Invirase

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests before and during your treatment to check your body's response to saquinavir. Your doctor may also order an electrocardiogram (ECG; test that measures the electrical activity in the heart) before and during your treatment.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Saquinavir is an antiviral medicine that prevents human immunodeficiency virus (HIV) cells from multiplying in your body.

Saquinavir is used together with ritonavir to treat HIV, which causes acquired immunodeficiency syndrome (AIDS). Neither saquinavir nor ritonavir will not cure HIV or AIDS.

Saquinavir may also be used for purposes not listed in this medication guide.

Saquinavir must be taken together with another medicine called ritonavir.

Life-threatening side effects may occur if you take saquinavir with certain other medicines. Tell your doctor about all medicines you use, and those you start or stop using during your treatment with saquinavir.

You should not take this medicine if you are allergic to saquinavir or ritonavir (Norvir, Kaletra), or if you have:

• a serious heart condition called "AV block" (unless you have a pacemaker);
• personal or family history of long QT syndrome;
• severe liver disease; or
• low levels of potassium or magnesium in your blood.

Life-threatening side effects may occur if you take saquinavir with:

• alfuzosin;
• atazanavir;
• oral midazolam, or triazolam;
• sildenafil (Revatio, for treating pulmonary arterial hypertension);
• tacrolimus;
• trazodone;
• anti-psychotic medication--chlorpromazine, clozapine, haloperidol, mesoridazine, pimozide, thioridazine, ziprasidone;
• certain anti-infective medicines--clarithromycin, dapsone, erythromycin, halofantrine, pentamidine, rifampin;
• cholesterol medication--lovastatin (Mevacor, Altoprev, Advicor) or simvastatin (Zocor, Simcor, Vytorin);
• ergot medicine--dihydroergotamine, ergotamine, ergonovine, methylergonovine; or
• heart rhythm medicine--amiodarone, dofetilide, flecainide, lidocaine, propafenone, or quinidine.

To make sure saquinavir is safe for you, tell your doctor if you have:

• heart disease;
• liver disease (including hepatitis B or C);
• a bleeding or blood clotting disorder such as hemophilia;
• diabetes; or
• high cholesterol or triglycerides.

Tell your doctor if you are pregnant or plan to become pregnant. HIV can be passed to your baby if you are not properly treated during pregnancy. Take all of your HIV medicines as directed to control your infection.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of saquinavir on the baby.

Saquinavir can make birth control pills less effective. Ask your doctor about using non hormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy.

Women with HIV or AIDS should not breast-feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

Saquinavir is not approved for use by anyone younger than 16 years old.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Saquinavir may increase your risk of certain infections or autoimmune disorders by changing the way your immune system works. Symptoms may occur weeks or months after you start treatment with saquinavir. Tell your doctor if you have:

• signs of a new infection--fever, night sweats, swollen glands, mouth sores, diarrhea, stomach pain, weight loss;
• chest pain (especially when you breathe), dry cough, wheezing, feeling short of breath;
• cold sores, sores on your genital or anal area;
• rapid heart rate, feeling anxious or irritable, weakness or prickly feeling, problems with balance or eye movement;
• trouble speaking or swallowing, severe lower back pain, loss of bladder or bowel control; or
• swelling in your neck or throat (enlarged thyroid), menstrual changes, impotence, loss of interest in sex.

Call your doctor at once if you have:

• any type of infection, skin infection, or open sores;
• cough with yellow or green mucus, stabbing chest pain, wheezing, feeling short of breath;
• high blood sugar--increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, weight loss; or
• liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common side effects may include:

• nausea, vomiting, diarrhea, stomach pain;
• tired feeling; or
• changes in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and waist).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Grapefruit and grapefruit juice may interact with Invirase and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.

Taking this medicine will not prevent you from passing HIV to other people. Do not have unprotected sex or share razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Saquinavir may increase your risk of certain infections or autoimmune disorders by changing the way your immune system works. Symptoms may occur weeks or months after you start treatment with saquinavir. Tell your doctor if you have:

• signs of a new infection--fever, night sweats, swollen glands, mouth sores, diarrhea, stomach pain, weight loss;

• chest pain (especially when you breathe), dry cough, wheezing, feeling short of breath;

• cold sores, sores on your genital or anal area;

• rapid heart rate, feeling anxious or irritable, weakness or prickly feeling, problems with balance or eye movement;

• trouble speaking or swallowing, severe lower back pain, loss of bladder or bowel control; or

• swelling in your neck or throat (enlarged thyroid), menstrual changes, impotence, loss of interest in sex.

