Abbott Laboratories Ireland Limited

In section 4.4 (Special warnings and precautions for use), the following additional wording has been added:

"Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono‑infected and in individuals treated for post-exposure prophylaxis as early as 7 days after the initiation of lopinavir/ritonavir in conjunction with other antiretroviral agents.  In some cases the hepatic dysfunction was serious.

Appropriate laboratory testing should be conducted prior to initiating therapy with lopinavir/ritonavir and close monitoring should be performed during treatment."

Section 4.1: The sentence "Most experience with Kaletra is derived from the use of the product in antiretroviral therapy naïve patients. " has been deleted.
Section 4.2: The sentence "Kaletra tablets should be swallowed whole - - -" changed to "Kaletra tablets must be swallowed whole - - -"
The sentence "Children less than 2 years of age: Kaletra is not recommended for use in children below 2 years of age due to insufficient data on safety and efficacy (see section 5.1)." has been changed to ""Children less than 2 years of age: the safety and efficacy of Kaletra in children aged less than 2 years have not yet been established.  Currently available data are described in section 5.2 but no recommendation on a posology can be made." 
The following text added "Method of administration -Kaletra tablets are administered orally and must be swallowed whole and not chewed, broken or crushed.  Kaletra tablets can be taken with or without food."
Section 4.3: Patient with severe hepatic insufficiency" changed to  "Severe hepatic insufficiency"
Section 4.4: Minor rewording and repositioning of text.
Section 4.5: Minor reformatting
Section 4.6: The heading "Pregnancy and lactation" changed to Fertility,  pregnancy and lactation" .  Subheadings for Pregnancy & Breastfeeding included.
Section 4.8: The following text deleted

Kaletra is indicated for the treatment of HIV-1 infected children above the age of 2 years and adults, in combination with other antiretroviral agents.

Most experience with Kaletra is derived from the use of the product in antiretroviral therapy naïve patients.  Data in heavily pretreated protease inhibitor experienced patients are limited.  There are limited data on salvage therapy on patients who have failed therapy with Kaletra.

The choice of Kaletra to treat protease inhibitor experienced HIV-1 infected patients should be based on individual viral resistance testing and treatment history of patients (see sections 4.4 and 5.1).

Section 4.8:
Some ADRs have been re-termed or regrouped e.g. lower respiratory tract infection, formerly bronchitis and bronchopnuemonia; vascularitis, formerly capillaritis
Other ADRs stay or have been deleted There is no rare category anymore as event < 1% is not included unless it is deemed an event of medically importance. No mild event is included

Section 5.1: please below track changes

5.1    Pharmacodynamic properties

Pharmaco-therapeutic group: protease inhibitor, ATC code: J05AE06

Mechanism of action: lopinavir provides the antiviral activity of Kaletra.  Lopinavir is an inhibitor of the HIV-1 and HIV-2 proteases.  Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein resulting in the production of immature, non-infectious virus.

Effects on the electrocardiogram: QTcF interval was evaluated in a randomised, 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) and 13.1(15.8) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily LPV/r, respectively.  The induced QRS interval prolongation from 6 ms to 9.5 ms with high dose lopinavir/ritonavir (800/200 mg twice daily) contributes to QT prolongation.  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 LPV/r doses at steady state.  No subject experienced an increase in QTcF of ³ 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec.

Modest prolongation of the PR interval was also noted in subjects receiving lopinavir/ritonavir in the same study on Day 3.  The mean changes from baseline in PR interval ranged from 11.6 ms to 24.4 ms in the 12 hour interval post dose.  Maximum PR interval was 286 msec and no second or third degree heart block was observed (see section 4.4).

Antiviral activity in vitro: the in vitro antiviral activity of lopinavir against laboratory and clinical HIV strains was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively.  In the absence of human serum, the mean IC₅₀ of lopinavir against five different HIV-1 laboratory strains was 19 nM.  In the absence and presence of 50% human serum, the mean IC₅₀ of lopinavir against HIV-1_IIIB in MT4 cells was 17 nM and 102 nM, respectively.  In the absence of human serum, the mean IC₅₀­ of lopinavir was 6.5 nM against several HIV-1 clinical isolates.

