Kaletra 200mg/50mg

Drug interaction studies reveal no clinically significant interaction between KALETRA and desipramine (CYP2D6 probe), stavudine, lamivudine, omeprazole or ranitidine.

Based on known metabolic profiles, clinically significant drug interactions are not expected between KALETRA and fluvastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin or fluconazole.

Concomitant use of KALETRA and St. John’s wort (Hypericum perforatum), or products containing St. John’s wort, is contraindictated (see Contraindications, Table 1). Co-administration of protease inhibitors, including KALETRA lopinavir/ritonavir, 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.

For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.

Based on results of a desipramine interaction study, KALETRA does not inhibit CYP2D6-mediated metabolism at clinically relevant concentrations. However, caution should be used when co-administering either flecainide or propafenone with KALETRA.

No drug interaction studies were performed with once daily KALETRA (lopinavir/ritonavir).

KALETRA is an inhibitor of CYP3A (cytochrome P450 3A) both in vitro and in vivo. Co-administration of KALETRA and drugs primarily metabolized by CYP3A (e.g., dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and erectile dysfunction drugs) may result in increased plasma concentrations of the other drugs that could increase or prolong their therapeutic and adverse effects (see Drug Interactions, Boxed Serious Drug Interactions, Table 9). 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 KALETRA.

KALETRA does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations.

KALETRA 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.

KALETRA is metabolized by CYP3A. Co-administration of KALETRA and drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce its therapeutic effect (see Drug Interactions, Boxed Serious Drug Interactions, Table 9). Co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.

Drug interaction studies were performed with KALETRA and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of KALETRA on the AUC, C_max and C_min are summarized in Table 7 (effect of other drugs on lopinavir) and Table 8 (effect of KALETRA 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). For information regarding clinical recommendations, see Drug Interactions, Boxed Serious Drug Interactions, Table 9.

KALETRA Tablets may be taken with or without food.

KALETRA Oral Solution must be taken with food.

KALETRA Tablets should be swallowed whole and not chewed, broken, or crushed.

The recommended oral dose of KALETRA (lopinavir/ritonavir) is as follows: (Please also refer to Indications and Clinical Use and Adverse Reactions):

If a dose of KALETRA 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.

Do not use once daily administration of KALETRA in:

• therapy-experienced patients

  
  

• combination with efavirenz, nevirapine, (fos)amprenavir or nelfinavir

  
  

• pediatric patients

  
  

KALETRA Tablets 400/100 mg (given as two 200/50 mg tablets) twice daily with or without food.

Once daily administration of KALETRA is not recommended in therapy experienced-patients.

KALETRA Tablets 400/100 mg (given as two 200/50 mg tablets) twice daily taken with or without food.

Omeprazole and Ranitidine:

• KALETRA can be used in combination with acid reducing agents (omeprazole and ranitidine) with no dose adjustment (see Drug Interactions, Table 7).

  
  

Efavirenz, nevirapine, amprenavir or nelfinavir:

• KALETRA 400/100 mg tablets (given as two 200/50 mg tablets) can be used twice daily in combination with these drugs with no dose adjustment in antiretroviral-naïve patients.

  
  

• A dose increase of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice-daily may be considered when used in combination with efavirenz, nevirapine, amprenavir or nelfinavir in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence) (see Drug Interactions and Table 9).

  
  

• A dose increase of KALETRA Oral Solution to 533/133 mg (6.5 mL) twice daily taken with food may be considered when used in combination with efavirenz, nevirapine, amprenavir or nelfinavir in the treatment of experienced patients where reduced susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence) (see Drug Interactions and Table 9).

  
  

Increasing the dose of KALETRA Tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily when co-administered with efavirenz significantly increased the lopinavir plasma concentrations approximately 35%, and ritonavir concentrations approximately 56% to 92%, compared to KALETRA Tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz (see Drug Interactions and Table 9). The clinical significance in terms of safety and efficacy is not known.