Call your doctor at once if you have:

• any type of infection, skin infection, or open sores;

• cough with yellow or green mucus, stabbing chest pain, wheezing, feeling short of breath;

• high blood sugar--increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, weight loss; or

• liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common side effects may include:

• nausea, vomiting, diarrhea, stomach pain;

• tired feeling; or

• changes in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and waist).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Administration

Oral Administration

Administer orally with low-dose ritonavir (ritonavir-boosted saquinavir) within 2 hours of a meal.1 15 51

Do not administer without low-dose ritonavir.1 200 201

Administer saquinavir dose at same time as ritonavir dose.1 In patients already receiving ritonavir as part of an antiretroviral regimen, no additional ritonavir is needed.1

For patients unable to swallow capsules, empty contents of appropriate number of saquinavir capsules into container and mix with 15 mL of sugar syrup, 15 mL of sorbitol syrup, or 3 teaspoons of jam.1 Stir mixture for 30–60 seconds.1 Allow mixture to reach room temperature and administer entire dose to the patient.1

Dosage

Available as saquinavir mesylate;1 dosage expressed as saquinavir.1

Saquinavir mesylate hard gelatin capsules and film-coated tablets are bioequivalent when given with low-dose ritonavir under fed conditions.1

Pediatric Patients

Adolescents >16 years of age: 1 g twice daily with low-dose ritonavir (100 mg twice daily).1

Treatment-naive adolescents >16 years of age: Use low initial dosage of 500 mg twice daily with low-dose ritonavir (100 mg twice daily) for 7 days, then 1 g twice daily with low-dose ritonavir (100 mg twice daily) thereafter.1

Previously treated adolescents >16 years of age receiving delavirdine or rilpivirine and switching to ritonavir-boosted saquinavir: 500 mg twice daily with low-dose ritonavir (100 mg twice daily) for 7 days, then 1 g twice daily with low-dose ritonavir (100 mg twice daily) thereafter.1

Previously treated adolescents >16 years of age receiving a different ritonavir-boosted PI or an NNRTI (except delavirdine or rilpivirine) and switching to ritonavir-boosted saquinavir: 1 g twice daily with low-dose ritonavir (100 mg twice daily).1

Adults

1 g twice daily with low-dose ritonavir (100 mg twice daily).1

Treatment-naive adults: Use low initial dosage of 500 mg twice daily with low-dose ritonavir (100 mg twice daily) for 7 days, then 1 g twice daily with low-dose ritonavir (100 mg twice daily) thereafter.1

Previously treated adults receiving delavirdine or rilpivirine and switching to ritonavir-boosted saquinavir: 500 mg twice daily with low-dose ritonavir (100 mg twice daily) for 7 days, then 1 g twice daily with low-dose ritonavir (100 mg twice daily) thereafter.1

Previously treated adults receiving a different ritonavir-boosted PI or an NNRTI (except delavirdine or rilpivirine) and switching to ritonavir-boosted saquinavir: 1 g twice daily with low-dose ritonavir (100 mg twice daily).1

1 g twice daily with low-dose ritonavir (100 mg twice daily).199 Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.199

Special Populations

Hepatic Impairment

Dosage adjustments not necessary in mild to moderate hepatic impairment;1 some experts recommend caution.200 Contraindicated in severe hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No initial dosage adjustments needed.1 Use with caution in severe renal impairment or end-stage renal disease.1

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Metabolized by CYP3A.1 83 94

Inhibits CYP3A.1 94

Substrate for P-glycoprotein (P-gp).1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A with possible alteration in metabolism of saquinavir and/or other drug.1 51 83 94

Drugs Affecting or Affected by P-gp Transport

Potential pharmacokinetic interaction with drugs that are inhibitors, inducers, or substrates of P-gp with possible alteration in pharmacokinetics of saquinavir and/or other drug.1

Drugs that Prolong the QT or PR Interval

Dose-dependent prolongation of QT and PR intervals has been reported in individuals receiving ritonavir-boosted saquinavir; additive effects on QT and/or PR interval prolongation may occur if ritonavir-boosted saquinavir is used concomitantly with other drugs known to have similar effects.1 Concomitant use with other drugs known to prolong QT and/or PR intervals (e.g., class IA and class III antiarrhythmic agents, neuroleptics, phosphodiesterase type 5 inhibitors if used for PAH, some antidepressants, some anti-infectives, some antihistamines) not recommended.1 119 (See Cardiovascular Effects under Cautions.)

Specific Drugs and Foods

• Saquinavir medication guide must be provided to the patient each time the drug is dispensed;1 importance of patient reading the medication guide prior to initiating saquinavir therapy and each time prescription is refilled.1

• Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1

• Importance of using in conjunction with other antiretroviralsnot for monotherapy.1

• Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1

• Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to acquired immunodeficiency syndrome (AIDS) and death.203

• Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 200

• Importance of taking within 2 hours of a meal, not on an empty stomach.1

• Advise patients that ECG changes (PR and/or QT interval prolongation) have occurred;1 importance of consulting clinician if symptoms such as dizziness, lightheadedness, fainting, or sensation of abnormal heartbeats occur.1

• Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), and any concomitant illnesses.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise HIV-infected women not to breast-feed.1

• Importance of advising patients of other important precautionary information.1 (See Cautions.)

