LOPINAVIR
DESCRIPTION
RITOMAX-L (lopinavir/ritonavir) is a co-formulation of lopinavir and ritonavir. Lopinavir is an inhibitor of the HIV protease. As co-formulated in RITOMAX-L, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.
Lopinavir is chemically designated as [1S-[1R*,(R*),3R*, 4R*]]-N-[4-[[(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5- phenyl-1-phenyl methyl)pentyl]tetrahydro-alpha-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide. Its molecular formula is C 37 H 48 N 4 O 5 , and its molecular weight is 628.80.
Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula is C 37 H 48 N 6 O 5 S 2 , and its molecular weight is 720.95.
Lopinavir is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.
RITOMAX-L capsules are available for oral administration in a strength of 133.3 mg lopinavir and 33.3 mg ritonavir with the following inactive ingredients: FD&C Yellow No. 6, gelatin, glycerin, oleic acid, polyoxyl 35 castor oil, propylene glycol, sorbitol special, titanium dioxide, and water.
CLINICAL PHARMACOLOGY
Microbiology
Mechanism of action: Lopinavir, an inhibitor of the HIV protease, prevents cleavage of the Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles.
Antiviral activity in vitro: The in vitro antiviral activity of lopinavir against laboratory HIV strains and clinical HIV isolates was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively. In the absence of human serum, the mean 50% effective concentration (EC 50 ) of lopinavir against five different HIV-1 laboratory strains ranged from 10-27 nM (0.006 - 0.017 µg/mL, 1 µg/mL = 1.6 µM) and ranged from 4-11 nM (0.003 - 0.007 µg/mL) against several HIV-1 clinical isolates (n=6). In the presence of 50% human serum, the mean EC 50 of lopinavir against these five laboratory strains ranged from 65 - 289 nM (0.04 - 0.18 µg/mL), representing a 7- to 11-fold attenuation. Combination drug activity studies with lopinavir and other protease inhibitors or reverse transcriptase inhibitors have not been completed.
Resistance: HIV-1 isolates with reduced susceptibility to lopinavir have been selected in vitro . The presence of ritonavir does not appear to influence the selection of lopinavir-resistant viruses in vitro .
The selection of resistance to RITOMAX-L in antiretroviral treatment naive patients has not yet been characterized. In a Phase III study of 653 antiretroviral treatment naive patients (Study 863), plasma viral isolates from each patient on treatment with plasma HIV >400 copies/mL at Week 24, 32, 40 and/or 48 were analyzed. No evidence of resistance to RITOMAX-L was observed in 37 evaluable RITOMAX-L-treated patients (0%). Evidence of genotypic resistance to nelfinavir, defined as the presence of the D30N and/or L90M mutation in HIV protease, was observed in 25/76 (33%) of evaluable nelfinavir-treated patients. The selection of resistance to RITOMAX-L in antiretroviral treatment naive pediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863).
Resistance to RITOMAX-L has been noted to emerge in patients treated with other protease inhibitors prior to RITOMAX-L therapy. In Phase II studies of 227 antiretroviral treatment naive and protease inhibitor experienced patients, isolates from 4 of 23 patients with quantifiable (>400 copies/mL) viral RNA following treatment with RITOMAX-L for 12 to 100 weeks displayed significantly reduced susceptibility to lopinavir compared to the corresponding baseline viral isolates. Three of these patients had previously received treatment with a single protease inhibitor (nelfinavir, indinavir, or saquinavir) and one patient had received treatment with multiple protease inhibitors (indinavir, saquinavir and ritonavir). All four of these patients had at least 4 mutations associated with protease inhibitor resistance immediately prior to RITOMAX-L therapy. Following viral rebound, isolates from these patients all contained additional mutations, some of which are recognized to be associated with protease inhibitor resistance. However, there are insufficient data at this time to identify lopinavir-associated mutational patterns in isolates from patients on RITOMAX-L therapy. The assessment of these mutational patterns is under study.
Cross-resistance -- Preclinical Studies: Varying degrees of cross-resistance have been observed among HIV protease inhibitors. Little information is available on the cross-resistance of viruses that developed decreased susceptibility to lopinavir during RITOMAX-L therapy.
