The AIDS Beacon™

Brand Name:	Invirase
Generic Name:	saquinavir mesylate
Company:	Hoffman-La Roche
FDA Clinical Phase:	Approved in 1995 for the treatment of HIV-1 infection

Description

Invirase (saquinavir mesylate) is part of a class of anti-HIV drugs known as Protease Inhibitors (PIs). By inhibiting the action of protease, an enzyme, Invirase ensures that replicated viruses cannot infect other CD4 cells. CD4 cells, also known as T cells, are a special type of white blood cell that help fight infections within the body.

Mechanism of Action

Invirase inhibits the action of protease, an enzyme that HIV needs in order to replicate. Protease cleaves viral protein chains into individual proteins that are found in HIV. Invirase binds to protease thereby preventing protease from cleaving protein chains. Thus, the virus makes immature copies of itself that cannot infect other CD4 cells.

History

In December of 1995, Invirase became the first protease inhibitor to be approved for the treatment of HIV infection.

At the time, the therapy required patients to take five hard gel capsules daily. These hard gel capsules were not well absorbed in the intestines, and so required patients to eat a full meal with each capsule to improve absorption.

Therefore, an alternative soft gel capsule was approved in November of 1997. This soft gel version was marketed as Fortovase (saquinavir). In 2006, Fortovase was discontinued as gastrointestinal side effects led to low tolerability among patients.

In its place, Invirase was marketed in combination with Norvir (ritonavir), both of which require 2 capsules to be taken daily. The combination of Invirase and Norvir proved to be more effective than Fortovase, as patients were better able to tolerate the combination.

Usage in HIV

Currently, Invirase is used to treat HIV infection. Although not FDA-approved for this use, Invirase is commonly used after exposure to HIV to reduce the likelihood of infection.

Dosage and Administration

Invirase is taken orally with Norvir, which increases the effectiveness of Invirase through boosting, which involves the combination of drugs to improve their overall effectiveness and to ensure that the virus does not undergo resistance to one particular drug.

The recommended dosage is 1000 mg Invirase and 100 mg Norvir taken twice per day. In order to meet the daily dosage requirement, patients may take Invirase as five 200 mg capsules or two 500 mg tablets twice a day along with one 100 mg capsule of Norvir twice a day.

Invirase and Norvir must be taken together within two hours after a full meal. To improve effectiveness, constant levels of the drug must be maintained in the blood throughout the day. To accomplish this, it is recommended that Invirase be taken at the same time every day, and that the doses be spread apart in even intervals throughout the day.

Side Effects

Generally, Invirase is well tolerated, and side effects are usually mild. The most common side effects reported are gastrointestinal problems, such as diarrhea.

Mild side effects also include loss of appetite, fatigue, abdominal pain, nausea, headaches, and vomiting. Patients should contact a doctor if any of these side effects become severe, or if they experience depression, yellowing of the eyes or skin, unusual bleeding, or blurry vision.

More serious side effects include increased fat levels (triglycerides and cholesterol), diabetes, and lipodystrophy, which is the change in body fat distribution. Specifically, lipodystrophy often leads to accumulation of fat on the stomach, breasts, and back of neck; fat loss often occurs in the face and limbs.

Drug Interactions

Invirase and Norvir should not be administered with any of the following drugs: Pacerone (amiodarone), Tambocor (flecainide), Rhythmol (propafenone), bepridil (Vascor), quinidine, Seldane (terfenadine), Orap (pimozide), Hismanal (astemizole), Propulsid (cisapride), Halcion (triazolam), Versed (midazolam), and ergot derivatives.

Invirase and Norvir should not be administered with St. John’s Wort, as it has been shown that co-administration of these drugs decreases the concentration of protease inhibitors (including Invirase) in the blood. This makes Invirase less effective and can cause HIV to become resistant to Invirase or the class of protease inhibitors.

Cholesterol lowering drugs should not be used with Invirase and Norvir, as they can lead to dangerous interactions. Specifically, simvastatin (Zocor) and lovastatin (Mevacor) should not be taken with Invirase and Norvir, as combining these drugs can lead to increased levels of simvastatin and lovastatin in the blood.

Certain protease inhibitors can increase the levels of Invirase in the blood, such as Crixivan (indinavir), Norvir (ritonavir), Kaletra (lopinavir/ ritonavir), Viracept (nelfinavir), Reyataz (atazanavir), and Lexiva (fosamprenavir). Certain non-nucleoside reverse transcriptase inhibitors (NNRTIs) can also react with Invirase. These include Sustiva (efavirenz) and Viramune (nevirapine), which decrease the amount of Invirase in the blood. Rescriptor (delavirdine) increases the amount of Invirase in the blood. When other drugs interfere with the blood concentrations of Invirase, the efficacy of Invirase will decrease, which can lead to potential failure of the therapy.

Invirase and Norvir should not be taken with rifampin, as this combination can reduce the level of Invirase in the blood, and even cause liver problems.

Precautions

Invirase does not cure HIV; thus, it is still possible to spread HIV to others, and it is possible to acquire HIV related illnesses, such as opportunistic infections. Opportunistic infections take advantage of weaknesses in the immune system, and do not normally occur in healthy individuals. These infections occur because the immune system is no longer capable of fighting off the bacteria and viruses that cause them.

