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Invirase

"The U.S. Food and Drug Administration today announced that new safety information has been added to the label for the HIV antiviral drug Invirase (saquinavir), describing potentially life-threatening side effects on the heart when used with Norvi"...

Invirase

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

INVIRASE must be used in combination with ritonavir. Please refer to the ritonavir full prescribing information for additional precautionary measures.

If a serious or severe toxicity occurs during treatment with INVIRASE, INVIRASE should be interrupted until the etiology of the event is identified or the toxicity resolves. At that time, resumption of treatment with full-dose INVIRASE may be considered. For antiretroviral agents used in combination with INVIRASE, physicians should refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions.

Drug Interactions

The combination INVIRASE/ritonavir is a potent inhibitor of CYP3A and may significantly increase the exposure of drugs primarily metabolized by CYP3A. See Table 1 for a listing of drugs that are contraindicated for use with INVIRASE/ritonavir due to potentially life-threatening adverse events or significant drug interactions [see CONTRAINDICATIONS]. See Table 3 for established and other potentially significant drug interactions [see DRUG INTERACTIONS].

PR Interval Prolongation

Saquinavir/ritonavir prolongs the PR interval in a dose-dependent fashion. Cases of second or third degree atrioventricular block have been reported rarely. Patients with underlying structural heart disease, pre-existing conduction system abnormalities, cardiomyopathies and ischemic heart disease may be at increased risk for developing cardiac conduction abnormalities. ECG monitoring is recommended in these patients.

The impact on the PR interval of co-administration of saquinavir/ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of saquinavir/ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A, and clinical monitoring is recommended [see CLINICAL PHARMACOLOGY].

QT Interval Prolongation

Saquinavir/ritonavir causes dose-dependent QT prolongation. Torsades de pointes has been reported rarely post-marketing. Avoid saquinavir/ritonavir in patients with long QT syndrome. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, hepatic impairment and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating saquinavir/ritonavir and monitor these electrolytes periodically during therapy. Do not use in combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval (see Tables 1 and 3) [see CLINICAL PHARMACOLOGY].

Patients initiating therapy with ritonavir-boosted INVIRASE:

An ECG should be performed prior to initiation of treatment. Patients with a QT interval > 450 msec should not receive ritonavir-boosted INVIRASE. For patients with a QT interval < 450 msec, an on-treatment ECG is suggested after approximately 3 to 4 days of therapy; patients with a QT interval > 480 msec or prolongation over pre-treatment by > 20 msec should discontinue ritonavir-boosted INVIRASE.

Patients requiring treatment with medications with the potential to increase the QT interval and concomitant ritonavir-boosted INVIRASE:

Such combinations should only be used where no alternative therapy is available and the potential benefits outweigh the potential risks. An ECG should be performed prior to initiation of the concomitant therapy, and patients with a QT interval > 450 msec should not initiate the concomitant therapy. If baseline QT interval < 450 msec, an on-treatment ECG should be performed after 3-4 days of therapy. For patients demonstrating a subsequent increase in QT interval to > 480 msec or increase by > 20 msec after commencing concomitant therapy, the physician should use best clinical judgment to discontinue either ritonavir-boosted INVIRASE or the concomitant therapy or both.

A cardiology consult is recommended if drug discontinuation or interruption is being considered on the basis of ECG assessment.

Diabetes Mellitus / Hyperglycemia

New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus and hyperglycemia have been reported during postmarketing surveillance in HIV-1-infected patients receiving protease-inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for the treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued protease-inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease-inhibitor therapy and these events has not been established.

Hepatotoxicity

In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism and/or other underlying liver abnormalities, there have been reports of worsening liver disease.

Hemophilia

There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In some patients additional factor VIII was required. In the majority of reported cases treatment with protease inhibitors was continued or restarted. A causal relationship between protease inhibitor therapy and these episodes has not been established.

Hyperlipidemia

Elevated cholesterol and/or triglyceride levels have been observed in some patients taking saquinavir in combination with ritonavir. Marked elevation in triglyceride levels is a risk factor for development of pancreatitis. Cholesterol and triglyceride levels should be monitored prior to initiating combination dosing regimen of INVIRASE with ritonavir, and at periodic intervals while on such therapy. In these patients, lipid disorders should be managed as clinically appropriate.

Lactose Intolerance

Each capsule contains lactose (anhydrous) 63.3 mg. This quantity should not induce specific symptoms of intolerance.

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), facial wasting, peripheral wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including INVIRASE. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

Resistance/Cross-resistance

Varying degrees of cross-resistance among HIV-1 protease inhibitors have been observed. Continued administration of INVIRASE therapy following loss of viral suppression may increase the likelihood of cross resistance to other protease inhibitors [see Microbiology].

Patient Counseling Information

A statement to patients and health care providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with INVIRASE.

INVIRASE is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using INVIRASE.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

  • Do not share needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
  • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
  • Do not breastfeed. We do not know if INVIRASE can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Drug Interactions

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. John's wort.