Resistance

In vitro selection of resistance:

HIV-1 isolates with reduced susceptibility to lopinavir have been selected in vitro.  HIV-1 has been passaged in vitro with lopinavir alone and with lopinavir plus ritonavir at concentration ratios representing the range of plasma concentration ratios observed during Kaletra therapy.  Genotypic and phenotypic analysis of viruses selected in these passages suggest that the presence of ritonavir, at these concentration ratios, does not measurably influence the selection of lopinavir-resistant viruses.  Overall, the in vitro characterisation of phenotypic cross-resistance between lopinavir and other protease inhibitors suggest that decreased susceptibility to lopinavir correlated closely with decreased susceptibility to ritonavir and indinavir, but did not correlate closely with decreased susceptibility to amprenavir, saquinavir, and nelfinavir.

Analysis of resistance in ARV-naïve patients: 

In clinical studies with a limited number of isolates analysed, the selection of resistance to lopinavir has not been observed in naïve patients without significant protease inhibitor resistance at baseline.  See further the detailed description of the clinical studies.In a Phase II study (M97-720) through 360 weeks of treatment, genotypic analysis of viral isolates was successfully conducted in 19 of 28 patients with confirmed HIV RNA above 400 copies/ml revealed no primary or active site mutations in protease (amino acids at positions 8, 30, 32, 46, 47, 48, 50, 82, 84 and 90) or protease inhibitor phenotypic resistance. 

In a Phase III study (M98-863) of 653 patients randomised to receive stavudine plus lamivudine with either lopinavir/ritonavir or nelfinavir, 113 nelfinavir-treated subjects and 74 lopinavir/ritonavir-treated subjects had an HIV RNA above 400 copies/ml while on treatment from Week 24 through Week 96.  Of these, isolates from 96 nelfinavir-treated subject and 51 lopinavir/ritonavir-treated subjects could be amplified for resistance testing.  Resistance to nelfinavir, defined as the presence of the D30N or L90M mutation in protease, was observed in 41/96 (43%) subjects.  Resistance to lopinavir, defined as the presence of any primary or active site mutations in protease (see above), was observed in 0/51 (0%) subjects.  Lack of resistance to lopinavir was confirmed by phenotypic analysis.

Analysis of resistance in PI-experienced patients:

The selection of resistance to lopinavir in patients having failed prior protease inhibitor therapy was characterised by analysing the longitudinal isolates from 19 protease inhibitor-experienced subjects in 2 Phase II and one Phase III studies who either experienced incomplete virologic suppression or viral rebound subsequent to initial response to Kaletra and who demonstrated incremental in vitro resistance between baseline and rebound (defined as emergence of new mutations or 2-fold change in phenotypic susceptibility to lopinavir).  Incremental resistance was most common in subjects whose baseline isolates had several protease inhibitor-associated mutations, but < 40-fold reduced susceptibility to lopinavir at baseline.  Mutations V82A, I54V and M46I emerged most frequently.  Mutations L33F, I50V and V32I combined with I47V/A were also observed.  The 19 isolates demonstrated a 4.3-fold increase in IC₅₀ compared to baseline isolates (from 6.2- to 43-fold, compared to wild-type virus).

Genotypic correlates of reduced phenotypic susceptibility to lopinavir in viruses selected by other protease inhibitors.  The in vitro antiviral activity of lopinavir against 112 clinical isolates taken from patients failing therapy with one or more protease inhibitors was assessed.  Within this panel, the following mutations in HIV protease were associated with reduced in vitro susceptibility to lopinavir: L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V and L90M.  The median EC₅₀ of lopinavir against isolates with 0  −  3, 4  −  5, 6  −  7 and 8  −  10 mutations at the above amino acid positions was 0.8, 2.7 13.5 and 44.0-fold higher than the EC₅₀ against wild type HIV, respectively.  The 16 viruses that displayed > 20-fold change in susceptibility all contained mutations at positions 10, 54, 63 plus 82 and/or 84.  In addition, they contained a median of 3 mutations at amino acid positions 20, 24, 46, 53, 71 and 90.  In addition to the mutations described above, mutations V32I and I47A have been observed in rebound isolates with reduced lopinavir susceptibility from protease inhibitor experienced patients receiving Kaletra therapy.

