ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of the labeling:PR Interval Prolongation [see Warnings and Precautions (5.3)] QT Interval Prolongation [see Warnings and Precautions (5.4)] PR Interval Prolongation [see Warnings and Precautions (5.3)] QT Interval Prolongation [see Warnings and Precautions (5.4)] The most common adverse reactions are nausea, vomiting, diarrhea, fatigue, pneumonia, lipodystrophy and abdominal pain. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trial Experience in Adult Subjects. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 lists Grade 2, and adverse events that occurred in >=2% of subjects receiving saquinavir mesylate capsules (soft gel) with ritonavir (1000/100 mg bid).Table Grade 2, and Adverse Events (All CausalityIncludes events with unknown relationship to study drug) Reported in >=2% of Adult Subjects in the MaxCmin Study of Saquinavir Mesylate Capsules (soft gel) in Combination with Ritonavir 1000/100 mg Twice DayAdverse EventsSaquinavir Mesylate Capsules (soft gel) 1000 mg plus Ritonavir 100 mg bid (48 weeks)N=148n (%=n/N)Endocrine Disorders Diabetes mellitus/hyperglycemia4 (3) Lipodystrophy8 (5)Gastrointestinal Disorders Nausea16 (11) Vomiting11 (7) Diarrhea12 (8) Abdominal Pain9 (6) Constipation3 (2)General Disorders and Administration Site Conditions Fatigue9 (6) Fever5 (3)Musculoskeletal Disorders Back Pain3 (2)Respiratory Disorders Pneumonia8 (5) Bronchitis4 (3) Influenza4 (3) Sinusitis4 (3)Dermatological Disorders Rash5 (3) Pruritus5 (3) Dry lips/skin3 (2) Eczema3 (2)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)].. Additional Adverse Reactions Reported During Clinical Trials with SaquinavirBlood and lymphatic system disorders: anemia, hemolytic anemia, leukopenia, lymphadenopathy, neutropenia, pancytopenia, thrombocytopeniaCardiac disorders: heart murmur, syncopeEar and labyrinth disorders: tinnitusEye disorders: visual impairmentGastrointestinal disorders: abdominal discomfort, ascites, dyspepsia, dysphagia, eructation, flatulence, gastritis, gastrointestinal hemorrhage, intestinal obstruction, mouth dry, mucosal ulceration, pancreatitisGeneral disorders and administration site conditions: anorexia, asthenia, chest pain, edema, lethargy, wasting syndrome, weight increasedHepatobiliary disorders: chronic active hepatitis, hepatitis, hepatomegaly, hyperbilirubinemia, jaundice, portal hypertensionImmune system disorders: allergic reactionInvestigations: ALT increase, AST increase, blood creatine phosphokinase increased, increased alkaline phosphatase, GGT increase, raised amylase, raised LDHMetabolism and nutrition disorders: increased or decreased appetite, dehydration, hypertriglyceridemiaMusculoskeletal and connective tissue disorders: arthralgia, muscle spasms, myalgia, polyarthritisNeoplasms benign, malignant and unspecified (including cysts and polyps): acute myeloid leukemia, papillomatosisNervous system disorders: confusion, convulsions, coordination abnormal, dizziness, dysgeusia, headache, hypoesthesia, intracranial hemorrhage leading to death, loss of consciousness, paresthesia, peripheral neuropathy, somnolence, tremorPsychiatric disorders: anxiety, depression, insomnia, libido disorder, psychotic disorder, sleep disorder, suicide attemptRenal and urinary disorders: nephrolithiasisRespiratory, thoracic and mediastinal disorders: cough, dyspneaSkin and subcutaneous tissue disorders: acne, alopecia, dermatitis bullous, drug eruption, erythema, severe cutaneous reaction associated with increased liver function tests, Stevens-Johnson syndrome, sweating increased, urticariaVascular disorders: hypertension, hypotension, thrombophlebitis, peripheral vasoconstriction. 6.2 Clinical Trial Experience in Pediatric Subjects. 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 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), 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.. 6.3 Postmarketing Experience. 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to INVIRASE exposure. In addition, torsade de pointes has been reported rarely [see Warnings and Precautions (5.4) ].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. INVIRASE is an antiretroviral agent [see Microbiology (12.4)] 12.2 Pharmacodynamics. QTcS interval was evaluated in 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 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 Day mean Cmax of INVIRASE approximately 40% higher than the mean Cmax observed on Day 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 Fridericias 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%) 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 dosing regimen of INVIRASE/ritonavir 500/100 mg twice daily in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) for the first days of treatment followed by INVIRASE/ritonavir 1000/100 mg twice daily in combination with two NRTIs in the subsequent 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 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 cross-study comparison to the moxifloxacin-controlled QTc study described above.. 12.3 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 AdultsSimilar bioavailability was demonstrated when 1,000 mg of INVIRASE tablets or 1,000 mg of saquinavir mesylate capsules (hard gel) was 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 saquinavir mesylate capsules (hard gel) averaged 4% (CV 73%, range: 1% to 9%) in healthy volunteers who received single 600 mg dose (3 200-mg) of saquinavir mesylate following high-fat breakfast (48 protein, 60 carbohydrate, 57 fat; 1006 kcal). The low bioavailability is thought to be due to combination of incomplete absorption and extensive first-pass metabolism.INVIRASE/ritonavir at dose of 1000/100 mg twice daily provides saquinavir systemic exposures over 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 3).Table Pharmacokinetic Parameters of Saquinavir at Steady-State after Administration of Different Regimens in HIV-1-Infected SubjectsDosing RegimenNAUC (ngh/mL)AUC24h (ngh/mL)Cmin (ng/mL) is the dosing interval (i.e., 8h if three times daily and 12h if twice daily)Saquinavir mesylate capsules (hard gel) 600 mg tid (arithmetic mean, %CV)10866 (62)259879Saquinavir mesylate capsules (soft gel) 1,200 mg tid (arithmetic mean)31724921747216Saquinavir mesylate capsules (hard gel) 1000 mg bid ritonavir 100 mg bid (geometric mean and 95% CI)2414607(10218-20882)29214371(245-561)Saquinavir mesylate capsules (soft gel) 1000 mg bid ritonavir 100 mg bid (geometric mean and 95% CI)2419085(13943-26124)38170433(301-622)In treatment-naive HIV-1 infected patients initiating INVIRASE/ritonavir treatment with modified INVIRASE/ritonavir dosing regimen of INVIRASE 500 mg twice daily with ritonavir 100 mg twice daily for the first 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 days, saquinavir systemic exposures on Day were approximately 70% lower compared to INVIRASE/ritonavir 1000/100 mg twice daily regimen on Day 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 and Table 4).Table 4: Mean (CV%) PK Parameters Following Administration of the Modified INVIRASE/ritonavir Regimen in Treatment Naive HIV-1 infected Patients Initiating Treatment with INVIRASE/ritonavirParameterDay 3500/100 mg(n=22)Day 7500/100 mg(n=21)Day 141000/100 mg(n=21)TQT StudyDay 3Historical data from the thorough QT study with INVIRASE/ritonavir 1000/100 mg BID conducted in healthy volunteers (1000/100 mg)(n=57)AUC (nghr/ml)27100 (35.7)12600 (54.5)31100 (49.6)94800 (32.2)Cmax (ng/ml)4030 (29.1)1960 (53.3)4860 (46.8)11200 (29.2)C12 (ng/ml)899 (64.9)416 (98.5)1120 (80.9)-. Food EffectThe mean 24-hour AUC after single 600 mg oral dose (6 100 mg) in healthy volunteers (n=6) was increased from 24 ngh/mL (CV 33%), under fasting conditions, to 161 ngh/mL (CV 35%) when INVIRASE was given following high-fat breakfast (48 protein, 60 carbohydrate, 57 fat; 1006 kcal). Saquinavir 24-hour AUC and Cmax (n=6) following the administration of higher calorie meal (943 kcal, 54 fat) were on average times higher than after lower calorie, lower fat meal (355 kcal, g fat). The effect of food has been shown to persist for up to hours.INVIRASE/ritonavir should be taken within hours after meal.. DistributionThe mean steady-state volume of distribution following intravenous administration of 12-mg dose of saquinavir (n=8) was 700 (CV 39%), suggesting saquinavir partitions into tissues. Saquinavir was approximately 98% bound to plasma proteins over concentration range of 15 to 700 ng/mL. In two 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 range of mono- and di-hydroxylated inactive compounds. In 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 days of dosing. In an additional subjects administered 10.5 mg 14C-saquinavir intravenously, 81% and 3% of the intravenously administered radioactivity was recovered in feces and urine, respectively, within 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 hours (n=8).. Special Populations. Renal ImpairmentSaquinavir 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 ImpairmentThe effect of hepatic impairment on the steady state pharmacokinetics of INVIRASE/ritonavir (1000/100 mg bid for 14 days) was investigated in HIV-1-infected subjects with moderate liver impairment (6 with Child-Pugh score of and with Child-Pugh score of 9). The study included control group consisting of 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%) ughr/mL and 3.6 (83%) ug/mL, respectively, for