Section 4.6 (Pregnancy and Lactation) has been updated to include information from the AntiViral Pregnancy register.

Also Section 4.1 (Indication) has been reordered in line with the Guideline on the Clinical Development of Medicinal Products for the Treatment of HIV Infection (EMEA/CPMP/EWP/633/02, Revision 2.

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.

4.4    Special warnings and precautions for use

PR interval prolongation

Lopinavir/ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some healthy adult subjects.  Rare reports of 2^nd or 3^rd degree atroventricular block in patients with underlying structural heart disease and pre-existing 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 lopinavir/ritonavir.  Kaletra should be used with caution in such patients (see section 5.1).

5.          Pharmacological properties

5.1          Pharmacodynamic properties

Pharmaco-therapeutic group:  antiviral for systemic use,  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).

10.    Date of revision of the text

20 June 2008

4.3          Contraindications

Rifampicin should not be used in combination with Kaletra because co-administration may cause large decreases in lopinavir concentrations which may in turn significantly decrease the lopinavir therapeutic effect (see section 4.5).

4.4    Special warnings and precautions for use

Interactions with medicinal products

Co‑administration of Kaletra with rifampicin is not recommended.  Rifampicin should not be used in combination with Kaletra because this may causes large decreases in lopinavir concentrations which may in turn significantly decrease the lopinavir therapeutic effect.  Adequate exposure to lopinavir/ritonavir may be achieved when a higher dose of Kaletra is used but this is associated with a higher risk of liver and gastrointestinal toxicity.  Therefore, this co‑administration should be avoided unless judged strictly necessary (see sections 4.3 and 4.5).

4.5          Interaction with other medicinal products and other forms of interaction

Rifampicin: co‑administration of Kaletra with rifampicin is not recommended.  Rifampicin administered with Kaletra causes large decreases in lopinavir concentrations which may in turn significantly decrease the lopinavir therapeutic effect.  A dose adjustment of Kaletra 400 mg/400 mg twice daily has allowed compensating for the CYP 3A4 inducer effect of rifampicin.  However, such a dose adjustment might be associated with ALT/AST elevations and with increase in gastrointestinal disorders.  Therefore, this co‑administration should be avoided unless judged strictly necessary.  If this co‑administration is judged unavoidable, increased dose of Kaletra at 400 mg/400 mg twice daily may be administered with rifampicin under close safety and therapeutic drug monitoring.  The Kaletra dose should be titrated upward only after rifampicin has been initiated due to large decreases in lopinavir concentrations, rifampicin should not be used in combination with Kaletra (see sections 4.3 and 4.4).

10.    Date of revision of the text

20 November 2007

1.      Name of the medicinal product

Kaletra (80 mg + 20 mg) / ml oral solution

4.4    Special warnings and precautions for use

Interactions with medicinal products

The HMG-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A for metabolism, thus concomitant use of Kaletra with simvastatin or lovastatin is not recommended due to an increased risk of myopathy including rhabdomyolysis.  Caution must also be exercised and reduced doses should be considered if Kaletra is used concurrently with rosuvastatin or with atorvastatin, which is metabolised to a lesser extent by CYP3A4.  If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (see section 4.5).

4.5          Interaction with other medicinal products and other forms of interaction

Anticancer agents (eg vincristine, vinblastine): these agents may have their serum concentrations increased when co‑administered with lopinavir/ritonavir resulting in the potential for increased adverse events usually associated with these anticancer agents.

In addition, co‑administration of phenytoin and lopinavir/ritonavir resulted in moderate decreases in steady-state phenytoin concentrations.  Phenytoin levels should be monitored when co‑administering with lopinavir/ritonavir.