The in vitro activity of lopinavir against clinical isolates from patients previously treated with a single protease inhibitor was determined. Isolates that displayed >4-fold reduced susceptibility to nelfinavir (n=13) and saquinavir (n=4), displayed <4-fold reduced susceptibility to lopinavir. Isolates with >4-fold reduced susceptibility to indinavir (n=16) and ritonavir (n=3) displayed a mean of 5.7- and 8.3-fold reduced susceptibility to lopinavir, respectively. Isolates from patients previously treated with two or more protease inhibitors showed greater reductions in susceptibility to lopinavir, as described in the following paragraph.
Clinical Studies -- Antiviral activity of RITOMAX-L in patients with previous protease inhibitor therapies: The clinical relevance of reduced in vitro susceptibility to lopinavir has been examined by assessing the virologic response to RITOMAX-L therapy, with respect to baseline viral genotype and phenotype, in 56 NNRTI-naive patients with HIV RNA >1000 copies/mL despite previous therapy with at least two protease inhibitors selected from nelfinavir, indinavir, saquinavir and ritonavir (Study 957). In this study, patients were initially randomized to receive one of two doses of RITOMAX-L in combination with efavirenz and nucleoside reverse transcriptase inhibitors. The EC 50 values of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold higher than the wild-type EC 50 . Fifty-five percent (31/56) of these baseline isolates displayed a >4-fold reduced susceptibility to lopinavir. These 31 isolates had a mean reduction in lopinavir susceptibility of 27.9-fold. Table 1 shows the 48 week virologic response (HIV RNA <400 and <50 copies) according to susceptibility and number of genotypic mutations at baseline in 50 evaluable patients enrolled in the study (957) described above. Because this was a select patient population and the sample size was small, the data depicted in Table 1 do not constitute definitive clinical susceptibility breakpoints. Additional data are needed to determine clinically significant breakpoints for RITOMAX-L.
Table 1: HIV RNA Response at Week 48 by baseline
RITOMAX-L susceptibility and by number
of protease inhibitor-associated mutations 1
Lopinavir susceptibility 2
at baseline HIV RNA < 400 copies/mL (%) HIV RNA < 50 copies/mL (%)
<10 fold 25/27 (93%) 22/27 (81%)
>10 and <40 fold 11/15 (73%) 9/15 (60%)
>/=40 fold 2/8 (25%) 2/8 (25%)
Number of protease inhibitor mutations at baseline
Up to 5 21/23 (91%) 3 19/23 (83%)
>5 17/27 (63%) 14/27 (52%)
1 Lopinavir susceptibility was determined by recombinant phenotypic technology performed by virologic; genotype also performed by virologic
2 Fold change in susceptibility from wild type
3 Thirteen of the 23 patient isolates contained PI mutations at positions 82, 84, and/or 90
There are insufficient data at this time to identify lopinavir-associated mutational patterns in isolates from patients on RITOMAX-L therapy. Further studies are needed to assess the association between specific mutational patterns and virologic response rates.
Pharmacokinetics
The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-infected patients; no substantial differences were observed between the two groups. Lopinavir is essentially completely metabolized by CYP3A. Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. Across studies, administration of RITOMAX-L 400/100 mg BID yields mean steady-state lopinavir plasma concentrations 15- to 20-fold higher than those of ritonavir in HIV-infected patients. The plasma levels of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg BID. The in vitro antiviral EC 50 of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of RITOMAX-L is due to lopinavir.
Figure 1 displays the mean steady-state plasma concentrations of lopinavir and ritonavir after RITOMAX-L 400/100 mg BID for 3-4 weeks from a pharmacokinetic study in HIV-infected adult subjects (n=21).
Absorption: In a pharmacokinetic study in HIV-positive subjects (n=21) without meal restrictions, multiple dosing with 400/100 mg RITOMAX-L BID for 3 to 4 weeks produced a mean ± SD lopinavir peak plasma concentration (C max ) of 9.6 ± 4.4 µg/mL, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 5.5 ± 4.0 µg/mL. Lopinavir AUC over a 12 hour dosing interval averaged 82.8 ± 44.5 µg•h/mL. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established. Under nonfasting conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of RITOMAX-L co-formulated capsules and liquid. When administered under fasting conditions, both the mean AUC and C max of lopinavir were 22% lower for the RITOMAX-L liquid relative to the capsule formulation.