Patients should inform their physicians of all medications that they are taking, including over-the-counter and herbal medications and should consult with them prior to starting or stopping their medications. Depending on other medications being used or preexisting conditions, such as strong allergic reactions, physicians may choose to alter the dosage of Invirase.

The effect of Invirase on pregnant women is not known; however, it is recommended that these women do not breast feed, as HIV can still be transmitted to the child.

Patients with hemophilia (a rare bleeding disorder where blood does not clot normally), diabetes or a family history of diabetes, kidney disease, hepatitis, and any other liver disease should speak with their physicians before taking Invirase.

Patients should speak with their doctors if they are taking Viagra (sildenafil citrate), Cialis (tadalafil), or Levitra (vardenafil) before taking Invirase.
Physicians should monitor patients’ blood cholesterol and triglyceride (fat) levels prior to beginning treatment with Invirase, as this drug can lead to elevated levels of cholesterol and triglycerides in the blood. High levels of such fats can lead to development of pancreatitis (inflammation of the pancreas).

Ongoing Clinical Trials

Open:

Phase 2/3:

• The HIV Netherlands Australia Thailand Research Collaboration: Studying pharmacokinetics of Invirase/Norvir once daily dosing along with Truvada (tenofovir/emtricitabine) once daily dosing in HIV pretreated patients (NCT00476983)

• University of California, San Diego; National Institutes of Health (NIH): Examining the effectiveness of highly active antiretroviral therapy (HAART) targeted at the central nervous system (CNS) (NCT00624195)

Phase 4:

• The HIV Netherlands Australia Thailand Research Collaboration: Examining clinical and immunological results of HAART in children (NCT00476606)

• Royal Free Hampstead NHS Trust; Hoffmann-La Roche: Benefits of switching from Kaletra (lopinavir/ritonavir) to Invirase, versus staying on Kaletra (NCT00438152)

• International Antiviral Therapy Evaluation Center; Hoffmann-La Roche; Gilead Sciences: Examining changes in plasma lipid levels (blood fat levels) in patients on boosted Invirase/Norvir versus boosted Reyataz (atazanavir)/Norvir (NCT00389402)

Closed:

Phase 1:

• Hoffmann – La Roche: Studying the efficacy of Invirase/Norvir in patients with liver impairment (NCT00435929)

• National Institute of Allergy and Infectious Diseases (NIAID) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): Studying the safety of treating HIV patients between the ages of 4 and 22 with 7 drugs, including Invirase (NCT00001108)

Phase 1/2:

• National Institute of Allergy and Infectious Diseases (NIAID): Studying the safety of Invirase and Kaletra in children with HIV (NCT00084058)

Phase 2:

• Hoffmann – La Roche: Studying the effects of Invirase/Norvir in HIV positive infants and children (NCT00623597)

For a more detailed listing of clinical trials involving Invirase, please see the U.S. government’s clinical trials Web site.

Clinical Trial Results

Invirase, in combination with Norvir and Combivir (lamivudine/zidovudine), is not effective for long-term treatment of pregnant women (2001): Of the four pregnant women who completed assessments to determine the efficacy of Invirase, none achieved the study’s target antiretroviral drug exposure. To be effective, the exposure must be maintained above a certain threshold level, which was not achieved in these patients. The results indicate that the absorption of Invirase is variable in pregnant women and Invirase should not be used by pregnant women for long term treatment of HIV. The full trial description and results can be found in the journal HIV Clinical Trials (pdf).

Invirase and Norvir are safe to use with methadone (2001): Methadone is commonly used to treat drug addiction and to help with pain management. This study evaluated whether it was safe to take methadone in combination with Invirase and Norvir. Administration of Invirase/Norvir caused a 19.6% decrease in concentration of active methadone. However, this decrease was not statistically significant, and no evidence of methadone withdrawal was observed. Therefore, the results of this study indicate that Invirase/Norvir can be used safely with methadone without any dosage adjustments. The full study can be found in the Journal of AIDS.

Invirase may enhance the efficacy of Kaletra in children and adolescents who have previously failed antiretroviral therapy (2008): This study showed that high doses of Kaletra, along with Invirase, can be safely used in children and adolescents with HIV. The addition of Invirase to Kaletra treatment was shown to enhance efficacy in patients who have failed prior antiretroviral therapy. However, the virologic response of the drug was limited, and the drug regimen may be difficult to adhere to, as it requires a high dosage and many pills. The full study can be found in the journal Antimicrobial Agents and Chemotherapy.

Patient Assistance Programs

RxAssist – Patient Assistance Program Center
http://rxassist.org/

Patient Assistance
http://www.patientassistance.com/

Roche Patient Assistance Foundation
http://www.rocheusa.com/programs/patientassist.asp

Needy Meds – Finding Help With The Cost of Medicine
http://www.needymeds.org/

The Access Project – HIV/AIDS and Hepatitis Programs
http://www.atdn.org/access/pa.html

Links of Interest

Invirase Product Web site
http://www.invirase.com/

Invirase Patient and Prescription Information
http://www.rocheusa.com/products/invirase/

The Body – Invirase Information
http://www.thebody.com/index/treat/Invirase.html