Section 3. Pharmaceutical Form

Removal of Abbott logo

Section 3. Pharmaceutical Form

Removal of Abbott logo

Section 3. Pharmaceutical Form

Removal of Abbott logo

Section 4.5 Interaction with other medicinal products and other forms of interaction

Update to Interaction table; addition of the following under anticoagulants:

Dabigatran etexilate, Edoxaban

Serum concentrations may be increased due to P‑gp inhibition by lopinavir/ritonavir

Clinical monitoring and/or dose reduction of the direct oral anticoagulants (DOAC) should be considered when a DOAC transported by P-gp but not metabolised by CYP3A4, including dabigatran etexilate and edoxaban, is co-administered with Kaletra.

Section 3

Change to tablet colour from yellow to red

Section 4.4

Under "Other"; the following text has been removed:

"While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines."

The following statement has been added:

"Sodium

This medicine contains less than 1  mmol sodium (23  mg) per tablet, that is to say essentially ‘sodium-free’"

Section 4.6

Section on Breast-feeding updated to:

Breast-feeding

Studies in rats revealed that lopinavir is excreted in the milk. It is not known whether this medicinal product is excreted in human milk.  As a general rule, it is recommended that women living with mothers infected by HIV do not breast-feed their babies under any circumstances in order to avoid transmission of HIV. 

Section 4.5

Uodate to include information regarding drug drug interaction with fostamatinib

Update to  section 4.8 Undesirable effects of the SmPCs to add information regarding nephrolithiasis.  

Minor editorial formating changes

Section 6.3 - Shelf life

Shelf of bottle presentation extended  from 36 months expiry to 48 months expiry.

Section 10 - Date of revision of text

Amended to 03/2020

Section 4.3 - Contraindications

•    Neratinib added
  Rationale: Increased plasma concentrations of neratinib which may increase the potential for serious and/or life‑threatening reactions (see section 4.5).
   

Section 4.5 -  Interaction with other medicinal products and other forms of interaction

The following amendments have been made to the Interaction table:

• Tenofovir 300mg QD amended to:
  
  Tenofovir disoproxil fumarate (DF), 300 mg QD
  (equivalent to 245 mg tenofovir disoproxil)
  
  
  This change is also reflected in section 5.1 (Paragraph relating to section M05-730).
  
   
• Abemaciclib added
  
  Serum concentrations may be increased due to CYP3A inhibition by ritonavir.
  
  Co‑administration of abemaciclib and Kaletra should be avoided.  If this co‑administration is judged unavoidable, refer to the abemaciclib SmPC for dosage adjustment recommendations.  Monitor for ADRs related to abemaciclib.
   
• Neratinib added
  
  Serum concentrations may be increased due to CYP3A inhibition by ritonavir.
  
  Concomitant use of neratinib with Kaletra is contraindicated due to serious and/or life‑threatening potential reactions including hepatotoxicity (see section 4.3).
  
   
• Glecaprevir/pibrentasvir added
  
  
  Serum concentrations may be increased due to P-glycoprotein, BCRP and OATP1B inhibition by lopinavir/ritonavir.
  
  Concomitant administration of glecaprevir/pibrentasvir and Kaletra is not recommended due to an increased risk of ALT elevations associated with increased glecaprevir exposure.
• Sofosbuvir/velpatasvir/ voxilaprevir added
  
  
  Serum concentrations of sofosbuvir, velpatasvir and voxilaprevir may be increased due to P-glycoprotein, BCRP and OATP1B1/3 inhibition by lopinavir/ritonavir.  However, only the increase in voxilaprevir exposure is considered clinically relevant.
  
  It is not recommended to co‑administer Kaletra and sofosbuvir/velpatasvir/ voxilaprevir.
  
   
• Boceprevir and Telaprevir removed from Interaction table
  
   

Section 4.3 – Contraindications and Section 4.5 - Interaction with other medicinal products and other forms of interaction

• Updated to include contraindication regarding concomitant use of Kaletra with lomitapide.
   

Section 10 - Date of Revision of the Text

• Updated to 04/2019

Update to sections 4.4 and 4.8 to include autoimmune hepatitis.

Section 4.4

Immune Reconstitution Inflammatory Syndrome

-----------------

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

 ---------------------

Section 4.8

Description of selected adverse reactions

 ------------
 

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.  Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and can occur many months after initiation of treatment (see section 4.4).

---------------------

Update to sections 4.4 and 4.8 to include autoimmune hepatitis.

Section 4.4

Immune Reconstitution Inflammatory Syndrome

-----------------

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

 ---------------------

Section 4.8

Description of selected adverse reactions

 ------------
 

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.  Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and can occur many months after initiation of treatment (see section 4.4).

---------------------

Section 4.5 Interaction with other medicinal products and other forms of interaction

Information added regarding the following interactions:

• Ibrutinib
  
  Serum concentrations may be increased due to CYP3A inhibition by lopinavir/ritonavir
  
  Co-administration of ibrutinib and Kaletra may increase ibrutinib exposure which may increase the risk of toxicity including risk of tumor lysis syndrome. Co‑administration of ibrutinib and Kaletra should be avoided.  If the benefit is considered to outweigh the risk and Kaletra must be used, reduce the ibrutinib dose to 140 mg and monitor patient closely for toxicity
   
• Levothyroxine
  
  Post‑marketing cases have been reported indicating a potential interaction between ritonavir containing products and levothyroxine.
  