KALETRA Tablets or Oral Solution should not be administered as a once daily regimen in combination with efavirenz, nevirapine, (fos)amprenavir or nelfinavir.

kidney calculus, and urine abnormality.

cholangitis, cholecystitis, constipation, dry mouth, enteritis, enterocolitis, eructation, esophagitis, fecal incontinence, gastritis, gastroenteritis, gastrointestinal disorder, hemorrhagic colitis, hepatitis, hepatomegaly, increased appetite, jaundice, liver fatty deposit, liver tenderness, mouth ulceration, pancreatitis, sialadenitis, stomatitis, and ulcerative stomatitis.

Hepatitis has been reported in patients on KALETRA therapy.

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing 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.

Stevens Johnson Syndrome and erythema multiforme have been reported.

Bradyarrhythmia has been reported.

lymphadenopathy.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

arthralgia, arthrosis, myalgia, bone necrosis, joint disorder, and myasthenia.

allergic reaction, back pain, chest pain, chest pain substernal, cyst, drug interaction, drug level increased, face edema, flu syndrome, hypertrophy, infection bacterial, malaise, neoplasm, redistribution/accumulation of body fat (see Warnings and Precautions, Fat Redistribution), and viral infection.

asthma, bronchitis, cough increased, dyspnea, lung edema, pharyngitis, rhinitis, and sinusitis.

abnormal vision and eye disorder.

KALETRA (lopinavir/ritonavir) has been studied in 891 patients as combination therapy in Phase I/II and Phase III clinical trials. The most common adverse event associated with KALETRA therapy was diarrhea, which was generally of mild to moderate severity, nausea, abdominal pain, asthenia, vomiting, headache, and dyspepsia. Rates of discontinuation of randomized therapy due to adverse events were 5.8% in KALETRA-treated and 4.9% in nelfinavir-treated patients in Study M98-863. The incidence of diarrhea was greater for KALETRA once-daily compared to KALETRA twice daily in Study M02-418 (see Table 2).

Drug related clinical adverse events of moderate or severe intensity in ≥2% of patients treated with combination therapy including KALETRA for up to 48 weeks (Phase III) and for up to 360 weeks (Phase I/II) are presented in Table 2. For other information regarding observed or potentially serious adverse events, see Warnings and Precautions.

Percentages of patients with selected treatment-emergent adverse events of moderate or severe intensity reported in ≥2% of adult protease inhibitor-experienced patients are listed in Table 3.

abnormal dreams, agitation, anxiety, apathy, confusion, emotional lability, nervousness, and abnormal thinking.

otitis media, and tinnitus.

abnormal ejaculation, amenorrhea, breast enlargement, gynecomastia, hypogonadism male, kidney calculus, nephritis, and urine abnormality.

allergic reaction.

amnesia, ataxia, cerebral infarct, convulsion, dizziness, dyskinesia, encephalopathy, extrapyramidal syndrome, facial paralysis, hypertonia, libido decreased, migraine, neuropathy, paresthesia, peripheral neuritis, somnolence, taste loss, taste perversion, tremor, and vertigo.

Treatment-emergent adverse events occurring in less than 2% of adult patients receiving KALETRA in all Phase II/III clinical trials and considered at least possibly related or of unknown relationship to treatment with KALETRA and of at least moderate intensity are listed below by body system.

avitaminosis, dehydration, diabetes mellitus, edema, glucose tolerance decreased, hypothyroidism, lactic acidosis, obesity, peripheral edema, weight gain, and weight loss.

acne, alopecia, dry skin, eczema, exfoliative dermatitis, furunculosis, maculopapular rash, nail disorder, pruritis, seborrhoea, skin benign neoplasm, skin discoloration, skin striae, skin ulcer, and sweating.

anemia and leukopenia.

abnormal ejaculation, breast enlargement, gynecomastia and impotence.

atrial fibrillation, deep vein thrombophlebitis, deep vein thrombosis, hypertension, myocardial infarct, palpitation, postural hypotension, thrombophlebitis, varicose vein, and vasculitis.