Effects of Food on Oral Absorption: Administration of a single 400/100 mg dose of RITOMAX-L capsules with a moderate fat meal (500-682 kcal, 23 to 25% calories from fat) was associated with a mean increase of 48 and 23% in lopinavir AUC and C max , respectively, relative to fasting. For RITOMAX-L oral solution, the corresponding increases in lopinavir AUC and C max were 80 and 54%, respectively. Relative to fasting, administration of RITOMAX-L with a high fat meal (872 kcal, 56% from fat) increased lopinavir AUC and C max by 97 and 43%, respectively, for capsules, and 130 and 56%, respectively, for oral solution. To enhance bioavailability and minimize pharmacokinetic variability RITOMAX-L should be taken with food.
Distribution: At steady state, lopinavir is approximately 98-99% bound to plasma proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin; however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg RITOMAX-L BID, and is similar between healthy volunteers and HIV-positive patients.
Metabolism: In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolized by the hepatic cytochrome P450 system, almost exclusively by the CYP3A isozyme. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir, and therefore increases plasma levels of lopinavir. A 14 C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg RITOMAX-L dose was due to parent drug. At least 13 lopinavir oxidative metabolites have been identified in man. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilizing after approximately 10 to 16 days.
Elimination: Following a 400/100 mg 14 C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an administered dose of 14 C-lopinavir can be accounted for in urine and feces, respectively, after 8 days. Unchanged lopinavir accounted for approximately 2.2 and 19.8% of the administered dose in urine and feces, respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The half-life of lopinavir over a 12 hour dosing interval averaged 5-6 hours, and the apparent oral clearance (CL/F) of lopinavir is 6 to 7 L/h.
Special Populations:
Gender, Race and Age: Lopinavir pharmacokinetics have not been studied in elderly patients. No gender related pharmacokinetic differences have been observed in adult patients. No clinically important pharmacokinetic differences due to race have been identified.
Pediatric Patients: The pharmacokinetics of RITOMAX-L 300/75 mg/m 2 BID and 230/57.5 mg/m 2 BID have been studied in a total of 53 pediatric patients, ranging in age from 6 months to 12 years. The 230/57.5 mg/m 2 BID regimen without nevirapine and the 300/75 mg/m 2 BID regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg BID regimen (without nevirapine).
The mean steady-state lopinavir AUC, C max , and C min were 72.6 ± 31.1 µg•h/mL, 8.2 ± 2.9 and 3.4 ± 2.1 µg/mL, respectively after RITOMAX-L 230/57.5 mg/m 2 BID without nevirapine (n=12), and were 85.8 ± 36.9 µg•h/mL, 10.0 ± 3.3 and 3.6 ± 3.5 µg/mL, respectively, after 300/75 mg/m 2 BID with nevirapine (n=12). The nevirapine regimen was 7 mg/kg BID (6 months to 8 years) or 4 mg/kg BID (>8 years).
Renal Insufficiency: Lopinavir pharmacokinetics have not been studied in patients with renal insufficiency; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency.
Hepatic Impairment: Lopinavir is principally metabolized and eliminated by the liver. Although RITOMAX-L has not been studied in patients with hepatic impairment, lopinavir concentrations may be increased in these patients (see PRECAUTIONS ).
Drug-Drug Interactions: See also CONTRAINDICATIONS , WARNINGS and PRECAUTIONS:
Drug Interactions .
RITOMAX-L is an inhibitor of the P450 isoform CYP3A in vitro . Co-administration of RITOMAX-L and drugs primarily metabolized by CYP3A may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects (see CONTRAINDICATIONS ).
RITOMAX-L inhibits CYP2D6 in vitro , but to a lesser extent than CYP3A. Clinically significant drug interactions with drugs metabolized by CYP2D6 are possible with RITOMAX-L at the recommended dose, but the magnitude is not known. RITOMAX-L does not inhibit CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations.
RITOMAX-L has been shown in vivo to induce its own metabolism and to increase the biotransformation of some drugs metabolized by cytochrome P450 enzymes and by glucuronidation.
RITOMAX-L is metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to increase the clearance of lopinavir, resulting in lowered plasma concentrations of lopinavir. Although not noted with concurrent ketoconazole, co-administration of RITOMAX-L and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.
Drug interaction studies were performed with RITOMAX-L and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of RITOMAX-L on the AUC, C max and C min are summarized in Table 2 (effect of other drugs on lopinavir) and Table 3 (effect of RITOMAX-L on other drugs). The effects of other drugs on ritonavir are not shown since they generally correlate with those observed with lopinavir (if lopinavir concentrations are decreased, ritonavir concentrations are decreased) unless otherwise indicated in the table footnotes. For information regarding clinical recommendations, see Table 9 in PRECAUTIONS .