HIV-1-infected subjects with moderate hepatic impairment. The corresponding values in the control group were 28.5 (71%) ughr/mL and 4.3 (68%) ug/mL. The geometric 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/ritonavir in HIV-1-infected patients with mild or moderate hepatic impairment [see Warnings and Precautions (5.6)].. Gender, Race, and AgeA 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 1,000 mg of INVIRASE tablets to 1,000 mg of saquinavir mesylate capsules (hard gel) in combination with ritonavir. There was no evidence that age and body weight explained the gender difference in this study. clinically significant difference in safety and efficacy between men and women has not been reported with the approved dosage regimen (saquinavir 1,000 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, five subjects less than years of age and 13 subjects between and less than years of age received 50 mg per kg saquinavir twice daily (not to exceed 1000 mg twice daily) combined with ritonavir at mg/kg for subjects with body weight ranging from 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 saquinavir mesylate capsules (hard gel), the contents of saquinavir mesylate capsules (hard gel) were mixed with sugar syrup, or sorbitol syrup (for subjects with Type diabetes or glucose intolerance), jam, or baby formula. The mean steady state saquinavir PK parameters for pediatric subjects to less than years of age were: AUC0-12h 37269 +- 18232 ngh/mL; Ctrough 1811+- 998 ng/mL; Cmax 5464+- 2782 ng/mL, and day exposures may be within the range of exposure associated with QT and PR prolongation [see Clinical Pharmacology (12.2) ]. The subject number was too low and the pharmacokinetic data too variable in subjects less than years to establish an appropriate dosing recommendation for this age group. Pharmacokinetic data for subjects ages to 16 years were not available for comparisons with observations from NV20911, as the data from HIVNAT 017 could not be validated [see Use in Specific Populations (8.4)].. Drug InteractionsTable summarizes the effect of saquinavir mesylate capsules (soft gel) and INVIRASE with and without ritonavir on the geometric mean AUC and Cmax of coadministered drugs. Table summarizes the effect of coadministered drugs on the geometric mean AUC and Cmax of saquinavir.Table Effect of Saquinavir (+/- Ritonavir) on the Pharmacokinetics of Coadministered DrugsCoadministered DrugSaquinavir Mesylate Capsules (soft gel) with and without RitonavirN% Change for Coadministered DrugDosageAUC (95% CI)Cmax (95% CI) Denotes an average increase in exposure by the percentage indicated. Denotes an average decrease in exposure by the percentage indicated.<-> Denotes no statistically significant change in exposure was observed.V Healthy VolunteersM Methadone-dependent, HIV negative subjects. None of the 12 subjects experienced withdrawal symptoms.NA Not AvailableClarithromycin 500 mg bid 7 days Clarithromycin 14-OH clarithromycin metabolite1200 mg tid 7 days12V45% (17-81%)24% (5-40%)39% (10-76%)34% (14-50%)Sildenafil 100-mg single dose1200 mg tid 8 days27V210% (150-300%)140% (80-230%)Efavirenz 600 mg qd1200 mg tid13V12%13%INVIRASE/ritonavirDosageDigoxin 0.5 mg single dose1000/100 mg bid 16 days16V49% (32-69%)90% Confidence Interval 27% (5-54%) R-Methadone 60-120 mg qd1000/100 mg bid 14 days12M19% (9-29%) NAKetoconazole 200 mg/day1000/100 mg bid12V168% (146-193%) 45% (32-59%) Midazolam 7.5 mg oral single dose1000/100 mg bid16V1144% (975-1339%) 327% (264-402%) Rifabutin 150 mg q4d1000/100 mg bid11V60%AUC0-96hr and Cmax of the active moiety (rifabutin 25-O-desacetyl rifabutin) Compared to rifabutin 150 mg QD (43-79%) <->AUC0-96hr and Cmax for rifabutin only (-10 to 13%) 111% (75-153%) 68% (38-105%) Table Effect of Coadministered Drugs on Saquinavir Pharmacokinetics Denotes an average increase in exposure by the percentage indicated. Denotes an average decrease in exposure by the percentage indicated.<-> Mean change <10%S SubjectsV Healthy VolunteersCoadministered DrugSaquinavir Mesylate Capsules (soft gel) with and without ritonavirN% Change for SaquinavirDosageAUC (95% CI)Cmax (95% CI)Clarithromycin 500 mg bid 7 days1200 mg tid 7 days12V177% (108-269%)187% (105-300%)Efavirenz 600 mg qd1200 mg tid13V62%50%Indinavir 800 mg q8h 2 days1200 mg single dose6V364% (190-644%)299% (138-568%)Ritonavir 400 mg bid 14 days400 mg bid 14 daysCompared to saquinavir mesylate capsules (soft gel) 1200 mg tid regimen (n=33). 8V121% (7-359%)64%Did not reach statistical significance. Lopinavir/ritonavirEvidence from several clinical trials indicates that saquinavir concentrations achieved with saquinavir 1000 mg lopinavir/ritonavir 400/100 mg BID are similar to those achieved following saquinavir/ritonavir 1000/100 mg BID.Coadministered DrugSaquinavir Mesylate Capsules (hard gel) or INVIRASE with and without ritonavirN% Change for SaquinavirDosageAUC (95% CI)Cmax (95% CI)Atazanavir 300 mg qd1600/100 mg qd18S60%(16-122%)42%(10-84%)Ritonavir 100 mg bid1000 mg bidCompared to saquinavir mesylate capsules (hard gel) 600 mg tid regimen (n=114). 24S1124%1325%Tenofovir 300 mg qd1000 mg bid/100 mg bid18S<-><->Tipranavir 500 mg ritonavir 200 mg bid600 mg bid/100 mg bid20S76%(68-81%)90% Confidence Interval 70%(60-77%) Omeprazole 40 mg qd 5 days1000/100 mg bid 15 days19V82%(37-234%) 75%(31-234%) Ketoconazole 200 mg/day1000 mg bid/100 mg bid20V<-> <->Rifabutin 150 mg q3d1000 mg bid/100 mg bid19V13%(-31% to 9%) 15%(-32% to 7%) 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.. 12.4 Microbiology. Mechanism of ActionSaquinavir 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 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 to 30 nM and to 80 nM, respectively. In the presence of 40% human serum, the mean EC50 value of saquinavir against laboratory strain HIV-1 RF in MT4 cells was 37.7+- nM representing 4-fold increase in the EC50 value. Saquinavir displayed antiviral activity in cell culture against HIV-1 clades A-H (EC50 values ranged from 0.9 to 2.5 nM). In cell culture, saquinavir was not antagonistic in combination with the protease inhibitors amprenavir, atazanavir and lopinavir, the non-nucleoside reverse transcriptase inhibitor nevirapine, and the nucleoside analog reverse transcriptase inhibitors didanosine, lamivudine, stavudine and zidovudine. 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 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-resistanceAmong 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 protease inhibitors, 12 of the 22 isolates (55%) retained susceptibility to at least one of the protease inhibitors and 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. INVIRASE/ritonavir is contraindicated in patients with congenital long QT syndrome, those with refractory hypokalemia or hypomagnesemia, and in combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.2)].INVIRASE/ritonavir is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers, or patients who are at high risk of complete AV block [see Warnings and Precautions (5.3)].INVIRASE/ritonavir is contraindicated in patients with clinically significant hypersensitivity (e.g., anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients.INVIRASE/ ritonavir is contraindicated in patients with severe hepatic impairment.INVIRASE/ritonavir is contraindicated with drugs that are CYP3A substrates for which increased plasma levels may result in serious or life-threatening reactions [see Warnings and Precautions (5.2), Drug Interactions (7) and Clinical Pharmacology (12.3)].INVIRASE/ritonavir is contraindicated in patients receiving the following co-administered drugs; however, it should be noted that this list is not intended to be exhaustive [see Drug Interactions (7) and Clinical Pharmacology (12.3)] -Alpha 1-adrenoreceptor antagonist: alfuzosin-Antiarrhythmics: amiodarone, bepridil, dofetilide, flecainide, lidocaine (systemic), propafenone, quinidine-Antidepressant: trazodone-Anti-infectives: clarithromycin, erythromycin, halofantrine, pentamidine-Antimycobacterial Agents: rifampin-Antipsychotics: lurasidone, clozapine, haloperidol, pimozide, sertindole, ziprasidone, phenothiazines (e.g. chlorpromazine, mesoridazine, thioridazine).-Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine-HIV-1 Protease Inhibitor: atazanavir-HMG-CoA Reductase Inhibitors: lovastatin, simvastatin-Immunosuppressant: tacrolimus-Non-nucleoside reverse transcriptase inhibitor (NNRTI): rilpivirine (concomitant use and switching from rilpivirine to INVIRASE/ritonavir without washout period of at least weeks is contraindicated)-PDE5 Inhibitors: sildenafil (Revatio(R))[for treatment of pulmonary arterial hypertension]-Sedative/Hypnotics: triazolam, and orally administered midazolam-Tyrosine kinase inhibitors: dasatinib, sunatinib-Other drugs that are CYP3A substrates: disopyramide, quinine. -Alpha 1-adrenoreceptor antagonist: alfuzosin. -Antiarrhythmics: amiodarone, bepridil, dofetilide, flecainide, lidocaine (systemic), propafenone, quinidine. -Antidepressant: trazodone. -Anti-infectives: clarithromycin, erythromycin, halofantrine, pentamidine. -Antimycobacterial Agents: rifampin. -Antipsychotics: lurasidone, clozapine, haloperidol, pimozide, sertindole, ziprasidone, phenothiazines (e.g. chlorpromazine, mesoridazine, thioridazine).. -Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine. -HIV-1 Protease Inhibitor: atazanavir. -HMG-CoA Reductase Inhibitors: lovastatin, simvastatin. -Immunosuppressant: tacrolimus. -Non-nucleoside reverse transcriptase inhibitor (NNRTI): rilpivirine (concomitant use and switching from rilpivirine to INVIRASE/ritonavir without washout period of at least weeks is contraindicated). -PDE5 Inhibitors: sildenafil (Revatio(R))[for treatment of pulmonary arterial hypertension]. -Sedative/Hypnotics: triazolam, and orally administered midazolam. -Tyrosine kinase inhibitors: dasatinib, sunatinib. -Other drugs that are CYP3A substrates: disopyramide, quinine. INVIRASE/ritonavir is contraindicated in patients with congenital or documented acquired QT prolongation, patients with refractory hypokalemia or hypomagnesemia, or those on concomitant therapy with other drugs that prolong the QT interval. (4)INVIRASE is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers, or patients who are at high risk of complete AV block. (4)INVIRASE is contraindicated in patients with clinically significant hypersensitivity (e.g., anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients. (4)INVIRASE/ritonavir is contraindicated in patients with severe hepatic impairment. (4)INVIRASE/ritonavir is contraindicated with CYP3A substrates for which increased plasma levels may result in serious or life-threatening reactions. (4)INVIRASE/ritonavir is contraindicated to be coadministered with rifampin due to the risk of severe hepatotoxicity. (4). INVIRASE/ritonavir is contraindicated in patients with congenital or documented acquired QT prolongation, patients with refractory hypokalemia or hypomagnesemia, or those on concomitant therapy with other drugs that prolong the QT interval. (4). INVIRASE is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers, or patients who are at high risk of complete AV block. (4). INVIRASE is contraindicated in patients with clinically significant hypersensitivity (e.g., anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients. (4). INVIRASE/ritonavir is contraindicated in patients with severe hepatic impairment. (4). INVIRASE/ritonavir is contraindicated with CYP3A substrates for which increased plasma levels may result in serious or life-threatening reactions. (4). INVIRASE/ritonavir is contraindicated to be coadministered with rifampin due to the risk of severe hepatotoxicity. (4).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. INVIRASE must be administered in combination with ritonavir. (2.1)Adults (over the age of 16 years): INVIRASE 1,000 mg twice daily (2 500 mg tablets) in combination with ritonavir 100 mg twice daily. (2.1)Treatment-naive patients initiating treatment with INVIRASE/ritonavir: First days of treatment: INVIRASE 500 mg twice daily with ritonavir 100 mg twice daily. After days: INVIRASE 1,000 mg twice daily with ritonavir 100 mg twice daily. (2.1)See Full Prescribing Information for dosing recommendations for patients switching immediately from treatment with another protease inhibitor taken with ritonavir or from non-nucleoside reverse transcriptase inhibitor based regimen, without wash-out period. (2.1)INVIRASE and ritonavir should be taken within hours after meal. (2.1). INVIRASE must be administered in combination with ritonavir. (2.1). Adults (over the age of 16 years): INVIRASE 1,000 mg twice daily (2 500 mg tablets) in combination with ritonavir 100 mg twice daily. (2.1). Treatment-naive patients initiating treatment with INVIRASE/ritonavir: First days of treatment: INVIRASE 500 mg twice daily with ritonavir 100 mg twice daily. After days: INVIRASE 1,000 mg twice daily with ritonavir 100 mg twice daily. (2.1). See Full Prescribing Information for dosing recommendations for patients switching immediately from treatment with another protease inhibitor taken with ritonavir or from non-nucleoside reverse transcriptase inhibitor based regimen, without wash-out period. (2.1). INVIRASE and ritonavir should be taken within hours after meal. (2.1). 2.1Recommended Dose. INVIRASE must be used in combination with ritonavir because ritonavir significantly inhibits saquinavirs 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-naive 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 days of treatment. After 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 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 regimen containing delavirdine, the recommended dose is 500 mg twice daily with ritonavir 100 mg twice daily for the first 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 hours after 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.. The standard recommended dose of INVIRASE is 1,000 mg twice daily in combination with ritonavir 100 mg twice daily.. For treatment-naive 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 days of treatment. After 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 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 regimen containing delavirdine, the recommended dose is 500 mg twice daily with ritonavir 100 mg twice daily for the first 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 hours after 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.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Drug interaction studies have been completed with INVIRASE and saquinavir mesylate capsules (hard gel and soft gel). Observations from drug interaction studies with saquinavir mesylate capsules (soft gel) may not be predictive for INVIRASE/ritonavir. Because ritonavir is coadministered with INVIRASE, prescribers should also refer to the prescribing information for ritonavir regarding drug interactions associated with this agent.. INVIRASE/ritonavir is potent inhibitor of CYP3A, significantly increasing the exposure of drugs primarily metabolized by CYP3A. (7.1)Coadministration of INVIRASE/ritonavir with drugs that induce CYP3A may result in decreased plasma concentrations of saquinavir and reduced efficacy. (7.2)Certain drugs or drug classes should not be coadministered with INVIRASE/ritonavir based on drug interaction studies or predicted drug interactions. (5.2, 7.2, 7.3). INVIRASE/ritonavir is potent inhibitor of CYP3A, significantly increasing the exposure of drugs primarily metabolized by CYP3A. (7.1). Coadministration of INVIRASE/ritonavir with drugs that induce CYP3A may result in decreased plasma concentrations of saquinavir and reduced efficacy. (7.2). Certain drugs or drug classes should not be coadministered with INVIRASE/ritonavir based on drug interaction studies or predicted drug interactions. (5.2, 7.2, 7.3). 7.1 Potential for INVIRASE/Ritonavir to Affect Other Drugs. The combination INVIRASE/ritonavir is 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 Contraindications [see Contraindications (4)]. Coadministration with other CYP3A substrates may require dose adjustment or additional monitoring (see Table 2).. 7.2 Potential for Other Drugs to Affect INVIRASE/Ritonavir. The metabolism of saquinavir is mediated primarily by CYP3A. Additionally, saquinavir is 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.. 7.3 Established and Other Potentially Significant Drug Interactions. 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 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.Table Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction with INVIRASE/RitonavirThis list provides examples of established or potentially clinically significant drug interactions drugs with INVIRASE/ritonavir and may not be exhaustive Concomitant Drug Class:Drug NameEffectObserved or predicted effect. on Concentration of Saquinavir or Concomitant DrugClinical CommentHIV-1 Antiviral AgentsNon-nucleoside reverse transcriptase inhibitor:Rilpivirine RilpivirineCo-administration with INVIRASE/ritonavir and switching from rilpivirine to Invirase/ritonavir within weeks is contraindicated due to the potential for life-threatening cardiac arrhythmia [see Contraindications (4)]. Non-nucleoside reverse transcriptase inhibitor:DelavirdineINVIRASE/ritonavir interaction has not been evaluated. SaquinavirEffect on delavirdine is not well establishedAppropriate doses of the combination with respect to safety and efficacy have not been established. Co-administration is not recommended.Liver function should be monitored frequently if this combination is prescribed.EfavirenzSee Pharmacokinetics, Drug Interactions (12.3), Table and Table for magnitude of interactions.,nevirapine Saquinavir<-> Efavirenz Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Co-administration is not recommended.HIV-1 protease inhibitor:Atazanavir Saquinavir Ritonavir AtazanavirCo-administration is contraindicated with INVIRASE/ritonavir due to the potential for serious and/or life-threatening cardiac arrhythmia [see Contraindications (4)]. HIV-1 protease inhibitor:Indinavir Saquinavir IndinavirAppropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Co-administration is not recommended.Increased concentrations of indinavir may result in nephrolithiasis. For further details see complete prescribing information for indinavir.Lopinavir/ritonavir (coformulated tablet)<-> Saquinavir<-> Lopinavir RitonavirEvidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following INVIRASE/ritonavir 1000/100 mg. The recommended dose for this combination is INVIRASE 1000 mg plus lopinavir/ritonavir 400/100 mg bid.Lopinavir/ritonavir in combination with INVIRASE should be used with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE [see Warnings and Precautions (5.3, 5.4)]. Nelfinavir SaquinavirCombining saquinavir/ritonavir