, it's impossible to predict," Butler-Jones said. "The sooner, the better."

According to a 2008 United Nations report on the global AIDS epidemic, 33 million people were living with HIV in 2007. Two million people died of causes related to the disease that year.

© The Canadian Press, 2009