Clinical studies of KALETRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of KALETRA in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The safety and pharmacokinetic profiles of KALETRA in pediatric patients below the age of 6 months have not been established. In HIV-infected patients age 6 months to 12 years, the adverse event profile seen during a clinical trial was similar to that for adult patients. The evaluation of the antiviral activity of KALETRA in pediatric patients in clinical trials is ongoing. KALETRA should not be administered once daily to pediatric patients <18 years of age.

Each mL of light yellow to orange-colored liquid contains: lopinavir 80 mg and ritonavir 20 mg. Nonmedicinal ingredients: acesulfame potassium, alcohol, artificial cotton candy flavor, citric acid, glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, natural and artificial vanilla flavor, peppermint oil, polyoxyl 40 hydrogenated castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride, sodium citrate and water. Alcohol: 42.4% (v/v). Amber-colored multiple-dose bottles of 160 mL, packaged with a marked dosing cup.

Each pale yellow, film-coated tablet, embossed with the Abbott logo and the Abbo-Code KC, contains: lopinavir 100 mg and ritonavir 25 mg. Nonmedicinal ingredients: colloidal silicon dioxide, copovidone, sodium stearyl fumarate and sorbitan monolaurate; film-coating: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide and yellow ferric oxide E172. Bottles of 60.

Each yellow, film-coated tablet, embossed with the Abbott logo and the Abbo-Code KA, contains: lopinavir 200 mg and ritonavir 50 mg. Nonmedicinal ingredients: colloidal silicon dioxide, copovidone, sodium stearyl fumarate and sorbitan monolaurate; film-coating: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, yellow ferric oxide E172 and titanium dioxide. Bottles of 120.

For a brief discussion, see Indications and Clinical Use.

In a Phase 1 study in healthy volunteers, mean change from baseline in PR interval of 11.6-31.2 msec was noted in subjects receiving KALETRA on study Day 3 when exposures were up to 3-fold higher than observed with recommended once-daily or twice-daily KALETRA doses at steady state. Maximum PR interval was 286 msec and no second or third degree heart block was observed.

There have been postmarketing reports of asymptomatic prolongation of the PR interval in some patients receiving combination antiretroviral therapy containing lopinavir/ritonavir. Reports of second or third degree atrioventricular block in patients with underlying structural heart disease and preexisting conduction system abnormalities or in patients receiving drugs known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving KALETRA. KALETRA should be used with caution in such patients. (See Action and Clinical Pharmacology, Pharmacokinetics, Effects on the Electrocardiogram.)

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

There are no adequate and well-controlled studies in pregnant women. KALETRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits. Embryonic and fetal developmental toxicities occurred in rats at a maternally toxic dose.

Pancreatitis has been observed in patients receiving KALETRA therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to KALETRA has not been established, marked triglyceride elevation is a risk factor for development of pancreatitis (see Warnings and 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 for recurrence during KALETRA therapy.

Treatment with KALETRA has resulted in large increases in the concentration of total cholesterol and triglycerides (see Adverse Reactions, Abnormal Hematologic and Clinical Chemistry Findings, Table 4 and Table 5). Triglyceride and cholesterol testing should be performed prior to initiating KALETRA therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate. See Table 9 for additional information on potential drug interactions with KALETRA and HMG-CoA reductase inhibitors.

Various degrees of cross-resistance among protease inhibitors have been observed. The effect of KALETRA therapy on the efficacy of subsequently administered protease inhibitors is under investigation. 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 KALETRA therapy in antiretroviral treatment naïve patients has not yet been characterized in vivo (see Action and Clinical Pharmacology, Resistance and Cross-resistance).

For a brief discussion, see Indications and Clinical Use.

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; however, the frequency of bleeding episodes should be closely monitored in patients on KALETRA.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including KALETRA. During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP and TB), which may necessitate further evaluation and treatment.

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing 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 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.

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.

HIV-infected mothers should not breast-feed their infants to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that lopinavir is secreted in milk. It is not known whether lopinavir is secreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving KALETRA.