HMG-CoA reductase inhibitorsLipid lowering agents: HMG-CoA reductase inhibitors which are highly dependent on CYP3A4 metabolism, such as lovastatin and simvastatin, are expected to have markedly increased plasma concentrations when co-administered with Kaletra.  Since increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis, the combination of these medicinal products with Kaletra is not recommended.  Atorvastatin is less dependent on CYP3A for metabolism.  When atorvastatin was given concurrently with Kaletra, a mean 4.7-fold and 5.9-fold increase in atorvastatin C_max and AUC, respectively, was observed.  When used with Kaletra, the lowest possible dose of atorvastatin should be administered.  Rosuvastatin is not dependent on CYP3A.  However, when given concurrently with Kaletra a mean 5‑fold and 2‑fold increase in rosuvastatin C_max and AUC, respectively, was observed.  Caution should be exercised when Kaletra is co‑administered with rosuvastatin.  Results from an interaction study with Kaletra and pravastatin reveal no clinically significant interaction.  The metabolism of pravastatin and fluvastatin is not dependent on CYP3A4, and interactions are not expected with Kaletra.  If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended.

Buprenorphine: buprenorphine (dosed at 16 mg daily) co‑administered with lopinavir/ritonavir (dosed at 400/100 mg twice daily) showed no clinically significant interaction.  Kaletra can be co‑administered with buprenorphine with no dose adjustment.

4.3          Contraindications

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A.  Kaletra should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events.  These medicinal products include astemizole, terfenadine, oral midazolam (for caution on parenterally administered midazolam, see section 4.5), triazolam, cisapride, pimozide, amiodarone, ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine and methylergonovine) and vardenafil.

4.5          Interaction with other medicinal products and other forms of interaction

Midazolam: midazolam is extensively metabolised by CYP3A4.  Co‑administration with Kaletra may cause a large increase in the concentration of this benzodiazepine.  A phenotyping cocktail study in 14 healthy volunteers showed an increase of AUC by about 13 fold with oral midazolam and an increase by about 4 fold with parenteral midazolam.  Therefore, Kaletra should not be co‑administered with orally administered midazolam (see section 4.3), whereas caution should be used with co‑administration of Kaletra and parenteral midazolam.  If Kaletra is co‑administered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.  Dosage adjustment for midazolam should be considered especially if more than a single dose of midazolam is administered.

4.5          Interaction with other medicinal products and other forms of interaction

Other medicinal products:

Acid reducing agents (omeprazole, ranitidine): in a study performed in healthy volunteers, no clinically relevant interaction has been observed when Kaletra tablets 400/100 mg twice daily was co‑administered with omeprazole or with ranitidine.  Kaletra can be co‑administered with acid reducing agents with no dose adjustment.

4.8          Undesirable effects

5.1          Pharmacodynamic properties

Clinical pharmacodynamic data

The effects of Kaletra (in combination with other antiretroviral agents) on biological markers (plasma HIV RNA levels and CD₄ counts) have been investigated in a controlled study of Kaletra of 48 weeks duration, and in additional studies of Kaletra of 204 360 weeks duration. 

Sustained virological response to Kaletra (in combination with nucleoside/nucleotide reverse transcriptase inhibitors lamivudine and stavudine) 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.  Sixty‑one patients completed the study (35 patients received the recommended 400/100 mg twice daily dose throughout the study).  Through 204 360 weeks of treatment, the proportion of patients with HIV RNA < 400 (< 50) copies/ml was 761% (7059%) [n=100 including 40 patients having received the recommended dose of Kaletra for the entire 204 weeks], and the corresponding mean increase in CD₄ cell count was 440 501 cells/mm³.  Twenty-eightThirty-nine patients (2839%) discontinued the study, including nine16 (916%) discontinuations due to adverse events and one (1%) death, one of which was associated with a death. 

4.5          Interaction with other medicinal products and other forms of interaction

Other medicinal products:

Acid reducing agents (omeprazole, ranitidine): in a study performed in healthy volunteers, no clinically relevant interaction has been observed when Kaletra tablets 400/100 mg twice daily was co‑administered with omeprazole or with ranitidine.  Kaletra can be co‑administered with acid reducing agents with no dose adjustment.

4.8          Undesirable effects

5.1          Pharmacodynamic properties

Clinical pharmacodynamic data

The effects of Kaletra (in combination with other antiretroviral agents) on biological markers (plasma HIV RNA levels and CD₄ counts) have been investigated in a controlled study of Kaletra of 48 weeks duration, and in additional studies of Kaletra of 204 360 weeks duration. 