In addition to the mutations described above, and mutations I47A and L76V have been observed in rebound isolates with reduced lopinavir susceptibility from patients receiving Kaletra therapy.

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.

Antiviral activity of Kaletra in patients failing protease inhibitor therapy: the clinical relevance of reduced in vitro susceptibility to lopinavir has been examined by assessing the virologic response to Kaletra therapy, with respect to baseline viral genotype and phenotype, in 56 patients previous failing therapy with multiple protease inhibitors.  The EC₅₀ of lopinavir against the 56 baseline viral isolates ranged from 0.6 to 96-fold higher than the EC₅₀ against wild type HIV.  After 48 weeks of treatment with Kaletra, efavirenz and nucleoside reverse transcriptase inhibitors, plasma HIV RNA £ 400 copies/ml was observed in 93% (25/27), 73% (11/15), and 25% (2/8) of patients with < 10‑fold, 10 to 40-fold, and > 40‑fold reduced susceptibility to lopinavir at baseline, respectively.  In addition, virologic response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) patients with 0  −  5, 6  −  7, and 8  −  10 mutations of the above mutations in HIV protease associated with reduced in vitro susceptibility to lopinavir.  Since these patients had not previously been exposed to either Kaletra or efavirenz, part of the response may be attributed to the antiviral activity of efavirenz, particularly in patients harbouring highly lopinavir resistant virus.  The study did not contain a control arm of patients not receiving Kaletra.

Cross‑resistance: Activity of other protease inhibitors against isolates that developed incremental resistance to lopinavir after Kaletra therapy in protease inhibitor experienced patients: The presence of cross resistance to other protease inhibitors was analysed in 18 rebound isolates that had demonstrated evolution of resistance to lopinavir during 3 Phase II and one Phase III studies of Kaletra in protease inhibitor-experienced patients.  The median fold IC₅₀ of lopinavir for these 18 isolates at baseline and rebound was 6.9- and 63-fold, respectively, compared to wild type virus.  In general, rebound isolates either retained (if cross-resistant at baseline) or developed significant cross-resistance to indinavir, saquinavir and atazanavir.  Modest decreases in amprenavir activity were noted with a median increase of IC₅₀ from 3.7- to 8-fold in the baseline and rebound isolates, respectively.  Isolates retained susceptibility to tipranavir with a median increase of IC₅₀ in baseline and rebound isolates of 1.9- and 1.8–fold, respectively, compared to wild type virus.  Please refer to the Aptivus Summary of Product Characteristics for additional information on the use of tipranavir, including genotypic predictors of response, in treatment of lopinavir-resistant HIV-1 infection.

Clinical resultspharmacodynamic data

The effects of Kaletra (in combination with other antiretroviral agents) on biological markers (plasma HIV RNA levels and CD4+ T-cell₄ counts) have been investigated in a controlled studyies of Kaletra of 48 to 360 weeks duration, and in additional studies of Kaletra of 360 weeks duration. 

Adult Use

Patients without prior antiretroviral therapy

Study M98-863 is was a randomised, double-blind trial of 653 antiretroviral treatment naïve patients investigating Kaletra (400/100 mg twice daily) compared to nelfinavir (750 mg three times daily)  plus stavudine and lamivudine.  Mean baseline CD4+ T-cell count was 259 cells/mm³ (range: 2 to 949 cells/ mm³) and mean baseline plasma HIV-1 RNA was 4.9 log₁₀ copies/ml (range: 2.6 to 6.8 log₁₀ copies/ml). 

Table 1

* intent to treat analysis where patients with missing values are considered virologic failures

† p<0.001

One-hundred thirteen nelfinavir-treated patients and 74 lopinavir/ritonavir-treated patients had an HIV RNA above 400 copies/ml while on treatment from Week 24 through Week 96.  Of these, isolates from 96 nelfinavir-treated patients and 51 lopinavir/ritonavir-treated patients could be amplified for resistance testing.  Resistance to nelfinavir, defined as the presence of the D30N or L90M mutation in protease, was observed in 41/96 (43%) patients.  Resistance to lopinavir, defined as the presence of any primary or active site mutations in protease (see above), was observed in 0/51 (0%) patients.  Lack of resistance to lopinavir was confirmed by phenotypic analysis.

nucleoside reverse transcriptase inhibitors. 