KALETRA is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment. KALETRA has not been studied in patients with severe hepatic impairment. Pharmacokinetic data suggests increases in lopinavir plasma concentrations of approximately 30% as well as decreases in plasma protein binding in HIV and HCV co-infected patients with mild to moderate hepatic impairment (see Action and Clinical Pharmacology, Pharmacokinetics). Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing or worsening of transaminases elevations or hepatic decompensation with use of KALETRA. There have been post-marketing 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 KALETRA therapy has not been established. Increased AST/ALT monitoring should be considered in these patients, especially during the first several months of KALETRA treatment.

Store KALETRA oral solution at 2 to 8°C until dispensed. Avoid exposure to excessive heat. Keep cap tightly closed. Product must be stored and dispensed in the original container. Refrigeration of KALETRA oral solution by the patients is not required if used within 42 days and stored below 25°C.

Store KALETRA film-coated tablets at 15 to 25°C. It is recommended that the product be stored and dispensed in the original container.

At steady-state, lopinavir is approximately 98 to 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 KALETRA b.i.d., and is similar between healthy volunteers and HIV-positive patients.

After a single dose of [¹⁴C]lopinavir/ritonavir (10/5 mg/kg) in rats the radioactivity was distributed well throughout the body. With the exception of the adrenal gland, thyroid gland, liver and gastrointestinal tract, at 4 hours the tissue to plasma ratios of the remaining tissues were less than one. The highest concentrations were found in the liver and the lowest concentrations in the brain. The brain concentrations were approximately equal to the free concentrations in the plasma (approximately 2%). Concentrations in the lymphatic system were 6 to 61% of those in the plasma.

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 KALETRA capsules 400/100 mg b.i.d. 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 b.i.d. The in vitro antiviral EC₅₀ of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of KALETRA is due to lopinavir.

At steady state, 400/100 mg b.i.d. taken without meal restrictions 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 area under the plasma concentration-time curve (AUC) over a 12-hour dosing interval averaged 82.8±44.5 µg·h/mL. Administration of a single 400/100 mg dose of KALETRA capsules with a moderate fat meal (500 to 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. To enhance bioavailability and minimize pharmacokinetic variability, KALETRA capsules should be taken with food.

Lopinavir is approximately 98 to 99% bound to plasma proteins. 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 ¹⁴C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg KALETRA capsule dose was due to parent drug. 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 to 6 hours, and the apparent oral clearance (CL/F) of lopinavir is 6 to 7 L/h.

In a pharmacokinetic study in HIV-positive subjects (n=19), multiple dosing with 400/100 mg KALETRA capsules b.i.d. with food for 3 weeks produced a mean±SD lopinavir peak plasma concentration (C_max) of 9.8±3.7 µg/mL, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 7.1±2.9 µg/mL and minimum concentration within a dosing interval was 5.5±2.7 µg/mL. Lopinavir AUC over a 12-hour dosing interval averaged 92.6±36.7 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 KALETRA co-formulated capsules and oral solution. When administered under fasting conditions, both the mean AUC and C_max of lopinavir were 22% lower for the KALETRA oral solution relative to the capsule formulation.

Figure 1 displays the mean steady-state plasma concentrations of lopinavir and ritonavir after KALETRA 400/100 mg b.i.d. capsules with food for 3 weeks from a pharmacokinetic study in HIV-infected adult subjects (n=19).

QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) differences in QTcF from placebo were 3.6 (6.3) msec and 13.1 (15.8) msec for 400/100 mg twice-daily and supratherapeutic 800/200 mg twice-daily KALETRA, respectively. The two regimens resulted in exposures on Day 3 which were approximately 1.5 and 3-fold higher than those observed with recommended once-daily or twice-daily KALETRA doses at steady state. No subject experienced an increase in QTcF of >60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec.

Mean change from baseline in PR interval of 11.6-31.2 msec was also noted in subjects receiving KALETRA in the same study on Day 3. Maximum PR interval was 286 msec and no second or third degree heart block was observed. (See Warnings and Precautions.)