  Thyroid‑stimulating hormone (TSH) should be monitored in patients treated with levothyroxine at least the first month after starting and/or ending lopinavir/ritonavir treatment
   

Section 10 Date of Revision of the Text

Updated to 13 September 2018

Section 4.3 - Contraindications

·         The list of medicinal products which Kaletra should not be co-administered with has been updated to include

o   Ranolazine (medical product class: antianginal)
Rationale: Increased plasma concentrations of ranolazine which may increase the potential for serious and/or life-threatening reactions (see section 4.5).

o   Lurasidone (medical product class: Antipsychotics/ Neuroleptics)
Rationale: Increased plasma concentrations of lurasidone which may increase the potential for serious and/or life-threatening reactions (see section 4.5).

Section 4.4 - Special warnings and precautions for use

Sub-heading: PDE5 inhibitors

The statement:

“Concomitant use of Kaletra and fluticasone or other glucocorticoids that are metabolised by CYP3A4, such as budesonide , is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression (see section 4.5).”

Has been  updated to read:

“Concomitant use of Kaletra and fluticasone or other glucocorticoids that are metabolised by CYP3A4, such as budesonide and triamcinolone, is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression (see section 4.5).”

Section 4.5 -  Interaction with other medicinal products and other forms of interaction

·   The following medicinal products have been added to the Interaction table:

o   Ranolazine

o   Lurasidone

Information relating to Fluticasone propionate has been updated to read:

“Inhaled, injectable or intranasal fluticasone propionate, budesonide, triamcinolone”


Effects on drug levels/Mechanism of interaction: 

“Fluticasone propionate, 50 mg intranasal 4 times daily:

Plasma concentrations ↑

Cortisol levels ↓ 86%”

Clinical recommendation concerning co-administration with Kaletra:

“Greater effects may be expected when fluticasone propionate is inhaled.  Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide and triamcinolone.  Consequently, concomitant administration of Kaletra and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.4).  A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclomethasone).  Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period.”

The following change only impacts Kaletra Oral Solution:

Section 10 – Date of Revision of Text

·   Updated to 24 May 2017

Section 4.2

The following statement (under Paediatric population (2 years of age and above) has been amended as follows:

FROM:

Based on the limited data currently available, Kaletra should not be administered once daily in paediatric patients (see section 5.1).

TO:

Based on the current data available, Kaletra should not be administered once daily in paediatric patients (see section 5.1).

Section 5.1

Paediatric Use sub-section:

The following statement has been amended:

FROM:

The percentage of patients achieving HIV-1 RNA <50 copies/ml at Week 24 was lower in the paediatric patients receiving lopinavir/ritonavir tablets once daily (88.2%) than in patients receiving the twice-daily dosing (96.6%, p = 0.040), mainly due to lower adherence in the once-daily group.

TO:

The percentage of patients with confirmed viral rebound >50 copies/ml during 48 weeks of follow-up was higher in the paediatric patients receiving lopinavir/ritonavir tablets once daily (12%) than in patients receiving the twice-daily dosing (8%, p = 0.19), mainly due to lower adherence in the once-daily group. 

SmPC updated to reflect approval of V142

The following is a summary of the changes

4.4      Special warnings and precautions for use

The following warning has been added:

The combination of Kaletra with:

- riociguat is not recommended (see section 4.5);

- vorapaxar is not recommended (see section 4.5);

4.5          Interaction with other medicinal products and other forms of interaction

The following interactions have been added:

Afatinib

(Ritonavir 200 mg twice daily)

The extent of increase depends on the timing of ritonavir administration.

Due to BCRP (breast cancer resistance protein/ABCG2) and acute P-gp inhibition by Kaletra

Caution should be exercised in administering afatinib with Kaletra.  Refer to the afatinib SmPC for dosage adjustment recommendations.  Monitor for ADRs related to afatinib

Kaletra SmPCs updated to reflect approval of V158 (Update sections 4.3 and 4.5 of the SmPC to add information regarding the interaction of Lopinavir/ritobavir and dronedarone.  Update sections 4.3, 4.4 and 4.5 of the SmPC to add information regarding the contraindication with colchicine in patients with renal or hepatic impairment.  This change is being made to align with the recent lopinavir/ritonavir CCDS update, issued on 29-Feb-2016.)  

The following are details of the changes:

Section 4.3 - Contraindications:

-          Dronedarone (Medicinal product class: Antiarrhythmics) added

-          Colchicine added (Medicinal product class: Anti-gout), Rationale: Increased plasma concentrations of colchicine.  Potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment (see sections 4.4 and 4.5).

Section 4.4 - Special warnings and precautions for use

-          The Subheading  “Immune Reactivation Syndrome” changed to “Immune Reconstitution Inflammatory Syndrome”

-          Sub-section: Interactions with medicinal products:

“Concomitant administration with colchicine, notably in patients with renal or hepatic impairment, should be avoided (see section 4.5).”