By intent to treat analysis where patients with missing values are considered virologic failures, the proportion of patients at 48 weeks with HIV RNA < 400 copies/ml in the Kaletra arm was 75% and 63% in the nelfinavir arm.  Mean baseline CD₄ cell count was 259 cells/mm³ (range: 2 to 949 cells/ mm³) and mean baseline plasma HIV-1 RNA was 4.9 log₁₀ copies/ml (range: 2.6 to 6.8 log₁₀ copies/ml).  Through 48 weeks of therapy, the proportion of patients in the Kaletra arm with plasma RNA < 50 copies/ml was 67% and 52% in the nelfinavir arm.  The mean increase from baseline in CD₄ cell count was 207 cells/mm³ in the Kaletra arm and 195 cells/mm³ in the nelfinavir arm.  Through 48 weeks of therapy, a statistically significantly higher proportion of patients in the Kaletra arm had HIV RNA < 50 copies/ml compared to the nelfinavir arm.

Study M05-730 was a randomised, open-label, multicentre trial comparing treatment with Kaletra 800/200 mg once daily plus tenofovir DF and emtricitabine versus Kaletra 400/100 mg twice daily plus tenofovir DF and emtricitabine in 664 antiretroviral treatment-naïve patients.  Given the pharmacokinetic interaction between Kaletra and tenofovir (see section 4.5), the results of this study might not be strictly extrapolable when other backbone regimens are used with Kaletra.  Patients were randomised in a 1:1 ratio to receive either Kaletra 800/200 mg once daily (n = 333) or Kaletra 400/100 mg twice daily (n = 331).  Further stratification within each group was 1:1 (tablet versus. soft capsule).  Patients were administered either the tablet or the soft capsule formulation for 8 weeks, after which all patients were administered the tablet formulation once daily or twice daily for the remainder of the study.  Patients were administered emtricitabine 200 mg once daily and tenofovir DF 300 mg once daily.  Protocol defined non-inferiority of once daily dosing compared with twice daily dosing was demonstrated if the lower bound of the 95% confidence interval for the difference in proportion of subjects responding (once daily minus twice daily) excluded -12% at Week 48.  Mean age of patients enrolled was 39 years (range: 19 to 71); 75% were Caucasian, and 78% were male.  Mean baseline CD4+ T-cell count was 216 cells/mm3 (range: 20 to 775 cells/mm³) and mean baseline plasma HIV-1 RNA was 5.0 log₁₀ copies/ml (range: 1.7 to 7.0 log₁₀ copies/ml). 

Table 2

Through Week 96, genotypic resistance testing results were available from 25 patients in the QD group and 26 patients in the BID group who had incomplete virologic response.  In the QD group, no patient demonstrated lopinavir resistance, and in the BID group, 1 patient who had significant protease inhibitor resistance at baseline demonstrated additional lopinavir resistance on study.

Sustained virological response to Kaletra (in combination with nucleoside/nucleotide reverse transcriptase inhibitors) has been also observed in a small Phase II study (M97-720) through 360 weeks of treatment.  One hundred patients were originally treated with Kaletra in the study (including 51 patients receiving 400/100 mg twice daily and 49 patients at either 200/100 mg twice daily or 400/200 mg twice daily).  All patients converted to open-label Kaletra at the 400/100 mg twice daily dose between week 48 and week 72.  Thirty‑nine patients (39%) discontinued the study, including 16 (16%) discontinuations due to adverse events, one of which was associated with a death.  Sixty‑one patients completed the study (35 patients received the recommended 400/100 mg twice daily dose throughout the study).  Through 360 weeks of treatment, the proportion of patients with HIV RNA < 400 (< 50) copies/ml was 61% (59%), and the corresponding mean increase in CD₄ cell count was 501 cells/mm³.  Thirty‑nine patients (39%) discontinued the study, including 16 (16%) discontinuations due to adverse events, one of which was associated with a death. 

