Saquinavir (Invirase)

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 (5.1)].

• The standard recommended dose of INVIRASE is 1,000 mg twice daily 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 1,000 mg twice daily with ritonavir 100 mg twice daily [see Warnings and Precautions (5.4) 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 (NNRTI) based regimen (not including delavirdine, rilpivirine) should initiate and continue INVIRASE/ritonavir at the standard recommended dose of 1,000 mg twice daily with ritonavir 100 mg twice daily. For patients switching from a regimen containing delavirdine, 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 (5.4) 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.

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

INVIRASE is not recommended for use in combination with cobicistat. Dosing recommendations for this combination have not been established. Cobicistat is also not recommended in combination with regimens containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A. Refer to the cobicistat full prescribing information for additional precautionary measures.

Initiation of INVIRASE/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving INVIRASE/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of INVIRASE/ritonavir, respectively. These interactions may lead to:

• Clinically significant adverse reactions potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications.
• Clinically significant adverse reactions from greater exposures of INVIRASE/ritonavir.
• Loss of therapeutic effect of INVIRASE/ritonavir and possible development of resistance.

See Table 2 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during INVIRASE/ritonavir therapy; review concomitant medications during INVIRASE/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7)].

If a serious or severe toxicity occurs during treatment with INVIRASE/ritonavir, discontinue INVIRASE/ritonavir. For concomitantly used drugs including antiretroviral agents used in combination with INVIRASE/ritonavir, prescribers should refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions.

INVIRASE/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 [see Warnings and Precautions (5.4)]. Discontinue INVIRASE/ritonavir if significant arrhythmias, QT or PR prolongation occur.

The impact on the PR interval of coadministration of INVIRASE/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, coadministration of INVIRASE/ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A, and clinical monitoring is recommended [see Clinical Pharmacology (12.2)].

For concomitantly used drugs, including antiretroviral agents used in combination with INVIRASE/ritonavir, physicians should refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions.

INVIRASE/ritonavir causes dose-dependent QT prolongation. Torsade de pointes has been reported rarely post-marketing. Avoid INVIRASE/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 INVIRASE/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 Table 2) [see Clinical Pharmacology (12.2)]. For concomitantly used drugs, including antiretroviral agents used in combination with INVIRASE/ritonavir, refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions [see Contraindications (4) and Drug Interactions (7)]. Discontinue INVIRASE/ritonavir if significant arrhythmias, QT or PR prolongation occurs.

New onset of 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.

In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism or other underlying liver abnormalities, there have been reports of worsening of the underlying liver disease and development of portal hypertension after starting INVIRASE/ritonavir. Jaundice and exacerbation of chronic liver disease with grade 4 elevated liver function tests were also observed. No dosage adjustment is necessary for patients with mild or moderate hepatic impairment based on limited data [see Clinical Pharmacology (12.3)]. INVIRASE/ritonavir is contraindicated in patients with severe hepatic impairment [see Contraindications (4)]. If a serious or severe toxicity occurs during treatment with INVIRASE/ritonavir, discontinue INVIRASE/ritonavir.

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.

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/ritonavir, and at periodic intervals while on such therapy. In these patients, lipid disorders should be managed as clinically appropriate.

Each tablet contains lactose (monohydrate) 38.5 mg. INVIRASE is not recommended in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption (autosomal recessive disorder).

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 has been reported in patients treated with combination antiretroviral therapy, including INVIRASE/ritonavir. 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.

Varying degrees of cross-resistance among HIV-1 protease inhibitors have been observed. Continued administration of INVIRASE/ritonavir therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors [see Microbiology (12.4)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The original INVIRASE safety database consisted of a total of 574 adult subjects who received 600 mg of saquinavir mesylate capsules (hard gel) alone or in combination with zidovudine (ZDV) or zalcitabine (ddC). Combination dosing with ritonavir is based on 352 HIV-1 infected subjects and 166 healthy subjects who received various combinations of either saquinavir mesylate capsules (hard gel or soft gel) with ritonavir.

The recommended dose of INVIRASE is 1,000 mg twice daily co-administered with ritonavir 100 mg twice daily. Table 1 lists Grade 2, 3 and 4 adverse events that occurred in ≥2% of subjects receiving saquinavir mesylate capsules (soft gel) with ritonavir (1000/100 mg bid).