Table 2: Drug Interactions: Pharmacokinetic Parameters for Lopinavir
in the Presence of the Co-administered drug
(See Precautions , Table 9 for Recommended Alterations in Dose or Regimen)
Co-administered Dose ofCo-
Drug
administered
Drug (mg) Dose of
RITOMAX-L
(mg) n Ratio (with/without co-administered drug) of Lopinavir Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
C max AUC C min
Amprenavir 1 450 BID,
5 d 400/100 BID, 12 0.89 0.85 0.81
750 BID,
5 d 22 d 10 (0.83, 0.95) (0.81, 0.90) (0.74, 0.89)
Atorvastatin 20 QD,
4 d 400/100 BID, 12 0.90 0.90 0.92
14 d (0.78, 1.06) (0.79, 1.02) (0.78, 1.10)
Efavirenz 2 600 QHS,
9 d 400/100 BID, 11, 7 * 0.97 0.81 0.61
9 d (0.78, 1.22) (0.64, 1.03) (0.38, 0.97)
Ketoconazole 200 single
dose 400/100 BID, 12 0.89 0.87 0.75
16 d (0.80, 0.99) (0.75, 1.00) (0.55, 1.00)
Nevirapine 200 BID, 400/100 BID, 22, 19 * 0.81 0.73 0.49
steady-state
(>1 yr) 3 steady-state
(>1 yr) (0.62, 1.05) (0.53, 0.98) (0.28, 0.74)
7 mg/kg
or 4 mg/kg 300/75 mg/m 2 12, 15 * 0.86 0.78 0.45
QD, 2 wk;
BID 1 wk 4 BID, 3 wk (0.64, 1.16) (0.56, 1.09) (0.25, 0.81)
Pravastatin 20 QD,
4 d 400/100 BID, 12 0.98 0.95 0.88
14 d (0.89, 1.08) (0.85, 1.05) (0.77, 1.02)
Rifabutin 150 QD,
10 d 400/100 BID, 14 1.08 1.17 1.20
20 d (0.97, 1.19) (1.04, 1.31) (0.96, 1.65)
Rifampin 600 QD, 1
0 d 400/100 BID, 22 0.45 0.25 0.01
20 d (0.40, 0.51) (0.21, 0.29) (0.01, 0.02)
Ritonavir 3 100 BID,
3-4 wk 400/100 BID, 8, 21 * 1.28 1.46 2.16
3-4 wk (0.94, 1.76) (1.04, 2.06) (1.29, 3.62)
All interaction studies conducted in healthy, HIV-negative subjects unless otherwise indicated.
1 Composite effect of amprenavir 450 and 750 mg Q12h regimens on lopinavir pharmacokinetics.
2 The pharmacokinetics of ritonavir are unaffected by concurrent efavirenz.
3 Study conducted in HIV-positive adult subjects.
4 Study conducted in HIV-positive pediatric subjects ranging in age from 6 months to 12 years.
* Parallel group design; n for RITOMAX-L + co-administered drug, n for RITOMAX-L alone.
Table 3: Drug Interactions: Pharmacokinetic Parameters for
Co-administered Drug in the Presence of RITOMAX-L
(See Precautions , Table 9 for Recommended Alterations in Dose or Regimen)
Co- Dose of Dose of Ratio (with/without RITOMAX-L) of
administered Co-administered RITOMAX-L Co-administered Drug Pharmacokinetic
Drug Drug (mg) (mg) n Parameters (90% CI); No Effect = 1.00
C max AUC C min
Amprenavir 450 BID, 5 d
750 BID, 5 d 400/100 BID,
22 d 12
10 See text below for discussion of interaction.
Atorvastatin 20 QD, 4 d 400/100 BID, 12 4.67 5.88 2.28
14 d (3.35, 6.51) (4.69, 7.37) (1.91, 2.71)
Efavirenz 600 QHS, 9 d 400/100 BID, 11, 12 * 0.91 0.84 0.84
9 d (0.72, 1.15) (0.62, 1.15) (0.58, 1.20)
Ethinyl
Estradiol 35 µg QD, 21 d
(Ortho Novum®) 400/100 BID,
14 d 12 0.59
(0.52, 0.66) 0.58
(0.54, 0.62) 0.42
(0.36, 0.49)
Indinavir 600 single dose 400/100 BID,
10 d 11 See text below for discussion of interaction.