Following a 400/100 mg ¹⁴C-lopinavir/ritonavir dose, approximately 10.4±2.3% and 82.6±2.5% of an administered dose of ¹⁴C-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 apparent oral clearance (CL/F) of lopinavir is 5.98±5.75 L/hr (mean±SD, N=19).

No gender related pharmacokinetic differences have been observed in adult patients.

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 ¹⁴C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg KALETRA (lopinavir/ritonavir) 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.

The pharmacokinetics of once daily KALETRA have been evaluated in HIV-infected subjects naïve to antiretroviral treatment. KALETRA 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir DF 300 mg as part of a once daily regimen. Multiple dosing of 800/200 mg KALETRA once a day for 4 weeks with food (n=24) produced a mean±SD lopinavir peak plasma concentration (C_max) of 11.8±3.7 µg/mL, occurring approximately 6 hours after administration. The mean steady-state lopinavir trough concentration prior to the morning dose was 3.2±2.1 µg/mL and minimum concentration within a dosing interval was 1.7±1.6 µg/mL. Lopinavir AUC over a 24 hour dosing interval averaged 154.1±61.4 µg·h/mL.

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 KALETRA 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 5.7-8.3-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 Clinical Studies section that follows.

The relative bioavailability of KALETRA 200/50 mg tablets compared to KALETRA capsules was assessed in two Phase 1 (Studies M03-616 and M04-703), single-center, open-label, randomized, cross-over studies in 111 healthy adults under fed conditions (moderate-fat meal, 490 to 560 Kcal, 20 to 30% of calories from fat) as a single 400/100 mg dose. Plasma concentrations of lopinavir and ritonavir after administration of two 200/50 mg KALETRA tablets are similar to three 133.3/33.3 mg KALETRA capsules under fed conditions with less pharmacokinetic variability. Following a moderate fat meal, relative to the KALETRA capsule, administration of KALETRA 200/50 mg tablets increased lopinavir AUC_t and C_max by 18% and 24%, respectively, and increased ritonavir AUC_t and C_max by 20% and 35%, respectively.

In a Phase 1 (Study M03-616), single-center, open-label, randomized, cross-over study in 63 healthy adults (46 males, 17 females), no clinically significant changes in C_max and AUC were observed following the administration of a single 400/100 mg dose of KALETRA 200/50 mg tablets under fasting conditions or following a moderate-fat meal (558 Kcal, 24.1% from fat) or a high fat meal (998 Kcal, 51.3% from fat) relative to the KALETRA capsule following a moderate fat meal. Relative to the KALETRA capsule following a moderate fat meal, administration of KALETRA 200/50 mg tablets under fasting conditions increased lopinavir C_max by 10% with no change in AUC_t, and increased ritonavir AUC_t and C_max by 10% and 33%, respectively. Relative to the KALETRA capsule following a moderate fat meal, administration of KALETRA 200/50 mg tablets following a moderate fat meal increased lopinavir AUC_t and C_max by 27 and 30%, respectively, and increased ritonavir AUC_t and C_max by 27% and 40%, respectively. Relative to the KALETRA capsule following a moderate fat meal, administration of KALETRA 200/50 mg tablets following a high fat meal showed no change in lopinavir AUC_t and C_max, and increased ritonavir AUC_t and C_max each by 15%.

In a Phase 1 (Study M04-703), single-center, open-label, randomized, cross-over study in 48 healthy adults (34 males, 14 females) following a moderate-fat meal (492 Kcal, 22.9% from fat) and a single 400/100 mg dose, the relative bioavailability of KALETRA 200/50 mg tablets from two (2) production lots compared to KALETRA capsules was increased for lopinavir AUC_t and C_max by 10 to 13% and 17 to 23%, respectively and increased for ritonavir AUC_t and C_max by 15% and 29% to 38%, respectively.

The relative bioavailability of KALETRA 100/25 mg tablets compared to KALETRA 200/50 mg tablets was assessed in a Phase I (Study M06-858), single-center, open-label, randomized, cross-over study in 44 healthy adults (35 males, 9 females) under fasting conditions as a single 400/100 mg dose. Plasma concentrations of lopinavir and ritonavir after administration of four 100/25 mg KALETRA tablets are similar to two 200/50 mg KALETRA tablets under fasting conditions.