with nelfinavir is not recommendedTipranavir/ritonavir SaquinavirCombining saquinavir with tipranavir/ritonavir is not recommended.HIV-1 CCR5 antagonist:Maraviroc MaravirocMaraviroc dose should be 150 mg twice daily when co-administered with INVIRASE/ritonavir. For further details see complete prescribing information for Selzentry(R) (maraviroc).Other AgentsAlpha 1-adrenoreceptor antagonist:Alfuzosin AlfuzosinCo-administration is contraindicated with INVIRASE/ritonavir as potentially increased alfuzosin concentrations can result in hypotension, and potentially life-threatening cardiac arrhythmia [see Contraindications (4)]. Antiarrhythmics:Amiodarone, bepridil, dofetilide, flecainide, lidocaine (systemic), propafenone, quinidine Amiodarone Bepridil Dofetilide Flecainide Lidocaine (systemic) Propafenone QuinidineCo-administration is contraindicated with INVIRASE/ritonavir due to the potential for serious and/or life-threatening cardiac arrhythmia [see Contraindications (4)]. Antiarrhythmics:IbutilideSotalolEffects on ibutilide, sotalol, and saquinavir concentrations are not well-establishedAdditive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.3, 5.4)]. Co-administration of INVIRASE/ritonavir and ibutilide or sotalol is not recommended.Anticoagulant:Warfarin WarfarinConcentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.Anticonvulsants:Carbamazepine, phenobarbital, phenytoin SaquinavirEffect on carbamazepine, phenobarbital, and phenytoin is not well establishedSaquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly. Co-administration is not recommended.Antidepressant:Trazodone TrazodoneCo-administration is contraindicated with INVIRASE/ritonavir as increased trazodone concentrations can result in potentially life-threatening cardiac arrhythmia [see Contraindications (4)]. Tricyclic antidepressants Amitriptyline, clomipramine, imipramine, maprotiline TricyclicsTherapeutic concentration monitoring is recommended for tricyclic antidepressants when co-administered with INVIRASE/ritonavir.Other antidepressants:Nefazodone Saquinavir Use with caution due to possible cardiac arrhythmias. Clinical monitoring for saquinavir toxicity is recommended.Antifungals: Ketoconazole,<-> Saquinavir<-> Ritonavir KetoconazoleWhen INVIRASE/ritonavir and ketoconazole are co-administered, plasma concentrations of ketoconazole are increased (see Table 5). Hence, doses of ketoconazole or itraconazole 200 mg/day are not recommended.Itraconazole Itraconazole SaquinavirClinical monitoring for saquinavir toxicity is recommended. Use with caution due to possible cardiac arrhythmias.Anti-gout:Colchicine ColchicineTreatment of gout flares-co-administration of colchicine in patients on INVIRASE/ritonavir:0.6 mg (1 tablet) 1 dose, followed by 0.3 mg (half tablet) hour later. Dose to be repeated no earlier than days. Treatment of familial Mediterranean fever (FMF) co-administration of colchicine in patients on INVIRASE/ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice day). Prophylaxis of gout flares-co-administration of colchicine in patients on INVIRASE/ritonavir: If the original colchicine regimen was 0.6 mg twice day, the regimen should be adjusted to 0.3 mg once day.If the original colchicine regimen was 0.6 mg once day, the regimen should be adjusted to 0.3 mg once every other day.Patients with renal or hepatic impairment should not be given colchicine with INVIRASE/ritonavir.Anti-infectives:Clarithromycin,ErythromycinHalofantrinePentamidine Clarithromycin Erythromycin Halofantrine<-> PentamidineCo-administration is contraindicated with INVIRASE/ritonavir due to the potential for serious and/or life-threatening cardiac arrhythmia [see Contraindications (4)]. Anti-infectives:Streptogramin antibiotics(quinupristin/dalfopristin)Streptogramin antibiotics such as quinupristin/ dalfopristin inhibit CYP3A4; saquinavir concentrations may be increased Monitoring for saquinavir toxicity is recommended. Use with caution due to possible cardiac arrhythmias.Fusidic Acid Saquinavir Fusidic Acid Ritonavir Concomitant use of fusidic acid and INVIRASE/ritonavir is not recommended due to potential for increased mutual toxicities.The interaction between INVIRASE/ritonavir and fusidic acid has not been formally evaluated. Co-administration of fusidic acid and INVIRASE/ritonavir can cause increased plasma concentrations of fusidic acid, saquinavir and ritonavir.Antimycobacterial: RifabutinDapsone<-> Saquinavir Rifabutin<-> Ritonavir DapsoneNo dose adjustment of INVIRASE/ritonavir (1000/100 mg bid) is required if INVIRASE/ritonavir is administered in combination with rifabutin.Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse events including neutropenia and liver enzyme levels is warranted in patients receiving the combination.Consider monitoring rifabutin concentrations to ensure adequate exposure.Co-administration of saquinavir/ritonavir with drugs that are metabolized by CYP3A4 pathway may result in elevated plasma concentrations of these drugs. Co-administration with oral dapsone is not recommended.Antimycobacterial:Rifampin RifampinCo-administration is contraindicated with INVIRASE/ritonavir as part of an ART regimen due to the risk of severe hepatocellular toxicity [see Contraindications (4)]. Antipsychotic:Quetiapine QuetiapineInitiation of INVIRASE with ritonavir in patients taking quetiapine:Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If co-administration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.Initiation of quetiapine in patients taking INVIRASE with ritonavir:Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.Antipsychotic:Lurasidone LurasidoneCo-administration is contraindicated with INVIRASE/ritonavir due to the potential for serious and/or life-threatening reactions [see Contraindications (4)]. Antipsychotics:clozapine, haloperidol, pimozide, sertindole, ziprasidone, phenothiazines (e.g. chlorpromazine, mesoridazine, thioridazine). Clozapine Haloperidol Pimozide Ziprasidone Chlorpromazine Mesoridazine Sertindole ThioridazineCo-administration is contraindicated with INVIRASE/ritonavir due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)]. Benzodiazepine:Triazolam, orally administered Midazolam Midazolam Triazolam Co-administration is contraindicated with INVIRASE/ritonavir due to the potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression [see Contraindications (4)]. Benzodiazepines :Alprazolam, clorazepate, diazepam, flurazepam BenzodiazepinesClinical significance is unknown. Careful monitoring of patients for benzodiazepine effects is warranted; decrease in benzodiazepine dose may be needed. Intravenously administered Midazolam MidazolamIf INVIRASE/ritonavir is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.Calcium channel blockers:Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine Calcium channel blockersClose clinical monitoring of patients is recommended.Systemic/Inhaled/Nasal/ Ophthalmic Corticosteroids: e.g. betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, mometasone, prednisone, triamcinolone SaquinavirCo-administration of INVIRASE/ritonavir with systemic dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to saquinavir. Consider alternative corticosteroids. Corticosteroids Co-administration of INVIRASE/ritonavir with corticosteroids of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushings syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone (for which PK and/or PD are less affected by strong CYP3A inhibitors relative to other steroids) should be considered, particularly for long term use. Digitalis Glycosides:Digoxin DigoxinIncreases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir.Caution should be exercised when INVIRASE/ritonavir and digoxin are co-administered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when co-administered with INVIRASE/ritonavir. Endothelin receptor antagonists:Bosentan BosentanCo-administration of bosentan in patients on INVIRASE/ritonavir:In patients who have been receiving INVIRASE/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.Co-administration of INVIRASE/ritonavir in patients on bosentan:Discontinue use of bosentan at least 36 hours prior to initiation of INVIRASE/ritonavir.After at least 10 days following the initiation of INVIRASE/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.Ergot derivatives:Dihydroergotamine, ergonovine, ergotamine, methylergonovine Dihydroergotamine, Ergonovine, Ergotamine, MethylergonovineCo-administration is contraindicated in INVIRASE/ritonavir due to the potential for serious and life-threatening reactions such as ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4)]. Herbal Product:St. Johns wort (hypericum perforatum) SaquinavirHerbal products containing St. Johns wort should not be used concomitantly with INVIRASE/ritonavir because co-administration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors.Garlic Capsules Co-administration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations.HMG-CoA reductase inhibitors:Lovastatin, Simvastatin Lovastatin SimvastatinCo-administration is contraindicated with INVIRASE/ritonavir due to the potential for myopathy including rhabdomyolysis [see Contraindications (4)]. HMG-CoA reductase inhibitors: Atorvastatin Atorvastatin Titrate atorvastatin dose carefully and use the lowest dose necessary; do not exceed atorvastatin 20 mg/day. Patients should be carefully monitored for signs and symptoms of myopathy (e.g., muscle weakness, muscle pain, rising creatine kinase).Immunosuppressants:TacrolimusTacrolimusCo-administration is contraindicated with INVIRASE/ritonavir due to the potential for serious and/or life-threatening cardiac arrhythmia [see Contraindications (4)]. Immunosuppressants:Cyclosporine, rapamycin ImmunosuppressantsTherapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with INVIRASE/ritonavir.Inhaled beta agonist:Salmeterol SalmeterolConcurrent administration of salmeterol with INVIRASE/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.Narcotic analgesic:Methadone MethadoneDosage of methadone may need to be increased when co-administered with INVIRASE/ritonavir.Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.3, 5.4)].Oral contraceptives:Ethinyl estradiol Ethinyl estradiolAlternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are co-administered.PDE5 inhibitors (phosphodiesterase type inhibitors):Sildenafil, vardenafil, tadalafil Sildenafil<-> Saquinavir Vardenafil TadalafilOnly the combination of sildenafil with saquinavir mesylate capsules (soft gel) has been studied at doses used for treatment of erectile dysfunction.May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Co-administration is contraindicated with INVIRASE/ritonavir when sildenafil (Revatio) is used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4)].The following dose adjustments are recommended for use of tadalafil (Adcirca(R)) with INVIRASE/ritonavir: Co-administration of Adcirca in patients on INVIRASE/ritonavir: In patients receiving INVIRASE/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of INVIRASE/ritonavir in patients on Adcirca: Avoid use of Adcirca during the initiation of INVIRASE/ritonavir. Stop Adcirca at least 24 hours prior to starting INVIRASE/ritonavir. After at least one week following the initiation of INVIRASE/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.Proton pump inhibitors:Omeprazole SaquinavirWhen INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, deep vein thrombosis, and QT prolongation.Use with caution due to possible cardiac arrhythmias.Tyrosine kinase inhibitors:DasatinibSunitinib Dasatinib SunitinibCo-administration is contraindicated with INVIRASE/ritonavir due to potentially life-threatening cardiac arrhythmia [see Contraindications (4)] Vasodilators (peripheral):Intravenously administered Vincamine VincamineMonitoring for vincamine toxicity is recommended. Use with caution due to potential cardiac arrhythmias.Other drugs that are substrates of CYP3A:DisopyramideQuinine Disopyramide QuinineCo-administration is contraindicated with INVIRASE/ritonavir due to the potential for serious and/or life-threatening cardiac arrhythmia [see Contraindications (4)]. Other drugs that are substrates of CYP3A:FentanylAlfentanil Fentanyl AlfentanilCo-administration with these drugs may accentuate the side effects reported with use of fentanyl or alfentanil including respiratory depression, apnea and bradycardia.. Co-administration is contraindicated with INVIRASE/ritonavir when sildenafil (Revatio) is used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4)].. 7.4 Drugs without Clinically Significant Interactions with INVIRASE/Ritonavir. 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.

PHARMACOKINETICS SECTION.

12.3 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 AdultsSimilar bioavailability was demonstrated when 1,000 mg of INVIRASE tablets or 1,000 mg of saquinavir mesylate capsules (hard gel) was 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 saquinavir mesylate capsules (hard gel) averaged 4% (CV 73%, range: 1% to 9%) in healthy volunteers who received single 600 mg dose (3 200-mg) of saquinavir mesylate following high-fat breakfast (48 protein, 60 carbohydrate, 57 fat; 1006 kcal). The low bioavailability is thought to be due to combination of incomplete absorption and extensive first-pass metabolism.INVIRASE/ritonavir at dose of 1000/100 mg twice daily provides saquinavir systemic exposures over 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 3).Table Pharmacokinetic Parameters of Saquinavir at Steady-State after Administration of Different Regimens in HIV-1-Infected SubjectsDosing RegimenNAUC (ngh/mL)AUC24h (ngh/mL)Cmin (ng/mL) is the dosing interval (i.e., 8h if three times daily and 12h if twice daily)Saquinavir mesylate capsules (hard gel) 600 mg tid (arithmetic mean, %CV)10866 (62)259879Saquinavir mesylate capsules (soft gel) 1,200 mg tid (arithmetic mean)31724921747216Saquinavir mesylate capsules (hard gel) 1000 mg bid ritonavir 100 mg bid (geometric mean and 95% CI)2414607(10218-20882)29214371(245-561)Saquinavir mesylate capsules (soft gel) 1000 mg bid ritonavir 100 mg bid (geometric mean and 95% CI)2419085(13943-26124)38170433(301-622)In treatment-naive HIV-1 infected patients initiating INVIRASE/ritonavir treatment with modified INVIRASE/ritonavir dosing regimen of INVIRASE 500 mg twice daily with ritonavir 100 mg twice daily for the first 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 days, saquinavir systemic exposures on Day were approximately 70% lower compared to INVIRASE/ritonavir 1000/100 mg twice daily regimen on Day 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 and Table 4).Table 4: Mean (CV%) PK Parameters Following Administration of the Modified INVIRASE/ritonavir Regimen in Treatment Naive HIV-1 infected Patients Initiating Treatment with INVIRASE/ritonavirParameterDay 3500/100 mg(n=22)Day 7500/100 mg(n=21)Day 141000/100 mg(n=21)TQT StudyDay 3Historical data from the thorough QT study with INVIRASE/ritonavir 1000/100 mg BID conducted in healthy volunteers (1000/100 mg)(n=57)AUC (nghr/ml)27100 (35.7)12600 (54.5)31100 (49.6)94800 (32.2)Cmax (ng/ml)4030 (29.1)1960 (53.3)4860 (46.8)11200 (29.2)C12 (ng/ml)899 (64.9)416 (98.5)1120 (80.9)-. Food EffectThe mean 24-hour AUC after single 600 mg oral dose (6 100 mg) in healthy volunteers (n=6) was increased from 24 ngh/mL (CV 33%), under fasting conditions, to 161 ngh/mL (CV 35%) when INVIRASE was given following high-fat breakfast (48 protein, 60 carbohydrate, 57 fat; 1006 kcal). Saquinavir 24-hour AUC and Cmax (n=6) following the administration of higher calorie meal (943 kcal, 54 fat) were on average times higher than after lower calorie, lower fat meal (355 kcal, g fat). The effect of food has been shown to persist for up to hours.INVIRASE/ritonavir should be taken within hours after meal.. DistributionThe mean steady-state volume of distribution following intravenous administration of 12-mg dose of saquinavir (n=8) was 700 (CV 39%), suggesting saquinavir partitions into tissues. Saquinavir was approximately 98% bound to plasma proteins over concentration range of 15 to 700 ng/mL. In two 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 range of mono- and di-hydroxylated inactive compounds. In 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 days of dosing. In an additional subjects administered 10.5 mg 14C-saquinavir intravenously, 81% and 3% of the intravenously administered radioactivity was recovered in feces and urine, respectively, within 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 hours (n=8).. Special Populations. Renal ImpairmentSaquinavir 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 ImpairmentThe effect of hepatic impairment on the steady state pharmacokinetics of INVIRASE/ritonavir (1000/100 mg bid for 14 days) was investigated in HIV-1-infected subjects with moderate liver impairment (6 with Child-Pugh score of and with Child-Pugh score of 9). The study included control group consisting of 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%) ughr/mL and 3.6 (83%) ug/mL, respectively, for HIV-1-infected subjects with moderate hepatic impairment. The corresponding values in the control group were 28.5 (71%) ughr/mL and 4.3 (68%) ug/mL. The geometric 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/ritonavir in HIV-1-infected patients with mild or moderate hepatic impairment [see Warnings and Precautions (5.6)].. Gender, Race, and AgeA 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 1,000 mg of INVIRASE tablets to 1,000 mg of saquinavir mesylate capsules (hard gel) in combination with ritonavir. There was no evidence that age and body weight explained the gender difference in this study. clinically significant difference in safety and efficacy between men and women has not been reported with the approved dosage regimen (saquinavir 1,000 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, five subjects less than years of age and 13 subjects between and less than years of age received 50 mg per kg saquinavir twice daily (not to exceed 1000 mg twice daily) combined with ritonavir at mg/kg for subjects with body weight ranging from 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 saquinavir mesylate capsules (hard gel), the contents of saquinavir mesylate capsules (hard gel) were mixed with sugar syrup, or sorbitol syrup (for subjects with Type diabetes or glucose intolerance), jam, or baby formula. The mean steady state saquinavir PK parameters for pediatric subjects to less than years of age were: AUC0-12h 37269 +- 18232 ngh/mL; Ctrough 1811+- 998 ng/mL; Cmax 5464+- 2782 ng/mL, and day exposures may be within the range of exposure associated with QT and PR prolongation [see Clinical Pharmacology (12.2) ]. The subject number was too low and the pharmacokinetic data too variable in subjects less than years to establish an appropriate dosing recommendation for this age group. Pharmacokinetic data for subjects ages to 16 years were not available for comparisons with observations from NV20911, as the data from HIVNAT 017 could not be validated [see Use in Specific Populations (8.4)].. Drug InteractionsTable summarizes the effect of saquinavir mesylate capsules (soft gel) and INVIRASE with and without ritonavir on the geometric mean AUC and Cmax of coadministered drugs. Table summarizes the effect of coadministered drugs on the geometric mean AUC and Cmax of saquinavir.Table Effect of Saquinavir (+/- Ritonavir) on the Pharmacokinetics of Coadministered DrugsCoadministered DrugSaquinavir Mesylate Capsules (soft gel) with and without RitonavirN% Change for Coadministered DrugDosageAUC (95% CI)Cmax (95% CI) Denotes an average increase in exposure by the percentage indicated. Denotes an average decrease in exposure by the percentage indicated.