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Invirase

Invirase - General Information

An HIV protease inhibitor which acts as an analog of an HIV protease cleavage site. It is a highly specific inhibitor of HIV-1 and HIV-2 proteases. [PubChem]

 

Pharmacology of Invirase

Invirase is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Invirase binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.

 

Invirase for patients

A statement to patients and health care providers is included on the productís bottle label:

ALERT: Find out about medicines that should NOT be taken with INVIRASE.

Patients should be informed that any change from INVIRASE to FORTOVASE or FORTOVASE to INVIRASE coadministered with a drug which inhibits its metabolism, such as ritonavir, should be made only under the supervision of a physician.

INVIRASE may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, nonprescription medication, or herbal products, particularly St. Johnís wort.

Patients should be informed that INVIRASE is not a cure for HIV infection and that they may continue to acquire illnesses associated with advanced HIV infection, including opportunistic infections. Patients should be advised that INVIRASE may be used only if it is combined with ritonavir, which significantly inhibits saquinavir's metabolism to provide plasma saquinavir levels at least equal to those achieved with FORTOVASE.

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time.

Patients should be told that the long-term effects of INVIRASE are unknown at this time. They should be informed that INVIRASE therapy has not been shown to reduce the risk of transmitting HIV to others through sexual contact or blood contamination.

Patients should be advised that INVIRASE administered with ritonavir should be taken within 2 hours after a full meal. When INVIRASE is taken without food, concentrations of saquinavir in the blood are substantially reduced and may result in no antiviral activity. Patients should be advised of the importance of taking their medication every day, as prescribed, to achieve maximum benefit. Patients should not alter the dose or discontinue therapy without consulting their physician. If a dose is missed, patients should take the next dose as soon as possible. However, the patient should not double the next dose.

 

About INVIRASE (in-ver-ase)

INVIRASE

(saquinavir mesylate) Capsules and Tablets

Generic Name: Saquinavir mesylate (sa-KWIN-a-veer mes-il-late)

ALERT: Find out about medicines that should NOT be taken with INVIRASE. Please also read the section MEDICINES YOU SHOULD NOT TAKE WITH INVIRASE.

Please read this product information carefully before you start taking INVIRASE and each time you renew your prescription. There may be new information. Reading this information can help you take this medicine correctly. However, it is not a substitute for your doctorís advice about the safety and benefits of INVIRASE. You should talk to your doctor about INVIRASE as part of your long-term treatment plan for HIV before you start taking your medication and ask any questions you may have at regular checkups. Remember, you should remain under a doctorís care when using INVIRASE and should not change or stop your therapy without talking to your doctor first.

What is INVIRASE?

INVIRASE belongs to a class of anti-HIV medicines called protease (PRO-tee-ase) inhibitors. INVIRASE Capsules and Tablets in combination with other anti-HIV drugs are used for the treatment of HIV, the virus that causes AIDS (acquired immunodeficiency syndrome).

How does INVIRASE work?

INVIRASE fights HIV as it grows inside cells by blocking an enzyme (protease) that HIV needs to reproduce.

How is INVIRASE different from FORTOVASE (saquinavir)?

Both INVIRASE and FORTOVASE contain the same active ingredientósaquinavir. When INVIRASE or FORTOVASE are taken two times a day with ritonavir, a similar amount of saquinavir gets into the blood to fight HIV. However, FORTOVASE can be taken three times a day without ritonavir and the correct amount of saquinavir can get into the blood.

INVIRASE should never be taken without ritonavir. FORTOVASE may be taken without ritonavir if you are not able to tolerate even a small amount of ritonavir.

You should not substitute one for the other. If the medicine you receive does not look like the light brown and green capsule (INVIRASE) it is not the right drug. Talk to your doctor, nurse or pharmacist if you are not sure that you have the right medication.

Who should not take INVIRASE?

Anyone who has had a severe allergic reaction to INVIRASE or any of the ingredients in the capsule or tablet should not take it. The use of INVIRASE in patients under 16 years of age, over 65 years of age, or patients with severe liver problems has not been fully investigated.

How should INVIRASE®/Norvir (ritonavir) be taken?

· The recommended dosage of INVIRASE in combination with Norvir® (ritonavir) is INVIRASE 5 capsules or 2 tablets twice a day taken with 1 capsule of Norvir twice a day. In some combinations, your dose may change.

· INVIRASE must be taken along with Norvir (ritonavir).

· INVIRASE must be taken with meals or up to 2 hours after a mealóbut it is easiest to remember if you take it with your meals. When INVIRASE is taken without food, the amount of INVIRASE in the blood is lower and may not fight HIV as well.