Table 3

Through 360 weeks of treatment, genotypic analysis of viral isolates was successfully conducted in 19 of 28 patients with confirmed HIV RNA above 400 copies/ml revealed no primary or active site mutations in protease (amino acids at positions 8, 30, 32, 46, 47, 48, 50, 82, 84 and 90) or protease inhibitor phenotypic resistance

Patients with prior antiretroviral therapy

Study M97-765 was a randomised, double-blind trial evaluating Kaletra at two dose levels (400/100 mg and 400/200 mg, both twice daily) plus nevirapine (200 mg twice daily) and two nucleoside reverse transcriptase inhibitors in 70 single protease inhibitor experienced, non-nucleoside reverse transcriptase inhibitor naïve patients.  Median baseline CD₄ cell count was 349 cells/mm³ (range 72 to 807 cells/mm³) and median baseline plasma HIV-1 RNA was 4.0 log₁₀ copies/ml (range 2.9 to 5.8 log₁₀ copies/ml).  By intent to treat analysis where patients with missing values are considered virologic failures, the proportion of patients with HIV RNA < 400 (< 50) copies/ml at 24 weeks was 75% (58%) and the mean increase from baseline in CD₄ cell count was 174 cells/mm³ for the 36 patients receiving the 400/100 mg dose of Kaletra.

M98-957 was a randomised, open-label study evaluating Kaletra treatment at two dose levels (400/100 mg and 533/133 mg, both twice daily) plus efavirenz (600 mg once daily) and nucleoside reverse transcriptase inhibitors in 57 multiple protease inhibitor experienced, non-nucleoside reverse transcriptase inhibitor naïve patients.  Between week 24 and 48, patients randomised to a dose of 400/100 mg were converted to a dose of 533/133 mg.  Median baseline CD₄ cell count was 220 cells/mm³ (range 13 to 1030 cells/mm³).  By intent-to-treat analysis of both dose groups combined (n=57), where patients with missing values are considered virologic failures, the proportion of patients with HIV RNA < 400 copies/ml at 48 weeks was 65% and the mean increase from baseline CD₄ cell count was 94 cells/mm³.

M06-802 was a randomised open-label study comparing the safety, tolerability and antiviral activity of once daily and twice daily dosing of lopinavir/ritonavir tablets in 599 subjects with detectable viral loads while receiving their current antiviral therapy.  Patients had not been on prior lopinavir/ritonavir therapy.  They were randomised in a 1:1 ratio to receive either lopinavir/ritonavir 800/200 mg once daily (n = 300) or lopinavir/ritonavir 400/100 mg twice daily (n = 299).  Patients were administered at least two nucleoside/nucleotide reverse transcriptase inhibitors selected by the investigator.  The enrolled population was moderately PI-experienced with more than half of patients having never received prior PI and around 80% of patients presenting a viral strain with less than 3 PI mutations.  Mean age of patients enrolled was 41 years (range: 21 to 73); 51% were Caucasian and 66% were male.  Mean baseline CD4+ T-cell count was 254 cells/mm³ (range: 4 to 952 cells/mm³) and mean baseline plasma HIV-1 RNA was 4.3 log₁₀ copies/ml (range: 1.7 to 6.6 log₁₀ copies/ml).  Around 85% of patients had a viral load of <100,000 copies/ml.

Table 4

Through Week 48, genotypic resistance testing results were available from 75 patients in the QD group and 75 patients in the BID group who had incomplete virologic response.  In the QD group, 6/75 (8%) patients demonstrated new primary protease inhibitor mutations (codons 30, 32, 48, 50, 82, 84, 90), as did 12/77 (16%) patients in the BID group.

Paediatric Use

M98-940 is was an open-label study of a liquid formulation of Kaletra in 100 antiretroviral naïve (44%) and experienced (56%) paediatric patients.  All patients were non-nucleoside reverse transcriptase inhibitor naïve.  Patients were randomised to either 230 mg lopinavir/57.5 mg ritonavir per m² or 300 mg lopinavir/75 mg ritonavir per m².  Naïve patients also received nucleoside reverse transcriptase inhibitors.  Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase inhibitors.  Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after 3 weeks of therapy in each patient.  Subsequently, all patients were continued on the 300/75 mg per m² dose.  Patients had a mean age of 5 years (range 6 months to 12 years) with 14 patients less than 2 years old and 6 patients one year or less.  Mean baseline CD4+₄ T-cell count was 838 cells/mm³ and mean baseline plasma HIV-1 RNA was 4.7 log₁₀ copies/ml.  Through 48 weeks of therapy, the proportion of patients with HIV RNA < 400 copies/ml was 84% for antiretroviral naïve patients and 75% for antiretroviral experienced patients and the mean increases from baseline in CD₄ cell count were 404 cells/mm³ and 284 cells/mm³ respectively.