Limited experience is available from three trials investigating the pharmacokinetics of the INVIRASE 500-mg film-coated tablet compared to the 200-mg saquinavir mesylate capsules (hard gel) in healthy volunteers (n=140). In two of these trials, saquinavir was combined with ritonavir; in the other trial, saquinavir was administered as single drug. The INVIRASE tablet and the saquinavir mesylate capsule (hard gel) were similarly tolerated. The most common adverse events were gastrointestinal disorders (nausea, vomiting, and diarrhea). Similar bioavailability was demonstrated and no clinically significant differences in saquinavir exposures were seen. Thus, similar safety profiles are expected between the two INVIRASE formulations.

A study investigating the drug-drug interaction of rifampin 600 mg/day daily and INVIRASE 1000 mg/ritonavir 100 mg twice daily enrolled 28 healthy volunteers. Eleven of 17 (65%) healthy volunteers exposed concomitantly to rifampin and INVIRASE/ritonavir developed severe hepatocellular toxicity which presented as increased hepatic transaminases. In some subjects, transaminases increased up to > 20-fold the upper limit of normal and were associated with gastrointestinal symptoms, including abdominal pain, gastritis, nausea, and vomiting. Following discontinuation of all three drugs, clinical symptoms abated and hepatic transaminases normalized [see Contraindications (4)].

Limited safety data are available from two pediatric clinical trials of saquinavir mesylate capsules (hard gel) (approximately 50 mg per kg twice daily) used in combination with either low dose ritonavir or lopinavir/ritonavir. These trials enrolled pediatric subjects aged 4 months to 16 years old. In the HIVNAT 017 study (saquinavir mesylate capsules (hard gel) + lopinavir/ritonavir), adverse events were reported in 90% of the 50 subjects enrolled. The most commonly reported adverse events considered related to study treatment were diarrhea (18%) and vomiting (10%). In the NV20911 study (saquinavir mesylate capsules (hard gel) + ritonavir), 4 subjects (22% of 18 enrolled) experienced adverse events that were considered related to INVIRASE + ritonavir. These events (n) were vomiting (3), abdominal pain (1) and diarrhea (1). All reported adverse events were mild or moderate in intensity. The adverse reaction profile of INVIRASE in the pediatric trials is similar to that observed in adult trials.

Additional adverse events identified during postmarketing use are similar to those observed in clinical trials with INVIRASE, saquinavir mesylate capsules (hard gel and soft gel) alone or in combination with ritonavir. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to INVIRASE exposure. In addition, torsade de pointes has been reported rarely [see Warnings and Precautions (5.4) ].

The combination INVIRASE/ritonavir is a potent inhibitor of CYP3A and may significantly increase the exposure of drugs primarily metabolized by CYP3A. Drugs that are contraindicated specifically due to the observed or expected magnitude of interaction and potential for serious or life-threatening adverse events are listed in Section 4 Contraindications [see Contraindications (4)]. Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring (see Table 2).

The metabolism of saquinavir is mediated primarily by CYP3A. Additionally, saquinavir is a substrate for P-glycoprotein (P-gp). Therefore, drugs that affect CYP3A and/or P-gp may modify the pharmacokinetics of saquinavir. Coadministration with drugs that are potent inducers of CYP3A (e.g., phenobarbital, phenytoin, carbamazepine) may result in decreased plasma concentrations of saquinavir and reduced therapeutic effect.

Based on the finding of dose-dependent prolongations of QT and PR intervals in healthy volunteers receiving INVIRASE/ritonavir, additive effects on QT and/or PR interval prolongation may occur with certain members of the following drug classes: antiarrhythmics class IA or class III, neuroleptics, antidepressants, PDE5 inhibitors (when used for pulmonary arterial hypertension), antimicrobials, antihistaminics and others. This effect might lead to an increased risk of ventricular arrhythmias, notably torsade de pointes. Therefore, concurrent administration of these agents with INVIRASE/ritonavir is contraindicated [see Contraindications (4)].

Table 2 provides examples of established or potentially clinically significant drug interactions. This table includes potentially significant interactions but is not all inclusive. Alteration in dose or avoidance of the combination may be recommended depending on the interaction.

Based on drug interaction studies conducted with INVIRASE/ritonavir, no clinically significant effect was observed for saquinavir when coadministered with fosamprenavir. No clinically significant effect was observed for enfuvirtide when coadministered with INVIRASE/ritonavir.

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

There are no data available regarding the presence of saquinavir in human milk, the effects on the breastfed infant, or the effects on milk production.

Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) adverse reactions in breastfed infants similar to those seen in adults, instruct mothers not to breastfeed if they are receiving INVIRASE.