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of saquinavir in children younger than 16 years. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of saquinavir in the elderly. However, elderly patients are more likely to have age-related liver, kidney, or heart problems, which may require caution in patients receiving saquinavir.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Alfuzosin
• Amifampridine
• Amiodarone
• Amisulpride
• Amitriptyline
• Anagrelide
• Apomorphine
• Aripiprazole
• Aripiprazole Lauroxil
• Arsenic Trioxide
• Artemether
• Asenapine
• Astemizole
• Atazanavir
• Azithromycin
• Bedaquiline
• Bepridil
• Buserelin
• Chloroquine
• Chlorpromazine
• Ciprofloxacin
• Cisapride
• Clarithromycin
• Clozapine
• Colchicine
• Conivaptan
• Crizotinib
• Cyclobenzaprine
• Dabrafenib
• Dapsone
• Dasatinib
• Degarelix
• Delamanid
• Deslorelin
• Deutetrabenazine
• Dihydroergotamine
• Dixyrazine
• Dofetilide
• Dolasetron
• Domperidone
• Donepezil
• Doxepin
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Dronedarone
• Droperidol
• Ebastine
• Efavirenz
• Eletriptan
• Eplerenone
• Ergoloid Mesylates
• Ergonovine
• Ergotamine
• Eribulin
• Erythromycin
• Escitalopram
• Famotidine
• Felbamate
• Fingolimod
• Flecainide
• Flibanserin
• Fluconazole
• Fluoxetine
• Fluphenazine
• Formoterol
• Foscarnet
• Galantamine
• Gatifloxacin
• Gemifloxacin
• Gonadorelin
• Goserelin
• Granisetron
• Grazoprevir
• Halofantrine
• Haloperidol
• Histrelin
• Hydroquinidine
• Hydroxychloroquine
• Hydroxyzine
• Ibutilide
• Iloperidone
• Imipramine
• Isavuconazonium Sulfate
• Ivabradine
• Ketoconazole
• Lapatinib
• Leuprolide
• Levofloxacin
• Lidocaine
• Lomitapide
• Lovastatin
• Lumefantrine
• Lurasidone
• Maraviroc
• Mefloquine
• Mesoridazine
• Methadone
• Methdilazine
• Methylergonovine
• Metopimazine
• Metronidazole
• Midazolam
• Mifepristone
• Mizolastine
• Moxifloxacin
• Nafarelin
• Naloxegol
• Nilotinib
• Nimodipine
• Norfloxacin
• Octreotide
• Ofloxacin
• Olanzapine
• Ondansetron
• Paliperidone
• Panobinostat
• Paroxetine
• Pasireotide
• Pazopanib
• Pentamidine
• Perazine
• Periciazine
• Perphenazine
• Pimavanserin
• Pimozide
• Pipamperone
• Piperaquine
• Pipotiazine
• Pitolisant
• Posaconazole
• Procainamide
• Prochlorperazine
• Promazine
• Promethazine
• Propafenone
• Propiomazine
• Quetiapine
• Quinidine
• Quinine
• Ranolazine
• Ribociclib
• Rifampin
• Riociguat
• Risperidone
• Romidepsin
• Sertindole
• Sevoflurane
• Sildenafil
• Silodosin
• Simvastatin
• Sodium Phosphate
• Sodium Phosphate, Dibasic
• Sodium Phosphate, Monobasic
• Solifenacin
• Sorafenib
• Sotalol
• Sparfloxacin
• Sulpiride
• Tacrolimus
• Tamoxifen
• Telaprevir
• Telavancin
• Telithromycin
• Terfenadine
• Tetrabenazine
• Thiethylperazine
• Thioproperazine
• Thioridazine
• Tizanidine
• Tolterodine
• Tolvaptan
• Toremifene
• Trazodone
• Triazolam
• Trifluoperazine
• Triflupromazine
• Trimipramine
• Triptorelin
• Vandetanib
• Vemurafenib
• Venetoclax
• Venlafaxine
• Vilanterol
• Vinflunine
• Voriconazole
• Vorinostat
• Ziprasidone
• Zuclopenthixol

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Ado-Trastuzumab Emtansine
• Afatinib
• Amprenavir
• Aprepitant
• Atorvastatin
• Avanafil
• Axitinib
• Boceprevir
• Bosentan
• Bosutinib
• Brentuximab Vedotin
• Brexpiprazole
• Brigatinib
• Bromocriptine
• Cabazitaxel
• Cabozantinib
• Calcifediol
• Carbamazepine
• Cariprazine
• Ceritinib
• Cilostazol
• Citalopram
• Clomipramine
• Cobicistat
• Cobimetinib
• Cyclophosphamide
• Daclatasvir
• Darunavir
• Deflazacort
• Delavirdine
• Dexamethasone
• Dexlansoprazole
• Digoxin
• Docetaxel
• Eluxadoline
• Enzalutamide
• Erlotinib
• Esomeprazole
• Eszopiclone
• Everolimus
• Fentanyl
• Fluticasone
• Fosamprenavir
• Fosaprepitant
• Fosphenytoin
• Fusidic Acid
• Garlic
• Hydrocodone
• Ibrutinib
• Idelalisib
• Ifosfamide
• Indinavir
• Irinotecan
• Irinotecan Liposome
• Ivacaftor
• Ixabepilone
• Lacosamide
• Lansoprazole
• Levomilnacipran
• Loperamide
• Lopinavir
• Macitentan
• Manidipine
• Midostaurin
• Nelfinavir
• Netupitant
• Nevirapine
• Nifedipine
• Olaparib
• Omeprazole
• Orlistat
• Oxycodone
• Palbociclib
• Pantoprazole
• Phenobarbital
• Phenytoin
• Pixantrone
• Ponatinib
• Primidone
• Rabeprazole
• Reboxetine
• Regorafenib
• Retapamulin
• Rifabutin
• Rifapentine
• Rosuvastatin
• Ruxolitinib
• Salmeterol
• Simeprevir
• Sirolimus
• Sonidegib
• St John's Wort
• Sunitinib
• Suvorexant
• Tadalafil
• Tamsulosin
• Temsirolimus
• Thiotepa
• Ticagrelor
• Tipranavir
• Trabectedin
• Valbenazine
• Vardenafil
• Vilazodone
• Vincristine
• Vincristine Sulfate Liposome
• Vorapaxar
• Zolpidem