Ketoconazole 200 single dose 400/100 BID, 12 1.13 3.04 N/A
16 d (0.91, 1.40) (2.44, 3.79)
Methadone 5 single dose 400/100 BID, 11 0.55 0.47 N/A
10 d (0.48, 0.64) (0.42, 0.53)
Nevirapine 200 QD, 14 d; 400/100 BID, 5, 6 * 1.05 1.08 1.15
BID, 6 d 20 d (0.72, 1.52) (0.72, 1.64) (0.71, 1.86)
Norethindrone 1 QD, 21 d 400/100 BID, 12 0.84 0.83 0.68
(Ortho Novum®) 14 d (0.75, 0.94) (0.73, 0.94) (0.54, 0.85)
Pravastatin 20 QD, 4 d 400/100 BID, 12 1.26 1.33 N/A
14 d (0.87, 1.83) (0.91, 1.94)
Rifabutin 300 QD, 10 d; 400/100 BID, 12 2.12 3.03 4.90
150 QD, 10 d 10 d (1.89, 2.38) (2.79, 3.30) (3.18, 5.76)
25- O -des- 23.6 47.5 94.9
acetyl rifabutin (13.7, 25.3) (29.3, 51.8) (74.0, 122)
Rifampin + 3.46 5.73 9.53
25- O -des- (3.07, 3.91) (5.08, 6.46) (7.56, 12.01)
acetyl rifabutin 1
Saquinavir 800 single dose 400/100 BID,
10 d 11 See text below for discussion of interaction.
All interaction studies conducted in healthy, HIV-negative subjects unless otherwise indicated.
1 Effect on the dose-normalized sum of rifabutin parent and 25-O-desacetyl rifabutin active metabolite.
*Parallel group design; n for RITOMAX-L + co-administered drug, n for co-administered drug alone.
N/A=not available.
Effect of RITOMAX-L on other Protease Inhibitors (PIs): The pharmacokinetics of single-dose indinavir and saquinavir, and multiple-dose amprenavir obtained in healthy subjects after at least 10 days of RITOMAX-L 400/100 mg BID were compared to historical data in HIV-infected subjects (refer to Table 3 for information on study design and doses). Because of the limitations in the study design and the use of comparisons between healthy and HIV infected subjects, it is not possible to recommend definitive dosing recommendations. However, based on these comparisons, amprenavir 750 mg BID and indinavir 600 mg BID, when co-administered with RITOMAX-L 400/100 mg BID, may produce a similar AUC, lower C max , and higher C min compared to their respective established clinical dosing regimens. Saquinavir 800 mg BID, when co-administered with RITOMAX-L 400/100 mg BID, may produce a similar AUC and higher C min to its respective established clinical dosing regimen (no comparative information regarding C max ). The clinical significance of the lower C max and higher C min is unknown. Appropriate doses of amprenavir, indinavir and saquinavir in combination with RITOMAX-L with respect to safety and efficacy have not been established (see PRECAUTIONS --Table 9 ).
INDICATIONS AND USAGE
RITOMAX-L is indicated in combination with other antiretroviral agents for the treatment of HIV-infection. This indication is based on analyses of plasma HIV RNA levels and CD 4 cell counts in controlled studies of RITOMAX-L of 48 weeks duration and in smaller uncontrolled dose-ranging studies of RITOMAX-L of 72 weeks duration.
Description of Clinical Studies
Patients Without Prior Antiretroviral Therapy
Study 863: RITOMAX-L BID + stavudine + lamivudine compared to nelfinavir TID + stavudine + lamivudine
Study 863 is an ongoing, randomized, double-blind, multicenter trial comparing treatment with RITOMAX-L (400/100 mg BID) plus stavudine and lamivudine versus nelfinavir (750 mg TID) plus stavudine and lamivudine in 653 antiretroviral treatment naive patients. Patients had a mean age of 38 years (range: 19 to 84), 57% were Caucasian, and 80% were male. Mean baseline CD 4 cell count was 259 cells/mm 3 (range: 2 to 949 cells/mm 3 ) and mean baseline plasma HIV-1 RNA was 4.9 log 10 copies/mL (range: 2.6 to 6.8 log 10 copies/mL).
Treatment response and outcomes of randomized treatment are presented in Figure 2 and Table 4, respectively.
*Roche AMPLICOR HIV-1 MONITOR Assay.
† Responders at each visit are patients who had achieved and maintained HIV-1 RNA <400 copies/mL without discontinuation by that visit.