Changed to:

“Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A like ritonavir.  Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment (see sections 4.3 and 4.5).”

Section 4.5 Interaction with other medicinal products and other forms of interaction

-    Amiodarone and Droneradarone added to interactions table, under Antiarrhythmics: Amiodarone, Dronedarone: Concentrations may be increased due to CYP3A4 inhibition by Kaletra.
Concomitant administration of Kaletra and amiodarone or dronedarone is contraindicated (see section 4.3) as the risk of arrhythmias or other serious adverse reactions may be increased.

-    Section on Colchicine amended to read:
Concomitant administration of Kaletra with colchicine in patients with renal and/or hepatic impairment is contraindicated due to a potential increase of colchicine-related serious and/or life‑threatening reactions such as neuromuscular toxicity (including rhabdomyolysis) (see sections 4.3 and 4.4).  A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with Kaletra is required.  Refer to colchicine prescribing information.

Section 4.8 Undesirable effects

-    Immune reactivation syndrome amended to Immune reconstitution inflammatory syndrome

"Co‑administration of delamanid with a strong inhibitor of CYP3A (as lopinavir/ritonavir) may increase exposure to delamanid metabolite, which has been associated with QTc prolongation.  Therefore, if co-administration of delamanid with lopinavir/ritonavir is considered necessary, very frequent ECG monitoring throughout the full delamanid treatment period is recommended (see section 4.5 and refer to the delamanid SmPC)."

Section 4.5
Information added regarding drug-drug interaction between delamanid and lopinavir/ritonavir



Minor editorial and formatting changes have been made throughout the document.

To update section 4.5 of the SmPC to add information regarding the interaction between Lopinavir/ritonavir and simeprevir.

Update section 4.2 of the SmPC to add dosing recommendation for HIV-1 infected women during pregnancy and postpartum.
Update section 4.4 of the SmPC according to CHMP requested class label on the risk of transmission of HIV.

Update section 4.6 of the SmPC with the results from the most recent interim report from the Antiretroviral Pregnancy Registry.

Update section 5.2 with the results from the pharmacokinetic data.

Section 4.3 Contraindications

Inclusion of Quetiapine and Avanafil to list of medicinal products which Kaletra must not be co-administered with.

Section 4.4 Special warnings and precautions for use

Under the sub-heading (Interactions with medicinal products), the statement  “Concomitant use of vardenafil and lopinavir/ritonavir is contraindicated (see section 4.3) has been amended to “Concomitant use of avanafil or vardenafil and lopinavir/ritonavir is contraindicated (see section 4.3).”

Section 4.5  Interaction with other medicinal products and other forms of interaction

Information regarding Kaletra and the concomitant use of the following medicinal products has been added to the Interaction table:

·         Etravirine, Rilpivirine, Quetiapine, Avanafil

·         Nelfinavir has been removed from the interaction table.

Section 4.8 Undesirable effects

The following has been added:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.  It allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare professionals are asked to report any suspected adverse reactions via the yellow card scheme or directly to the IMB Pharmacovigilance Section:

Irish Medicines Board,
Kevin O’Malley House,
Earlsfort Centre,
Earlsfort Terrace,
Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie

Section 5.2          Pharmacokinetic properties

·   Under the sub-heading Special Populations, Gender, Race and Age, “the elderly” has been changed to “older people”.

Section 6.5: Nature and Contents of Container

“Two pack sizes are available:

-               1 bottle of 120 tablets

-               3 bottles of 120 tablets (360 tablets)

Blisters packs 

Two pack sizes are available:

-            Polyvinyl chloride (PVC) blisters with fluoropolymer foil backing in a carton containing 120 film-coated tablets

-            Polyvinyl chloride (PVC) blisters with fluoropolymer foil backing in a carton containing 40 film-coated tablets.  Each pack contains 3 cartons (120 tablets).”

has been amended to:

“Two pack sizes are available:

-               1 bottle of 120 tablets

-               Multipack containing 360 (3 bottles of 120) film-coated tablets

Blisters packs - polyvinyl chloride (PVC) blisters with fluoropolymer foil backing 

Two pack sizes are available:

-            carton containing 120 film-coated tablets”

-            multipack containing 120 (3 cartons of 40) film-coated tablets”

Section 4.4
The following has been added under the heading "Immune Reactivation Syndrome":

Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

Section 4.8
The following has been added under c. Description of selected adverse reactions:
Autoimmune disorders (such as Graves’ disease) have also been reported; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

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."

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

In section 4.4 (Special warnings and precautions for use), under the heading Immune Reactivation Syndrome, "Pneumocystis carinii" has been changed to "Pneumocystis jiroveci".

In section 4.5 (Interactions with other medicinal products and other forms of interaction", information relating to interactions between Kaletra and the following medicinal products have been added:  Fentanyl (Analgesics),  tyrosine kinase inhibitors such as dasatinib and nilotinib (Anticancer agents)

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

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

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. 

4.4    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