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Cerivastatin
• Cimetidine
• Cyclosporine
• Flunarizine
• Gallopamil
• Itraconazole
• Lacidipine
• Nilvadipine
• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcoholism, history of or
• Arrhythmias (abnormal heart beats), history of or
• Congestive heart failure, history of or
• Heart disease, history of or
• Heart rhythm problems, history of or
• Hemophilia (a bleeding problem) or
• Hyperlipidemia (high cholesterol in the blood) or
• Liver disease (eg, hepatitis B or C)—Use with caution. May increase your chance for serious side effects.

• Diabetes or
• Hyperglycemia (high blood sugar)—Use with caution. May make these conditions worse.

• Heart block, without a pacemaker or
• Heart rhythm problems (eg, congenital long QT syndrome), history of or
• Liver disease, severe—Should not be used in patients with these conditions.

• Lactose intolerance—Use with caution. Saquinavir capsules contain lactose.

Invirase must be used in combination with ritonavir because ritonavir significantly inhibits saquinavir's metabolism to provide increased plasma saquinavir levels.

Cobicistat is not interchangeable with ritonavir to increase systemic exposure of saquinavir [see Warnings and Precautions (5)].

Recommended Dose

• The standard recommended dose of Invirase is 1000-mg twice daily (5 × 200-mg capsules or 2 × 500-mg tablets) in combination with ritonavir 100-mg twice daily.
• For treatment-naïve patients initiating treatment with Invirase/ritonavir, the recommended starting dose of Invirase is 500-mg twice daily with ritonavir 100-mg twice daily for the first 7 days of treatment. After 7 days, the recommended dose of Invirase is 1000-mg twice daily with ritonavir 100-mg twice daily [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.2)].
• Patients switching immediately (no washout period) from treatment with another ritonavir containing regimen or from a non-nucleoside reverse transcriptase inhibitor based regimen (not including delavirdine, rilpivirine) should initiate and continue Invirase at the standard recommended dose of 1000-mg twice daily with ritonavir 100-mg twice daily. For patients switching from a regimen containing delavirdine or rilpivirine, the recommended dose is 500-mg twice daily with ritonavir 100-mg twice daily for the first 7 days of treatment [see Warnings and Precautions (5.3) and Drug Interactions (7.3)].
• Ritonavir should be taken at the same time as Invirase.
• Invirase and ritonavir should be taken within 2 hours after a meal.
• For patients already taking ritonavir 100-mg twice daily as part of their antiretroviral regimen, no additional ritonavir is needed.
• Pediatric dose recommendations that are both reliably effective and below thresholds of concern for QT and PR interval prolongation could not be determined.

Administration for Patients Unable to Swallow Capsules

Open the Invirase capsules and place the contents into an empty container. Add 15 mL of either sugar syrup or sorbitol syrup (for patients with Type 1 diabetes or glucose intolerance) OR 3 teaspoons of jam to the contents of Invirase capsules that are in the container. Stir with a spoon for 30 to 60 seconds. Administer the full amount prepared for each dose. Suspensions should be at room temperature before administering.

There is limited experience of overdose with saquinavir.

No acute toxicities or sequelae were noted in 1 subject who ingested 8 grams of Invirase as a single dose. The subject was treated with induction of emesis within 2 to 4 hours after ingestion. A second subject ingested 2.4 grams of Invirase in combination with 600 mg of ritonavir and experienced pain in the throat that lasted for 6 hours and then resolved. In an exploratory Phase II study of oral dosing with Invirase at 7200 mg per day (1200 mg q4h), there were no serious toxicities reported through the first 25 weeks of treatment.

Treatment of overdose with saquinavir should consist of general supportive measures including monitoring of vital signs and ECG and observations of the patient's clinical status. Since saquinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

Invirase brand of saquinavir mesylate is an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease.

The chemical name for saquinavir mesylate is N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide methanesulfonate with a molecular formula C38H50N6O5∙CH4O3S and a molecular weight of 766.96. The molecular weight of the free base is 670.86. Saquinavir mesylate has the following structural formula:

Saquinavir mesylate is a white to off-white, very fine powder with an aqueous solubility of 2.22 mg per mL at 25°C.