PR and QT Interval Prolongation

Patients should be informed that INVIRASE may produce changes in the electrocardiogram (PR interval or QT interval prolongation). Patients should consult their health care provider if they are experiencing symptoms such as dizziness, lightheadedness, or palpitations.

Fat Redistribution

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.

Dosing Instructions

Patients should be advised that INVIRASE must be used in combination with ritonavir, which significantly inhibits saquinavir's metabolism to provide increased plasma saquinavir levels.

Patients should be advised that INVIRASE administered with ritonavir should be taken within 2 hours after a full meal [see CLINICAL PHARMACOLOGY]. 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.

Nonclinical Toxicology

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 boosted 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 boosted with ritonavir.

Use In Specific Populations

Pregnancy

Pregnancy Category B

Reproduction studies conducted with saquinavir have shown no embryotoxicity or teratogenicity in both rats and rabbits. Because of limited bioavailability of saquinavir in animals and/or dosing limitations, the plasma exposures (AUC values) in the respective species were approximately 29% (using rat) and 21% (using rabbit) of those obtained in humans at the recommended clinical dose boosted with ritonavir. Clinical experience in pregnant women is limited. Saquinavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral medications, including INVIRASE, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.

It is not known whether saquinavir is excreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving INVIRASE.

Pediatric Use

The safety and activity of saquinavir have been evaluated in 68 pediatric subjects 4 months to less than 16 years of age treated with INVIRASE boosted with either ritonavir or with lopinavir/ritonavir in two clinical trials. Data from the NV20911 trial demonstrated that saquinavir boosted with low dose ritonavir provided plasma levels of saquinavir that were significantly higher than those historically observed in adults at the approved dose [see CLINICAL PHARMACOLOGY]. The HIVNAT 017 trial provided long term 96-week activity and safety data; however, pharmacokinetic data from this study could not be validated.

HIVNAT 017 was an open-label, single-arm trial at two centers in Thailand that evaluated the use of INVIRASE (50 mg per kg twice daily given as 200 mg capsules) with lopinavir/ritonavir (230/57.5 mg/m² twice daily) for 96 weeks. Fifty subjects 4 years to less than 16 years of age were enrolled. In this trial population, treatment resulted in HIV-1 RNA < 400 copies/mL at week 96 in 78% of subjects (HIV-1 RNA < 50 copies per mL at week 96 in 66%). Mean CD4 lymphocyte percentage increased from 8% at screening to 22% at week 96.

NV20911 was an open label, multinational trial that evaluated the pharmacokinetics, safety, and activity of INVIRASE (50 mg per kg twice daily as 200 mg capsules, up to the adult dose of 1000 mg twice daily) and ritonavir oral solution plus ≥ 2 background ARVs. Eighteen subjects 4 months to less than 6 years of age were enrolled. Treatment with INVIRASE/ritonavir resulted in HIV-1 RNA < 400 copies per mL at week 48 in 72% of subjects (HIV-1 RNA < 50 copies per mL at week 48 in 61%). The percentage of subjects with HIV-1 RNA < 50 copies per mL at week 48 was 61%. Mean CD4 lymphocyte percentage increased from 29% at screening to 34% at week 48.

Steady state saquinavir exposures observed in pediatric trials were substantially higher than historical data in adults where dose- and exposure-dependent QTc and PR prolongation were observed [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY]. Although electrocardiogram abnormalities were not reported in these pediatric trials, the trials were small and not designed to evaluate QT or PR intervals. Modeling and simulation assessment of pharmacokinetic/pharmacodynamic relationships in pediatric subjects suggest that reducing the INVIRASE dose to minimize risk of QT prolongation is likely to reduce antiviral efficacy. In addition, no clinical efficacy data are available at INVIRASE doses less than 50 mg per kg in pediatric subjects. Therefore, pediatric dose recommendations that are both reliably effective and below thresholds of concern with respect to QT and PR prolongation could not be determined.

Geriatric Use

Clinical trials of INVIRASE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dosing INVIRASE in elderly patients should be undertaken with caution keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Impaired Renal Function

Renal clearance is a minor elimination pathway; the principal route of excretion for saquinavir is by hepatic metabolism. Therefore, no initial dose adjustment is necessary for patients with renal impairment. However, patients with severe renal impairment or end-stage renal disease (ESRD) have not been studied, and caution should be exercised when prescribing INVIRASE in this population.

Impaired Hepatic Function

No dosage adjustment is necessary for HIV-1-infected patients with mild or moderate hepatic impairment based on limited data. In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism and/or other underlying liver abnormalities, there have been reports of worsening liver disease [see CLINICAL PHARMACOLOGY]. INVIRASE when administered with ritonavir is contraindicated in patients with severe hepatic impairment [see CONTRAINDICATIONS].

Last reviewed on RxList: 12/18/2012
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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