· When taking INVIRASE and other anti-HIV medicines, it is very important to follow the directions exactly and take your medication every day. If you skip dosesóor take less than the prescribed doseóthe medicine will not work as well, and your disease could get worse.

ñ If you miss a dose, you should take the next dose as soon as possible. However, do not double the dose.

What results have been seen with INVIRASE?

INVIRASE with ritonavir has been shown to reduce the amount of virus in the blood ("viral load") and increase CD4 (T) cells when taken with other HIV therapy.

What are the side effects of INVIRASE?

People treated with INVIRASE in combination with Norvir may have side effects. The majority of these have been described as mild. In clinical studies of patients who received saquinavir in combination with Norvir and other HIV drugs the side effects seen most often were: body fat change (5.4%), nausea (10.8%), vomiting (7.4%), diarrhea (6.8%), stomach pain (6.1%), tiredness (6.1%), and pneumonia (5.4%).

Diabetes (new onset or worsening) and increased blood sugar levels have been reported with the use of protease inhibitors. In addition, increased bleeding in patients with hemophilia has also been associated with these drugs.

When saquinavir is taken with ritonavir, some patients may experience large increases in triglyceride and lipid levels. The long-term chance of getting complications such as heart attack and stroke due to increases in triglyceride and cholesterol levels caused by protease inhibitors is not known at this time.

Changes in body fat have been seen in some patients taking anti-HIV medications. These changes may include increased amount of fat in the upper back and neck ("buffalo hump"), breasts, and around the trunk. Loss of fat from the legs and arms may also happen. The cause and long-term health effects of these conditions are not known at this time.

These are not the only side effects that can occur with INVIRASE. Your doctor can discuss with you a more complete list of side effects and laboratory abnormalities that may accompany this medication.

If any side effects or unusual symptoms do occur, contact your doctor immediately. Do not stop or decrease your dose on your own. Lowering the dose may make INVIRASE less effective in fighting HIV.

Are there other medications that I should not take with INVIRASE/Norvir (ritonavir)?

There are some drugs that should not be taken with INVIRASE. Before starting therapy with INVIRASE, be sure to tell your doctor all of the medicinesóprescription medications, as well as over-the-counter drugs and nutritional supplementsóthat you are now taking or plan to take.

MEDICINES YOU SHOULD NOT TAKE WITH INVIRASE

Drug Class

Drugs Within Class Not to Be Taken with INVIRASE/Norvir (ritonavir)

Antiarrhythmics

Pacerone® (amiodarone), Tambocor® (flecainide), Rhythmol® (propafenone), bepridil, quinidine

Antihistamines

Seldane® (terfenadine)*, Hismanal® (astemizole)*

Antimigraines

Ergot medications (eg, Wigraine® and Cafergot®)

GI motility agents

Propulsid® (cisapride)*

Sedatives, hypnotics

Versed® (midazolam), Halcion® (triazolam)

Antimycobacterial agents

Rifampin

Neuroleptics

Pimozide

* No longer sold in the US.

INVIRASE causes increased blood levels of these compounds. This can lead to serious or life-threatening reactions such as irregular heartbeat or prolonged sedation.

Taking INVIRASE with St. Johnís wort (hypericum perforatum), an herbal product sold as a dietary supplement, or products containing St. Johnís wort is not recommended. Talk with your doctor if you are taking or are planning to take St. Johnís wort. Taking St. Johnís wort may decrease INVIRASE levels and lead to increased viral load and possible resistance to INVIRASE or cross-resistance to other antiretroviral drugs.

Garlic capsules should not be used while taking FORTOVASE as the sole protease inhibitor due to the risk of decreased saquinavir in the blood. No data are available for the coadministration of FORTOVASE and Norvir with garlic capsules or INVIRASE and Norvir with garlic capsules.

Your doctor may want to change your medicine if you are taking rifampin (known as Rifadin®, Rifamate®, Rifater® or Rimactane®) or Mycobutin® (rifabutin); these drugs substantially reduce the level of INVIRASE in the blood.

The following drugs increase blood levels of INVIRASE: Norvir® (ritonavir)á, Viracept® (nelfinavir)§, Rescriptor® (delavirdine)§||, Nizoral® (ketoconazole), Crixivan® (indinavir)§ and Biaxin (clarithromycin).

Talk to your doctor if you are taking lipid (cholesterol) lowering drugs and Viagra® (sildenafil citrate), Levitra® (vardenafil), and Cialis® (tadalafil).

Does INVIRASE cure HIV/AIDS?

INVIRASE does not cure AIDS, and it does not prevent you from getting other illnesses that result from advanced HIV infection. In addition, INVIRASE has not been shown to reduce the risk that you may transmit HIV to others through sexual contact or infected blood. You must continue to follow all of your doctorís recommendations for managing your illness.

What else should I discuss with my doctor?