Invirase is available as light brown and green, opaque hard gelatin capsules for oral administration in a 200-mg strength (as saquinavir free base). Each capsule also contains the inactive ingredients lactose, microcrystalline cellulose, povidone K30, sodium starch glycolate, talc, and magnesium stearate. Each capsule shell contains gelatin and water with the following dye systems: red iron oxide, yellow iron oxide, black iron oxide, FD&C Blue #2, and titanium dioxide.

Invirase is also available as a light orange to greyish- or brownish-orange, oval cylindrical, biconvex film-coated tablet for oral administration in 500-mg strength (as saquinavir free base). Each tablet also contains the inactive ingredients lactose, microcrystalline cellulose, povidone K30, croscarmellose sodium, and magnesium stearate. Each film coat contains hypromellose, titanium dioxide, talc, iron oxide yellow, iron oxide red, and triacetin.

Mechanism of Action

Invirase is an antiviral agent [see Microbiology (12.4)]

Pharmacodynamics

QTcS interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 59 healthy adults, with ECG measurements on Day 3. The maximum mean (95% upper confidence bound) differences in QTcS interval from placebo after baseline-correction were 18.9 (22.0) and 30.2 (33.4) ms for 1000/100 mg twice daily and supratherapeutic 1500/100 mg twice daily of Invirase/ritonavir, respectively. There is a delayed effect between QTc interval change and drug concentrations, with the maximum placebo-adjusted baseline-corrected QTcS observed at about 12-20 h post-dose. Invirase/ritonavir 1500/100 mg twice daily resulted in a Day 3 mean Cmax of Invirase approximately 40% higher than the mean Cmax observed on Day 3 with the approved therapeutic dose in healthy volunteers (within the same study). QTcS in this study was QT/RR0.319 for males and QT/RR0.337 for females, which are similar to Fridericia's correction (QTcF=QT/RR0.3333).

PR and QRS interval prolongations were also noted in subjects receiving Invirase/ritonavir in the same study on Day 3. The maximum mean (95% upper confidence bound) difference from placebo in the PR interval after baseline-correction were 28.6 (31.6) and 38.4 (41.4) ms for 1000/100 mg twice daily and supratherapeutic 1500/100 mg twice daily saquinavir/ritonavir respectively. The maximum mean (95% upper confidence bound) difference from placebo in QRS interval after baseline correction were 2.9 (3.9) and 4.4 (5.3) ms for 1000/100 mg twice daily and supratherapeutic 1500/100 mg twice daily Invirase/ritonavir respectively. In this study using healthy subjects, PR interval prolongation of >200 ms was also observed in 40% and 47% of subjects receiving Invirase/ritonavir 1000/100 mg bid and 1500/100 mg bid, respectively, on Day 3. Three (3%) of subjects in the active control moxifloxacin arm and 5% in the placebo arm experienced PR prolongation of >200 ms.

The effect of treatment initiation with a dosing regimen of Invirase/ritonavir 500/100 mg twice daily in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) for the first 7 days of treatment followed by Invirase/ritonavir 1000/100 mg twice daily in combination with two NRTIs in the subsequent 7 days on QTc interval, PK, and viral load was evaluated in an open-label 2-week observational study in 23 HIV-1 infected, treatment-naive patients. ECG and PK measurements were collected on Days 3, 4, 7, 10, and 14 of treatment. Two of 21 (9%) patients across all study days had maximum QTcF change from dense predose baseline ≥ 30 msec following administration of the modified Invirase/ritonavir regimen and the maximum mean change from dense predose baseline in the QTcF was < 10 msec across all study days. The proportion of patients with a reported PR interval prolongation >200 msec in this study ranged from 3/22 (14%) (Day 3) to 8/21 (38%) (Day 14). These results suggest that the risk of QTc interval prolongation is reduced with the modified Invirase/ritonavir dosing regimen, based on a cross-study comparison to the moxifloxacin-controlled QTc study described above.

Pharmacokinetics

The pharmacokinetics of Invirase/ritonavir 1000/100 mg twice daily have been evaluated in HIV-1-infected subjects and healthy subjects. Steady-state saquinavir AUC, Cmax, and Cmin in healthy subjects are approximately 50% higher than observed in HIV-1-infected subjects.

Adults

Absorption and Bioavailability in Adults

Similar bioavailability was demonstrated when Invirase 500 mg film-coated tablet (2 × 500 mg) and Invirase 200 mg capsule (5 × 200 mg) were administered with low-dose ritonavir (100 mg) under fed conditions. The ratio of mean exposures (90% confidence intervals) of tablets vs capsules was 1.10 (1.04-1.16) for AUC0-∞ and 1.19 (1.14-1.25) for Cmax.

Absolute bioavailability of saquinavir administered as Invirase averaged 4% (CV 73%, range: 1% to 9%) in 8 healthy volunteers who received a single 600-mg dose (3 × 200 mg) of saquinavir mesylate following a high-fat breakfast (48 g protein, 60 g carbohydrate, 57 g fat; 1006 kcal). The low bioavailability is thought to be due to a combination of incomplete absorption and extensive first-pass metabolism.