Table 5

5.          Pharmacological properties

5.1          Pharmacodynamic properties

Genotypic correlates of reduced phenotypic susceptibility to lopinavir in viruses selected by other protease inhibitors.  The in vitro antiviral activity of lopinavir against 112 clinical isolates taken from patients failing therapy with one or more protease inhibitors was assessed.  Within this panel, the following mutations in HIV protease were associated with reduced in vitro susceptibility to lopinavir: L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V and L90M.  The median EC₅₀ of lopinavir against isolates with 0  −  3, 4  −  5, 6  −  7 and 8  −  10 mutations at the above amino acid positions was 0.8, 2.7 13.5 and 44.0-fold higher than the EC₅₀ against wild type HIV, respectively.  The 16 viruses that displayed > 20-fold change in susceptibility all contained mutations at positions 10, 54, 63 plus 82 and/or 84.  In addition, they contained a median of 3 mutations at amino acid positions 20, 24, 46, 53, 71 and 90.  In addition to the mutations described above, mutations V32I and I47A have been observed in rebound isolates with reduced lopinavir susceptibility from protease inhibitor experienced patients receiving Kaletra therapy.

In addition to the mutations described above, mutations I47A and L76V have been observed in rebound isolates with reduced lopinavir susceptibility from protease inhibitor experienced patients receiving Kaletra therapy.

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.

10.    Date of revision of the text

30 October 2008

4.4    Special warnings and precautions for use

Patients with coexisting conditions

Liver disease Hepatic impairment: the safety and efficacy of Kaletra has not been established in patients with significant underlying liver disorders.  Kaletra is contraindicated in patients with severe liver impairment (see section 4.3).  Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events reactions.  In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.

Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice.  If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered. 

Renal disease impairment: since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment.  Because lopinavir and ritonavir are highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.

4.5          Interaction with other medicinal products and other forms of interaction

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A in vitro.  Co-administration of Kaletra and medicinal products primarily metabolised by CYP3A may result in increased plasma concentrations of the other medicinal product, which could increase or prolong its therapeutic and adverse effects reactions.  Kaletra does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations (see section 4.3).

Fosamprenavir: co-administration of standard doses of lopinavir/ritonavir with fosamprenavir results in a significant reduction in amprenavir concentrations.  Co-administration of increased doses of fosamprenavir 1400 mg twice daily with lopinavir/ritonavir 533/133 mg twice daily to protease inhibitor‑experienced patients resulted in a higher incidence of gastrointestinal adverse events and elevations in triglycerides with the combination regimen without increases in virological efficacy, when compared with standard doses of fosamprenavir/ritonavir.  Therefore, concomitant administration of these medicinal products is not recommended a study has shown that co‑administration of Kaletra 400/100 mg twice daily with fosamprenavir/ritonavir 700/100 mg twice daily results in a 30 - 52% increase in lopinavir concentrations and a 58-65% decrease in amprenavir concentrations.  Administration of Kaletra 533/133 mg twice daily with fosamprenavir 1400 mg twice daily (no additional ritonavir) results in similar lopinavir concentrations to Kaletra 400/100 mg alone and 26 - 42% lower amprenavir AUC and C_min compared to fosamprenavir/ritonavir 700/100 mg alone.  Appropriate doses of the combination of fosamprenavir and Kaletra with respect to safety and efficacy have not been established.

Indinavir: indinavir 600 mg twice daily in combination with Kaletra produces similar indinavir AUC, higher C_min (by 3.5-fold) and lower C_max relative to indinavir 800 mg three times daily alone.  Furthermore, concentrations of lopinavir do not appear to be affected when both drug medicinal products, Kaletra and indinivir, are combined, based on historical comparison with Kaletra alone.