Table 4: Outcomes of Randomized Treatment
Through Week 48 (Study 863) Outcome RITOMAX-L
+d4T + 3TC
(N=326) Nelfinavir
+d4T + 3TC
(N=327)
Responder * 1 75% 62%
Virologic failure 2 9% 25%
Rebound 7% 15%
Never suppressed through Week 48 2% 9%
Death 2% 1%
Discontinued due to adverse event 4% 4%
Discontinued for other reasons 3 10% 8%
* Corresponds to rates at Week 48 in Figure 2.
1 Patients achieved and maintained confirmed HIV RNA <400 copies/mL through Week 48.
2 Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48.
3 Includes lost to follow-up, patient's withdrawl, non-compliance, protocol violation and other reasons.
Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the RITOMAX-L arm compared to the nelfinavir arm with HIV RNA <400 copies/mL (75% vs. 62%, respectively) and HIV RNA <50 copies/mL (67% vs. 52%, respectively). Treatment response by baseline HIV RNA level subgroups is presented in Table 5.
Table 5: Proportion of Responders Through Week 48 by Baseline Viral Load (Study 863) Baseline Viral Load
(HIV-1 RNA copies/mL) RITOMAX-L
+d4T + 3TC Nelfinavir
+d4T+ 3TC
<400
copies/mL 1 <50
copies/mL 2 n <400
copies/mL 1 <50
copies/mL 2 n
<30,000 74% 71% 82 79% 72% 87
>/=30,000 to <100,000 81% 73% 79 67% 54% 79
>/=100,000 to <250,000 75% 64% 83 60% 47% 72
>/=250,000 72% 60% 82 44% 33% 89
1 Patients achieved and maintained confirmed HIV RNA <400 copies/mL through Week 48.
2 Patients achieved HIV RNA <50 copies/mL at Week 48.
Through 48 weeks of therapy, the mean increase from baseline in CD 4 cell count was 207 cells/mm 3 for the RITOMAX-L arm and 195 cells/mm 3 for the nelfinavir arm.
Patients with Prior Antiretroviral Therapy
Study 888: RITOMAX-L BID + nevirapine + NRTIs compared to investigator-selected protease inhibitor(s) + nevirapine + NRTIs.
Study 888 is a randomized, open-label, multicenter trial comparing treatment with RITOMAX-L (400/100 mg BID) plus nevirapine and nucleoside reverse transcriptase inhibitors versus investigator-selected protease inhibitor(s) plus nevirapine and nucleoside reverse transcriptase inhibitors in 288 single protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive patients. Patients had a mean age of 40 years (range: 18 to 74), 68% were Caucasian, and 86% were male. Mean baseline CD 4 cell count was 322 cells/mm 3 (range: 10 to 1059 cells/mm 3 ) and mean baseline plasma HIV-1 RNA was 4.1 log 10 copies/mL (range: 2.6 to 6.0 log 10 copies/mL).
Treatment response and outcomes of randomized treatment through Week 48 are presented in Figure 3 and Table 6, respectively.
Table 6. Outcomes of Randomized Treatment Through Week 48 (Study 888) Outcome RITOMAX-L +
nevirapine + NRTIs
(n=148) Investigator-Selected
Protease
Inhibitor(s) +
nevirapine + NRTIs
(n=140)
Responder * 1 57% 33%
Virologic Failure 2 24% 41%
Rebound 11% 19%
Never suppressed through Week 48 13% 23%
Death 1% 2%
Discontinued due to adverse events 5% 11%
Discontinued for other reasons 3 14% 13%
*Corresponds to rates at Week 48 in Figure 3.
1 Patients achieved and maintained confirmed HIV RNA <400 copied/mL, through Week 48.
2 Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48.
3 Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons.
Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the RITOMAX-L arm compared to the investigator-selected protease inhibitor(s) arm with HIV RNA <400 copies/mL (57% vs. 33%, respectively).
Through 48 weeks of therapy, the mean increase from baseline in CD 4 cell count was 111 cells/mm 3 for the RITOMAX-L arm and 112 cells/mm 3 for the investigator-selected protease inhibitor(s) arm.