<-> Denotes no statistically significant change in exposure was observed.V Healthy VolunteersM Methadone-dependent, HIV negative subjects. None of the 12 subjects experienced withdrawal symptoms.NA Not AvailableClarithromycin 500 mg bid 7 days Clarithromycin 14-OH clarithromycin metabolite1200 mg tid 7 days12V45% (17-81%)24% (5-40%)39% (10-76%)34% (14-50%)Sildenafil 100-mg single dose1200 mg tid 8 days27V210% (150-300%)140% (80-230%)Efavirenz 600 mg qd1200 mg tid13V12%13%INVIRASE/ritonavirDosageDigoxin 0.5 mg single dose1000/100 mg bid 16 days16V49% (32-69%)90% Confidence Interval 27% (5-54%) R-Methadone 60-120 mg qd1000/100 mg bid 14 days12M19% (9-29%) NAKetoconazole 200 mg/day1000/100 mg bid12V168% (146-193%) 45% (32-59%) Midazolam 7.5 mg oral single dose1000/100 mg bid16V1144% (975-1339%) 327% (264-402%) Rifabutin 150 mg q4d1000/100 mg bid11V60%AUC0-96hr and Cmax of the active moiety (rifabutin 25-O-desacetyl rifabutin) Compared to rifabutin 150 mg QD (43-79%) <->AUC0-96hr and Cmax for rifabutin only (-10 to 13%) 111% (75-153%) 68% (38-105%) Table Effect of Coadministered Drugs on Saquinavir Pharmacokinetics Denotes an average increase in exposure by the percentage indicated. Denotes an average decrease in exposure by the percentage indicated.<-> Mean change <10%S SubjectsV Healthy VolunteersCoadministered DrugSaquinavir Mesylate Capsules (soft gel) with and without ritonavirN% Change for SaquinavirDosageAUC (95% CI)Cmax (95% CI)Clarithromycin 500 mg bid 7 days1200 mg tid 7 days12V177% (108-269%)187% (105-300%)Efavirenz 600 mg qd1200 mg tid13V62%50%Indinavir 800 mg q8h 2 days1200 mg single dose6V364% (190-644%)299% (138-568%)Ritonavir 400 mg bid 14 days400 mg bid 14 daysCompared to saquinavir mesylate capsules (soft gel) 1200 mg tid regimen (n=33). 8V121% (7-359%)64%Did not reach statistical significance. Lopinavir/ritonavirEvidence from several clinical trials indicates that saquinavir concentrations achieved with saquinavir 1000 mg lopinavir/ritonavir 400/100 mg BID are similar to those achieved following saquinavir/ritonavir 1000/100 mg BID.Coadministered DrugSaquinavir Mesylate Capsules (hard gel) or INVIRASE with and without ritonavirN% Change for SaquinavirDosageAUC (95% CI)Cmax (95% CI)Atazanavir 300 mg qd1600/100 mg qd18S60%(16-122%)42%(10-84%)Ritonavir 100 mg bid1000 mg bidCompared to saquinavir mesylate capsules (hard gel) 600 mg tid regimen (n=114). 24S1124%1325%Tenofovir 300 mg qd1000 mg bid/100 mg bid18S<-><->Tipranavir 500 mg ritonavir 200 mg bid600 mg bid/100 mg bid20S76%(68-81%)90% Confidence Interval 70%(60-77%) Omeprazole 40 mg qd 5 days1000/100 mg bid 15 days19V82%(37-234%) 75%(31-234%) Ketoconazole 200 mg/day1000 mg bid/100 mg bid20V<-> <->Rifabutin 150 mg q3d1000 mg bid/100 mg bid19V13%(-31% to 9%) 15%(-32% to 7%) 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.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: September 2020Medication GuideINVIRASE(R) (in-ver-ase)(saquinavir mesylate) TabletsImportant: Ask your healthcare provider or pharmacist about medicines that should not be taken with INVIRASE. For more information, see the section Who should not take INVIRASERead this Medication Guide before you start taking INVIRASE and each time you get refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about your treatment with INVIRASE before you start taking it and at regular checkups. You should stay under healthcare providers care when taking INVIRASE.Also read the Medication Guide for ritonavir.What is the most important information should know about INVIRASEINVIRASE must be taken along with ritonavir.INVIRASE taken along with ritonavir should not be taken with cobicistat.INVIRASE may cause serious side effects including:Interactions with other medicines. It is important to know the medicines that should not be taken with INVIRASE. See the section What should tell my healthcare provider before taking INVIRASE Changes in your heart rhythm and the electrical activity of your heart. These changes may be seen on an EKG (electrocardiogram) and can lead to serious heart problems. Your risk for these problems may be higher if you: have history of abnormal heart rhythm, including Congenital Long QT Syndrome, or other types of heart disease.take other medicines that can affect your heart rhythm during treatment with INVIRASE.Tell your healthcare provider right away if you have any of these symptoms during treatment with INVIRASE:dizzinesslightheadednessfaintingsensation of abnormal heartbeatsSee the section below What are the possible side effects of INVIRASE for more information about serious side effects. What is INVIRASEINVIRASE is prescription medicine used with ritonavir and other antiretroviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) in people over 16 years of age.HIV is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).In children under 16 years of age, INVIRASE doses that are both effective and safe could not be determined.Do not take INVIRASE with ritonavir if you have the following conditions:a condition called Congenital Long QT Syndrome.complete AV (atrioventricular) heart block and you do not have pacemaker, or you are at risk for complete AV heart block.low potassium or low magnesium in your blood.you have had severe allergic reaction to saquinavir, saquinavir mesylate or any of the ingredients in INVIRASE. See the end of this Medication Guide for complete list of ingredients in INVIRASE.severe liver problems. you have taken medicine that contains rilpivirine within the last weeks.Talk to your healthcare provider before taking INVIRASE if you have any of the conditions listed above. Taking INVIRASE with certain medicines can cause serious problems or life-threatening reactions. Do not take INVIRASE with ritonavir if you take any of the following medicines:alfuzosin amiodarone atazanavir bepridil clarithromycin clozapine dasatinibdofetilidedisopyramideErgot containing medicines, including: dihydroergotamineergonovine, ergonovine and methylergonovineergotamine erythromycinflecainide halofantrinehaloperidol lidocainelovastatin lurasidonemidazolam pentamidine Phenothiazine containing medicines, Including:chlorpromazinemesoridazinethioridazine pimozide propafenonequinidinequininerifampinrilpivirinesertindolesildenafil simvastatin sunitinibtacrolimus trazodone triazolam ziprasidoneTalk to your healthcare provider before taking any medicines listed above during treatment with INVIRASE and ritonavir. Though not complete, this is list of medicines that should not be taken when INVIRASE is taken with ritonavir. Before taking INVIRASE, tell your healthcare provider about all of your medical conditions, including if you:have any heart problems, including condition called Congenital Long QT Syndrome.have diabetes. have liver problems, including Hepatitis or Hepatitis C.a history of alcoholism.have hemophilia. are pregnant or plan to become pregnant. It is not known if INVIRASE will harm your unborn baby. Pregnancy Registry: There is pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. are breastfeeding or plan to breastfeed. Do not breastfeed if you take INVIRASE. You should not breastfeed if you have HIV-1 because of the risk of passing HIV to your baby.It is not known if INVIRASE passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby. Tell your healthcare provider about all the medicines you take, including prescriptions and over-the-counter medicines, vitamins and herbal supplements. INVIRASE may affect the way other medicines work, and other medicines may affect how INVIRASE works. You can ask your healthcare provider or pharmacist for list of medicines that interact with INVIRASE. Do not start taking new medicine without talking with your healthcare provider. Your healthcare provider can tell you if it is safe to take INVIRASE with other medicines. How should take INVIRASETake INVIRASE exactly as your healthcare provider tells you.Do not change your dose of INVIRASE or stop treatment without first talking with your healthcare provider. Stay under the care of your healthcare provider during treatment with INVIRASE.Take INVIRASE and ritonavir at the same time. Take INVIRASE and ritonavir times each day. Take INVIRASE and ritonavir within hours after meal.Do not miss dose of INVIRASE. It is very important to take your medicine every day. If you skip doses or take less than the prescribed dose, the medicine will not work as well, and the virus may become harder to treat.If you miss dose of INVIRASE, you should take the next dose as soon as possible. Do not double your dose. If you take too much INVIRASE, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of INVIRASEINVIRASE can cause serious side effects. See What is the most important information should know about INVIRASE Diabetes and high blood sugar. Some people who take protease inhibitors including INVIRASE get new or more serious diabetes, or high blood sugar. Tell your healthcare provider if you notice an increase in thirst or urinate more often than normal during treatment with INVIRASE.Liver problems. People with liver problems such as Hepatitis or C, cirrhosis or have history of alcoholism may have worsening liver problems. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems:loss of appetiteyellowing of your skin or whites of your eyes (jaundice)dark-colored urinepale colored stools (bowel movements)itchy skinstomach area (abdominal) painIncreased bleeding in people with hemophilia. Some people with hemophilia have increased bleeding with protease inhibitors including INVIRASE. Increase in certain fat (cholesterol and triglycerides) levels in your blood. Your healthcare provider will check your blood for high levels of cholesterol and triglycerides before you start INVIRASE and during treatment with INVIRASE. Changes in body fat can happen in people who take HIV-1 medicine. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breasts, and around the middle of your body (trunk). Loss of fat from the legs, arms and face may also happen. The exact cause and long-term health effects of these conditions are not known.Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider if you start having new or worse symptoms of infection after starting your HIV-1 medicine. The most common side effects of INVIRASE include: nauseavomitingdiarrheastomach area (abdominal) paintirednesspneumoniachanges in body fatThese are not all of the possible side effects of INVIRASE. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Genentech at 1-888-835-2555.How should store INVIRASEStore INVIRASE at room temperature between 68F to 77F (20C to 25C).Keep INVIRASE in tightly closed container.Keep INVIRASE and all medicine out of the reach of children. General information about the safe and effective use of INVIRASE.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use INVIRASE for condition for which it was not prescribed. Do not give INVIRASE to other people even if they have the same condition you have. It may harm them. You can ask your pharmacist or healthcare provider for information about INVIRASE that is written for health professionals.Active ingredient: saquinavir mesylate Inactive ingredients: 500 mg Tablet: lactose, microcrystalline cellulose, povidone K30, croscarmellose sodium, and magnesium stearate. Film coat: hypromellose, titanium dioxide, talc, iron oxide yellow, iron oxide red, and triacetin. INVIRASE is registered trademark of Hoffmann-La Roche Inc.Distributed by: Genentech, Inc., Member of the Roche Group, DNA Way, South San Francisco, CA 94080-4990 (C) 2020 Genentech, Inc. All rights reserved.For more information, go to http://www.gene.com/gene/products/information/invirase or call 1-877-436-3683.Representative sample of labeling (see the HOW SUPPLIED section for complete listing):. INVIRASE must be taken along with ritonavir.. INVIRASE taken along with ritonavir should not be taken with cobicistat.. Interactions with other medicines. It is important to know the medicines that should not be taken with INVIRASE. See the section What should tell my healthcare provider before taking INVIRASE Changes in your heart rhythm and the electrical activity of your heart. These changes may be seen on an EKG (electrocardiogram) and can lead to serious heart problems. Your risk for these problems may be higher if you: have history of abnormal heart rhythm, including Congenital Long QT Syndrome, or other types of heart disease.take other medicines that can affect your heart rhythm during treatment with INVIRASE.Tell your healthcare provider right away if you have any of these symptoms during treatment with INVIRASE:. have history of abnormal heart rhythm, including Congenital Long QT Syndrome, or other types of heart disease.. take other medicines that can affect your heart rhythm during treatment with INVIRASE.. dizziness. lightheadedness. fainting. sensation of abnormal heartbeats. condition called Congenital Long QT Syndrome.. complete AV (atrioventricular) heart block and you do not have pacemaker, or you are at risk for complete AV heart block.. low potassium or low magnesium in your blood.. you have had severe allergic reaction to saquinavir, saquinavir mesylate or any of the ingredients in INVIRASE. See the end of this Medication Guide for complete list of ingredients in INVIRASE.. severe liver problems. you have taken medicine that contains rilpivirine within the last weeks.. alfuzosin amiodarone atazanavir bepridil clarithromycin clozapine dasatinib. dofetilide. disopyramide. Ergot containing medicines, including: dihydroergotamineergonovine, ergonovine and methylergonovineergotamine dihydroergotamine. ergonovine, ergonovine and methylergonovine. ergotamine. erythromycin. flecainide halofantrine. haloperidol lidocaine. lovastatin lurasidone. midazolam pentamidine Phenothiazine containing medicines, Including:chlorpromazinemesoridazinethioridazine chlorpromazine. mesoridazine. thioridazine. pimozide propafenone. quinidine. quinine. rifampin. rilpivirine. sertindole. sildenafil simvastatin sunitinib. tacrolimus trazodone triazolam ziprasidone. have any heart problems, including condition called Congenital Long QT Syndrome.. have diabetes. have liver problems, including Hepatitis or Hepatitis C.. history of alcoholism.. have hemophilia. are pregnant or plan to become pregnant. It is not known if INVIRASE will harm your unborn baby. Pregnancy Registry: There is pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. are breastfeeding or plan to breastfeed. Do not breastfeed if you take INVIRASE. You should not breastfeed if you have HIV-1 because of the risk of passing HIV to your baby.It is not known if INVIRASE passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby. You should not breastfeed if you have HIV-1 because of the risk of passing HIV to your baby.. It is not known if INVIRASE passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby.. You can ask your healthcare provider or pharmacist for list of medicines that interact with INVIRASE. Take INVIRASE exactly as your healthcare provider tells you.. Do not change your dose of INVIRASE or stop treatment without first talking with your healthcare provider. Stay under the care of your healthcare provider during treatment with INVIRASE.. Take INVIRASE and ritonavir at the same time. Take INVIRASE and ritonavir times each day. Take INVIRASE and ritonavir within hours after meal.. Do not miss dose of INVIRASE. It is very important to take your medicine every day. If you skip doses or take less than the prescribed dose, the medicine will not work as well, and the virus may become harder to treat.. If you miss dose of INVIRASE, you should take the next dose as soon as possible. Do not double your dose. If you take too much INVIRASE, call your healthcare provider or go to the nearest hospital emergency room right away.. Diabetes and high blood sugar. Some people who take protease inhibitors including INVIRASE get new or more serious diabetes, or high blood sugar. Tell your healthcare provider if you notice an increase in thirst or urinate more often than normal during treatment with INVIRASE.. Liver problems. People with liver problems such as Hepatitis or C, cirrhosis or have history of alcoholism may have worsening liver problems. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems:. loss of appetite. yellowing of your skin or whites of your eyes (jaundice). dark-colored urine. pale colored stools (bowel movements). itchy skin. stomach area (abdominal) pain. Increased bleeding in people with hemophilia. Some people with hemophilia have increased bleeding with protease inhibitors including INVIRASE. Increase in certain fat (cholesterol and triglycerides) levels in your blood. Your healthcare provider will check your blood for high levels of cholesterol and triglycerides before you start INVIRASE and during treatment with INVIRASE. Changes in body fat can happen in people who take HIV-1 medicine. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breasts, and around the middle of your body (trunk). Loss of fat from the legs, arms and face may also happen. The exact cause and long-term health effects of these conditions are not known.. nausea. vomiting. diarrhea. stomach area (abdominal) pain. tiredness. pneumonia. changes in body fat. Store INVIRASE at room temperature between 68F to 77F (20C to 25C).. Keep INVIRASE in tightly closed container.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. (8.1)Lactation: Breastfeeding is not recommended due to risk of HIV-1 transmission. (8.2)Geriatric Use: Caution should be exercised due to greater frequency of decreased hepatic, renal or cardiac function in elderly population. (8.5). Pregnancy: Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. (8.1). Lactation: Breastfeeding is not recommended due to risk of HIV-1 transmission. (8.2). Geriatric Use: Caution should be exercised due to greater frequency of decreased hepatic, renal or cardiac function in elderly population. (8.5). 