Sustained virological response to Kaletra (in combination with nucleoside/nucleotide reverse transcriptase inhibitors lamivudine and stavudine) 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.  Sixty‑one patients completed the study (35 patients received the recommended 400/100 mg twice daily dose throughout the study).  Through 204 360 weeks of treatment, the proportion of patients with HIV RNA < 400 (< 50) copies/ml was 761% (7059%) [n=100 including 40 patients having received the recommended dose of Kaletra for the entire 204 weeks], and the corresponding mean increase in CD₄ cell count was 440 501 cells/mm³.  Twenty-eightThirty-nine patients (2839%) discontinued the study, including nine16 (916%) discontinuations due to adverse events and one (1%) death, one of which was associated with a death. 

4.4    Special warnings and precautions for use

Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported in patients with advanced HIV‑disease and/or long‑term exposure to combination antiretroviral therapy (CART).  Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

4.8          Undesirable effects

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).  The frequency of this is unknown (see section 4.4).

4.3          Contraindications

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A.  Kaletra should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events.  These medicinal products include astemizole, terfenadine, midazolam, triazolam, cisapride, pimozide, amiodarone, ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine and methylergonovine) and vardenafil.

4.4     Special warnings and precautions for use

Interactions with medicinal products

Particular caution must be used when prescribing Kaletra and medicinal products known to induce QT interval prolongation such as: chlorpheniramine, quinidine, erythromycin, clarithromycin.  Indeed, Kaletra could increase concentrations of the co-administered medicinal products and this may result in an increase of their associated cardiac adverse events.  Cardiac events have been reported with Kaletra in preclinical studies; therefore, the potential cardiac effects of Kaletra cannot be currently ruled out (see sections 4.8 and 5.3).

Rifampicin should not be used in combination with Kaletra because this may cause large decreases in lopinavir concentrations which may in turn significantly decrease the lopinavir therapeutic effect (see sections 4.3 and 4.5).

Oral Contraceptives: since levels of ethinyl oestradiol may be decreased when oestrogen-based oral contraceptives are co-administered with Kaletra alternative or additional contraceptive measures are to be used (see section 4.5).

4.5          Interaction with other medicinal products and other forms of interaction

Antiretroviral agents

Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs):

Stavudine and Lamivudine: no change in the pharmacokinetics of lopinavir was observed when Kaletra was given alone or in combination with stavudine and lamivudine in clinical studies.

Didanosine: it is recommended that didanosine be administered on an empty stomach; therefore, didanosine is to be given one hour before or two hours after Kaletra (given with food).  The gastroresistant formulation of didanosine should be administered at least two hours after a meal.

Zidovudine and Abacavir: Kaletra induces glucuronidation, therefore Kaletra has the potential to reduce zidovudine and abacavir plasma concentrations.  The clinical significance of this potential interaction is unknown.

Tenofovir: when tenofovir disoproxil fumarate was co‑administered with Kaletra, tenofovir concentrations were increased by approximately 30% with no changes noted in lopinavir or ritonavir concentrations.  Higher tenofovir concentrations could potentiate tenofovir associated adverse events, including renal disorders.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs):

Co-administration with other HIV protease inhibitors (PIs):

Fosamprenavir: 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.

Other medicinal products:

Trazodone:  in a pharmacokinetic study performed in healthy volunteers, concomitant use of low dose ritonavir (200 mg twice daily) with a single dose of trazodone led to an increase in plasma concentrations of trazodone (AUC increased by 2.4 fold).  Adverse events of nausea, dizziness, hypotension and syncope were observed following co-administration of trazodone and ritonavir in this study.  However, it is unknown whether the combination of lopinavir/ritonavir cause a similar increase in trazodone exposure.  The combination should be used with caution and a lower dose of trazodone should be considered..

Digoxin: plasma concentrations of digoxin may be increased when co‑administered with Kaletra.  Caution is warranted and therapeutic drug monitoring of digoxin concentrations, if available, is recommended in case of co‑administration of Kaletra and digoxin.  Particular caution should be used when prescribing Kaletra in patients taking digoxin as the acute inhibitory effect of ritonavir on Pgp is expected to significantly increase digoxin levels.  The increased digoxin level may lessen over time as Pgp induction develops.  Initiation of digoxin in patients already taking Kaletra is expected to result in lower increase of digoxin concentrations.