Invirase in combination with ritonavir at a dose of 1000/100 mg twice daily provides saquinavir systemic exposures over a 24-hour period that are similar to those achieved with saquinavir soft gel capsules with ritonavir 1000/100 mg twice daily and greater than that achieved with saquinavir soft gel capsules 1200 mg three times daily (see Table 4).

In treatment-naïve HIV-1 infected patients initiating Invirase/ritonavir treatment with a modified Invirase/ritonavir dosing regimen of Invirase 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days of treatment followed by an increase in the Invirase dose to 1000 mg twice daily with ritonavir 100 mg twice daily for an additional 7 days, saquinavir systemic exposures on Day 3 were approximately 70% lower compared to Invirase/ritonavir 1000/100 mg twice daily regimen on Day 3 in healthy volunteers. Saquinavir systemic exposures across study days generally approached or exceeded the range of historical steady-state values with the standard Invirase/ritonavir 1000 mg/100 mg twice daily dosing regimen (see Table 4 and Table 5).

Food Effect

The mean 24-hour AUC after a single 600-mg oral dose (6 × 100 mg) in healthy volunteers (n=6) was increased from 24 ng∙h/mL (CV 33%), under fasting conditions, to 161 ng∙h/mL (CV 35%) when Invirase was given following a high-fat breakfast (48 g protein, 60 g carbohydrate, 57 g fat; 1006 kcal). Saquinavir 24-hour AUC and Cmax (n=6) following the administration of a higher calorie meal (943 kcal, 54 g fat) were on average 2 times higher than after a lower calorie, lower fat meal (355 kcal, 8 g fat). The effect of food has been shown to persist for up to 2 hours.

Invirase/ritonavir should be taken within 2 hours after a meal.

Distribution

The mean steady-state volume of distribution following intravenous administration of a 12-mg dose of saquinavir (n=8) was 700 L (CV 39%), suggesting saquinavir partitions into tissues. Saquinavir was approximately 98% bound to plasma proteins over a concentration range of 15 to 700 ng/mL. In 2 subjects receiving saquinavir mesylate 600 mg three times daily, cerebrospinal fluid concentrations were negligible when compared to concentrations from matching plasma samples.

Metabolism and Elimination

In vitro studies using human liver microsomes have shown that the metabolism of saquinavir is cytochrome P450 mediated with the specific isoenzyme, CYP3A4, responsible for more than 90% of the hepatic metabolism. Based on in vitro studies, saquinavir is rapidly metabolized to a range of mono- and di-hydroxylated inactive compounds. In a mass balance study using 600 mg 14C-saquinavir mesylate (n=8), 88% and 1% of the orally administered radioactivity was recovered in feces and urine, respectively, within 5 days of dosing. In an additional 4 subjects administered 10.5 mg 14C-saquinavir intravenously, 81% and 3% of the intravenously administered radioactivity was recovered in feces and urine, respectively, within 5 days of dosing. In mass balance studies, 13% of circulating radioactivity in plasma was attributed to unchanged drug after oral administration and the remainder attributed to saquinavir metabolites. Following intravenous administration, 66% of circulating radioactivity was attributed to unchanged drug and the remainder attributed to saquinavir metabolites, suggesting that saquinavir undergoes extensive first-pass metabolism.

Systemic clearance of saquinavir was rapid, 1.14 L/h/kg (CV 12%) after intravenous doses of 6, 36, and 72 mg. The mean residence time of saquinavir was 7 hours (n=8).

Special Populations

Renal Impairment

Saquinavir pharmacokinetics in patients with renal impairment has not been investigated. Only 1% of saquinavir is excreted in the urine, so the impact of renal impairment on saquinavir elimination would likely be minimal. However, subjects with severe renal impairment or end-stage renal disease (ESRD) have not been studied, and concentrations of saquinavir may be elevated in these populations.

Hepatic Impairment

The effect of hepatic impairment on the steady state pharmacokinetics of Invirase/ritonavir (1000/100 mg bid for 14 days) was investigated in 7 HIV-1-infected subjects with moderate liver impairment (6 with Child-Pugh score of 7 and 1 with Child-Pugh score of 9). The study included a control group consisting of 7 HIV-1-infected subjects with normal hepatic function matched with hepatically impaired subjects for age, gender, weight and tobacco use. The mean (% coefficient of variation in parentheses) values for Invirase AUC0-12 and Cmax were 24.3 (102%) µg∙hr/mL and 3.6 (83%) µg/mL, respectively, for HIV-1-infected subjects with moderate hepatic impairment. The corresponding values in the control group were 28.5 (71%) µg∙hr/mL and 4.3 (68%) µg/mL. The geometic mean ratio (ratio of pharmacokinetic parameters in hepatically impaired subjects to subjects with normal liver function) (90% confidence interval) was 0.7 (0.3 to 1.6) for both AUC0-12 and Cmax, which suggests approximately 30% reduction in saquinavir exposure in subjects with moderate hepatic impairment. No dose adjustment is warranted for Invirase in HIV-1-infected patients with mild or moderate hepatic impairment [see Warnings and Precautions (5.5)].