Other Studies
Study 720: RITOMAX-L BID + stavudine + lamivudine
Study 765: RITOMAX-L BID + nevirapine + NRTIs
Study 720 (patients without prior antiretroviral therapy) and study 765 (patients with prior protease inhibitor therapy) are randomized, blinded, multi-center trials evaluating treatment with RITOMAX-L at up to three dose levels (200/100 mg BID [720 only], 400/100 mg BID, and 400/200 mg BID). Patients in study 720 had a mean age of 35 years, 70% were Caucasian, and 96% were male, while patients in study 765 had a mean age of 40 years, 73% were Caucasian, and 90% were male. Mean (range) baseline CD 4 cell counts for patients in study 720 and study 765 were 338 (3-918) and 372 (72-807) cells/mm 3 , respectively. Mean (range) baseline plasma HIV-1 RNA levels for patients in study 720 and study 765 were 4.9 (3.3 to 6.3) and 4.0 (2.9 to 5.8) log 10 copies/mL, respectively.
Through 72 weeks of treatment, for patients randomized to the 400/100 mg BID dose of RITOMAX-L, the proportion of patients with plasma HIV-1 RNA <400 (<50) copies/mL was 80% (78%) in study 720 [n=51] and 75% (58%) in study 765 [n=36]. The corresponding mean increase in CD 4 cell count was 256 cells/mm 3 for study 720 and 174 cells/mm 3 for study 765. At 72 weeks, 13 patients (13%) had discontinued study 720 for any reason, including four discontinuations (4%) secondary to adverse events or laboratory abnormalities with one of these discontinuations (1%) being attributed to a RITOMAX-L adverse event. In study 765, 13 patients (19%) had discontinued the study for any reason at 72 weeks, including six discontinuations (9%) secondary to adverse events or laboratory abnormalities with three of these discontinuations (4%) being attributed to RITOMAX-L adverse events.
CONTRAINDICATIONS
RITOMAX-L is contraindicated in patients with known hypersensitivity to any of its ingredients, including ritonavir.
Co-administration of RITOMAX-L is contraindicated with drugs that are highly dependent on CYP3A or CYP2D6 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 7.
Table 7: Drugs That Are Contraindicated
With RITOMAX-L Drug Class Drugs Within Class That Are Contraindicated With RITOMAX-L
Antiarrhythmics Flecainide, Propafenone
Antihistamines Astemizole, Terfenadine
Ergot Derivatives Dihydroergotamine, Ergonovine, Ergotamine, Methylergonovine
GI motility agent Cisapride
Neuroleptic Pimozide
Sedative/hypnotics Midazolam, Triazolam
WARNINGS
ALERT: Find out about medicines that should NOT be taken with RITOMAX-L. This statement is included on the product's bottle label.
Drug Interactions
RITOMAX-L is an inhibitor of the P450 isoform CYP3A. Co-administration of RITOMAX-L and drugs primarily metabolized by CYP3A or CYP2D6 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects (see Pharmacokinetics : Drug-Drug Interactions , CONTRAINDICATIONS -- Table 7: Drugs That Are Contraindicated With RITOMAX-L , PRECAUTIONS -- Table 8: Drugs That Should Not Be Co-administered With RITOMAX-L and Table 9: Established and Other Potentially Significant Drug Interactions ).
Particular caution should be used when prescribing sildenafil in patients receiving RITOMAX-L. Co-administration of RITOMAX-L with sildenafil is expected to substantially increase sildenafil concentrations and may result in an increase in sildenafil-associated adverse events including hypotension, syncope, visual changes and prolonged erection (see PRECAUTIONS : Drug Interactions and the complete prescribing information for sildenafil).
Concomitant use of RITOMAX-L with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including RITOMAX-L, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin). The risk of myopathy, including rhabdomyolysis may be increased when HIV protease inhibitors, including RITOMAX-L, are used in combination with these drugs.
Concomitant use of RITOMAX-L and St. John's wort (hypericum perforatum), or products containing St. John's wort, is not recommended. Co-administration of protease inhibitors, including RITOMAX-L, with St. John's wort is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of lopinavir and lead to loss of virologic response and possible resistance to lopinavir or to the class of protease inhibitors.
Pancreatitis
Pancreatitis has been observed in patients receiving RITOMAX-L therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to RITOMAX-L has not been established, marked triglyceride elevations is a risk factor for development of pancreatitis (see PRECAUTIONS -- Lipid Elevations ). Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk of recurrence during RITOMAX-L therapy.
Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and RITOMAX-L and/or other antiretroviral therapy should be suspended as clinically appropriate.