The safety and activity of INVIRASE have been evaluated in 68 pediatric subjects 4 months to less than 16 years of age treated with saquinavir mesylate capsules (hard gel) combined with either ritonavir or with lopinavir/ritonavir in two clinical trials. Data from the NV20911 trial demonstrated that saquinavir mesylate capsules (hard gel) combined 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 (12.3)]. 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 saquinavir mesylate capsules (hard gel) (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 saquinavir mesylate capsules (hard gel) (50 mg per kg twice daily as 200-mg capsules, up to the adult dose of 1,000 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 (5.3, 5.4), Clinical Pharmacology (12.2, 12.3)]. 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.

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/ritonavir 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.

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/ritonavir in this population.

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 (12.3)]. INVIRASE/ritonavir is contraindicated in patients with severe hepatic impairment [see Contraindications (4)].

INVIRASE is an antiretroviral agent [see Microbiology (12.4)]

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 hours post-dose. INVIRASE/ritonavir 1500/100 mg twice daily resulted in a Day 3 mean C_max of INVIRASE approximately 40% higher than the mean C_max observed on Day 3 with the approved therapeutic dose in healthy volunteers (within the same study). QTcS in this study was QT/RR^0.319 for males and QT/RR^0.337 for females, which are similar to Fridericia's correction (QTcF=QT/RR^0.3333).

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%) 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%) (Day14). 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.

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, C_max, and C_min in healthy subjects are approximately 50% higher than observed in HIV-1-infected subjects.

In a randomized, double-blind clinical study NV14256 in zidovudine-experienced, HIV-1-infected adult subjects, saquinavir mesylate capsules (hard gel) in combination with zalcitabineNo longer available in the US. was shown to be superior to monotherapy with either saquinavir mesylate capsules (hard gel) or zalcitabine in decreasing the cumulative incidence of clinical disease progression to AIDS-defining events or death. In another randomized study ACTG229/NV14255, subjects with advanced HIV-1 infection with history of prolonged zidovudine treatment were administered saquinavir mesylate capsules (hard gel) 600 mg (three times daily) + zidovudine + zalcitabine. Subjects receiving this regimen experienced greater increases in CD4⁺ cell counts as compared to those who received saquinavir mesylate capsules (hard gel) + zidovudine or zalcitabine + zidovudine. It should be noted the HIV treatment regimens that were used in these clinical trials are no longer considered standard of care.

In the MaxCmin1 trial, saquinavir gel capsule 1,000 mg twice daily coadministered with ritonavir 100 mg twice daily was evaluated in a heterogeneous population of 148 HIV-1-infected subjects. A total of 42 subjects enrolled were treatment naïve, and 106 subjects were treatment experienced (of which 52 subjects had HIV-1 RNA < 400 copies/mL at baseline). Results showed that 91/148 (61%) subjects achieved and/or sustained an HIV-1 RNA < 400 copies per mL at the completion of 48 weeks of treatment.

Important Dosing Instructions

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

Advise patients that INVIRASE administered with ritonavir should be taken within 2 hours after a meal [see Clinical Pharmacology (12.3) ]. When INVIRASE/ritonavir is taken without food, concentrations of saquinavir in the blood are substantially reduced and may result in no antiviral activity. Advise patients 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.

Risk of Serious Adverse Reactions Drug Interactions

INVIRASE/ritonavir may interact with many drugs; therefore, advise patients to report the use of any other prescription, nonprescription medication, or herbal products, particularly St. John's wort [see Contraindications (4), Warnings and Precautions (5.2), and Drug Interactions (7)].

PR and QT Interval Prolongation

Inform patients that INVIRASE/ritonavir may produce changes in the electrocardiogram (PR interval or QT interval prolongation). Advise patients to consult their health care provider if they are experiencing symptoms such as dizziness, lightheadedness, or palpitations [see Warnings and Precautions (5.3, 5.4)].

Diabetes Mellitus/Hyperglycemia

Inform patients that new onset of diabetes or exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during INVIRASE/ritonavir use. Advise patients to notify their healthcare provider if they develop signs and symptoms of diabetes [see Warnings and Precautions (5.5)].

Hepatotoxicity

Inform patients with underlying liver abnormalities that there have been reports of worsening liver disease and development of portal hypertension with INVIRASE/ritonavir. Advise patients about the signs and symptoms of liver problems [see Warnings and Precautions (5.6)]

Hyperlipidemia

Advise patients that treatment with INVIRASE/ritonavir can result in substantial increases in total cholesterol and triglycerides [see Warnings and Precautions (5.8)]

Fat Redistribution

Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including INVIRASE/ritonavir, and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.10)].

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.11)].

Pregnancy Exposure Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiretrovirals during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].