Gender, Race, and Age

A gender difference was observed, with females showing higher saquinavir exposure than males (mean AUC 56% higher, mean Cmax 26% higher), in the relative bioavailability study comparing Invirase 500 mg film-coated tablets to the Invirase 200 mg capsules in combination with ritonavir. There was no evidence that age and body weight explained the gender difference in this study. A clinically significant difference in safety and efficacy between men and women has not been reported with the approved dosage regimen (saquinavir 1000-mg/ritonavir 100-mg twice daily).

The effect of race on the pharmacokinetics of saquinavir has not been investigated.

The pharmacokinetics of saquinavir have not been evaluated in the elderly.

Pediatric Subjects

Steady-state pharmacokinetic information is available from HIV-1 infected pediatric subjects from study NV20911. In this study, 5 subjects less than 2 years of age and 13 subjects between 2 and less than 6 years of age received 50 mg per kg saquinavir twice daily (not to exceed 1000 mg twice daily) combined with ritonavir at 3 mg/kg for subjects with body weight ranging from 5 to <15 kg or 2.5 mg per kg for subjects with body weight ranging from 15 to 40 kg (not to exceed 100 mg twice daily). For subjects unable to swallow the Invirase capsules, the contents of Invirase 200 mg capsules were mixed with sugar syrup, or sorbitol syrup (for subjects with Type I diabetes or glucose intolerance), jam, or baby formula. The mean steady state saquinavir PK parameters for pediatric subjects 2 to less than 6 years of age were: AUC0-12h 37269 ± 18232 ng∙h/mL; Ctrough 1811 ± 998 ng/mL; Cmax 5464 ± 2782 ng/mL, and day 3 exposures may be within the range of exposure associated with QT and PR prolongation [see Clinical Pharmacology: Pharmacodynamics (12.2)]. The subject number was too low and the pharmacokinetic data too variable in the subjects less than 2 years to establish an appropriate dosing recommendation for this age group. Pharmacokinetic data for subjects ages 6 to 16 years were not available for comparisons with observations from NV20911 [see Use in Specific Populations: Pediatric Use (8.4)] as the data from HIVNAT 017 could not be validated.

Drug Interactions

Table 6 summarizes the effect of saquinavir soft gel capsules and Invirase with and without ritonavir on the geometric mean AUC and Cmax of coadministered drugs. Table 7 summarizes the effect of coadministered drugs on the geometric mean AUC and Cmax of saquinavir.

The HIV-1 antiviral drugs didanosine, tenofovir, and zidovudine are not predicted to have any clinically significant effect on the pharmacokinetics of saquinavir with and without ritonavir. No clinically significant effect on the pharmacokinetic parameters of enfuvirtide was observed with coadministration of Invirase/ritonavir. No clinically significant effect on the pharmacokinetic parameters of saquinavir was observed with coadministration of fosamprenavir.

Microbiology

Mechanism of Action

Saquinavir is an inhibitor of HIV-1 protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of viral polyprotein precursors into individual functional proteins found in HIV-1 particles. Saquinavir is a peptide-like substrate analogue that binds to the protease active site and inhibits the activity of the enzyme. Saquinavir inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature noninfectious viral particles.

Antiviral Activity

The antiviral activity of saquinavir was assessed in lymphoblastoid and monocytic cell lines and in peripheral blood lymphocytes in cell culture. Saquinavir inhibited HIV-1 activity in both acutely and chronically infected cells. EC50 and EC90 values (50% and 90% inhibitory concentrations) ranged from 1 to 30 nM and 5 to 80 nM, respectively. In the presence of 40% human serum, the mean EC50 of saquinavir against laboratory strain HIV-1 RF in MT4 cells was 37.7± 5 nM representing a 4-fold increase in the EC50 value. In cell culture, saquinavir demonstrated additive to synergistic effects against HIV-1 in combination with reverse transcriptase inhibitors (didanosine, lamivudine, nevirapine, stavudine and zidovudine) without enhanced cytotoxicity. Saquinavir in combination with the protease inhibitors amprenavir, atazanavir, or lopinavir resulted in synergistic antiviral activity. Saquinavir displayed antiviral activity in cell culture against HIV-1 clades A-H (EC50 values ranged from 0.9 to 2.5 nM). The EC50 and EC90 values of saquinavir against HIV-2 isolates in cell culture ranged from 0.25 nM to 14.6 nM and 4.65 nM to 28.6 nM, respectively.

Resistance

HIV-1 isolates with reduced susceptibility to saquinavir have been selected during passage in cell culture. Genotypic analyses of these isolates showed several amino acid substitutions in the HIV-1 protease. Only the G48V and L90M substitutions were associated with reduced susceptibility to saquinavir, and conferred an increase in the EC50 value of 8- and 3-fold, respectively.