Saquinavir: saquinavir 800 mg twice daily co-administered with Kaletra produces an increase of saquinavir AUC by 9.6-fold relative to saquinavir 1200 mg three times daily given alone. 

Saquinavir 800 mg twice daily co-administered with Kaletra resulted in an increase of saquinavir AUC by approximately 30% relative to saquinavir/ritonavir 1000/100 mg twice daily, and produces similar exposure to those reported after saquinavir/ritonavir 400/400 mg twice daily. 

When saquinavir 1200 mg twice daily was combined with Kaletra, no further increase of concentrations was noted.  Furthermore, concentrations of lopinavir do not appear to be affected when both drugs medicinal products, Kaletra and saquinavir, are combined, based on historical comparison with Kaletra alone.

Bupropion: in healthy volunteers, the AUC and C_max of bupropion and of its active metabolite, hydroxybupropion, were decreased by about 50% when co-administered with lopinavir/ritonavir capsules 400/100 mg twice daily at steady-state.  This effect may be due to induction of bupropion metabolism.  Therefore, if the co‑administration of lopinavir/ritonavir with bupropion is judged unavoidable, this should be done under close clinical monitoring for bupropion efficacy, without exceeding the recommended dosage, despite the observed induction.

Rifabutin: when rifabutin and Kaletra were co-administered for 10 days, rifabutin (parent drug substance and active 25-O-desacetyl metabolite) C_max and AUC were increased by 3.5- and 5.7-fold, respectively.  On the basis of these data, a rifabutin dose reduction of 75% (i.e. 150 mg every other day or 3 times per week) is recommended when administered with Kaletra.  Further reduction may be necessary.

4.7    Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.  Patients should be informed that nausea has been reported during treatment with Kaletra (see section 4.8).

4.8          Undesirable effects

Adult patients

Adverse events reactions:

The following adverse reactions of moderate to severe intensity with possible or probable relationship to Kaletra have been reported.  The adverse reactions are displayed by system organ class.  Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: very common >1/10, common > 1/100, < 1/10, uncommon > 1/1000, < 1/100.

¹ This event had a fatal outcome.

² See section 4.4: pancreatitis and lipids

Paediatric patients

In children 2 years of age and older, the nature of the safety profile is similar to that seen in adults.

5.          Pharmacological properties

5.1          Pharmacodynamic properties

Pharmaco-therapeutic group: antiviral for systemic use protease inhibitor, ATC code: J05AE06

Mechanism of action: Lopinavir provides the antiviral activity of Kaletra.  Lopinavir is an inhibitor of the HIV-1 and HIV-2 proteases.  Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein resulting in the production of immature, non-infectious virus.

5.2          Pharmacokinetic properties

Metabolism: in vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism.  Lopinavir is extensively metabolised by the hepatic cytochrome P450 system, almost exclusively by isozyme CYP3A.  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 dose was due to parent drug active substance.  At least 13 lopinavir oxidative metabolites have been identified in man.  The 4-oxo and 4-hydroxymetabolite epimeric pair are the major metabolites with antiviral activity, but comprise only minute amounts of total plasma radioactivity.  Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism, and likely the induction of lopinavir metabolism.  Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilising after approximately 10 days to 2 weeks.

5.3         Preclinical safety data

During in vitro studies, cloned human cardiac potassium channels (HERG) were inhibited by 30% at the highest concentrations of lopinavir/ritonavir tested, corresponding to a lopinavir exposure 7-fold total and 15-fold free peak plasma levels achieved in humans at the maximum recommended therapeutic dose.  In contrast, similar concentrations of lopinavir/ritonavir demonstrated no repolarisation delay in the canine cardiac Purkinje fibres.  Lower concentrations of lopinavir/ritonavir did not produce significant potassium (HERG) current blockade.  Tissue distribution studies conducted in the rat did not suggest significant cardiac retention of the drug active substance; 72-hour AUC in heart was approximately 50% of measured plasma AUC.  Therefore, it is reasonable to expect that cardiac lopinavir levels would not be significantly higher than plasma levels.

9.      Date of first authorisation/renewal of THE authorisation

Date of first authorisation: 20 March 2001

Date of last renewal: 220 March 2006

10.    Date of revision of the text

August 2008