Inform your doctor:

· If you are pregnant or become pregnant while taking INVIRASE. The effects of INVIRASE on pregnant women or unborn babies are not yet fully known. In addition, experts advise against breast-feeding if you are HIV positive, to reduce the risk of passing the virus to your baby.

· If you are taking anti-HIV medications. Your doctor may want to change one or more of your anti-HIV drugs in order to achieve the best results when you start treatment with INVIRASE.

· If you have diabetes or a family history of diabetes, or if you have hemophilia, hepatitis or other liver disease, your doctor should decide if INVIRASE is right for you.

· If you have ever taken FORTOVASE, discuss with your doctor whether INVIRASE is right for you.

How is INVIRASE supplied?

INVIRASE is available as light brown and green capsules in a 200-mg strength. INVIRASE comes in bottles of 270 capsules.

INVIRASE is also available as light orange to greyish- or brownish-orange tablets in a 500-mg strength. INVIRASE comes in bottles of 120 tablets.

How should I store INVIRASE?

INVIRASE capsules and tablets should be stored at room temperature. The bottles should be kept tightly closed.

INVIRASE has been prescribed specifically for you, and only for a particular condition. Do not use it for anything else. Do not give it to anyone else. If you think you have taken more than your prescribed dose, seek medical attention.

Keep this medication and all other medications out of the reach of children. Do not keep medicine that is out of date or that you no longer need. Be sure that if you throw any medicine away, it is out of the reach of children.

This provides only a brief summary of product information about INVIRASE. If you have any questions about INVIRASE or HIV, talk to your doctor.

Ü Below the amount that could be found using a standard test.

á Dosages greater than 100 mg twice a day of ritonavir when taken in combination with saquinavir were associated with an increase in side effects.

§ The safety and efficacy of INVIRASE in combination with these drugs has not been established. Dosage adjustments may be required.

|| Use of this combination should be accompanied by close monitoring of liver enzymes.

FORTOVASE and Versed are registered trademarks of Hoffmann-La Roche Inc. Norvir, Rhythmol, and Biaxin are registered trademarks of Abbott Laboratories. Halcion, Mycobutin and Rescriptor are registered trademarks of Pharmacia & Upjohn Co. Hismanal, Propulsid and Nizoral are registered trademarks of Janssen Pharmaceutica Inc. Seldane, Rifadin, Rifamate and Rifater are registered trademarks of Hoechst Marion Roussel. Rimactane and Cafergot are registered trademarks of Novartis Pharmaceuticals Corporation. Viracept is a registered trademark of Agouron Pharmaceuticals Inc. Crixivan is a registered trademark of Merck & Co., Inc. Viagra is a registered trademark of Pfizer, Inc. Levitra is a registered trademark of Bayer Pharmaceuticals Corp. Cialis is a registered trademark of Eli Lilly and Company. Tambocor is a registered trademark of 3M. Pacerone is a registered trademark of Upsher-Smith.

If you have any questions about INVIRASE, call toll free at 1-800-910-4687.

Distributed by: Pharmaceuticals, Roche Laboratories Inc. 340 Kingslan Street, Nutley, New Jersey 07110-1199, 27898778, 20304972, Revised: December 2004, Copyright© 1999-2004 by Roche Laboratories Inc. All rights reserved.

 

Invirase Interactions

DRUG INTERACTIONS

Several drug interaction studies have been completed with both INVIRASE and FORTOVASE. Observations from drug interaction studies
with FORTOVASE may not be predictive for INVIRASE. Because ritonavir is coadministered, prescribers should also refer to the
prescribing information for ritonavir regarding drug interactions associated with this agent.

The metabolism of saquinavir is mediated by cytochrome P450, with the specific isoenzyme CYP3A4 responsible for 90% of the hepatic
metabolism. Additionally, saquinavir is a substrate for P-Glycoprotein (Pgp). Therefore, drugs that affect CYP3A4 and/or Pgp, may
modify the pharmacokinetics of saquinavir. Similarly, saquinavir might also modify the pharmacokinetics of other drugs that are
substrates for CYP3A4 or Pgp.

Drugs that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events
are listed CONTRAINDICATIONS. Additional drugs that are not recommended for coadministration with INVIRASE and ritonavir are included
below. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of
interaction and potential for serious events or loss of efficacy.

When coadministering INVIRASE/ritonavir with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants,
and antiarrhythmics, special attention is warranted. With some agents, the metabolism may be induced, resulting in decreased
concentrations.
Drugs That Should Not Be Coadministered With INVIRASE/Ritonavir

Drug Class: Drug Name
Clinical Comment


Antiarrhythmics: Amiodarone, bepridil, flecainide, propafenone, quinidine
CONTRAINDICATED due to potential for serious and/or life-threatening reactions.