Lopinavir is virologically ten-fold more active than ritonavir, with an EC₅₀ of 0.07 µg/mL against HIV-1_IIIB activity in MT₄ cells in a medium containing 50% human serum and 10% calf serum. The protein binding corrected EC₅₀ against wild-type HIV for ritonavir under the same conditions is 0.9 µg/mL. Against ritonavir-resistant HIV, lopinavir displays potency similar to that observed by ritonavir against wild-type HIV. In the Phase II and Phase III trials, lopinavir has been tested in HIV protease inhibitor (PI)-naïve subjects, as well as HIV-infected subjects with single PI experience who have developed various degrees of genotypic and phenotypic resistance to PIs and to nucleoside reverse transcriptase inhibitors (NRTIs). Pharmacokinetic/pharmacodynamic modelling of the antiviral effect of lopinavir in these studies has shown little relationship between exposure and virologic outcome. In a study that evaluated subjects who were multiple PI experienced, the C_trough to EC₅₀ (of the pretreatment HIV viral isolate) ratio was determined to be an important factor for durable virologic suppression with lopinavir/ritonavir.

The incidence of diarrhea showed increased rates with increased dose within individual studies; however, no statistically significant dose group differences were observed. Also, no apparent difference was observed in the incidence of diarrhea between the antiretroviral-naïve and experienced groups. The incidence of nausea was higher for treatment naïve subjects who received KALETRA capsules 400/200 mg than subjects who received 400/100 mg dose. In addition, across-study comparisons suggested that naïve subjects receiving a KALETRA capsule 400/200 mg dose tended to have higher incidence rates of nausea compared to experienced subjects receiving the same dose.

The pharmacokinetics of KALETRA 300/75 mg/m² b.i.d. and 230/57.5 mg/m² b.i.d. have been studied in a total of 53 pediatric patients, ranging in age from 6 months to 12 years. The 230/57.5 mg/m² b.i.d. regimen without nevirapine and the 300/75 mg/m² b.i.d. regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg b.i.d. regimen (without nevirapine). KALETRA once daily has not been evaluated in pediatric patients.

The following describes the KALETRA—nevirapine interaction. The nevirapine regimen was 7 mg/kg b.i.d. (6 months to 8 years) or 4 mg/kg b.i.d. (>8 years). The lopinavir mean steady-state 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 KALETRA 230/57.5 mg/m² b.i.d. 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/m² b.i.d. with nevirapine (n=12).

The relative bioavailability of KALETRA 200/50 mg tablets under fasting conditions was compared to KALETRA 200/50 mg tablets following meals in a Phase 1 (Study M03-616), single-center, open-label, randomized, cross-over study in 63 healthy adults as a 400/100 mg dose. No clinically significant changes in C_max and AUC were observed following administration of KALETRA 200/50 mg tablets under fed conditions compared to fasted conditions. Relative to fasting, administration of KALETRA 200/50 mg tablets with a moderate fat meal (558 Kcal, 24.1% calories from fat) increased lopinavir AUC_t and C_max by 26.9% and 17.6%, respectively, and ritonavir AUC_t and C_max by 15.6% and 4.9%, respectively. Relative to fasting, administration of KALETRA 200/50 mg tablets with a high fat meal (998 Kcal, 51.3% from fat) increased lopinavir AUC_t by 18.7% but not C_max, and ritonavir AUC_t and C_max were increased 24.7% and 10.3%, respectively. The average lopinavir T_max for the 200/50 mg tablet under fasting conditions, following a moderate-fat meal and following a high fat meal were 3.6 h, 4.0 h and 5.4h, respectively. The average ritonavir T_max for the 200/50 mg tablet under fasting conditions, following a moderate-fat meal and following a high fat meal were 3.4 h, 4.0 h and 5.4 h, respectively. The lopinavir terminal phase half-lives were similar for all regimens and ranged, on average, from 2.6 to 2.7 hours. The ritonavir terminal phase half-lives were similar for all regimens and ranged, on average, from 4.2 to 4.7 hours. Additional details regarding the pharmacokinetics of the KALETRA capsule and 200/50 mg tablet formulations under various meal conditions may be found in Pharmacokinetics, Absorption. KALETRA tablets may therefore be taken with or without food.