HIV-1 isolates with reduced susceptibility (≥4-fold increase in the EC50 value) to saquinavir emerged in some subjects treated with Invirase. Genotypic analysis of these isolates identified resistance conferring primary amino acid substitutions in the protease G48V and L90M, and secondary substitutions L10I/R/V, I54V/L, A71V/T, G73S, V77I, V82A and I84V that contributed additional resistance to saquinavir. Forty-one isolates from 37 subjects failing therapy with Invirase had a median decrease in susceptibility to saquinavir of 4.3-fold.

The degree of reduction in cell culture susceptibility to saquinavir of clinical isolates bearing substitutions G48V and L90M depends on the number of secondary substitutions present. In general, higher levels of resistance are associated with greater number of substitutions only in association with either or both of the primary substitutions G48V and L90M. No data are currently available to address the development of resistance in patients receiving saquinavir/ritonavir.

Cross-resistance

Among protease inhibitors, variable cross-resistance has been observed. In one clinical study, 22 HIV-1 isolates with reduced susceptibility (>4-fold increase in the EC50 value) to saquinavir following therapy with Invirase were evaluated for cross-resistance to amprenavir, indinavir, nelfinavir and ritonavir. Six of the 22 isolates (27%) remained susceptible to all 4 protease inhibitors, 12 of the 22 isolates (55%) retained susceptibility to at least one of the protease inhibitors and 4 out of the 22 isolates (18%) displayed broad cross-resistance to all protease inhibitors. Sixteen (73%) and 11 (50%) of the 22 isolates remained susceptible (<4-fold) to amprenavir and indinavir, respectively. Four of 16 (25%) and nine of 21 (43%) with available data remained susceptible to nelfinavir and ritonavir, respectively.

After treatment failure with amprenavir, cross-resistance to saquinavir was evaluated. HIV-1 isolates from 22/22 subjects failing treatment with amprenavir and containing one or more substitutions M46L/I, I50V, I54L, V32I, I47V, and I84V were susceptible to saquinavir.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies found no indication of carcinogenic activity in rats and mice administered saquinavir for approximately 2 years. Because of limited bioavailability of saquinavir in animals, the plasma exposures (AUC values) in the respective species were approximately 29% (using rat) and 65% (using mouse) of those obtained in humans at the recommended clinical dose combined with ritonavir.

Mutagenesis

Mutagenicity and genotoxicity studies, with and without metabolic activation where appropriate, have shown that saquinavir has no mutagenic activity in vitro in either bacterial (Ames test) or mammalian cells (Chinese hamster lung V79/HPRT test). Saquinavir does not induce chromosomal damage in vivo in the mouse micronucleus assay or in vitro in human peripheral blood lymphocytes, and does not induce primary DNA damage in vitro in the unscheduled DNA synthesis test.

Impairment of Fertility

No adverse effects were reported in fertility and reproductive performance study conducted in rats. Because of limited bioavailability of saquinavir in animals, the maximal plasma exposures achieved in rats were approximately 26% of those obtained in humans at the recommended clinical dose combined with ritonavir.

You should not take Invirase if you are allergic to saquinavir or ritonavir (Norvir, Kaletra), or if you have:

• a serious heart condition called "AV block" (unless you have a pacemaker);

• personal or family history of long QT syndrome;

• severe liver disease; or

• low levels of potassium or magnesium in your blood.

Life-threatening side effects may occur if you take Invirase with:

• alfuzosin;

• atazanavir;

• oral midazolam, or triazolam;

• sildenafil (Revatio, for treating pulmonary arterial hypertension);

• tacrolimus;

• trazodone;

• anti-psychotic medication - chlorpromazine, clozapine, haloperidol, mesoridazine, pimozide, thioridazine, ziprasidone;

• certain anti-infective medicines - clarithromycin, dapsone, erythromycin, halofantrine, pentamidine, rifampin;

• cholesterol medication - lovastatin (Mevacor, Altoprev, Advicor) or simvastatin (Zocor, Simcor, Vytorin);

• ergot medicine - dihydroergotamine, ergotamine, ergonovine, methylergonovine; or

• heart rhythm medicine - amiodarone, dofetilide, flecainide, lidocaine, propafenone, or quinidine.

To make sure Invirase is safe for you, tell your doctor if you have:

• heart disease;

• liver disease (including hepatitis B or C);

• a bleeding or blood clotting disorder such as hemophilia;

• diabetes; or

• high cholesterol or triglycerides.

Tell your doctor if you are pregnant or plan to become pregnant. HIV can be passed to your baby if you are not properly treated during pregnancy. Take all of your HIV medicines as directed to control your infection.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of Invirase on the baby.

Invirase can make birth control pills less effective. Ask your doctor about using non hormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy.

Women with HIV or AIDS should not breast-feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

Invirase is not approved for use by anyone younger than 16 years old.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Try not to miss any of your doses. Skipping doses may increase the risk of your virus becoming resistant to antiviral medicine.

Common side effects of Invirase include: abdominal distress, diarrhea, and nausea. Other side effects include: vomiting. See below for a comprehensive list of adverse effects.