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CATIE News - Health agencies issue caution on saquinavir use

2010 Oct 26 - The anti-HIV drug saquinavir (Invirase), a protease inhibitor, is used with a small amount of another protease inhibitor, ritonavir (Norvir), as part of combination therapy for HIV infection. In general, saquinavir-based regimens are well tolerated.

The European Medicines Agency (EMA) in the European Union and the Food and Drug Administration (FDA) in the United States have been reviewing data from studies of saquinavir. This review was done because of the potential of saquinavir (and other protease inhibitors) to affect the electrical activity of the heart and heart rhythms. As a result of this review, prescribing information for saquinavir in the EU and U.S. has changed.

Arrhythmia

Each heartbeat is triggered by a tiny electrical signal that cascades from the top to the bottom of the heart. As this signal or wave moves across the heart, it causes this organ to contract and pump blood. With each new heartbeat the process is repeated.

When the heart's electrical control system malfunctions, abnormal heartbeats can occur. The interval between heartbeats can become too long or too short or heartbeats may become irregular.

Arrhythmias are generally not harmful but in some cases can have serious consequences.  For instance, slower-than-normal heartbeats (bradycardia) will affect the heart's ability to pump enough blood to vital organs. When starved of fresh oxygen-rich blood, organs such as the brain and heart can become damaged.

Causes of arrhythmia

Smoking tobacco, excessive alcohol intake, excessive exercise and exposure to stress, caffeine or nicotine can cause arrhythmias. Powerful stimulants such as cocaine or amphetamine can also cause this problem.

Some commonly used medicines can also affect the heart's electrical control system.

Symptoms of arrhythmia

Sometimes arrhythmia can have no noticeable symptoms, while at other times the following can occur:

  • unexpected rapid beating of the heart (tachycardia)
  • unexpected slowed beating of the heart
  • chest pain
  • unexpected shortness of breath
  • dizziness, weakness or lightheadedness
  • fainting

These are serious symptoms and you should seek immediate medical attention should they occur.

Monitoring

The heart's electrical patterns can be detected with sensors placed on the chest and seen on a cardiogram. This is called an EKG or ECG (electrocardiogram). This simple, painless and non-invasive test can be performed in a few minutes. Cardiograms can capture changes to the heart's rhythms and its electrical activity.

QT interval

An important measurement on a cardiogram is the QT interval. This is a reflection of the length of time of electrical activity that controls the contraction of the heart. In healthy people, the QT interval stays within a normal range. However, some medications can interfere with the heart's electrical activity and prolong the QT interval, leading to complications. Only in rare circumstances does a prolonged QT interval lead to death.

Protease inhibitors

In 2005, researchers in the United States found an association between exposure to some protease inhibitors and possibly prolonged QT intervals in 25 people. Unfortunately, their study design precluded drawing firm conclusions about this association; that is, they could not prove that exposure to protease inhibitors caused arrhythmia. However, experiments with cells and animals suggested that arrhythmias might be a problem with protease inhibitors. Faced with this finding, the FDA asked pharmaceutical companies to conduct studies to explore the possible effect of protease inhibitors on the heart's electrical rhythms.

Hoffmann-La Roche, the manufacturer of saquinavir, conducted a randomized placebo crossover study with saquinavir-ritonavir, placebo and the antibiotic moxifloxacin (Avelox) in 59 healthy HIV-negative volunteers. The study found that exposure to saquinavir-ritonavir may affect the electrical activity of the heart by prolonging the QT interval. In turn, this prolongation may result in abnormal heart rhythms.

Hoffman-La Roche and both the EMA and FDA recommend the following courses of action:

  • Saquinavir should not be prescribed to patients who have a history of QT problems or who are taking other medicines known to prolong the QT interval.
  • Cardiogram monitoring must be done prior to initiating and after the start of therapy with saquinavir-ritonavir.
  • Doctors initiating therapy with saquinavir-ritonavir need to reduce the dose of saquinavir to 500 mg twice daily during the first week of use in patients who have never previously been treated for HIV infection. The reason for this dose reduction is that researchers think that the greatest risk for arrhythmia with this drug is during the first week of its use. After the first week the dose of saquinavir is increased to the normal dose of 1,000 mg twice daily.