Diabetes Mellitus/Hyperglycemia
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
PRECAUTIONS
Hepatic Impairment and Toxicity
RITOMAX-L is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment, because lopinavir concentrations may be increased. Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with RITOMAX-L therapy has not been established. Increased AST/ALT monitoring should be considered in these patients, especially during the first several months of RITOMAX-L treatment.
Resistance/Cross-resistance
Various degrees of cross-resistance among protease inhibitors have been observed. The effect of RITOMAX-L therapy on the efficacy of subsequently administered protease inhibitors is under investigation (see MICROBIOLOGY ).
Hemophilia
There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Lipid Elevations
Treatment with RITOMAX-L has resulted in large increases in the concentration of total cholesterol and triglycerides (see ADVERSE REACTIONS -- Table 11). Triglyceride and cholesterol testing should be performed prior to initiating RITOMAX-L therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate. See PRECAUTIONS Table 9: Established and Other Potentially Significant Drug Interactions for additional information on potential drug interactions with RITOMAX-L and HMG-CoA reductase inhibitors.
Information for Patients
A statement to patients and health care providers is included on the product's bottle label: "ALERT: Find out about medicines that should NOT be taken with RITOMAX-L." A Patient Package Insert (PPI) for RITOMAX-L is available for patient information.
Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using RITOMAX-L. Patients should be advised to take RITOMAX-L and other concomitant antiretroviral therapy every day as prescribed. RITOMAX-L must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their doctor. If a dose of RITOMAX-L is missed patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose.
Patients should be informed that RITOMAX-L is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. The long-term effects of RITOMAX-L are unknown at this time. Patients should be told that there are currently no data demonstrating that therapy with RITOMAX-L can reduce the risk of transmitting HIV to others through sexual contact.
RITOMAX-L may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort.
Patients taking didanosine should take didanosine one hour before or two hours after RITOMAX-L.
Patients receiving sildenafil should be advised that they may be at an increased risk of sildenafil-associated adverse events including hypotension, visual changes, and sustained erection, and should promptly report any symptoms to their doctor.
Patients receiving estrogen-based hormonal contraceptives should be instructed that additional or alternate contraceptive measures should be used during therapy with RITOMAX-L.
RITOMAX-L should be taken with food to enhance absorption.
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time.
Drug Interactions
RITOMAX-L is an inhibitor of CYP3A (cytochrome P450 3A) both in vitro and in vivo . Co-administration of RITOMAX-L and drugs primarily metabolized by CYP3A (e.g., dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and sildenafil) may result in increased plasma concentrations of the other drugs that could increase or prolong their therapeutic and adverse effects (see Table 9: Established and Other Potentially Significant Drug Interactions ). Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (>3-fold) when co-administered with RITOMAX-L.
RITOMAX-L inhibits CYP2D6 in vitro , but to a lesser extent than CYP3A. Clinically significant drug interactions with drugs metabolized by CYP2D6 are possible with RITOMAX-L at the recommended dose, but the magnitude is not known. RITOMAX-L does not inhibit CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations.
RITOMAX-L has been shown in vivo to induce its own metabolism and to increase the biotransformation of some drugs metabolized by cytochrome P450 enzymes and by glucuronidation.
RITOMAX-L is metabolized by CYP3A. Co-administration of RITOMAX-L and drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce its therapeutic effect (see Table 9: Established and Other Potentially Significant Drug Interactions ). Although not noted with concurrent ketoconazole, co-administration of RITOMAX-L and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.
Drugs that are contraindicated and not recommended for co-administration with RITOMAX-L are included in Table 8: Drugs That Should Not Be Co-administered With RITOMAX-L . These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.
Table 8: Drugs That Should Not Be Co-administered With RITOMAX-L Drug Class: Drug Name Clinical Comment
Antiarrhythmics:
flecainide, propafenone CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antihistamines:
astemizole, terfenadine CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterial:
rifampin May lead to loss of virologic response and possible resistance to RITOMAX-L or to the class of protease inhibitors or other co-administered antiretroviral agents.
Ergot Derivatives:
dihydroergotamine, ergonovine,
ergotamine, methylergonovine CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent:
cisapride CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products:
St. John's wort (hypericum perforatum) May lead to loss of virologic response and possible resistance to RITOMAX-L or to the class of protease inhibitors.
HMG-CoA Reductase Inhibitors:
lovastatin, simvastatin Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic:
pimozide CONTRAINDICATED due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/Hypnotics:
midazolam, triazolam CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.