8.1Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to antiretrovirals during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.. Risk SummaryProspective pregnancy data from the APR are not sufficient to adequately assess drug-associated risk of birth defects or fetal outcomes. Limited number of reports on the use of saquinavir during pregnancy has been submitted to the APR and the number of exposures to saquinavir is insufficient to make risk assessment compared to reference population. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. The estimated background rate for major birth defects is 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The estimated rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the U.S. general population is 15-20%.In animal reproduction studies with saquinavir, no evidence of adverse developmental effects were observed at the highest achievable plasma exposures (AUC) in both rats and rabbits, resulting in exposures approximately 25% of those obtained in humans at the recommended human dose (RHD) combined with ritonavir. Saquinavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see Data).. Data. Human DataBased on prospective reports to the APR following exposure to saquinavir-containing regimens, there were birth defects reported in 183 first trimester exposures and birth defects reported in 221 second and third trimester exposures. Insufficient numbers of pregnancies with exposure to saquinavir have been reported to the APR to calculate the prevalence (95% CI) or for detailed assessment about the risk of saquinavir with regard to birth defects in this population. The background rate for major birth defects is 2.7% in U.S. reference population of the MACDP. Prospective reports from the APR of overall major birth defects in pregnancies exposed to saquinavir are compared with the U.S. background major birth defect rate. Methodological limitations of the APR include the use of the MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations as well as confounding due to the underlying disease.. Animal DataIn animal reproduction studies, no evidence of harm to the fetus was detected when saquinavir was administered orally to pregnant rats and rabbits twice-daily during the period of organogenesis at dose levels up to 1200 (rats) or 1000 (rabbits) mg/kg/day. However, because of limited bioavailability of saquinavir in animals and/or dosing limitations, plasma exposures (AUC) in these species were only 29% (rat) and 21% (rabbits) of those obtained in humans at the RHD combined with ritonavir. In pre- and postnatal development study, saquinavir was administered orally to pregnant rats (up to 1600 mg/kg/day) from gestation day 15 to post-partum day 20. No adverse effects were observed in the offspring exposed daily from before birth through lactation at maternal exposures (AUC) approximately 27% of those obtained in humans at the RHD combined with ritonavir.. 8.2 Lactation. 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.. 8.4 Pediatric Use. The safety and activity of INVIRASE have been evaluated in 68 pediatric subjects 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 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 >= background ARVs. Eighteen subjects months to less than 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. 8.5 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/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.. 8.6 Impaired Renal Function. Renal clearance is 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.. 8.7 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 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. INVIRASE must be used in combination with ritonavir. Cobicistat is not interchangeable with ritonavir and is not recommended for use in combination with INVIRASE. (5.1)The concomitant use of INVIRASE/ritonavir and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.2, 7.3)QT and PR interval prolongations have been observed in healthy volunteer study. Use with caution in patients with preexisting conduction system abnormalities and certain heart diseases. (5.3, 5.4, 12.2)Patients on INVIRASE therapy may develop new onset or exacerbations of diabetes mellitus (5.5), hyperglycemia (5.5), elevated cholesterol and/or triglyceride concentrations (5.6), redistribution/accumulation of body fat (5.10), and immune reconstitution syndrome (5.11). Monitor cholesterol and triglycerides prior to therapy and periodically thereafter. (5.8)In patients with underlying hepatitis or C, cirrhosis, chronic alcoholism and/or other underlying liver abnormalities there have been reports of worsening liver disease. (5.6)Hemophilia: Spontaneous bleeding may occur and additional factor VIII may be required. (5.7)Each tablet contains lactose monohydrate. INVIRASE is not recommended in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. (5.9)Various degrees of cross-resistance have been observed. (5.12). INVIRASE must be used in combination with ritonavir. Cobicistat is not interchangeable with ritonavir and is not recommended for use in combination with INVIRASE. (5.1). The concomitant use of INVIRASE/ritonavir and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.2, 7.3). QT and PR interval prolongations have been observed in healthy volunteer study. Use with caution in patients with preexisting conduction system abnormalities and certain heart diseases. (5.3, 5.4, 12.2). Patients on INVIRASE therapy may develop new onset or exacerbations of diabetes mellitus (5.5), hyperglycemia (5.5), elevated cholesterol and/or triglyceride concentrations (5.6), redistribution/accumulation of body fat (5.10), and immune reconstitution syndrome (5.11). Monitor cholesterol and triglycerides prior to therapy and periodically thereafter. (5.8). In patients with underlying hepatitis or C, cirrhosis, chronic alcoholism and/or other underlying liver abnormalities there have been reports of worsening liver disease. (5.6). Hemophilia: Spontaneous bleeding may occur and additional factor VIII may be required. (5.7). Each tablet contains lactose monohydrate. INVIRASE is not recommended in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. (5.9). Various degrees of cross-resistance have been observed. (5.12). 5.1 Importance of Co-administration with Ritonavir. 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.. 5.2 Risk of Serious Adverse Reactions Due to Drug Interactions. Initiation of INVIRASE/ritonavir, 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 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 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.. 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.. 5.3 PR Interval Prolongation. INVIRASE/ritonavir prolongs the PR interval in 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 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.. 5.4 QT Interval Prolongation. 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.. Patients initiating therapy with INVIRASE/ritonavir:An ECG should be performed prior to initiation of treatment. Patients with QT interval >= 450 msec should not initiate treatment with INVIRASE/ritonavir.Treatment-naive patients initiating treatment with INVIRASE/ritonavir should receive reduced starting dose of INVIRASE 500 mg twice daily with ritonavir 100 mg twice daily for the first days of treatment followed by INVIRASE/ritonavir 1000/100 mg twice daily due to potential for an increased risk of PR and QT interval prolongation with the standard 1000/100 mg twice daily dose [see Clinical Pharmacology (12.2)].For patients with baseline QT interval 450 msec, an on-treatment ECG is recommended after approximately 10 days of therapy.Discontinue INVIRASE/ritonavir in patients with QT interval prolongation 20 msec over pre-treatment.. Patients requiring treatment with medications with the potential to increase the QT interval and concomitant INVIRASE/ritonavir: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 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 subsequent increase in QT interval by 20 msec after commencing concomitant therapy, the physician should use best clinical judgment to discontinue either INVIRASE/ritonavir 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.. 5.5 Diabetes Mellitus/Hyperglycemia. 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 causal relationship between protease-inhibitor therapy and these events has not been established.. 5.6 Hepatotoxicity. In patients with underlying hepatitis 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 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 serious or severe toxicity occurs during treatment with INVIRASE/ritonavir, discontinue INVIRASE/ritonavir.. 5.7 Hemophilia. There have been reports of spontaneous bleeding in patients with hemophilia and 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. causal relationship between protease inhibitor therapy and these episodes has not been established.. 5.8 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 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.. 5.9 Lactose Intolerance. 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).. 5.10 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. causal relationship has not been established.. 5.11 Immune Reconstitution Syndrome. 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-Barre 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.. 5.12 Resistance/Cross-resistance. 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)].