If you are taking saquinavir-ritonavir, do not stop taking it without your doctor's advice.

If you have concerns about your heart health, speak to your doctor and review your medical history and your family medical history and disclose all medicines (both prescription and over the counter), supplements and herbs that you are taking.

There are many drugs with the potential to disturb the heart's electrical signals. Always consult your doctor and pharmacist about potential drug interactions and medication side effects.

Research

The EMA has asked Hoffmann-La Roche to conduct a study to explore the potential risk for arrhythmia in HIV-positive people who have not previously been exposed to anti-HIV medicines who are given saquinavir. This is important because some previous studies have yielding conflicting information.

Healthy heart

For information on HIV and heart health, see our in-depth Fact Sheet " HIV and cardiovascular disease: keeping your heart and blood vessels healthy " available at:

www.catie.ca/facts.nsf

Reporting side effects-Canada

Health Canada encourages doctors and their patients to report side effects. You can do this by contacting the Canada Vigilance Program in the following ways:

Electronic reporting

Go to this site and enter information electronically:
https://webprod4.hc-sc.gc.ca/medeffect-medeffet/index-eng.jsp

Telephoning the Canada Vigilance Regional Office

Go to this link and select the office in your region to contact:
www.hc-sc.gc.ca/contact/dhp-mps/hpfb-dgpsa/cvro-brcv-eng.php

Reporting side effects-United States

Health care professionals and patients can go to this site and choose the relevant links to begin the process of reporting drug side effects:
www.fda.gov/Safety/MedWatch/HowToReport/default.htm

Acknowledgement

We thank cardiologist Dr. Michal Odermarsky, PhD, Lund University, Sweden, for his helpful discussion, research assistance and expert review.

-Sean R. Hosein

 

                                                                                                           

REFERENCES:

  1. Goldberger AL. Electrocardiography (221). In: Fauci AS, Braunwald E, Kasper DL, editors. Harrison's Principles of Internal Medicine . 17th ed. McGraw-Hill Companies, Inc.; 2008.
  2. Tomaselli Gordon F. Principles of Electrophysiology (224). In: Fauci AS, Braunwald E, Kasper DL, editors. Harrison's Principles of Internal Medicine . 17th ed. McGraw-Hill Companies, Inc.; 2008.
  3. Anson BD, Weaver JG, Ackerman MJ, et al. Blockade of HERG channels by HIV protease inhibitors. Lancet . 2005 Feb 19-25;365(9460):682-6.
  4. Hoffman-La Roche corporate communications. Changes to the Invirase (saquinavir mesylate) prescribing information in the E.U. Statement . 21 October 2010.
  5. EMA. European Medicines Agency concludes that benefit-risk balance of Invirase remains positive: agency recommends reduced starting dose of Invirase in treatment-naïve patients. Press release . 21 October 2010.
  6. FDA. Invirase (saquinavir) labels now contain updated risk information on abnormal heart rhythms. Drug safety communication . 21 October 2010.
  7. Reinsch N, Buhr C, Krings P, et al. Prevalence and risk factors of prolonged QTc interval in HIV-infected patients: results of the HIV-HEART study. HIV Clinical Trials . 2009 Jul-Aug;10(4):261-8.
  8. Charbit B, Rosier A, Bollens D, et al. Relationship between HIV protease inhibitors and QTc interval duration in HIV-infected patients: a cross-sectional study. British Journal of Clinical Pharmacology. 2009 Jan;67(1):76-82.
  9. Gallagher DP, Kieran J, Sheehan G, et al. Ritonavir-boosted atazanavir, methadone, and ventricular tachycardia: 2 case reports. Clinical Infectious Diseases . 2008 Aug 1;47(3):e36-8.
  10. Peeters M, Janssen K, Kakuda TN, et al. Etravirine has no effect on QT and corrected QT interval in HIV-negative volunteers. Annals of Pharmacotherapy . 2008 Jun;42(6):757-65.
  11. Iwamoto M, Kost JT, Mistry GC, et al. Raltegravir thorough QT/QTc study: a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. Journal of Clinical Pharmacology . 2008 Jun;48(6):726-33.

 

CATIE-News is written by Sean Hosein, with the collaboration of other members of the Canadian AIDS Treatment Information Exchange, in Toronto.

From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca

Source: CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE


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