Antihistamines: astemizole*, terfenadine*
CONTRAINDICATED due to potential for serious and/or life-threatening cardiac arrhythmias.

Ergot Derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine
CONTRAINDICATED due to potential for serious and life-threatening reactions such as acute ergot toxicity characterized by peripheral
vasospasm and ischemia of the extremities and other tissues.

Antimycobacterial Agents: rifampin
CONTRAINDICATED since the coadministration of this product with saquinavir in an antiretroviral regimen reduces the plasma concentrations
of saquinavir.

Garlic Capsules
Garlic capsules should not be used while taking saquinavir (FORTOVASE) as the sole protease inhibitor due to the risk of decreased
saquinavir plasma concentrations.

No data are available for the coadministration of INVIRASE/ritonavir or FORTOVASE/ritonavir and garlic capsules.

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)
WARNING coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease
inhibitors.

HMG-CoA Reductase Inhibitors: lovastatin, simvastatin
WARNING potential for serious reactions such as risk of myopathy including rhabdomyolysis.

Sedatives/Hypnotics: triazolam, midazolam
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory
depression.

* No longer marketed in the US.

Drugs That Are Mainly Metabolized by CYP3A4

Although specific studies have not been performed, coadministration with drugs that are mainly metabolized by CYP3A4 (eg, calcium channel
blockers, dapsone, disopyramide, quinine, amiodarone, quinidine, warfarin, tacrolimus, cyclosporine, ergot derivatives, pimozide,
carbamazepine, fentanyl, alfentanyl, alprazolam, and triazolam) may have elevated plasma concentrations when coadministered with saquinavir;
therefore, these combinations should be used with caution. Since INVIRASE is coadministered with ritonavir, the ritonavir label should be
reviewed for additional drugs that should not be coadministered.

Inducers of CYP3A4

Coadministration with compounds that are potent inducers of CYP3A4 (eg, phenobarbital, phenytoin, dexamethasone, carbamazepine) may result
in decreased plasma levels of saquinavir.

 

Invirase Contraindications

CONTRAINDICATIONS

INVIRASE may be used only if it is combined with ritonavir, which significantly inhibits saquinavir's metabolism and
provides plasma saquinavir levels at least equal to those achieved with FORTOVASE.

INVIRASE is contraindicated in patients with clinically significant hypersensitivity to saquinavir or to any of the
components contained in the capsule.

INVIRASE/ritonavir should not be administered concurrently with terfenadine, cisapride, astemizole, pimozide, triazolam,
midazolam or ergot derivatives. Inhibition of CYP3A4 by saquinavir could result in elevated plasma concentrations of
these drugs, potentially causing serious or life-threatening reactions, such as cardiac arrhythmias or prolonged sedation.

INVIRASE when administered with ritonavir is contraindicated in patients with severe hepatic impairment.

INVIRASE should not be administered concurrently with drugs listed drug interaction section and drugs below

Drugs That Are Contraindicated With INVIRASE/Ritonavir

Drug Class
Drugs Within Class That Are Contraindicated With INVIRASE

Antiarrhythmics
Amiodarone, bepridil, flecainide, propafenone, quinidine

Antihistamines
Astemizole, terfenadine

Ergot Derivatives
Dihydroergotamine, ergonovine, ergotamine, methylergonovine

Antimycobacterial Agents
Rifampin*

GI Motility Agent
Cisapride

Neuroleptics
Pimozide

Sedative/Hypnotics
Triazolam, midazolam

*INVIRASE used as a sole protease inhibitor

 

Additional information about Invirase

Invirase Indication: For the treatment of HIV-1 with advanced immunodeficiency together with antiretroviral nucleoside analogues.
Mechanism Of Action: Invirase inhibits the HIV viral proteinase enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles.
Drug Interactions: Not Available
Food Interactions: Take after a full meal.
Generic Name: Saquinavir
Synonyms: Saquinavir Mesylate; SQV
Drug Category: Anti-HIV Agents
Drug Type: Small Molecule; Approved; Investigational

Other Brand Names containing Saquinavir: Fortovase; Invirase; ROC;
Absorption: Absolute bioavailability averages 4%
Toxicity (Overdose): Probably experience pain in the throat
Protein Binding: 98%
Biotransformation: Hepatic
Half Life: Not Available
Dosage Forms of Invirase: Tablet Oral
Capsule Oral
Chemical IUPAC Name: (2S)-N-[(2S,3R)-4-[(3S)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-(quinoline-2-carbonylamino)butanediamide
Chemical Formula: C38H50N6O5
Saquinavir on Wikipedia: https://en.wikipedia.org/wiki/Saquinavir
Organisms Affected: Human Immunodeficiency Virus