Phosphodiesterase inhibitors: phosphodiesterase inhibitors which are dependent on CYP3A4 metabolism, such as tadalafil and sildenafil, are expected to result in an approximately 2‑fold and 11‑fold increase in AUC respectively, when co-administered with ritonavir containing regimens including Kaletra and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, synope, visual changes and prolonged erection.  Particular caution must be used when prescribing sildenafil or tadalafil in patients receiving Kaletra with increased monitoring for adverse events.  Co-administration of vardenafil with rtionavir containing regimens including Kaletra is expected to result in 49‑fold increase in vardenafil AUC.  The use of vardenafil with Kaletra is contraindicated (see section 4.3). Sildenafil: co-administration of sildenafil 100 mg single dose with ritonavir 500 mg twice daily at steady-state resulted in a 1000% increase in sildenafil plasma AUC.  On the basis of these data, concomitant use of sildenafil with Kaletra is not recommended and in no case should the starting dose of sildenafil exceed 25 mg within 48 hours (see section 4.4).

Voriconazole: due to the potential for reduced voriconazole concentrations, co‑administration of voriconazole and low dose ritonavir (100 mg twice daily) as contained in Kaletra should be avoided unless an assessment of the benefit/risk to patient justifies the use of voriconazole.

Oral Contraceptives: since levels of ethinyl oestradiol maybe are were decreased when oestrogen-based oral contraceptives are were co-administered with Kaletra.  In case of co‑administration of Kaletra with contraceptives containing ethinyl oestradiol (whatever the contraceptive formulation e.g. oral or patch), alternative methods of contraception are to be used alternative or additional contraceptive measures are to be used.

4.8          Undesirable effects

Stevens‑Johnson syndrome and erythema multiforme have been reported.

5.1          Pharmacodynamic properties

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 a Phase II study (M97-720) through 204 weeks of treatment, genotypic analysis of viral isolates was successfully conducted in 11 of 16 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.

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 Aptivis 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 pharmacodynamic data. Selection of viral resistance during Kaletra therapy: in Phase II studies of 227 antiretroviral treatment naïve and protease inhibitor experienced patients, isolates from four patients with quantifiable (> 400 copies/ml) viral load following treatment with Kaletra for ³ 12 weeks displayed significantly reduced susceptibility to lopinavir compared to the corresponding baseline viral isolates.  The mean EC₅₀ of lopinavir against the four baseline isolates was 2.8 fold (range: 0.7 to 5.2 fold) higher than the EC₅₀ against wild type HIV, and each of the four baseline isolates contained four or more mutations in HIV protease associated with resistance to protease inhibitors.  Following treatment of the four patients with Kaletra, the mean EC₅₀ of lopinavir increased to 55-fold (range: 9.4 to 99-fold) compared to wild type HIV, and 2  −  3 additional mutations at amino acids 10, 24, 33, 46, 54, 63, 71 and/or 82 were observed. 

In a Phase II study (M97-720) through 204 weeks of treatment, genotypic analysis of viral isolates was successfully conducted in 11 of 16 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, 36, 47, 48, 50, 82, 84 and 90) or protease inhibitor phenotypic resistance.

Cross-resistance: at this stage of development, little information is available on the cross-resistance of viruses selected during therapy with Kaletra.  Isolates from 4 patients previously treated with one or more protease inhibitors that developed increased lopinavir phenotypic resistance during Kaletra therapy either remained or developed cross-resistance to ritonavir, indinavir, and nelfinavir.  All rebound viruses either remained fully sensitive or demonstrated modestly reduced susceptibility to amprenavir (up to 8.6-fold concurrent with 99-fold resistance to lopinavir).  The rebound isolates from the two patients with no prior saquinavir treatment remained fully sensitive to saquinavir.

10.    Date of revision of the text

05 December 2006

1.            Name of the medicinal product

Kaletra 80 mg/20 mg oral solution

2.            Qualitative and quantitative composition

Each 5 ml of Kaletra oral solution contains 400 mg of lopinavir co-formulated with 100 mg of ritonavir as a pharmacokinetic enhancer.