The selection of resistance to KALETRA therapy in antiretroviral treatment naïve patients has not yet been characterized. In a Phase III study of 653 antiretroviral treatment naïve patients (Study M98-863), plasma viral isolates from each patient on treatment with plasma HIV >400 copies/mL at Week 24, 32, 40 and/or 48 were analysed. No evidence of resistance to KALETRA was observed in 37 evaluable KALETRA-treated patients (0%). Evidence of genotypic resistance to nelfinavir, defined as the presence of D30N and/or L90M mutation in HIV protease, was observed in 25/76 (33%) of evaluable nelfinavir-treated patients. The selection of resistance to KALETRA in antiretroviral naïve pediatric patients (Study M98-940) appears to be consistent with that seen in adult patients (Study M98-863).

There are insufficient data at this time to identify lopinavir-associated mutational patterns in isolates from patients on KALETRA therapy. However, in Phase II studies of 227 antiretroviral treatment naïve and protease inhibitor experienced patients, isolates from 4 of 23 patients with quantifiable (>400 copies/mL) viral RNA following treatment with KALETRA 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 KALETRA therapy. Following viral rebound, isolates from these patients all contained additional mutations, some of which were recognized to be associated with protease inhibitor resistance.

Lopinavir is principally metabolized and eliminated by the liver. Multiple dosing of KALETRA 400/100 mg twice daily to HIV and HCV co-infected patients with mild to moderate hepatic impairment (n=12) resulted in a 30% increase in lopinavir AUC and 20% increase in C_max compared to HIV-infected subjects with normal hepatic function (n=12). Additionally, the plasma protein binding of lopinavir was lower in both mild and moderate hepatic impairment compared to controls (99.09 vs. 99.31% respectively). Caution should be exercised when administering KALETRA to subjects with hepatic impairment. KALETRA has not been studied in patients with severe hepatic impairment (see Warnings and Precautions, Hepatic/Biliary/Pancreatic).

Lopinavir pharmacokinetics have not been studied in elderly patients.

Lopinavir, an inhibitor of the HIV protease, prevents cleavage of the Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles. Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. The antiviral activity of KALETRA (lopinavir/ritonavir) is due to lopinavir.

Relative to fasting, KALETRA oral solution dosed with a moderate fat meal (500 to 683 Kcal, 23 to 25% calories from fat) was associated with increases in lopinavir AUC and C_max of 80 and 54%, respectively. Relative to fasting, administration of KALETRA oral solution with a high fat meal (872 Kcal, 56% from fat) increased lopinavir AUC and C_max by 130% and 56%, respectively. To enhance bioavailability and minimize pharmacokinetic variability KALETRA oral solution should be taken with food.

No clinically important pharmacokinetic differences due to race have been identified.

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 (EC₅₀) of lopinavir against five different HIV-1 laboratory strains ranged from 10 to 27 nM (0.006 to 0.017 µg/mL, 1 µg/mL=1.6 microM) and ranged from 4 to 11 nM (0.003 to 0.007 µg/mL) against several HIV-1 subtype B clinical isolates (n=6). In the presence of 50% human serum, the mean EC₅₀ of lopinavir against these five laboratory strains ranged from 65 to 289 nM (0.04 to 0.18 µg/mL), representing a 7- to 11-fold attenuation.

Lopinavir pharmacokinetics have not been studied in patients with renal insufficiency; however, since less than 3% of the dose of lopinavir is eliminated unchanged in the urine, a decrease in total body clearance is not expected in patients with renal insufficiency.

Virologic Response (HIV RNA <400 copies/mL) at Week 48 by Baseline KALETRA Susceptibility and by Number of Protease Substitutions Associated with Reduced Response to KALETRA^a